Yau, T. (Thomas)
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- Association of inflammatory biomarkers with clinical outcomes in nivolumab-treated patients with advanced hepatocellular carcinoma(2020) Yau, T. (Thomas); El-Khoueiry, A. (Anthony); Tang, H.T. (Hao Tracy); Park, J.W. (Joong-Won); Boyd, Z. (Zachary); Shen, Y. (Yun); Furuse, J. (Junji); Wadhawan, S. (Samir); Sangro, B. (Bruno); Neely, J. (Jaclyn); Melero, I. (Ignacio); Tschaika, M. (Marina); Finn, R.S. (Richard S.); Cheng, A.L. (Ann-Lii); Abou-Alfa, G.K. (Ghassan K.)Background & Aims: Nivolumab, a programmed death (PD)-1 (PD-1) inhibitor, led to durable responses, manageable safety, and increased survival in patients with advanced hepatocellular carcinoma (HCC). In our retrospective analysis, we studied the immunobiology and potential associations between biomarkers and outcomes with nivolumab in HCC. Methods: Fresh and archival tumour samples from dose-escalation and dose-expansion phases of the CheckMate 040 trial were analysed by immunohistochemistry and RNA sequencing to assess several inflammatory gene expression signatures, including CD274 (PD-ligand 1 [PD-L1]), CD8A, LAG3, and STAT1. Biomarkers were assessed for association with clinical outcomes (best overall response by blinded independent central review per RECIST v1.1 and overall survival [OS]). Results: Complete or partial tumour responses were observed in PD-L1-positive and PD-L1-negative patients treated with nivolumab monotherapy. Median OS was 28.1 (95% CI 18.2-n.a.) vs. 16.6 months (95% CI 14.2-20.2) for patients with tumour PD-L1 >= 1% vs. <1% (p = 0.03). Increased CD3 and CD8 showed a non-significant trend towards improved OS (both p = 0.08), and macrophage markers were not associated with OS. Tumour PD-1 and PD-L1 expression were associated with improved OS (p = 0.05 and p = 0.03, respectively). An inflammatory gene signature consisting of 4 genes was associated with improved objective response rate (p = 0.05) and OS (p = 0.01). Conclusions: PD-1 and PD-L1 expression, biomarkers of inflammation, and inflammatory gene signatures trended with improved survival and response. While further confirmation within a larger phase III trial is needed to evaluate predictive value of these biomarkers, these exploratory analyses suggest that anti-tumour immune response may play a role in the treatment benefit of nivolumab in HCC. Lay summary: Certain tests may be used to provide a picture of how a tumour is escaping the immune system, allowing it to continue to grow and create more tumours. Therapies such as nivolumab are designed to help the immune system fight the tumour. These tests may be used to determine how effective such therapies will be in the treatment of advanced liver cancer. (C) 2020 European Association for the Study of the Liver. Published by Elsevier B.V.
