Asim Amin

A Randomized, Double-Blind, Placebo-Controlled, Phase II Study Comparing the Tolerability and Efficacy of Ipilimumab Administered with or without Prophylactic Budesonide in Patients with Unresectable Stage III or IV Melanoma

Purpose: Diarrhea (with or without colitis) is an immune-related adverse event (irAE) associated with ipilimumab. A randomized, double-blind, placebo-controlled, multicenter, multinational phase II trial was conducted to determine whether prophylactic budesonide (Entocort EC), a nonabsorbed oral steroid, reduced the rate of grade ≥2 diarrhea in ipilimumab-treated patients with advanced melanoma. Experimental Design: Previously treated and treatment-naïve patients (N = 115) with unresectable stage III or IV melanoma received open-label ipilimumab (10 mg/kg every 3 weeks for four doses) with daily blinded budesonide (group A) or placebo (group B) through week 16. The first scheduled tumor evaluation was at week 12; eligible patients received maintenance treatment starting at week 24. Diarrhea was assessed using Common Terminology Criteria for Adverse Events (CTCAE) 3.0. Patients kept a diary describing their bowel habits. Results: Budesonide did not affect the rate of grade ≥2 diarrhea, which occurred in 32.7% and 35.0% of patients in groups A and B, respectively. There were no bowel perforations or treatment-related deaths. Best overall response rates were 12.1% in group A and 15.8% in group B, with a median overall survival of 17.7 and 19.3 months, respectively. Within each group, the disease control rate was higher in patients with grade 3 to 4 irAEs than in patients with grade 0 to 2 irAEs, although many patients with grade 1 to 2 irAEs experienced clinical benefit. Novel patterns of response to ipilimumab were observed. Conclusions: Ipilimumab shows activity in advanced melanoma, with encouraging survival and manageable adverse events. Budesonide should not be used prophylactically for grade ≥2 diarrhea associated with ipilimumab therapy. (Clin Cancer Res 2009;15(17):5591–8)

Nivolumab alone and nivolumab plus ipilimumab in recurrent small-cell lung cancer (CheckMate 032): a multicentre, open-label, phase 1/2 trial

