Background

Metastatic melanoma (MM) is widely treated with both kinase inhibitors and immunotherapies, providing meaningful survival benefit. Contrasting CGP and TMB results across MM subtypes provides a blueprint for rational decision making in light of increasing effective therapeutic options.

Methods

CGP for 2,225 MM evaluated up to 315 genes plus introns of 28 genes commonly rearranged in cancer using hybrid-capture, adaptor ligation-based libraries (mean coverage >620X). TMB was calculated from ∼1.1 Mb of sequenced DNA. Base substitutions, insertions and deletions (short variants; SV); rearrangements; and copy number changes were assessed.

Results

We evaluated 9 MM subtypes: routine cutaneous (CT), desmoplastic (DM), acral lentiginous (AL), Spitzoid (SP), gynecologic mucosal (GMC), head and neck mucosal (HN), anorectal (ARM) and ocular (OC). Each group harbored characteristic genomic alterations (GA) (Table). BRAF was mutated in 38% of CT (92% SV; 8% amplifications, fusions or cases with >1 BRAF GA). Patients with TMB ≥20 mut/Mb were common in CT and DM, but 5% or less in all other subtypes. The frequency of BRAF GA was lower in AL, GMC, HN, ARM and OC. SP commonly harbored fusions in BRAF (60%) and other kinases. KIT GA were prominent in GMC and AL. Key findings include novel drivers of BRAF inhibitor resistance including BRAF rearrangements, kinase duplications and MEK GA.Table:

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Conclusions

In the largest cohort of MM with CGP to date, genomic profiles and TMB differ across MM subtypes. Highly prevalent BRAF GA in CT and high TMB in CT and DM permit effective use of targeted and immunotherapies, although novel BRAF inhibitor resistance mechanisms were observed. In addition, a variety of non-BRAF kinase targets are apparent in some MM subtypes.

Legal entity responsible for the study

Jeffrey S Ross

Funding

None

Disclosure

J.S. Ross: Employee, leader and owns stock in Foundation Medicine J.A. Elvin: Employee and owns stock in Foundation Medicine J-A. Vergilio, J. Suh, S. Ramkissoon, E. Severson, S. Daniel, S.M. Ali, A.B. Schrock, D. Fabrizio, G.M. Frampton, L.M. Gay: Employee and owns stock in Foundation medicine V.A. Miller, P.J. Stephens: Employee, leader and owns stock in Foundation medicine All other authors have declared no conflicts of interest.

Background

There is no standard active treatment for metastatic uveal melanoma. Precision medicine with high-throughput genomics could improve the outcome of patients suffering of “hard-to-treat” cancer.

Methods

Metastatic uveal melanoma included in the prospective TREAT20Plus study had fresh tumor biopsies that were subjected to a complete genomic analysis program (WGS, whole exome seq, RNAseq, Methylome, Proteome and cell culture). Integrative data analysis was performed and generated a comprehensive molecular tumor analysis (CMTA). An interdisciplinary molecular tumour board interpreted the data and provided treatment recommendations.

Results

Thirteen patients (6 F, 7 M) were biopsied. Age: 68 (33-81). Site of biopsy: soft tissue: 5, liver: 4, lung: 2, pleura: 1, lymph node: 1. Pre-treatment number: 2 (0-4) and type: iv chemotherapy: 10, checkpoint Inh:6, intra-hepatic: 8. Genomic results were available in the first 10 patients within 34 days (31-40). The number of mutations was low: median 25 (16-44.). Mutations were found in GNAQ: 11, GNA11: 6, BAP1; 3, SF3B1: 4. We detected one gene-fusion: ZNF704-PKIA. The most frequent gene overexpression affected the following genes: MYC: 7, MET: 5, BCL2: 4, CCND2: 1, ERBB3: 1. There was a loss of expression of: CDKN2A: 2, PTEN: 1, EFS: 1. A slightly up-regulated expression of ALK was detected in one patient and confirmed as an oncogenic ALK^ATI isoform that originates from an alternative internal transcription start site in intron 19. At time of recurrence a second biopsy showed a complete loss of CDKN2A expression through a bi-allelic loss of chromosome 9. Treatment recommendations were the following: inhibitor of MEK: 10, of MET: 5, of CDK4/6: 3, of ALK: 1, of PI3K: 1. Treatment was initiated in 7 patients: 5 received Trametinib, one patient each received Palbociclib, Crizotinib or Cabozantinib, respectively. Among the 6 currently evaluable patients one showed minor response (15%), one a stable disease, one progressive disease, and 3 patients cannot yet be evaluated.

