Discussion
NSCLC, cancer, NSCLCA
LIVER METASTASES, CANCER, RECRUITMENT, NSCLC, EVENTS
This Phase II, randomized, double-blind trial evaluated the efficacy of dostarlimab plus chemotherapy and pembrolizumab plus chemotherapy in newly diagnosed patients with metastatic, non-squamous NSCLC without known targetable oncogenic driver mutations, with the primary endpoint (ORR) assessed based on BICR. An earlier small (N = 68) single-center randomized trial compared the PD-1 inhibitors sintilimab and pembrolizumab as 1 L treatment in advanced NSCLC; however, to our knowledge, the PERLA trial is the first global study that prospectively compared anti-PD-1 therapies head-to-headORR was similar across both treatment groups and at both data-cuts, though numerical differences in ORR were observed overall and between subgroups, with a 6% and 13% difference favoring dostarlimab, by BICR and investigator-assessment, respectively, in the updated analysis. ORR based on BICR numerically favored dostarlimab plus chemotherapy in the PD-L1-positive subgroups (TPS ≥ 1%, TPS 1–49%, and TPS ≥ 50%); however, this study was not formally designed to demonstrate, or statistically powered to test for, superiority. The ORR for dostarlimab plus chemotherapy in this analysis was similar to that observed for pembrolizumab plus chemotherapy in the KEYNOTE-189 trial (45% and 48%, respectively), which evaluated pembrolizumab plus the same chemotherapy regimen (pemetrexed plus cisplatin or carboplatin) versus placebo plus chemotherapy in patients with metastatic non-squamous NSCLCA key difference in patient characteristics between KEYNOTE-189 and PERLA is the slightly higher percentage of patients with brain or liver metastases who received pembrolizumab plus chemotherapy in KEYNOTE-189 (18% and 16%, respectively)PFS and OS were also similar between patients treated with dostarlimab plus chemotherapy and those treated with pembrolizumab plus chemotherapy. PFS (data cut-off: August 4, 2022) was broadly consistent across PD-L1-positive subgroups, with some small differences observed. The median PFS of 8.8 months for dostarlimab plus chemotherapy was numerically higher versus pembrolizumab plus chemotherapy (6.7 months) in the current study and compared favorably to that observed in patients treated with pembrolizumab plus chemotherapy in KEYNOTE-189 (9.0 months)OS data from the August 4, 2022, data-cut were immature (37% maturity, with 90 events in a total of 243 patients; Supplementary Table The evidence of a delayed treatment effect for dostarlimab plus chemotherapy was more prominent in the PD-L1 TPS ≥ 1% subgroup (Supplementary Fig. Safety results were consistent with previously published data on PD-1 inhibitors, with no new safety signals identified. In both treatment groups, 98% of patients experienced any TEAE; in the pembrolizumab plus chemotherapy arm of KEYNOTE-189 this was 99.8%Overall, the antitumor activity of dostarlimab plus chemotherapy in PERLA is in line with previously published data on other 1 L PD-1 inhibitor-chemotherapy combinations in similar non-squamous NSCLC patient populations. Although studies are not directly comparable due to differences in design and populations, the current findings support the hypotheses that dostarlimab plus chemotherapy is effective and tolerable in patients with metastatic non-squamous NSCLC, and that dostarlimab is a suitable PD-1 inhibitor backbone for future combinations under investigation.There is interest among the scientific and clinical community in the comparability of PD-1 inhibitors and whether they show clinically relevant intra-class differences. Cross-trial comparisons suggest that there may be differences in safetyThis study has several strengths and limitations. Strengths include the use of BICR to assess response rates for the primary endpoint of ORR and the global nature of the study, which allowed a diverse patient population to be recruited, including patients from East Asia, South America, the US, and Europe. Global recruitment was facilitated using dynamic eligibility criterion regarding genomic aberrations. In terms of limitations, this is a Phase II study with a small sample size that was not designed to be powered to statistically confirm superiority. While the study design was based on a non-inferiority trial, the large non-inferiority margin and type I error rate (dictated by consideration of the feasible sample size) precluded a hypothesis of true non-inferiority. As such, the pre-specified hypothesis was that the two treatments were ‘similar’. This limits inferences of differences between the two PD-1 inhibitors.In conclusion, dostarlimab plus chemotherapy demonstrates strong clinical efficacy, similar to pembrolizumab plus chemotherapy, in 1 L metastatic non-squamous NSCLC. Safety profiles were also similar and were consistent with published data in PD-(L)1 inhibitors. These results support the further investigation of dostarlimab as a backbone for future use in combination with standard of care and future novel cancer therapies.