European Society of Medical Oncology 2016 Congress

European Society of Medical Oncology 2016 Congress
CCO Independent Conference Highlights* of the 2016 ESMO Annual Congress; October, 7-11, 2016; Copenhagen, Denmark *CCO is an independent medical education company that provides state-of-the-art medical information to healthcare professionals through conference coverage and other educational programs. In this activity, experts review the most clinically relevant study results presented at the 2016 ESMO annual meeting across multiple tumor types, including: Shirish Gadgeel, MD, on advanced non-small-cell lung cancer (NSCLC); Margaret Callahan, MD, PhD, on melanoma; Joyce O’Shaughnessy, MD, on breast cancer; Bradley J. Monk, MD, FACS, FACOG, on ovarian cancer; and, Ryan T. Merrell, MD, on glioblastoma. This activity is supported by educational grants from AbbVie, Genentech, Incyte, and Merck.

About These Slides Please feel free to use, update, and share some or all of these slides in your noncommercial presentations to colleagues or patients When using our slides, please retain the source attribution: These slides may not be published, posted online, or used in commercial presentations without permission. Please contact for details Slide credit: clinicaloptions.com Disclaimer: The materials published on the Clinical Care Options Web site reflect the views of the authors of the CCO material, not those of Clinical Care Options, LLC, the CME providers, or the companies providing educational grants. The materials may discuss uses and dosages for therapeutic products that have not been approved by the United States Food and Drug Administration. A qualified healthcare professional should be consulted before using any therapeutic product discussed. Readers should verify all information and data before treating patients or using any therapies described in these materials.

Faculty Margaret Callahan, MD, PhD Assistant Attending Department of Medicine Memorial Sloan Kettering Cancer Center New York, New York Shirish Gadgeel, MD Professor Department of Oncology Karmanos Cancer Center/Wayne State University Detroit, Michigan Ryan T. Merrell, MD Assistant Professor Department of Neurology Northshore University Health System Evanston, Illinois This slide lists the faculty who were involved in the production of these slides.

Faculty Bradley J. Monk, MD, FACS, FACOG Professor Division of Gynecologic Oncology Arizona Oncology (US Oncology Network) University of Arizona College of Medicine--Phoenix Creighton University School of Medicine at St Joseph’s Hospital Phoenix, Arizona Joyce O’Shaughnessy, MD Director, Breast Cancer Research Program Baylor Charles A. Sammons Cancer Center Texas Oncology US Oncology Dallas, Texas This slide lists the faculty who were involved in the production of these slides.

Faculty Disclosures Margaret Callahan, MD, PhD, has disclosed that she has received funds for research support from Bristol-Myers Squibb. Shirish Gadgeel, MD, has disclosed that he has received consulting fees from ARIAD, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Genentech, and Pfizer and fees or non-CME/CE services fees for non-CME services received directly from a commercial interest or their agents (eg, speaker bureaus) from AstraZeneca and Genentech/Roche. Ryan T. Merrell, MD, has disclosed that he has received consulting fees from AbbVie. This slide lists the disclosure information of the faculty and staff involved in the development of these slides.

Faculty Disclosures Bradley J. Monk, MD, FACS, FACOG, has disclosed that he has received consulting fees from Advaxis, Amgen, AstraZeneca, Bayer, Clovis, Gradalis, Insys, Matcon, Merck, Pfizer, PPD, Roche/Genentech, and TESARO; fees for non-CME services received directly from a commercial interest or their agents (eg, speaker bureaus) from AstraZeneca, Janssen/Johnson & Johnson, and Roche/Genentech; and funds for research support from Amgen, Array, Genentech, Janssen/Johnson & Johnson, Lilly, Morphotek, and TESARO. Joyce O’Shaughnessy, MD, has disclosed that she has received consulting fees from Arno, AstraZeneca, Celgene, Corcept Therapeutics, Lilly, Novartis, and Pfizer. This slide lists the disclosure information of the faculty and staff involved in the development of these slides.

Lung Cancer

Pembrolizumab vs CT as First-line Therapy for Adv NSCLC (KEYNOTE-024)
Stratified by ECOG PS (0 vs 1), histology (squamous vs nonsquamous), and enrollment region Pts with stage IV NSCLC and ECOG PS 0/1, no previous systemic therapy, no actionable EGFR/ALK mutations, and PD-L1 TPS ≥ 50%* (N = 305) Pembrolizumab 200 mg IV Q3W for up to 35 cycles (n = 154) Until PD or unacceptable toxicity Until PD (crossover to pembrolizumab allowed) Chemotherapy (histology based) for up to 6 cycles (n = 151) Adv, advanced; CT, chemotherapy; ECOG, Eastern Cooperative Oncology Group; NSCLC, non-small-cell lung cancer; PD, progressive disease; PS, performance status; TPS, tumor proportion score. Shirish Gadgeel, MD: Of the major results in lung cancer reported at ESMO 2016, the phase III KEYNOTE-024 trial was the most important and practice‑changing study. In KEYNOTE-024, 305 patients with advanced NSCLC and at least 50% tumor PD‑L1 expression, but without actionable EGFR mutations and ALK rearrangements, were randomized to first-line pembrolizumab therapy or standard platinum‑based chemotherapy.[1] PD-L1 expression was determined with the 22C3 companion diagnostic IHC assay. Of a total of 1934 patients who were screened for enrollment, 30.2% had 50% or greater tumor PD-L1 expression, which is consistent with the observed incidence of approximately 25% to 30% of patients with this high level of tumor PD-L1 expression. Pembrolizumab was administered at a standard dose of 200 mg IV every 3 weeks for a total of 35 cycles. In previous studies,[2-4] pembrolizumab was evaluated at a dose of either 2 mg/kg or 10 mg/kg, but subsequent analysis of the data has led to a flat dose of 200 mg IV every 3 weeks now being administered in all pembrolizumab studies and in routine clinical care where pembrolizumab is approved.[5] The median duration of pembrolizumab treatment in KEYNOTE-024 was 7 months (range: 1 day to 18.7 months), with a median of 10.5 treatment cycles (range: 1-26).[1] In the chemotherapy arm, the median duration of treatment was 3.5 months (range: 1 day to 16.8 months), with a median of 4 cycles (range: 1-6). Upon disease progression, 43.7% of patients in the chemotherapy arm crossed over to pembrolizumab. *≥ 50% tumor cell staining using 22C3 companion diagnostic IHC assay. Primary endpoint: PFS Secondary endpoints: ORR, OS, and safety Slide credit: clinicaloptions.com Reck M, et al. N Engl J Med. 2016;[Epub ahead of print].

KEYNOTE-024: Survival Outcomes
PFS OS Pembrolizumab HR for PFS: 0.50 (95% CI: ; P < .001) 100 100 Chemotherapy 80 80 60 60 PFS (%) OS (%) 40 40 10.3 20 20 6.0 Shirish Gadgeel, MD: The primary endpoint of the study was PFS. At the second planned interim analysis with a median follow-up of 11.4 months the study met its primary endpoint. The median PFS was significantly improved in patients who received pembrolizumab vs those who received chemotherapy (10.3 vs 6.0 months, respectively; HR: 0.50; 95% CI: ; P < .001).[1] The ORR was also higher for pembrolizumab vs chemotherapy (44.8% vs 27.8%, respectively), with a similar median time to response of 2.2 months for both arms. The study was also positive for OS for patients who received pembrolizumab (HR: 0.60; 95% CI: ; P = .005), but the median OS had not been reached in either arm at the time of data analysis. HR for OS: 0.60 (95% CI: ; P = .005) 3 6 9 12 15 18 3 6 9 12 15 18 21 Mos Mos Pts at Risk, n Pembrolizumab Chemotherapy 104 99 89 70 44 18 22 9 3 1 1 0 82 64 39 34 11 7 2 1 0 0 Slide credit: clinicaloptions.com Reck M, et al. N Engl J Med. 2016;[Epub ahead of print].

KEYNOTE-024: Select Treatment-Related Adverse Events
Adverse Event (≥ 10% in Either Arm), % Pembrolizumab (n = 154) Chemotherapy (n = 150) Any Grade Grade ≥ 3 Any 73.4 26.6 90.0 53.3 Nausea 9.7 43.3 2.0 Diarrhea 14.3 3.9 13.3 1.3 Vomiting 2.6 0.6 20.0 0.7 Anemia 5.2 1.9 44.0 19.3 Fatigue 10.4 28.7 3.3 Pyrexia 5.3 Neutropenia 22.7 Thrombocytopenia 11.3 Shirish Gadgeel, MD: The toxicities observed in KEYNOTE-024 were as expected for each of the treatment arms.[1] Overall toxicity was less in patients who received pembrolizumab, with any grade and grade ≥ 3 treatment-related adverse events occurring in 73.4% and 26.6% of patients who received pembrolizumab vs 90.0% and 53.3% of patients who received chemotherapy. The incidence of serious treatment-related adverse events was similar between arms (21.4% for pembrolizumab vs 20.7% for chemotherapy), leading to death in 1 patient receiving pembrolizumab and 3 patients receiving chemotherapy. In the pembrolizumab arm, 7.1% of patients discontinued due to treatment-related toxicities vs 10.7% in the chemotherapy arm. In patients who received chemotherapy, there was a higher incidence of nausea, fatigue, and cytopenias, specifically neutropenia and thrombocytopenia, whereas pembrolizumab was associated with a higher incidence of immune‑mediated adverse events, including 9.1% grade 1/2 hypothyroidism, 7.8% grade 1/2 grade hyperthyroidism, and 5.8% any grade pneumonitis, of which 2.6% was grade ≥ 3. Although immune‑related toxicities were observed in patients who received pembrolizumab, they were primarily low grade. Slide credit: clinicaloptions.com Reck M, et al. N Engl J Med. 2016;[Epub ahead of print].

Nivolumab vs CT as First-line Therapy for Advanced NSCLC (CheckMate-026)
Stratified by PD-L1 expression (< 5% vs ≥ 5%) and histology (squamous vs nonsquamous) Pts with stage IV/recurrent NSCLC, no previous systemic therapy, no actionable EGFR/ALK mutations, PD-L1 expression ≥ 1% (N = 541) Nivolumab 3 mg/kg IV Q2W (n = 271) Until PD or unacceptable toxicity Chemotherapy (histology based) for up to 6 cycles (n = 270) Until PD (crossover to nivolumab allowed) CT, chemotherapy; NSCLC, non-small-cell lung cancer; PD, progressive disease. Shirish Gadgeel, MD: Similar to KEYNOTE-024, the phase III CheckMate-026 trial assessed nivolumab as frontline therapy in patients with advanced NSCLC.[6] In CHECKMATE-026, patients (N = 541) with at least 1% PD‑L1 positivity, but negative for EGFR mutations and ALK rearrangements, were randomized to either nivolumab at the standard dose of 3 mg/kg every 2 weeks or standard platinum‑based chemotherapy for 6 cycles. PD-L1 expression was determined with the 28-8 complementary diagnostic IHC assay. Unlike KEYNOTE‑024 where pembrolizumab was administered for a total of 35 cycles, nivolumab could be continued indefinitely in the absence of unacceptable toxicity or evidence of disease progression. Furthermore, patients who developed progressive disease on chemotherapy could cross over to nivolumab. Although the entry criteria for patients for CheckMate-026 was to have at least 1% tumor PD‑L1 expression, the study was designed to assess the efficacy of nivolumab vs standard chemotherapy in patients whose tumors had at least 5% tumor PD‑L1 expression. This is in contrast to KEYNOTE-024, which evaluated pembrolizumab in NSCLC patients with at least 50% tumor PD‑L1 expression.[1] Primary endpoint: PFS (≥ 5% PD-L1 positive) Secondary endpoints: PFS (≥ 1% PD-L1 positive), ORR, OS Slide credit: clinicaloptions.com Socinski M, et al. ESMO Abstract LBA7_PR.

CheckMate-026: PFS by IRRC in Pts With ≥ 5% PD-L1 Expression
Nivolumab (n = 211) CT (n = 212) 100 Median PFS, mos (95% CI) 1-yr PFS rate, % 4.2 ( ) 5.9 ( ) 80 60 23.6 23.2 PFS (%) 40 Nivolumab 20 Chemotherapy CT, chemotherapy; IRRC, independent radiologic review committee. Shirish Gadgeel, MD: CheckMate-026 did not meet its primary endpoint of improvement in PFS with nivolumab.[6] The median PFS was 4.2 months with nivolumab and 5.9 months with chemotherapy (HR: 1.15; 95% CI: ; P = .2511). The 1-year PFS rate was almost identical at 23.6% vs 23.2%. 3 6 9 12 15 18 21 24 27 Mos Pts at Risk, n Nivolumab CT 71 74 49 47 35 28 24 21 6 8 3 1 1 0 0 0 Slide credit: clinicaloptions.com Socinski M, et al. ESMO Abstract LBA7_PR.