Conclusions

Genomic integrative analysis showed a net advantage over exome-only or panel sequencing. This strategy is clinically feasible and led to individualized treatment recommendations. Treatment outcome will be presented for the whole cohort.

Legal entity responsible for the study

Charité Comprehensive Cancer Center

Funding

German Federal Ministry of Research and Education (BMBF) grant Nr. 031A512 Max Planck Society

Disclosure

M. Schuette, C. Wierling, B. Lange: Employees of Alacris Theranostics. T. Kessler: Employee of Alacris Theranostics GmbH. F. Kiecker: Advisory Boards: Novartis, Bristol-Myers Squibb, MSD, Roche, Amegen, Merck Serono. H. Lehrach: Board of direction of Alacris Theranostics. U. Keilholz: Speaker honoraria and advisory board roles are with AstraZeneca, Bristol-Myers Squibb, Merck, MSD, Pfizer, Novartis, Innate Corporate-sponsored research is with AstraZeneca and Merck. All other authors have declared no conflicts of interest.

Background

After enucleation or radiotherapy of the primary lesion, 50% of uveal melanoma (UM) patients develop distant metastases. In contrast to cutaneous melanoma, targeted therapies and checkpoint inhibitors failed to improve overall survival (OS) in UM. Chemoembolization or intrahepatic artery perfusion improved local control, but failed to show OS benefit. The anti-CTLA-4 antibody ipilimumab (IPI), showed limited clinical activity in UM, thus combination therapies may be required. Preclinical experiments in a murine melanoma model indicated that additional radiofrequency ablation(RFA) enhanced antigen presentation and induced durable responses.

Methods

We therefore have set-up a phase 1b/2 study to assess safety and efficacy of the combination of RFA and IPI in UM patients with at least 2 unresectable liver lesions. In the phase 1b part patients underwent RFA of one liver lesion and received 4 courses IPI 0,3mg/kg, 3mg/kg or 10mg/kg q3wk in a 3 + 3 design. Primary endpoint of the phase 1b part was safety in terms of dose limiting toxicities per cohort to define the recommended phase 2 dose(RP2D). Primary endpoints of the phase 2 part were confirmed objective response rate (ORR) and disease control rate (DCR) according to RECIST 1.1 (only non-RFA lesions), secondary endpoints were progression free survival (PFS) and OS.

Results

IPI 10mg/kg + RFA was defined as the RP2D. After 19 patients had been treated, the study was amended to adjust the RP2D to IPI 3mg/kg + RFA, because 9 patients (47%) had developed grade 3 colitis. In the 3mg/kg IPI + RFA cohort also 19 patients have been treated, and baseline characteristics were balanced between the cohorts. Treatment related grade ≥3 AEs were seen in 53% of patients in the 10mg/kg cohort versus 32% in the 3mg/kg cohort. No confirmed objective responses were observed; the confirmed DCR was 21% in the 10mg/kg cohort and 11% in the 3mg/kg cohort. Median PFS was 2.8 months and was comparable for both groups, median OS was 13.6 months for the 10mg/kg cohort versus 9.5 months for the 3mg/kg cohort (p = 0.23).

Conclusions

The combination of IPI 3mg/kg +RFA was safe but showed limited clinical activity in UM. However, overall survival seems to be longer compared to other study cohorts of UM patients, especially in the IPI 10mg/kg cohort.

Clinical trial identification

EudraCT Number: 2011-004200-38

Legal entity responsible for the study

NKI-AVL

Funding

Bristol-Myers Squibb

Disclosure

J.V. Thienen: Advisory board: MSD, Bristol-Myers Squibb. J.B. Haanen: Advisory role: Bristol-Myers Squibb. MSD, Pfizer, Roche, Novartis, Neon Therapeutics Research grants: Bristol-Myers Squibb, MSD, GSK. C.U. Blank: Advisory board: Bristol-Myers Squibb, MSD, Novartis, GSK, Pfizer, Lilly, Roche Research grant: Bristol-Myers Squibb, Novartis. All other authors have declared no conflicts of interest.

