Literature
Clinical Pearls & Morning Reports
Published June 7, 2023
Did dostarlimab plus carboplatin-paclitaxel lower the risk of disease progression or death in the trial by Mirza et al.?
The combination of chemotherapy and immunotherapy may have synergistic effects in the treatment of endometrial cancer. Mirza et al. conducted a phase 3 trial that evaluated the efficacy and safety of dostarlimab in combination with carboplatin and paclitaxel as compared with placebo plus carboplatin and paclitaxel in patients with primary advanced endometrial cancer or a first recurrence of endometrial cancer. Read the NEJM Original Article here.
Clinical Pearls
Q: What is the median overall survival of patients with primary advanced endometrial cancer after standard first-line treatment with chemotherapy?
A: Carboplatin plus paclitaxel is standard chemotherapy for first-line treatment of primary advanced or recurrent endometrial cancer; however, long-term outcomes remain poor, with median overall survival of less than 3 years.
Q: Why might dostarlimab be an effective therapy for endometrial cancer?
A: Mismatch repair–deficient (dMMR), microsatellite instability–high (MSI-H) tumors account for 25 to 30% of endometrial cancers. Increased expression of programmed cell death 1 (PD-1) receptor and its ligands (PD-L1 and PD-L2) and the high tumor mutational burden associated with dMMR–MSI-H tumors make them potentially susceptible to anti–PD-1 and anti–PD-L1 therapies. Dostarlimab is an active immune-checkpoint inhibitor targeting the PD-1 receptor.
Morning Report Questions
Q: Did dostarlimab plus carboplatin-paclitaxel lower the risk of disease progression or death in the trial by Mirza et al.?
A: The dostarlimab regimen was associated with a 72% lower risk of progression or death than the placebo regimen (hazard ratio, 0.28; 95% CI, 0.16 to 0.50; P<0.001) among patients with dMMR-MSI-H tumors. In the overall population, progression-free survival at 24 months was 36.1% (95% CI, 29.3 to 42.9) in the dostarlimab group and 18.1% (95% CI, 13.0 to 23.9) in the placebo group (hazard ratio for progression or death, 0.64; 95% CI, 0.51 to 0.80; P<0.001). Among patients with dMMR-MSI-H tumors, 7 (13%) in the dostarlimab group and 24 (37%) in the placebo group died. Overall survival at 24 months was 83.3% (95% CI, 66.8 to 92.0) in the dostarlimab group and 58.7% (95% CI, 43.4 to 71.2) in the placebo group (hazard ratio, 0.30; 95% CI, 0.13 to 0.70). The authors also observed a benefit with the dostarlimab regimen among patients with mismatch repair-proficient (pMMR), microsatellite-stable (MSS) tumors, although it was smaller in magnitude than that in the dMMR-MSI-H population.
Q: What were some additional findings of the trial?
A: The safety profile of dostarlimab–carboplatin–paclitaxel was consistent with that of the individual components of the regimen. The frequencies of severe and serious adverse events were approximately 10 percentage points higher with the dostarlimab regimen than with the placebo regimen. Rash and maculopapular rash were the adverse events with the largest differences between the treatment groups and were reported more frequently in the dostarlimab group than in the placebo group (22.8% vs. 13.8% for rash and 14.1% vs. 3.7% for maculopapular rash). The frequency of discontinuations of chemotherapy was similar in the two groups. Quality of life was also similar in the two groups during the chemotherapy period.