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Safety Profile of Nivolumab Plus Ipilimumab Combination Therapy in Advanced Hepatocellular Carcinoma

This study evaluates the safety profile of nivolumab plus ipilimumab combination therapy in patients with advanced hepatocellular carcinoma (HCC), focusing on hepatic safety. The results show that the combination therapy leads to durable responses in sorafenib-treated HCC patients.

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Safety Profile of Nivolumab Plus Ipilimumab Combination Therapy in Advanced Hepatocellular Carcinoma

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  1. Safety Profile of Nivolumab Plus Ipilimumab Combination Therapy in Patients With Advanced Hepatocellular Carcinoma in the CheckMate 040 Study Anthony B. El-Khoueiry,1 Chiun Hsu,2 Yoon-Koo Kang,3 Tae-You Kim,4 Armando Santoro,5 Bruno Sangro,6Ignacio Melero,7 Masatoshi Kudo,8 Ming-Mo Hou,9 Ana Matilla,10 Francesco Tovoli,11 Jennifer J. Knox,12 Aiwu Ruth He,13 Bassel El-Rayes,14 Mirelis Acosta-Rivera,15 Jaclyn Neely,16 Yun Shen,16 Jeffrey Anderson,16 Thomas Yau17 1USC Norris Comprehensive Cancer Center, Los Angeles, CA, USA ; 2National Taiwan University Hospital, Taipei, Taiwan; 3Asan Medical Center, University of Ulsan, Seoul, South Korea; 4Seoul National University, Seoul, South Korea; 5Istituto Clinico Humanitas, Rozzano, Italy; 6Clinica Universidad de Navarra and CIBEREHD, Pamplona, Spain; 7Universidad de Navarra, Pamplona, Spain; 8Kindai University Faculty of Medicine, Osaka, Japan; 9Chang Gung Memorial Hospital, Taipei, Taiwan; 10Servicio de Digestivo, Hospital General Universitario Gregorio Marañón, Madrid, Spain; 11Department of Medical & Surgical Sciences, University of Bologna, Bologna, Italy; 12Princess Margaret Cancer Centre, Toronto, Canada; 13Georgetown University Hospital, Washington, DC, USA; 14Emory University Winship Cancer Institute, Atlanta, GA, USA; 15Fundacion de Investigacion, San Juan, Puerto Rico; 16Bristol- Myers Squibb, Princeton, NJ, USA; 17University of Hong Kong, Hong Kong, China

  2. Introduction • Nivolumab monotherapy is approved in several countries for sorafenib-treated patients with HCC based on data from the CheckMate 040 study (NCT01658878), which reported an ORR of 14% and median OS of 15 months1 • The clinical efficacy observed with nivolumab monotherapy has led to investigation of nivolumab combination therapy to achieve durable responses in higher proportions of patients • The combination of nivolumab, a PD-1 checkpoint inhibitor, and ipilimumab, a CTLA-4 immune checkpoint inhibitor, promotes synergistic antitumor immune response using distinct but complementary mechanisms2 and has shown durable responses in other tumor types (RCC, NSCLC, melanoma, and MSI-H/dMMR CRC)3-6 • The first report on the combination of nivolumab plus ipilimumab in sorafenib-treated patients with advanced HCC indicated that the combination led to robust and durable responses in sorafenib-treated patients7 • Here we report results for the nivolumab plus ipilimumab combination in sorafenib-treated patients with advanced HCC, with a focus on hepatic safety CTLA-4, cytotoxic T-lymphocyte–associated protein 4; HCC, hepatocellular carcinoma; MSI-H/dMMR CRC, microsatellite instability–high/DNA mismatch repair–deficient metastatic colorectal cancer; NSCLC, non-small cell lung cancer; ORR, objective response rate; PD-1, programmed death-1; RCC, renal cell carcinoma. 1. El-Khoueiry AB, et al. American Society of Clinical Oncology – Gastrointestinal Cancers Symposium 2018; January 18–20, 2018; San Francisco, CA. Abstract 475; 2. Das R, et al. J Immunol 2015;194:950–959; 3. Hellmann MD, et al. Lancet Oncol 2017;18:31–41; 4. Hodi FS, et al. Lancet Oncol 2016;17:1558–1568; 5. Motzer RJ, et al. N Engl J Med 2018;378:1277–1290; 6. Overman MJ, et al. J Clin Oncol 2018;36:773–779; 7. Yau T, et al. American Society of Clinical Oncology Annual Meeting 2019; Poster 4012.

