Background

In clinical studies, 10-15% of patients (pts) treated with anti-PD-1 monotherapies achieved durable CRs. Combination treatment with NIVO+IPI resulted in higher response rates, longer progression-free survival (PFS), and improved overall survival (OS) vs IPI alone, but with an increased frequency of adverse events (AEs). Here, we characterized CRs among pts who received combination therapy vs NIVO or IPI alone.

Methods

In this post hoc analysis, efficacy and safety data were pooled for NIVO+IPI (N = 409), NIVO (N = 526), and IPI (N = 362) from the phase 2 CheckMate 069, phase 3 CheckMate 066, and phase 3 CheckMate 067 studies in pts with MEL. Across studies, the minimum duration of follow-up was 24 months (median ∼31 months).

Results

In the pooled analysis, the CR rate was 18% for NIVO+IPI, 16% for NIVO, and 4% for IPI, with partial responses (PRs) in 41%, 28%, and 14% of pts, respectively (Table). Among the 75 CR pts in the NIVO+IPI cohort, the majority (77%) are off treatment and 8% received a subsequent systemic therapy; 15% had elevated LDH levels and 32% had M1c disease. Median duration of CR has not been reached, with 63/75 pts (84%) remaining in response. After an additional follow-up of 12 months (from the 1-year initial follow-up), 24/166 pts (14%) with a PR converted to a CR. For the 75 CR pts in the NIVO+IPI cohort, 2-year PFS and OS rates were 86% and 92%, respectively. Treatment-related AEs of grade 3-4 occurred in 60% of NIVO+IPI-treated pts with a CR, 65% with a PR, and in 60% with stable disease; 31%, 36%, and 35%, respectively, led to discontinuation. There were no treatment-related deaths.Table:

1213O

Conclusions

MEL pts treated with NIVO+IPI had a high rate of durable CRs, with the majority remaining in response and often not requiring additional treatment at a median follow-up of ∼31 months. Some pts with a PR convert to a CR over time. Updated analyses based on 3-year data will be presented.

Clinical trial identification

NCT01844505 (067) NCT01721772 (066) NCT01927419 (069)