Background

Combination D+T improves the overall survival (OS) of patients (pts) with BRAF V600 mutant advanced melanoma, and an adjuvant trial is in progress (NCT01682083). We sought to explore neoadjuvant D+T for pts with bulky but resectable stage III melanoma.

Methods

In this phase 2 study, 35 pts received standard dose D+T for 12 wks prior to complete resection of the pre-therapy tumour bed (RES), then 40 wks of further D+T. Eligible pts had ECOG PS ≤ 1 with histologically confirmed resectable bulky AJCC v7 stage IIIB/C BRAF V600 mutant melanoma. CT and PET scans were performed at baseline and 12 wks just prior to RES for RECIST and metabolic complete response (rCR and mCR respectively). CT monitoring was continued 12 wkly thereafter to 2 yrs then 6 monthly to 3 yrs. Biopsies were taken at baseline and wk 1. The primary endpoints were the complete pathological response (pCR) and RECIST response rate (rRR) at wk 12. Secondary endpoints were surgical morbidity, mCR, relapse free survival (RFS), OS, toxicity and translational endpoints.

Results

At data cut 18^th April 2017, 35 had commenced D+T. 33 had reached RES (27 stage IIIC [8 in-transit only], 6 IIIB; 32 V600E, 1 V600K; 12 LDH >ULN). At RES, 17/33 (52%) had pCR, 16 (48%) had rCR (rRR 88%), and 16 (48%) had mCR. The pathologic response was discordant with RECIST response in 7 (21%) pts and metabolic response in 9 (27%) pts; only 11 (65%) pts with pCR had rCR and mCR. No pt discontinued D+T and no pt progressed during the neoadjuvant period, D+T did not make surgery more difficult in any pt, and in 16 (48%) surgery was deemed easier. Median F/U post RES was 12.1 mo (95% CI 8.8-14.8). 12 (36%) pts had recurred (median 12.9 mo), 4 while on D+T, 6 with prior pCR, 8 at distant sites, and 1 pt had died. 26 (79%) pts developed drug fever. 18 (55%) had ≥ 1 surgical complication post RES; 11 had a wound infection requiring antibiotics, 5 had a seroma, 2 bled. Updated data will be presented including tumour biopsy and and ctDNA biomarker data.

Conclusions

Neoadjuvant D+T has a high response rate and high pCR rate in resectable stage III melanoma. Surgical complication rates were consistent with historic controls and stage of disease.

Clinical trial identification

NCT01972347

Legal entity responsible for the study

Melanoma Institute Australia

Funding

Novartis

Disclosure

A.M. Menzies: Advisory board - MSD, Novartis, Chugai, Pierre Fabre. Honoraria - Bristol-Myers Squibb, Roche G.V. Long: Advisory board - Bristol-Myers Squibb, MSD, Novartis, Amgen, Pierre Fabre. All other authors have declared no conflicts of interest.

Background

The combination of IPI+NIVO induces high response rates and improved overall survival in late stage melanoma. T cell checkpoint inhibition is of greatest value at the moment of TCR triggering and therefore dependent on the amount of antigen present, indicating that adjuvant immunotherapy will work most efficiently, when initiated prior to surgery.

Methods

Two-arm Phase 1b feasibility trial consisting of 20 high risk AJCC stage 3B/C melanoma patients with palpable nodal disease receiving the combination of IPI 3mg/kg and NIVO 1mg/kg, either adjuvant four courses after surgery, or split neo-adjuvant and adjuvant.

