Alexandre Lambert

Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial

BACKGROUND Nivolumab, a fully human IgG4 PD-1 immune checkpoint inhibitor antibody, can result in durable responses in patients with melanoma who have progressed after ipilimumab and BRAF inhibitors. We assessed the efficacy and safety of nivolumab compared with investigators choice of chemotherapy (ICC) as a second-line or later-line treatment in patients with advanced melanoma. METHODS In this randomised, controlled, open-label, phase 3 trial, we recruited patients at 90 sites in 14 countries. Eligible patients were 18 years or older, had unresectable or metastatic melanoma, and progressed after ipilimumab, or ipilimumab and a BRAF inhibitor if they were BRAF(V 600) mutation-positive. Participating investigators randomly assigned (with an interactive voice response system) patients 2:1 to receive an intravenous infusion of nivolumab 3 mg/kg every 2 weeks or ICC (dacarbazine 1000 mg/m(2) every 3 weeks or paclitaxel 175 mg/m(2) combined with carboplatin area under the curve 6 every 3 weeks) until progression or unacceptable toxic effects. We stratified randomisation by BRAF mutation status, tumour expression of PD-L1, and previous best overall response to ipilimumab. We used permuted blocks (block size of six) within each stratum. Primary endpoints were the proportion of patients who had an objective response and overall survival. Treatment was given open-label, but those doing tumour assessments were masked to treatment assignment. We assessed objective responses per-protocol after 120 patients had been treated with nivolumab and had a minimum follow-up of 24 weeks, and safety in all patients who had had at least one dose of treatment. The trial is closed and this is the first interim analysis, reporting the objective response primary endpoint. This study is registered with ClinicalTrials.gov, number NCT01721746. FINDINGS Between Dec 21, 2012, and Jan 10, 2014, we screened 631 patients, randomly allocating 272 patients to nivolumab and 133 to ICC. Confirmed objective responses were reported in 38 (31·7%, 95% CI 23·5-40·8) of the first 120 patients in the nivolumab group versus five (10·6%, 3·5-23·1) of 47 patients in the ICC group. Grade 3-4 adverse events related to nivolumab included increased lipase (three [1%] of 268 patients), increased alanine aminotransferase, anaemia, and fatigue (two [1%] each); for ICC, these included neutropenia (14 [14%] of 102), thrombocytopenia (six [6%]), and anaemia (five [5%]). We noted grade 3-4 drug-related serious adverse events in 12 (5%) nivolumab-treated patients and nine (9%) patients in the ICC group. No treatment-related deaths occurred. INTERPRETATION Nivolumab led to a greater proportion of patients achieving an objective response and fewer toxic effects than with alternative available chemotherapy regimens for patients with advanced melanoma that has progressed after ipilimumab or ipilimumab and a BRAF inhibitor. Nivolumab represents a new treatment option with clinically meaningful durable objective responses in a population of high unmet need. FUNDING Bristol-Myers Squibb.

Nivolumab for Metastatic Renal Cell Carcinoma: Results of a Randomized Phase II Trial

PURPOSE Nivolumab is a fully human immunoglobulin G4 programmed death-1 immune checkpoint inhibitor antibody that restores T-cell immune activity. This phase II trial assessed the antitumor activity, dose-response relationship, and safety of nivolumab in patients with metastatic renal cell carcinoma (mRCC). PATIENTS AND METHODS Patients with clear-cell mRCC previously treated with agents targeting the vascular endothelial growth factor pathway were randomly assigned (blinded ratio of 1:1:1) to nivolumab 0.3, 2, or 10 mg/kg intravenously once every 3 weeks. The primary objective was to evaluate the dose-response relationship as measured by progression-free survival (PFS); secondary end points included objective response rate (ORR), overall survival (OS), and safety. RESULTS A total of 168 patients were randomly assigned to the nivolumab 0.3- (n = 60), 2- (n = 54), and 10-mg/kg (n = 54) cohorts. One hundred eighteen patients (70%) had received more than one prior systemic regimen. Median PFS was 2.7, 4.0, and 4.2 months, respectively (P = .9). Respective ORRs were 20%, 22%, and 20%. Median OS was 18.2 months (80% CI, 16.2 to 24.0 months), 25.5 months (80% CI, 19.8 to 28.8 months), and 24.7 months (80% CI, 15.3 to 26.0 months), respectively. The most common treatment-related adverse event (AE) was fatigue (24%, 22%, and 35%, respectively). Nineteen patients (11%) experienced grade 3 to 4 treatment-related AEs. CONCLUSION Nivolumab demonstrated antitumor activity with a manageable safety profile across the three doses studied in mRCC. No dose-response relationship was detected as measured by PFS. These efficacy and safety results in mRCC support study in the phase III setting.

Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): a multicentre, single-arm, phase 2 trial

BACKGROUND Patients with metastatic urothelial carcinoma have a dismal prognosis and few treatment options after first-line chemotherapy. Responses to second-line treatment are uncommon. We assessed nivolumab, a fully human IgG4 PD-1 immune checkpoint inhibitor antibody, for safety and activity in patients with metastatic or surgically unresectable urothelial carcinoma whose disease progressed or recurred despite previous treatment with at least one platinum-based chemotherapy regimen. METHODS In this multicentre, phase 2, single-arm study, patients aged 18 years or older with metastatic or surgically unresectable locally advanced urothelial carcinoma, measurable disease (according to Response Evaluation Criteria In Solid Tumors v1.1), Eastern Cooperative Oncology Group performance statuses of 0 or 1, and available tumour samples for biomarker analysis received nivolumab 3 mg/kg intravenously every 2 weeks until disease progression and clinical deterioration, unacceptable toxicity, or other protocol-defined reasons. The primary endpoint was overall objective response confirmed by blinded independent review committee in all treated patients and by tumour PD-L1 expression (≥5% and ≥1%). This trial is registered with ClinicalTrials.gov, number NCT02387996, and is completed. Follow-up is still ongoing. FINDINGS Between March 9, 2015, and Oct 16, 2015, 270 patients from 63 sites in 11 countries received nivolumab, and 265 were evaluated for activity. Median follow-up for overall survival was 7·00 months (IQR 2·96-8·77). Confirmed objective response was achieved in 52 (19·6%, 95% CI 15·0-24·9) of 265 patients. Confirmed objective response was achieved in 23 (28·4%, 95% CI 18·9-39·5) of the 81 patients with PD-L1 expression of 5% or greater, 29 (23·8%, 95% CI 16·5-32·3) of the 122 patients with PD-L1 expression of 1% or greater, and 23 (16·1%, 95% CI 10·5-23·1) of the 143 patients with PD-L1 expression of less than 1%. Grade 3-4 treatment-related adverse events occurred in 48 (18%) of 270 patients-most commonly grade 3 fatigue and diarrhoea, which each occurred in five patients. Three deaths were attributed to treatment (pneumonitis, acute respiratory failure, and cardiovascular failure). INTERPRETATION Nivolumab monotherapy provided meaningful clinical benefit, irrespective of PD-L1 expression, and was associated with an acceptable safety profile in previously treated patients with metastatic or surgically unresectable urothelial carcinoma. FUNDING Bristol-Myers Squibb.

