Strong Clinical Efficacy With Dostarlimab and Chemo in Advanced NSCLC

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Chemotherapy plus dostarlimab-gxly (Jemperli) demonstrated a higher objective response rate (ORR) and delivered improved overall survival (OS) compared with chemotherapy and pembrolizumab (Keytruda) in patients with treatment-naïve, nonsquamous non–small cell lung cancer (NSCLC), according to data from a preplanned updated OS analysis of the phase 2 PERLA trial (NCT04581824) presented at the 2023 ESMO Congress.¹

With a median follow-up of 20.7 months (95% CI, 19.3-22.3) in the dostarlimab arm (n = 121) and 21.6 months (95% CI, 19.6-23.1) in the pembrolizumab arm (n = 122), and OS data maturity at 55.1% (n = 134/243), the median OS was 19.4 months (95% CI, 14.5-not reached [NR]) and 15.9 months (95% CI, 11.6-19.3), respectively (HR, 0.75; 95% CI, 0.53-1.05).

Dostarlimab plus chemotherapy induced an ORR of 45% (95% CI, 36.4%-54.8%) vs 39% (95% CI, 30.6%-48.6%) with pembrolizumab plus chemotherapy, which translated to a difference of 6.04% (95% CI, –6.17% to 18.24%). In the dostarlimab arm, the complete response rate was 3%, the partial response rate was 42%, and the stable disease rate was 40%; in the pembrolizumab arm, these rates were 5%, 34%, and 39%, respectively. Twelve patients in each arm experienced progressive disease (PD).

“Results are consistent with the study hypothesis that dostarlimab and pembrolizumab have similar efficacy,” Solange Peters, MD, ESMO past president, full professor and chair of medical oncology and the Thoracic Malignancies Program in the Department of Oncology at the University Hospital of Lausanne in Switzerland, said in a presentation of the data. “…These results support further investigation of dostarlimab as a treatment backbone in combination with standard-of-care treatments and future novel cancer therapies in patients with NSCLC.”

It is known the PD-1/PD-L1 inhibition improves outcomes in patients with metastatic nonsquamous NSCLC, both as single agents and when paired with chemotherapy compared with chemotherapy alone. Dostarlimab binds to PD-1 at distinct binding sites with different binding orientations from other PD-1 inhibitors, Peters noted.

In August 2021, the FDA granted accelerated approval to dostarlimab for use in adult patients with mismatch repair–deficient (dMMR) recurrent or advanced solid tumors that have progressed on or after prior treatment and who have no satisfactory alternative options.2 In February 2023, dostarlimab received full approval for use in dMMR recurrent or advanced endometrial cancer that has progressed on or following a platinum-based regimen in any setting and who are not eligible to undergo curative surgery or radiation.³ Most recently, in July 2023, dostarlimab plus chemotherapy followed by single-agent dostarlimab was FDA approved for use in adult patients with primary advanced or recurrent endometrial cancer that is dMMR or microsatellite instability high.⁴

PERLA, the first global, randomized, double-blind, head-to-head study of 2 PD-1 inhibitors, enrolled patients with histologically or cytologically confirmed metastatic nonsquamous NSCLC without known targetable oncogenic driver mutations.1 Patients were required to have documented PD-L1 status, an ECOG performance status of 0 or 1, and acceptable organ function. They could not have previously received systemic treatment for metastatic disease.

Study participants were randomly assigned 1:1 to receive 500 mg of dostarlimab plus chemotherapy every 3 weeks or 200 mg of pembrolizumab plus chemotherapy every 3 weeks. Chemotherapy consisted of pemetrexed at 500 mg/m2 every 3 weeks for up to 35 cycles and carboplatin at area under the curve 5 mg/mL/min or cisplatin at 75 mg/m2 every 3 weeks for up to 4 cycles. Treatment continued until PD, intolerable toxicity, death, or up to 35 cycles.

Key stratification factors included PD-L1 expression (tumor proportion score [TPS] of <1% vs 1% to 49% vs ≥50%) and smoking status (never vs former/current).

Confirmed ORR by blinded independent central review (BICR) and RECIST v1.1 criteria served as the trial’s primary end point. Secondary end points included OS; progression-free survival by RECIST v1.1 criteria and investigator assessment; and safety. Duration of response by RECIST v1.1 criteria and BICR represented an exploratory end point of interest.

“The primary analysis was allowed to confirm that the ORR was met, with equivalence of the 2 compounds, and I’m sure you have the question in mind, it meant that the study could detect this equivalence in response rate with an 85% power, enabling us to detect the 15% difference in response rate between the 2 arms at a 10% one-sided type I error rate, [when the true ORR is] 45% [for] both arms,” Peters said.

