Subgroup Analysis Shows Consistent Benefit for Dostarlimab Plus Chemo in Nonsquamous NSCLC

Ana Laura Ortega Granados, MD

Overall response rates (ORRs) were similar across subgroups of patients with nonsquamous non–small cell lung cancer (NSCLC) for the combinations of dostarlimab-gxly (Jemperli) plus chemotherapy and pembrolizumab (Keytruda) plus chemotherapy, and responses numerically favored the dostarlimab-based combination in most subgroups, according to a subgroup analysis of the phase 2 PERLA trial (NCT04581824) presented at the 2023 European Lung Cancer Congress.¹

Previously reported findings from the primary analysis of PERLA showed that patients treated with dostarlimab plus chemotherapy (n = 121) experienced an overall response rate (ORR) of 46% (95% CI, 37.2%-55.6%), compared with 37% (95% CI, 28.3%-46.1%) for those given pembrolizumab plus chemotherapy (n = 122).²

At a median follow-up of 5.8 months (interquartile range [IQR], 3.9-0.0) for the dostarlimab arm and 5.0 months (IQR, 2.6-7.1) for the pembrolizumab arm, the subgroup analysis examined ORR by age (less than 65 years of age vs at least 65 years of age), sex, ECOG performance status, PD-L1 status, baseline brain metastases, and type of platinum-based chemotherapy, which were prespecified exploratory analyses.1 Post-hoc exploratory analyses evaluated ORR by age (less than 75 years of age vs at least 75 years of age) and baseline liver metastases.

ORRs favored dostarlimab plus chemotherapy over pembrolizumab plus chemotherapy across all age groups, including less than 65 years of age (46% [95% CI, 33.7%-59.0%] vs 35% [95% CI, 22.9%-48.9%]), at least 65 years of age (46% [95% CI, 33.0%-60.3%] vs 38% [95% CI, 26.7%-51.4%]), less than 75 years of age (46% [95% CI, 36.1%-55.7%] vs 37% [95% CI, 27.6%-47.0%]), and at least 75 years of age (50% [95% CI, 23.0%-77.0%] vs 37% [95% CI, 16.3%-61.6%]).

Male patients treated in the dostarlimab arm experienced an ORR of 48% (95% CI, 37.3%-59.3%), compared with 39% (95% CI, 28.0%-50.8%) in the pembrolizumab arm. Similarly, female patients in the dostarlimab arm achieved an ORR of 42% (95% CI, 25.5%-59.2%) vs 33% (95% CI, 20.0%-49.0%) for those in the pembrolizumab arm. Patients with an ECOG performance status of 1 had an ORR of 46% (95% CI, 35.5%-55.8%) in the dostarlimab arm, compared with 31% (95% CI, 20.2%-42.5%) in the pembrolizumab arm. For patients with an ECOG performance status of 0, the ORR was 46% (95% CI, 29.5%-63.1%) and 46% (95% CI, 31.8%-60.7%) in the dostarlimab and pembrolizumab groups, respectively.

Patients with baseline brain metastases treated with dostarlimab experienced an ORR of 50% (95% CI 28.2%-71.8%), compared with 27% (95% CI, 7.8%-55.1%) for those administered pembrolizumab. Those without baseline brain metastases in the dostarlimab arm had an ORR of 45% (95% CI, 35.4%-55.8%) compared with 38% (95% CI, 29.1%-48.2%) for the pembrolizumab arm.

Patients without liver metastases given dostarlimab achieved an ORR of 50% (95% CI, 39.9%-60.1%), compared with 36% (95% CI, 27.1%-45.9%) for those treated with pembrolizumab. However, dostarlimab plus chemotherapy elicited an ORR of 26% (95% CI, 9.1%-51.2%) in patients with liver metastases, compared with 43% (95% CI, 17.7%-71.1%) for pembrolizumab plus chemotherapy.

When dostarlimab was combined with carboplatin, it produced an ORR of 47% (95% CI, 37.3%-57.8%), compared with 37% (95% CI, 27.9%-46.9%) for pembrolizumab plus carboplatin. Dostarlimab plus cisplatin elicited an ORR of 41% (95% CI, 20.7%-63.6%) vs 36% (95% CI, 12.8%-64.9%) for pembrolizumab plus cisplatin.

