Pembrolizumab Plus SBRT Fails to Improve Survival in Unresected Stage I/II NSCLC

The addition of pembrolizumab (Keytruda) to stereotactic body radiotherapy (SBRT) did not lead to improvements in event-free survival (EFS) or overall survival (OS) compared with SBRT plus placebo in patients with unresected stage I or II non–small cell lung cancer (NSCLC), according to data from the phase 3 KEYNOTE-867 trial (NCT03924869).

Findings presented at the 2024 ESMO Immuno-Oncology Congress showed that patients treated with pembrolizumab plus SBRT (n = 227) experienced a median EFS of 31.2 months (95% CI, 22.5-39.1) compared with 28.3 months (95% CI, 19.8-33.1) for those given SBRT plus placebo (n = 221; HR, 0.92; 95% CI, 0.69-1.24; stratified log-rank P = .29).

The median OS was 54.7 months (95% CI, 33.5-not reached [NR]) in the pembrolizumab arm vs NR (95% CI, 44.4-NR) in the placebo arm (HR, 1.33; 95% CI, 0.93-1.90).

“Based on the benefit:risk profile assessed during the interim analysis, [KEYNOTE-867] was stopped, and all study treatment was discontinued,” Andreas Pircher, MD, PhD, of the Medical University of Innsbruck in Austria, said during a presentation of the data.

KEYNOTE-867 Overview

KEYNOTE-867 was a randomized, placebo-controlled trial that enrolled patients at least 18 years of age with untreated, unresected, biopsy-confirmed stage I or II NSCLC who were unable or unwilling to undergo thoracic surgery. Patients were required to have an ECOG performance status of 0 to 2 and be able to receive SBRT.

Patients were randomly assigned 1:1 to receive pembrolizumab at 200 mg once every 3 weeks plus SBRT for 17 cycles; or placebo once every 3 weeks plus SBRT for 17 cycles. In both arms, SBRT consisted of 45 to 60 Gy in 3 fractions, 48 to 50 Gy in 4 fractions, or 50 to 55 Gy in 5 fractions for patients with peripheral tumors; 48 to 50 Gy in 4 fractions or 50 to 55 Gy in 5 fractions for those with tumors abutting the chest wall; or 50 to 55 Gy in 5 fractions or 60 to 70 Gy in 8 fractions for patients with central tumors.

Patients were stratified by stage (I vs II), ECOG performance status (0 or 1 vs 2), geographic region (East Asia vs non–East Asia), and reason for not receiving surgery (medically inoperable vs refusal).

EFS per blinded independent central review assessment served as the trial’s primary end point. Secondary end points included OS; time to death or distant metastases; safety and tolerability; and global health status/quality of life.

At a median follow-up of 20.6 months (range, 1.3-56.8), 226 of 227 allocated patients in the experimental arm received at least 1 dose of study treatment; 95 patients completed treatment, 26 were ongoing treatment at data cutoff, and 105 discontinued treatment due to adverse effects (AEs; n = 62), patient withdrawal (n = 21), physician decision (n = 10), relapse/recurrence (n = 10), and protocol violation (n = 2).

In the control arm, 218 of 221 allocated patients received at least 1 dose of study treatment; 124 patients completed treatment, and 26 were ongoing with treatment. In the 68 patients who discontinued treatment, reasons for discontinuation comprised AEs (n = 24), patient withdrawal (n = 10), physician decision (n = 6), relapse/recurrence (n = 27), and protocol violation (n = 1).

The median age was 73.0 years (range, 50-93) in the pembrolizumab arm vs 73.0 years (range, 49-87) in the placebo arm. The majority of patients were male (pembrolizumab arm, 60.8%; placebo arm, 54.8%), from a region other than East Asia (87.2%; 88.2%), had an ECOG performance status of 0 or 1 (92.1%; 93.2%), were medically inoperable (81.1%; 83.7%), had a smoking history (90.7%; 91.9%), had stage I disease (89.9%; 89.1%), and had nonsquamous histology (63.4%; 63.3%).

Tumor locations included abutting the chest wall (pembrolizumab arm, 46.3%; placebo arm, 47.5%), peripheral (38.8%; 39.4%), central (14.5%; 11.3%), and missing (0.4%; 1.8%).