In the primary analysis, the combination of dostarlimab and chemotherapy showed numerical trends in ORR and PFS compared with pembrolizumab plus chemotherapy, meeting the primary end point.1,5 The ORR in the dostarlimab arm was 46% (95% CI, 37.2%-55.6%) vs 37% (95% CI, 28.3%-46.1%) in the pembrolizumab arm.⁶ Subgroup analyses showed similar ORRs across the subsets of patients with nonsquamous NSCLC for both combinations, with responses numerically favoring the dostarlimab combination in most subgroups.

At the 2023 ESMO Congress, Peters shared insights from the preplanned updated OS analysis.¹

“[When looking at the] demographics and baseline characteristics, you can see in bold what has been seen to be different between the 2 treatment arms in favor of the pembrolizumab plus chemotherapy,” Peters said. “There were more males, more patients with brain metastases, more patients with liver metastases, and more patients with an ECOG performance status of 1 in the dostarlimab plus chemotherapy arm. In favor of the dostarlimab plus chemotherapy arm, there were more patients [who were over] 60 years old in the pembrolizumab plus chemotherapy arm. Of interest, if you look at PD-L1 [expression,] it was, of course, a stratification factor and well balanced. But more than 40% of the patients are negative for PD-L1, which is a bit more than what would be expected based on all the data we have and recent clinical trials.”

At the data cutoff date of July 7, 2023, 48% of patients in the dostarlimab arm were still receiving treatment vs 34% of those on the pembrolizumab arm.

“Importantly, more patients had died due to any reason in the pembrolizumab plus chemotherapy arm, at 61%, as compared with 49% in the dostarlimab plus chemotherapy arm,” Peters noted.

Patients in the dostarlimab arm received a median of 13 treatment cycles (range, 1-35) vs 7.5 cycles (range, 1-35) in the pembrolizumab arm. The median duration of exposure was 9 months (range, 0.3-26.8) and 6 months (range, 0.2-25.3) in the dostarlimab and pembrolizumab arms, respectively.

Investigators also examined OS by PD-L1 TPS status. “This numerical difference in OS [with dostarlimab vs pembrolizumab] was seen in all patients with positive PD-L1 assessment, as you can see in the strata of [TPS of] more than 1%, 1% to 49%, and more than 50%,” Solange said.

In the group of patients with a PD-L1 TPS of 1% or higher, the median OS was 18.0 months (95% CI, 12.7-NR) and 15.9 months (95% CI, 7.8-NR) with dostarlimab and pembrolizumab, respectively. In the subset of patients with a PD-L1 TPS ranging from 1% to 49%, the median OS with dostarlimab was 17.6 months (95% CI, 10.5-NR) vs 14.5 months (95% CI, 6.5-NR) with pembrolizumab. In those with a PD-L1 TPS of 50% or higher, the median OS in the dostarlimab arm was 19.4 months (95% CI, 9.9-NR) vs 17.6 months (95% CI, 6.2-22.2) in the pembrolizumab arm.

In those with a PD-L1 TPS of less than 1%, the median OS in the dostarlimab and pembrolizumab arms was 20.8 months (95% CI, 11.4-NR) and 16.1 months (95% CI, 11.6-20.1), respectively. “In the negative PD-L1 patients, the Kaplan-Meier curves cross more than once, making the difference difficult to assess,” she noted. “However, the drug seems equivalent, and if anything, the median OS is still numerically superior for dostarlimab plus chemotherapy as compared with pembrolizumab plus chemotherapy.”

Regarding safety, the proportion of patients experiencing adverse effects (AEs), including grade 3 or higher AEs, proved to be comparable between the treatment arms. Any-grade AEs were experienced by 98% of those who received dostarlimab and 98% of those given pembrolizumab; 71% vs 57% of patients experienced immunotherapy (IO)-related AEs, and 64% of patients in both arms had grade 3 or higher AEs. The most common IO-related AEs occurring in at least 10% of patients of either arm included anemia, asthenia, and rash.

The proportion of patients who experienced AEs that led to treatment discontinuation proved to be lower in the dostarlimab arm vs the pembrolizumab arm, at 29% and 38%, respectively; this was also true with regard to IO-related AEs resulting in discontinuation (17% vs 24%).

Moreover, immune-related AEs occurred in 31% and 39% of patients in the dostarlimab and pembrolizumab arms, respectively. Serious toxicities were observed in 41% of those in the dostarlimab arm vs 48% of those in the pembrolizumab arm, with IO-related serious AEs occurring in 12% and 14% of patients, respectively. Twelve percent of patients in the dostarlimab arm had a fatal AE vs 10% of those in the pembrolizumab arm; fatal IO-related AEs occurred in 2% of patients in both arms.

“Safety profiles were similar and consistent with the primary analysis and other published data,” Peters concluded.