- Efficacy and Safety of Nivolumab Plus Ipilimumab in Patients With Advanced Hepatocellular Carcinoma Previously Treated With Sorafenib The CheckMate 040 Randomized Clinical Trial(2020) He, A.R. (Aiwu Ruth); Yau, T. (Thomas); El-Khoueiry, A. (Anthony); Knox, J.J. (Jennifer J.); Acosta-Rivera, M. (Mirelis); Wisniewski, T. (Tami); Kang, Y.K. (Yoon-Koo); Shen, Y. (Yun); Lim, H.Y. (Ho-Yeong); Sangro, B. (Bruno); Anderson, J. (Jeffrey); Hsu, C. (Chiun); Kudo, M. (Masatoshi); Neely, J. (Jaclyn); Matilla, A. (Ana); Melero, I. (Ignacio); Kim, T.Y. (Tae-You); El-Rayes, B.F. (Bassel F.); Hou, M.M. (Ming-Mo); Santoro, A. (Armando); Tovoli, F. (Francesco)IMPORTANCE Most patients with hepatocellular carcinoma (HCC) are diagnosed with advanced disease not eligible for potentially curative therapies; therefore, new treatment options are needed. Combining nivolumab with ipilimumab may improve clinical outcomes compared with nivolumab monotherapy. OBJECTIVE To assess efficacy and safety of nivolumab plus ipilimumab in patients with advanced HCC who were previously treated with sorafenib. DESIGN, SETTING, AND PARTICIPANTS CheckMate 040 is a multicenter, open-label, multicohort, phase 1/2 study. In the nivolumab plus ipilimumab cohort, patients were randomized between January 4 and September 26, 2016. Treatment group information was blinded after randomization. Median follow-up was 30.7 months. Data cutoff for this analysis was January 2019. Patients were recruited at 31 centers in 10 countries/territories in Asia, Europe, and North America. Eligible patients had advanced HCC (with/without hepatitis B or C) previously treated with sorafenib. A total of 148 patients were randomized (50 to arm A and 49 each to arms B and C). INTERVENTIONS Patients were randomized 1:1:1 to either nivolumab 1 mg/kg plus ipilimumab 3 mg/kg, administered every 3 weeks (4 doses), followed by nivolumab 240 mg every 2 weeks (arm A); nivolumab 3 mg/kg plus ipilimumab 1 mg/kg, administered every 3 weeks (4 doses), followed by nivolumab 240 mg every 2 weeks (arm B); or nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks (arm C). MAIN OUTCOMES AND MEASURES Coprimary end points were safety, tolerability, and objective response rate. Duration of response was also measured (investigator assessed with the Response Evaluation Criteria in Solid Tumors v1.1). RESULTS Of 148 total participants, 120 were male (81%). Median (IQR) age was 60 (52.5-66.5). At data cutoff (January 2019), the median follow-up was 30.7 months (IQR, 29.9-34.7). Investigator-assessed objective response rate was 32% (95% CI, 20%-47%) in arm A, 27% (95% CI, 15%-41%) in arm B, and 29% (95% CI, 17%-43%) in arm C. Median (range) duration of response was not reached (8.3-33.7+) in arm A and was 15.2 months (4.2-29.9+) in arm B and 21.7 months (2.8-32.7+) in arm C. Any-grade treatment-related adverse events were reported in 46 of 49 patients (94%) in arm A, 35 of 49 patients (71%) in arm B, and 38 of 48 patients (79%) in arm C; there was 1 treatment-related death (arm A; grade 5 pneumonitis). CONCLUSIONS AND RELEVANCE In this randomized clinical trial, nivolumab plus ipilimumab had manageable safety, promising objective response rate, and durable responses. The arm A regimen (4 doses nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks then nivolumab 240 mg every 2 weeks) received accelerated approval in the US based on the results of this study. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT01658878
- Nivolumab in sorafenib-naive and sorafenib-experienced patients with advanced hepatocellular carcinoma: 5-year follow-up from CheckMate 040(Elsevier, 2023) Yau, T. (Thomas); El-Khoueiry, A. (Anthony); Welling, T.H. (T. H.); Choo, S.P. (Su-Pin); Kang, Y.K. (Yoon-Koo); Meyer, T. (Tim); Sangro, B. (Bruno); Hsu, C. (Chiun); Kudo, M. (Masatoshi); Neely, J. (Jaclyn); Yeo, W. (W.); Chopra, A. (A.); Soleymani, S. (S.); Yao, J. (J.); Melero, I. (Ignacio); Trojan, J. (Jörg); Kim, T.Y. (Tae-You); Tschaika, M. (Marina)Background: Patients with advanced hepatocellular carcinoma (aHCC) have a poor prognosis and high mortality. Nivolumab monotherapy demonstrated clinical benefit with an acceptable safety profile in patients with aHCC in the CheckMate 040 study. Five-year follow-up of the sorafenib-naive and