Adding TIGIT Targeting Tops PD-1 Alone in Mid-Stage NSCLC Trial

Use of a PD-1/TIGIT inhibitor combination in patients with metastatic non-small cell lung cancer (NSCLC) and high PD-L1 expression resulted in improved response rates and progression-free survival (PFS) compared with PD-1 inhibition alone, according to interim results from a small phase II randomized study.

In an analysis based on data from 133 evaluable patients, the combination of the investigational PD-1 inhibitor zimberelimab plus domvanalimab — a novel monoclonal antibody targeting TIGIT (T cell immunoreceptor with Ig and ITIM domains) — induced an overall response rate (ORR) of 41%, as compared with 27% with zimberelimab alone.

And with a follow-up of 11.8 months, the median PFS was 12.0 months with the combination versus 5.4 months with zimberelimab monotherapy (HR 0.55, 95% CI 0.31-1.00), reported Melissa Johnson, MD, of Sarah Cannon Research Institute at Tennessee Oncology in Nashville.

A third study arm testing etrumadenant, a small-molecule dual adenosine receptor antagonist, as part of a triplet regimen with zimberelimab plus domvanalimab showed similar to the doublet. The ORR with the three-drug regimen was 40%, while median PFS reached 10.9 months (HR 0.65 vs zimberelimab alone, 95% CI 0.37-1.10).

“The improved response rates seen in the domvanalimab-containing arms were consistent across multiple subgroup analyses, including PD-L1 status, tobacco use history, race, and disease histology,” Johnson said during an American Society of Clinical Oncology virtual plenary session

Additionally, she observed that the 35-45% reduction in the risk of progression or death with the combinations compared with the anti-PD-1 alone translated into a substantial improvement in landmark 6-month PFS:

• Doublet: 65%
• Triplet: 63%
• Zimberelimab alone: 43%

The ARC-7 findings “provide support for the further development of domvanalimab and zimberelimab combinations,” Johnson concluded, adding that ongoing phase III trials include ARC-10, STAR-121, and PACIFIC-8.

She noted that while the study was designed to estimate treatment benefit and evaluate safety, “there was no formal statistical testing or hypothesis.”

Thus, said discussant Solange Peters, MD, PhD, of Centre Hospitalier Universitaire Vaudois in Lausanne, Switzerland, “neither comparisons between arms nor statistical significance, can be concluded from this study.”

Nevertheless, she said, “blocking TIGIT consistently demonstrates activity in combination with a backbone of anti-PD-1/L1 blockade in advanced non-small cell lung cancer.”

Peters pointed to the currently “crazy landscape” of more than 30 anti-TIGIT monoclonal antibodies in development in all phases, across all disease types, with many being developed in NSCLC.

“A meaningful magnitude of benefit will be needed to change our standards,” she said, adding that it will require an adequate trial design, and potentially innovative combinations to increase activity and enlarge the target patient population.

The ARC-7 trial was a randomized, open-label phase II study that enrolled 150 previously untreated patients with stage IV squamous or non-squamous NSCLC, with locally assessed high PD-L1 expression (tumor proportion score ≥50%), no EGFR or ALK alterations, and an ECOG performance status of 0 or 1.

Patients were randomized to either:

• Zimberelimab intravenously every 3 weeks, with patients whose disease progressed allowed to crossover to the triplet regimen

• Zimberelimab/domvanalimab IV every 3 weeks

• Zimberelimab/domvanalimab plus oral etrumadenant once daily

Regarding safety, “treatment with [the triplet] was well tolerated with similar safety profiles across arms, with the majority of patients experiencing at least one adverse event during treatment,” Johnson said.

The most common treatment-emergent adverse events (TEAEs) across all arms (≥15%) were fatigue, nausea, constipation, dyspnea, decreased appetite, and pneumonia. Grade ≥3 TEAEs were also similar across treatment arms, with pneumonia (8.7%) and anemia (5.4%) the most frequent. The rate of infusion-related reactions was low across arms.

Rates of TEAEs leading to study discontinuation were 28% in the zimberelimab arm, 16% in the zimberelimab/domvanalimab arm, and 20% in the triplet arm.

There were four fatal TEAEs, including a case of interstitial lung disease in the zimberelimab-monotherapy group, myocarditis in the doublet group, and pneumonitis and congestive heart failure in the triplet group.