BACKGROUND Treatments for small-cell lung cancer (SCLC) after failure of platinum-based chemotherapy are limited. We assessed safety and activity of nivolumab and nivolumab plus ipilimumab in patients with SCLC who progressed after one or more previous regimens. METHODS The SCLC cohort of this phase 1/2 multicentre, multi-arm, open-label trial was conducted at 23 sites (academic centres and hospitals) in six countries. Eligible patients were 18 years of age or older, had limited-stage or extensive-stage SCLC, and had disease progression after at least one previous platinum-containing regimen. Patients received nivolumab (3 mg/kg bodyweight intravenously) every 2 weeks (given until disease progression or unacceptable toxicity), or nivolumab plus ipilimumab (1 mg/kg plus 1 mg/kg, 1 mg/kg plus 3 mg/kg, or 3 mg/kg plus 1 mg/kg, intravenously) every 3 weeks for four cycles, followed by nivolumab 3 mg/kg every 2 weeks. Patients were either assigned to nivolumab monotherapy or assessed in a dose-escalating safety phase for the nivolumab/ipilimumab combination beginning at nivolumab 1 mg/kg plus ipilimumab 1 mg/kg. Depending on tolerability, patients were then assigned to nivolumab 1 mg/kg plus ipilimumab 3 mg/kg or nivolumab 3 mg/kg plus ipilimumab 1 mg/kg. The primary endpoint was objective response by investigator assessment. All analyses included patients who were enrolled at least 90 days before database lock. This trial is ongoing; here, we report an interim analysis of the SCLC cohort. This study is registered with ClinicalTrials.gov, number NCT01928394. FINDINGS Between Nov 18, 2013, and July 28, 2015, 216 patients were enrolled and treated (98 with nivolumab 3 mg/kg, three with nivolumab 1 mg/kg plus ipilimumab 1 mg/kg, 61 with nivolumab 1 mg/kg plus ipilimumab 3 mg/kg, and 54 with nivolumab 3 mg/kg plus ipilimumab 1 mg/kg). At database lock on Nov 6, 2015, median follow-up for patients continuing in the study (including those who had died or discontinued treatment) was 198·5 days (IQR 163·0-464·0) for nivolumab 3 mg/kg, 302 days (IQR not calculable) for nivolumab 1 mg/kg plus ipilimumab 1 mg/kg, 361·0 days (273·0-470·0) for nivolumab 1 mg/kg plus ipilimumab 3 mg/kg, and 260·5 days (248·0-288·0) for nivolumab 3 mg/kg plus ipilimumab 1 mg/kg. An objective response was achieved in ten (10%) of 98 patients receiving nivolumab 3 mg/kg, one (33%) of three patients receiving nivolumab 1 mg/kg plus ipilimumab 1 mg/kg, 14 (23%) of 61 receiving nivolumab 1 mg/kg plus ipilimumab 3 mg/kg, and ten (19%) of 54 receiving nivolumab 3 mg/kg plus ipilimumab 1 mg/kg. Grade 3 or 4 treatment-related adverse events occurred in 13 (13%) patients in the nivolumab 3 mg/kg cohort, 18 (30%) in the nivolumab 1 mg/kg plus ipilimumab 3 mg/kg cohort, and ten (19%) in the nivolumab 3 mg/kg plus ipilimumab 1 mg/kg cohort; the most commonly reported grade 3 or 4 treatment-related adverse events were increased lipase (none vs 5 [8%] vs none) and diarrhoea (none vs 3 [5%] vs 1 [2%]). No patients in the nivolumab 1 mg/kg plus ipilimumab 1 mg/kg cohort had a grade 3 or 4 treatment-related adverse event. Six (6%) patients in the nivolumab 3 mg/kg group, seven (11%) in the nivolumab 1 mg/kg plus ipilimumab 3 mg/kg group, and four (7%) in the nivolumab 3 mg/kg plus ipilimumab 1 mg/kg group discontinued treatment due to treatment-related adverse events. Two patients who received nivolumab 1 mg/kg plus ipilimumab 3 mg/kg died from treatment-related adverse events (myasthenia gravis and worsening of renal failure), and one patient who received nivolumab 3 mg/kg plus ipilimumab 1 mg/kg died from treatment-related pneumonitis. INTERPRETATION Nivolumab monotherapy and nivolumab plus ipilimumab showed antitumour activity with durable responses and manageable safety profiles in previously treated patients with SCLC. These data suggest a potential new treatment approach for a population of patients with limited treatment options and support the evaluation of nivolumab and nivolumab plus ipilimumab in phase 3 randomised controlled trials in SCLC. FUNDING Bristol-Myers Squibb.

Safety and clinical activity of ipilimumab in melanoma patients with brain metastases: retrospective analysis of data from a phase 2 trial.

Melanoma has a high propensity to metastasize to the brain, and this is often responsible for treatment failure in patients with advanced disease. Melanoma patients with brain metastases are usually excluded from clinical trials because of their expected survival of approximately 5 months. A growing body of evidence suggests that ipilimumab, a human monoclonal antibody that blocks cytotoxic T-lymphocyte antigen-4, has activity against melanoma brain metastases. We conducted a retrospective analysis of data from a phase II study of ipilimumab in advanced melanoma patients. Twelve of 115 patients randomized in the parent trial had stable brain metastases at baseline, as identified by an Independent Review Committee, and were evaluated for efficacy. Two of the 12 patients achieved a partial response and three had stable disease. Both patients with a partial response and one with stable disease were alive at the last follow-up, with survival time of more than 4 years. The median overall survival of the 12 patients was 14 months (range: 2.7–56.4+). An additional four patients with stable brain metastases at baseline were identified by a secondary Independent Review Committee reviewer, and were evaluated for safety. Central nervous system-related adverse events of grade 3–4, specifically cerebral edema and convulsion/seizure, occurred in two of 16 patients. Although the present study is limited by the fact that it is a retrospective analysis of a small number of patients, the results provide further evidence for the safety and efficacy of ipilimumab in melanoma patients with stable brain metastases.

