Responses/Survival Improved With Zimberelimab Triplet Combination in Advanced NSCLC

Improvements in progression-free survival (PFS) and objective response rate (ORR) were observed following treatment with zimberelimab, etrumadenant, and domvanalimab in the first-line to treat patients with metastatic, PD-L1-high non–small cell lung cancer, according to results from the phase 2 ARC-7 trial (NCT04262856) which was presented during the American Society of Clinical Oncology Plenary Session.

The median PFS in the zimberelimab monotherapy arm was 5.4 months (95% CI, 1.8-9.6), 12.0 months (95% CI, 5.5-not estimable [NE]) in the zimberelimab plus domvanalimab arm, and 10.9 months (95% CI, 4.8-NE) in the triplet arm. In the zimberelimab monotherapy arm, the median ORR was 27% (95% CI, 15.0%-42.8%), in the doublet arm it was 41% (95% CI, 26.3%-56.8%), and 40% (95% CI, 25.7%-55.7%) in the triplet arm.

Partial response occurred in 27% in the monotherapy arm, 41% in the doublet arm, and 40% in the triplet arm, while stable disease occurred in 32%, 34%, and 36%. Additionally, progressive disease occurred in 25%, 5%, and 13%, respectively.

“There was approximately a 13% improvement in ORR compared with zimberelimab alone, and there was approximately a 40% reduction in the risk of progression or death compared with anti–PD-1 alone with substantial improvement in median PFS,” Melissa L. Johnson, MD, director of Lung Cancer Research at Sarah Cannon Research Institute at Tennessee Oncology in Nashville, Tennessee, said during the presentation.

A total of 150 patients were randomized 1:1:1 to either the zimberelimab monotherapy arm (n = 50); the zimberelimab plus domvanalimab arm (n = 50); or zimberelimab, etrumadenant, and domvanalimab arm (n = 50). The monotherapy arm received 360 mg of treatment intravenously every 3 weeks; the doublet arm received 15 mg/kg of domvanalimab intravenously every 3 weeks and matched zimberelimab therapy; and the triplet arm received zimberelimab and domvanalimab matched treatment along with etrumadenant at 150 mg by mouth every day. Those in the monotherapy arm had the option to crossover to the triplet arm.

The scanning interval was every 6 weeks for 6 months, every 9 weeks for 9 months, then every 12 weeks thereafter.

The primary end points were investigator-assessed ORR and PFS. The secondary end points were duration of response (DOR), disease control rate, overall survival, safety, and pharmacokinetics. The clinical cut-off date was 11.8 months, and about half of the patients in the doublet and triplet arms remain on study vs 28% in the monotherapy arm.

In the monotherapy arm, the median age was 66 years, with 56% of patients being 65 years or older. Additionally, 18% of patients had squamous cell carcinoma. Eighty patients had local PD-L1 scoring between 50% to 100%.

In the zimberelimab plus domvanalimab arm, the median age was 69 years and 68% of patients were 65 years or older. Squamous cell carcinoma was present in 32% of patients, and 70 patients had local PD-L1 scoring between 50% to 100%.

Lastly, in the zimberelimab, etrumadenant, and domvanalimab arm, patients had a median age of 69 years, with 70% of patients being 65 years or older. Squamous cell carcinoma was present in 32% of patients, and 78 patients had local PD-L1 scoring between 50% to 100%.

In the overall intent-to-treat population, 31 patients experienced a partial response, and 14 with stable disease remain on treatment. The time to initial response was between 1.2 months to 14.6 months in all arms. In all 3 treatment arms, the median DOR has not yet been reached.

Grade 3 or higher treatment-emergent adverse effects (TEAEs) occurred in 58%, 47%, and 52%, while grade 5 TEAEs were observed in 2%, 2%, and 4% of patients in the monotherapy, doublet, and triplet arms, respectively. Serious TEAEs occurred in 54% of patients in the monotherapy arm, 33% in the doublet arm, and 52% in the triplet arm.

Drug discontinuation because of TEAEs occurred in 28% in the zimberelimab arm, 16% in the zimberelimab plus domvanalimab arm, and 20% in the zimberelimab, etrumadenant, and domvanalimab arm. Across all 3 arms, immune-related TEAEs occurred in 48%, 47%, and 60% of patients, respectively, with infusion-related reactions being observed in 4%, 4%, and 10%.

Of note, the most common grade 3 or higher TEAEs were pneumonia (8.7%) and anemia (5.4%). In the monotherapy arm, related grade 5 TEAEs were interstitial lung disease, in the doublet arm it was myocarditis, and in the triplet arm, it was pneumonitis and congestive heart failure.

The median treatment duration in the monotherapy arm was 9.8 weeks, 21.0 weeks in the doublet arm, and 24.3 weeks in the triplet arm.

Immune-related TEAEs included pneumonitis that was grade 3 or higher occurred in 6%, 2%, and 4% of all treatment arms, respectively. Additionally, pruritus (16% vs 6% vs 10%), and rash (12% vs 10% vs 18%) were also observed.

Of the 12 patients who crossed over to the triplet arm, 5 remain on treatment. The confirmed ORR was 17% (95% CI, 2.1%-48.4%), with a partial response in 17%, stable disease in 67%, and progressive disease in 8%. The disease control rate was 33% (95% CI, 9.9%-65.1%). Of note, the safety data for those who crossed over remained consistent with those already enrolled in the triplet arm.

Reference

Johnson ML, Fox W, Lee YG, et al. ARC-7: Randomized phase 2 study of domvanalimab + zimberelimab ± etrumadenant versus zimberelimab in first-line, metastatic, PD-L1-high non-small cell lung cancer (NSCLC). J Clin Oncol. 2022;40(suppl36):397600. doi:10.1200/JCO.2022.40.36_suppl.397600