Dados do Resumo

Título

Chemotherapy plus PD-1/PD-L1 inhibitor versus chemotherapy alone in first-line treatment for recurrent or advanced endometrial cancer: a systematic review and meta-analysis of randomized controlled trials.

Introdução

Chemotherapy (CT) combined with PD-1/PD-L1 inhibitors is emerging as a new standard of care for primary advanced or recurrent endometrial cancer. Recently, studies have been published showing a clinical benefit of adding immunotherapy to chemotherapy, particularly in DNA mismatch repair deficient (MMRd)/microsatellite instability-high (MSI-H) disease. Whether this should also be applied to patients with mismatch repair proficient (MMRp)/microsatellite stable (MSS) tumors is still an open question.

Objetivo

Despite existing data, trials typically lack sufficient power for definitive assessment of secondary outcomes, especially in subgroups. Therefore, we conducted a systematic review and meta-analysis examining the efficacy of PD-1/PD-L1 inhibitors plus chemotherapy compared to chemotherapy alone, focusing on subpopulations, such as the biomarker-negative population.

Métodos

PubMed, Embase, and Cochrane database were searched for randomized controlled trials (RCTs) comparing first-line CT plus PD-1/PD-L1 inhibitor versus CT, with or without (w/w) placebo, for patients with primary advanced or recurrent endometrial cancer. The primary endpoints of interest were progression free survival (PFS), overall survival (OS), overall response rate (ORR), complete response rate (CRR), and adverse events (AE) grade ≥ 3. Heterogeneity was examined with I2 statistics, and a fixed-effects model was employed for analysis. Statistical analysis was performed using Review Manager Web.

Resultados

We included 5 RCTs with 2460 patients, of whom 1143 (46.5%) received CT plus PD- 1/PD-L1 inhibitor, and 1672 (68.0%) had MMRp/MSS tumors. Mean follow-up ranged from 7.9 to 28.3 months. The combination of CT plus anti-PD-1/PD-L1 demonstrated superiority in PFS (HR 0.72; 95% CI 0.65-0.80; p < 0.0001) and OS (HR 0.77; 95% CI 0.65-0.91; p = 0.002), compared to CT w/w placebo in the all-comer population. In MMRd/MSI-H patients, PFS (HR 0.34; 95% CI 0.27-0.44; p < 0.00001) and OS (HR 0.37; 95% CI 0.24-0.59; p < 0.0001) were statistically significantly better in combination group. For patients with MMRp/MSS disease, PFS was improved (HR 0.76; 95% CI 0.68-0.86; p < 0.0001), but OS was not significantly different between groups (HR 0.92; 95% CI 0.74- 1.14; p = 0.44). CT plus PD-1/PD-L1 inhibitor also led to a higher ORR (OR 1.50; 95% CI 1.13-2.00; p = 0.006) and CRR (OR 1.56; 95% CI 1.12-2.18; p = 0.009) in MMRp/MSS patients. AE grade ≥ 3 were more often when immune checkpoint inhibitor was added (HR 1.46; 95% CI 1.23-1.75; p < 0.0001).

Conclusões

These findings suggest that combining a PD-1/PD-L1 inhibitor with CT improves PFS, but not OS, in first-line treatment for recurrent or advanced MMRp/MSS endometrial cancer, with greater toxicity. It is worth noting that, given the immaturity of OS data, a survival benefit may still be observed with longer follow-up, albeit of lower magnitude, compared with MMRd/MSI-H tumors. Therefore, we still need to identify better treatment options for non-biomarker-selected patients.

Palavras Chave

endometrial cancer; immunotherapy; biomarker