CheckMate-026: Survival Outcomes by Subgroup
Pts, n Unstratified HR Unstratified HR (95% CI) Nivolumab Chemotherapy PFS OS Overall 271 270 1.19 1.08 ≥ 65 yrs 123 137 1.21 1.04 < 65 yrs 148 133 1.17 1.13 Male 184 1.05 0.97 Female 87 122 1.36 1.15 ECOG PS = 0 85 93 1.69 1.11 ECOG PS ≥1 185 177 1.01 1.02 Squamous 65 64 0.83 0.82 Nonsquamous 206 1.29 Never smoker 30 29 2.51 Former smoker 186 182 1.14 1.09 Current smoker 52 55 1.03 ≥ 50% PD-L1+ 88 126 1.07 0.90 ECOG, Eastern Cooperative Oncology Group; PS, performance status. Shirish Gadgeel, MD: There was clearly an interest in assessing whether survival was improved with nivolumab in patients with 50% or greater tumor PD‑L1 expression, similar to what was observed with pembrolizumab in the KEYNOTE‑024 study. However, a subgroup analysis showed no difference in either PFS or OS for these patients whether they received nivolumab or chemotherapy. In fact, subgroup analyses did not identify any specific subgroups that appeared to benefit from nivolumab over chemotherapy. A caveat to consider regarding the subgroup analysis is that, despite a reasonably large study of more than 500 patients, there were some patient subgroup imbalances between the 2 arms of this study. The nivolumab arm had fewer patients with at least 50% PD‑L1 expression as compared with the chemotherapy arm (88 vs 126, respectively). Similarly, there was a lower number of female patients in the nivolumab arm vs the chemotherapy arm (87 vs 122, respectively). It is unclear whether this imbalance may explain the lack of benefit observed with nivolumab in CheckMate-026, but it is somewhat surprising that there were these imbalances for such a large randomized study. 0.5 1.0 2.0 4.0 0.5 1.0 2.0 4.0 Nivolumab Chemotherapy Nivolumab Chemotherapy Slide credit: clinicaloptions.com Socinski M, et al. ESMO Abstract LBA7_PR.

CheckMate-026: Select Treatment-Related Adverse Events
Nivolumab (n = 267) Chemotherapy (n = 263) Any Grade Grade 3/4 Any 71.2 17.6 92.4 50.6 Diarrhea 13.9 1.1 12.9 1.9 Fatigue 21.0 35.4 5.3 Nausea 11.6 0.4 48.3 Vomiting 5.6 22.8 Anemia 3.4 43.0 17.5 Neutropenia 18.3 11.0 Thrombocytopenia 0.7 14.4 8.4 Shirish Gadgeel, MD: The toxicities observed in CheckMate-026 were as expected.[6] Similar to pembrolizumab in KEYNOTE-024, nivolumab was better tolerated than chemotherapy, which had a higher rate of any grade nausea, vomiting, and cytopenias. The number of treatment‑related deaths was also the same between the 2 arms. The major question raised after the back‑to‑back presentations of KEYNOTE-024 on first-line pembrolizumab and CheckMate-026 on first-line nivolumab was: Why was the pembrolizumab study positive and the nivolumab study negative for the primary endpoint of PFS? Possibly it is because of the imbalances in patient numbers for specific categories. Also, the assays used to assess PD‑L1 expression were different between the studies; the antibody used in the pembrolizumab study was 22C3, whereas the nivolumab study used antibody In the end, there is no clear answer to explain the differences in the results of these 2 studies of first-line immune checkpoint therapy in NSCLC. Treatment-related deaths: 2 with nivolumab and 3 with chemotherapy Slide credit: clinicaloptions.com Socinski M, et al. ESMO Abstract LBA7_PR.

Pemetrexed maintenance
Pembrolizumab + CT as First-line Therapy for Adv Nonsq NSCLC (KEYNOTE-021) Stratified by PD-L1 TPS (< 1% vs ≥ 1%) Pts with stage IIIB/IV nonsquamous NSCLC and ECOG PS 0/1, no previous systemic therapy, no actionable EGFR/ALK mutations (N = 123) Pembrolizumab 200 mg IV + Cb/Pem* Q3W x 4 (n = 60) Pembrolizumab up to 24 mos + Pemetrexed maintenance (optional) Cb/Pem* Q3W x 4 (n = 63) Pemetrexed maintenance (optional) Adv, advanced; AUC, area under the concentration curve; Cb, carboplatin; CT, chemotherapy; DoR, duration of response; ECOG, Eastern Cooperative Oncology Group; Nonsq, nonsquamous; NSCLC, non-small-cell lung cancer; Pem, pembrolizumab; PS, performance status; RECIST, Response Evaluation Criteria in Solid Tumors; TPS, tumor proportion score. Shirish Gadgeel, MD: The other notable study results in the frontline for advanced NSCLC presented at ESMO 2016 were for the phase II cohort G of KEYNOTE‑021, which evaluated whether the addition of pembrolizumab to standard pemetrexed plus carboplatin provided additional benefit over standard chemotherapy alone for nonsquamous NSCLC.[7] Overall, KEYNOTE‑021 is a phase I/II multicohort study assessing the combination of pembrolizumab with various standard-of-care lung cancer therapies, including carboplatin and paclitaxel (phase I cohort A; any histology); carboplatin, paclitaxel, and bevacizumab (phase I cohort B; nonsquamous); or pemetrexed and carboplatin (phase I cohort C; phase II cohort G; nonsquamous) as well as 3 other therapies (phase I cohorts D-F with erlotinib, gefitinib, or ipilimumab; phase II cohort H).[8] The phase I results for cohorts A-C demonstrated promising antitumor activity regardless of PD-L1 expression, with manageable safety profiles for cohorts A and C.[7,9] The results for cohort C were particularly promising, with the combination of pembrolizumab, pemetrexed, and carboplatin achieving an ORR of 71% and median PFS of 10.2 months in 24 patients with nonsquamous NSCLC. For the open-label, randomized phase II part of KEYNOTE-021, patients with advanced nonsquamous NSCLC in cohort G were randomized to standard carboplatin/pemetrexed chemotherapy every 3 weeks with or without pembrolizumab at the standard dose of 200 mg IV every 3 weeks for 4 cycles, followed by 24 months of pembrolizumab and optional pemetrexed maintenance therapy indefinitely. Patients were required to be negative for EGFR mutations and ALK rearrangements, to have Eastern Cooperative Oncology Group performance status 0-1, and to submit their tumor biopsies for PD‑L1 assessment, although PD‑L1 expression results were masked. Maintenance pemetrexed was administered to 85% (50/59) of treated patients in the experimental arm vs 69% (43/62) of patients in the control arm. *Cb AUC 5 mg/mL/min; Pem 500 mg/m2. Primary endpoint: ORR (RECIST v1.1) Secondary endpoints included: PFS, DoR, OS, and safety Slide credit: clinicaloptions.com Langer C, et al. Lancet Oncol. 2016;[Epub ahead of print].

KEYNOTE-021: Efficacy 100 80 60 PFS (%) 40 20 5 10 15 20 Mos
Pembro + CT (n = 60) CT Alone (n = 63) ORR,* n (%) PD-L1 TPS < 1% 1% - 49% ≥ 50% 33 (55) 12 (57) 5 (26) 16 (80) 18 (29) 3 (13) 9 (39) 6 (35) SD, n (%) 20 (33) 26 (41) PD, n (%) 2 (3) 11 (17) Median TTR, mos (IQR) 1.5 ( ) 2.7 ( ) Median DoR, mos (IQR) NR ( ) NR ( ) Pembro + CT CT Alone mPFS, mos 13.0 8.9 HR (95% CI) 0.53 ( ) P value .01 100 80 60 PFS (%) 40 20 CT, chemotherapy; DoR, duration of response; IQR, interquartile range; mPFS, median PFS; NR, not reached; Pembro, pembrolizumab; PD, progressive disease; SD, stable disease; TPS, tumor proportion score; TTR, time to response. Shirish Gadgeel, MD: KEYNOTE-021 showed a statistically significant improvement in the primary endpoint of ORR for the addition of pembrolizumab to carboplatin/pemetrexed vs chemotherapy alone (55% vs 29%, respectively; P = .0016).[7] This translated into a longer median PFS of 13.0 months for patients who received pembrolizumab and chemotherapy vs 8.9 months for chemotherapy alone (HR: 0.53; 95% CI: ; P = .01). Both endpoints were assessed by independent central review. The ORR benefit for addition of pembrolizumab to chemotherapy appeared to be regardless of tumor PD‑L1 expression status, with a similar proportion of patients whose tumors had less than 1% expression and more than 1% expression achieving an objective response. There was no significant difference in OS between the 2 arms, although it is possible that the median follow‑up of 10.6 months was not long enough to reveal a difference. 5 10 15 20 *P = .0016 Mos Pts at Risk, n Pembro + CT CT 60 (0) 63 (0) 43 (5) 32 (10) 20 (20) 13 (21) 1 (36) 1 (29) 0 (37) 3 (30) Slide credit: clinicaloptions.com Langer C, et al. Lancet Oncol. 2016;[Epub ahead of print].

KEYNOTE-021: Safety No unexpected treatment-related toxicities reported All grade treatment-related toxicities with > 10% higher incidence with pembrolizumab + CT were fatigue (64% vs 40%), nausea (58% vs 44%), rash (27% vs 15%), and alopecia (14% vs 3%) Grade ≥ 3 treatment-related toxicities occurring in at least 3 pts were similar across arms and included anemia, decreased neutrophil count, thrombocytopenia, neutropenia, decreased lymphocyte count, and sepsis Presumed immunologic AEs of special interest 22% incidence with pembrolizumab + CT compared with 11% with chemotherapy alone AE, adverse event; CT, chemotherapy. Shirish Gadgeel, MD: Again, treatment‑related toxicities observed in the KEYNOTE-021 study were as expected.[7] All grade treatment‑related toxicities (eg, fatigue, nausea, rash, and alopecia) were higher in patients who received pembrolizumab plus chemotherapy by more than 10% vs patients who received chemotherapy alone. However, grade ≥ 3 treatment‑related toxicities were similar across both treatment arms. Addition of pembrolizumab was associated with a higher incidence of immunologic adverse events, with a 22% incidence in patients who received pembrolizumab plus chemotherapy vs 11% who received chemotherapy alone. Slide credit: clinicaloptions.com Langer C, et al. Lancet Oncol. 2016;[Epub ahead of print].

Clinical Perspectives: First-line Immunotherapy for NSCLC
Pembrolizumab is a recently approved standard of care for some pts with newly diagnosed metastatic NSCLC PD-L1 positive (≥ 50% tumor cell staining) with FDA approved assay using mAb 22C3 No EGFR, ALK, or ROS1 genetic aberrations Combination first-line therapy with pembrolizumab + chemotherapy appears promising Multiple ongoing phase III trials are evaluating the combination of checkpoint blockade + chemotherapy in the first-line setting NSCLC, non-small-cell lung cancer. Shirish Gadgeel, MD: Based on the results of KEYNOTE‑024, the FDA recently approved pembrolizumab as first‑line therapy in advanced NSCLC patients whose tumors have at least 50% PD‑L1 expression as determined with the companion diagnostic assay.[5] Therefore, the results of KEYNOTE‑024 have clearly changed the standard of care for the approximately 25% to 30% of NSCLC patients with 50% or greater tumor PD-L1 expression who previously would have received first-line platinum‑based chemotherapy. Although at present the promising results of the randomized phase II KEYNOTE-021 trial cannot be considered practice changing, they can be viewed as hypothesis generating, as they set the stage for a number of ongoing phase III studies that are assessing the addition of immune checkpoint inhibitors to chemotherapy vs chemotherapy alone in NSCLC. For example, the ongoing, placebo-controlled, randomized phase III KEYNOTE‑189 study is evaluating first-line carboplatin or cisplatin plus pemetrexed with or without pembrolizumab in patients with advanced, nonsquamous NSCLC.[10] It is expected that such phase III studies will define the benefits of combining a PD-1 inhibitor (eg, pembrolizumab or nivolumab) or a PD-L1 inhibitor (eg, atezolizumab) with chemotherapy vs chemotherapy alone. Slide credit: clinicaloptions.com

Atezolizumab vs Docetaxel in Progressive Advanced NSCLC (OAK)
Stratified by PD-L1 expression, histology, prior chemotherapy regimens Atezolizumab 1200 mg IV Q3W until loss of clinical benefit Metastatic or locally advanced NSCLC (2L/3L), PD on prior platinum-based treatment (N = 1225) No crossover allowed Docetaxel 75 mg/m2 IV Q3W until PD DoR, duration of response; ITT, intent to treat; NSCLC, non-small-cell lung cancer; PD, progressive disease. Shirish Gadgeel, MD: The results of the phase III OAK trial were practice changing in the second-line setting for advanced NSCLC. In OAK, patients (N = 1225) with advanced NSCLC who had previously been treated with 1 or 2 previous lines of chemotherapy, including at least 1 platinum‑based regimen, were randomized to the PD-L1 inhibitor atezolizumab at a flat dose of 1200 mg IV every 3 weeks until loss of clinical benefit or an expected toxicity vs docetaxel 75 mg/m2 every 3 weeks until progressive disease.[11] No crossover was allowed. Patients were stratified according to PD‑L1 expression, histology, and the number of previous chemotherapy regimens. Based on predefined study criteria, primary endpoints were assessed for the first 850 patients enrolled. Primary endpoints (first 850 pts enrolled): OS in ITT population; OS in pts with ≥ 1% PD-L1 expression Secondary endpoints: ORR, PFS, DoR, safety Slide credit: clinicaloptions.com Barlesi F, et al. ESMO Abstract LBA44_PR.

