Pembrolizumab Combo Shows Promise in Elderly Metastatic NSCLC Cohort

"[O]ur findings suggest that pembrolizumab and pemetrexed are promising and novel treatment strategies for older patients with [nonsquamous] NSCLC, indicating significant therapeutic advancement," according to the study authors.

Pembrolizumab (Keytruda) in combination with pemetrexed demonstrated promise as a frontline therapy option for older patients with metastatic nonsquamous non–small cell lung cancer (NSCLC) harboring a PD-L1 tumor proportion score (TPS) of less than 50%, according to findings from a phase 2 trial (NCT04396457) published in JTO Clinical and Research Reports.¹

After a median follow-up of 15.4 months (range, 0.3-34.5), data showed an objective response rate (ORR) of 36.7% (95% CI, 23.4%-51.7%; P = .005), which included 1 complete response (CR) and 17 partial responses (PRs). Additionally, the disease control rate (DCR) was 65.3% (95% CI, 50.4%-78.3%).

Among those with a response, the median duration of response (DOR) was 13.3 months (95% CI, 6.1-22.8), with 61.1% experiencing a sustained response for 12 months or longer. Study treatment yielded a median time to response of 1.5 months (range, 1.2-8.9).

The pembrolizumab combination produced a median progression-free survival (PFS) of 7.6 months (95% CI, 4.8-16.2) and a 12-month PFS rate of 41.8% (95% CI, 27.6%-55.4%). Data highlighted a median overall survival (OS) of 19.4 months (95% CI, 11.8-not reached [NR]) and a 12-month OS rate of 65.2% (95% CI, 49.6%-77.1%).

Although responses occurred regardless of PD-L1 TPS, a higher ORR was noted in patients with a TPS of 1% to 49% (46.4%) compared with those who had a TPS of less than 1% (23.8%).

“To the best of our knowledge, this is the first study to investigate the efficacy and safety of pembrolizumab and pemetrexed, a cytotoxic monotherapy, in older patients with advanced [nonsquamous] NSCLC,” Yoshihito Kogure, MD, PhD, from the Department of Respiratory Medicine at NHO Nagoya Medical Center in Nagoya, Japan, wrote with study coauthors.¹ “[O]ur findings suggest that pembrolizumab and pemetrexed are promising and novel treatment strategies for older patients with [nonsquamous] NSCLC, indicating significant therapeutic advancement.”

In this multicenter, open-label phase 2 trial, investigators assessed 49 elderly patients with metastatic or recurrent nonsquamous NSCLC at 42 institutions across Japan. Patients were assigned to receive intravenous pemetrexed at 500 mg/m² plus pembrolizumab at 200 mg on day 1 of each 21-day cycle. Investigators also administered folinic acid plus vitamin B12 at 1 week before patients received pemetrexed.

The trial’s primary end point was ORR per investigator assessment. Secondary end points included DCR, DOR, PFS, OS, and safety.

Patients 75 years and older with histologically or cytologically confirmed nonsquamous NSCLC, no prior systemic therapy, and a PD-L1 TPS of less than 50% were eligible for enrollment on the trial.² Additional eligibility criteria included having at least 1 measurable lesion per RECIST v1.1 guidelines, an ECOG performance status of 0 or 1, no activating ALK translocations or EGFR mutations, and a life expectancy of at least 12 weeks. Having major surgery within 3 weeks of the first study treatment dose or palliative radiotherapy within 7 days of beginning therapy were grounds for exclusion from enrollment.

The median patient age was 79.0 years (range, 75-91), and most were male (77.6%). Most of the cohort had an ECOG performance status of 1 (67.3%), adenocarcinoma (98.0%), stage IV disease (75.5%), former smoking history (63.3%), a PD-L1 TPS of 1% to 49% (57.1%), and hypertension (46.9%).

The most common causes of treatment discontinuation included progressive disease (38.3%), physician discretion (23.4%), and adverse effects (AEs; 21.3%). All patients experienced any AE (100%), with the most common including anemia (85.4%), lymphocytopenia (62.5%), aspartate aminotransferase elevation (62.5%), leukopenia (56.3%), and neutropenia (54.2%).

Grade 3 to 5 toxicity affected 62.5% of patients, with the most common including neutropenia (31.3%), leukopenia (20.8%), and anemia (12.5%). Treatment-related serious AEs occurred in 25.0% of the population and consisted of pneumonitis (8.3%), decreased appetite (4.2%), and febrile neutropenia (4.2%). Investigators reported no treatment-related deaths in the study.

References

1. Kogure Y, Hashimoto H, Daga H, et al. Pembrolizumab and pemetrexed for older patients with nonsquamous NSCLC and programmed cell death-ligand 1 tumor proportion scores of less than 50. JTO Clin Res Rep. 2024;6(3):100784. doi:10.1016/j.jtocrr.2024.100784
2. Pembrolizumab plus pemetrexed for elderly patients with non-sq NSCLC with PD-L1 < 50%: CJLSG1901. ClinicalTrials.gov. Updated March 23, 2023. Accessed February 28, 2025. https://tinyurl.com/exhd2rmz