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Background: Nivolumab plus ipilimumab demonstrated promising clinical activity and durable responses in sorafenib-treated patients with advanced hepatocellular carcinoma (HCC) in the CheckMate 040 study at 30.7-month median follow-up. Here, we present 5-year results from this cohort., Patients and Methods: Patients were randomized 1 : 1 : 1 to arm A [nivolumab 1 mg/kg plus ipilimumab 3 mg/kg Q3W (four doses)] or arm B [nivolumab 3 mg/kg plus ipilimumab 1 mg/kg Q3W (four doses)], each followed by nivolumab 240 mg Q2W, or arm C (nivolumab 3 mg/kg Q2W plus ipilimumab 1 mg/kg Q6W). The primary objectives were safety, tolerability, investigator-assessed objective response rate (ORR), and duration of response (DOR) per RECIST version 1.1., Results: A total of 148 patients were randomized across treatment arms. At 60-month minimum follow-up (62.6-month median follow-up), the ORR was 34% (n = 17), 27% (n = 13), and 29% (n = 14) in arms A, B, and C, respectively. The median DOR was 51.2 months [95% confidence interval (CI) 12.6 months-not estimable (NE)], 15.2 months (95% CI 7.1 months-NE), and 21.7 months (95% CI 4.2 months-NE), respectively. The median overall survival (OS) was 22.2 months (34/50; 95% CI 9.4-54.8 months) in arm A, 12.5 months (38/49; 95% CI 7.6-16.4 months) in arm B, and 12.7 months (40/49; 95% CI 7.4-30.5 months) in arm C; 60-month OS rates were 29%, 19%, and 21%, respectively. In an exploratory analysis of OS by response (6-month landmark), the median OS was meaningfully longer for responders versus nonresponders for all arms. No new safety signals were identified with longer follow-up. There were no new discontinuations due to immune-mediated adverse events since the primary analysis., Conclusions: Consistent with the primary analysis, the arm A regimen of nivolumab plus ipilimumab continued to demonstrate clinically meaningful responses and long-term survival benefit, with no new safety signals in patients with advanced HCC following sorafenib treatment, further supporting its use as a second-line treatment in these patients., Competing Interests: Disclosure IM reports consultancy fees from AstraZeneca/MedImmune, Bayer, Bristol Myers Squibb, EMD Serono, F-Star, Genmab, Gossamer Bio, Lilly, Merck Sharp & Dohme, Numab, PharmaMar, Roche, Tusk Therapeutics, Highlight Therapeutics, Alligator Bioscience, Genentech, CatalYm GmbH, BioLineRx, Boston Pharma, Janssen, HotSpot Therapeutics, Inc., ImmuneSensor Therapeutics, Inc., and Monopteros Therapeutics; honoraria from Alligator Biosciences, AstraZeneca/MedImmune, Bayer, Bristol Myers Squibb, Lilly, Roche/Genentech, Tusk Therapeutics, Moderna, and CatalYm GmbH; travel support from Bristol Myers Squibb, Incyte, Merck Sharp & Dohme, and Roche/Genentech; and research grants from Alligator Biosciences, Bristol Myers Squibb, AstraZeneca, Genmab, Pfizer, and Roche/Genentech. TY reports consultancy fees from AstraZeneca, Bristol Myers Squibb, and Merck Sharp & Dohme Oncology. YKK reports consulting fees from ALX Oncology, Amgen, Blueprint, Bristol Myers Squibb, Daehwa, MacroGenics, Merck, Novartis, Roche, Surface Oncology, and Zymeworks. TYK is the founder of IMBdx, Inc. and has received research funds from Bayer Korea. AS reports consulting role at Bayer, Bristol Myers Squibb, Eisai, Gilead Sciences, Incyte, Merck Sharp & Dohme, Pfizer, Sanofi, and Servier; and speakers’ bureau participation for AbbVie, Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Celgene, Eisai, Gilead Sciences, Lilly, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Sandoz, Servier, and Takeda. BS reports consultancy fees from Adaptimmune, AstraZeneca, Bayer, Bristol Myers Squibb, Boston Scientific, Eisai, Eli Lilly, Incyte, Ipsen, Novartis, Roche, Sirtex Medical, Terumo; speaker fees from AstraZeneca, Bayer, Bristol Myers Squibb, Eisai, Eli Lilly, Incyte, Ipsen, Roche, Sirtex Medical, and Terumo; and research grants (to institution) from Bristol Myers Squibb and Sirtex Medical. MK reports consultancy fees