Pembrolizumab Falls Short in Confirmatory HCC Trial

Merck, the developer of pembrolizumab, has announced that the coprimary endpoints of the KEYNOTE-240 trial were not met, as adding the agent to best supportive care failed to improve progression-free or overall survival in patients with advanced hepatocellular carcinoma who were previously treated with systemic therapy.

Roy Baynes, MD, PhD

Merck, the developer of pembrolizumab, has announced that the coprimary endpoints of the KEYNOTE-240 trial (NCT02702401) were not met, as adding the agent to best supportive care failed to improve progression-free or overall survival (OS) in patients with advanced hepatocellular carcinoma (HCC) who were previously treated with systemic therapy.1

Althought results from the final analysis showed that the pembrolizumab regimen did improve OS versus placebo, it was not deemed statistically significant per the prespecified statistical plan (HR, 0.78; 95% CI, 0.611-0.998;P= .0238). Additionally, there was a progression-free survival (PFS) improvement with pembrolizumab that also did not reach statistical significance (HR, 0.78; 95% CI, 0.61-0.99;P= .0219). Since superiority was not reached in either primary endpoint, overall response rate (ORR), which was a key secondary endpoint, was not formally tested, according to Merck.

KEYNOTE-240 is the confirmatory trial for pembrolizumab, which was granted an accelerated approval in November 2018 for patients with HCC who were previously treated with sorafenib (Nexavar), based on data from the phase II KEYNOTE-224 trial.

The safety profile of pembrolizumab in KEYNOTE-240 was consistent with what has been observed in prior studies with the PD-1 inhibitor. Full findings will be presented at an upcoming medical meeting and have been shared with the FDA for discussions.

“While we are disappointed KEYNOTE-240 did not meet its coprimary endpoints, the results for overall survival, progression-free survival and objective response rate are generally consistent with findings from the phase II study, KEYNOTE-224, which led to the accelerated approval of Keytruda for the treatment of patients with hepatocellular carcinoma who have been previously treated with sorafenib,” said Roy Baynes, MD, PhD, senior vice president and head of global clinical development, chief medical officer, Merck Research Laboratories. “We sincerely thank the patients and investigators for their participation in this study and are committed to helping patients diagnosed with this common and difficult-to-treat type of liver cancer.”

In the double-blind, phase III KEYNOTE-240 trial, 413 patients were randomized to receive pembrolizumab plus best supportive care versus placebo plus best supportive care in patients with advanced HCC who previously received systemic therapy. In the experimental arm, pembrolizumab was administered at 200 mg every 3 weeks for up to 35 cycles of treatment plus best supportive care, which included pain management and management of other potential complications including ascites per local standards of care.

To be eligible for enrollment, patients had to have Barcelona Clinic Liver Cancer (BCLC) Stage C disease, or BCLC Stage B disease not amenable to locoregional therapy or refractory to locoregional therapy, and not amenable to a curative treatment approach. Additionally, patients must have had a Child-Pugh Class A liver score within 7 days of the first dose of study drug, an estimated life expectancy >3 months, ≥1 measurable lesion based on RECIST v1.1 criteria, an ECOG performance status of 0 or 1, objective radiographic progression during or after treatment with sorafenib or intolerance to sorafenib, select cases of chronic hepatitis C virus or hepatitis B virus, and adequate organ function.

In the phase II KEYNOTE-224 trial, single-agent pembrolizumab induced an ORR of 17% (95% CI, 11-26) among 104 patients with advanced HCC previously treated with sorafenib.2Among the 18 patients who responded, there was 1 complete response and 17 partial responses. Additionally, 46 patients had stable disease, 34 patients had progressive disease, and 6 patients were not evaluable.

Also, the median time to response was 2.1 months (2.1-4.1), and 12 of the 18 responses were ongoing and the median duration of response (DOR) was not reached (range, 3.1-14.6+ months) at the time of data cutoff. Eighty-nine percent of the responders had a DOR ≥6 months, and 56% had a DOR ≥12 months.

Results also showed that the median PFS was 4.9 months (95% CI, 3.4-7.2), and the 1-year PFS rate was 28% (95% CI, 19-37). The median OS was 12.9 months (95% CI, 9.7-15.5) and the 1-year OS rate was 54% (95% CI, 44-63).

Patients received pembrolizumab for a median of 4.2 months (range, 2.1-7.7). Progressive disease (57%) and adverse events (AEs; 23%) were the most frequent cause of treatment discontinuation. Post-progression treatment included cabozantinib (Cabometyx) in 1 patient and regorafenib (Stivarga) in 20 patients.

Regarding safety, 24% (n = 25) of patients experienced grade 3 treatment-related AEs, with the most common being increased aspartate aminotransferase (7%), increased alanine aminotransferase (4%), and fatigue (4%). There was 1 case of grade 4 treatment-related hyperbilirubinemia, and 1 patient death associated with ulcerative esophagitis was linked to treatment. Additionally, 3 patients had immune-mediated hepatitis, but no incidents of viral flares were reported.

Pembrolizumab is being investigated across multiple settings and lines of therapy for HCC through a broad clinical program of 10 clinical trials. Pembrolizumab is also being tested in the ongoing, double-blind, randomized phase III KEYNOTE-394 trial (NCT03062358), which is evaluating pembrolizumab in combination with best supportive care compared with placebo in combination with best supportive care in Asian patients with advanced HCC who previously received systemic therapy.


  1. Merck Provides Update on KEYNOTE-240, a Phase 3 Study of KEYTRUDA® (pembrolizumab) in Previously Treated Patients with Advanced Hepatocellular Carcinoma. Merck. Published February 20, 2019. Accessed February 20, 2019.
  2. Zhu AX, Finn RS, Edeline J, et al. Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-randomised, open-label phase 2 trial.Lancet Oncol. 2018;19(7):940-952. doi: 10.1016/S1470-2045(18)30351-30356.