1. Fuerst, Mark L.

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Adding the novel, engineered antibody domvanalimab to immunotherapy improves overall response rates (ORR) and progression-free survival (PFS) compared to treatment with immunotherapy alone for patients with Stage IV non-small cell lung cancer (NSCLC).

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The introduction of programmed death 1 (PD-1) inhibitors has revolutionized treatment and dramatically improved outcomes for patients with programmed death-ligand 1 (PD-L1)-high NSCLC. However, fewer than half of these patients achieve long-term benefit with anti-PD-1 monotherapy. Recent data suggest that targeting additional, non-overlapping immune checkpoints and immunosuppressive pathways in combination with PD-1 inhibition may provide further clinical benefit.


ARC-7 is a randomized, open-label Phase II study evaluating whether the addition of domvanalimab (dom), a monoclonal antibody targeting the T-cell immunoglobulin and ITIM domain, also known as the TIGIT receptor, and etrumadenant (etruma), a selective adenosine receptor antagonist, can augment the activity of the anti-PD-1 antibody zimberelimab (zim) in patients with PD-L1-high metastatic NSCLC.


At the December 2022 ASCO Plenary Series, Melissa Johnson, MD, Director of Lung Cancer Research at the Sarah Cannon Research Institute, presented safety and efficacy results of ARC-7 from the most recent interim analysis (Abstract 397600). ARC-7 randomized 150 patients, median age 68 years, equally to one of three treatment arms: zim monotherapy; the doublet dom plus zim; or the triple combination of etruma, dom, and zim. "Of note, patients initially randomized to zim monotherapy were given the option to cross over to triplet combination therapy upon radiographic confirmation of progressive disease," said Johnson.


At the median follow-up time of 11.8 months, 133 of the 150 patients were evaluable. Roughly half of the patients in both dom-containing arms remained on study treatment, compared to 28 percent of patients randomized to zim monotherapy. All patients were considered PD-L1-high. Following treatment, higher confirmed objective responses were seen in both dom-containing treatment arms compared to zim monotherapy.


"ORRs were 41 percent and 40 percent in Arms 2 and 3, respectively, versus 27 percent in Arm 1. Three additional patients in Arm 3 have had a response on treatment and are awaiting confirmatory scans. The improved response rates seen in the dom-containing arms are consistent across multiple subgroup analyses, including PD-L1 status, tobacco use history, race, and disease histology," said Johnson.


Six-month PFS was 43 percent in Arm 1, 65 percent in Arm 2, and 63 percent in Arm 3. The median PFS was 5.4 months in Arm 1, 12 months in Arm 2, and 10.9 months in Arm 3. "And there was a reduction in probability of progression or death of 45 percent and 35 percent for Arms 2 and 3, respectively, relative to zim monotherapy," said Johnson.


In the safety population, the proportion of patients who experienced treatment-emergent adverse events was broadly similar across the treatment arms, with the majority of patients experiencing at least one adverse event during treatment. The most common adverse events across all arms were fatigue, nausea, constipation, dyspnea, decreased appetite, and pneumonia. The frequency of Grade 3 or higher adverse events was similar across treatment arms, with the most common events reported being pneumonia (8.7%) and anemia (5.4%). "The rate of adverse events leading to study discontinuation was 28 percent in Arm 1, but less, 16 percent and 20 percent, in the combination arms," Johnson noted.


Approximately half of the patients in Arm 1 and 2 experienced at least one immune-related adverse event compared to 60 percent of patients in the etruma-containing triplet, with the difference primarily driven by a low-grade rash. Importantly, the rate of infusion-related reactions remained low across all arms, even with the addition of dom. Four fatal adverse events considered related to study treatment were reported-one case of interstitial lung disease in Arm 1, one case of myocarditis in Arm 2, and one case each of pneumonitis and congestive heart failure in Arm 3.


For immune-related adverse events, pneumonitis was reported at similar frequencies across treatment arms, and most events were Grade 1 or 2. There was no clear increase in the rates of pneumonitis or any other immune-related adverse events in the dom-containing arms compared to zim monotherapy. Incidence of rash was consistent between Arms 1 and 2. However, events were more commonly observed in the etruma-containing arm. All cases of rash were Grade 1 and 2, and most resolved with topical corticosteroids. No cases of rash led to treatment discontinuation. Twelve patients crossed over to treatment with etruma, dom, and zim; two (17%) patients had confirmed partial responses. Crossover patients exhibited a safety profile roughly similar to that of the larger study group.


"In this interim analysis, data from ARC-7 demonstrated the addition of dom results in improved ORR and PFS as compared with zim monotherapy," Johnson noted. "Patients in combination treatment arms, including anti-TIGIT, experienced an approximately 13 percent improvement in ORR compared to zim alone and approximately 40 percent reduction in risk of progression or death compared to anti-PD-1 alone, with an improvement in landmark 6-month and median PFS."


The clinical activity and safety of zim were consistent with that expected of agents in the anti-PD-1 class, and treatment with zim, dom, and etruma was well-tolerated, with similar safety profiles across treatment arms. Low rates of infusion-related reactions were observed.


"These data also provide support for further development of dom and zim combinations, including the Phase III studies ARC-10, STAR-121, and PACIFIC-8, all of which are currently ongoing in patients with advanced NSCLC," Johnson concluded.


Mark L. Fuerst is a contributing writer.