Pembrolizumab (pembro) vs placebo (pbo) in patients (pts) with advanced hepatocellular carcinoma (aHCC) previously treated with sorafenib: Updated data from the randomized, phase III KEYNOTE-240 study.

Abstract

268 Background: KEYNOTE-240 (NCT02702401) examined the anti-PD-1 antibody pembro and demonstrated improvement in OS and PFS vs pbo in pts with aHCC previously treated with sorafenib. However, the study did not meet prespecified statistical significance criteria for OS and PFS. Median OS (final analysis) was 13.9 mo for pembro vs 10.6 mo for pbo (HR 0.781; 95% CI 0.611-0.998). At the first interim analysis when PFS and ORR were prespecified to be tested, median PFS was 3.0 mo for pembro vs 2.8 mo for pbo (HR 0.775; 95% CI 0.609-0.987) and ORR was 16.9% (CR, n = 3) for pembro and 2.2% (CR, n = 0) for pbo. AEs were consistent with the known safety profile of pembro. Longer-term data from KEYNOTE-240 after ~1.5 years of additional follow-up are reported. Methods: Adults with confirmed aHCC who experienced failure (progression or intolerance) to sorafenib therapy were randomized 2:1 to pembro 200 mg IV Q3W + best supportive care (BSC) or pbo + BSC for ≤35 cycles or until confirmed progression/unacceptable toxicity, pt withdrawal of consent, or investigator decision. Dual primary end points were OS and PFS, assessed by blinded independent central review (BICR) per RECIST v1.1. Secondary end points included ORR, DOR, DCR, TTP (all assessed by BICR per RECIST v1.1), and safety. Results: Of 413 pts, 278 were randomized to pembro and 135 to pbo. As of July 13, 2020, median time from randomization to data cutoff was 39.6 mo (range 31.7-48.8) for pembro and 39.8 mo (31.7-47.8) for pbo. Median OS was 13.9 mo (95% CI 11.6-16.0) for pembro and 10.6 mo (8.3-13.5) for pbo (HR 0.771; 95% CI 0.617-0.964). Estimated OS rates at 24 and 36 mo for pembro and pbo were 28.8% and 20.4% and 17.7% and 11.7%, respectively. Median PFS was 3.3 mo (95% CI 2.8-4.1) for pembro and 2.8 mo (1.6-3.0) for pbo (HR 0.703; 95% CI 0.559-0.885). Estimated PFS rate at 24 mo was 11.8% for pembro and 4.8% for pbo. ORR was 18.3% (95% CI 14.0-23.4) for pembro and 4.4% (1.6-9.4) for pbo. Median time to response was 2.7 mo (95% CI 1.2-16.9) for pembro and 2.9 mo (1.1-6.9) for pbo. Median DOR was 13.9 mo (range 1.5+ to 41.9+) for pembro and 15.2 mo (2.8-21.9) for pbo; 45.1% of responders in pembro arm and 33.3% of responders in pbo arm had DOR ≥12 mo. DCR was 61.9% for pembro and 53.3% for pbo. Best overall responses were 10 CR, 41 PR, 121 SD, and 85 PD for pembro and 0 CR, 6 PR, 66 SD, and 54 PD for pbo. The median TTP was 4.0 mo (95% CI 2.8-5.3) for pembro and 2.8 mo (1.6-3.0) for pbo. No new or unexpected AEs occurred. The frequency of sponsor-assessed immune-mediated hepatitis events did not increase with additional follow-up. There continued to be no HBV or HCV viral flare events. Conclusions: In previously treated pts with aHCC, improvement in OS and PFS was maintained over time with pembro vs pbo, and the safety profile remained consistent over time. These data support the benefit:risk profile of pembro. Clinical trial information: NCT02702401.

Hepatobiliary Cancers, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology

“…246 Updated data from the KEYNOTE-240 trial, published in an abstract, showed that the median OS with pembrolizumab versus placebo was 13.9 vs 10.6 months, respectively (HR, 0.77) and the median PFS was 3.3 vs 2.8 months, respectively (HR, 0.70). 247 Also, a clinically meaningful difference in ORR was seen favoring pembrolizumab (18.3% vs 4.4%), and the median duration of response on pembrolizumab was 13.9 months. Pembrolizumab has maintained its accelerated approval in patients previously treated with sorafenib.…”

Systematic Literature Review of Trials Assessing Recommended Systemic Treatments in Hepatocellular Carcinoma

“…Finally, 57 records (representing 50 trials) were included in the SLR. These 50 trials included 34 trials in the 1L setting (six single arm [30][31][32][33][34][35], six RCTs comparing against a recommended treatment or placebo [36][37][38][39][40][41][42][43], one trial with both single arm and randomized groups [44], and 26 RCTs comparing against a non-recommended treatment ) and 11 trials in the 2L setting (five single arm [71][72][73][74][75][76], five RCTs comparing against placebo [77][78][79][80][81][82], and one trial with both single arm and randomized groups [83][84][85][86]).…”

“…Last, the comparison of atezolizumab + bevacizumab versus atezolizumab alone found an improvement in PFS, but OS was not reported ( Figure 4 ) [ 44 ]. In the 2L setting, cabozantinib and regorafenib were associated with significant improvements in PFS and OS over placebo [ 77 , 79 ]; results for ramucirumab were mixed [ 78 , 80 ], and pembrolizumab did not significantly lower PFS and OS per the trial's specified criteria [ 81 , 82 ] ( Supplementary Figure 7 ).…”

Hepatocellular Carcinoma Immunotherapy and the Potential Influence of Gut Microbiome

“…Based on these results, the FDA granted accelerated approval for the use of pembrolizumab in patients progressing on sorafenib. Another phase III trial comparing pembrolizumab to placebo in the second-line treatment of advanced HCC did not meet its primary endpoints (OS and PFS) based on the rigorous statistical plan [75]. The combination of lenvantanib, an inhibitor of vascular endothelial growth factor receptor (VEGFR), of fibroblast growth factor receptor, of platelet-derived growth factor receptor (PDGFR), and other growth signaling kinases, and pembrolizumab was assessed in the phase Ib trial of 104 patients with unresectable HCC [76].…”