sorafenib-experienced cohorts of CheckMate 040 are presented here. Patients and methods: Patients received nivolumab monotherapy at dose levels of 0.1-10.0 mg/kg (dose-escalation phase) or 3 mg/kg (dose-expansion phase) every 2 weeks until disease progression or unacceptable toxicity. Primary endpoints were safety and tolerability (dose escalation), and objective response rate (ORR) by blinded independent central review (BICR) and by investigator per RECIST version 1.1 (dose expansion). Results: Eighty sorafenib-naive and 154 sorafenib-experienced patients were treated. Minimum follow-up in both groups was 60 months. ORR per BICR was 20% (95% CI 12-30) and 14% (95% CI 9-21) in the sorafenib-naive and sorafenib-experienced groups, respectively. Responses occurred regardless of HCC etiology or baseline tumor cell programmed death ligand 1 (PD-L1) expression levels. Median overall survival (OS) was 26.6 months (95% CI 16.6-30.6) and 15.1 months (95% CI 13.0-18.2) in sorafenib-naive and sorafenib-experienced patients, respectively. The 3-year OS rates were 28% in the sorafenib-naive and 20% in the sorafenib-experienced group; 5-year OS rates were 14% and 12%, respectively. No new safety signals were identified; grade 3/4 treatment-related adverse events were observed in 33% and 21% in the sorafenib-naive and sorafenib-experienced patients, respectively. Biomarker analyses showed that baseline PD-L1 expression ≥1% was associated with higher ORR and longer OS compared with PD-L1 <1%. In the sorafenib-naive group, patients with OS ≥3 years exhibited higher baseline CD8 T-cell density compared with those with OS <1 year. Conclusion: With 5 years of follow-up, nivolumab monotherapy continued to provide durable clinical benefit with manageable safety in sorafenib-naive and sorafenib-experienced patients with aHCC.
- Plain language summary of the HIMALAYA study: tremelimumab and durvalumab for unresectable hepatocellular carcinoma (liver cancer)(2023) Lau, G. (George); Sukeepaisarnjaroen, W. (Wattana); Vasilyev, A. (Alexander); Yau, T. (Thomas); Azevedo, S. (Sergio); Galle, P.R. (Peter R.); Tam, V.C. (Vicent C.); Kang, Y.K. (Yoon-Koo); Chan, S.L. (Stephen L.); Thungappa, S.C. (Satheesh Chiradoni); Furuse, J. (Junji); Heurgué, A. (Alexandra); Kate-Kelley, R. (Robin); Sangro, B. (Bruno); Rimassa, L. (Lorenza); Kudo, M. (Masatoshi); Qin, S. (Shukui); Varela, M. (Maria); Ali, S. (Sajid); Dao, T.V. (Tu Van); De-Toni, E.N. (Enrico N.); Kurland, J.F. (John F.); Makowsky, M. (Mallory); Gupta, C. (Charu); Ostapenko, Y. (Yurii); Negro, A. (Alejandra); Mody, K. (Kabir); Cheng, A.L. (Ann-Lii); Breder, V. (Valeriy); Abou-Alfa, G.K. (Ghassan K.)What is this summary about?: This is a summary of results from a phase 3 clinical study called HIMALAYA. HIMALAYA looked at treatment with one dose of a medication called tremelimumab combined with multiple doses of a medication called durvalumab (the STRIDE regimen) or multiple doses of durvalumab alone. These treatments were compared with a medication called sorafenib in participants with unresectable hepatocellular carcinoma (HCC). HCC is a type of liver cancer that is difficult to treat because it is often diagnosed when it is unresectable, meaning it can no longer be removed with surgery. Sorafenib has been the main treatment for unresectable HCC since 2007. However, people who take sorafenib may experience side effects that can reduce their quality of life, so alternative medicines are being trialed. Tremelimumab and durvalumab are types of drugs called immunotherapies, and they both work in different ways to help the body's immune system fight cancer. What were the results of the study?: Participants who took STRIDE lived longer than participants who took sorafenib, whilst participants who took durvalumab alone lived a similar length of time as participants who took sorafenib. Participants who took STRIDE or durvalumab had a lower relative risk of experiencing worsening in their quality of life than participants who took sorafenib. The side effects that participants who received STRIDE or durvalumab experienced were expected for these types of treatments and could mostly be managed. What do the results of the study mean?: Overall, STRIDE is more effective than sorafenib for people with unresectable HCC.