Results

In this update 20 patients are evaluable. Neo-adjuvant application of IPI+NIVO was feasible and no surgery-associated adverse events were attributed to (neo-) adjuvant therapy. 18/20 patients had to stop earlier due to grade 3/4 toxicities. Neo-adjuvant IPI+NIVO reduced tumor load in 8/10 patients (3 pCR, 4 near pCRs [minimal remaining micro metastases], 1 pPR [<50% vital tumor cells], 1 pSD and 1 pPD). So far, none of the responders in the neo-adjuvant arm has relapsed. Relapse was observed for the 2 non-responders within the neo-adjuvant arm and for 3 patients within the adjuvant arm. We will present at ESMO 2017 the 18 months RFS update and in detail the biomarker analyses. Latter comprises RNA sequencing and Nanostring^TM microscope spatial profiling to identify biomarkers for response, and TCR sequencing, with the aim to distinguish T cell responses between both, the two treatment arms and between patients relapsing or remaining free of disease.

Conclusions

The combination of IPI+NIVO in the (neo-)adjuvant treatment setting for high risk stage 3 melanoma patients is promising and currently tested in an international phase 2 randomized trial comparing different combination schemes (OpACIN-neo trial, NCT02977052) with the aim of preserving efficacy, but reducing toxicity. Biomarkers identifying patients responding upon neo-adjuvant IPI+NIVO and remaining relapse-free for a long time, will help to select the patients that need to be exposed to IPI+NIVO associated toxicity.

Clinical trial identification

NCT02437279

Legal entity responsible for the study

NKI-AVL

Funding

Bristol-Myers Squib

Disclosure

P. Kvistborg: Advisory board: Neon therapeutics, Merck, Personalis. J.V. Thienen: Advisory board: MSD, Bristol-Myers Squibb. B. Stegenga, B. Lamon: Employee of Bristol-Myers Squibb. J.B. Haanen: Advisory role: Bristol-Myers Squibb, MSD, Pfizer, Roche, Novartis, Neon Therapeutics Research grants: Bristol-Myers Squibb, MSD, GSK. C.U. Blank: Advisory role: Bristol-Myers Squibb, MSD, GSK, Roche, Novartis, Lilly, Pfizer Research grants: Bristol-Myers Squibb, Novartis. All other authors have declared no conflicts of interest.

Background

NIVO+IPI and NIVO significantly improved PFS and OS vs. IPI alone in the CheckMate 067 study. Descriptively, NIVO+IPI showed longer OS than NIVO (hazard ratio: 0.88), with 2-year OS rates of 64% and 59%, respectively. Post-hoc analyses by region were performed to evaluate potential differences between patients (pts) treated in the EU and those treated in the USA.

Methods

Baseline patient characteristics, safety and efficacy were evaluated in the two highest enrolling regions (EU, 55% and USA, 22%) using data from the CheckMate 067 study. Minimum follow-up of the pts was 28 months.

Results

EU pts were more likely to have M1c disease than USA pts (60% vs 53%), and more likely to have BRAF wild-type (WT) tumors (69% vs 59%). In a multivariate analysis, which adjusted for baseline factors, the only significant interaction between NIVO+IPI and NIVO was by region. Adjusted hazard ratios (HRs) for OS in the NIVO+IPI vs NIVO groups were 0.90 (0.66–1.23) for the EU and 0.53 (0.29–0.98) for the USA. Across all arms, 2-year OS rates were lower in the EU vs USA pts, particularly for pts with BRAF WT tumors (Table). In pts with BRAF mutant tumors, similar OS outcomes were observed between regions. Treatment exposure, safety, management of adverse events, and use of subsequent therapies did not differ substantially between the two regions. Objective response rates and progression-free survival were also similar between the two regions.Table:

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Conclusions

Differences in OS between the EU and the USA appear to be largely due to poorer survival outcomes in EU pts with BRAF WT tumors, which likely impacted OS differences between NIVO+IPI and NIVO in the overall population. Additional analyses by region, the first report of 3-year OS, as well as analyses by tumor mutational burden will be presented. Acknowledgement: J. Larkin and J.D. Wolchok contributed equally to this study.

