Domvanalimab-Based Combinations Generate Clinically Meaningful Responses in NSCLC

Melissa Lynne Johnson, MD

The combination of the TIGIT inhibitor domvanalimab (AB154) and the A2R antagonist etrumadenant (AB928) enhances the clinical activity of the PD-1 inhibitor zimberelimab (AB122) when administered as triplet therapy in patients with PD-L1–high, metastatic non–small cell lung cancer (NSCLC), according to updated findings from the phase 2 ARC-7 trial (NCT04262856), which were presented during the 2023 ASCO Annual Meeting.¹

At a data cutoff of February 7, 2023, patients who received the triplet had an overall response rate (ORR) of 44% (n = 22; 95% CI, 30%-58.7%), all of whom achieved a confirmed partial response (PR). In addition, 32% (n = 16), 14% (n = 7), and 10% (n = 5) of patients in this arm achieved stable disease (SD), progressive disease (PD), and unevaluable responses, respectively.

“With this updated analysis of ARC-7, with a longer median follow-up of 18-and-a-half months, domvanalimab-containing arms continued to demonstrate clinically meaningful improvements in ORR and progression-free survival [PFS] as compared with zimberelimab monotherapy,” Melissa Lynne Johnson, MD, of Sarah Cannon Research Institute in Nashville, Tennessee, said in a presentation of the data.

ARC-7 is evaluating whether the addition of domvanalimab with or without etrumadenant increases the efficacy of zimberelimab in patients with PD-L1–high, metastatic NSCLC.

Previously, at a data cutoff of August 31, 2022, the ORR was 27% (n = 12; 95% CI, 15.0%-42.8%), 41% (n = 18; 95% CI, 26.3%-56.8%), and 40% (n = 18; 95% CI, 25.7%-55.7%) in the monotherapy, doublet, and triplet arms, respectively, with a median PFS of 5.4 months (95% CI, 1.8-9.6), 12.0 months (95% CI, 5.5-not evaluable [NE]), and 10.9 months (95% CI, 4.8-NE), respectively.²

The updated data from ARC-7 includes findings from 150 patients with stage IV EGFR or ALK wild-type NSCLC.1 Eligible patients included those who had received no prior treatment for metastatic disease and had a PD-L1 score of at least 50%.

Patients were stratified by ECOG performance status (PS; 0 or 1) and sex and were randomized 1:1:1 to receive intravenous (IV) zimberelimab at 360 mg every 3 weeks alone (arm 1; n = 50), with IV domvanalimab at 15 mg/kg every 3 weeks (arm 2; n = 50), or in the arm 2 regimen plus oral etrumadenant at 150 mg daily (arm 3; n = 50). Patients in arm 1 had the option to cross over to a separate, second-line cohort and receive the arm 3 regimen upon radiographically confirmed disease progression.

The co-primary end points of this 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 pharmacokinetic/anti-drug antibody analysis.

At baseline, the median ages were 66 years (range, 43-84), 69 years (range, 45-92), and 69 years (range, 49-83) in arms 1, 2, and 3, respectively, and 56% (n = 28), 68% (n = 34), and 70% (n = 35) of patients in each respective arm were at least 65 years of age. Additionally, 68% (n = 34), 66% (n = 33), and 68% (n = 34) of patients in arms 1, 2, and 3, respectively, were male, and 50% (n = 25), 44% (n = 22), and 54% (n = 27) of patients in each respective arm were Asian. Never smokers comprised 14% (n = 7), 10% (n = 5), and 10% (n = 5) of the patients in arms 1, 2, and 3, respectively, and 74% (n = 37), 72% (n = 36), and 70% (n = 35) of patients in arms 1, 2, and 3, respectively, had an ECOG PS of 1.

In arm 1, 18% (n = 9), 14% (n = 7), and 18% (n = 9) of patients had squamous cell carcinoma, baseline brain metastases, and baseline liver metastases. In arm 2, 30% (n = 15), 16% (n = 8), and 22% (n = 11) of patients had squamous cell carcinoma, baseline brain metastases, and baseline liver metastases. In arm 3, 32% (n = 16), 16% (n = 8), and 8% (n = 4) of patients had squamous cell carcinoma, baseline brain metastases, and baseline liver metastases. In arms 1, 2, and 3, the median local PD-L1 scores were 80% (range, 50%-100%), 70% (range, 50%-100%), and 78% (range, 50%-100%), respectively. 

