ASCO-GI – a second colorectal win for Bristol's combo

Bristol Myers Squibb's Checkmate-8HW study has delivered again, showing a striking progression-free survival benefit for Opdivo plus Yervoy versus Opdivo alone in MSI-high/MMR-deficient colorectal cancer. The late-breaking data came at the ASCO Gastrointestinal Cancers symposium, a year after the combo beat chemo alone on PFS in a subset of patients with first-line disease.

One curiosity arises from this trial's co-primary endpoints, which both concern PFS, but which use a different active comparator for all-comers and for treatment-naive patients. A second is that the EMA has already approved the combo in first-line MSI-H/dMMR colorectal cancer, but Bristol has been rather vague about its plans in the US.

A presentation at this month's JP Morgan healthcare conference revealed that Bristol expects US approval for Opdivo plus Yervoy in first-line MSI-H/dMMR colorectal cancer this year, but the group has said nothing about whether a filing has been submitted yet. It has also not said why its US regulatory strategy has lagged behind the EU, where the combo was approved on the back of Checkmate-8HW in December.

The US and EU market dynamics in MSI-H/dMMR colorectal cancer are fairly similar: Merck & Co's Keytruda is approved first line (it also has a US second-line nod as part of a tumour-agnostic label), while Opdivo plus Yervoy is available in the second-line setting. In the US Opdivo monotherapy is also approved second line, and both Bristol FDA green lights are currently on an accelerated basis.

As such, one clear outcome of the first results from Checkmate-8HW at last year's ASCO-GI was that they should formalise at least the combo's second-line accelerated approval.

Now data from the Opdivo-only cohort could formalise the monotherapy nod, though clearly Bristol will be hoping for much more. That monotherapy, however, is in Checkmate-8HW a comparator – not an active treatment cohort – and its results are only being revealed for patients across all therapy lines, not in the all-important front-line setting.

Two wins on PFS

At ASCO-GI over the weekend Bristol revealed a 38% reduction in risk of progression or death for Yervoy plus Opdivo, versus Opdivo alone, across all lines of treatment (p=0.0003). Last year the combo beat chemo on PFS with a 0.21 hazard ratio (p<0.0001) specifically in first-line patients – Checkmate-8HW's other co-primary endpoint.

Though the combo was already hailed last year as a new standard of care, one question will be whether it should be used in preference to Opdivo alone, given Yervoy's toxicity. The ASCO-GI presentation showed increases in severe immune-mediated adverse events for the combo versus Opdivo monotherapy, particularly as regards endocrine events including adrenal insufficiency and hypophysitis.

However, with Opdivo's PFS numbers not split out by line of therapy it's unclear whether the monotherapy has a chance to be used first line – and Bristol's JP Morgan disclosure suggests that a first-line approval filing isn't being pursued.

Key cross-trial comparisons for Checkmate-8HW are Merck's first-line Keynote-177 and second-line Keynote-164 studies of Keytruda monotherapy. On a PFS basis Bristol's combo appears superior, and even Opdivo monotherapy across all lines looks better than first-line Keytruda, with the caveat that Bristol's PFS curves include a high degree of censoring so are liable to change.

More guidance from Bristol as to its US plans in this cancer type will be eagerly awaited.

Cross-trial comparison in MSI-H/dMMR colorectal cancer

Notes: ^HR for OS is 0.74 (not statistically significant); *data for intent-to-treat population, but the trial’s PFS endpoints related specifically to ~80% of patients whose MSI-H/dMMR status was centrally confirmed, and in whom the HR for PFS was 0.62. Source: OncologyPipeline & ASCO.