Legal entity responsible for the study

Bristol-Myers Squibb

Funding

Bristol-Myers Squibb

Disclosure

C. Robert: Served as a consultant for Amgen, Bristol-Myers Squibb, Merck, and Roche; paid honoraria from Amgen, Bristol-Myers Squibb, GSK, Merck, Novartis, and Roche. J. Larkin: Received research funding from Bristol-Myers Squibb, MSD, Novartis, and Pfizer; travel funding from Bristol-Myers Squibb, GSK, MSD, Esai, Pfizer, and Roche. P.A. Ascierto: Served as a consultant for Amgen, Array, Bristol-Myers Squibb, Merck-Serono, MSD, Novartis, Pierre-Fabre, and Roche-Genentech; institution received research funding from Array, Bristol-Myers Squibb, and Roche-Genentech. G.V. Long: Served as a consultant for Amgen, Bristol-Myers Squibb, Merck, MSD, Novartis, Pierre-Fabre, and Roche; paid honoraria from Bristol-Myers Squibb, Merck, MSD, and Roche. J.C. Hassel: Funding for trial procedures according to study protocol from Bristol-Myers Squibb; honoraria from Amgen, Bristol-Myers Squibb, GSK, MSD, Novartis, and Roche; research grant/funding from Bristol-Myers Squibb; travel funding from Amgen, Bristol-Myers Squibb, GSK, MSD, Novartis, and Roche. D. Schadendorf: Served as a consultant or advisor for Roche/Genentech, Novartis, Bristol-Myers Squibb, Merck Sharp & Dohme, Merck Serono, Sysmex, Amgen, Grunenthal Group, Immunocore; participated on a speakers’ bureau for Roche, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Amgen, Incyte, Pierre Fabre; travel funding from Roche/Genentech, Bristol-Myers Squibb, Amgen, Merck, Merck Serono, Novartis; paid honoraria from Roche/Genentech, Novartis, Amgen, Bristol-Myers Squibb, Merck Sharp & Dohme, Sysmex, Immunocore, Grunenthal Group, Merck Serono, Agenus, Array BioPharma, LEO Pharma, Incyte, Pfizer, Pierre Fabre, Philogen, Regeneron; received institutional research funding from Bristol-Myers Squibb and Novartis. F.S. Hodi: Consultant: Amgen, EMD Serono, MSD, Novartis, Roche-GNE; travel funding: Bristol-Myers Squibb and Novartis; patent pending royalties per institutional policy; other: B Bristol-Myers Squibb MS; institutional research funding: Bristol-Myers Squibb, MSD, Novartis, Roche-GNE. C. Lebbé: Served on an advisory board for Bristol-Myers Squibb, GSK, MSD, Novartis, and Roche. J-J. Grob: Served as a consultant to Amgen, Bristol-Myers Squibb, GSK, Merck, Novartis, and Roche; participated on speakers’ bureau for Bristol-Myers Squibb, GSK, and Roche; travel funding from Roche; recipient of research funding from Bristol-Myers Squibb and Roche. J. Wagstaff: Honoraria from Astellas, Bristol-Myers Squibb, Merck, Novartis, Pfizer, and Roche; consultant to Astellas, Bristol-Myers Squibb, Merck, Novartis, Pfizer, and Roche; served on speakers’ bureaus for Astellas, Bristol-Myers Squibb, and Novartis; travel funding from Astellas, Bristol-Myers Squibb, and Novartis. J. Chesney: Served as a consultant to Bristol-Myers Squibb; received research funding from Bristol-Myers Squibb. D. Hogg: Served as a consultant to Bristol-Myers Squibb, GSK, Novartis, and Roche. O. Bechter: Served as a consultant or advisor to Bristol-Myers Squibb; and received travel funding from Roche. I. Márquez-Rodas: Honoraria from Bristol-Myers Squibb, MSD, Novartis, and Roche; served as a consultant to Amgen, Bioncotech, Bristol-Myers Squibb, MSD, Novartis, and Roche; travel funding from Amgen, Bristol-Myers Squibb, and MSD. D. Walker: Employee of Bristol-Myers Squibb; immediate family member has stock or other ownership in Antares Pharma. R. Bhore: Employee of and owns stock in Bristol-Myers Squibb. M.A. Postow: Served on an advisory board for Bristol-Myers Squibb; recipient of research grant support from Bristol-Myers Squib. J.D. Wolchok: Consultant: Bristol-Myers Squibb, GSK, Jounce, MedImmune, Merck, Polaris, Polynoma, and Ziopharm; research funding: Bristol-Myers Squibb, GSK, MedImmune, and Merck; patent issued for DNA vaccine of cancer in companion animals (co-investor). All other authors have declared no conflicts of interest.

Background

Tumors can evade immunosurveillance through upregulation of indoleamine 2,3-dioxygenase 1 (IDO1). Epacadostat (E) is a potent, selective inhibitor of the IDO1 enzyme. The combination of E + the PD-1 inhibitor pembrolizumab (P) is being evaluated in an open-label, phase 1/2 study in multiple tumor types (ECHO-202/KEYNOTE-037). We report phase 1 and 2 efficacy and safety data for patients (pts) with advanced melanoma (27Feb2017 data cutoff).

Methods

Pts previously treated with checkpoint inhibitors were excluded. Pts received E (25, 50, 100, or 300 mg PO BID) + P (2 mg/kg or 200 mg IV Q3W) during phase 1. MTD was not exceeded. E (100 mg BID) + P (200 mg Q3W) was selected for phase 2. Responses were assessed in RECIST 1.1 evaluable pts.

