Low-Dose Pembrolizumab May Prove Equal Efficacy as a Standard Dose for Stage IV NSCLC

Michel M van den Heuvel, MD

The 1-year survival difference between patients with stage IV non-small cell lung cancer (NSCLC) treated with either a standard or reduced dose of pembrolizumab (Keytruda) met the established criteria for continued enrollment of the NVALT-30 trial (NCT04909684), according to recent study findings presented at the 2024 ESMO Congress.¹

“There’s a notion that trials on the optimization of dosing, duration, and personalization of treatment are really underrepresented in the current research,” Michel M van den Heuvel, a professor at the Radboud Institute for Molecular Life Sciences in Nijmegen, Netherlands, said during the presentation.

The 1-year overall survival rate was 57.7% (95% CI, 49.5%-67.3%) in the standard-dose group and 55.0% (95% CI, 47.0%-64.4%) in the reduced dose group. Median overall survival was 17.0 months (95% CI, 11.8-23.2) in the standard-dose group and 13.9 months (95% CI, 10.8-16.9) in the reduced-dose group. There was no significant difference in overall survival between the groups (P = .45).

Median progression-free survival was 6.9 months (95% CI, 6.0-9.8) in the standard-dose group compared with 7.6 months (95% CI, 5.8-11.3) in the reduced-dose groups.

In addition, the 1-year disease control rate was 37% (95% CI, 29.2%-46.7%) in the standard-dose arm and 39.2% (95% CI, 31.6%-48.7%) in the reduced-dose arm. The objective response rate was 50.9% (95% CI, 41.3%-60.4%) in patients assigned the standard dose vs 54.5% (95% CI, 45.2-63.6%) in those assigned the reduced dose.

Trial Design

Researchers performed an open-label, non-inferiority trial to compare either the standard dose (n = 123; median age, 69 years; 59% men) or reduced dose (n = 133; median age, 68 years; 58% men) of pembrolizumab. Patients in the standard-dose group received pembrolizumab either 400 mg every 6 weeks, 150 mg every 3 weeks, or 200 mg every 3 weeks. For patients in the reduced-dose group, patients received 300 mg every 6 weeks or 100 mg every 3 weeks.

“The primary objective of this study is to investigate the non-inferiority of reduced-dose pembrolizumab vs standard of treatment of advanced stage non-small cell lung cancer in terms of overall survival,” van den Heuvel said.

The trial enrolled patients with NSCLC who were eligible for pembrolizumab-based treatment. An interim analysis was planned after the first 250 patients were enrolled and then followed for 1 year. A difference of 10% in 1-year overall survival between the groups was considered clinically significant and may lead to early termination of the trial.

Secondary objectives of the study included disease control rate, progression-free survival, 1-year disease control rate, overall response rate, and to develop, assess, and validate immune checkpoint inhibitor response biomarkers.

The median cumulative dose of pembrolizumab was 1600 mg in the standard-dose arm compared with 1200 in the reduced-dose arm. Thirty-four percent of patients assigned the standard dose arm were still on treatment after 1 year compared with 28% assigned the reduced dose. The most common reason for treatment termination was progressive disease, van den Heuvel noted.

Immunotherapy and NSCLC Treatment

As immunotherapy is the “backbone of treatment of non-small cell lung cancer,” as van den Heuvel noted, it has its disadvantages despite improving survival and quality of life. One of these disadvantages is the fact that the response rate is nearly 50%.

“The toxicity is also, although acceptable and manageable, sometimes worrisome, and bothersome especially the long-term toxicity,” said van den Heuvel. “In fact, limited data on the optimal dosing, as we know from all types of ex vivo models, we see that there is a clear dose relation.”

There are several current standard-of-care doses of Keytruda, including 200 mg every 3 weeks, 400 mg every 6 weeks, and 150 mg every 3 weeks, among others.

“But could we improve on this dosing and, thereby, for instance, reduce healthcare costs and maybe redundant exposure to pembrolizumab,” van den Heuvel said.

Reference

Van den Heuvel, M., Van der Noort, V., Ter Heine, R., et al. (2024). Low dose versus standard dose pembrolizumab for treatment of stage IV non-small cell lung carcinoma: Results of the pre-planned interim analysis of the NVALT-30 clinical trial. Presented at: 2024 ESMO Congress; September 13-17, 2024; Barcelona, Spain. Abstract 1258MO