Potent, transient inhibition of BCR-ABL with dasatinib 100 mg daily achieves rapid and durable cytogenetic responses and high transformation-free survival rates in chronic phase chronic myeloid leukemia patients with resistance, suboptimal response or intolerance to imatinib

Background Dasatinib 100 mg once daily achieves intermittent BCR-ABL kinase inhibition and is approved for chronic-phase chronic myeloid leukemia patients resistant or intolerant to imatinib. To better assess durability of response to and tolerability of dasatinib, data from a 2-year minimum follow-up for a dose-optimization study in chronic-phase chronic myeloid leukemia are reported here. Design and Methods In a phase 3 study, 670 chronic-phase chronic myeloid leukemia patients with resistance, intolerance, or suboptimal response to imatinib were randomized to dasatinib 100 mg once-daily, 50 mg twice-daily, 140 mg once-daily, or 70 mg twice-daily. Results Data from a 2-year minimum follow-up demonstrate that dasatinib 100 mg once daily achieves major cytogenetic response and complete cytogenetic response rates comparable to those in the other treatment arms, and reduces the frequency of key side effects. Comparable 2-year progression-free survival and overall survival rates were observed (80% and 91%, respectively, for 100 mg once daily, and 75%–76% and 88%–94%, respectively, in other arms). Complete cytogenetic responses were achieved rapidly, typically by 6 months. In patients treated with dasatinib 100 mg once daily for 6 months without complete cytogenetic response, the likelihood of achieving such a response by 2 years was 50% for patients who had achieved a partial cytogenetic response, and only 8% or less for patients with minor, minimal, or no cytogenetic response. Less than 3% of patients suffered disease transformation to accelerated or blast phase. Conclusions Intermittent kinase inhibition can achieve rapid and durable responses, indistinguishable from those achieved with more continuous inhibition.

Dasatinib-associated major molecular responses in patients with chronic myeloid leukemia in chronic phase following imatinib failure: response dynamics and predictive value.

Dasatinib is a highly potent BCR–ABL inhibitor that has shown durable efficacy in patients with chronic phase (CP) chronic myeloid leukemia (CML) after resistance, suboptimal response, or intolerance to prior imatinib. In patients with CML, BCR–ABL transcript measurement is the most sensitive method for assessing minimal residual disease. Here, molecular responses were analyzed in 1067 patients with CML-CP treated with dasatinib during phase II/III trials. After 3, 6, 12, and 24 months of follow-up, a major molecular response (MMR) was achieved by 12, 22, 35, and 40% of patients, respectively. The 24-month MMR rate was 34% in patients with resistance or suboptimal response to imatinib (n=829) and 63% in imatinib-intolerant patients (n=238). Among patients who had achieved a complete cytogenetic response (CCyR), 72% also achieved MMR. Responses with dasatinib 100 mg once daily were similar to other doses. In landmark analyses, 24-month progression-free survival was higher in patients who had achieved MMR or CCyR at 12 months than in those without MMR or CCyR at 12 months. MMR at 12 months was associated with a longer duration of CCyR. Overall, this analysis shows that dasatinib treatment results in high MMR rates in patients with CML-CP after imatinib failure.

A Phase II, single-arm study of nivolumab in patients with metastatic or unresectable urothelial cancer who have progressed following treatment with a platinum agent

Meeting abstracts Clinical trials in patients with advanced bladder cancer have reported response rates of up to approximately 30% and 60% with single-agent and multi-agent regimens, respectively, and minimal improvements in survival over best supportive care. Guidance on second-line treatment

810ORANDOMIZED, DOSE-RANGING PHASE II TRIAL OF NIVOLUMAB FOR METASTATIC RENAL CELL CARCINOMA (MRCC)