  3. CheckMate 040 Nivolumab Plus Ipilimumab Combination Cohort Study Design Study endpoints Primary Arm A: • Safety and tolerability NIVO1 + IPI3 • Key eligibility criteria • Advanced HCC, sorafenib treated, intolerant, or progressors • Uninfected, HCV infected, or HBV infected • CP score A5–A6 • ECOG PS 0–1 using NCI CTCAE v4.0 Q3W × 4 Nivolumab • ORR and DOR based on 240 mg IV Unacceptable investigator assessmenta Q2W toxicity flat dose Arm B: Secondary or R NIVO3 + IPI1 disease 1:1:1 • DCR • TTP Q3W × 4 progression • PFS • TTR • OS Other Arm C: NIVO3 Q2W + • BOR and ORR based on IPI1 Q6W BICR-assessed tumor responsea BICR, blinded independent central review; BOR, best overall response; CP, Child-Pugh; DCR, disease control rate; DOR, duration of response; ECOG PS, Eastern Cooperative Oncology Group performance status; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; IPI1, ipilimumab 1 mg/kg; IPI3, ipilimumab 3 mg/kg; IV, intravenous; NCI CTCAE, National Cancer Institute Common Terminology Criteria for Adverse Events; NIVO1, nivolumab 1 mg/kg; NIVO3, nivolumab 3 mg/kg; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; Q2W, every 2 weeks; Q3W, every 3 weeks; Q6W, every 6 weeks; R, randomization; RECIST, Response Evaluation Criteria in Solid Tumors; TTP, time to progression; TTR, time to response. aUsing RECIST v1.1. Minimum follow-up at time of data cutoff: 28 months.

  4. Patient Demographics and Baseline Characteristics AFP, alpha-fetoprotein; BCLC, Barcelona Clinic Liver Cancer. Yau T, et al. Presented at the American Society of Clinical Oncology Annual Meeting 2019; May 31–June 4, 2019; Chicago, IL. Poster 4012.

  5. Patient Exposure and Disposition • Disease progression was the most common reason for treatment discontinuation, with the lowest rate of discontinuation due to disease progression observed in arm A (51%) CI, confidence interval; NA, not applicable. Yau T, et al. Presented at the American Society of Clinical Oncology Annual Meeting 2019; May 31–June 4, 2019; Chicago, IL. Poster 4012.

  6. Efficacy Results 100 Arm A mOS (95% CI) = 22.8 mo (9.4–NE) 90 Arm B mOS (95% CI) = 12.5 mo (7.6–16.4) • Similar ORR, DCR, and DOR were observed across treatment arms, with consistently high ORR (> 30%) achieved in all treatment arms • The greatest survival benefit was observed in arm A, with a median OS of 22.8 months and the highest OS rate of 44% through 30 months Arm C mOS (95% CI) = 12.7 mo (7.4–33.0) 80 70 60 Overall survival (%) 50 40 30 20 10 0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 Time (months) CR, complete response; NE, not estimable; PD, progressive disease; PR, partial response; SD, stable disease. Yau T, et al. Presented at the American Society of Clinical Oncology Annual Meeting 2019; May 31–June 4, 2019; Chicago, IL. Poster 4012.