OAK: Overall Survival 100 90 80 70 60 OS (%) 50 40 30 20 10 3 6 9 12
Atezolizumab (n = 425) Docetaxel Median OS, mos 13.8 9.6 HR (95% CI) 0.73 ( ) P value .0003 100 90 80 70 60 OS (%) 50 40 30 Shirish Gadgeel, MD: OAK met its primary endpoint of improvement in OS with atezolizumab. The median OS was 13.8 months with atezolizumab vs 9.6 months with docetaxel (HR: 0.73; 95% CI: ; P = .0003).[11] 20 10 3 6 9 12 15 18 21 24 27 Mos Slide credit: clinicaloptions.com Barlesi F, et al. ESMO Abstract LBA44_PR.

OAK: OS in Select Pt Subgroups
Female Male < 65 yrs ≥ 65 yrs ECOG PS 0 ECOG PS 1 1 prior therapy 2 prior therapies Never smokers Current/previous smokers KRAS mutant KRAS wild type EGFR mutant EGFR wild type n (%) 330 (39) 520 (61) 453 (53) 397 (47) 315 (37) 535 (63) 640 (75) 210 (25) 156 (18) 694 (82) 59 (7) 203 (24) 85 (10) 628 (74) ECOG, Eastern Cooperative Oncology Group; ITT, intent to treat; PS, performance status. Shirish Gadgeel, MD: In an OAK patient subgroup analysis, atezolizumab appeared to provide an OS benefit to almost all of the subgroups tested, except for patients with EGFR mutation–positive disease, where OS was similar for both arms.[11] ITT 850 (100) Favors Atezolizumab Favors Docetaxel Slide credit: clinicaloptions.com Barlesi F, et al. ESMO Abstract LBA44_PR.

More Frequent With Docetaxel More Frequent With Atezolizumab
OAK: Safety Atezolizumab Docetaxel Fatigue Alopecia Diarrhea Anemia Nausea Myalgia Neutropenia Peripheral edema Peripheral neuropathy Stomatitis Febrile neutropenia Dysgeusia Musculoskeletal pain Pruritus More Frequent With Docetaxel AE, adverse event. Shirish Gadgeel, MD: In general, toxicity was lower in patients who received atezolizumab vs docetaxel.[11] Except for musculoskeletal pain and pruritus, which were more common with atezolizumab, most observed toxicities were more common in patients who received docetaxel. Grade 1/2 AEs Grade 3/4 AEs Grade 1/2 AEs Grade 3/4 AEs More Frequent With Atezolizumab 40% 30% 20% 10% 0% 10% 20% 30% 40% Slide credit: clinicaloptions.com Barlesi F, et al. ESMO Abstract LBA44_PR.

Clinical Perspectives: Checkpoint Inhibition for Progressive NSCLC
Atezolizumab is a recently approved treatment option for pts with metastatic NSCLC and disease progression on or following platinum-based chemotherapy Pts with EGFR and ALK genetic aberrations should have progression on appropriate approved targeted therapy No PD-L1 testing is required for this indication of atezolizumab NSCLC, non-small-cell lung cancer. Shirish Gadgeel, MD: Based on the results of the OAK trial, atezolizumab received FDA approval for metastatic NSCLC in patients with progression during or following platinum‑based chemotherapy,[12] thereby providing another immune checkpoint inhibitor to choose from for progressive, advanced NSCLC. No PD-L1 testing is required, and patients with EGFR mutations or ALK rearrangements are required to have progressed on an approved targeted therapy. The OAK trial was the first randomized phase III study to evaluate an anti–PD‑L1 agent in the management of NSCLC, with atezolizumab providing a benefit in the second‑line and third‑line setting similar to what has been observed for the approved anti–PD‑1 inhibitors nivolumab and pembrolizumab. In contrast to previous studies of nivolumab and pembrolizumab that only allowed 1 previous platinum-based doublet chemotherapy,[2,13,14] 25% of patients in both arms of the OAK trial had received 2 previous therapies.[11] Furthermore, the OAK trial showed a benefit regardless of PD-L1 expression, which is similar to second-line studies with nivolumab.[13,14] However, in the subgroup analysis of the CHECKMATE‑057 study, which evaluated nivolumab in nonsquamous patients, nivolumab did not appear to provide greater benefit than docetaxel in patients whose tumors did not express PD‑L1.[13] By contrast, second‑line studies with pembrolizumab were conducted only in patients with at least 1% tumor PD‑L1 expression.[2] It is important to note that subgroup analysis of any of these trials should be viewed only as hypothesis generating and should not necessarily define routine care of our patients. Based on available data that suggest similar efficacy and toxicity for these agents, any of the 3 approved immune checkpoint inhibitors is a reasonable option in the second-line setting for patients with NSCLC without actionable mutations, especially considering that no trial has directly compared any of these agents. At this point, the choice of immune checkpoint inhibitor is up to the provider and the patient, with dosing schedule potentially playing a role in the decision (ie, every 2 weeks for nivolumab and every 3 weeks for pembrolizumab and atezolizumab). However, with the very recent approval of pembrolizumab in the first-line setting, what should now be happening is that all patients with an NSCLC diagnosis should be tested for PD‑L1, since it is required to give pembrolizumab. Then, if their tumors exhibit at least 50% PD-L1 expression using the companion diagnostic assay, they receive pembrolizumab, and if not, they get standard platinum-based doublet chemotherapy, followed by either nivolumab or atezolizumab or pembrolizumab (if the tumor has > 1% PD-L1 expression) upon disease progression. For patients who progress on first-line pembrolizumab, I would consider platinum‑based chemotherapy in the second line because, currently, there are no data to suggest that atezolizumab, being a PD‑L1 inhibitor, or a different PD-1 inhibitor such as nivolumab would have any benefit. Slide credit: clinicaloptions.com

Afatinib Vs Gefitinib in EGFRm+ NSCLC: Updated PFS and TTF (LUX-Lung 7)
LUX-Lung 7 first prospective randomized trial comparing EGFR TKI agents head to head in first-line NSCLC setting[1] Randomized 319 pts (1:1) Coprimary endpoints of PFS, TTF, and OS PFS (updated results) significantly improved with afatinib (HR: 0.74; P = .0178)[2] TTF (updated results) significantly improved with afatinib (HR: 0.75; P = .0136)[2] m+, mutation positive; NSCLC, non-small-cell lung cancer; TKI, tyrosine kinase inhibitor; TTF, time to treatment failure. Shirish Gadgeel, MD: Updated results from the phase IIb LUX-Lung 7 trial, which was the first prospective, randomized trial comparing EGFR tyrosine kinase inhibitor (TKI) agents head to head in the first‑line treatment of EGFR‑mutation–positive NSCLC, were also presented at ESMO 2016.[15,16] In this trial, 319 patients with activating EGFR mutations, either the exon 19 deletion or exon 21 L858R point mutation, were randomized to afatinib or gefitinib. The updated results for both PFS and time to treatment failure (coprimary endpoints) showed significant improvements with afatinib vs gefitinib (HR: 0.74, P = and HR: 0.75, P = .0138, respectively).[16] 1. Park K, et al. Lancet Oncol. 2016;17: Paz-Ares L, et al. ESMO Abstract LBA43. Slide credit: clinicaloptions.com

LUX-Lung 7: OS 100 80 60 Estimated OS (%) 40 20
Median OS, mos HR (95% CI) P value 27.9 24.5 0.86 ( ) Afatinib (n = 160) Gefitinib (n = 159) 100 80 60 Estimated OS (%) 40 20 Nonsignificant trend in OS favoring afatinib across prespecified pt subgroups including EGFR del19 and L858R Shirish Gadgeel, MD: Median OS data were also presented at ESMO 2016, with no significant difference in OS observed for patients who received afatinib vs gefitinib (27.9 vs 24.5 months, respectively; P = .2580).[16] Although the results of LUX-Lung 7 suggested that there may be a small advantage with afatinib in terms of PFS and time to treatment failure, there does not appear to be an OS benefit. When the PFS data were originally presented, I and others started to prefer afatinib over the other TKIs. However, with the release of the OS data, that has been tempered. Furthermore, for PFS, the curves separate after the median PFS is reached, which suggests that only a small minority of patients may be deriving a PFS benefit with afatinib over gefitinib and may explain why a difference in OS was not observed. Overall, these data suggest that either of these EGFR TKIs are acceptable as frontline therapy in EGFR-mutant NSCLC. In my opinion, without data to suggest that one is more efficacious than the other, each of the 3 approved EGFR TKIs—afatinib, gefitinib, and erlotinib—should be considered equivalent in this setting, with choice of which specific EGFR TKI to use being decided on a case-by-case basis by the provider and the patient. 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 Mos Pts at Risk, n Afatinib Gefitinib 104 90 94 80 81 71 74 62 61 56 50 48 36 44 30 27 12 7 2 0 0 0 Slide credit: clinicaloptions.com Paz-Ares L, et al. ESMO Abstract LBA43.

