Upfront Dostarlimab/Chemotherapy Yields Better Risk Reduction Than Pembrolizumab/Chemotherapy in NSCLC

Solange Peters, MD

Phase 2 findings showed that dostarlimab (Jemperli) led to a superior reduction in the risk of disease progression or death than pembrolizumab (Keytruda) plus chemotherapy as a frontline treatment for patients with metastatic non-squamous non–small cell lung cancer (NSCLC). Findings were presented at the ESMO Immuno-Oncology Congress 2022. The reduction in risk of disease reduction or death was 30% compared better than with pembrolizumab.¹

In the randomized phase 2 PERLA study (NCT04581824), the median progression-free survival (PFS), which was a secondary end point, with dostarlimab/chemotherapy was 8.8 months (95% CI, 6.7-10.4) compared with 6.7 months (95% CI, 4.9-7.1) with pembrolizumab/chemo (HR, 0.70; 95% CI, 0.50-0.98). The objective response rate (ORR) by blinded independent review, which was the primary end point, was 46% with dostarlimab compared with 37% for pembrolizumab.

“PERLA is the first large global, randomized, double-blind, phase 2 study to directly compare PD-1 inhibitors,” Solange Peters, MD, head of the Medical Oncology Service and chair of Thoracic Oncology at Centre Hospitalier Universitaire Vaudois in Lausanne, Switzerland, said in a presentation during the meeting. “These results therefore support the further investigation of dostarlimab as a treatment backbone for use in combination with standard of care and/or future novel cancer therapies.”

In the study, 243 patients were randomized to chemotherapy combined with either dostarlimab (n = 121) at 500 mg every 3 weeks or pemetrexed (n = 122) at 200 mg every 3 weeks. Chemotherapy consisted of pemetrexed combined with carboplatin or cisplatin at standard doses. Patients were stratified by PD-L1 status, which was assessed using the 22C3 pharmDx assay using tumor proportion score. Median follow up was 5.8 months in the dostarlimab arm and 5.0 months for pembrolizumab.

Baseline characteristics between the arms were balanced, with nearly half of patients aged 65 or older (46% vs 53%, for dostarlimab and pembrolizumab arms, respectively). ECOG status was either 0 or 1, with most patients having a score of 1 (69% and 59%, respectively). Most patients were former smokers (86%) and half were enrolled in Europe (51% vs 53%), with few enrolled in the United States (n = 3). Brain metastases were diagnosed in 18% of patients in the dostarlimab arm and in 12% of those in the pembrolizumab group. Liver metastases were present at baseline in 16% and 11% of patients in each group, respectively.

ORR in the dostarlimab/chemotherapy arm consisted primarily of partial responses (n = 54; 45%), with 2 patients achieving a complete response (2%). Additionally, 40% of patients (n = 48) experienced stable disease. In the pembrolizumab/chemotherapy arm, 42 patients had a partial response (34%) and 3 experienced a complete response (2%). The stable disease rate in this group was 43%. The rates of progressive disease were 10% and 9%, respectively.

In patient with a PD-L1 TPS of less than1%, the ORR was 28% with dostarlimab/chemotherapy (N = 50) and 33% for pembrolizumab/chemotherapy (N = 51) and the PFS was 7.0 months and 6.9 months, respectively (HR, 0.77; 95% CI, 0.46-1.28). In patients with a PD-L1 TPS of 1% or greater, the ORR was 59% with dostarlimab/chemotherapy (N = 71) vs 39% with pembrolizumab/chemotherapy (N = 71). The PFS in this population was 10.4 months compared with 6.1 months, respectively (HR, 0.66; 95% CI, 0.41-1.03).

In those with a PD-L1 TPS of 1% to 49%, the ORR was 50% with dostarlimab/chemotherapy (N = 44) vs 34% with pembrolizumab/chemo (N = 44) and the PFS was 9.0 months vs 5.4 months (HR, 0.67; 95% CI, 0.38-1.19). In patients with a TPS of 50% or more, the ORR was 74% with dostarlimab/chemotherapy (N = 27) and 48% with pembrolizumab/chemotherapy (N = 27). The median PFS in this group was 10.4 months with dostarlimab/chemotherapy and 6.7 months with pembrolizumab/chemotherapy (HR, 0.60; 95% CI, 0.27-1.29).

Adverse events (AE) of any grade occurred in 97% of patients in both arms, with treatment-related AEs (TRAEs) occurring in 82% of those in the dostarlimab/chemotherapy arm and for 79% of those in the pembrolizumab/chemotherapy arm. TRAEs of grade 3 or higher in severity occurred in 36% of those in the dostarlimab/chemotherapy arm and for 42% of those in the pembrolizumab/chemo arm. The most common TRAEs were anemia, asthenia, nausea, and neutropenia.

AEs led to discontinuation for 25% of those in the dostarlimab/chemotherapy arm compared with 32% of those in the pembrolizumab/chemo arm. Serious AEs (SAEs) were reported in 38% and 45% of patients, with 12% and 10% experiencing a fatal SAE, in the dostarlimab/chemotherapy and pembrolizumab/chemo arms, respectively. The rate of fatal treatment-related SAEs was 2% with dostarlimab/chemotherapy and 4% with pembrolizumab/chemo.

Immune-related AEs (irAEs) were seen in 26% of patients treated with dostarlimab plus chemotherapy and for 34% of those receiving pembrolizumab and chemotherapy. The rates of grade 3 or higher irSAEs were 5% and 8%, for the dostarlimab and pembrolizumab groups, respectively.

“The proportion of patients experiencing TRAEs was similar between groups. Safety profiles were similar and broadly consistent with published data, and no new safety signals were identified for either therapy,” Peters said. “A numerical trend in the number of grade 3 or higher TRAEs, AEs leading to treatment discontinuation, SAEs, and irEAs in favor of dostarlimab was noted between groups.”

Dostarlimab is currently being investigated across several clinical trials, including those for endometrial cancer and rectal cancer. In August 2021, the PD-1 inhibitor received an accelerated approval as a treatment for adult patients with mismatch repair deficient recurrent or advanced solid tumors, following progression on other treatments and when no other satisfactory alternative treatment options existed.² In addition to PERLA, dostarlimab is being explored in combination with docetaxel and cobolimab, a TIM-3 antagonist, in the COSTAR Lung study (NCT04655976).

Reference

1. Peters S, Lim SM, Ortega Granados AL, et al. Randomized double-blind phase II trial (PERLA) of dostarlimab (dostar) + chemotherapy (CT) vs pembrolizumab (pembro) + CT in metastatic non-squamous NSCLC: primary results. Presented at ESMO Immuno-Oncology Congress 2022; December 7-9, 2022; Geneva, Switzerland.
2. FDA grants accelerated approval to dostarlimab-gxly for dMMR advanced solid tumors. News release. FDA. August 17, 2021. Accessed December 13, 2022. bit.ly/3YxfApx