  7. Summary of TRAEs by Category • Although rates of any-grade TRAEs were higher in arm A, the types of TRAEs observed were similar across treatment arms • No new safety signals were observed, and most TRAEs were manageable and reversible • Serious TRAEs were reported in 11 patients (22%) in arm A, 9 patients (18%) in arm B, and 7 patients (15%) in arm C • One serious hepatobiliary disorder was reported in arm A (drug-induced liver injury); 3 serious hepatic investigations were reported (elevated AST in arm A; elevated AST and elevated ALT in arm B) TRAE, treatment-related adverse event. Listed in the table are any-grade TRAEs that occurred in ≥10% of patients in any arm and grade 3/4 TRAEs that occurred in ≥5% of patients in any arm. Includes events reported between first dose and 30 days after last dose of study therapy.

  8. Hepatic Investigations and Hepatobiliary TRAEs • Increased AST and ALT were the most common abnormalities in hepatic investigations in all treatment arms, and the vast majority were without concomitant bilirubin elevation • A total of 5 patients had hepatobiliary TRAEs (3 in arm A and 1 each in arms B and C) • Four patients had hepatic TRAEs leading to discontinuation: 2 in arm A (ALT increased and drug-induced liver injuryb) and 2 in arm B (AST increased) ALT, alanine aminotransferase; AST, aspartate aminotransferase; ULN, upper limit of normal. aTotal includes all investigations; individual hepatic investigations are reported. bDrug induced liver injury was reported per investigator; however, drug-induced liver injury did not meet protocol-specified definition of elevated bilirubin (> 2× ULN) and ALT (> 10× ULN).

  9. Summary of Select TRAEs • Hepatic select TRAEs were reported in 13 patients (27%) in arm A, 12 patients (24%) in arm B, and 8 patients (17%) in arm C • Systemic corticosteroids were used to treat select TRAEs in 25 patients (51%) in arm A, 12 patients (24%) in arm B, and 11 patients (23%) in arm C Select TRAEs are events with a potential inflammatory mechanism requiring more frequent monitoring and/or unique intervention such as immunosuppressants and/or endocrine replacement therapy.

  10. Summary of IMAEs • Higher rates of IMAEs were observed in arm A compared with arms B and C, with similar rates of AEs observed in arms B and C • The majority of IMAEs resolved across treatment arms, including hepatic IMAEs; in arm A, 90% of patients had resolution of hepatic IMAEs • Of the 10 patients in arm A who had a hepatic IMAE, 7 received glucocorticoids (≥ 40 mg of prednisone per day or equivalent) for a median of 2 weeks (range, 0.4–147.6 weeks) • No patients experienced a recurrence of any category of IMAE after rechallenge with nivolumab or ipilimumab AE, adverse event; IMAE, immune-mediated adverse event. Yau T, et al. Presented at the American Society of Clinical Oncology Annual Meeting 2019; May 31–June 4, 2019; Chicago, IL. Poster 4012.

