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Merck’s Keytruda closes on second FDA verdict in genetic cancer

Merck’s application is based on data from the ongoing KeyNote-158 trial


The FDA has started a priority review of Merck & Co’s Keytruda in cancers with high tumour mutational burden (TMB-H), wherever they occur in the body.

If approved by the deadline of 16 June, Keytruda (pembrolizumab) will claims its second approval for a ‘tumour agnostic’ indication, with patients selected for treatment purely based on the TMB biomarker.

The PD-1 inhibitor became the first drug to be cleared by the FDA with this type of label in 2017, when it got a green light as a second-line treatment for patients who have microsatellite instability-high (MSI-H) or mismatch repair deficiency (dMMR) mutations.

Since then, it has also generated positive clinical results as a first-line therapy for colorectal cancer patients with these biomarkers.

The priority review is for people with solid tumours with TMB-H – diagnosed using an FDA-approved test from Foundation Medicine – who have progressed following prior treatment and who have no satisfactory alternative treatment options.

Merck’s threshold for treatment with Keytruda is ten mutations per megabase million base pairs in the tumour cell genome, according to the marketing application.

Merck’s application is based on data from the ongoing KeyNote-158 trial, which also supported Keytruda’s approval in MSI-H/dMMR tumours, that was presented at last year’s ESMO conference.

“From the start, biomarker research has been a critical aspect of our clinical programme evaluating Keytruda monotherapy,” said Scot Ebbinghaus, vice president of clinical research at Merck.

“TMB has been an area of scientific interest to help identify patients most likely to benefit from Keytruda,” he added.

If the FDA does give Keytruda the go-ahead for TMB-H tumours, it will be a boost for Bristol-Myers Squibb, which has been trying to get approval for a combination of its PD-1 drug Opdivo (nivolumab) with CTLA4 inhibitor Yervoy (ipilimumab) in treatment-naïve non-small cell lung cancer (NSCLC) patients with TMB-H tumours for some time.

That has proved a challenge, however, and it has had to pull marketing applications in Europe and the US after some pushback from regulators, mainly because of amendments to the protocol of the CheckMate-227 trial that underpinned its filing.

BMS still has a chance for a US approval for the combination, however, based on one part of the CheckMate-227 data which evaluated Opdivo/Yervoy versus chemotherapy in patients with previously untreated NSCLC.

There are two co-primary endpoints in the study, namely overall survival (OS) in patients whose tumours express PD-L1, and progression-free survival (PFS) in patients with TMB mutations of ten per megabase or more regardless of PD-L1 expression. The FDA is due to have its say on that by 15 May.

Article by
Phil Taylor

8th April 2020

From: Research



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