Kudo, M. (Masatoshi)
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- CheckMate 040 cohort 5: A phase I/II study of nivolumab in patients with advanced hepatocellular carcinoma and Child-Pugh B cirrhosis(Elsevier BV, 2021) Di-Costanzo, F. (Francesco); Numata, K. (Kazushi); El-Khoueiry, A. (Anthony); Acosta-Rivera, M. (Mirelis); Itoh, Y. (Yoshito); Choo, S.P. (Su-Pin); Kuromatsu, R. (Ryoko); Wisniewski, T. (Tami); Shen, Y. (Yun); Reig, M. (Maria); Sangro, B. (Bruno); Kudo, M. (Masatoshi); Neely, J. (Jaclyn); Matilla, A. (Ana); Melero, I. (Ignacio); Crysler, O. (Oxana); El-Rayes, B.F. (Bassel F.); Tschaika, M. (Marina); Cubillo-Gracián, A. (Antonio); Santoro, A. (Armando)Background & Aims: Patients with advanced hepatocellular carcinoma (aHCC) and Child-Pugh B liver function are often excluded from clinical trials. In previous studies, overall survival for these patients treated with sorafenib was 3–5 months; thus, new treatments are needed. Nivolumab, alone or in combination with ipilimumab, is conditionally approved in the United States to treat patients with aHCC who previously received sorafenib. We describe nivolumab monotherapy outcomes in patients with Child-Pugh B status. Methods: This phase I/II, open-label, non-comparative, multicentre trial (27 centres) included patients with Child-Pugh B (B7–B8) aHCC. Patients received intravenous nivolumab 240 mg every 2 weeks until unacceptable toxicity or disease progression. Primary endpoints were objective response rate (ORR) by investigator assessment (using Response Evaluation Criteria in Solid Tumors v1.1) and duration of response. Safety was assessed using National Cancer Institute Common Terminology Criteria for Adverse Events v4.0. Results: Twenty-five sorafenib-naive and 24 sorafenib-treated patients began treatment between November 2016 and October 2017 (median follow-up, 16.3 months). Investigatorassessed ORR was 12% (95% CI 5–25%) with 6 patients responding; disease control rate was 55% (95% CI 40–69%). Median time to response was 2.7 months (interquartile range, 1.4–4.2), and median duration of response was 9.9 months (95% CI 9.7–9.9). Treatment-related adverse events (TRAEs) were reported in 25 patients (51%) and led to discontinuation in 2 patients (4%). The most frequent grade 3/4 TRAEs were hypertransaminasemia (n = 2), amylase increase (n = 2), and aspartate aminotransferase increase (n = 2). The safety of nivolumab was comparable to that in patients with Child-Pugh A aHCC. Conclusions: Nivolumab showed clinical activity and favourable safety with manageable toxicities, suggesting it could be suitable for patients with Child-Pugh B aHCC. Lay summary: In patients with advanced hepatocellular carcinoma, almost all systemic therapies require very good liver function, i.e. Child-Pugh A status. The evidence from this study suggests that nivolumab shows clinical activity and an acceptable safety profile in patients with hepatocellular carcinoma with Child-Pugh B status who have mild to moderate impairment of liver function or liver decompensation that might rule out other therapies. Further studies are warranted to assess the safety and efficacy of nivolumab in this patient population.
- 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); Yeong Lim, H. (Ho); 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.
- Prediction of survival among patients receiving transarterial chemoembolization for hepatocellular carcinoma: A response-based approach(American Association for the Study of Liver Diseases, 2020) Ottaviani, D. (Diego); Jang, J.W. (Jeong W.); Elshaarawy, O. (Omar); Waked, I. (Imam); Berhane, S. (Sarah); García-Fiñana, M. (Marta); Peck-Radosavljevic, M. (Markus); Aithal, G.P. (Guru P.); Han, G. (Guohong); Hucke, F. (Florian); Pinato, D.J. (David J.); Sharma, R. (Rohini); Pirisi, M. (Mario); Kirstein, M. (Martha); Rewisha, E. (Eman); Chan, S.L. (Stephen L.); Meyer, T. (Tim); Sangro, B. (Bruno); Kudo, M. (Masatoshi); Vogel, A. (Arndt); Stern, N. (Nick); Palmer, D. (Daniel); Bettinger, D. (Dominik); Cucchetti, A. (Alessandro); Travis, S. (Simon); Gomaa, A. (Asmaa); Labeur, T.A. (Tim A.); Delden, O.M. (Otto M.) van; Mosconi, C. (Cristina); Takkenberg, R.B. (R. B.); Chan, A.W.H. (Anthony W. H.); Johnson, P.J. (Philip J.); Toyoda, H. (Hidenori); Fateen, W. (Waleed)Background and aims: The heterogeneity of intermediate-stage hepatocellular carcinoma (HCC) and the widespread use of transarterial chemoembolization (TACE) outside recommended guidelines have encouraged the development of scoring systems that predict patient survival. The aim of this study was to build and validate statistical models that offer individualized patient survival prediction using response to TACE as a variable. Approach and results: Clinically relevant baseline parameters were collected for 4,621 patients with HCC treated with TACE at 19 centers in 11 countries. In some of the centers, radiological responses (as assessed by modified Response Evaluation Criteria in Solid Tumors [mRECIST]) were also accrued. The data set was divided into a training set, an internal validation set, and two external validation sets. A pre-TACE model ("Pre-TACE-Predict") and a post-TACE model ("Post-TACE-Predict") that included response were built. The performance of the models in predicting overall survival (OS) was compared with existing ones. The median OS was 19.9 months. The factors influencing survival were tumor number and size, alpha-fetoprotein, albumin, bilirubin, vascular invasion, cause, and response as assessed by mRECIST. The proposed models showed superior predictive accuracy compared with existing models (the hepatoma arterial embolization prognostic score and its various modifications) and allowed for patient stratification into four distinct risk categories whose median OS ranged from 7 months to more than 4 years. Conclusions: A TACE-specific and extensively validated model based on routinely available clinical features and response after first TACE permitted patient-level prognostication
- Safety, efficacy, and pharmacodynamics of tremelimumab plus durvalumab for patients with unresectable hepatocellular carcinoma: randomized expansion of a phase I/II study(ASCO, 2021) Kate-Kelley, R. (Robin); Sangro, B. (Bruno); Harris, W. (William); Ikeda, M. (Masafumi); Okusaka, T. (Takuji); Kang, Y.K. (Yoon-Koo); Qin, S. (Shukui); Tai, D. W.-M. (David W.-M.); Yeong Lim, H. (Ho); Yau, T. (Thomas); Yong, W.-P. (Wei-Peng); Cheng, A.L. (Ann-Lii); Gasbarrini, A. (Antonio); Damian, S. (Silvia); Bruix, J. (Jordi); Borad, M. (Mitesh); Bendell, J. (Johanna); Kim, T.Y. (Tae-You); Standifer, N. (Nathan); He, P. (Philip); Makowsky, M. (Mallory); Negro, A. (Alejandra); Kudo, M. (Masatoshi); Abou-Alfa, G.K. (Ghassan K.)This phase I/II study evaluated tremelimumab (anticytotoxic T-lymphocyte–associated antigen-4 monoclonal antibody) and durvalumab (antiprogrammed death ligand-1 monoclonal antibody) as monotherapies and in combination for patients with unresectable hepatocellular carcinoma (HCC), including a novel regimen featuring a single, priming dose of tremelimumab (ClinicalTrials.gov identifier: NCT02519348).