Keytruda fluffs its lines in prostate, liver cancer trials

Two phase 3 trials of Merck & Co's Keytruda in metastatic castration-resistant prostate cancer (CRPC) and advanced liver cancer have ended in failure, proving once again that cancer immunotherapy studies can be a hit-and-miss affair.

The CRPC trial – KEYNOTE-921 – looked at the combination of Keytruda (pembrolizumab) with docetaxel in more than 1,000 patients who had not been treated with chemotherapy before, but who had seen disease progression despite earlier treatment with an anti-hormonal therapy.

The combination was compared to placebo plus docetaxel in the study, but was unable to show a significant improvement in overall survival (OS) or radiographic progression-free survival (rPFS) – the trial's two primary endpoints.

Merck said there were "modest trends" towards improvement with Keytruda, but overall the study was a failure, reflecting that metastatic CRPC is very difficult to treat.

It unfortunately ties in with a prevailing trend of late-stage trial failures for checkpoint inhibitors in CRPC, including the recently-reported KEYLYNK-010 trial of Keytruda and Merck/AstraZeneca's PARP inhibitor Lynparza (olaparib) in CRPC patients previously treated with hormonal therapy and chemo.

Keytruda has struggled to make an impact in prostate cancer, and the disease does not feature on the drug's very long list of approved indications, despite considerable clinical testing on Merck's part, or indeed on the label' of other drugs in the PD-1/PD-L1 inhibitor class like Bristol-Myers Squibb's Opdivo (nivolumab).

Merck is still plugging away with Keytruda though, and has two phase 3 trials on the go – the KEYNOTE-641 in post-hormonal therapy metastatic CRPC patients, and KEYNOTE-991 in metastatic hormone-sensitive prostate cancer (HSPC).

It is also running two phase 2 studies, KEYNOTE-199 looking at Keytruda as a monotherapy for later-line treatment of metastatic CRPC, and KEYNOTE-365 which is investigating multiple combinations with other drugs given on top of first-line hormonal therapy.

Lenvima combination

Hepatocellular carcinoma (HCC) – the most common form of liver cancer – is another head-to-treat malignancy, but one which has seen improvements in therapy with targeted tyrosine kinase inhibitors (TKIs) like Eisai's Lenvima (lenvatinib).

The issue with TKIs is that their effects tend to be short-lived, as tumours develop random mutations in target receptors and downstream pathways that allow them to resist treatment.

In the LEAP-002 study, Merck hoped to show that combining Keytruda with Lenvima would improve outcomes over two years' follow-up in patients with unresectable HCC.

However, the duo was unable to show significant gains in OS and PFS compared to Lenvima alone, although once again found trends towards improvement. One thing that could have skewed the result was that the median OS with Lenvima on its own was longer than usual, making it harder for the combination to show an improvement, said Merck.

Keytruda is already approved for use after first-line therapy with Bayer's older TKI Nexavar (sorafenib) for HCC, but Merck was hoping to break into the previously-untreated patient category with the Lenvima combination. Eisai's drug was cleared for first-line use in HCC by the FDA in 2018.

"We remain confident in the potential of this combination based on the body of evidence we've seen to date and will continue to investigate its role across multiple types of cancer," said Merck's head of global clinical development Dr Gregory Lubiniecki.