Anti-TIGIT regimens improve outcomes vs. anti-PD-1 alone in lung cancer subgroup
Click Here to Manage Email Alerts
A novel anti-TIGIT antibody improved overall response rates and extended PFS when added to anti-PD-1 therapy and to anti-PD-1 therapy plus an adenosine receptor antagonist for patients with advanced, PD-L1-high non-small cell lung cancer.
Results of the randomized phase 2 ARC-7 trial, presented during an ASCO Plenary Series session, showed tolerability of the agents, which exhibited similar safety profiles across treatment groups.
Background
Although PD-1 inhibitors have improved outcomes vs. chemotherapy for patients with PD-L1-high NSCLC, fewer than half of patients derive long-term benefit from anti-PD-1 monotherapy.
“Recent data suggest that targeting additional, nonoverlapping immune checkpoints and immunosuppressive pathways in combination with PD-1 inhibition may provide further clinical benefit to these patients,” Melissa L. Johnson, MD, director of lung cancer research at Sarah Cannon Research Institute at Tennessee Oncology, said during a presentation.
The ARC-7 study examined whether domvanalimab (Arcus Biosciences, Gilead Sciences) — an Fc-silent monoclonal antibody that blocks the T-cell immunoglobulin and ITIN domain (TIGIT) — with or without the dual A2a/A2b adenosine receptor antagonist etrumadenant (Arcus Biosciences, Gilead Sciences) would augment the activity of the anti-PD-1 antibody zimberelimab (Arcus Biosciences, Gilead Sciences) in patients with PD-L1-high, metastatic NSCLC.
Methodology
Johnson and colleagues randomly assigned 150 patients with stage IV NSCLC who had not received treatment for metastatic disease and had locally assessed high PD-L1 expression ( 50%) and no EGFR or ALK alterations to one of three treatment groups. Patients in group 1 and the other two groups received 360 mg IV zimberelimab every 3 weeks. Group 2 also received 15 mg/kg IV domvanalimab every 3 weeks, and group 3 received 15 mg/kg IV domvanalimab every 3 weeks plus 150 mg etrumadenant orally once per day.
The groups had similar baseline characteristics, included median age (group 1, 66 years; groups 2 and 3, 69 years) and percentages of Asian patients (50% vs. 46% vs. 54%), patients with squamous cell carcinoma (18% vs. 32% vs. 32%) and patients with a PD-L1 score of 75% or greater (60% vs. 46% vs. 58%).
Patients in the zimberelimab monotherapy group who experienced disease progression had the option to cross over to group 3.
Investigator-assessed ORR and PFS according to RECIST v.1.1 served as co-primary endpoints. Secondary endpoints included duration of response, disease control rate, OS and safety.
Median follow-up was 11.8 months (range, 0.03-23.5).
Researchers analyzed efficacy for the interim analysis among 133 patients who had been randomly assigned to treatment at least 13 weeks before data cutoff.
Key findings
Results showed higher ORRs in group 2 (41%; 95% CI, 26.3-56.8) and group 3 (40%; 95% CI, 25.7-55.7) compared with the zimberelimab monotherapy group (27%; 95% CI, 15-42.8). The groups that received domvanalimab had higher response rates across subgroups, Johnson said, including those based on PD-L1 status, tobacco history, disease histology and race.
Median duration of response had not yet been reached in any of the treatment groups.
Median PFS, compared with the zimberelimab monotherapy group (5.4 months; 95% CI, 1.8-9.6), more than doubled with the addition of domvanalimab (12 months; HR = 0.55; 95% CI, 0.31-1) and domvanalimab plus etrumadenant (10.9 months; HR = 0.65; 95% CI, 0.37-1.1). Researchers reported 6-month PFS rates of 43% in the zimberelimab monotherapy group, 65% in the doublet therapy group and 63% in the triplet therapy group.
The groups had similar rates of treatment-emergent adverse events (group 1, 100%; groups 2 and 3, 96%), the most common of which included fatigue, nausea and constipation, and grade 3 or higher treatment-emergent adverse events (58% vs. 47% vs. 52%), which included pneumonia (8.7%) and anemia (5.4%). Discontinuation of treatment due to these events occurred less frequently in groups 2 (16%) and 3 (20%) vs. group 1 (28%). Group 3 had a higher rate of immune-related treatment-emergent adverse events (60%) than groups 1 (48%) and 2 (47%), a difference driven primarily by low-grade rash, Johnson said.
Four fatal adverse events related to study treatment occurred, one in group 1, one in group 2 and two in group 3.
Among 12 patients who crossed over from group 1 to group 3, two had partial responses.
Next steps
The data provide support for further development of domvanalimab and etrumadenant combinations, Johnson said.
Solange Peters, MD, PhD, of the medical oncology service and chair of thoracic oncology at Lausanne University Hospital in Switzerland, noted that TIGIT blockade consistently shows activity in combinations with anti-PD-1 therapy in NSCLC. However, a “meaningful magnitude of benefit” will be needed to change standards, she said.
“This will require an adequate trial design [and] the definition of CD226 pathway-related biomarkers,” Peters said. “We also will potentially need innovative combinatorial strategies in order to increase the activity and enlarge the target patient population in advanced non-small cell lung cancer.”
Collapse
Johnson ML, et al. Abstract 397600. Presented at: ASCO Plenary Series: December 2022 Session; Dec. 20, 2022.
Read more about
Click Here to Manage Email Alerts