Clinical trial identification

NCT01844505

Legal entity responsible for the study

Bristol-Myers Squibb

Funding

Bristol-Myers Squibb

Disclosure

J-J. Grob: Served as a consultant for Bristol-Myers Squibb, GSK, Novartis, Roche, Merck, Amgen; participated on speakers’ bureau for Bristol-Myers Squibb, GSK, Roche; travel funding from Roche; recipient of research funding from Bristol-Myers Squibb 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. J. Wagstaff: Paid honoraria from Bristol-Myers Squibb, Merck, Roche, Astellas, Pfizer, Novartis; Consultant for Bristol-Myers Squibb, Merck, Roche, Astellas, Pfizer, Novartis; participated in speakers’ bureau for Bristol-Myers Squibb, Novartis, Astellas; travel funding from Bristol-Myers Squibb, Novartis, Astellas. I. Márquez-Rodas: Paid honoraria from Novartis, Roche, MSD, Bristol-Myers Squibb; served as a consultant for Novartis, Roche, MSD, Bristol-Myers Squibb, Amgen, Bioncotech; travel funding from MSD, Bristol-Myers Squibb, Amgen C. Lebbé: Served on an advisory board for Bristol-Myers Squibb, MSD, Roche, GSK, and Novartis. P.A. Ascierto: Served as a consultant for Bristol-Myers Squibb, Roche-GNE, MSD, Novartis, Array, Amgen, Merck-Serono, Pierre-Fabre; institution received research funding from Bristol-Myers Squibb, Roche-Genentech, Array F.S. Hodi: Employee: Dana-Farber Cancer Institute; consultant: MSD, Novartis, GNE/Roche, Amgen, EMD Serono; travel: Novartis and Bristol-Myers Squibb; patent pending royalties per inst policy; other Bristol-Myers Squibb & GNE/Roche; institutional research funding: Bristol-Myers Squibb, MSD, GNE/Roche, Novartis. J.C. Hassel: Payments for trial procedures according to study protocol from Bristol-Myers Squibb; honoraria: Bristol-Myers Squibb, MSD, Roche, GSK, Novartis, Amgen; research grant/funding: Bristol-Myers Squibb; travel: Bristol-Myers Squibb, MSD, Roche, GSK, Novartis, Amgen. D. Walker: Employed by Bristol-Myers Squibb; Immediate family member has stock or other ownership in Antares Pharma. R. Bhore: Employed by Bristol-Myers Squibb and owns stock in Bristol-Myers Squibb J. Larkin: Received research funding from Bristol-Myers Squibb, MSD, Novartis, and Pfizer; travel funding from Bristol-Myers Squibb, MSD, Pfizer, EISAI, GSK, and Roche. J.D. Wolchok: Consultant: Bristol-Myers Squibb, Merck, MedImmune, Ziopharm, Polynoma, Polaris, Jounce, GSK; Research funding: Bristol-Myers Squibb, Merck, MedImmune, GSK; patent issued for DNA vaccine of cancer in companion animals (co-investor). All other authors have declared no conflicts of interest.

Background

We compared quality-adjusted survival (OS) of combined NIVO+IPI or NIVO alone vs IPI among treatment-naïve pts with advanced MEL enrolled in the CheckMate 067 trial.

Methods

The Q-TWiST approach was used to partition OS into 3 health states: time without disease progression or symptoms of toxicity (TWiST), time with grade ≥3 treatment-related AE toxicity after randomization but before progression (TOX), and time after progression (REL). Q-TWiST was calculated by multiplying mean time spent in each state at 36 months (mos) by their utility (TWiST=1.0, TOX=0.5, and REL=0.5). Q-TWiST differences were assessed at various times ranging from 3 to 36 mos. A ≥ 15% relative Q-TWiST gain (vs mean IPI OS) was considered clearly clinically important.

Results

Compared with IPI, NIVO+IPI pts had longer (difference in mean mos, 95% CI) TWiST (9.6, 7.4 to 11.7) and TOX (0.3, 0.1 to 0.4) but shorter REL time (-5.2, -7.1 to -3.2). Compared with IPI, NIVO pts had a longer TWiST (7.3, 5.0 to 9.6), shorter REL time (-3.4, -5.5 to -1.3), and shorter TOX (-0.1, -0.2 to 0.1). Q-TWiST was highest for NIVO+IPI, followed by NIVO, and IPI (Table). Relative Q-TWiST gains were also favorable for NIVO+IPI (+34.0% v IPI) and NIVO (+26.4% v IPI) and increased as follow-up increased from 3 to 36 months for all comparisons.

