Сравнительный анализ современных систем стадирования гепатоцеллюлярного рака – TNM/AJCC, CUPI, CLIP И BCLC в российской онкологической практике. Опыт Российского онкологического научного центра им. Н. Н. Блохина

Aims: to explore the prognostic and practical utilit y of several internationally validated hepatocellular cancer (HCC) staging systems for Russian patient’s cohor t. Methods: retrospective trial of 380 HCC cases referred to Russian Cancer Research center n. a.N.N.Blokhin from Jan 2006 till Dec 2015. Results: median follow-up duration was 16,5 months. All HCC staging systems showed statistical significance for prognosis by univariate analysis: TNM/AJCC (p<0,0001; HR1,294; 95% CI 1,207–1,398); BCLC (p<0,0001; HR1,782; 95% CI 1,518–2,093); CLIP (p<0,0001; HR1,777; 95% CI 1,565–2,017); CUPI (p<0,0001; HR2,537; 95% CI 1,985–3,234). Significant sur vival difference was found across groups of early and late TNM/AJCC stages only. At multivariate analysis, prognosis was independently predicted by CUPI (HR1,512, р=0,004), CLIP (HR1,392, р<0,0001) and BCLC (HR1,337, р=0,001) for Russian patient’s cohort.Conclusions: the Barcelona Clinic Liver Cancer (BCLC) system was shown to have excellent discrimination of survival in patients with HCC and had a practically meaningful for Russian HCC patient’s cohort staging. BCLC staging and Child-Pugh-driven liver function assessment have to be obligatory supplement to TNM/AJCC in HCC diagnosis.Цель исследования: сравнить прогностическую и практическую ценность современных международных систем стадирования гепатоцеллюлярного рака (ГЦР) в российской популяции. Материалы и методы: ретроспективно проведено стадирование 380 случаев ГЦР, наблюдавшихся в ФГБУ «РОНЦ им. Н. Н. Блохина» МЗ РФ с 2006 по 2015 гг. Результаты: медиана наблюдения составила 16,5 мес. При однофакторном анализе все системы стадирования ГЦР обладают достоверной прогностической значимостью: TNM/AJCC (p<0,0001; OP 1,294 95% ДИ 1,207–1,398); BCLC (p<0,0001; OP 1,782 95% ДИ 1,518–2,093); CLIP (p<0,0001; OP 1,777 95% ДИ 1,565–2,017); CUPI (p<0,0001; OP 2,537 95% ДИ 1,985–3,234). TNM/AJCC обладает прогностической значимостью только при ранних стадиях ГЦР, различие кривых ОВ между другими стадиями недостоверно. Многофакторный анализ подтвердил независимую прогностическую значимость индекса CUPI (ОР 1,512, р=0,004), CLIP (ОР 1,392, р<0,0001) и стадии BCLC (ОР 1,337, р=0,001) в российской когорте больных ГЦР. Заключение: стадирование ГЦР по классификации BCLC обладает очевидной прогностической и практической ценностью в российской популяции больных ГЦР. Учитывая технические сложности стадирования по CUPI и CLIP, классификация BCLC и определение функционального статуса печени (Child-Pugh) должны быть обязательным дополнением при стадировании печеночно-клеточного рака по TNM/AJCC

Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial

Background There are no systemic treatments for patients with hepatocellular carcinoma (HCC) whose disease progresses during sorafenib treatment. We aimed to assess the efficacy and safety of regorafenib in patients with HCC who have progressed during sorafenib treatment. Methods In this randomised, double-blind, parallel-group, phase 3 trial done at 152 sites in 21 countries, adults with HCC who tolerated sorafenib (â\u89¥400 mg/day for â\u89¥20 of last 28 days of treatment), progressed on sorafenib, and had Child-Pugh A liver function were enrolled. Participants were randomly assigned (2:1) by a computer-generated randomisation list and interactive voice response system and stratified by geographical region, Eastern Cooperative Oncology Group performance status, macrovascular invasion, extrahepatic disease, and α-fetoprotein level to best supportive care plus oral regorafenib 160 mg or placebo once daily during weeks 1â\u80\u933 of each 4-week cycle. Investigators, patients, and the funder were masked to treatment assignment. The primary endpoint was overall survival (defined as time from randomisation to death due to any cause) and analysed by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01774344. Findings Between May 14, 2013, and Dec 31, 2015, 843 patients were screened, of whom 573 were enrolled and randomised (379 to regorafenib and 194 to placebo; population for efficacy analyses), and 567 initiated treatment (374 received regorafenib and 193 received placebo; population for safety analyses). Regorafenib improved overall survival with a hazard ratio of 0·63 (95% CI 0·50â\u80\u930·79; one-sided p<0·0001); median survival was 10·6 months (95% CI 9·1â\u80\u9312·1) for regorafenib versus 7·8 months (6·3â\u80\u938·8) for placebo. Adverse events were reported in all regorafenib recipients (374 [100%] of 374) and 179 (93%) of 193 placebo recipients. The most common clinically relevant grade 3 or 4 treatment-emergent events were hypertension (57 patients [15%] in the regorafenib group vs nine patients [5%] in the placebo group), handâ\u80\u93foot skin reaction (47 patients [13%] vs one [1%]), fatigue (34 patients [9%] vs nine patients [5%]), and diarrhoea (12 patients [3%] vs no patients). Of the 88 deaths (grade 5 adverse events) reported during the study (50 patients [13%] assigned to regorafenib and 38 [20%] assigned to placebo), seven (2%) were considered by the investigator to be related to study drug in the regorafenib group and two (1%) in the placebo group, including two patients (1%) with hepatic failure in the placebo group. Interpretation Regorafenib is the only systemic treatment shown to provide survival benefit in HCC patients progressing on sorafenib treatment. Future trials should explore combinations of regorafenib with other systemic agents and third-line treatments for patients who fail or who do not tolerate the sequence of sorafenib and regorafenib. Funding Bayer

Pembrolizumab As Second-Line Therapy in Patients With Advanced Hepatocellular Carcinoma in KEYNOTE-240: A Randomized, Double-Blind, Phase III Trial

PURPOSE Pembrolizumab demonstrated antitumor activity and safety in the phase II KEYNOTE-224 trial in previously treated patients with advanced hepatocellular carcinoma (HCC). KEYNOTE-240 evaluated the efficacy and safety of pembrolizumab in this population. PATIENTS AND METHODS This randomized, double-blind, phase III study was conducted at 119 medical centers in 27 countries. Eligible patients with advanced HCC, previously treated with sorafenib, were randomly assigned at a two-to-one ratio to receive pembrolizumab plus best supportive care (BSC) or placebo plus BSC. Primary end points were overall survival (OS) and progression-free survival (PFS; one-sided significance thresholds, P = .0174 [final analysis] and P = .002 [first interim analysis], respectively). Safety was assessed in all patients who received ≥ 1 dose of study drug. RESULTS Between May 31, 2016, and November 23, 2017, 413 patients were randomly assigned. As of January 2, 2019, median follow-up was 13.8 months for pembrolizumab and 10.6 months for placebo. Median OS was 13.9 months (95% CI, 11.6 to 16.0 months) for pembrolizumab versus 10.6 months (95% CI, 8.3 to 13.5 months) for placebo (hazard ratio [HR], 0.781; 95% CI, 0.611 to 0.998; P = .0238). Median PFS for pembrolizumab was 3.0 months (95% CI, 2.8 to 4.1 months) versus 2.8 months (95% CI, 2.5 to 4.1 months) for placebo at the first interim analysis (HR, 0.775; 95% CI, 0.609 to 0.987; P = .0186) and 3.0 months (95% CI, 2.8 to 4.1 months) versus 2.8 months (95% CI, 1.6 to 3.0 months) at final analysis (HR, 0.718; 95% CI, 0.570 to 0.904; P = .0022). Grade 3 or higher adverse events occurred in 147 (52.7%) and 62 patients (46.3%) for pembrolizumab versus placebo; those that were treatment related occurred in 52 (18.6%) and 10 patients (7.5%), respectively. No hepatitis C or B flares were identified. CONCLUSION In this study, OS and PFS did not reach statistical significance per specified criteria. The results are consistent with those of KEYNOTE-224, supporting a favorable risk-to-benefit ratio for pembrolizumab in this population

