Epacadostat/Pembrolizumab Does Not Improve Therapeutic Effect for mNSCLC

The combination therapy was well tolerated and had a safety profile consistent with pembrolizumab monotherapy, while no new safety concerns were identified.

Epacadostat, a selective oral inhibitor of IDO1, added to pembrolizumab (Keytruda) therapy did not improve therapeutic effect in patients with PD-L1–high metastatic non–small cell lung cancer (NSCLC), according to data from the randomized phase 2 KEYNOTE-654-05/ECHO-305-05 study (NCT03322540) published in BMC Central.1

Data from the study showed a median follow-up of 6.8 months (range, 0.1-11.4) and 7.0 months (range, 0.2-11.9) among patients in the combination and control groups, respectively. Confirmed objective response rate (ORR) was 32.5% (95% CI, 22.2%-44.1%) in the combination arm and 39.0% (95% CI, 28.0%-50.8%) in the control arm (1-sided P = .8000). The combination therapy was well tolerated and had a safety profile consistent with pembrolizumab monotherapy; no new safety concerns were identified.

“In this primary analysis, addition of epacadostat 100 mg [twice daily] to pembrolizumab therapy for metastatic NSCLC was generally well tolerated but did not demonstrate improved outcomes when compared with placebo plus pembrolizumab,” Takaaki Tokito, MD, PhD, an assistant professor in the Division of Respirology, Neurology, and Rheumatology of the Department of Internal Medicine at Kurume University School of Medicine in Fukuoka, Japan, wrote in the publication with study coinvestigators. “However, the pharmacodynamic findings suggest that further combination studies testing higher doses of epacadostat and using circulating kynurenine levels or other appropriate pharmacodynamic biomarkers to guide dose selection are warranted.”

Originally designed as a phase 3 study, the protocol was amended on May 31, 2018 after results from the phase 3 ECHO-301/KEYNOTE-252 study (NCT02752074) in unresectable or metastatic melanoma showed that the epacadostat/pembrolizumab combination therapy did not meet the primary end point of progression-free survival (PFS). The phase 2 study randomly assigned adult patients 1:1 (n = 154) with previously untreated, confirmed stage IV NSCLC not suitable for primary EGFR-, ALK-, or ROS1-directed therapy to receive either epacadostat (n = 77) or placebo (n = 77) in combination with pembrolizumab. Stratification factors were based on tumor histology, ECOG performance score, and geographical region.

Epacadostat at 100 mg or placebo was taken orally twice daily with 200 mg of intravenous pembrolizumab administered on day 1 of every 21-day cycle for a maximum of 35 doses. Pembrolizumab could be withheld for up to 12 weeks, and epacadostat could be reduced to 50 mg or 25 mg twice daily to mitigate immune-related adverse effects (AEs).

The primary end point of the study was ORR in each group. Secondary end points included PFS, overall survival (OS), duration of response (DOR), safety, and tolerability.

Among those who received treatment in the combination (n = 75) and placebo (n = 77) arms, the median treatment duration was 172.0 days (range, 1.0-350.0) and 168.0 days (range, 2.0-362.0), respectively, with a median of 8 cycles for both arms. Upon end of study, treatment was unblinded, epacadostat was discontinued, and patients had the option to continue open-label pembrolizumab alone.

PFS findings were inconclusive at data cut-off, with only 71 of the required 95 PFS events reported, including 37 of 77 (48.1%) in the combination group and 34 of 77 (44.2%) in the control group. Median PFS was 6.7 and 6.2 months, respectively (HR, 1.10; 95% CI, 0.69-1.76). Additionally, median OS was not reached in either group, with only 13 events reported in the combination group and 17 events reported in the control group (HR, 0.74; 95% CI, 0.36-1.52).

Any-grade AEs and drug-related AEs occurred in 92.0% and 70.7% of the combination arm and 93.5% and 63.6% of the control arm. The most common any-grade AEs in the combination and control arms were constipation (24.0%, 20.8%), decreased appetite (18.7%, 10.4%), diarrhea (17.3%, 19.5%), nausea (16.0%, 9.1%), pruritus (12.0%, 15.6%), and fatigue (9.3%, 18.2%).

Grade 3 or greater AEs and serious AEs occurred in 49.3% and 33.3% of the combination arm and 44.2% and 33.8% of the control arm. Discontinuation due to an AE occurred in 13.3% of the experimental arm and 11.7% of the placebo arm, with SAE-related discontinuation occurring in 6.7% and 7.8% in each arm, respectively. There were 3 deaths in the combination arm nonattributable to drug-related AEs; 7 deaths in the placebo arm included 2 attributable to drug-related AEs.

Reference

Tokito T, Kolesnik O, Sørensen J, et al. Epacadostat plus pembrolizumab versus placebo plus pembrolizumab as first-line treatment for metastatic non-small cell lung cancer with high levels of programmed death-ligand 1: a randomized, double-blind phase 2 study. BMC Cancer. 2024;23(suppl 1):1251. doi:10.1186/s12885-023-11203-8