Frontline Domvanalimab Plus Zimberelimab Improves Responses in PD-L1–High Metastatic NSCLC

The combination of domvanalimab (AB154) plus zimberelimab (AB122) with or without etrumadenant (AB928) generated an improvement in overall response rate (ORR) and progression-free survival (PFS) compared with zimberelimab alone in patients with PD-L1–high metastatic non–small cell lung cancer, according to findings from the phase 2 ARC-7 trial (NCT04262856).¹

Data presented during the 2022 December ASCO Plenary Series showed that at a median follow-up of 11.8 months (range, 0.03-23.5), patients treated with domvanalimab plus zimberelimab and etrumadenant (n = 45) achieved an ORR of 40% (95% CI, 25.7%-55.7%), with all responders experiencing a partial response (PR). The stable disease and progressive disease rates were 36% and 13%, respectively, and 11% of patients were not evaluable.

In patients who received domvanalimab plus zimberelimab (n = 44), the ORR was 41% (95% CI, 26.3%-56.8%), with a PR rate of 41%, a stable disease rate of 34%, and a progressive disease rate of 5%. Twenty-one percent of patients were not evaluable. In those treated with zimberelimab alone (n = 44), the ORR was 27% (95% CI, 15.0%-42.8%) with a PR rate of 27%, a stable disease rate of 32%, and a progressive disease rate of 25%. Additionally, 16% of patients were not evaluable.

“This is the first presentation of quantitative data [from ARC-7], and it includes both a look at response rate and PFS,” Melissa L. Johnson, MD, program director of lung cancer research at Sarah Cannon Cancer Institute in Nashville, Tennessee, said following a presentation of the data. “It coincides with the intent-to-treat–13 population, where all the patients that were included, 133 of the 150 [enrolled], had at least 13 weeks follow-up [with] 2 scans so their response could be confirmed.”

Although PD-1 inhibitors have improved outcomes for patients with PD-L1–high NSCLC, less than half of patients experience long-term benefit with PD-1 inhibitor monotherapy. The ARC-7 trial evaluated the addition domvanalimab, an anti-TIGIT monoclonal antibody, with the anti–PD-1 monoclonal antibody zimberelimab with or without the adenosine receptor antagonist etrumadenant in patients with PD-L1–high metastatic NSCLC.

Patients were required to have treatment-naïve metastatic NSCLC with a PD-L1 expression of at least 50% per local assessment by SP263 or 22C3. EGFR/ALK wild-type disease was permitted; however, patients with EGFR/ALK genetic tumor aberrations were excluded.² Patients were also required to have an ECOG performance status of 0 or 1, and adequate bone marrow and organ function.

Enrolled patients were randomly assigned 1:1:1 to intravenous (IV) zimberelimab alone, IV domvanalimab plus IV zimberelimab, or IV domvanalimab plus IV zimberelimab and oral etrumadenant at 150 mg every day. Domvanalimab was administered at 15 mg/kg every 3 weeks in both experimental arms, and zimberelimab was given at 360 mg every 3 weeks in all arms. Crossover from the zimberelimab monotherapy arm to the triplet arm was permitted.

The co-primary end points of the trial were investigator-assessed ORR and PFS per RECIST v1.1 criteria. Secondary end points included duration of response (DOR), disease control rate, overall survival, safety, and pharmacokinetics.

Fifty patients were randomly assigned to each study arm, and all patients from the zimberelimab monotherapy and triplet arms were evaluable for safety. In the domvanalimab/zimberelimab arm, 49 of 50 patients were evaluable for safety. At data cutoff, 28%, 50%, and 48% of patients were in ongoing treatment in the zimberelimab monotherapy, doublet, and triplet arms, respectively.

Baseline characteristics were similar across all 3 arms. The majority of patients were at least 65 years of age (56%, 68%, and 70% in the zimberelimab monotherapy, doublet, and triplet arms, respectively), were male (68%, 66%, and 68%), were smokers (86%, 90%, and 90%), had an ECOG performance status of 1 (74%, 70%, and 70%), did not have brain metastases at baseline (86%, 86%, and 84%), and did not have liver metastases at baseline (82%, 78%, and 92%).

Additionally, 18%, 32%, and 32% of patients in the zimberelimab monotherapy, doublet, and triplet arms had squamous cell carcinoma, respectively. The median PD-L1 scoring was 80% (range, 50%-100%) in the zimberelimab monotherapy arm compared with 70% (range, 50%-100%) in the doublet arm and 78% (range, 50%-100%) in the triplet arm.