Results

64 pts enrolled (phase 1, n = 22; phase 2, n = 42). Median age, 65; male, 70%; BRAF+, 30%; M1c disease, 52%. Median duration of follow-up was 253+ days (range, 5 to 904+ days). Among 54 efficacy evaluable pts, ORR was 56% (30/54; 8 CR, 22 PR) and DCR (CR+PR+SD) was 78% (42/54). In treatment-naïve pts (n = 45), ORR was 56% (25/45; 6 CR, 19 PR) and DCR was 78% (35/45). Among treatment-naïve pts receiving E 100 mg BID (n = 30), ORR was 60% (18/30; 2 CR, 16 PR). Responses were observed regardless of PD-L1 and BRAF mutation status. At data cutoff, 28/30 responses in the melanoma cohort were ongoing (median duration of response = 287.5+ days, range 1+ to 763+ days). Median PFS was 12.4 mo; PFS rates at 6, 12, and 18 mo were 70%, 54%, and 50%, respectively. In treatment-naïve pts, median PFS has not been reached; PFS rates at 6, 12, and 18 mo were 68%, 52%, and 52%. The most common (>15%) all-grade treatment-related AEs (TRAEs) were fatigue (39.1%), rash (32.8%), pruritus (26.6%), and arthralgia (15.6%). Grade ≥3 TRAEs were observed in 17.2% of pts (most common: lipase increased, n = 4; rash, n = 3; and amylase increased, n = 2). 3 pts discontinued for TRAEs (lipase increased, n = 1; arthralgia, n = 2). No treatment-related deaths occurred. Biomarker evaluation is ongoing.

Conclusions

Consistent with the phase 1 results, E + P continues to be well tolerated and showed promising clinical activity. A phase 3 study in pts who are treatment-naive for advanced melanoma is ongoing (NCT02752074).

Clinical trial identification

NCT02178722

Legal entity responsible for the study

Incyte Corporation, Wilmington, DE

Funding

Incyte Corporation, Wilmington, DE; Merck & Co., Inc., Kenilworth, NJ

Disclosure

O. Hamid: Advisory Board - Merck & Co., Inc, Amgen, Novartis, Roche, Bristol-Myers Squibb; Corporate-sponsored Research - Incyte Corporation (Institution), Merck & Co., Inc. (Institution); Speaker’s Bureau – Bristol-Myers Squibb, Genetech, Novartis, Amgen; Honoraria – Genetech, Bristol-Myers Squibb, Novartis. T.F. Gajewski: Advisory Board - Merck & Co., Inc; Corporate-sponsored Research - Incyte Corporation (Institution), Merck & Co., Inc. (Institution). T.M. Bauer: Corporate-sponsored Research - Incyte Corporation (Institution), Merck & Co., Inc. (Institution) A.J. Olszanski: Advisory Board - Merck & Co., Inc, Bristol-Myers Squib; Corporate-sponsored Research - Incyte Corporation (Institution), Merck & Co., Inc. (Institution), Bristol-Myers Squibb, Novartis, Teva, Takeda, Pfizer; Other Substantive Relationships - Data Safety Monitoring Board: Takeda. J.J. Luke: Consult: Amgen, Array, AstraZeneca, BeneVir, Bristol-Myers Squibb, Castle, CheckMate, EMD Serono, Gilead, Novartis, Merck; Inst res supp: AbbVie, BostonBiomedical, Bristol-Myers Squibb, Celldex, Corvus, Delcath, 5Prime, Genentech, Immunocore, Incyte, Intensity, MedImmune, Macrogenics, Novartis, Pharmacyclics, Merck, Tesaro. A.S. Balmanoukian: Corporate-sponsored Research – MedImmune/AstraZeneca, Merck Serono, Genentech, Incyte Corporation (Institution), Merck & Co., Inc. (Institution); Other Substantive Relationships - Speaker’s Bureau at Bristol-Myers Squibb, Merck, Genentech, AstraZeneca. E.V. Schmidt: Employment and stock ownership at Merck & Co., Inc. B. Sharkey, J. Maleski, M.J. Jones: Employment and stock ownership at Incyte Corporation T.C. Gangadhar: Corporate-sponsored Research - Incyte Corporation (Institution), Merck & Co., Inc. (Institution), Bristol-Myers Squibb, Roche, Cerulean; Honoraria - Merck & Co., Inc., Novartis; Advisory Role - Bristol-Myers Squibb All other authors have declared no conflicts of interest.