from Chugai, Roche, Eisai, and AstraZeneca; speaker fees from Eli Lilly, Bayer, Eisai, Chugai, Takeda, and AstraZeneca; research grants (to institution) from Taiho, Otsuka, EA Pharma, AbbVie, Eisai, Chugai, GE Healthcare, and Ono Pharmaceutical Company. AM reports consulting role at Bayer, Eisai, Merck Sharp & Dohme, Roche, and Sirtex Medical; and speakers’ bureau participation for Bayer, Boston Biologics, Eisai, Merck Sharp & Dohme. FT reports consultancy role for Ipsen, Eisai, and Roche. JK reports consultancy fees from AstraZeneca, Ibsen, Taiho, and Hoffman-La Roche; and research support from AstraZeneca, Merck, Ibsen, and Roche. ARH reports consulting role at Eisai, Genentech/Roche, and Merck; speakers’ bureau participation for Bristol Myers Squibb, Eisai, and Exelixis; and research grants from Genentech and Merck. BER reports research grants from AstraZeneca, Bristol Myers Squibb, EUSA Pharmaceuticals, Exelixis, Merck, Novartis, and Xencor; consulting fees from AstraZeneca, Bristol Myers Squibb, Deciphera, Ipsen, NeoGenomics, Roche, and Seagen; and advisory role at Exelixis. HYL reports honoraria from AstraZeneca, Bayer, Bristol Myers Squibb/Medarex, Eisai, and MSD Oncology; consulting role at AstraZeneca, Bayer, Bristol Myers Squibb, and Eisai; and speakers’ bureau participation for Bayer. SS, JY, JN, and MT report being employees of and owning stock in Bristol Myers Squibb. CH reports honoraria from AstraZeneca, Bayer, Bristol Myers Squibb, Ono Pharmaceuticals, Eisai, Ipsen, Merck Sharp & Dohme, Novartis, PharmaEngine, Roche, and TTY Biopharm. ABEK reports consultancy fees from ABL Bio, Agenus, AstraZeneca/MedImmune, Bayer, Bristol Myers Squibb, Eisai, Exelixis, Gilead Sciences, Merck, Pieris Pharmaceuticals, QED Therapeutics, Qurient, Roche, Senti Biosciences, Servier, and Tallac Therapeutics; honoraria from ABL Bio, Agenus, AstraZeneca/MedImmune, Bayer, Bristol Myers Squibb, Eisai, Exelixis, EMD Serono, Gilead Sciences, Merck, Roche/Genentech, QED Therapeutics, Qurient, Roche, Senti Biosciences, Servier, and Tallac Therapeutics; and research grants from AstraZeneca, Astex Pharmaceuticals, and Fulgent Genetics. All other authors have declared no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: We carried out a phase I trial of the vascular endothelial growth factor inhibitor pazopanib and the histone deacetylase inhibitor vorinostat to determine the safety and efficacy. Because these agents are known to target factors activated by TP53 mutation and facilitate mutant p53 degradation, a subgroup analysis may be interesting in patients with TP53 mutant malignancies., Patients and Methods: Patients with advanced solid tumors (n = 78) were enrolled following a 3 + 3 design, with dose expansion for those with responsive tumors. Hotspot TP53 mutations were tested when tumor specimens were available., Results: Adverse events of ≥grade 3 included thrombocytopenia, neutropenia, fatigue, hypertension, diarrhea and vomiting. Overall, the treatment produced stable disease for at least 6 months or partial response (SD ≥6 months/PR) in 19% of the patients, median progression-free survival (PFS) of 2.2 months, and median overall survival (OS) of 8.9 months. In patients with detected hotspot TP53 mutant advanced solid tumors (n = 11), the treatment led to a 45% rate of SD ≥6 months/PR (1 PR and 3 SD ≥6 months), median PFS of 3.5 months, and median OS of 12.7 months, compared favorably with the results for patients with undetected hotspot TP53 mutations (n = 25): 16% (1 PR and 3 SD ≥6 months, P = 0.096), 2.0 months (P = 0.042), and 7.4 months (P = 0.1), respectively., Conclusion: The recommended phase II dosage was oral pazopanib at 600 mg daily plus oral vorinostat at 300 mg daily. The preliminary evidence supports further evaluation of the combination in cancer patients with mutated TP53, especially in those with metastatic sarcoma or metastatic colorectal cancer., Clinical Trial Registration: www.clinicaltrials.gov, NCT01339871., (© The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)