Study showing feasibility and possible improvements in DFS with chemo + pembro vs. chemo alone in the adjuvant setting of resected endometrial cancer in dMMR patients. While a nice idea / proof of principle, I would be more interested in how IO alone performs vs. chemo in this setting, particularly if a brief course of neoadjuvant IO is given prior to surgery.
Mismatch repair-deficient (dMMR) endometrial cancer (EC) is an inflamed phenotype with poor outcomes when meeting high-risk criteria and limited treatment options in the adjuvant setting. We report protocol-prespecified subgroup analysis of patients with dMMR tumors from the phase III ENGOT-en11/GOG-3053/KEYNOTE-B21 study (ClinicalTrials.gov identifier: NCT04634877) in newly diagnosed, high-risk EC after surgery with curative intent. Patients were randomly assigned to pembrolizumab 200 mg or placebo (six cycles) plus carboplatin-paclitaxel (four to six cycles) once every 3 weeks, then pembrolizumab 400 mg or placebo once every 6 weeks (six cycles), respectively. MMR status was a stratification factor. Patients received radiotherapy at investigator discretion. Investigator-assessed disease-free survival (DFS) was a primary end point. No formal hypothesis testing was performed for subgroup analysis. 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, hazard ratio for DFS favored pembrolizumab (0.31 [95% CI, 0.14 to 0.69]); median DFS was not reached in either group. Two-year DFS rates were 92.4% (95% CI, 84.4 to 96.4) and 80.2% (95% CI, 70.8 to 86.9), respectively. No new safety signals occurred. Longer-term follow-up of outcomes will be evaluated at final analysis. Preplanned subgroup analysis on the basis of the study’s stratification factors suggests that pembrolizumab plus chemotherapy improves DFS and is clinically relevant for patients with dMMR tumors in the curative-intent setting.
For patients with local recurrences of endometrial cancer, XRT alone is extremely effective, and the addition of cisplatin does not offer any benefit while increasing toxicity. These patients with low-grade and vaginal recurrences have a good prognosis and most should be treated with XRT alone.
Initial results from the DUO-E study in metastatic endometrial cancer. The preliminary report suggests that maintenance durvalumab and maintenance durvalumab + olaparib were superior to standard observation after systemic carbo/taxol. As the trial data matures, the question will be: is this in all patients or driven by those with dMMR or HDR mutations?
This is another possibility for maintenance therapy. It will require further study.
An interesting study where the authors performed a post hoc analysis of randomized trials using molecular classification of endometrial cancers. There was good evidence to omit RT for those with POLE mutations and def-MMR. There seems to be a higher degree of benefit in those with a p53 mutation.
Large phase III study of carbo/taxol+pembro x 6 followed by pembro alone x 14 cycles in metastatic endometrial cancer. There was a benefit in both pMMR and dMMR patients, although the magnitude was unsurprisingly higher in those with dMMR. OS results are still pending, and carcinosarcoma-type histology was excluded. This combination has been approved and is on NCCN as a cat-1 recommendation.
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