  11. Time to Onset and Resolution of Select TRAEs Patients,n/n (%) Arm A (NIVO1/IPI3 Q3W)a,b Patients,n/n (%) Arm B (NIVO3/IPI1 Q3W)a,c Patients,n/n (%) Arm C (NIVO3 Q2W/IPI1 Q6W)a,d Skin onset 3.1 0.1–29.1 5.3 0.1–108.3 4.4 0.1–55.6 63.1 0.6–149.1+ 12.9 0.4–139.0+ 0.1–143.3+ 123.1 Skin resolution 16/29 (55) 16/24 (67) 11/21 (52) Endocrine onset 12.2 5.9–70.3 6.7 5.9–122.1 11.1 4.0–120.1 Endocrine resolution 5/16 (31) 3/9 (33) 1.9–145.6+ 6.1–126.1+ 6.3+ –153.1+ 3/10 (30) Hepatic onset 5.3 2.9–16.0 4.6 3.0–15.0 4.1 2.0–25.9 Hepatic resolution 12/13 (92) 3.1 0.4–58.7 1 1/12 (92) 4.1 0.6–51.0+ 12.0 3.0–19.1 7/8 (88) Gastrointestinal 7.3 0.3–90.1 6.3 0.3–80.0 2.4 0.1–33.4 onset Gastrointestinal 13/13 (100) 4.3 0.6–76.1 7/7 (100) 2.4 0.3–4.3 22.3 0.6–141.3+ 5/8 (63) resolution Pulmonary onset 21.5 5.4–76.0 Pulmonary resolution 4/4 (100) 3.2 2.4–9.0 0/0 0/0 1.0 0 20 40 60 80 100 120 140 160 0 20 40 60 80 100 120 140 160 0 20 40 60 80 100 120 140 160 Weeks Weeks Weeks • In general, select TRAEs occurred early during treatment; time to onset for hepatic select TRAEs ranged from 4.1 to 5.3 weeks • The vast majority of select TRAEs resolved, with the exception of endocrine events; across all treatment arms, ≈90% of hepatic select TRAEs resolved TTO, time to onset; TTR, time to resolution. aTime to onset measured from treatment initiation and time to resolution measured from select TRAE onset; bIn arm A, 4 patients had hypersensitivity/infusion reactions; all events resolved (median TTO: 10.3 weeks [range: 0.1–21.1]; median TTR: 0.4 week [range: 0.1–9.1]); cIn arm B, 1 patient had a renal select TRAE (TTO: 15.0 weeks; TTR: 6.0 weeks), and 1 patient had a hypersensitivity/infusion reaction (TTO: 61.4 weeks; TTR: 0.1 week); dIn arm C, 1 patient had an unresolved renal select TRAE (TTO: 34.3 weeks), and 1 patient had a hypersensitivity/infusion reaction (TTO: 2.0 weeks; TTR: 1.0 week).

  12. Conclusions • The combination of nivolumab plus ipilimumab led to clinically meaningful responses in sorafenib-treated patients, with ORR > 30% in each treatment arm • Patients in arm A had a median OS of 22.8 months and the highest OS rate of 44% through 30 months • Nivolumab plus ipilimumab had a manageable safety profile in this patient population with advanced HCC • No new safety signals were seen with the addition of ipilimumab in any treatment arms • The safety profile of nivolumab plus ipilimumab in HCC was consistent with that observed in studies of other tumor types1-5 • Higher rates of TRAEs, IMAEs, and discontinuation due to study drug toxicity were observed in arm A compared with arms B and C, with similar rates of AEs observed in arms B and C • The majority of select TRAEs resolved across treatment arms with steroid use; ≈90% of patients in each arm had resolution of hepatic select TRAEs • The favorable benefit/risk profile observed with nivolumab plus ipilimumab warrants further investigation • The CheckMate 9DW phase 3 study of this combination in patients with HCC is planned (NCT04039607) 1. Hellmann MD, et al. Lancet Oncol 2017;18:31–41; 2. Hodi FS, et al. Lancet Oncol 2016;17:1558–1568; 3. Motzer RJ, et al. N Engl J Med 2018;378:1277–1290; 4. Hammers HJ, et al. J Clin Oncol 2017;35:3851–3858; 5. Sznol M, et al. J Clin Oncol 2017;35:3815–3822.

  13. Acknowledgments • The patients and families, as well as the investigators and participating study teams, who made this study possible • Dako, an Agilent Technologies, Inc. company, for collaborative development of the PD-L1 IHC 28-8 pharmDx assay • Bristol-Myers Squibb (Princeton, NJ) and ONO Pharmaceutical Company Ltd. (Osaka, Japan) • The study was supported by Bristol-Myers Squibb and ONO Pharmaceutical Co. Ltd. • All authors contributed to and approved the presentation; professional medical writing and editorial assistance was provided by Andrea L. Hammons, PhD, of Parexel International, funded by Bristol-Myers Squibb

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