Conclusions

At 36 months, NIVO and NIVO+IPI pts had a clinically important improvement in Q-TWiST vs IPI. As these benefits continue to accrue over time, future analyses with longer follow-up are planned.Table:

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Clinical trial identification

QoL study based on the 067 trial NCT01844505 protocol number is CA209-067 (CheckMate 067)

Legal entity responsible for the study

Bristol-Myers Squibb

Funding

Bristol-Myers Squibb

Disclosure

M. Botteman: Employed by and owns stock in Pharmerit International. Pharmerit International has received research funding from BMS to conduct this research. Pharmerit International is a global health economics and outcomes research consulting firm that receives researching funding and fees related to consulting and other advisory roles from numerous private organizations from the pharmaceutical, biotech, device, and medical industry. R. Shah, L. Luo: Employed by Pharmerit International. Pharmerit International has received research funding from BMS to conduct this research. K. Gupte-Singh, J. Sabater, S. Rao: Employed by and owns stock in Bristol-Myers Squibb. D.F. McDermott: David McDermott served as a consultant or advisor for Pfizer and Genentech. M.B. Atkins: Served as a consultant or advisor for GNE, Pfizer, Novartis, GSK, C-Cam, X4 Pharma, Amgen, Lilly, Alkermes, Infinity Pharmaceuticals, Genoptix, Bristol-Myers Squibb, Nektar, Merck; received honoraria from Bristol-Myers Squibb. All other authors have declared no conflicts of interest.

Background

Treatment with checkpoint inhibitors can result in durable responses and deepening of responses over time with conversion of SD to PR or CR, and PR to CR. In the randomized KEYNOTE-002 study (NCT01704287), pembro 2 mg/kg or 10 mg/kg improved PFS (HR 0.57 and 0.50; P<0.0001 for both) vs chemo in pts with ipi-refractory melanoma. In this post hoc analysis, we assessed evolution of response and survival for 361 pembro-treated pts.

Methods

Pts were treated until disease progression (PD), unacceptable toxicity or investigator/pt decision. Response (RECIST v1.1; investigator review) was assessed at wk 12, every 6 wk until wk 48, then every 12 wk, and confirmed by subsequent scan. Survival was assessed every 12 wk during follow-up. Pembro arms were combined given no difference in efficacy of doses.

Results

As of 3 Feb 2017, median follow-up duration was 42.7 mo. In pembro-treated pts, median PFS was 4.2 mo (95% CI 3.3-5.6), and 36-mo PFS rate was 16%. Median OS was 14.0 mo (11.8-16.2), and 36-mo OS rate was 30%. 99 of 361 pts had CR (n = 29) or PR (n = 70) for ORR of 27.4% (95% CI 22.9-32.3); 88 pts had SD. Median time to response was 2.9 mo. Of 29 pts with CR, 5 converted from SD, 21 from PR. Of 70 pts with PR, 28 converted from SD. Median time from SD to PR was 2.7 mo (range 0.9-25.2), from SD to CR was 6.9 mo (3.9-21.9), and from PR to CR was 8.0 mo (1.4-25.2). Median DOR was not reached in pts with CR or PR (Table). Median duration of SD was 6.9 mo (range 0.8+ to 38.8+). 9 (31%) pts with CR, 28 (40%) with PR and 63 (72%) with SD had subsequent PD; in these pts, median duration of CR was 17.1 mo (5.5-36.1), PR 7.7 mo (2.0-31.8), and SD 5.8 mo (2.7-25.3). Median PFS and OS were longer in pts with CR or PR (Table).

Conclusions

Responses to pembro are durable and associated with prolonged OS in ipi-refractory melanoma. Even in these heavily pretreated pts best response can evolve over time, with late conversions from SD to PR/CR and PR to CR observed.Table:

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Clinical trial identification

mk-3475-002 ClinicalTrials.gov NCT01704287 First received: October 8, 2012 Last updated: March 28, 2017 Last verified: March 2017

Legal entity responsible for the study

Merck & Co., Inc.

Funding

Merck & Co., Inc.

