Solange Peters, MD, PhD
The formal discussant of ARC-7 was Solange Peters, MD, PhD, Chair of Medical Oncology, Centre D’Oncologie Chuv, Lausanne University Hospital, Switzerland, and President of the European Society for Medical Oncology. Dr. Peters described how TIGIT (T-cell immunoglobulin and ITIM domain) plays a role in cancer and how targeting TIGIT might improve outcomes.
Dr. Peters briefly commented: “TIGIT is part of the complex signaling pathway for the immune response. Its inhibitory receptor is expressed on multiple types of immune cells, including T cells and natural killer cells. Basically, TIGIT prevents CD8-positive T-cell activation,” she explained.
Several Clinical Trials Underway or Planned
ARC-71 joins several other phase II trials in suggesting that targeting TIGIT could pay off. They include the phase II CITYSCAPE trial of tiragolumab plus atezolizumab in PD-L1–positive patients.2 In patients with PD-L1 expression of at least 50%, 66% responded, and median overall survival was not reached (vs 12.8 months with atezolizumab; hazard ratio = 0.23). However, Dr. Peters added, a doubling in rash and infusion-related reactions was concerning.
For the subsequent phase III SKYSCRAPER-01 trial, the sponsor has indicated (unpublished) that tiragolumab plus atezolizumab may convey numerical improvements in the co-primary endpoints of progression-free and overall survival, though no significant improvement in progression-free survival. “We are still waiting for the overall survival data to see the magnitude of benefit,” she added.
Dr. Peters noted that the ARC-7 results are “in line with what the field has been showing.” With the addition of anti-TIGIT (with or without the adenosine inhibitor), there was a “striking” difference in progression-free survival, with a reduction in risk of about 50%, she noted.
It is possible, she added, that domvanalimab may offer a better safety profile than tiragolumab, based on less frequent rash and infusion-related reactions. “Might Fc inactivation reduce toxicity while maintaining activity?” she asked.
Of note, the addition of etrumadenant did not contribute benefit above that of domvanalimab alone, even though the adenosine pathway is upregulated upon PD-L1 resistance, and there have been early signals of activity when these agents are combined with PD-L1 blockade.“Longer follow-up will not significantly alter the picture in this specific trial,” she predicted.
Cautious Optimism
However, Dr. Peters was cautious in drawing firm conclusions from ARC-7. “The open-label trial was designed to estimate the potential treatment benefit and safety rather than to conduct formal statistical hypothesis testing. Thus, neither comparisons between the arms nor statistical significance can be concluded from this study. Keep this in mind before making final decisions about the trial,” she suggested.
“A meaningful magnitude of benefit is needed to change our standards,” Dr. Peters added. Demonstration of “meaningful benefit” will require an adequate trial design, 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, according to Dr. Peters.
More than 30 anti-TIGIT monoclonal antibodies are in development, which indicates the tremendous interest in this approach. Some have active Fc regions, and others, such as domvanalimab, have inactive Fc regions. Most are being studied in combination with other drugs.
DISCLOSURE: Dr. Peters has reported financial relationships with AbbVie, Amgen, Arcus, AstraZeneca, Bayer, BeiGene, Biocartis, BioInvent, Blueprint Medicines, Boehringer Ingelheim, Bristol Myers Squibb, Clovis, Daiichi Sankyo, Debiopharm, ecancer, Eli Lilly, Elsevier, F-Star, Fishawack, Foundation Medicine, Genzyme, Gilead Sciences, GSK, IIlumina, Imedex, IQVIA, Incyte, iTeos, Janssen, Medscape, Merck Sharp and Dohme, Merck Serono, Merrimack, Mirati, Novartis, Novocure, Oncology Education, PharmaMar, Phosplatin Therapeutics, PER, Pfizer, PRIME, Regeneron, RMEI, Roche/Genentech, RTP, Sanofi, Seattle Genetics, Takeda, and Vaccibody.
REFERENCES
1. Johnson ML, Fox W, Lee YG, et al: ARC-7: Randomized phase 2 study of domvanalimab + zimberelimab ± etrumadenant vs zimberelimab in first-line, metastatic, PD-L1–high non–small cell lung cancer. ASCO Plenary Series. Abstract 397600. Presented December 20, 2022.
2. Cho BC, Abreu DR, Hussein M, et al: Tiragolumab plus atezolizumab versus placebo plus atezolizumab as a first-line treatment for PD-L1-selected non-small-cell lung cancer (CITYSCAPE): Primary and follow-up analyses of a randomised, double-blind, phase 2 study. Lancet Oncol 23:781-792, 2022.