Background

The addition of a MEK inhibitor (MEKi) to a BRAF inhibitor (BRAFi) in BRAF V600-mutant metastatic melanoma improves efficacy, including progression-free survival (PFS) and objective response rate (ORR), and attenuates some BRAFi−associated toxicities. Part 1 of the COLUMBUS study met its primary endpoint. The BRAFi ENCO 450 mg once daily (QD) + the MEKi BINI 45 mg twice daily (BID; COMBO450) improved PFS vs vemurafenib (VEM) alone and ENCO 300 mg QD (ENCO300) alone in patients (pts) with advanced BRAF V600-mutant melanoma. The tolerability of COMBO450 was favorable compared with VEM or ENCO300. In Part 2, the contribution of BINI to the combination was further evaluated by maintaining the same dose of ENCO in the combination (ENCO 300 mg QD + BINI 45 mg BID; COMBO300) and comparator arms (ENCO300 alone; ClinicalTrials.gov, NCT01909453; EudraCT, 2013-001176-38).

Methods

Pts were randomized 3:1 to COMBO300 or ENCO300. Data from ENCO300 arms in Parts 1 + 2 were combined for the primary efficacy comparison of PFS by independent blinded central review (BCR). Other analyses included PFS for COMBO300 vs ENCO300 (Part 2 only), ORR, complete response (CR) and partial response (PR) by BCR and local review, and safety.

Results

Pt characteristics are presented in the Table. Median PFS (95% CI) for COMBO300 was 12.9 mo (10.1–14.0) vs 9.2 mo (7.4–11.0) for ENCO300 (Parts 1 + 2) and 7.4 mo (5.6–9.2) for ENCO300 (Part 2). The hazard ratio (HR) for COMBO300 was 0.77 (0.61–0.97; P = 0.029, 2-sided) vs ENCO300 (Parts 1 + 2) and 0.57 (0.41–0.78; P<0.001, 2-sided) vs ENCO300 (Part 2). ORR, CR, and PR by BCR/local review (%) were 66/72, 8/11, and 58/62 for COMBO300, 50/56, 5/8, and 45/49 for ENCO300 (Parts 1 + 2), and 50/53, 3/3, and 47/50 for ENCO300 (Part 2). Safety profiles were consistent with Part 1 (Table).Table:

1215O COLUMBUS Part 2: Baseline Characteristics, Duration of Exposure, and Safety

Conclusions

COMBO300 meaningfully improved PFS, ORR, and tolerability vs ENCO300, confirming the contribution of BINI to both efficacy and safety.

Clinical trial identification

Trial protocol number, CMEK162B2301 (release date, July 13, 2015)

