Old drugs from Bristol Myers Squibb and Pfizer have delivered what the companies and researchers believe could establish them as new standard treatments for certain colorectal cancer patients.
In BMS’ case, the company’s dual immunotherapy of Opdivo and Yervoy showed it could work better than Opdivo alone in patients with certain metastatic colorectal cancer. The combo lowered the risk of disease progression or death by 38% in patients with microsatellite instability-high or mismatch repair-deficient (MSI-H/dMMR) tumors, according to data from the phase 3 CheckMate-8HW trial to be presented at the ASCO Gastrointestinal Cancers Symposium.
The study randomized 707 patients across various lines of treatment, with 55% of participants in the Opdivo-Yervoy arm and 52% of the Opdivo monotherapy arm entering in the first-line setting.
After 47 months of median follow-up, more than half of Opdivo-Yervoy takers were still alive and had no disease progression, while the median progression-free survival mark was reached at 39.3 months for the Opdivo arm.
The latest CheckMate-8HW update was expected. Previously, the trial had already met its other dual primary endpoint, showing the Opdivo-Yervoy combo slashed the risk of tumor progression or death by 79% versus chemo alone in first-line patients with centrally confirmed MSI-H/dMMR metastatic colorectal cancer. The new analysis was carried out between Opdivo-Yervoy and Opdivo in patients regardless of line of treatment.
MSI-H/dMMR tumors are known to respond better to immunotherapy because these cancer cells look more foreign to the immune system. Therefore, adding Yervoy, a CTLA4 immune checkpoint inhibitor, marks a rational treatment strategy.
But Yervoy in its currently FDA-approved indications has only captured some markets, partly because of its toxicity.
In CheckMate-8HW, investigators didn’t record any new safety concerns from the Opdivo-Yervoy combo, which showed a higher 22% rate of grade 3 or 4 treatment-related adverse events, versus 14% for Opdivo alone. There were two treatment-related deaths out of 352 patients in the combo arm, versus one such death out of 351 individuals in the monotherapy arm.
“These results establish [Opdivo and Yervoy] as the potential new standard-of-care treatment for MSI-H/dMMR mCRC,” the trial investigators wrote in an abstract.
Separately, also at the ASCO GI conference, Pfizer unveiled detailed data that recently got its Braftovi approved alongside Eli Lilly’s Erbitux and chemotherapy as a first-line treatment of BRAF V600E-mutant metastatic colorectal cancer. Tumors with this biomarker constitute about 8% to 12% of all metastatic colorectal cancer, according to academic studies.
The year-end accelerated approval was unique in that it was exactly what the FDA has envisioned under Project FrontRunner—using a surrogate endpoint from a randomized phase 3 trial to first facilitate an accelerated approval while the same trial continues toward a more mature readout to potentially support a full approval.
In the phase 3 BREAKWATER trial, the Braftovi-Erbitux-chemo combo was more likely to trigger a response than standard chemotherapy with or without bevacizumab. The overall response rate was 60.9% for the new regimen, versus 40% for the control arm. The study has therefore met one of its dual primary endpoints.
At the data cutoff in late 2023, a very strong trend for an overall survival improvement was observed as the combo was linked to a 53% reduction in the risk of death. The showing has not reached statistical significance at that interim analysis, and additional follow-up is ongoing.
In terms of safety, the new combo showed no substantial increase in chemotherapy dose reduction or discontinuation due to adverse events compared with the control arm, according to a presentation. Overall, 15.6% of patients in the experimental arm had their chemo discontinued, versus 14.9% in the control arm. Dose reduction of chemo happened in 55.8% and 47.8% of patients, respectively.
The BREAKWATER study supports Braftovi-Erbitux-chemo as a new first-line standard-of-care for patients with BRAF V600E-mutant metastatic colorectal cancer, the study researchers said in the presentation.
Before the FDA’s December nod, the Braftovi-Erbitux combo—without chemo—has been available for previously treated BRAF V600E-mutant colorectal cancer since 2020, competing with Novartis’ Tafinlar-Mekinist duo, which boasts a second-line tumor-agnostic indication for any solid tumors that have a BRAF V600E mutation.