In the phase II ARC-7 study, when domvanalimab, a novel antibody that blocks T-cell immunoglobulin and ITIM domain (TIGIT), was added to immunotherapy for patients with stage IV non–small cell lung cancer (NSCLC), the combination resulted in improved response rates and progression-free survival compared to immunotherapy alone, according to results presented during the December 2022 session of the ASCO Plenary Series by Melissa L. Johnson, MD (Abstract 397600).
“Specifically, TIGIT combinations resulted in approximately a 13% improvement in objective response rate and approximately 40% reduction in risk of progression or death, with a substantial improvement in median progression-free survival,” said Dr. Johnson, Director of Lung Cancer Research for Sarah Cannon Research Institute at Tennessee Oncology, Nashville.
Melissa L. Johnson, MD
More About the Agents
The phase II ARC-7 trial evaluated the addition of two novel agents—domvanalimab and etrumadenant—to the immunotherapy zimberelimab in advanced NSCLC. Domvanalimab is an Fc-silent humanized IgG1 monoclonal antibody that, by blocking TIGIT, could ameliorate the immunosuppression of T cells and natural killer cells and promote antitumor activity. Etrumadenant is a selective dual antagonist of the adenosine receptors (A2a and A2b) expressed on immune cells, thereby reducing immunosuppressive extracellular adenosine and potentially modulating immune response. Zimberelimab is a monoclonal antibody directed against PD-1. The study evaluated whether the inhibition of TIGIT and adenosine pathways augments the activity of zimberelimab as a first-line treatment of PD-L1–high stage IV NSCLC.
“The current standard of care for many patients with stage IV NSCLC is a single immunotherapy drug, but only a fraction of patients will truly benefit over the long term. Identifying novel combination treatments is critical to improving patient outcomes,” Dr. Johnson said. “We are particularly encouraged by the number of patients benefiting at 6 months, as evidenced by tumors being stable or shrinking. It should be noted that this is an interim analysis, and the data will continue to mature with longer follow-up.”
ARC-7 Details
ARC-7 enrolled 150 previously untreated patients with stage IV NSCLC who had high expression of PD-L1 (tumor proportion score [TPS] ≥ 50%) and no EGFR or ALK alterations. They were randomly assigned to one of three treatment regimens:
- Arm Z: Zimberelimab at 360 mg intravenously every 3 weeks, with crossover at disease progression to Arm EDZ allowed
- Arm DZ: Domvanalimab at 15 mg/kg intravenously every 3 weeks plus zimberelimab
- Arm EDZ: Etrumadenant at 150 mg orally once a day in addition to the DZ regimen.
The study’s co-primary endpoints were overall response rate and progression-free survival per investigator assessment. Efficacy for this modified intent-to-treat interim analysis included 133 patients randomly assigned at least 13 weeks prior to data cutoff, allowing for at least two postbaseline scans.
Improved Outcomes with Domvanalimab
After a median follow-up of 11.8 months, patients in both the arms containing domvanalimab—DZ and EDZ—demonstrated improved response rates and progression-free survival compared to Arm Z (zimberelimab alone), Dr. Johnson reported.
Objective response rates were 27% in Arm Z, 41% in Arm DZ, and 40% in Arm EDZ. Median progression-free survival was 5.4 months, 12.0 months, and 10.9 months, respectively, representing relative risk reductions of 45% and 35%, respectively, vs monotherapy. At 6 months, the percentage of patients who were progression-free was 43% in Arm Z, 65% in Arm DZ, and 63% in Arm EZD.
Grade ≥ 3 treatment-related adverse events occurred in about half of patients enrolled in all the arms—specifically, 58% of Arm Z, 47% of Arm DZ, and 52% of Arm EDZ. All cases of rash were grade 1 or 2; they were most common in Arm EDZ and were manageable with topical corticosteroids. The addition of domvanalimab to zimberelimab did not significantly increase the occurrence of immune-related adverse events, which were seen in 47% of patients receiving the two drugs and 48% of patients receiving only zimberelimab.
There were four deaths that were potentially treated-related, including one from interstitial lung disease in Arm Z, one from myocarditis in Arm Z, and one due to pneumonitis and one due to congestive heart failure in Arm EZD.
With proof-of-concept established by this phase II trial, several global phase III trials are now in progress to confirm the activity of domvanalimab in combination with other agents in NSCLC, Dr. Johnson said.
Encouraging, but More Formal Testing Needed
ASCO Expert in lung cancer, Lauren Byers, MD, commented on the findings, “There have been mixed signals from prior studies looking at TIGIT targeting. The promising results of the combination immunotherapy treatment in this study support further investigation, and if confirmed, could lead to a new standard of care for patients with advanced lung cancer.”
Lauren Byers, MD
Solange Peters, MD, PhD
A note of caution, however, was struck by the study’s formal discussant, Solange Peters, MD, PhD, Chair and Professor of Medical Oncology at the University Hospital of Lausanne, Switzerland. “A meaningful magnitude of benefit is needed to change our standards,” she offered, noting that the addition of etrumadenant did not seem to contribute to benefit.
Showing this “meaningful benefit” will require an adequate trial design (ARC-7 did not formally test for statistical significance), definitions of CD226 pathway-related biomarkers (TIGIT is part of the CD226 signaling pathway), and potential innovative combinatorial strategies to increase activity and enlarge the target patient population, Dr. Peters maintained.
But the interest in anti-TIGIT agents is tremendous, she added, as evidenced by the fact that more than 30 monoclonal antibodies are in development and at least two dozen clinical trials of these agents, mostly in combination with other drugs, are active.
Disclosure: For full disclosures of the study authors, visit coi.asco.org.