Legal entity responsible for the study

Array BioPharma Inc

Funding

Array BioPharma Inc and Novartis Pharmaceuticals Corporation

Disclosure

R. Dummer: Honoraria from and consulting/advisory role for Roche, Bristol-Myers Squibb, GSK, MSD, Novartis, and Amgen; research funding from Roche, Bristol-Myers Squibb, GSK, MSD, and Novartis. P.A. Ascierto: Consulting fees from Bristol-Myers Squibb, Roche/Genentech, MSD, Ventana, Novartis, Amgen, and Array BioPharma; research funding from Bristol-Myers Squib, Roche/Genentech, Ventana, and Array BioPharma H. Gogas: Consultant for Roche, Bristol-Myers Squibb, MSD, Novartis, and Amgen. A. Arance: Honoraria from and consulting/advisory role and speakers bureau for Novartis, Roche, MSD, and Bristol-Myers Squibb; travel expenses from Roche and Bristol-Myers Squibb. M. Mandala: Honoraria from Novartis, GSK, Bristol-Myers Squibb, MSD, and Roche; speakers bureau for Novartis, GSK, Roche, and Bristol-Myers Squibb; advisory board member for Novartis, Amgen, MSD, and Bristol-Myers Squibb; research funding from Roche. C. Garbe: Honoraria and travel expenses from and served in a consulting/advisory role and speakers bureau member for Amgen, Bristol-Myers Squibb, MSD, Novartis, Roche, and Philogen; research funding for University Hospital Tübingen from Bristol-Myers Squibb, Novartis, and Roche. D. Schadendorf: Honoraria and travel expenses from and consulting/advisory role and speakers bureau for Amgen, Bristol-Myers Squibb, Novartis, Roche, and MSD; research funding for University Hospital Essen from Amgen, Bristol-Myers Squibb, Novartis, Roche, and MSD. I. Krajsová: Advisory board member for Bristol-Myers Squibb, Novartis, Roche, MSD; travel expenses from Bristol-Myers Squibb and MSD. R. Gutzmer: Consulting fees and/or honoraria from Roche, Bristol-Myers Squibb, MSD, GSK, Novartis, Almirall, LEO, Amgen, Pfizer, Merck Serono, Boehringer Ingelheim; research funding from Roche, Novartis, Pfizer, Pierre Fabre, Johnson & Johnson; travel expenses from Bristol-Myers Squibb, Roche. V. Chiarion Sileni: Honoraria received from Novartis, GSK, Bristol-Myers Squib, MSD, and Roche; speakers bureau for Novartis, GSK, Roche, and Bristol-Myers Squibb; advisory board member for Novartis, Amgen, MSD, Bristol-Myers Squibb, and Roche. J.W.B. de Groot: Consulting/advisory role for Amgen, Bayer, Celgene, Roche, Bristol-Myers Squibb, GSK, MSD, and Merck Serono. N. Yamazaki: Advisory role for Chugai Pharma, Bristol-Myers Squibb Japan, and Ono Pharmaceutical; honoraria from Chugai Pharma, Bristol-Myers Squibb Japan, Ono Pharmaceutical, GlaxoSmithKline, Takeda, AstraZeneca Japan, Boehringer Ingelheim, and Maruho. C. Loquai: Advisory board member for Roche, Novartis, Bristol-Myers Squibb, MSD, BioNTech, Pierre Fabre, and Amgen; speakers fees from Roche, Novartis, B Bristol-Myers Squibb MS, and MSD; travel expenses from Roche, Novartis, Bristol-Myers Squibb, MSD, and Amgen. L.A. de Parseval: Employee of Novartis Pharma AG; may own stock or stock options. M. Pickard: Employee of Array BioPharma; may own stock or stock options. V. Sandor: Employee/leadership role at Array BioPharma; stock or other ownership of Array BioPharma and Incyte Corp. C. Robert: Consultant for Roche, Novartis, Bristol-Myers Squibb, MSD, and Amgen. K.T. Flaherty: Honoraria from and consulting/advisory role for Novartis and Array BioPharma; research funding from Novartis. All other authors have declared no conflicts of interest.

Background

Combination of anti–PD-1 agents with BRAF/MEK inhibitors (i) may provide synergistic antitumor effects in BRAF-mutant melanoma. The ph 1/2 KEYNOTE-022 study (NCT02130466) is assessing safety and antitumor activity of recommended doses of pembro + BRAFi D + MEKi T; updated and additional ph 1 results are reported.

Methods

Treatment-naive pts with BRAF^V600E/K-mutant stage III/IV melanoma received pembro 2 mg/kg Q3W + D 150 mg BID + T 2 mg QD. Primary end point was safety; AEs were graded per CTCAE v4.0. Efficacy end points were ORR, PFS, and OS. Data cutoff: Mar 1, 2017.