Selumetinib + Doc in Previously Treated KRAS-mutant NSCLC (SELECT-1)
Randomized, double-blind phase III trial comparing selumetinib (a MEK1/2 inhibitor) + docetaxel with placebo + docetaxel as second-line therapy in KRAS-mutant advanced NSCLC 1:1 randomization (N = 510) Primary endpoint: PFS PFS was similar in both arms (HR: 0.93; P = .44) No significant difference in secondary endpoints of OS and ORR Selumetinib + docetaxel was associated with more grade ≥ 3 and serious adverse events Doc, docetaxel; NSCLC, non-small-cell lung cancer. Shirish Gadgeel, MD: Among molecularly driven NSCLC, KRAS mutations are the most common, constituting approximately 30% of lung adenocarcinomas and approximately 5% of squamous cell NSCLC.[17] Despite its prevalence, developing targeted therapy for patients with KRAS mutation–positive NSCLC remains a challenge. The MEK‑ERK pathway is the primary signaling pathway downstream of KRAS. Therefore, there is interest in evaluating MEK inhibitors in patients with KRAS mutation–positive NSCLC. A previous randomized phase II study demonstrated a PFS and ORR benefit for the addition of the MEK1/2 inhibitor selumetinib to docetaxel vs docetaxel alone as second‑line therapy in KRAS mutation–positive NSCLC,[18] laying the foundation for the randomized, placebo-controlled phase III SELECT-1 trial presented by Jänne and colleagues[19] at ESMO 2016. In SELECT-1, 510 patients with KRAS mutation–positive NSCLC who previously received platinum‑based chemotherapy were randomized to docetaxel plus selumetinib or placebo. The primary endpoint of PFS was similar in both arms (HR: 0.93; P = .44) and there were no significant differences in the secondary endpoints of OS and ORR. In addition, selumetinib plus docetaxel was associated with more toxicity than docetaxel alone, with more grade ≥ 3 and serious adverse events observed in the patients who received the combination treatment. One possible explanation as to why SELECT‑1 did not confirm the results of the previous randomized phase II study is that the combination of selumetinib and docetaxel might be beneficial in specific subgroups of KRAS mutation–positive patients and not others. It may be that tumors with specific KRAS mutations such as G12C may respond better to selumetinib or that the presence of comutations, such as p53 or LKB1, could influence the response. The phase II SWOG S1507 study is evaluating the MEK1/2 inhibitor trametinib, which is approved in BRAF-positive melanoma,[20] in combination with docetaxel in stage IV KRAS mutation–positive NSCLC, but is specifically assessing the efficacy in subgroups of patients based on specific KRAS mutations, as well as presence of comutations.[21] SWOG S1507 promises to clarify the utility of MEK inhibitors in this patient population. With the presentation of truly practice‑changing trial results, ESMO 2016 was a very important conference for lung cancer patients and providers. Based on the results of the phase III KEYNOTE-024 trial, we now have a single‑agent PD‑1 inhibitor, pembrolizumab, approved as frontline therapy for a specific subset of advanced NSCLC patients. With the approval of atezolizumab in the progressive disease setting based on the results of the phase III OAK trial, we also have a third immune checkpoint inhibitor option for these patients with advanced NSCLC. Based on these changes, here is how I would approach patients with advanced NSCLC who are being considered for first‑line therapy. I would first determine the histology of their tumor, whether squamous or nonsquamous. In patients with squamous-cell NSCLC, I would then test for PD‑L1 expression and give pembrolizumab in the presence of 50% or greater tumor PD-L1 expression; in its absence, I would prescribe standard platinum‑based chemotherapy. In patients with nonsquamous NSCLC, I would test for EGFR mutations, ALK rearrangements, and ROS1 translocations. If any of these molecular markers were identified, I would then give the appropriate targeted treatment. I would also assess for tumor PD‑L1 expression and give pembrolizumab if it were 50% or greater. In the absence of molecular markers or high PD‑L1 expression, I would give platinum‑based chemotherapy. In general, tumors with molecular alterations usually do not exhibit high PD‑L1 expression. However, if a patient had both, my approach would be to use targeted therapy first because there are much more data on targeted treatments as frontline therapy in this patient population. In fact, EGFR‑positive and ALK‑positive patients were excluded from KEYNOTE‑024, so there are no data on whether first-line pembrolizumab has a benefit in these patients. Lung Cancer References: Reck M, Rodríguez-Abreu D, Robinson AG, et al. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med. 2016;[Epub ahead of print]. Herbst RS, Baas P, Kim DW, et al. Lancet Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet. 2016;387: Garon EB, Rizvi NA, Hui R, et al. Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med. 2015;372: Chatterjee M, Turner DC, Felip E, et al. Systematic evaluation of pembrolizumab dosing in patients with advanced non-small-cell lung cancer. Ann Oncol. 2016;27: Keytruda [package insert]. Whitehouse Station, NJ: Merck & Co, Inc; 2016. Socinski M, Creelan B, Horn L, et al. CheckMate 026: a phase 3 trial of nivolumab vs investigator’s choice (IC) of platinum-based doublet chemotherapy (PT-DC) as first-line therapy for state iv/recurrent programmed cell death ligand 1 (PD-L1)–positive NSCLC. Program and abstracts of the 2016 European Society for Medical Oncology Annual Congress; October 7-11, 2016; Copenhagen, Denmark. Abstract LBA7_PR. Langer C, Gadgeel SM, Borghaei H, et al. Carboplatin and pemetrexed with or without pembrolizumab for advanced, non-squamous non-small-cell lung cancer: a randomised, phase 2 cohort of the open-label KEYNOTE-021 study. Lancet Oncol. 2016;[Epub ahead of print]. ClincalTrials.gov. A study of pembrolizumab (MK-3475) in combination with chemotherapy or immunotherapy in participants with lung cancer (MK /KEYNOTE-021). Available at: Accessed December 16, 2016. Gadgeel SM, Stevenson J, Langer CJ, et al. Pembrolizumab (pembro) plus chemotherapy as front-line therapy for advanced NSCLC: KEYNOTE-021 cohorts A-C. Program and abstracts of the 2016 American Society of Clinical Oncology Annual Meeting; June 3-7, 2016; Chicago, Illinois. Abstract 9016. ClinicalTrials.gov. Study of platinum+pemetrexed chemotherapy with or without pembrolizumab (MK-3475) in participants with first line metastatic non-squamous non-small cell lung cancer (MK /KEYNOTE-189). Available at: Accessed December 16, 2016. Barlesi F, Park K, Ciardiello F, et al. Primary analysis from OAK, a randomized phase III study comparing atezolizumab with docetaxel in 2L/3L NSCLC. Program and abstracts of the 2016 European Society for Medical Oncology Annual Congress; October 7-11, 2016; Copenhagen, Denmark. Abstract LBA44_PR. Tecentriq [package insert]. South San Francisco, CA: Genentech, Inc; 2016. Borghaei H, Paz-Ares L, Horn L, et al. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med. 2015;373: Brahmer J, Reckamp KL, Baas P, et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med. 2015;373: Park K, Tan EH, O’Byrne K, et al. Afatinib versus gefitinib as first-line treatment of patients with EGFR mutation-positive non-small-cell lung cancer (LUX-Lung 7): a phase 2B, open-label, randomised controlled trial. Lancet Oncol. 2016;17: Paz-Ares L, Tan EH, Zhang L, et al. Afatinib (A) vs gefitinib (G) in patients (pts) with EGFR mutation-positive (EGFRm+) non-small-cell lung cancer (NSCLC): overall survival (OS) data from the phase IIb trial LUX-Lung 7 (LL7). Program and abstracts of the 2016 European Society for Medical Oncology Annual Congress; October 7-11, 2016; Copenhagen, Denmark. Abstract LBA43. Karachaliou N, Mayo C, Costa C, et al. KRAS mutations in lung cancer. Clin Lung Cancer. 2013;14: Jänne PA, Shaw AT, Pereira JR, et al. Selumetinib plus docetaxel for KRAS-mutant advanced non-small-cell lung cancer: a randomised, multicentre, placebo-controlled, phase 2 study. Lancet Oncol. 2013;14:38-47. Jänne PA, van den Heuvel M, Barlesi F, et al. Selumetinib in combination with docetaxel as second-line treatment for patients with KRAS-mutant advanced NSCLC: Results from the phase III SELECT-1 trial. Program and abstracts of the 2016 European Society for Medical Oncology Annual Congress; October 7-11, 2016; Copenhagen, Denmark. Abstract LBA47_PR. Mekinist [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2015. ClinicalTrials.gov. Trametinib and docetaxel in treating patients with recurrent or stage IV non-small cell lung cancer. Available at: Accessed December 16, 2016. Slide credit: clinicaloptions.com Jänne PA, et al. ESMO Abstract LBA47.

Melanoma

EORTC 18071: Adjuvant Ipilimumab vs Placebo for Resected Stage III Disease
Stratified by stage (IIIa with ≥ 1 metastasis measuring > 1 mm vs IIIb vs IIIc with 1-3 positive LN vs IIIc with ≥ 4 positive LN), region (North America, Europe, Australia) Ipilimumab 10 mg/kg Q3w x 4 then Q12W for up to 3 yrs (n = 475) Patients with high-risk, completely resected stage III melanoma and ECOG PS 0/1 (N = 951) Placebo Q3W x 4 then Q12W for up to 3 yrs (n = 476) DMFS, distant metastasis free survival; ECOG, Eastern Cooperative Oncology Group; IRC, independent review committee; LN, lymph node; PS, performance status; RFS, relapse-free survival. Margaret Callahan, MD, PhD: In melanoma, the most clinically impactful data presented at ESMO this year were the results of the phase III EORTC study, which randomized 951 high-risk stage III melanoma patients to receive either adjuvant ipilimumab or placebo.[22] All patients underwent a complete resection prior to enrollment in the study. Ipilimumab was administered as indicated by the FDA for adjuvant melanoma at a dose of 10 mg/kg once every 3 weeks for 4 doses, followed by once every 12 weeks for up to 3 years or until unacceptable toxicity or disease progression. This is distinct from the previously approved dosing of 3 mg/kg once every 3 weeks for 4 doses in patients with unresectable or metastatic melanoma.[23] Previously reported data on the primary endpoint of relapse-free survival showed an approximately 9-month improvement with ipilimumab (HR: 0.75; P = .001) and led to its FDA approval for melanoma in the adjuvant setting in 2015.[22] The current analysis reports on the long-awaited, important secondary endpoint of OS. Primary endpoint: RFS per IRC (Met – approximately 9-mo improvement [HR: 0.75; P = .0013]; approved by FDA in 2015) Secondary endpoints including: OS, DMFS Slide credit: clinicaloptions.com Eggermont AMM, et al. N Engl J Med. 2016;[Epub ahead of print].

EORTC 18071: Survival RFS OS 100 90 80 70 60 50 40 30 20 10 8 1 2 3 4 5 6 7 100 90 80 70 60 50 40 30 20 10 Pts (%) 8 1 2 3 4 5 6 7 Yr Placebo Ipilimumab Yr Placebo Ipilimumab Pts (%) RFS, relapse-free survival. Margaret Callahan, MD, PhD: In the updated information from the trial presented at ESMO this year, both the 5-year relapse-free survival and 5-year OS were significantly improved in the patients randomized to receive ipilimumab.[22] Relapse-free survival was 40.8% with ipilimumab vs 30.3% for placebo (HR: 0.76; 95% CI: ; P < .001), and OS was 65.4% vs 54.4%, respectively (HR: 0.72; 95.1% CI: ; P = .001). Ipilimumab (n = 475) Placebo (n = 476) 5-yr RFS, % 40.8 30.3 HR (95% CI) 0.76 ( ) P < .001 Ipilimumab (n = 475) Placebo (n = 476) 5-yr OS, % 65.4 54.4 HR (95.1% CI) 0.72 ( ) P .001 Slide credit: clinicaloptions.com Eggermont AMM, et al. N Engl J Med. 2016;[Epub ahead of print].

EORTC 18071: Safety Higher incidence of grade 3/4 immune-related adverse events with ipilimumab (41.6% vs 2.7%) Most common were gastrointestinal (16.1%), hepatic (10.8%), and endocrine (7.9%) 5 pts (1.1%) treated with ipilimumab died due to treatment-related toxicities 3 from colitis (2 perforations) 1 from myocarditis 1 from multiorgan failure (Guillain-Barré syndrome) Margaret Callahan, MD, PhD: However, as expected, ipilimumab was associated with a higher incidence of grade 3/4 toxicities vs placebo (41.6% vs 2.7%, respectively). Common toxicities included gastrointestinal toxicities, like colitis; hepatic toxicities, like hepatitis; and endocrinopathies.[22] Notably, 5 patients treated with ipilimumab died due to treatment-related toxicities, including complications from colitis, myocarditis, and organ failure. This is a relatively high toxicity burden for an adjuvant treatment and should be weighed appropriately when considering patient options. Although this dosing regimen of ipilimumab has already been FDA approved for adjuvant treatment of advanced stage III melanoma based on the initial primary endpoint of relapse-free survival, the new data on the benefit in OS provides additional evidence for the benefit of ipilimumab in the adjuvant setting. However, this potential benefit appears to come with a significant rate of serious toxicity. Although many of the toxicities are reversible, there was an approximately 1% risk of death with ipilimumab in this study. It is worth noting that this study focused on high-risk stage III melanoma patients and excluded stage IIIa patients with a lower burden of disease in the lymph nodes (< 1 mm) and a lower risk of recurrence. Although it is an unanswered question as to how a lower-risk stage III melanoma patient population would respond to adjuvant ipilimumab, based on these results, one might question whether it would be worth exposing them to the toxicity of this regimen. Another thing to consider regarding these data is that newer, very effective therapies for the treatment of advanced melanoma (eg, PD-1 blocking antibodies, BRAF/MEK combination therapies) may not have been readily available when these patients progressed to metastatic disease since accrual to this study began in If they would have had access to the newer melanoma treatments presently available, would this have influenced some of the results in this study? I am looking forward to seeing the results of adjuvant therapy trials incorporating newer agents including the PD-1 inhibitors pembrolizumab and nivolumab, and am hopeful that these agents will be more effective and less toxic and therefore have a better risk/benefit ratio for this patient population. Currently, nivolumab is being compared with ipilimumab in the adjuvant setting in the randomized, double-blind phase III CheckMate 238 trial for stage IIIb/c or stage IV melanoma.[24] Adjuvant pembrolizumab is being compared to placebo in the randomized, double-blind phase III KEYNOTE-054 trial for high-risk stage III melanoma with complete resection.[25] The primary results from these studies are expected in the next few years. Slide credit: clinicaloptions.com Eggermont AMM, et al. N Engl J Med. 2016;[Epub ahead of print].

PD-L1 Expression and Outcomes With Nivo + Ipi vs Nivo in Advanced Melanoma
Nivolumab associated with higher ORR than chemotherapy regardless of PD-L1 expression level (≥ or < 5% groups) Nivolumab + ipilimumab associated with higher ORR than nivolumab regardless of PD-L1 expression level (descriptive subset analysis) PFS similar in pts with high PD-L1 expression Current pooled analysis evaluated PD-L1 expression as a biomarker for advanced melanoma CheckMate 066, CheckMate 067, and CheckMate 069 Ipi, ipilimumab; Nivo, nivolumab. Margaret Callahan, MD, PhD: Another very interesting study reported at ESMO 2016 is a pooled analysis of 3 studies (ie, CheckMate 066, 067, and 069), evaluating expression of PD-L1 on tumor cells as a potential biomarker for response to immunotherapy in patients with newly diagnosed, advanced melanoma treated with either nivolumab or the combination of ipilimumab and nivolumab.[26] In a previously published study, higher tumor expression of PD-L1 was associated with a higher response rate to nivolumab monotherapy.[27] However, regardless of PD-L1 expression, patients treated with nivolumab had a higher ORR compared with patients treated with chemotherapy. In a prior study of the combination of ipilimumab and nivolumab, patients who received both drugs, had a higher ORR than those who received nivolumab alone whether they were PD-L1 high or PD-L1 low.[28] Slide credit: clinicaloptions.com Long G, et al. ESMO Abstract 1112PD.

