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Adding immunotherapy to chemotherapy in the adjuvant setting for endometrial cancer patients with mismatch repair-deficient (dMMR) tumors significantly increased disease-free survival (DFS), according to a phase III study.

The randomized, double-blind evaluated pembrolizumab or placebo plus adjuvant chemotherapy with or without radiotherapy in patients with newly diagnosed, high-risk endometrial cancer.

As Brian Slomovitz, MD, of Mount Sinai Medical Center in Miami Beach, and colleagues noted in the study in the , patients were randomized to receive pembrolizumab at 200 mg or placebo every 3 weeks for six cycles added to carboplatin-paclitaxel followed by pembrolizumab at 400 mg (545 patients) or placebo every 6 weeks for six cycles (550 patients) per treatment assignment. Radiotherapy was at the investigator's discretion.

Adjuvant pembrolizumab plus chemotherapy did not extend DFS in the overall population of patients with newly diagnosed, high-risk endometrial cancer, but did in the subgroup (a preplanned analysis) of patients with dMMR cancers.

In the following interview, Slomovitz, who is director of Gynecologic Oncology and co-chair of the Cancer Research Committee, elaborated on the results.

What does this article add to the literature?

Slomovitz: Immunotherapy with checkpoint inhibitors such as pembrolizumab has been shown to help prevent disease recurrence in endometrial cancer patients in the first line and second line. We looked at whether earlier treatment in the adjuvant setting will work as well once we identified patients with dMMR tumors using molecular profiling. We saw results in the dMMR population not seen in the general population.

Among all 1,095 patients in the intention-to-treat population, 141 patients in the pembrolizumab arm and 140 in the placebo arm had dMMR tumors. At this interim analysis, the hazard ratio for DFS favored pembrolizumab (0.31, 95% CI 0.14-0.69). Median DFS was not reached in either group. Two-year DFS rates were 92.4% (95% CI 84.4-96.4) and 80.2% (95% CI 70.8-86.9), respectively.

We demonstrated in the adjuvant setting the DFS for this subpopulation with a higher risk of disease recurrence had a 69% reduction in that risk when treated with a checkpoint inhibitor.

Based upon these results, adding pembrolizumab to chemotherapy deserves serious consideration as adjuvant therapy for these patients.

How do you explain the greater benefit in the dMMR population?

Slomovitz: We know that immunotherapy works in dMMR tumors. The boost in immune response may jump-start the immune system and therefore have a larger therapeutic impact.

In patients with no measurable disease, immunotherapy does not work as well as for those in the recurrent setting with measurable disease. One explanation may be due to a microenvironment effect. Checkpoint inhibitors do not need more bulky disease to have a therapeutic effect.

Why do you believe a double-blind, placebo-controlled study would be a more reliable assessment of disease status?

Slomovitz: The hazard ratio was slightly higher with blinded independent central review (BICR) than investigator assessment -- 0.6 vs 0.3. However, prolonged follow-up of recurrences by BICR showed no clinical or radiological evidence of disease.

The disease course was more aligned with clinical assessment, which is more than just an independent radiologist looking at disease. BICR has limitations in the absence of other clinical information, including symptoms, physical examination findings, laboratory values such as tumor markers/ctDNA, intermittent medical diagnoses, adverse events that appear as recurrence, and biopsies for confirmation.

How would you characterize the safety profile of the combination therapy?

Slomovitz: The safety profile of the combination therapy was manageable in the dMMR subgroup, with no new safety concerns. No clinically meaningful between-group differences were observed in quality-of-life scores. Safety and patient-reported outcome findings were consistent with those in all-comers, and the types of adverse events were as expected based on the safety profiles of the individual agents.

What do you expect from the results of ongoing studies in patients with dMMR endometrial cancer in the adjuvant setting?

Slomovitz: Studies in patients with dMMR endometrial cancer in the adjuvant setting are anticipated to yield data in the near future. is a phase III, randomized, open-label study evaluating first-line pembrolizumab versus carboplatin-paclitaxel chemotherapy in patients with dMMR advanced or recurrent endometrial cancer, and has finished accruing patients.

We have learned that colon cancers with dMMR tumors may not need chemotherapy, and we may be able to expand this experience to endometrial cancer patients with dMMR tumors. Checkpoint inhibitors alone in the first-line setting are as good as chemotherapy in endometrial cancer. We could look further to eliminate chemotherapy in the adjuvant setting as well.

What is the main message for practicing oncologists?

Slomovitz: We are finding ways to enhance the curative intent, and adding pembrolizumab to chemotherapy provides one such opportunity. The goal is to cure patients and reduce toxicity.

We look forward to further studies to change the standard of care for endometrial cancer patients with dMMR tumors. We may be able to incorporate immunotherapy into all lines of therapy, including the adjuvant setting.

Read the study here and expert commentary about it here.