Prevalence of BRCA1 and BRCA2 mutations in Pakistani breast and ovarian cancer patients

Among Asian countries, Pakistan has the highest rates of breast and ovarian cancer. To assess the contribution of the BRCA1 and BRCA2 germ line mutations to these high rates, we conducted the first study of 176 Pakistani breast and ovarian cancer patients, selected on family history and on age of diagnosis. Comprehensive BRCA mutation screening was performed using a range of techniques, including denaturing high‐pressure liquid chromatography, single strand conformational polymorphism analysis and protein truncation test, followed by DNA sequencing. Thirty deleterious germ‐line mutations were identified in the 176 families (17.0%), including 23 in BRCA1 and 7 in BRCA2. Four mutations, 185delAG, 185insA, S1503X and R1835X, were recurrent; these accounted for 52% of all identified BRCA1 mutations. Haplotype analyses suggested founder effects for 3 of these. The prevalence of BRCA1 or BRCA2 mutations was 42.8% for families with multiple cases of breast cancer, and was 50.0% for the breast/ovarian cancer families. The prevalence of mutations was 11.9% for single cases of early‐onset breast cancer (≤30 years) and was 9.0% for single cases of early‐onset ovarian cancer (≤45 years). Our findings show that BRCA mutations account for a substantial proportion of hereditary breast/ovarian cancer and early‐onset breast and ovarian cancer cases in Pakistan.

Safety and Efficacy of Nivolumab in Combination With Ipilimumab in Metastatic Renal Cell Carcinoma: The CheckMate 016 Study

Purpose Combination treatment with immune checkpoint inhibitors has shown enhanced antitumor activity compared with monotherapy in tumor types such as melanoma. The open-label, parallel-cohort, dose-escalation, phase I CheckMate 016 study evaluated the efficacy and safety of nivolumab plus ipilimumab in combination, and nivolumab plus a tyrosine kinase inhibitor in metastatic renal cell carcinoma (mRCC). Safety and efficacy results from the nivolumab plus ipilimumab arms of the study are presented. Patients and Methods Patients with mRCC received intravenous nivolumab 3 mg/kg plus ipilimumab 1 mg/kg (N3I1), nivolumab 1 mg/kg plus ipilimumab 3 mg/kg (N1I3), or nivolumab 3 mg/kg plus ipilimumab 3 mg/kg (N3I3) every 3 weeks for four doses followed by nivolumab monotherapy 3 mg/kg every 2 weeks until progression or toxicity. End points included safety (primary), objective response rate, and overall survival (OS). Results All patients in the N3I3 arm (n = 6) were censored at the time of analysis as a result of dose-limiting toxicity or other reasons. Forty-seven patients were treated in both the N3I1 and the N1I3 arm, and baseline patient characteristics were balanced between arms. Grade 3 to 4 treatment-related adverse events were reported in 38.3% and 61.7% of the patients in the N3I1 and N1I3 arms, respectively. At a median follow-up of 22.3 months, the confirmed objective response rate was 40.4% in both arms, with ongoing responses in 42.1% and 36.8% of patients in the N3I1 and N1I3 arms, respectively. The 2-year OS was 67.3% and 69.6% in the N3I1 and N1I3 arms, respectively. Conclusion Nivolumab plus ipilimumab therapy demonstrated manageable safety, notable antitumor activity, and durable responses with promising OS in patients with mRCC.

1050OPHASE I STUDY OF NIVOLUMAB IN COMBINATION WITH IPILIMUMAB IN METASTATIC RENAL CELL CARCINOMA (MRCC)