PFS by PD-L1 Expression Level: A Pooled Analysis of Nivo + Ipi Vs Nivo Alone
Pts With PD-L1 < 5% Pts With PD-L1 ≥ 5% 100 100 90 90 80 80 70 70 60 60 PFS (%) 50 50 40 40 30 30 20 Nivo + Ipi Nivo 20 Nivo + Ipi Nivo 10 10 3 6 9 12 15 18 21 24 27 3 6 9 12 15 18 21 24 27 Mos Mos Pts at Risk, n Ipi, ipilimumab; Nivo, nivolumab. Margaret Callahan, MD, PhD: In the current pooled analysis, the combination of nivolumab plus ipilimumab demonstrated a higher ORR vs nivolumab, regardless of whether patients had high or low PD-L1 expression as defined using thresholds of either 1%, 5%, or 10% of tumor cell staining.[26] For PFS, patients with PD-L1 expression lower than 5% achieved a superior PFS with the combination regimen vs nivolumab alone (11.1 vs 4.9 months, respectively; HR: 0.70; 99.5% CI: ; P = .0014), whereas there was no difference in PFS between the combination regimen and nivolumab alone for patients with 5% or greater PD-L1 expression (not reached vs 22.0 months, respectively; HR: 0.99; 99.5% CI: ; P = .9471). This study highlights some of the complexities of using PD-L1 as a biomarker to predict a response to immunotherapeutic agents in patients with advanced melanoma. It has been suggested that PD-L1 expression could be used to choose between the combination regimen and nivolumab monotherapy. For example, in looking at the PFS data alone, one might conclude that patients who have low PD-L1 levels get the most benefit from the combination whereas patients with high PD-L1 levels tend to do well with single agent PD-1 blockade and the benefit with the combination regimen is lower. However, we should remember that the ORR is higher for the combination regardless of the PD-L1 expression level. Lastly, because patients who test negative or have low PD-L1 expression certainly can respond to immunotherapy, whether nivolumab or the combination of ipilimumab and nivolumab, I would recommend exercising caution in applying this biomarker in determining clinical decisions. I think understanding PD-L1 expression tells us something about the disease biology, but whether and how to apply it in our melanoma patient population remains unclear at this time. Instead, I think it is very important to have a risk/benefit discussion with every patient. Clearly, higher response rates have been seen for nivolumab plus ipilimumab vs nivolumab monotherapy, but that benefit is balanced by a higher rate of toxicity. With my patients, we discuss the potential risks and benefits of the combination regimen compared with single agent PD-1 blockade. Factors like the patients’ overall health, how advanced or clinically symptomatic their disease is, and their personal preferences are all part of the context of that discussion. Nivo + Ipi Nivo 103 93 83 80 31 40 5 11 0 0 92 139 72 99 58 87 51 80 44 70 42 61 31 58 13 25 3 2 0 0 Combination nivolumab + ipilimumab demonstrated higher ORR than nivolumab alone regardless of high or low PD-L1 expression with thresholds of 1%, 5%, and 10% Slide credit: clinicaloptions.com Long G, et al. ESMO Abstract 1112PD.

Phase III Study of Ipilimumab 10 mg/kg vs 3 mg/kg: Trial Design
Previous results suggested improved survival with increased toxicity for higher dose ipilimumab Stratified by extent of metastases (M0/M1a/M1b vs M1c/no brain mets vs M1c with brain mets), previous systemic therapy (yes vs no), ECOG PS (0 vs 1) Ipilimumab 10 mg/kg Q3W x 4 (n = 362) Patients with unresectable stage III/IV melanoma, no previous BRAF or checkpoint inhibitors, and ECOG PS 0/1 (N = 727) DCR, disease control rate; ECOG, Eastern Cooperative Oncology Group; PS, performance status. Margaret Callahan, MD, PhD: As previously mentioned, ipilimumab is FDA-approved for the treatment of advanced or metastatic melanoma at a dose of 3 mg/kg given every 3 weeks for 4 doses.[23,27,29] In a previously published randomized, double-blind phase II study, Wolchok and colleagues[30] showed that 10-mg/kg ipilimumab was associated with an improved OS but higher incidence of treatment-related grade 3/4 adverse events vs 3-mg/kg ipilimumab in patients with previously treated stage III (unresectable) or stage IV melanoma. This phase III study, reported at ESMO 2016 by Ascierto and colleagues, compared ipilimumab at a dose of 10 mg/kg vs 3 mg/kg in 727 patients with newly diagnosed unresectable stage III/IV metastatic melanoma and no previous BRAF or checkpoint inhibitor therapy.[31] Ipilimumab 3 mg/kg Q3W x 4 (n = 365) Primary endpoint: OS Secondary endpoints including: PFS, ORR, DCR Ascierto PA, et al. ESMO Abstract 1106O. Wolchok J, et al. Lancet Oncol. 2010;11: Slide credit: clinicaloptions.com

Phase III Study of Ipilimumab 10 mg/kg vs 3 mg/kg: Efficacy
Ipi 10 mg/kg (n = 365) Ipi 3 mg/kg (n = 362) HR (95% CI) P Median OS,* mos 15.7 11.5 0.84 ( ) .04 Median PFS, mos 2.8 0.89 ( ) .16 ORR % 15 12 NR DCR, % 32 28 *Minimum follow-up of approximately 43 mos. DCR, disease control rate; Ipi, ipilimumab; NR, not reported. Margaret Callahan, MD, PhD: With a follow-up of 43 months, patients who received the higher 10-mg/kg dose of ipilimumab showed a significant OS benefit vs the lower 3-mg/kg dose (15.7 vs 11.5 months, respectively; HR: 0.84; 95% CI: ; P = .04). However, this benefit appeared to be out of proportion to the outcomes for PFS, ORR, and disease control rate, which were not significantly different between the 2 treatment arms.[31] Slide credit: clinicaloptions.com Ascierto PA, et al. ESMO Abstract 1106O.

Phase III Study of Ipilimumab 10 mg/kg vs 3 mg/kg: Safety
Adverse Event, % Ipilimumab 10 mg/kg (n = 364) Ipilimumab 3 mg/kg (n = 362) Any Grade Grade ≥ 3 Any grade Treatment-related adverse event 79 34 63 19 Adverse event leading to discontinuation 31 26 16 Immune-related adverse event 74 30 54 14 Margaret Callahan, MD, PhD: Consistent with previous studies,[30] patients who received 10-mg/kg ipilimumab had a higher incidence of both overall and high-grade toxicity.[31] Grade ≥ 3 treatment-related toxicity was observed in 34% of patients treated with 10-mg/kg ipilimumab vs 19% for the 3-mg/kg dose, with 26% vs 16% of patients experiencing toxicities that led to study drug discontinuation. There were a total of 6 patient deaths attributed to ipilimumab, 4 in the 10-mg/kg dose group and 2 in the 3-mg/kg dose group. Although 10-mg/kg dosing of ipilimumab showed some superiority to 3 mg/kg regarding efficacy, whether this is worth the additional burden of toxicity bears further scrutiny. I think an important caveat to consider when interpreting these data is that the study population does not resemble the population of patients who are presently being treated with melanoma. The patients in this study were BRAF inhibitor naive and checkpoint inhibitor naive, whereas most of our patients with melanoma would currently receive either a PD‑1 blocking agent (alone or in combination with ipilimumab) or a BRAF/MEK inhibitor combination in the frontline setting, not ipilimumab monotherapy. In fact, with the ascendance of nivolumab and pembrolizumab, PD‑1–inhibitor/ipilimumab combinations, and BRAF/MEK inhibitor combinations, patients receiving frontline ipilimumab monotherapy tend to be rare, limiting the impact of these findings. Deaths on study: 4 pts (10 mg/kg) and 2 pts (3 mg/kg) Slide credit: clinicaloptions.com Ascierto PA, et al. ESMO Abstract 1106O.

Epacadostat + Pembrolizumab in Advanced Melanoma: Rationale
Epacadostat is a small molecule inhibitor of indoleamine-2,3- dioxygenase 1 (IDO1) IDO1 is an intracellular enzyme present in tumor cells, DC, MΦ, B lymphocytes Catalyzes the breakdown of tryptophan to kynurenine leading to suppression of CTL and expansion of Treg cells Inflamed Tumor Microenvironment Treg Tumor PD-L1 T PD1 CTL DC MΦ Margaret Callahan, MD, PhD: For the phase I KEYNOTE-037 study, Gangadhar and colleagues[33] combined epacadostat with the PD‑1–blocking antibody pembrolizumab. (-) IDO (+) TRP → KYN Slide credit: clinicaloptions.com Gangadhar, et al. ESMO Abstract 1110PD.

Epacadostat + Pembrolizumab in Advanced Melanoma: KEYNOTE-037
Phase I with dose escalation and dose expansion Epacadostat 25 – 300 mg BID + pembrolizumab 2 mg/kg or mg Q3W Enrolled 62 pts with a variety of solid tumors; 22 pts with advanced melanoma No MTD for epacadostat combination therapy reached Grade 3/4 adverse events in 19% of pts Rash (8%) and increased lipase (5%) most frequent ORR: 11 of 19 (58%) treatment-naive pts with adv melanoma All responses confirmed and ongoing with a follow-up ranging from wks adv, advanced; MTD, maximum tolerated dose. Margaret Callahan, MD, PhD: Patients with a variety of solid tumors were enrolled, including 22 with advanced melanoma. No maximum tolerated dose for the combination was reached. Grade 3/4 adverse events were reported in 19% of patients, with the most common toxicities being rash and lipase elevation. In comparison to the grade 3/4 adverse event rate of 55% observed for the combination of ipilimumab and nivolumab,[28] 19% is a relatively favorable rate for a combination regimen.[33] Of 19 treatment‑naive patients with advanced melanoma evaluable for response, 11 patients (58%) achieved a response to epacadostat plus pembrolizumab, with all of the responses ongoing and a follow-up ranging from 46 to 90+ weeks. In the context of a 57.6% ORR for the combination of ipilimumab and nivolumab,[28] the preliminary data for epacadostat plus pembrolizumab appear promising. Based on these results, the randomized, phase III KEYNOTE-252/ECHO-301 study has been initiated to compare pembrolizumab plus epacadostat with pembrolizumab plus placebo in patients with treatment-naive advanced melanoma.[35] Slide credit: clinicaloptions.com Gangadhar, et al. ESMO Abstract 1110PD.

Genomic Features of Response to Vemurafenib ± Cobimetinib
Retrospective study compared baseline tumor genomic features of pts with BRAFV600-mutant melanoma and CR or rapid PD to treatment with vemurafenib ± cobimetinib Pts enrolled in BRIM-2, -3, -7, or coBRIM Whole exome sequencing analysis CR group (n = 37): genetic alterations in NF1 more common PD group ( n = 70): genetic alterations in MITF and TP53 more common Mutational load similar in both pt groups RNA sequencing analysis indicates enriched gene expression CR group (n = 32): immune response processes PD group (n = 40): keratinization PD, progressive disease. Margaret Callahan, MD, PhD: In this retrospective analysis of patients enrolled in BRIM-2, -3, -7, or coBRIM, Yan and colleagues[36] evaluated baseline tumor genomic features of patients with BRAF-mutant melanoma who either had a CR or rapid progression of disease after treatment with the BRAF/MEK inhibitor combination vemurafenib with or without cobimetinib. Tumor samples underwent whole exome and RNA sequencing analysis to identify genetic alterations in the DNA or changes in expression of RNA, respectively. Whole exome sequencing analysis identified that genetic alterations in the NF1 gene for neurofibromin 1 were more common in patients with a CR, whereas genetic alterations in TP53 and MITF (melanogenesis associated transcription factor) were more common in the patients with disease progression. In contrast to observations that have come out of analyses of patients treated with immunotherapy, the mutational load present in tumors was similar regardless of response to vemurafenib/cobimetinib. RNA sequencing analysis indicated that expression of genes involved in an ongoing immune response were enriched in patients with a CR, whereas patients with disease progression were more likely to have a gene expression pattern consistent with keratinization. The study results are thought‑provoking as they suggest an ongoing immune response may be a good prognostic factor for patients with advanced melanoma. This type of analysis takes us 1 step closer to identifying and refining potential biomarkers to select patients for specific melanoma treatments. Slide credit: clinicaloptions.com Yan Y, et al. ESMO Abstract 1111O.