ABSTRACT Aim: Nivolumab, a fully human IgG4 programmed death-1 immune checkpoint inhibitor antibody, has shown encouraging survival and manageable safety in pretreated mRCC patients (pts). This phase II trial (NCT01354431) assesses 3 nivolumab doses in mRCC pts pretreated with targeted VEGF pathway agents. We previously reported no dose response relationship with 3 doses of nivolumab (primary objective). Here we present updated overall survival (OS) and duration of response (DOR) data. Methods: Pts with clear-cell mRCC (≥1 agent targeting VEGF pathway; ≤3 prior systemic therapies) were randomized (blinded 1:1:1) to IV nivolumab 0.3, 2, or 10 mg/kg every 3 weeks until progression or toxicity. The primary objective was to evaluate the dose response relationship measured by progression-free survival (PFS). Secondary objectives included OS, objective response rate (ORR), and safety. Results: All pts (N = 168) received prior systemic therapy (70% received ≥2) including VEGF receptor TKIs (98%), mTOR inhibitors (38%), and immunotherapy (24%). 25% were MSKCC poor risk. PFS and ORR were similar across doses (Table). The median DOR was not reached for 0.3 and 2 mg/kg, and was 22.3 months for 10 mg/kg (Table). Median OS was 18.2 months for 0.3 mg/kg and approximately 25 months for 2 and 10 mg/kg (Table). Across doses, 19/35 responders (54%) had objective responses lasting >12-20+ months. Rates of grade 3-4–related adverse events (AEs) were ≤17% for all doses (Table). There was no grade 3-4 pneumonitis. For 0.3, 2, and 10 mg/kg, 1 (2%), 6 (11%), and 4 (7%) pts, respectively, had treatment-related AEs that led to discontinuation. Conclusions: In this phase II trial nivolumab was associated with encouraging efficacy, with no dose response relationship observed for PFS or ORR. Median OS range was 18.2-25.5 months; longer median OS was reported at 2 and 10 mg/kg. The safety profile of nivolumab was acceptable for all doses with no grade 3-4 pneumonitis observed. Nivolumab 0.3 mg/kg n = 60a 2 mg/kg n = 54 10 mg/kg n = 54 Median PFS, months (80% CI) 2.7 (1.9-3.0) 4.0 (2.8-4.2) 4.2 (2.8-5.5) ORR, n (%) 12 (20) 12 (22) 11 (20) Median DOR, months NR NR (4.2-NR) 22.3 (4.8-NR) Median OS, months (80% CI) 18.2 (16.2-24.0) 25.5 (19.8-28.8) 24.7 (15.3-26.0) Treatment-related AEs, n(%) 44 (75) 36 (67) 42 (78) Grade 3-4 AEs, n (%) 3 (5) 9 (17) 7 (13) aSafety analysis included 59 treated pts. CI, confidence interval; NR, not reached. Disclosure: R.J. Motzer: I have: consulted for the following companies: Pfizer, Merck, Genentech received funding for research from the following companies: Bristol Myers Squibb, Pfizer, GSK, Novartis provided expert testimony for the following companies: Pfizer; B.I. Rini: I have consulted for the following companies: Pfizer, BMS, Merck, GSK; received funding for research from: Pfizer, BMS, Immatics, GSK, Roche, Acceleron; D.F. McDermott: I have received honoraria from and worked as a consultant/ in an advisory capacity to Bristol-Myers Squibb; T. Kuzel: I have received funding for research from Bristol Myers Squibb; M.R. Harrison: I have: • consulted/worked in advisory role to: Novartis, AVEO, Exelixis, Bayer • received honoraria from: Novartis, Prometheus • received funding for research from: BMS, Argos, Exelixis, Pfizer, Exelixis; S. George: I have consulted/worked in advisory role to: Bayer/ Algeta, Novartis, Sanofi and Astellas (Aveo/ Medivation). Received research funding from: GSK; T. Logan: consulted to and received research funding from: Argos,Aveo, BMS, Celgene, GSK, Novartis, Pfizer, Prometheus, Schering Plough, Wyeth research funding from: Entremed, Exelixis, Genetech, GSK, Inmatics, Lilly, MedImmune, Roche, Synta, Threshold; E.R. Plimack: Has received grants and/or personal fees from: BMS, GSK, Dendreon, Astellas, Pfizer, Amgen, Acceleron, MedImmune, Merck, Lilly, AZ; I. Waxman: I am an employee of Bristol Myers Squibb; A. Lambert: I am an employee of and have stock or other ownership interest in BMS; H. Hammers: Has received Honoraria from Ono Pharma USA. All other authors have declared no conflicts of interest.