ABSTRACT Aim: Nivolumab, a fully human IgG4 PD-1 immune checkpoint inhibitor antibody, has shown durable responses and encouraging overall survival (OS) data in mRCC. IPI, a fully human monoclonal antibody to CTLA-4, improved OS in melanoma and has antitumor activity in mRCC. The combination of these agents showed encouraging antitumor activity and an acceptable safety profile in advanced melanoma. We report preliminary results of this combination in mRCC. Methods: Patients (pts) with mRCC were randomized to nivolumab 3 mg/kg + IPI 1 mg/kg (arm N3 + I1) or nivolumab 1 mg/kg + IPI 3 mg/kg (N1 + I3) IV every 3 wk for 4 doses then nivolumab 3 mg/kg IV every 2 wk until progression/toxicity (protocol-defined post-progression treatment allowed). The primary objective was to assess safety; secondary objective was to assess efficacy (RECIST 1.1). Results: 21 and 23 pts were randomized to the N3 + I1 and N1 + I3 arms, respectively. Most pts (n = 35; 80%) had prior systemic therapy (N3 + I1: 17; N1 + I3: 18). Treatment-related adverse events (AEs) were seen in 39 pts (89%); 8 pts (18%; N3 + I1: 2; N1 + I3: 6) discontinued due to related AEs. Grade 3-4-related AEs occurred in 20 pts (46%; N3 + I1: 6; N1 + I3: 14), most commonly ↑ lipase (21%, n = 9), ↑ ALT (14%, n = 6), diarrhea (9%, n = 4), and ↑ AST (7%, n = 3). No grade 3-4 pneumonitis was seen. Objective response rate (ORR) was 43% (N3 + I1) and 48% (N1 + I3); median duration of response (DOR) was 31.1 wk (7 ongoing) in N3 + I1 and not reached (9 ongoing) in N1 + I3 (Table). Responses occurred by first tumor assessment (wk 6) in 44% of pts in the N3 + I1 arm and 55% of pts in the N1 + I3 arm. Stable disease (SD) as best overall response was seen in 5 (24%) (N3 + I1) and 8 (35%) (N1 + I3) pts. Arm N3 + I1 n = 21 Arm N1 + I3 n = 23 ORR, n (%) 9 (43) 11 (48) SD, n (%) 5 (24) 8 (35) DOR, range (wk) 4.1+ - 42.1+ 12.1+ - 35.1 + Median progression-free survival, wk (95% CI) 36.6 (6.0, ) 38.3 (18.3, ) CI, confidence interval Conclusions: Nivolumab + IPI showed acceptable safety and encouraging antitumor activity in mRCC, with most responses ongoing. Studies are ongoing to explore this combination in a Phase III trial. Disclosure: H. Hammers: Has received Honoraria from Ono Pharma USA; E.R. Plimack: Has received grants and/or personal fees from: BMS, GSK, Dendreon, Astellas, Pfizer, Amgen, Acceleron, MedImmune, Merck, Lilly, AZ; M. Ernstoff: I have received funding for research from Bristol Myers Squibb, and hold stocks in BMS; 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; M. Voss: Dr. Voss reports grants from BMS, outside the submitted work; P. Sharma: I have served as a consultant for: MedImmune, GSK, BMS, Jounce, Janssen, Pfizer, and Helsinn Therapeutics. I also own stock in Jounce; D. Heng: I have worked as a consultant for the following: BMS, Bayer, Pfizer, Novartis; Y. Shen: I am an employee of Bristol-Myers Squibb, and immediate family member employed at BM.; J. Kurland: I am an employee of and have stock or other ownership interest in BMS; P. Gagnier: I am an employee of and have stock or other ownership interest in BMS; A. Amin: I have worked as a consultant/ in an advisory capacity to: Bristol Myers Squibb. I have received Honoraria from: Bristol Myers Squibb. All other authors have declared no conflicts of interest.

Prolonged Survival with Personalized Immunotherapy (AGS-003) in Combination with Sunitinib in Unfavorable Risk Metastatic RCC (mRCC)

357 Background: During the past decade, VEGF targeted therapies have become standard treatment for advanced RCC. While targeted therapies have yielded improved efficacy, durable remissions are rare, particularly in unfavorable risk subjects. In a pivotal trial, treatment with sunitinib yielded a median OS of 5.3 months for poor risk and 20.7 months for intermediate risk subjects. Similarly, the validation dataset for the Heng risk model (ASCO 2011) revealed a median OS of 8 months for poor risk and 21 months for intermediate risk patients treated with VEGF targeted therapies. Durable responses have been elicited by immunotherapy in RCC. We report an update on patients with mRCC treated with combined VEGF TKI (sunitinib) plus autologous immunotherapy (AGS-003). METHODS In this phase II study, subjects with unfavorable prognosis mRCC (poor and intermediate risk) were treated with sunitinib plus autologous dendritic cell immunotherapy (AGS-003). Treatment consisted of standard 6-week cycles of sunitinib plus AGS-003 (once every 3 weeks x5 doses, then every 12 weeks until PD). Tumor response was assessed per RECIST and subjects were followed for PFS and OS. Immune monitoring samples were taken at screening, baseline and after the third and fifth doses of AGS-003 and analyzed by multiparametric flow cytometry. RESULTS 21 subjects were treated. As previously reported, the median overall PFS was 11.2 months and the final median OS was 30.2 months. When analyzed by baseline Heng risk status, the median PFS was 19.4 months for intermediate (n=11) and 5.8 months for subjects with poor risk features (n=10) at baseline. The median OS is 39.5+ months for intermediate and 9.1 months for subjects with poor risk. CONCLUSIONS The results from this single-arm phase II study represent a near doubling of expected PFS and OS for unfavorable risk subjects treated with AGS-003 plus sunitinib. Updated survival and immunologic findings will be presented, as 8 of 21 subjects are still alive and continue to be followed. These results support the ongoing phase III ADAPT study, which is designed to validate these encouraging clinical and immunologic findings. CLINICAL TRIAL INFORMATION NCT00678119.