- Nivolumab versus sorafenib in advanced hepatocellular carcinoma (CheckMate 459): a randomised, multicentre, open-label, phase 3 trial(Lancet Pub. Group, 2022) Yau, T. (Thomas); El-Khoueiry, A. (Anthony); Edeline, J. (Julien); Chen, G. (Gong); Park, J.W. (Joong-Won); Wyrwicz, L. (Lucjan); Choo, S.P. (Su-Pin); Wisniewski, T. (Tami); Harding, J.J. (James J.); Schott, E. (Eckart); Begic, D. (Damir); Furuse, J. (Junji); Assenat, E. (Eric); Sieghart, W. (Wolfgang); Kate-Kelley, R. (Robin); Sangro, B. (Bruno); Kudo, M. (Masatoshi); Neely, J. (Jaclyn); Zaucha, R. (Renata); Melero, I. (Ignacio); Rosmorduc, O. (Olivier); Merle, P. (Philippe); Tschaika, M. (Marina); Finn, R.S. (Richard S.); Cheng, A.L. (Ann-Lii); Mathurin, P. (Philippe); Abou-Alfa, G.K. (Ghassan K.)Background: Single-agent nivolumab showed durable responses, manageable safety, and promising survival in patients with advanced hepatocellular carcinoma in the phase 1-2 CheckMate 040 study. We aimed to investigate nivolumab monotherapy compared with sorafenib monotherapy in the first-line setting for patients with advanced hepatocellular carcinoma. Methods: In this randomised, open-label, phase 3 trial done at medical centres across 22 countries and territories in Asia, Australasia, Europe, and North America, patients at least 18 years old with histologically confirmed advanced hepatocellular carcinoma not eligible for, or whose disease had progressed after, surgery or locoregional treatment; with no previous systemic therapy for hepatocellular carcinoma, with Child-Pugh class A and Eastern Cooperative Oncology Group performance status score of 0 or 1, and regardless of viral hepatitis status were randomly assigned (1:1) via an interactive voice response system to receive nivolumab (240 mg intravenously every 2 weeks) or sorafenib (400 mg orally twice daily) until disease progression or unacceptable toxicity. The primary endpoint was overall survival assessed in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study drug. This completed trial is registered with ClinicalTrials.gov, NCT02576509. Findings: Between Jan 11, 2016, and May 24, 2017, 743 patients were randomly assigned to treatment (nivolumab, n=371; sorafenib, n=372). At the primary analysis, the median follow-up for overall survival was 15·2 months (IQR 5·7-28·0) for the nivolumab group and 13·4 months (5·7-25·9) in the sorafenib group. Median overall survival was 16·4 months (95% CI 13·9-18·4) with nivolumab and 14·7 months (11·9-17·2) with sorafenib (hazard ratio 0·85 [95% CI 0·72-1·02]; p=0·075; minimum follow-up 22·8 months); the protocol-defined significance level of p=0·0419 was not reached. The most common grade 3 or worse treatment-related adverse events were palmar-plantar erythrodysaesthesia (1 [<1%] of 367 patients in the nivolumab group vs 52 [14%] of patients in the sorafenib group), aspartate aminotransferase increase (22 [6%] vs 13 [4%]), and hypertension (0 vs 26 [7%]). Serious treatment-related adverse events were reported in 43 (12%) patients receiving nivolumab and 39 (11%) patients receiving sorafenib. Four deaths in the nivolumab group and one death in the sorafenib group were assessed as treatment related. Interpretation: First-line nivolumab treatment did not significantly improve overall survival compared with sorafenib, but clinical activity and a favourable safety profile were observed in patients with advanced hepatocellular carcinoma. Thus, nivolumab might be considered a therapeutic option for patients in whom tyrosine kinase inhibitors and antiangiogenic drugs are contraindicated or have substantial risks.