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

The failed Checkmate-651 study hints at a survival benefit in some PD-L1 expressers, but will this be enough to file?

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.

Checkmate-651 summary
  Opdivo + Yervoy Control (Extreme regimen)
All-comers N 472 475
mOS 13.9mth 13.5mth
Stats HR=0.95 (p=0.4951, not significant)
PD-L1 ≥20% N 185 178
mOS 17.6mth 14.6mth
Stats HR=0.78 (p=0.0469, not significant)
PD-L1 ≥1% N 355 372
mOS 15.7mth 13.2mth
Stats HR=0.82 (no stat testing)
Source: Esmo. 

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.

Immunotherapy in head & neck cancer
  Hit Miss
Opdivo (Bristol Myers Squibb) Checkmate-141 (2L)
OS basis for 2016 approval
Checkmate-714 (1L)
Opdivo vs Yervoy combo
Checkmate-615 (1L)
Yervoy combo
Keytruda (Merck & Co) Keynote-048 (1L)
OS basis for monotherapy (PD-L1≥1%) & chemo combo approvals;
confirmatory trial for 2L label
Keynote-040 (2L)
Imfinzi (Astrazeneca) Eagle (2L)
tremelimumab combo
Kestrel (1L)
tremelimumab combo
Bavencio (Merck KGaA/Pfizer) Javelin Head & Neck 100 (1L)
Source: company statements. 1L=1st line; 2L=2nd line.

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