A new phase II randomized clinical trial has compared the efficacy and safety of two PD-1 inhibitors, dostarlimab and pembrolizumab, in combination with chemotherapy as first-line treatment for patients with metastatic non-squamous non-small cell lung cancer (NSCLC). The PERLA study, funded by GlaxoSmithKline (GSK), was published in Nature Communications on November 15, 2023.
This global, multicenter, double-blind study aimed to evaluate whether dostarlimab plus chemotherapy could demonstrate similar efficacy to the current standard of care, pembrolizumab plus chemotherapy, in previously untreated metastatic non-squamous NSCLC patients without known targetable genomic aberrations. The trial was conducted at 54 study sites across 12 countries, including South Korea, Taiwan, several European countries, Argentina, Brazil, Chile, and the United States.
The study enrolled 243 patients between November 19, 2020 and February 18, 2022. Eligible patients were adults (≥18 years) with metastatic non-squamous NSCLC and measurable disease per RECIST v1.1 criteria. Key inclusion criteria were documented PD-L1 status assessed using the 22C3 pharmDx assay, ECOG performance status of 0-1, and life expectancy ≥3 months. Patients were excluded if they had received prior systemic therapy for metastatic NSCLC or prior therapy with a PD-(L)1/2 inhibitor or another immunotherapy agent.
Patients were randomized 1:1 to receive either 500 mg dostarlimab or 200 mg pembrolizumab intravenously every 3 weeks for up to 35 cycles (~24 months), in combination with standard platinum-based chemotherapy. The chemotherapy regimen consisted of pemetrexed (500 mg/m2 IV Q3W) for up to 35 cycles plus either cisplatin (75 mg/m2 IV Q3W) or carboplatin (AUC 5 mg/mL/min IV Q3W) for the first four cycles.
Baseline demographics and disease characteristics were generally well-balanced between the two treatment arms, with some minor differences. The dostarlimab group had slightly fewer patients aged ≥65 years (46% vs 53%) and fewer female patients (30% vs 37%) compared to the pembrolizumab group. There was also a higher percentage of patients with ECOG performance status 1 in the dostarlimab arm (69% vs 59%), as well as a greater proportion of patients with brain metastases (18% vs 12%) and liver metastases (16% vs 11%).
The primary endpoint was confirmed objective response rate (ORR) as measured by blinded independent central review (BICR) per RECIST v1.1 criteria. Key secondary endpoints included progression-free survival (PFS) based on investigator assessment, overall survival (OS), and safety.
At the July 7, 2023 data cutoff, with a median follow-up of 20.7 months for dostarlimab and 21.6 months for pembrolizumab, the study met its pre-specified endpoint of similar efficacy between the two treatment arms. The confirmed ORR was 45% (95% CI: 36-55%) for dostarlimab plus chemotherapy and 39% (95% CI: 31-49%) for pembrolizumab plus chemotherapy, with a 6% difference (80% CI: -1.95-14.02%; 95% CI: -6.17-18.24%).
Subgroup analyses showed that the ORR numerically favored dostarlimab in PD-L1 positive patients. In the PD-L1 TPS ≥50% subgroup, ORR was 74% for dostarlimab vs 48% for pembrolizumab. For PD-L1 TPS ≥1%, ORR was 59% vs 39%, respectively. However, in PD-L1 negative patients (TPS <1%), pembrolizumab showed a numerically higher ORR (39% vs 26%).
Progression-free survival data from the August 4, 2022 cutoff showed a median PFS of 8.8 months (95% CI: 6.7-10.4) for dostarlimab plus chemotherapy compared to 6.7 months (95% CI: 4.9-7.1) for pembrolizumab plus chemotherapy (HR 0.70; 95% CI: 0.50-0.98). The 9-month PFS rate was 46% vs 36%, respectively.
Overall survival data from the July 7, 2023 cutoff demonstrated a median OS of 19.4 months (95% CI: 14.5-NR) for dostarlimab plus chemotherapy versus 15.9 months (95% CI: 11.6-19.3) for pembrolizumab plus chemotherapy (HR 0.75; 95% CI: 0.53-1.05). The 12-month OS rate was 63% vs 58%, respectively.