Clinical Perspectives
Ipilimumab provides both RFS and OS benefit for pts with high-risk stage III melanoma Clinicians and their pts should discuss the risks and benefits to individualize treatment decisions Ongoing phase III trials are evaluating anti–PD-1 agents in the adjuvant setting Investigation continues to identify new biomarkers to help guide clinical decisions using newer immune checkpoint inhibitors and targeted agents RFS, relapse-free survival. Margaret Callahan, MD, PhD: Of the 5 studies presented at ESMO 2016 that I have discussed, EORTC 18071, examining the role of ipilimumab in the adjuvant setting, has the most potential to affect clinical practice.[22] This study showed a relapse-free survival and OS benefit with ipilimumab, supporting its efficacy for patients with high‑risk stage III disease. However, because this treatment carries a significant burden of toxicity, clinicians and their patients should discuss the risks and benefits of ipilimumab to individualize treatment decisions. As such, we eagerly await the results of ongoing phase III studies evaluating nivolumab and pembrolizumab in the adjuvant setting. Our hope is that these anti–PD-1 agents will be more active and less toxic compared with ipilimumab in the adjuvant setting. The studies by Long and colleagues[26] and Yan and colleagues[36] highlight that we still have a lot to learn about how to select patients that will most benefit from the newer agents that we are using in practice. There are still no gold‑standard biomarkers to select patients for immunotherapy treatment in advanced melanoma, although identification of high-quality biomarkers to guide treatment decisions with newer immune checkpoint inhibitors and targeted agents is ongoing. Melanoma References: Eggermont AMM, Chiarion-Sileni V, Grob JJ, et al. Prolonged survival in stage III melanoma with ipilimumab adjuvant therapy. N Engl J Med. 2016;[Epub ahead of print]. Yervoy [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2015. ClincialTrials.gov. Efficacy study of nivolumab compared to ipilimumab in prevention of recurrence of melanoma after complete resection of stage IIIb/c or stage IV melanoma (CheckMate 238). Available at: Accessed December 16, 2016. ClinicalTrials.gov. Study of pembrolizumab (MK-3475) versus placebo after complete resection of high-risk stage III melanoma (MK /KEYNOTE-054). Available at: Accessed December 16, 2016. Long G, Larkin J, Ascierto PA, et al. PD-L1 expression as a biomarker for nivolumab (NIVO) plus ipilimumab (IPI) and NIVO alone in advanced melanoma (MEL): a pooled analysis. Program and abstracts of the 2016 European Society for Medical Oncology Annual Congress; October 7-11, 2016; Copenhagen, Denmark. Abstract 1112PD. Robert C, Long GV, Brady B, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med. 2015;372: Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015;373:23-34. Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363: Wolchok J, Neyns B, Linette G, et al. Ipilimumab monotherapy in patients with pretreated advanced melanoma: a randomised, double-blind, multicentre, phase 2, dose-ranging study. Lancet Oncol. 2010;11: Ascierto PA, Del Vecchio M, Robert C, et al. Overall survival (OS) and safety results from a phase 3 trial of ipilimumab (IPI) at 3 mg/kg vs 10 mg/kg in patients with metastatic melanoma (MEL). Program and abstracts of the 2016 European Society for Medical Oncology Annual Congress; October 7-11, 2016; Copenhagen, Denmark. Abstract 1106O. Zhai L, Spranger S, Binder DC, et al. Molecular pathways: targeting IDO1 and other tryptophan dioxygenases for cancer immunotherapy. Clin Cancer Res, 2015;21: Gangadhar TC, Hamid O, Smith DC, et al. Epacadostat plus pembrolizumab in patients with advanced melanoma and select solid tumors: updated phase 1 results from ECHO-202/KEYNOTE-037. Program and abstracts of the 2016 European Society for Medical Oncology Annual Congress; October 7-11, 2016; Copenhagen, Denmark. Abstract 1110PD. Holtzhausen A, Zhao F, Evans K, et al. Melanoma derived Wnt5a promotes local dendritic-cell expression of IDO and immunotolerance: opportunities for pharmacologic enhancement of immunotherapy. Cancer Immunol Res. 2015;3: ClinicalTrials.gov. A phase 3 study of pembrolizumab + epacadostat or placebo in subjects with unresectable or metastatic melanoma (Keynote-252/ECHO-301). Available at: Accessed December 16, 2016. Yan Y, Robert C, Larkin J, et al. Genomic features of complete responders (CR) versus fast progressors (PD) in patients with BRAFV600-mutated metastatic melanoma treated with cobimetinib + vemurafenib or vemurafenib alone. Program and abstracts of the 2016 European Society for Medical Oncology Annual Congress; October 7-11, 2016; Copenhagen, Denmark. Abstract 1111O. Slide credit: clinicaloptions.com

Metastatic Breast Cancer

Ribociclib + Letrozole as Initial Therapy for Adv HR+/HER2- MBC (MONALEESA-2)
Stratified by liver/lung metastases (present/absent) Ribociclib 600 mg/day PO 3 wks on, 1 wk off + Letrozole 2.5 mg/day (n = 334) Recurrent or MBC, postmenopausal, no previous systemic therapy for advanced disease, ECOG PS 0/1 (N = 668) No crossover allowed Placebo PO daily 3 wks on, 1 wk off + Letrozole 2.5 mg/day (n = 334) Adv, advanced; CBR, clinical benefit rate; ECOG, Eastern Cooperative Oncology Group; HR, hormone receptor; MBC, metastatic breast cancer; PS, performance status; QoL, quality of life. Joyce O’Shaughnessy, MD: For patients with breast cancer, the first important results reported at ESMO 2016 with impact on the first-line treatment of metastatic breast cancer (MBC) were for the randomized, first‑line phase III MONALEESA‑2 trial.[37] MONALEESA-2 compared the addition of the CDK4/6 inhibitor ribociclib to the aromatase inhibitor letrozole vs placebo plus letrozole in 668 postmenopausal patients with ER‑positive, HER2-negative MBC and no previous systemic therapy for metastatic disease. Similar to palbociclib in the PALOMA trials,[38,39] ribociclib was administered 3 weeks on and 1 week off. The primary endpoint was PFS. Primary endpoint: PFS Secondary endpoint: OS, ORR, CBR, safety, QoL Slide credit: clinicaloptions.com Hortobagyi GN, et al. N Engl J Med. 2016;375:

MONALEESA-2: PFS 100 80 60 PFS (%) 40 20 2 4 6 18 10 12 14 16 18 20 22
mPFS, mos HR (95% CI) P value NR 14.7 0.56 ( ) 3.29 x 10-6 Ribo + Let (n = 334) Pbo + Let (n = 334) 100 80 60 PFS (%) 40 20 Let, letrozole; mPFS, median PFS; NR, not reached; Pbo, placebo; Ribo, ribociclib. Joyce O’Shaughnessy, MD: The addition of ribociclib to letrozole achieved a very substantial, highly statistically significant improvement in PFS vs the addition of placebo (not reached vs 14.7 months, respectively; HR: 0.56; 95% CI: ; P = 3.29 x 10-6 for superiority).[37] In this intent‑to‑treat, event‑driven, final primary analysis, the median duration of PFS for ribociclib plus letrozole was so long it has not yet been reached. Furthermore, the PFS curve for ribociclib plus letrozole appears to be flattening out at the tail with the majority of patients not experiencing disease progression, which is what we all really like to see—it means that a substantial proportion of patients may be in store for a substantially prolonged PFS. My hope is that some of these patients will have a multiyear PFS with ribociclib plus letrozole. 2 4 6 18 10 12 14 16 18 20 22 24 Mos Pts at Risk, n Ribociclib Placebo 119 88 68 44 20 23 6 5 1 0 0 0 Slide credit: clinicaloptions.com Hortobagyi GN, et al. N Engl J Med. 2016;375:

Ribociclib + Letrozole
MONALEESA-2: Safety Adverse Event, % Ribociclib + Letrozole (n = 334) Placebo + Letrozole (n = 330) Any Grade Grade 3/4 Any 98.5 81.1 97 32.7 Neutropenia 74.3 59.3 5.2 0.9* Leukopenia 32.9 21.0 3.9 0.6* ALT/AST 52/50 9.3/5.7 13/12 1.2*/1.2* Nausea 51.5 2.4* 28.5 Infections 50.3 4.2 42.4 2.4 Fatigue 36.5 30.0 Diarrhea 35.0 1.2* 22.1 ALT, alanine aminotransferase; AST, aspartate aminotransferase. Joyce O’Shaughnessy, MD: Similar to palbociclib,[38] neutropenia is the main toxicity observed for ribociclib: 74.3% and 59.3% of patients experienced any grade and grade 3/4 neutropenia, respectively, vs 5.2% and 0.9% with placebo.[37] Of importance, only 1.5% of patients treated with the ribociclib had febrile neutropenia vs no patients treated with placebo. Also of note is that with ribociclib, approximately one half of patients had any grade transaminitis (ie, liver function test abnormalities) and 9.3% and 5.7% of patients had grade 3/4 elevations in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, respectively. Therefore, liver function needs to be monitored with ribociclib, but liver toxicities are readily reversible by holding the ribociclib, followed by a dose reduction. The efficacy and safety results of MONALEESA-2 are very exciting and bolster the use of CDK4/6 inhibitors in the first‑line setting of ER‑positive MBC. *Grade 3 only Febrile neutropenia reported in 1.5% of pts treated with ribociclib + letrozole and no pts treated with placebo + letrozole Slide credit: clinicaloptions.com Hortobagyi GN, et al. N Engl J Med. 2016;375:

Until disease progression or other event requiring discontinuation
Phase III FALCON: First-line Fulvestrant vs Anastrozole for Advanced Breast Cancer Fulvestrant 500 mg IM injection Days 1, 14, 28, and every 28 days thereafter + Placebo PO daily (n = 232) Postmenopausal women with previously untreated hormone receptor–positive advanced breast cancer (N = 462) Until disease progression or other event requiring discontinuation Anastrozole 1 mg/day PO + Placebo IM injection Days 1, 14, 28, and every 28 days thereafter (n = 230) CBR, clinical benefit rate; DoR, duration of response. Joyce O’Shaughnessy, MD: The second practice-changing trial from ESMO 2016 in breast cancer was the phase III FALCON trial, which was essentially a comparison of first-line single-agent endocrine therapy. FALCON randomized 462 previously untreated patients with ER‑positive, postmenopausal MBC to the selective ER degrader fulvestrant plus placebo vs the aromatase inhibitor anastrozole plus placebo.[40] The key about this patient population is that they were endocrine therapy naive. In fact, most of the patients never had any therapy whatsoever, except a minority who had prior chemotherapy. The primary endpoint was PFS. Primary endpoint: PFS Secondary endpoints including: OS, ORR, DoR, CBR, and safety Slide credit: clinicaloptions.com Ellis MJ, et al. ESMO Abstract LBA14_PR.

FALCON: Fulvestrant Extends PFS Compared With Anastrozole
Median PFS of 16.6 mos with fulvestrant vs 13.8 mos with anastrozole (HR: 0.797; P = .0486) No visceral disease (n = 208): 22.3 mos with fulvestrant vs 13.8 mos with anastrozole (HR: 0.59; P < .01) Visceral disease (n = 254): 13.8 mos with fulvestrant vs mos with anastrozole (not significant) No significant differences in ORR, CBR, or median DoR Fulvestrant was associated with an increased incidence of grade ≥ 3 adverse events (22.4 % vs % and all grade arthralgia (16.7% vs 10.3%) CBR, clinical benefit rate; DoR, duration of response. Joyce O’Shaughnessy, MD: The results of FALCON demonstrated a statistically significant improvement in median PFS with fulvestrant vs anastrozole (16.6 vs 13.8 months, respectively; HR: 0.797; 95% CI: ; P = .0486).[40] Furthermore, a retrospective subset analysis suggests that fulvestrant is substantially superior to anastrozole in endocrine therapy–naive patients with nonvisceral disease (ie, no lung or liver metastases). Patients with no visceral disease but with bone, lymph node, chest wall, or breast soft tissue disease had a median PFS of 22.3 months with fulvestrant vs 13.8 months with anastrozole (HR: 0.59; P < .01) whereas, for patients with visceral disease, the median PFS was not significantly different between arms (13.8 and 15.9 months with fulvestrant or anastrozole, respectively). However, no difference in response rate, clinical benefit rate, or median duration of response was shown for these 2 agents, which can be attributed to the curves splitting later in the course of treatment. Clinical benefit rate measures benefit at 6 months and a lot of the benefit from fulvestrant vs anastrozole came later as more patients recurred on anastrozole over time but did not on fulvestrant. Finally, fulvestrant was associated with an increase in the incidence of grade ≥ 3 adverse events (22.4% vs 17.7%) and of all-grade arthralgia (16.7% vs 10.3%), but these were not substantial increases. Slide credit: clinicaloptions.com Ellis MJ, et al. ESMO Abstract LBA14_PR.

The PFS benefit seen with ribociclib + letrozole in hormone receptor–positive/HER2-negative MBC supports the use of CDK4/6 inhibitors as first-line therapy Fulvestrant is superior to anastrozole as first-line therapy in previously untreated pts with hormone receptor–positive/HER2- negative MBC based on results from FALCON phase III study The median PFS of 22.3 mos with first-line fulvestrant suggests that it is a reasonable option for patients with nonvisceral hormone receptor–positive MBC as this PFS is comparable to that observed with first-line letrozole + CDK4/6 inhibitor therapy Coming OS data from the PALOMA-2, MONALEESA-2, and FALCON trials will aid in choosing first-line MBC therapy for patients with de novo, visceral and nonvisceral disease MBC, metastatic breast cancer. Joyce O’Shaughnessy, MD: The results of both the MONALEESA-2 and FALCON trials will have implications for the treatment of newly diagnosed ER-positive/HER2-negative MBC.[37,40] In the MONALEESA-2 trial, the significantly improved PFS observed for the combination regimen of ribociclib plus letrozole further bolsters the use of CDK4/6 inhibitors as first‑line treatment in ER‑positive MBC. It is encouraging that these results are consistent with those of PALOMA‑2, which also showed a significant improvement in PFS with the addition of the CDK4/6 inhibitor palbociclib to letrozole in postmenopausal patients with ER-positive/HER2-negative MBC and no previous treatment for advanced disease.[39] In the FALCON trial, the significantly improved PFS observed for fulvestrant identified it as the superior choice of monotherapy in this setting, especially for patients without any previous endocrine therapy. But how do we choose between a CDK4/6 inhibitor plus letrozole and fulvestrant monotherapy for our patients with newly diagnosed ER-positive MBC? Exactly where to use a CDK4/6 inhibitor combination regimen vs fulvestrant monotherapy will be clarified with the availability of the OS data from PALOMA‑2 with palbociclib, MONALEESA‑2 with ribociclib, and FALCON with fulvestrant monotherapy. We will be able to look at OS in the subsets of de novo metastatic disease and visceral vs nonvisceral disease. In the meantime, I think it is reasonable to use fulvestrant monotherapy in patients with small‑volume metastatic disease, particularly those previously untreated with an endocrine agent. Patients with nonvisceral disease in the FALCON trial had a median PFS of 22.3 months, which is very similar to what has been seen with the addition of CDK4/6 inhibitors to letrozole in the first‑line setting. In addition to patients with bone-only metastases or soft tissue disease, I would even use fulvestrant in patients with asymptomatic, small‑volume parenchymal lung metastases, which although technically visceral, have a different natural history than liver metastases. That being said, I think most of our first‑line metastatic patients will be treated with a CDK4/6 inhibitor with letrozole. Regarding the choice of CDK4/6 inhibitor, palbociclib is currently approved by the FDA in combination with letrozole as initial endocrine therapy for newly diagnosed postmenopausal women with HR-positive/HER2-negative advanced MBC and in combination with fulvestrant in women with HR-positive/HER2-negative advanced MBC and progression on previous endocrine therapy. Ribociclib is not yet approved but was given FDA Breakthrough Therapy designation, with a decision for approval expected by Spring It has also been accepted by the European Medicines Agency for review. Because the data from palbociclib and ribociclib look very similar, if ribociclib is approved, it may be that we use one vs the other depending on a patient’s individual tolerability. However, the final OS data may also further distinguish between palbociclib and ribociclib other than just an individual patient’s tolerance of them. Breast Cancer References: Hortobagyi GN, Stemmer SM, Burris HA, et al. Ribociclib as first-line therapy for HR-positive, advanced breast cancer. N Engl J Med. 2016;375: Cristofanilli M, Turner NC, Bondarenko I, et al. Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): final analysis of the multicentre, double-blind, phase 3 randomised controlled trial. Lancet Oncol. 2016;17: Finn RS, Martin M, Rugo HS, et al. PALOMA-2: primary results from a phase III trial of palbociclib (P) with letrozole (L) compared with letrozole alone in postmenopausal women with ER+/HER2- advanced breast cancer (ABC). Program and abstracts of the 2016 American Society of Clinical Oncology Annual Meeting; June 3-7, 2016; Chicago, Illinois. Abstract 507. Ellis MJ, Bondarenko I, Trishkina E, et al. FALCON: a phase III randomised trial of fulvestrant 500 mg vs. anastrozole for hormone receptor-positive advanced breast cancer. Program and abstracts of the 2016 European Society for Medical Oncology Annual Congress; October 7-11, 2016; Copenhagen, Denmark. Abstract LBA14_PR. Slide credit: clinicaloptions.com

