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Pembrolizumab for advanced hepatocellular carcinoma reduces mortality risk in 'technically ... negative study'
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CHICAGO — Patients with previously treated advanced hepatocellular carcinoma demonstrated reduced risk for death and improved PFS with the addition of pembrolizumab vs. placebo to best supportive care, according to findings from the randomized phase 3 KEYNOTE-240 study presented at ASCO Annual Meeting.
The difference, however, did not reach the study’s prespecified statistical criteria for significance.
“Advanced liver cancer is a difficult disease to treat in the second-line setting; historically, we haven’t had any drugs that have been shown to improve survival,” Richard S. Finn, MD, assistant professor of medicine in the department of medicine, division of hematology/internal medicine at David Geffen School of Medicine at UCLA, said in an interview with HemOnc Today. “Over the past few years, we’ve seen a lot of robust activity in terms of the approvals of regorafenib [Stivarga, Bayer] and cabozantinib [Cabometyx, Exelixis], but the checkpoint inhibitors nivolumab [Opdivo, Bristol-Myers Squibb] and pembrolizumab [Keytruda, Merck] have shown very interesting activity based on single-arm, phase 2 studies. Both drugs have FDA accelerated approval, and KEYNOTE-240 is the first phase 3 randomized study of a checkpoint inhibitor in second-line liver cancer.”
Finn and colleagues evaluated 413 patients with a radiographic or pathologic diagnosis of HCC, radiographic progression on or intolerance to sorafenib (Nexavar, Bayer), Child-Pugh A disease and an ECOG performance score of 0 or 1.
The researchers randomly assigned participants 2:1 to best supportive care, including management of pain and other potential complications per local standards of care, and either 200 mg pembrolizumab (n = 278) or placebo (n = 135) via IV every 3 weeks. Researchers stratified participants by geographic region, macrovascular invasion and alpha-fetoprotein levels and administered treatment for as many as 35 cycles or until confirmed progressive disease or intolerable toxicity. They evaluated response every 6 weeks per RECIST version 1.1 criteria by central imaging review.
OS and PFS served as the co-primary endpoints. Secondary endpoints included objective response rate, duration of response and safety. Data cutoff occurred on Jan. 2, 2019, for OS, and March 26, 2018, for PFS and ORR.
“The statistical design was complex, with a multiplicity strategy that had dual endpoints of PFS and OS, and this affected the distribution of alpha type 1 error throughout the study,” Finn said. “It was then accounted for through a series of interim analyses for OS and then final analysis.”
After a median follow-up of 13.8 months, 10.1% of patients continued to receive pembrolizumab and 3% remained on placebo. Compared with placebo, pembrolizumab improved OS (HR = 0.78; one-sided P = .0238) and PFS (HR = 0.78; one-sided P = .0209); however, these improvements did not reach significance per the prespecified statistical plan.
ORR was 16.9% (95% CI, 12.7-21.8) for pembrolizumab vs. 2.2% (95% CI, 0.5-6.4) for placebo (nominal one-sided P = .00001). Pembrolizumab conferred durable responses, with median duration of response of 13.8 months (range, 1.5-23.6 +).
Researchers noted the likely impact of subsequent anticancer therapy in the placebo group on OS results. Rates of new therapy use off-study were 42% with pembrolizumab and 47% with placebo. The regimen demonstrated a safety profile comparable to that seen in previous pembrolizumab studies, including incidence of hepatitis and other immune-mediated events. No cases of hepatitis B or hepatitis C virus flare were reported.
Finn said the study results technically could not be considered positive.
“At the end of the day, we saw a clinically meaningful improvement in OS from about 10 months until just under 14 months, with an HR of 0.78; the upper limit of the CI was less than 1 and the P value was 0.023, which appears to be a positive study,” he told HemOnc Today. “However, for the statistics to be considered positive, it had to be 0.017, so technically, statistically, it is a negative study. Yet when we look at things like PFS, the response rate and the duration of response, it’s all very similar to what has been seen in the phase 2 studies.”
Finn said it is not yet known what these findings ultimately will mean for the future use of pembrolizumab in this setting.
“It’s a challenging place to be, because we have increasing evidence that these drugs are active in this setting, but we have not proven without a doubt statistically that they improve OS,” he said. “However, many of us continue to use these drugs because we are convinced of the data we’ve seen in KEYNOTE-240 and in the phase 2 studies.” – by Jennifer Byrne
Reference:
Finn RS, et al. Abstract 4004 Presented at: ASCO Annual Meeting; May 31-June 4, 2019; Chicago.
Disclosures: Finn reports consultant/advisory roles with AstraZeneca, Bayer, Bristol-Myers Squibb, Eisai, Eli Lilly, Exelixis, Genentech/Roche, Merck, Novartis, and Pfizer; and research funding to his institution from Novartis, Pfizer and Roche/Genentech. Please see the abstract for all other authors’ relevant financial disclosures.
Perspective
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Rohit Chandwani, MD
Checkpoint blockade has shown a signal in about 20% of patients, and nivolumab has been approved as second-line therapy in an expedited fashion for patients with HCC, but that is based on a phase 1/phase 2 trial.
Although the study by Finn and colleagues did not reach their threshold of statistical significance, patients who were pretreated with sorafenib trended toward an overall decrease in the risk for death. This is the first phase 3 study of its kind to suggest that checkpoint blockade has efficacy in these pretreated patients, with again the caveat that the findings were not significant.
That this study did not demonstrate benefit in the entire cohort raises the big questions in the field that have not been answered. These are (1) to what extent should immunotherapy be employed as a first-line therapy?; and (2) as the vast majority of patients did not experience any radiographic response, or likely any clinical benefit, how do we define who is going to benefit from immunotherapy?
This is an incremental, yet important, advance to establish the role of immunotherapy in the second-line setting, but it does not change practice insofar as we already have FDA approval based on the phase 2 data. Pembrolizumab is already being used in the second-line setting with great frequency, and the two critical questions — both of which are currently being investigated in multiple trials — remain unanswered.
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