FDA looks at Opdivo/Yervoy in first-line colorectal cancer

The FDA has started a priority review of Bristol Myers Squibb's Opdivo and Yervoy as a first-line therapy for patients with a particular form of colorectal cancer (CRC), providing an alternative to rival therapy Keytruda from MSD.

BMS' application covers the use of PD-1 inhibitor Opdivo (nivolumab) with CTLA4 inhibitor Yervoy (ipilimumab) in patients aged 12 and over with previously untreated metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) colorectal cancer that cannot be treated with surgery. The US regulator is due to deliver a verdict by 23rd June.

The application is based on data from the phase 3 CheckMate-8HW study, which showed that Opdivo/Yervoy reduced the risk of disease progression or death by 38% compared to Opdivo plus investigator's choice of chemotherapy.

After approximately four years of follow-up, more than half of patients taking Opdivo plus Yervoy were still alive with no disease progression, down from 79% at the two-year time point reported last year, with median progress-free survival (PFS) of just over 39 months.

Opdivo-Yervoy was given accelerated approval by the FDA in 2018 as a second-line treatment for MSI-H/dMMR CRC after chemo, and the results of CheckMate-8HW could help transform that into a full approval, as well as expand the labelling to include previously-untreated patients. The new first-line indication was approved in the EU and China towards the end of last year.

If approval is forthcoming, it will allow BMS to compete head-to-head in the CRC category with MSD's PD-1 inhibitor Keytruda (pembrolizumab), which was approved in 2020 as a first-line monotherapy for MSI-H/dMMR CRC on the strength of the KEYNOTE-177 trial and is now the standard of care for these patients.

That made the immunotherapy the first alternative to chemo in these patients, on the strength of a 40% reduction in the risk of disease progression or death at two years. After five years of follow-up, the PFS rate was 34% with overall survival (OS) of nearly 55%, although the latter was not a statistically significant difference compared to chemo. OS data for CheckMate-8HW is not yet mature.

"Today's milestone brings us one step closer to providing an effective dual immunotherapy treatment option to adult and paediatric patients with [MSI-H and dMMR CRC]," said Dana Walker, BMS' Opdivo global programme lead.

"We look forward to potentially bringing a new standard of care treatment option to this patient population."

One question for oncologists is whether BMS' dual immunotherapy data can convince them to choose the regimen over Keytruda for their treatment-naïve patients, given that Yervoy adds to the side-effect burden of treatment, with a higher incidence of treatment-related adverse events (TRAEs) compared with Opdivo alone in CheckMate-8HW and a treatment discontinuation rate of 9% versus 4%, respectively.