Results

Of the 15 pts enrolled, 10 (66.7%) had PD-L1+ tumors (≥1% staining), 13 (86.7%)/2 (13.3%) had ECOG PS 0/1, and 1 (6.7%) had stable brain metastases. Median follow-up was 19.7 mo (range, 15.9-31.1). 3/15 (20.0%) pts had DLTs (pt 1 had gr 4 neutropenia; pt 2 had gr 4 ALT increase; and pt 3 had gr 4 ALT, gr 3 AST, and gr 3 GGT increase); all resolved. Thus, this dose was the MTD and recommended ph 2 regimen. 11 (73%) pts had gr 3-4 TRAEs; ALT increase, AST increase, and pyrexia occurred in ≥ 20% of pts. 7 (46.7%) pts had immune-mediated AEs, most commonly hyperthyroidism in 3 pts (2 gr 1 and 1 gr 2) and hypothyroidism in 4 pts (all gr 1). Treatment was discontinued (d/c) for 2 events (1 gr 2 pneumonitis and 1 gr 3 autoimmune hepatitis) and was interrupted for 3 events (1 gr 1 hyperthyroidism, 1 gr 2 anterior uveitis, and 1 gr 3 erythematous rash); all resolved. ORR (RECIST v.1.1, investigator; confirmed + unconfirmed) was 67%; 1 pt had CR, 9 had PR; an additional 2 pts had SD and 3 had PD. ORR (RECIST v.1.1, investigator; confirmed only) was 53%; 8 pts had PR; an additional 3 pts had SD and 4 had PD. Median time to response was 2.8 mo (range, 2.2-3.0); median DOR was not reached (range, 2.8-26.5 mo). Among the 8 pts with confirmed ORR, 6 had ongoing responses and 2 had progression at data cutoff. 2 pts remained on triplet therapy, 2 d/c D + T, and 4 d/c pembro + D + T as of last follow-up.

Conclusions

Updated results show that approved doses of pembro + D + T continue to demonstrate promising antitumor activity for BRAF-mutant melanoma. A randomized ph 2 study is currently evaluating this triplet regimen as first-line therapy for BRAF-mutant melanoma.

Clinical trial identification

NCT02130466, May 1, 2014

Legal entity responsible for the study

Merck & Co., Inc., Kenilworth, NJ, USA

Funding

Merck & Co., Inc., Kenilworth, NJ, USA

Disclosure

A. Ribas: Stock ownership with Kite Pharma; honoraria with Amgen, Pfizer, Roche, and Merck F.S. Hodi: Advisory board member with Merck, Genentech, Novartis, EMD Serono, and Amgen; research funding from Bristol-Myers Squibb. V. Atkinson: Advisory board member with MSD, Novartis, and Pierre Fabre; speakers\' bureau involvement with MSD, Bristol-Myers Squibb, and Novartis; honoraria with MSD, Bristol-Myers Squibb, and Novartis; travel expenses from MSD, Bristol-Myers Squibb, and Novartis. M.S. Carlino: Advisory board member with Bristol-Myers Squibb, Merck, Amgen, and Novartis; honoraria from Merck and Bristol-Myers Squibb. G.V. Long: Advisory board member with Amgen, Bristol-Myers Squibb, Array, Merck MSD, Novartis, Pierre-Fabre, and Roche; honoraria from Bristol-Myers Squibb, Roche, and Merck MSD. W.H. Miller: Consultant fees from Bristol-Myers Squibb, Roche, Novartis, Merck, GSK, and Amgen. Y. Huang: Employment with Novartis. B. Homet Moreno: Employment with Merck; stock ownership with Merck. N. Ibrahim: Employment with Merck; stock ownership with Merck and GSK. O. Hamid: Advisory board member Amgen, Novartis, Roche, Bristol-Myers Squib, Merck; speakers\' bureau Bristol-Myers Squibb, Genentech, Novartis, Amgen; research funding AstraZeneca, Bristol-Myers Squibb, Celldex, Genentech, Immunocore, Incyte, Merck, Merck Serono, MedImmune, Novartis, Pfizer, Rinat, Roche. All other authors have declared no conflicts of interest.