Bristol-Myers Squibb might have seen its PD-1 inhibitor Opdivo comprehensively outmanoeuvred by Merck & Co’s Keytruda in lung cancer, but the opposite could be the case in hepatocellular carcinoma.
Updated data from the dose-expansion stage of Bristol’s large Checkmate-040 phase I/II study reported at Asco-GI suggest that the drug confers a durable response in around 20% of hepatocellular patients – irrespective of whether it is given first or second line (see tables below). With a near-term phase III study readout Bristol looks to have first-mover advantage over its arch-rival.
The response to Opdivo also seems to be consistent irrespective of disease aetiology – whether it is caused by prior hepatitis B or C infection or alcohol, or another factor. The survival data seen so far look likely to translate into a survival advantage.
This bodes well for the outcome of Bristol’s first-line, phase III Checkmate-459 study, testing Opdivo against Bayer’s Nexavar, the long-standing standard of care. This trial is due to read out in July.
If Checkmate-459 is positive Bristol could seek a registration in hepatocellular carcinoma with a more than 18 months’ lead over Keytruda. Merck’s Keynote-240 study, in the second-line setting, is not due to render results until early 2019.
Moreover, a win in Checkmate-459 would give Opdivo front-line status, leaving few patients who have not already been exposed to an anti-PD-1 agent in the later therapy lines.
Hepatocellular carcinoma is also unusual in that PD-L1 expression is low in all patients and, where examined, it does not seem to correlate with response, so there is no opportunity to segregate the patients in the same way as with NSCLC. New biomarkers will, however, ultimately have to be identified in future to predict the responders.
|Checkmate-040 dose-expansion data reported at Asco-GI|
|Enrolment (first/second line)||214 (145/69)|
|Overall response rate (investigator-assessed)||20%|
|23% in first-line, non-HBV/HCV infected|
|21% in second line, non-HBV/HCV infected|
|Duration of response||9.9 months|
|9-mth overall survival||74%|
Further complicating the competitive landscape for Merck is the imminent approval of Bayer’s Stivarga as a second-line option, based on the outcome of the Resorce trial. Other studies could also read out that could introduce other new later-line agents, including Eisai’s Lenvima, Arqule/Kyowa Hakko’s tivantinib and Lilly’s Cyramza.
Merck is running Keynote-224, a single-arm phase II study due to report data later this year, and Astrazeneca is conducting a three-arm, non-controlled trial of its PD-L1 agent durvalumab alone and with the CTLA4-antibody tremelimumab.
Both the Merck and Astra studies are in second-line disease, and look unlikely to support an early registration. Unless there is a major upset with Checkmate-459, hepatocellular carcinoma could become one indication where the PD-1/PD-L1 market does not even split three ways.
|Key trials of checkpoint inhibitors in hepatocellular carcinoma|
|Project||Study||Enrolment||Comparator||Tx line||Trial ID||Data|
|Keytruda||Keynote-240||408||Best supportive care||Second||NCT02702401||Feb 2019|
|Keytruda||Keynote-224||100||None (single arm)||Second||NCT02702414||Nov 2017|
|durvalumab, tremelimumab, durva+treme||-||144||None (three arms)||Second||NCT02519348||Apr 2018|