Patients in arm 1 had an ORR of 30% (n = 15; 95% CI, 17.9%-44.6%), of whom 2% (n = 1) achieved a complete response (CR) and 28% (n = 14) achieved a confirmed PR. In addition, 32% (n = 16), 24% (n = 12), and 14% (n = 7) of patients in this arm achieved SD, PD, and unevaluable responses, respectively. Patients in arm 2 had an ORR of 40% (n = 20; 95% CI, 26.4%-54.8%), of whom 2% (n = 1) achieved a CR, 36% (n = 18) achieved a confirmed PR, and 2% (n = 1) achieved a pending PR, which was confirmed after the data cutoff date. In addition, 36% (n = 18), 8% (n = 4), and 16% (n = 8) of patients in this arm achieved SD, PD, and unevaluable responses, respectively.

As of the data cutoff, 9, 16, and 20 patients remain on the study treatment in arms 1, 2, and 3, respectively.

The median DORs were 13.2 months (range, 1.4+ to 19.4+), not reached (range, 0.03+ to 26.6+), and 23.7 months (range, 2.6-23.7) in arms 1, 2, and 3, respectively.

In arms 1 and 2, the median PFS was 5.4 months (95% CI, 2.7-9.7) with 32 events (64%) and 9.3 months (95% CI, 4.1-NE) with 27 events (54%), respectively, with a hazard ratio (HR) of 0.67 (95% CI, 0.40-1.13), translating to a 33% reduction in the risk of progression or death with the doublet vs zimberelimab alone. In arm 3, the median PFS was 9.9 months (95% CI, 4.8-14.6) with 30 events (60%), and the HR vs arm 1 was 0.72 (95% CI, 0.44-1.20). In arm 1, the 6- and 12-month PFS rates were 45% and 25%, respectively, compared with 58% and 41% in arm 2, respectively, and 62% and 44% in arm 3, respectively.

In the subset of patients with centrally confirmed PD-L1 expression of at least 50%, the ORR was 33% (n = 8), 48% (n = 13), and 43% (n = 12) in arm 1 (n = 24), arm 2 (n = 27), and arm 3 (n = 28), respectively. The median PFS in this population was 5.7 months (95% CI, 3.5-9.7), 12.0 months (95% CI, 3.5-NE), and 7.6 months (95% CI, 3.9-13), respectively. Compared with arm 1, the HR in arm 2 was 0.60 (95% CI, 0.29-1.26) and the HR in arm 3 was 0.85 (95% CI, 0.43-1.67).

Across arms 1, 2, and 3, respectively, 100% (n = 50), 98% (n = 49), and 98% (n = 49) of patients experienced any treatment-emergent adverse effects (TEAEs), and 64% (n = 32), 46% (n = 23), and 60% (n = 30) of patients had TEAEs of grade 3 or higher. One patient each in arms 1 and 2 and 2 patients in arm 3 experienced grade 5 TEAEs related to the study treatment. Additionally, serious TEAEs occurred in 56% (n = 28), 34% (n = 17), and 52% (n = 26) of patients in arms 1, 2, and 3, respectively, and 28% (n = 14), 18% (n = 9), and 18% (n = 9) of patients, respectively, experienced TEAEs leading to study treatment discontinuation.

Immune-related TEAEs were observed in 48% (n = 24), 50% (n = 25), and 66% (n = 33) of patients in arms 1, 2, and 3, respectively. Two patients each in arms 1 and 2 and 6 patients in arm 3 experienced infusion-related reactions. The median durations of treatment were 16.9 weeks (range, 0-103), 26.2 weeks (range, 0-130), and 36.1 weeks (range, 2-130) in arms 1, 2, and 3, respectively.

The most common TEAEs were nausea, fatigue, constipation, dyspnea, pneumonia, decreased appetite, and diarrhea. Pneumonia and anemia were the most common TEAEs of grade 3 or higher, occurring in 12% and 7% of patients, respectively. The most common immune-related TEAEs were rash, pneumonitis, and pruritus, occurring in 13%, 11%, and 11% of patients, respectively. The investigators noted no clear increase in the rates of pneumonitis in the domvanalimab-containing arms vs treatment with zimberelimab alone.

“Domvanalimab plus zimberelimab combinations are well tolerated, and in particular, the rates of infusion reactions were low in all domvanalimab-containing arms, which is consistent with the Fc-silent design of domvanalimab,” Johnson concluded.

The findings from ARC-7 support ongoing phase 3 studies with domvanalimab, including ARC-10 (NCT04736173), PACIFIC-8 (NCT05211895), STAR-121 (NCT05502237), and STAR-221 (NCT05568095)

References 

1. Johnson ML. Updates on abstract 397600: 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). Presented at: 2023 ASCO Annual Meeting; June 2-6, 2023; Chicago, IL. Abstract 397600.
2. 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(suppl 36):397600. doi:10.1200/JCO.2022.40.36_suppl.397600