Ovarian Cancer

Sporadic Ovarian Cancer and Homologous Repair Deficiency
HRD is observed in ~ 50% of ovarian cancer[1] gBRCA1 and BRCA2 mutations Somatic mutations of BRCA gene Epigenetic inactivation of BRCA BRCA-independent defects in HR pathway, ie, alterations in other DNA repair pathway molecules HRD correlates with platinum sensitivity[2] PARP inhibitors block DNA repair pathways in HRD cells[3] HRD, homologous repair deficiency. Bradley J. Monk, MD, FACS, FACOG: There is a high, unmet medical need in the treatment of epithelial ovarian cancer. Most patients are diagnosed in advanced stages, get multiple lines of therapy, recur, and ultimately succumb to their disease. In fact, ovarian cancer is the most common cause of mortality among the gynecologic cancers.[41] Regarding molecular pathogenesis, ovarian cancer is a disease of neovascularization and genetic instability. Angiogenesis has proven to be a valid target in the treatment of this disease,[42,43] with the current paradigm being to target the DNA repair pathway.[44] Homologous DNA repair deficiency is observed in approximately 50% of ovarian cancers, most of which are attributable to mutations in BRCA, whether germline or somatic.[45] In fact, testing for germline BRCA mutations is recommended by ASCO, NCCN, and Society of Gynecologic Oncology in all patients with epithelial ovarian cancer.[46-48] In addition to BRCA, there are other genes (eg, BRCA-like genes) involved in the double‑stranded DNA repair pathway that create a repair deficiency genotype when mutated.[49] Patients who have a BRCA deficiency or a mutation in a BRCA-like gene cannot repair double‑stranded DNA breaks, a scenario that can be exploited in the treatment of these cancers—if we can create double-stranded DNA breaks in the cancer cells of these patients, ultimately, the cancer will die and the patient will survive. Platinum-based chemotherapy has commonly been used to induce double‑stranded DNA breaks in the cancer cells of patients with ovarian cancer, with germline or somatic BRCA mutations being particularly susceptible to these agents.[49,50] More recently, inhibition of PARP, a DNA repair enzyme involved in base-excision repair of single-stranded breaks, has been used to exacerbate DNA repair deficiencies.[51] PARP inhibitors prevent the repair of single‑stranded breaks, which become double‑stranded breaks, and, in the setting of a BRCA or BRCA‑like mutation, cannot be repaired.[44] 1. Cancer Genome Atlas Research Network. Nature. 2011;474: Liu JF, et al. Gynecol Oncol. 2014;133: Fong PC, et al. J Clin Oncol. 2010;28: Slide credit: clinicaloptions.com

Niraparib vs Placebo in Recurrent Platinum-Sensitive Ovarian Cancer
Niraparib 300 mg QD (n = 136) Germline BRCA mutation cohort (n = 203) Platinum-sensitive, recurrent ovarian, fallopian tube, or primary peritoneal cancer; ≥ 2 prior platinum-based regimens with CR/PR and progression > 6 mos after most recent platinum-based therapy (N = 553) Placebo QD (n = 65) Niraparib 300 mg QD (n = 231) No germline BRCA mutation cohort (n = 350) Placebo QD (n = 114) Bradley J. Monk, MD, FACS, FACOG: The multicenter randomized phase III NOVA (ENGOT-OV16) trial[52] was the first phase III trial evaluating a PARP inhibitor in ovarian cancer. It compared maintenance therapy with the PARP inhibitor niraparib vs placebo in recurrent, platinum-sensitive ovarian cancer. The trial enrolled 553 patients with recurrent ovarian, fallopian tube, or primary peritoneal cancer who had responded to more than 2 platinum-based regimens. Patients were first categorized into 2 cohorts: those with germline BRCA mutations (n = 203) and those with nongermline BRCA mutations (ie, somatic BRCA mutations or BRCA‑like genes; n = 350). Homologous recombination deficiency (HRD) was measured using a specific assay that uses 3 algorithms—telomeric allelic imbalances, large scale state transitions, and loss of heterozygosity—to evaluate patients’ tumors for genomic instability and potential PARP inhibitor susceptibility. Patients in each of these cohorts were randomized 2:1 to receive 300-mg/day niraparib vs placebo. The patients in the NOVA trial were typical of patients in my practice who respond to platinum-based regimens again and again and are eligible for maintenance therapy. However, because one half of the patients in NOVA only had a PR (eg, were asymptomatic but CT scan positive) and therefore at some level were being treated with active disease, calling niraparib maintenance therapy in this context is a bit of a misnomer. Treatment until disease progression with no crossover allowed Primary endpoint: PFS Slide credit: clinicaloptions.com Mirza MR, et al. N Engl J Med. 2016;[Epub ahead of print].

Niraparib vs Placebo in Recurrent Plt-Sensitive Ovarian Cancer: PFS
No gBRCA Mutation 100 HR: (95% CI: ; P < .001) 75 PFS (%) 50 Niraparib 25 gBRCA mutation Placebo 100 HR: (95% CI: ; P < .001) 2 4 6 8 10 12 14 16 18 20 22 24 75 Mos Since Randomization Pts at Risk, n Niraparib Placebo Niraparib PFS (%) 50 188 88 145 52 113 33 88 23 75 19 57 10 41 8 23 4 21 4 16 3 7 1 3 1 25 Placebo No gBRCA Mutation and HRD+ 100 2 4 6 8 10 12 14 16 18 20 22 24 HR: (95% CI: ; P < .001) 75 Mos Since Randomization No. at Risk Niraparib Placebo HRD, homologous repair deficiency; Plt, platinum. Bradley J. Monk, MD, FACS, FACOG: Overall, NOVA met its primary endpoint of PFS.[52] Niraparib achieved a significantly longer duration of PFS vs placebo regardless of germline BRCA mutation or BRCA-like mutation status (P < .001). In the germline BRCA mutation group, there was a very dramatic, significant, and clinically important difference in median time to progression: 21.0 months with niraparib vs 5.5 months with placebo (HR: 0.27; 95% CI: ; P < .001), with 50% of patients still receiving niraparib treatment at 18 months vs 16% still receiving placebo. In the nongermline BRCA group and in its HRD-positive subgroup, PFS was 9.3 months vs 3.9 months (HR: 0.45; 95% CI: ; P < .001) and 12.9 months vs 3.8 months (HR: 0.38; 95% CI: ; P < .001), respectively. These are significant, clinically important improvements in PFS, even if the HRs are not quite as dramatic as what was observed for patients with germline BCRA mutations. The dramatic improvements in PFS with niraparib observed in the NOVA trial are practice changing: patients with a germline BRCA mutation who respond to a platinum-based regimen a second or a third time should be treated with niraparib. Patients with somatic BRCA mutations or with evidence of HRD should also be treated with niraparib or another PARP inhibitor. Furthermore, I think knowing HRD status adds valuable information for patients and providers to consider when deciding whether to use niraparib in this maintenance setting. PFS (%) 50 Niraparib 138 65 125 52 107 34 98 21 89 12 79 8 63 6 44 2 28 2 26 2 16 1 3 1 1 0 25 Placebo 2 4 6 8 10 12 14 16 18 20 22 24 Mos Since Randomization Pts at Risk, n Niraparib Placebo 106 56 90 41 75 26 64 16 52 11 46 9 40 4 29 3 16 1 14 1 11 1 4 1 2 1 Slide credit: clinicaloptions.com Mirza MR, et al. N Engl J Med. 2016;[Epub ahead of print].

Niraparib vs Placebo in Recurrent Plt-Sensitive Ovarian Cancer: Select AEs
Adverse Event, % Niraparib (n = 367) Placebo (n = 179) Any grade Grade 3/4 Thrombocytopenia 61.3 33.8 5.6 0.6 Anemia 50.1 25.3 6.7 Neutropenia 30.2 19.6 6.1 1.7 Nausea 73.6 3.0 35.2 1.1 Fatigue 59.4 8.2 41.3 Hypertension 19.3 4.5 2.2 AE, adverse event; AML, acute myeloid leukemia; MDS, myelodysplastic syndromes. Bradley J. Monk, MD, FACS, FACOG: PARP inhibitors clearly have a level of toxicity that needs to be considered, including myelosuppression.[50] In particular, niraparib causes thrombocytopenia, anemia, and neutropenia.[52] Approximately two thirds of patients will need dose reductions or dose delay due to myelosuppression. During the first cycle, patients should be monitored for myelosuppression on a weekly basis. After an optimal dose has been established for a particular patient, monitoring can be extended to monthly. In addition, patients can experience cumulative fatigue, which can be managed with dose delay or reduction, as well as gastrointestinal issues (eg, nausea, dyspepsia, or diarrhea), which can be managed with supportive care. Patient‑reported quality-of-life outcomes were also measured in the NOVA trial. There were no differences in the Functional Assessment of Cancer Therapy–Ovarian Symptom Index or in the European Quality of Life–5 Dimensions test. In conjunction with the dramatic prolongation of PFS by just under 16 months and the manageable toxicity profile, I think the quality-of-life results are supportive of using niraparib in this setting. Finally, because PARP inhibitors interfere with DNA repair, I think it is important to note that induction of myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML) has been of concern with their use to treat cancer. However, in NOVA, there really was no increase in MDS or AML, with MDS reported in 5 patients treated with nariparib and 1 patient treated with placebo. AML was reported in 1 patient treated with placebo. This corresponds to MDS/AML events in 1.4% of patients receiving niraparib and 1.1% receiving placebo, which is very similar. Despite a relatively short median follow-up of 16.9 months, I think the take‑home message is that the risk for MDS and AML is low. It is clear that PARP inhibitors promise to change standard of care in the treatment of epithelial ovarian cancer. NOVA is the first randomized phase III trial of a PARP inhibitor in ovarian cancer.[52] It was strongly positive for niraparib across all groups tested: patients with germline BRCA mutations (HR: 0.27), patients with nongermline BRCA mutations (HR: 0.45), and patients positive for HRD (HR: 0.38). An exploratory analysis showed a statistical improvement in PFS even for patients who were HRD negative (HR: 0.58; 95% CI: ; P = .0226). In November 2016, a New Drug Application was submitted to the FDA for approval based on the dramatic prolongation of PFS by maintenance niraparib in patients with platinum-sensitive ovarian cancer, fallopian tube, or peritoneal cancer as demonstrated in the phase III NOVA trial. MDS reported in 5 pts treated with niraparib and 1 pt treated with placebo; 1 pt treated with placebo developed AML Discontinuations due to AEs: 14.7% with niraparib, 2.2% with placebo Pt-reported outcomes similar with niraparib and placebo Slide credit: clinicaloptions.com Mirza MR, et al. N Engl J Med. 2016;[Epub ahead of print].

