Reig, M. (Maria)

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    Nivolumab after selective internal radiation therapy for the treatment of hepatocellular carcinoma: a phase 2, single-arm study
    (Bmj, 2022) Reig, M. (Maria); Sangro, B. (Bruno); Testillano, M. (Milagros); Lledó, J.L. (José Luis); Iñarrairaegui, M. (Mercedes); Matilla, A. (Ana); Bilbao, J.I. (José I.); Da-Fonseca, L. (Leonardo); Márquez, L. (Laura); Rodriguez-Fraile, M. (Macarena); Lorente, S. (Sara); Varela, M.R. (María Rosario); Arenas, J.I. (Juan Ignacio); Torre-Aláez, M.A. (Manuel Antonio) de la; Argemí, J. (Josepmaria); Gómez-Martin, C. (Carlos)
    Purpose: To evaluate the safety and efficacy of selective internal radiation therapy (SIRT) in combination with a PD-1 inhibitor in patients with unresectable hepatocellular carcinoma (uHCC) and liver-only disease ineligible for chemoembolization. Patients and methods: NASIR-HCC is a single-arm, multicenter, open-label, phase 2 trial that recruited from 2017 to 2019 patients who were naïve to immunotherapy and had tumors in the BCLC B2 substage (single or multiple tumors beyond the up-to-7 rule), or unilobar tumors with segmental or lobar portal vein invasion (PVI); no extrahepatic spread; and preserved liver function. Patients received SIRT followed 3 weeks later by nivolumab (240 mg every 2 weeks) for up to 24 doses or until disease progression or unacceptable toxicity. Safety was the primary endpoint. Secondary objectives included objective response rate (ORR), time to progression (TTP), and overall survival (OS). Results: 42 patients received SIRT (31 BCLC-B2, 11 with PVI) and were followed for a median of 22.2 months. 27 patients discontinued and 1 never received Nivolumab. 41 patients had any-grade adverse events (AE) and 21 had serious AEs (SAE). Treatment-related AEs and SAEs grade 3-4 occurred in 8 and 5 patients, respectively. Using RECIST 1.1 criteria, ORR reported by investigators was 41.5% (95% CI 26.3% to 57.9%). Four patients were downstaged to partial hepatectomy. Median TTP was 8.8 months (95% CI 7.0 to 10.5) and median OS was 20.9 months (95% CI 17.7 to 24.1). Conclusions: The combination of SIRT and nivolumab has shown an acceptable safety profile and signs of antitumor activity in the treatment of patients with uHCC that were fit for SIRT.
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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.