Ipilimumab in treatment-naive and previously treated patients with metastatic melanoma: retrospective analysis of efficacy and safety data from a phase II trial.

Ipilimumab is a fully human, monoclonal antibody that blocks cytotoxic T-lymphocyte antigen-4 to potentiate antitumor T-cell responses. In a phase III trial, ipilimumab monotherapy at 3 mg/kg demonstrated an improvement in overall survival (OS) in patients with previously treated, metastatic melanoma. Here, we conducted a retrospective analysis of efficacy and safety data from a phase II clinical trial in which treatment-naive and previously treated patients with metastatic melanoma received ipilimumab at an investigational dose of 10 mg/kg. Patients were randomized 1:1 to receive oral budesonide or placebo, and ipilimumab at 10 mg/kg every 3 weeks for 4 doses, to determine whether prophylactic budesonide affected the rate of grade ≥2 diarrhea. One hundred fifteen patients were randomized and treated: 62 had received prior systemic therapy for metastatic disease and 53 had not. No efficacy endpoint was affected by budesonide therapy, and the efficacy data were therefore pooled for budesonide and placebo subgroups. Median OS was 30.5 months for treatment-naive patients who received ipilimumab, with survival rates of 69.4%, 62.9%, and 56.9% at 12, 18, and 24 months. In previously treated patients who received ipilimumab, median OS was 13.6 months, with survival rates of 50.0%, 37.7%, and 28.5% at 12, 18, and 24 months. There were no meaningful differences in the number of objective responses or rate of grade ≥2 diarrhea between groups. These retrospective analyses are the first to provide survival data for ipilimumab in treatment-naive and previously treated patients within the same clinical trial.

Phase II study combining personalized dendritic cell (DC)-based therapy, AGS-003, with sunitinib in metastatic renal cell carcinoma (mRCC).

348 Background: AGS-003 is a personalized immunotherapy that employs autologous DCs co-electroporated with the subjects amplified tumor mRNA and synthetic CD40L RNA. Based on previous results with single agent AGS-003 and acceptance of TKIs as the standard of care for mRCC, AGS-003 was evaluated in combination with sunitinib as initial treatment for advanced RCC. Progression free survival (PFS) results for the combination have been previously presented and show improvement compared to historical data in unfavorable risk patients treated with sunitinib alone. METHODS AGS-003-006 is an open label phase II study that included subjects with newly diagnosed, metastatic clear cell RCC. Tumor was harvested by nephrectomy or metastasectomy for mRNA. Autologous monocytes were collected by leukapheresis for the production of DCs. Subjects subsequently received sunitinib (4wks on, 2wks off) combined with AGS-003 (every 3wks X 5 doses, then every 12wks) until progression. AGS-003 doses consisted of 1 X 107 cells administered by intradermal injection to a single lymph node basin. Response was evaluated per RECIST and subjects followed for PFS and OS. Immune responses were assessed at baseline and after five AGS-003 doses using multiparametric flow cytometry. RESULTS 25 subjects were enrolled; 21 received treatment. The median PFS from registration for subjects receiving at least one dose of AGS-003 was 11.9 months. For subjects with 1-2 MSKCC risk factors (intermediate risk), PFS = 14.9 months and for subjects with 3-4 MSKCC risk factors (poor risk), PFS = 6.0 months. Median OS from registration has not been reached. Median OS for poor risk subjects = 7.9 months. Median OS for intermediate risk subjects has yet to be reached, but will exceed 28.3+ months. CONCLUSIONS AGS-003 is well tolerated with no immunotherapy-related SAEs or grade 3/4 AEs reported. Interim data indicate that AGS-003 in combination with sunitinib yields a median OS higher than that reported for sunitinib alone in unfavorable risk subjects. Updated OS and immune response correlates will be presented. These results support the ongoing, randomized phase III ADAPT study.