Disclosure

A. Daud: Received research funding from and is an advisory board member of Merck & Co., Inc. R. Dummer: Received honoraria from MSD, Merck & Co., Inc.\'s international counterpart. D. Schadendorf: Received research, honoraria and travel funding from Merck & Co., Inc. Serves as an advisory board member and on speaker\'s bureau for Merck & Co., Inc. O. Hamid: Serves on an advisory board for and has received research funding from Merck & Co., Inc. C. Robert: Received honoraria from Merck & Co., Inc. F.S. Hodi: Advisory board member for Merck & Co., Inc. J. Schachter: Received honoraria from MSD, an international division of Merck & Co., Inc. A.C. Pavlick: Been a consultant for Merck & Co., Inc. R. Gonzalez: Received travel funding, research grants and honoraria from Merck & Co., Inc. Served as an advisory board member for Merck & Co., Inc. C.U. Blank: Served on advisory board and on speaker\'s bureau for Merck & Co., Inc. Received honoraria from Merck & Co., Inc. S.J. O’day: Received research funding for and served as an advisory board member of Merck & Co., Inc. A.K. Salama: Received research funding for and has been an advisory board member of Merck & Co., Inc. K. Margolin: Received researched funding from Merck & Co., Inc. J. Yang: Employee of Merck & Co., Inc. and may own stock options in the company. B. Homet Moreno: Employee of Merck & Co., Inc. and may own stock options in the company. N. Ibrahim: Employee of Merck & Co., Inc. and may own stock options in the company. A. Ribas: Received honoraria from Merck & Co., Inc. All other authors have declared no conflicts of interest.

Background

Imaging with FDG-PET allows early recognition of metabolic response to targeted agents. We evaluated the timing of complete metabolic response (CMR) on PET as a predictor of clinical outcome in BRAF V600 mutant melanoma patients treated with vemurafenib and cobimetinb, as part of the BRIM-7 trial.

Methods

BRAF inhibitor naïve patients from BRIM-7 were included if they had evaluable PET scans at baseline, in cycle 1 (C1) (D10-15) and in C2 (D35-49). Metabolic response was evaluated by percentage injected dose (%ID). 52 of 63 BRAF-naïve patients were eligible for analysis (3 excluded - no C1 scan; 6 no C2 scan; 2 unevaluable scans due to excessive physiological muscle uptake). The primary aim was to evaluate the prognostic significance of an early CMR to combination vemurafenib and cobimetinib therapy. We divided patients into 3 groups, based on timing of CMR attainment.

Results

13 patients achieved CMR in cycle 1 (CMR1), 15 patients achieved CMR in cycle 2 (CMR2) and 24 patients did not achieve CMR within the first 2 cycles of treatment (noCMR). The median, 2 year and 3 year progression free survival (PFS) and overall survival (OS) of the 3 above groups are summarized in Table.Table:

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Conclusions

Attainment of CMR on an early D10-14 PET was highly predictive of long-term survival with BRAF and MEK inhibition. However, attainment of CMR at a later time point at D35-49 did not appear predictive of a survival benefit. In fact, no difference in PFS or OS could be observed in patients who achieved CMR at D35-49, compared to those patients who did not attain CMR. Correlative science analysis to investigate the mechanism of these observations are underway.

Clinical trial identification

number: NCT01271803

Legal entity responsible for the study

Genentech Roche

Funding

Genentech Roche

Disclosure

J. Frederickson: Employer of Genentech and has Roche stocks D. Colburn, N. Choong, M. Wongchenko: Employee of Roche-Genentech. All other authors have declared no conflicts of interest.

Background

BRAF mutations are found in 50% of patients (pts) with advanced melanoma. Previously, the METRIC trial (NCT01245062) demonstrated that the MEK inhibitor trametinib (T) increased PFS in this population of patients with a clinical benefit that could last ≥ 2 yrs in some pts. We report findings from the 5-year follow-up analysis

Methods

METRIC is an open-label, randomized Ph3 study of pts who received ≤ 1 prior regimen of chemotherapy (C) for histologically confirmed unresectable stage IIIC or IV cutaneous BRAF V600E/K–mutant metastatic melanoma (MM). Pts were randomized (2:1) to T (2 mg/day) or intravenous C (dacarbazine [1000 mg/m²] or paclitaxel [175 mg/m²] every 3 wks). Pts were stratified according to baseline lactate dehydrogenase level and previous C for advanced disease. Pts who progressed on C were allowed to crossover and receive T. The primary endpoint was progression-free survival (PFS); secondary endpoints included overall survival (OS), duration of response and safety.