The safety profiles were comparable between the two treatment arms and consistent with the known safety profiles of PD-1 inhibitors. The incidence of any-grade treatment-emergent adverse events (TEAEs) was 98% in both groups. Grade ≥3 TEAEs occurred in 64% of patients in both arms. The most common TEAEs were anemia, diarrhea, asthenia, nausea, and neutropenia.
While more patients experienced dostarlimab-related adverse events compared to pembrolizumab-related adverse events (71% vs 57%), there was a numerical trend favoring dostarlimab in several safety parameters. These included lower rates of immune-related adverse events (31% vs 39%), serious adverse events (41% vs 48%), adverse events leading to treatment discontinuation (29% vs 38%), and adverse events leading to immunotherapy discontinuation (17% vs 24%).
The study authors concluded that dostarlimab plus chemotherapy demonstrated similar efficacy to pembrolizumab plus chemotherapy, with a numerically favorable trend in several efficacy parameters. They noted that the efficacy of dostarlimab plus chemotherapy in this study was comparable to previously published data on other first-line PD-1 inhibitor-chemotherapy combinations in similar NSCLC patient populations.
This phase II trial has several strengths, including its global nature which allowed recruitment of a diverse patient population, the use of blinded independent central review for assessing the primary endpoint, and the head-to-head comparison of two PD-1 inhibitors in the same indication. However, there are also some important limitations to consider.
First, as a phase II study with a relatively small sample size, it was not designed or powered to statistically confirm superiority or non-inferiority between the treatments. The pre-specified hypothesis was that the two treatments were "similar," which limits the ability to draw definitive conclusions about differences between dostarlimab and pembrolizumab.
Second, there were some imbalances in baseline characteristics between the treatment arms, particularly in factors like age, gender, ECOG status, and presence of brain/liver metastases. While these differences were relatively small, they could potentially impact the interpretation of the efficacy results.
Third, the pembrolizumab plus chemotherapy arm in this study showed lower efficacy than what was observed in the pivotal KEYNOTE-189 trial, particularly for overall survival. The reasons for this discrepancy are not entirely clear, although differences in patient populations, standards of care over time, and geographical factors may play a role. This highlights the challenges of making cross-trial comparisons and emphasizes the need for caution when interpreting the results in the context of other studies.
Despite these limitations, the PERLA trial represents an important contribution to the field as the first large global study to directly compare two PD-1 inhibitors head-to-head in the same indication. The results suggest that dostarlimab may be a viable alternative to pembrolizumab in combination with chemotherapy for first-line treatment of metastatic non-squamous NSCLC.
The potential clinical impact of this study is significant. If confirmed in larger phase III trials, the findings could provide oncologists with an additional treatment option for patients with metastatic NSCLC. The numerical trends favoring dostarlimab in PD-L1 positive patients and in certain safety parameters may be of particular interest, although these findings require further investigation and validation.
Moreover, this study opens the door for further research into potential differences between PD-1 inhibitors. While these drugs are often considered interchangeable, the PERLA results hint at the possibility of clinically relevant intra-class differences. Future analyses of pharmacodynamic and pharmacokinetic data from this trial may provide additional insights into the underlying mechanisms of any observed differences.
In conclusion, the PERLA trial demonstrates that dostarlimab plus chemotherapy has comparable efficacy to the current standard of care, pembrolizumab plus chemotherapy, as first-line treatment for patients with metastatic non-squamous NSCLC. While larger phase III studies are needed to confirm these findings, this study provides valuable data supporting the further investigation of dostarlimab as a backbone for combination therapies in NSCLC and potentially other cancer types. As our understanding of immune checkpoint inhibitors continues to evolve, studies like PERLA play a crucial role in refining treatment strategies and ultimately improving outcomes for patients with advanced lung cancer.
References
Lim SM, Peters S, Ortega Granados AL, et al. Dostarlimab or pembrolizumab plus chemotherapy in previously untreated metastatic non-squamous non-small cell lung cancer: the randomized PERLA phase II trial. Nat Commun. 2023;14(1):7301. Published 2023 Nov 11. doi:10.1038/s41467-023-42900-4