1052PDNIVOLUMAB (N) (ANTI-PD-1; BMS-936558, ONO-4538) IN COMBINATION WITH SUNITINIB (S) OR PAZOPANIB (P) IN PATIENTS (PTS) WITH METASTATIC RENAL CELL CARCINOMA (MRCC)

ABSTRACT Aim: Antiangiogenic agents S and P are standard of care in mRCC, but effects are not durable. N, a fully human IgG4 PD-1 immune checkpoint inhibitor antibody, has clinical activity in mRCC. VEGF TKIs have been shown to suppress Tregs and MDSCs making the immune environment more conducive for T cell-mediated antitumor activity. Combining VEGF TKIs with positive immune modulation may result in greater and more durable therapeutic benefit. We report preliminary results of a phase I trial of N in combination with S or P in mRCC. Methods: mRCC pts received N in combination with S (50 mg, 4 wk on/2 wk off; arm S) or P (800 mg daily; arm P) until progression/unacceptable toxicity. Starting dose of N was 2 mg/kg IV every 3 wk (N2), with planned escalation to 5 mg/kg IV every 3 wk (N5). Based on tolerability, arm S N5 was expanded to treatment-naive pts. Primary objectives were safety/tolerability and determination of maximum tolerated dose (MTD) for the combinations; secondary objective was antitumor activity. Results: 7 pts each were treated on arms S N2 and N5. No dose-limiting toxicities (DLTs) were observed and MTD was not reached; thus N5 was expanded by 19 pts (total n = 33). Arm P had 20 pts at N2; 4 DLTs (elevated ALT/AST [n = 3], fatigue [n = 1]) were observed, leading to closure of the arm. Grade 3-4-related adverse events (AEs) were observed in 27/33 pts (82%) in arm S and 14/20 pts (70%) in arm P. Most common related grade 3-4 AEs were elevated ALT and hypertension (18% each), hyponatremia and lymphocyte count decreased (15% each) in arm S, and elevated ALT and AST, and diarrhea (20% each) and fatigue (15%) in arm P. Grade 3 pneumonitis occurred in 1 pt (arm S, N5). Grade 3-4-related AEs led to discontinuation in 10/33 pts (30%; 2 N2, 8 N5) in arm S and 4/20 pts (20%) in arm P. Objective response rate was 52% (17/33) in arm S and 45% (9/20) in arm P. Responses occurred by first assessment (6 wk) in 41% (arm S) and 56% (arm P) of pts. Duration of response (wk) was 18.1-80+ in arm S and 12.1-90.1+ in arm P. Progression-free survival rate at 24 wk was 79% for arm S and 55% for arm P. Conclusions: N plus S showed encouraging antitumor activity and a manageable safety profile in pts with mRCC. Arm P was closed due to DLTs. Disclosure: A. Amin: I have worked as a consultant/ in an advisory capacity to: Bristol Myers Squibb I have received Honoraria from: Bristol Myers Squibb; E.R. Plimack: I have received grants and/or personal fees from: BMS, GSK, Dendreon, Astellas, Pfizer, Amgen, Acceleron, MedImmune, Merck, Lilly, AZ; M. Ernstoff: I have received funding for research from Bristol Myers Squibb, and hold stocks in BMS; 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; M. Voss: Dr. Voss reports grants from BMS, outside the submitted work; P. Sharma: I have served as a consultant for: MedImmune, GSK, BMS, Jounce, Janssen, Pfizer, and Helsinn Therapeutics. I also own stock in Jounce; D. Heng: Has worked as a consultant for the following: BMS, Bayer, Pfizer, Novartis; Y. Shen: I am an employee of Bristol-Myers Squibb, and immediate family member employed at BMS; J. Kurland: I am an employee of and have stock or other ownership interest in BMS; P. Gagnier: 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.