Patients with a PD-L1 tumor proportion score (TPS) of at least 1%, 1% to 49%, and at least 50% who received dostarlimab plus chemotherapy achieved ORRs of 59% (95% CI, 46.8%-70.7%), 50% (95% CI, 46.8%-70.7%), and 74% (95% CI, 53.7%-88.9%), respectively. For patients given pembrolizumab plus chemotherapy, the ORRs in those subgroups were 39% (95% CI, 28.0%-51.7%), 34% (95% CI, 20.5%-49.9%), and 48% (95% CI, 28.7%-68.7%), respectively. However, in patients with PD-L1 TPS of less than 1%, dostarlimab plus chemotherapy generated an ORR of 28% (95% CI, 16.2%-42.5%), compared with 33% (95% CI, 20.8%-47.9%) for pembrolizumab plus chemotherapy.

“Overall, the PERLA trial had a relatively small sample size for a large global trial, leading to small sample sizes for some subgroups,” Ana Laura Ortega Granados, MD, and colleagues, wrote in a poster presentation of the data. “In particular, there were few patients who were [at least] 75 years of age or who had liver [metastases] at baseline, leading to wide confidence intervals for these subgroups.”

Ortega Granados is part of the Medical Oncology Unit at the University Hospital of Jaén in Jaén, Spain.

The anti–PD-1 antibody dostarlimab had previously been approved by the FDA for adult patients with mismatch repair–deficient (dMMR), recurrent or advanced endometrial cancer that has progressed on or after a prior platinum-containing regimen in any setting and who are not candidates for curative surgery or radiation,³ and for adult patients with dMMR recurrent or advanced solid tumors, as determined by an FDA-approved test, who have progressed on or following previous treatment and who have no satisfactory alternative options.⁴

The randomized, double-blind PERLA trial was the first global head-to-head comparative trial of two PD-1 inhibitors in NSCLC.¹

Investigators enrolled patients with histologically/cytologically confirmed metastatic nonsquamous NSCLC with no mutations for which a targeted therapy is currently available. Patients were also required to have a documented PD-L1 status, an ECOG performance status of 0 or 1, adequate organ function, and no prior systemic therapy for NSCLC.

Upon enrollment, patients were randomly assigned in a 1:1 fashion to receive 500 mg of intravenous (IV) dostarlimab once every 3 weeks plus chemotherapy, or 200 mg of IV pembrolizumab once every 3 weeks plus chemotherapy. Stratification factors included smoking status (never vs former/current) and PD-L1 status (TPS <1% vs 1%-49% vs ≥50%).

Clinic visits occurred once every 3 weeks, and serial imaging was done at weeks 6 and 12, then once every 9 weeks until week 48, then every 12 weeks thereafter. Treatment continued until disease progression, unacceptable toxicity, or death, for up to 35 cycles.

The primary end point was confirmed ORR by RECIST v1.1 criteria per blinded independent central review. Secondary end points included investigator-assessed progression-free survival (PFS) per RECIST v1.1 criteria and safety.

The median age of patients in the dostarlimab treatment arm was 64.0 years (range, 25-80) and the majority of patients were White (72%), were from Europe (51%), were former or current smokers (86%), and had nonsquamous histology (97%).

The median age of patients reported in the pembrolizumab treatment arm was 65.0 years (range, 46-86). The majority were White (69%), were from Europe (53%), were former or current smokers, and had nonsquamous histology (>99%).

The dostarlimab arm had a higher proportion of patients who were less than 65 years of age compared with the pembrolizumab arm (54% vs 47%), although 88% ad 84% of patients were less than 75 years of age in the dostarlimab and pembrolizumab arms, respectively. Seventy percent of patients in the dostarlimab arm were male vs 63% in the pembrolizumab arm. There was a greater number of patients who had an ECOG performance status of 1 in the dostarlimab group vs the pembrolizumab group (69% vs 59%).

Additionally, more patients had a baseline brain metastases (18% vs 12%) and baseline liver metastases (16% vs 11%) in the dostarlimab group vs the pembrolizumab group. Eighty-two percent of patients in the dostarlimab arm received carboplatin, compared with 89% in the pembrolizumab arm.

In the dostarlimab arm, the rates of patients with a PD-L1 TPS of less than 1%, between 1% and 49%, and at least 50% were 41%, 36%, and 22%, respectively. In the pembrolizumab arm, those rates were 42%, 36%, and 22%, respectively.

References

1. 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.
2. Peters S, Lim SM, Ortega Granados ALO, 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. Immunooncol Technol. 2022;16(suppl 1):100162. doi:10.1016/j.iotech.2022.100162
3. FDA grants regular approval to dostarlimab-gxly for dMMR endometrial cancer. News release. FDA. February 9, 2023. Accessed April 17, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/
4. 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 April 17, 2023. https://www.gsk.com/en-gb/media/press-releases/