Results

322 pts (V600E: 281, 600K: 40, V600E/K mutation: 1) were enrolled (T: 214; C: 108). At data cutoff (Dec 16, 2016), median follow-up was 12.3 months (mo). The median OS for the T arm was 15.6 mo vs 11.3 mo for the C arm (HR = 0.84 [95% CI, 0.63–1.11], P = 0.19). Landmark OS for the T arm vs the C arm at 1, 2, 3, and 5 yrs were 60.9% vs 49.6%; 32.0% vs 29.4%; 20.6% vs 22.6%; and 13.3% vs 17.0%, respectively. Most pts (n = 70, 65%) in the C arm crossed over and received T. Median time to crossover was 3.1 (1–20) mo; median duration of follow-up after crossover was 8.8 (0–67) mo. Among pts who received post-tx anti-cancer therapy (n = 208), most received targeted therapy (n = 118), immunotherapy (n = 90), or C (n = 84). No new safety signals were observed.

Conclusions

This is the longest reported follow up for T monotherapy in pts with BRAF V600E/K–mutant MM and demonstrates that some of these pts experience long-term benefit with targeted therapy. Pts with extended follow-up after initiation of T, contributed to long-term survival for those randomized to the C arm.

Clinical trial identification

NCT01245062

Legal entity responsible for the study

Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA

Funding

Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA

Disclosure

D. Schadendorf: Reports grants and personal fees from Novartis, MSD/Merck, Amgen, GSK, Sysmex, Boehringer Ingelheim, Bristol-Myers Squibb, outside the submitted work K.T. Flaherty: Consulted for Novartis in relation to this abstract P. Nathan: Reports personal fees from Novartis, outside the submitted work. C. Garbe: Reports grants and personal fees from Novartis, during the conduct of the study; personal fees from Amgen, MSD, Philogen, grants and personal fees from Roche and Bristol-Myers Squibb, outside the submitted work. P. Mohr: Reports personal fees and other from Novartis, during the conduct of the study; personal fees and other from Amgen, grants, personal fees and other Bristol-Myers Squibb, MSD, Merck, Roche, outside the submitted work. J.C. Hassel: Reports other from GSK, during the conduct of the study; personal fees from Bristol-Myers Squibb, MSD, Roche, Novartis, Amgen, MSD, other from MSD, Bristol-Myers Squibb, Novartis, outside the submitted work. P. Rutkowski: Reports personal fees from Novartis, Bristol-Myers Squibb, Roche, MSD, GSK, Amgen, outside the submitted work. R. Dummer: Receives research funding and and has a consultant or has advisory board relationship with Novartis, MSD, Bristol-Myers Squibb, Roche, GSK, Amgen, outside the submitted work J. Utikal: Reports to be on the advisory board and has received travel support from Amgen, Bristol-Myers Squibb, GSK, MSD, Novartis and Roche F. Kiecker: Reports personal fees from Amgen, personal fees from Bristol-Myers Squibb, personal fees from MSD, personal fees from Novartis, personal fees from Roche, outside the submitted work. J. Larkin: Research support, Bristol-Myers Squibb, MSD, Novartis, Pfizer, Consultancy: Eisai, Bristol-Myers Squibb, MSD, GSK, Kymab, Pfizer, Novartis, Roche/Genentech, Secarna, Pierre Fabre, EUSA, Support, NIHR RM/ICR Biomedical Research Centre for Cancer A. D’Amelio Jr: Reports personal fees from Novartis Pharmaceuticals, during the conduct of the study; other from Novartis Pharmaceuticals, other from GlaxoSmithKline, outside the submitted work Y. Huang: Employee of Novartis. B. Mookerjee: Employee of Novartis, stock and other ownership, Novartis, GSK, Incyte, AstraZeneca C. Robert: Participated in advisory boards for Roche, GSK, Merck, Novartis, Amgen, Bristol-Myers Squibb, Novartis. All other authors have declared no conflicts of interest.