Pembrolizumab is an immunotherapy drug that works by blocking a protein called PD-1 on immune cells. PD-1 normally acts as a brake on the immune system. By releasing this brake, pembrolizumab allows the patient's own immune cells to recognize and attack cancer cells more effectively.
The NRG GY018 trial tested whether adding pembrolizumab to standard chemotherapy (paclitaxel plus carboplatin) improves outcomes for patients with advanced or recurrent endometrial cancer compared to chemotherapy alone.
This was a Phase 3 randomized controlled trial, the gold standard for evaluating new cancer treatments. A total of 810 patients with stage III, stage IV, or recurrent endometrial cancer were enrolled. They were randomly assigned to receive either pembrolizumab plus chemotherapy or placebo plus chemotherapy.
Patients were stratified based on their tumor's mismatch repair (MMR) status, which reflects the tumor's ability to fix errors in DNA replication. Tumors with deficient mismatch repair (dMMR) tend to respond better to immunotherapy, while proficient mismatch repair (pMMR) tumors are generally less responsive.
The primary endpoint was progression-free survival (PFS), meaning the time until the cancer worsened or the patient died. Adding pembrolizumab produced a striking benefit in both tumor groups.
In patients with dMMR tumors, the hazard ratio was 0.34, meaning that at any given point in time, the risk of progression or death was 66% lower in the pembrolizumab group compared to placebo. In patients with pMMR tumors, the hazard ratio was 0.57, a 43% reduction in the risk of progression or death. Both results were highly statistically significant.
Overall survival (OS) data were not yet mature at the time of this report, meaning not enough deaths had occurred to draw definitive conclusions. However, early trends favored the pembrolizumab group in both MMR subgroups.
The trial will continue follow-up to capture final OS results. Given the strong PFS benefit, many oncologists anticipate that an OS benefit will also emerge with longer follow-up, particularly for the dMMR subgroup where the effect was largest.
Mismatch repair deficiency (dMMR) causes tumors to accumulate many mutations, which the immune system can more easily recognize as foreign. This makes dMMR tumors particularly sensitive to checkpoint inhibitor immunotherapy like pembrolizumab. Tumors can be tested for MMR status using standard immunohistochemistry staining of surgical or biopsy tissue.
The NRG GY018 results suggest that MMR testing should now be a routine part of evaluating advanced endometrial cancer so that patients with dMMR tumors can receive the greatest benefit from immunotherapy-based treatment.
The safety profile of pembrolizumab combined with chemotherapy was consistent with what has been observed in other cancer types. Immune-related adverse events, such as thyroid problems, skin rashes, and colitis, occurred in some patients receiving pembrolizumab. These are generally manageable and reversible with appropriate medical care.
The overall tolerability allowed most patients to complete the planned treatment course. The added immunotherapy did not dramatically worsen the known side effects of chemotherapy, supporting its use as an addition to the standard regimen.
The NRG GY018 trial establishes that pembrolizumab added to paclitaxel-carboplatin chemotherapy significantly improves progression-free survival for patients with advanced or recurrent endometrial cancer, regardless of MMR status, though the benefit is particularly large for dMMR tumors.
Based on these and parallel results from other trials, pembrolizumab plus chemotherapy has been approved and is now considered a standard first-line treatment option for advanced endometrial cancer. This represents one of the most significant advances in endometrial cancer treatment in many years.