Esmo 2021 – Opdivo’s glimmer of hope in front-line head and neck cancer

The use of Bristol Myers Squibb’s Opdivo in squamous head and neck cancer might be limited to the second line – at least in all-comers. However, front-line patients expressing high levels of PD-L1 might derive some benefit in combination with Yervoy, full data from the failed Checkmate-651 study, just unveiled at an Esmo late-breaker, suggest.

However, the benefit is not overwhelming, and it is not clear whether it might be enough for a regulatory filing that would enable Bristol to catch up with Merck & Co’s Keytruda. Either way, the head and neck cancer space will remain tricky for immunotherapy, with numerous first and second-line trials having already failed.

Big miss

Checkmate-651 had been toplined as a bust in July, and the Esmo abstract reveals a big miss in all-comer overall survival, with medians of 13.9 months for Opdivo plus Yervoy versus 13.5 for the Extreme (Erbitux plus chemo) regimen, and a highly non-significant p value of 0.5.

The study had a co-primary endpoint of overall survival in PD-L1 expressers, and here the picture improves: ≥20% expressers derived a 22% reduction in risk of death versus Extreme, while for ≥1% expressers the reduction was 18%. The former analysis yielded a p value of 0.047, which was not significant given the statistical powering spent in the all-comers failure.

Moreover, the upper bound of the confidence interval in the PD-L1 ≥20% analysis was above 1.00, suggesting that some patients might have done better on Extreme. However, the presenters said Checkmate-651 showed “evidence of clinical activity” in PD-L1 expressers, and said overall survival in the comparator cohort had come out better than historical data.

It will be up to Bristol how to take this forward. Opdivo monotherapy was approved in 2016 for second-line squamous head and neck cancer on the back of Checkmate-141, the first study to back an immuno-oncology therapy with a survival benefit in this cancer.

Keytruda got accelerated approval for second-line use, failed the Keynote-040 confirmatory study, but then succeeded first line in Keynote-048, and now boasts two front-line labels: as monotherapy in PD-L1 ≥1% expressers, and as part of a chemo combo in all-comer patients.

Bristol probably has little to lose in pursuing a PD-L1 expression-based filing for the Yervoy combo, though Checkmate-651 is not its first head and neck trial to fail. Checkmate-714, a curiously designed first-line study comparing Opdivo monotherapy against a Yervoy combo, was deemed a bust in 2019.

Astrazeneca’s Imfinzi and Merck KGaA/Pfizer’s Bavencio are other anti-PD-(L)1 drugs that have failed in head and neck cancer.