Rucaparib in HGOC With BRCA Mutations: A Pooled Analysis of 2 Phase II Trials
Pts with platinum-sensitive, relapsed high-grade ovarian, peritoneal, or fallopian tube carcinoma enrolled in Study 10 (NCT ) ARIEL2 (NCT ) Treatment: rucaparib 600 mg BID Efficacy evaluated for 106 eligible pts with relapsed BRCAmut HGOC who received ≥ 2 previous chemotherapy regimens Safety evaluated for 377 eligible pts regardless of BRCAmut status HGOC, high-grade ovarian cancer. Bradley J. Monk, MD, FACS, FACOG: Another PARP inhibitor, rucaparib, also has been submitted to the FDA for review and approval based on the pooled analysis of 2 phase II trials, Study 10 and ARIEL2, presented at ESMO 2016.[53] Patients with platinum-sensitive, relapsed high-grade ovarian, peritoneal, or fallopian tube carcinoma were treated with 600-mg rucaparib twice daily. Slide credit: clinicaloptions.com Kristeleit RS, et al. ESMO Abstract 856O.

Rucaparib in HGOC With BRCAmut: Efficacy Outcomes
80 BRCA1 BRCA2 Germline BRCA mutation Somatic BRCA mutation BRCA mutation origin uncertain 60 40 20 Change From Baseline in Sum of the Diameter of Target Lesions†(%) -20 -40 -60 -80 ORR (investigator assessed): 53.8% CR: 8.5% -100 DoR, duration of response; HGOC, high-grade ovarian cancer. Bradley J. Monk, MD, FACS, FACOG: For 106 patients with BRCA mutation–positive high-grade ovarian cancer who received more than 2 previous chemotherapy regimens, the investigator-assessed ORR was 53.8%, the duration of response was 9.2 months, and the median PFS was 10.0 months, with 41% of patients remaining progression-free at 1 year. -120 Median DoR of 9.2 mos Median PFS of 10.0 mos 41% of pts progression free at 1 yr Slide credit: clinicaloptions.com Kristeleit RS, et al. ESMO Abstract 856O.

Rucaparib in HGOC With BRCAmut: Safety
Adverse Event, n (%) Pts Treatment related, grade ≥ 3 177 (46.9) Treatment related, leading to dose reduction 167 (44.3) Treatment related, leading to discontinuation 30 (8.0) Grade 3/4 adverse events reported in > 10% of pts: Anemia (24.9%) Asthenia/fatigue (10.9%) Elevated AST/ALT (10.9%) No treatment-related deaths reported ALT, alanine aminotransferase; AST, aspartate aminotransferase; HGOC, high-grade ovarian cancer. Bradley J. Monk, MD, FACS, FACOG: For 377 patients regardless of BRCA mutation status, grade ≥ 3 toxicities were reported in 46.9% of patients, with 44.3% leading to dose reduction and 8.0% leading to discontinuation. The most common grade 3/4 toxicities (reported in > 10% of patients) included anemia (24.9%), asthenia/fatigue (10.9%), and elevated ALT/AST (10.9%). Rucaparib was granted accelerated approval by the US FDA on December 19, 2016 for the treatment of patients with advanced ovarian cancer and deleterious BRCA germline and/or somatic mutations who have been treated with at least 2 previous lines of chemotherapy. Slide credit: clinicaloptions.com Kristeleit RS, et al. ESMO Abstract 856O.

Niraparib reduced the risk of disease progression or death by 73% for pts with recurrent, platinum- sensitive epithelial ovarian cancer and a gBRCA mutation PFS also significantly extended in pts without a gBRCA mutation Risk of MDS or AML appears low Rucaparib also efficacious for pts with recurrent, platinum-sensitive epithelial ovarian cancer and a gBRCA mutation AML, acute myeloid leukemia; MDS, myelodysplastic syndromes. Ovarian Cancer References: Centers for Disease Control and Prevention. Ovarian cancer statistics. Available at: Accessed December 16, 2016. Jayson GC, Kerbel R, Ellis LM, Harris AL. Antiangiogenic therapy in oncology: current status and future directions. Lancet. 2016;388: Reinthaller A. Antiangiogenic therapies in ovarian cancer. Memo. 2016;9: Chung C, Lee R. An update on current and emerging therapies for epithelial ovarian cancer: Focus on poly(adenosine diphosphate-ribose) polymerase inhibition and antiangiogenesis. J Oncol Pharm Pract. 2016;[Epub ahead of print]. Cancer Genome Atlas Research Network. Nature. 2011;474: Wright AA, Bohlke K, Armstrong DK, et al. Neoadjuvant chemotherapy for newly diagnosed, advanced ovarian cancer: Society of Gynecologic Oncology and American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol. 2016;34: National Comprehensive Cancer Network. Clinical practice guidelines in oncology: genetic/familial high-risk assessment: breast and ovarian. Available at: Accessed December 16, 2016. Society of Gynecological Oncology. SGO clinical practice statement: genetic testing for ovarian cancer. Available at: Accessed December 16, 2016. Ledermann JA, Drew Y, Kristeleit RS. Homologous recombination deficiency and ovarian cancer. Eur J Cancer. 2016;60:49-58. Liu JF, Konstantinopoulos PA, Matulonis UA, et al. PARP inhibitors in ovarian cancer: current status and future promise. Gynecol Oncol. 2014;133: Fong PC, et al. Poly(ADP)-ribose polymerase inhibition: frequent durable responses in BRCA carrier ovarian cancer correlating with platinum-free interval. J Clin Oncol. 2010;28: Mirza MR, Monk BJ, Herrstedt J, et al. Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer. N Engl J Med. 2016;[Epub ahead of print]. Kristeleit R, Shapira-Frommer R, Oaknin A, et al. Clinical activity of the poly(ADP-ribose) polymerase (PARP) inhibitor rucaparib in patients (pts) with high-grade ovarian carcinoma (HGOC) and a BRCA mutation (BRCAmut): Analysis of pooled data from Study 10 ( parts 1, 2a, and 3) and ARIEL2 (parts 1 and 2). Program and abstracts of the 2016 European Society for Medical Oncology Annual Congress; October 7-11, 2016; Copenhagen, Denmark. Abstract 856O. Slide credit: clinicaloptions.com

Glioblastoma

Depatuxizumab Mafodotin + TMZ in Recurrent Glioblastoma: Background
Depatuxizumab mafodotin (ABT-414): an antibody– drug conjugate with an EGFR mAb and the antitubulin agent monomethyl auristatin F Limited binding to EGFR in normal tissue Adult patients with recurrent glioblastoma and EGFR amplification (n = 51); expansion cohort from phase Ib trial (NCT ) Treatment: TMZ rechallenge + ABT mg/kg every 2 wks TMZ, temozolomide. Ryan T. Merrell, MD: Glioblastoma (GBM) is a highly malignant brain tumor that, in most patients, leads to a short OS on the order of 14-18 months.[54,55] The current standard of care is maximal surgical resection followed by fractionated radiation in combination with temozolomide and adjuvant temozolomide. Therapeutic options for recurrent GBM are an urgent unmet clinical need. The EGFR pathway is an important driver for tumor growth in GBM, with EGFR amplification being found in approximately 40% to 50% of patients with GBM.[56] EGFR amplification and EGFR overexpression is often found in tandem with EGFRvIII mutations that result in oncogenic activation of the receptor via deletion of the extracellular ligand binding domain.[57] In this phase I study, adult patients with either newly diagnosed (Arm A and B) or recurrent (Arm C) GBM were treated with a new EGFR-directed therapy called depatuxizumab mafodotin (ABT-414), which is an antibody–drug conjugate consisting of an EGFR monoclonal antibody and the antitubulin agent monomethyl auristatin F; the antibody component binds to the EGFR receptor on cancer cells and the microtubule toxin is released into the cell.[58-60] This phase I study was designed to assess the safety and maximum tolerated dose of ABT-414—not to directly assess its efficacy. In Arm C, temozolomide-refractory patients (N = 51) were enrolled at the time of GBM recurrence.[58] All patient tumors were tested for EGFR amplification, many of which were found to have both EGFR amplification and EGFRvIII mutations. Patients were also required to have normal end-organ function and a Karnofsky performance status score of ≥ 70. ABT‑414 was administered every 2 weeks in combination with temozolomide, which was given at the typical adjuvant schedule of mg/m2 on Days 1-5 of a 28‑day cycle. Patients were followed closely for toxicity and neurologic deficits and radiographically assessed for response. Some of the patients underwent a second surgery. Ultimately, the maximum tolerated dose of ABT-414 was determined to be 1.25 mg/kg, given intravenously. Slide credit: clinicaloptions.com Lassman AB, et al. ESMO Abstract 326PD.

ABT-414 + Temozolomide in Recurrent Glioblastoma: Safety and Efficacy
TEAE, n (%) Pts (N = 51) Any Grade Grade 3/4 Overall 51 (100) 35 (69) Ocular Blurred vision Keratitis Photophobia 32 (63) NR 17 (33) 2 (4) 7 (14) Thrombocytopenia/decreased platelets 24 (47) 11 (22) Headache 18 (35) Fatigue Characteristic Pts (N = 51) ORR, n (%) 6 (8.7) SD, n (%) 23 (46) PFS rate at 6 mos, % 23.5 OS rate at 6 mos, % 69.7 NR, not reported; TEAE, treatment-emergent adverse event; SD, stable disease. Ryan T. Merrell, MD: ABT-414 was mostly well tolerated in this phase I study. The most notable and common adverse event observed for ABT‑414 was a unique corneal toxicity that manifests as blurred vision, sensitivity to light, and dryness of the eyes—any grade and grade 3/4 corneal inclusions occurred in 63% and 4% of patients, respectively.[58] These visual adverse events are manageable with opthamologic intervention and were reversible in most patients. ABT-414 did not cause adverse events typical of other EGFR-targeted monoclonal antibodies (eg, cetuximab and necitumumab), including skin or gastrointestinal toxicities.[61,62] Despite being a phase I study, preliminary efficacy results were reported that suggest ABT-414 may be active in GBM. Of the 31 patients who were treated with ABT-414, 3 had a PR, 18 had stable disease, and 10 had disease progression. This is an encouraging result, as GBM is a very difficult tumor to treat and patients with recurrent GBM are an especially refractory patient population to any kind of treatment. Despite great efforts for more than a decade to find targeted agents effective against GBM, most have failed in clinical trials. Based on the encouraging results of this phase I study,[58,59] a multicenter, randomized, controlled phase II study of ABT-414 in newly diagnosed GBM already has been launched in the United States and in Europe.[63] In particular, there was a suggestion that ABT-414 may have synergy with radiation and temozolomide for newly diagnosed GBM, which is why the decision was made to launch the phase II in the newly diagnosed setting. There is also a phase I study of ABT‑414 for newly diagnosed GBM that is currently ongoing, the results of which have yet to be reported. For progressing GBM patients with EGFR amplification, there is an ongoing phase II study that is primarily being conducted by the EORTC where adult patients were randomized to receive either ABT‑414 alone or with temozolomide vs temozolomide or lomustine.[64] The hope is that the results from phase II will be positive and ultimately lead to approval of this drug for this patient population in urgent need of new and improved therapeutic options. Glioblastoma References: Khosla D. Concurrent therapy to enhance radiotherapeutic outcomes in glioblastoma. Ann Transl Med. 2016;4:54. Gallego O. Nonsurgical treatment of recurrent glioblastoma. Curr Oncol. 2015;22:e273-e281. Crespo I, Vital AL, Gonzalez-Tablas M, et al. Molecular and genomic alternations in Glioblastoma Multiforme. Am J Pathol. 2015;185: Roskoski R Jr. The ErbB/HER family of protein-tyrosine kinases and cancer. Pharmacol Res. 2014;79:34-74. Lassman AB, van den Bent M, Gan HK, et al. Efficacy of a novel antibody-drug conjugate (ADC), ABT-414, with temozolomide (TMZ) in recurrent glioblastoma (rGBM). Program and abstracts of the 2016 European Society for Medical Oncology Annual Congress; October 7-11, 2016; Copenhagen, Denmark. Abstract 326PD. van den Bent M, Kong Gan H, Gassman AB, et al. Efficacy of a novel antibody-drug conjugate (ADC), ABT-414, as monotherapy in epidermal growth factor receptor (EGFR) amplified, recurrent glioblastoma (GBM). Program and abstracts of the 2016 Annual Meeting of the American Society of Clinical Oncology; June 3-7, 2016; Chicago, Illinois. Abstract 2542. ClinicalTrials.gov. Evaluating the safety and pharmacokinetics of ABT-414 for subjects with glioblastoma multiforme. Available at: Accessed December 16, 2016. Genova C, Hirsch FR. Clinical potential of necitumumab in non-small cell lung carcinoma. Onco Targets Ther. 2016;9: Rolfo C, Bronte G, Passiglia F, et al. Management of toxicity induced by anti-EGFR therapy in metastatic colorectal cancer. Curr Colorectal Cancer Rep. 2013;9: ClinicalTrials.gov. A study of ABT-414 in subjects with newly diagnosed glioblastoma (GBM) with epidermal growth factor receptor (EGFR) amplification (Intellance 1). Available at: Accessed December 16, 2016. ClinicalTrials.gov. Adult study: ABT-414 alone or ABT-414 plus temozolomide vs. lomustine or temozolomide for recurrent glioblastoma Pediatric study: evaluation of ABT-414 in children with high grade gliomas (INTELLANCE 2). Available at: Accessed December 16, 2016. Slide credit: clinicaloptions.com Lassman AB, et al. ESMO Abstract 326PD.

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