Additional Efficacy and Safety Data

Trends favoring the pembrolizumab regimen were observed in patients under 65 years of age in regard to EFS (HR, 0.44; 95% CI, 0.18-1.24) and OS (HR, 0.53; 95% CI, 0.18-1.56). These trends for EFS (HR, 1.00; 95% CI, 0.73-1.36) and OS (HR, 1.53; 95% CI, 1.04-2.24) were not observed in patients 65 years of age or older.

Regarding safety, the median duration of exposure to pembrolizumab was 295.0 days (range, 1.0-488.0) in the experimental arm; the median duration of exposure to placebo was 337.0 days (range, 1.0-473.0) in the control arm. The median duration of exposure to SBRT was 8.0 days (range, 3.0-19.0) in the experimental arm vs 8.0 days (range, 3.0-17.0) in the control arm.

Any-grade treatment-related AEs (TRAEs) occurred in 73.5% of patients in the experimental arm vs 50.0% of patients in the control arm. The respective rates of grade 3 or higher TRAEs were 20.4% and 3.7%. Serious TRAEs were reported in 14.2% and 2.3% of patients, respectively. TRAEs led to treatment discontinuation in 15.9% and death in 2.2% of patients in the experimental arm, respectively. These respective rates were 2.3% and 0% in the control arm.

The most common any-grade TRAEs included hypothyroidism (pembrolizumab arm, 13.7%; placebo arm, 2.8%), rash (12.4%; 5.0%), pruritus (11.9%; 5.5%), fatigue (11.5%; 8.7%), pneumonitis (9.7%; 1.8%), radiation pneumonitis (9.7%; 8.3%), diarrhea (8.0%; 7.3%), arthralgia (6.2%; 2.3%), and hyperthyroidism (6.2%; 1.4%).

Any-grade immune-mediated AEs and infusion-related reactions occurred in 38.5% of patients in the experimental arm vs 11.5% of patients in the control arm. Grade 3 or higher events were reported in 9.3% and 0.9% of patients, respectively. Serious immune-related AEs/infusion reactions occurred in 7.1% of patients in the pembrolizumab arm vs 0.5% of patients in the placebo arm. In the experimental arm, immune-mediated AEs/infusion reactions led to treatment discontinuation in 8.4% of patients and death in 0.4% of patients. These respective rates were 0.5% and 0% in the control arm.

The most common any-grade immune-mediated AEs comprised hypothyroidism (pembrolizumab arm, 15.9%; placebo arm, 3.7%), pneumonitis (11.5%; 2.8%), hyperthyroidism (7.1%; 2.8%), colitis (2.2%; 0.5%), skin reactions (1.8%; 0%), hepatitis (1.3%; 0%), pancreatitis (0.9%; 0%), encephalitis (0.4%; 0%), infusion reactions (0.4%; 0.9%), myocarditis (0.4%; 0%), adrenal insufficiency (0.4%; 1.8%), gastritis (0.4%; 0.5%), arthritis (0.4%; 0.5%), myositis (0.4%; 0.5%), exocrine pancreatic insufficiency (0.4%; 0%), nephritis (0.4%; 0%), sarcoidosis (0.4%; 0%), thyroiditis (0.4%; 0%), and uveitis (0.4%; 0%).

Disclosures: Dr Pircher reported receiving honoraria or consultation fees, from AstraZeneca, Bristol Myers Squibb, Böhringer Ingelheim, MSD, Pfizer, Roche, Sanofi Aventis, and Takeda; and participating in a company-sponsored bureau with AstraZeneca, Bristol Myers Squibb, Böhringer Ingelheim, MSD, Pfizer, Roche, Sanofi Aventis, and Takeda.

Reference

Pircher A, Sótér S, Eaton M, et al. Stereotactic body radiotherapy (SBRT) with pembrolizumab (pembro) for unresected stage I/II non-small-cell lung cancer (NSCLC): the randomized, double-blind, phase 3 KEYNOTE-867 study. Ann Oncol. 2024;24(suppl 1):1-26. doi:10.1016/iotech/iotech100745