Subsequently, Noemi Reguart, MD, PhD, of the Hospital Clinic in Barcelona, Spain, shared her thoughts on the PERLA study, stating that the data “confirm the efficacy of dostarlimab plus chemotherapy in nonsquamous NSCLC, [and are] overall comparable with other landmark trials.” She stressed that the “subgroup outcomes and numerical trends must be taken with caution,” that it is important to remember that PERLA had a “randomized phase 2 design” and that there is “limited interpretation of subgroups.”

She agreed that the findings do support the examination of dostarlimab as part of novel combinations and mentioned that the phase 2 GALAXIES LUNG-201 study (NCT05565378) is recruiting and will examine the safety, efficacy, pharmacokinetics, and pharmacodynamics of novel IO combinations vs single-agent IO drugs in patient with PD-L1–high, previously untreated, unresectable, locally advanced or metastatic NSCLC.7 Dostarlimab is one of the drugs that will be evaluated in the trial.

Editor’s Note: Dr Peters disclosed that she serves in an advisory role for AbbVie, AiCME, Amgen, Arcus, AstraZeneca, Bayer, BeiGene, Biocartis, BioInvent, Blueprint Medicines, Boehringer Ingelheim, Bristol Myers Squibb, Clovis, Daiichi Sankyo, Debiopharm, ecancer, Eli Lilly, Elsevier, F-Star, Fishawack, Foundation Medicine, Genzyme, Gilead, GlaxoSmithKline, Illumina, Imedex, IQVIA, Incyte, iTeos, Janssen, Medscape, Medtoday, Merck Sharp and Dohme, Merck Serono, Merrimack, Novartis, Novocure, OncologyEducation, Pharma Mar, Phosplatin Therapeutics, PER, Peerview, Pfizer, PRIME, Regeneron, RMEI, Roche/Genentech, RTP, Sanofi, Seattle Genetics, Takeda, and Vaccibody.

She is also an invited speaker for AiCME, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, ecancer, Eli Lilly, Foundation Medicine, Illumina, Imedex, Medscape, Merck Sharp and Dohme, Mirati, Novartis, PER, Peerview, Pfizer, Prime, Roche/Genentech, RTP, Sanofi, and Takeda. She disclosed that institutional research grants were received from Amgen, AstraZeneca, Beigene, Bristol Myers Squibb, GlaxoSmithKline, Merck Sharp and Dohme, and Roche/Genentech.

REFERENCES:

1. Peters S, Granados ALOO, de Marinis F, et al. LBA64 overall survival from a phase II randomised double-blind trial (PERLA) of dostarlimab (dostar) + chemotherapy (CT) vs pembrolizumab (pembro) + CT in metastatic non-squamous NSCLC. Ann Oncol. 2023;34(suppl 2):S1309. doi:10.1016/j.annonc.2023.10.065

2. GSK receives FDA accelerated approval for Jemperli (dostarlimab-gxly) for adult patients with mismatch repair-deficient (dMMR) recurrent or advanced solid tumors. News release. GlaxoSmithKline. August 17, 2021. Accessed October 20, 2023. https://www.gsk.com/en-gb/media/press-releases/gsk-receives-fda-accelerated-approval-for-jemperli-dostarlimab-gxly-for-adult-patients-with-mismatch-repair-deficient-dmmr-recurrent-or-advanced-solid-tumours/

3. FDA grants regular approval to dostarlimab-gxly for dMMR endometrial cancer. News release. FDA. February 9, 2023. Accessed October 20, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-regular-approval-dostarlimab-gxly-dmmr-endometrial-cancer

4. Jemperli (dostarlimab) plus chemotherapy approved in the US as the first new frontline treatment option in decades for dMMR/MSI-H primary advanced or recurrent endometrial cancer. News release. GlaxoSmithKline. July 31, 2023. Accessed October 20, 2023. https://www.gsk.com/en-gb/media/press-releases/jemperli-plus-chemotherapy-approved-in-us-for-new-indication/

5. Peters S, Lim SM, Granados ALOO, et al. 57O randomized double-blind phase II trial (PERLA) of dostarlimab (dostar) + chemotherapy (CT) vs pembrolizumab (pembro) + CT in metastatic non-squamous NSCLC: primary results. Immunooncol Technol. 2022;16(suppl 1):100162. doi:10.1016/j.iotech.2022.100162

6. Ortega Granados ALO, Lim SM, Schenker M, et al. Dostarlimab (dos) or pembrolizumab (pem) + chemotherapy (CT) in previously untreated metastatic non-squamous non-small cell lung cancer (NSCLC): patient (Pt) and disease characteristics subgroup analyses from the PERLA trial. Presented at: 2023 European Lung Cancer Congress; March 29-April 1, 2023; Copenhagen, Denmark. Poster 44P.

7. A platform study of novel immunotherapy combinations in participants with previously untreated, advanced/metastatic non-small-cell lung cancer. ClinicalTrials.gov. Updated September 7, 2023. Accessed October 20, 2023. https://clinicaltrials.gov/study/NCT05565378