Additional data showed patients who received domvanalimab plus zimberelimab and etrumadenant achieved a median PFS of 10.9 months (95% CI, 4.8-not evaluable [NE]) compared with 5.4 months (95% CI, 1.8-9.6) in the zimberelimab monotherapy arm (HR, 0.65; 95% CI, 0.37-1.1). The median PFS was 12.0 months (95% CI, 5.5-NE) in the domvanalimab plus zimberelimab arm (HR vs zimberelimab monotherapy, 0.55; 95% CI, 0.31-1.0). The 6-month PFS rates were 43%, 65%, and 63% in the zimberelimab monotherapy, doublet, and triplet arms, respectively.

The median DOR was not yet reached in any treatment arm (range, 1.3+ months to 17.8+ months). The time to initial response ranged from 1.2 months to 14.6 months across all 3 arms.

Among 12 patients who crossed over from zimberelimab monotherapy to domvanalimab plus zimberelimab and etrumadenant, the confirmed ORR was 17% (95% CI, 2.1%-48.4%), with both responders achieving a PR. The stable disease and progressive disease rates were 67% and 8%, respectively, and 1 patient was not evaluable. Five patients remained on crossover treatment at data cutoff, and the safety profile was consistent with findings from first-line treatment with domvanalimab plus zimberelimab and etrumadenant.

Regarding safety, any-grade treatment-emergent adverse effects (TEAEs) were experienced by all patients in the zimberelimab monotherapy arm compared with 96% in the doublet arm and 96% in the triplet arm. Rates of grade 3 or higher TEAEs were 58%, 47%, and 52%, respectively, and rates of serious TEAEs were 54%, 33%, and 52%, respectively. TEAEs led to study drug discontinuation in 28%, 16%, and 20% of patients, respectively.

The most common any-grade TEAEs occurring in at least 15% of patients in all arms included fatigue, nausea, constipation, dyspnea, decrease appetite, and pneumonia. Grade 3 or higher TEAEs observed in at least 5% of patients included pneumonia (8.7%) and anemia (5.4%).

One patient in the zimberelimab monotherapy arm experienced grade 5 interstitial lung disease. One patient in the doublet group had grade 5 myocarditis. In the triplet arm, 1 patient had grade 5 pneumonitis and 1 patient had grade 5 congestive heart failure.

Immune-related TEAEs occurred in 48%, 47%, and 60% of patients in the zimberelimab monotherapy, doublet, and triplet arms, respectively, and the rates of infusion-related reactions were 4%, 4%, and 10%, respectively. Any-grade pneumonitis was reported in 14%, 8%, and 10% of patients, respectively, and the rates of grade 3 or higher pneumonitis were 6%, 2%, and 4%, respectively.

Any-grade pruritus occurred in 16% of patients in the zimberelimab monotherapy arm compared with 6% in the doublet arm and 10% in the triplet arm. Rates of any-grade rash were 12%, 10%, and 18%, respectively. No cases of rash led to study treatment discontinuation.

The median treatment duration was 9.8 weeks (range, 0-97) in the zimberelimab monotherapy arm compared with 21.0 weeks (range, 0-105) for the doublet and 24.3 (range, 2-107) for the triplet.

The combination of domvanalimab and zimberelimab is under further investigation in patients with NSCLC in the phase 3 ACR-10 (NCT04736173) and STAR-121 (NCT05502237) trials. Domvanalimab is also being evaluated in combination with durvalumab (Imfinzi) in the phase 3 PACIFIC-8 trial (NCT05211895).

References

1. Johnson M, Fox W, Lee YG, et al. ARC-7: randomized phase 2 study of domvanalimab + zimberelimab +/- etrumadenant vs zimberelimab in first-line, metastatic, PD-L1–high non–small cell lung cancer (NSCLC). J Clin Oncol. 2022; 40(suppl 36):397600. doi:10.1200/JCO.2022.40.36_suppl.397600
2. Study to evaluate monotherapy and combination immunotherapies in participants with PD-L1 positive non-small cell lung cancer (ARC-7). ClinicalTrials.gov. Updated December 8, 2022. Accessed December 22, 2022. https://clinicaltrials.gov/ct2/show/NCT04262856