Pembrolizumab as Second-Line Therapy for Advanced Hepatocellular Carcinoma: Longer-Term Follow-Up From the Phase 3 KEYNOTE-240 Trial

International audienceIntroduction: KEYNOTE-240 showed a favorable benefit/risk profile for pembrolizumab versus placebo in patients with sorafenib-treated advanced hepatocellular carcinoma (HCC); however, prespecified statistical significance criteria for overall survival (OS) and progression-free survival (PFS) superiority were not met at the final analysis. Outcomes based on an additional 18 months of follow-up are reported. Methods: Adults with sorafenib-treated advanced HCC were randomized 2:1 to pembrolizumab 200 mg intravenously every 3 weeks or placebo. Dual primary endpoints were OS and PFS assessed per RECIST v1.1 by blinded independent central review (BICR). Secondary endpoints included objective response rate (ORR), assessed per RECIST v1.1 by BICR, and safety. Results: 413 patients were randomized (pembrolizumab, n = 278; placebo, n = 135). As of July 13, 2020, median (range) time from randomization to data cutoff was 39.6 (31.7–48.8) months for pembrolizumab and 39.8 (31.7–47.8) months for placebo. Estimated OS rates (95% CI) were 17.7% (13.4–22.5%) for pembrolizumab and 11.7% (6.8–17.9%) for placebo at 36 months. The estimated PFS rate (95% CI) for pembrolizumab was 8.9% (5.3–13.6%) and 0% for placebo at 36 months. ORR (95% CI) was 18.3% (14.0–23.4%) for pembrolizumab and 4.4% (1.6–9.4%) for placebo. Immune-mediated hepatitis events did not increase with follow-up. No viral hepatitis flare events were reported. Conclusion: With extended follow-up, pembrolizumab continued to maintain improvement in OS and PFS and was associated with a consistent adverse event profile compared with placebo in patients with sorafenib-treated advanced HCC. Although KEYNOTE-240 did not meet prespecified statistical significance criteria at the final analysis, these results together with the antitumor activity of second-line pembrolizumab observed in KEYNOTE-224 and the statistically significant and clinically meaningful OS and PFS benefits of second-line pembrolizumab in patients from Asia observed in KEYNOTE-394 reinforce the clinical activity of pembrolizumab in previously treated patients with advanced HCC

Atezolizumab plus Bevacizumab in Unresectable Hepatocellular Carcinoma.

International audienceThe combination of atezolizumab and bevacizumab showed encouraging antitumor activity and safety in a phase 1b trial involving patients with unresectable hepatocellular carcinoma.Methods: In a global, open-label, phase 3 trial, patients with unresectable hepatocellular carcinoma who had not previously received systemic treatment were randomly assigned in a 2:1 ratio to receive either atezolizumab plus bevacizumab or sorafenib until unacceptable toxic effects occurred or there was a loss of clinical benefit. The coprimary end points were overall survival and progression-free survival in the intention-to-treat population, as assessed at an independent review facility according to Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST 1.1).Results: The intention-to-treat population included 336 patients in the atezolizumab-bevacizumab group and 165 patients in the sorafenib group. At the time of the primary analysis (August 29, 2019), the hazard ratio for death with atezolizumab-bevacizumab as compared with sorafenib was 0.58 (95% confidence interval [CI], 0.42 to 0.79; P<0.001). Overall survival at 12 months was 67.2% (95% CI, 61.3 to 73.1) with atezolizumab-bevacizumab and 54.6% (95% CI, 45.2 to 64.0) with sorafenib. Median progression-free survival was 6.8 months (95% CI, 5.7 to 8.3) and 4.3 months (95% CI, 4.0 to 5.6) in the respective groups (hazard ratio for disease progression or death, 0.59; 95% CI, 0.47 to 0.76; P<0.001). Grade 3 or 4 adverse events occurred in 56.5% of 329 patients who received at least one dose of atezolizumab-bevacizumab and in 55.1% of 156 patients who received at least one dose of sorafenib. Grade 3 or 4 hypertension occurred in 15.2% of patients in the atezolizumab-bevacizumab group; however, other high-grade toxic effects were infrequent.Conclusions: In patients with unresectable hepatocellular carcinoma, atezolizumab combined with bevacizumab resulted in better overall and progression-free survival outcomes than sorafenib