Bristol-Myers Squibb scored a huge win the other day because it was able to receive FDA approval of OPDIVO and YERVOY for the treatment of pediatric patients and adults ages 12 and older for 1st-line and 2nd-line treatment of unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) colorectal cancer (CRC).
The thing is that it was already granted Accelerated Approval of OPDIVIO as a monotherapy or in combination with YERVOY for the treatment of 2nd-line patients with MSI-H/dMMR metastatic colorectal cancer. In this setting, such patients are in dire shape because they progressed in disease, despite having received treatments of fluoropyrimidine, oxaliplatin, and irinotecan.
Thus, the win here is that the company was able to convert such an accelerated approval of the OPDIVO and YERVOY combination to full approval. Besides nabbing this win for the combination therapy, it was able to receive FDA approval for treating pediatric and adult patients ages 12 and older with 1st-line MSI-H/dMMR colorectal cancer.
The ability to convert FDA accelerated approval to full approval of the 2nd-line setting, plus receive FDA approval in the 1st-line setting, was thanks to the phase 3 CheckMate-8HW trial. This specific study was a large one, in that it recruited a total of 839 patients with this type of colorectal cancer (CRC). In essence, it is believed to be the largest immunotherapy study of its kind to target MSI-H/dMMR CRC patients.
However, this study set up the ability to be split up in terms of what was being targeted. For instance, with respect to comparing the use of OPDIVO and YERVOY versus OPDIVO monotherapy, this was compared to that of targeting all-lines setting. On the flip side, the OPDIVO and YERVOY combination in the other portion of the study was being compared to that of the investigator’s choice of chemotherapy (mFOLFOX-6 or FOLFIRI) with or without AVASTIN (bevacizumb) in the 1st-line setting.
The basis for these FDA wins was because of achieving the primary endpoint of progression-free survival in both all-line settings and the 1st-line setting. With respect to the first-line setting, OPDIVO and YERVOY reduced the risk of disease progression or death by 79% versus chemotherapy. In the all-lines therapy portion of this phase 3 CheckMate-8HW trial, it reduced the risk of disease progression or death by 38%.
The FDA was committed to getting this combination out to these patients because the Prescription Drug User Fee Act, or PDUFA date was set for June 23, 2025. This approval occurred two months ahead of this expected review date, which underscores the need for these therapies to help these MSI-H/dMMR CRC patients.
This is not the end of what can be achieved with respect to this particular phase 3 study. Investors can expect to see other data from this very same trial later on. The reason why is because Bristol-Myers Squibb is still in the process of evaluating secondary endpoints from the study, like overall survival (OS). This endpoint and other secondary efficacy endpoints are to be presented by investigators of this study at a future medical meeting. The bottom line here is that this marks the 9th indication that OPDIVO had received approval for in the gastrointestinal space.
In terms of the science, PD-1 inhibitors like OPDIVO have a major task at hand. The goal of this drug is to bind to PD-1 on a T-cell’s surface, and the reason why is to block the attachment and signaling of PD-L1 on a tumor cell’s surface. This is important because if left unchecked, the PD-1 signal sent creates an inhibitor action, which tells the T-cell to no attack the cancer cell itself. This leaves the tumor with the ability to avoid attack from T-cells. This drug is set in place to block this inhibitory signal from even happening, thus leading to the T-cell being able to attack and kill it. The CTLA-4 protein component in cancer cells is responsible for downregulating T-cell response. Thus, YERVOY is an anti-CTLA4 that removes the dormant nature of T-cells [immune cells] to attack and kill cancer cells. The combination of these two drugs is ideal because they have a synergistic effect in targeting two different types of immune checkpoints to allow a significant immune response.