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Expert Point of View: Yun Fan, MD, and Deborah Doroshow, MD, PhD


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Yun Fan, MD

Yun Fan, MD

Invited discussant of KEYNOTE-598,1Yun Fan, MD, Director of Thoracic Tumor Center at Zhejiang Cancer Hospital in Hangzhou, China, suggested that patients with non–small cell lung cancer (NSCLC) with low PD-L1 expression and those with high tumor mutational burden may, in fact, derive the most benefit from dual checkpoint inhibition, which was suggested by the results of CheckMate 227.2 KEYNOTE-598 included high–PD-L1 expressors alone.

“CTLA-4 blockade allows for activation and proliferation of extra T-cell clones,” Dr. Fan said. High–PD-L1 expressors (≥ 50%) already present with higher levels of preactivated CD8-positive T cells in the microenvironment. Additional CTLA-4 blockade, therefore, may not produce more clinical benefit,” she said. Tumor mutational burden as a predictive biomarker for combination immunotherapy is still somewhat in doubt, she added.

It is also possible that the negative results of KEYNOTE-598 may be explained by the influence of increased toxicity with the combination, which led to higher rates of treatment discontinuation, she added.

Ongoing combination trials involving anti–PD-1/PD-L1 plus other types of drugs may help to clarify the role of combinations in this population. Trials evaluating such combinations as atezolizumab plus tiragolumab and pembrolizumab plus lenvatinib are now under way.

Additional Commentary

Also offering thoughts on KEYNOTE-598 for The ASCO Post was Deborah Doroshow, MD, PhD, Assistant Professor of Medicine, Early Phase Trials Unit and Thoracic Oncology at Tisch Cancer Institute, Icahn School of Medicine, Mount Sinai, New York. According to Dr. Doroshow, KEYNOTE-598 shows that “giving more is not always better.”

Deborah Doroshow, MD, PhD

Deborah Doroshow, MD, PhD

In this case, “more” was the addition, in the first-line setting, of ipilimumab to pembrolizumab for patients with a PD-L1 tumor proportion score (TPS) of at least 50%. “In fact, in this case, it was worse,” she pointed out. “Although patients in the two arms had similar clinical outcomes, patients in the ipilimumab arm had more serious side effects and were more likely to discontinue the regimen.”

The reasons for this are unclear, but Dr. Doroshow agreed with Dr. Fan: It is possible that patients with a high PD-L1 TPS do not benefit from additional T-cell activation induced by ipilimumab. “These results are also notable in light of the current U.S. Food and Drug Administration approval of the combination of first-line ipilimumab and nivolumab for patients with advanced NSCLC and a PD-L1 TPS of at least 1%, given the survival benefit seen with this combination in comparison to chemotherapy alone in this population in the CheckMate 227 study.”

“To me, the KEYNOTE-598 findings confirm that our current standard of care for patients with advanced NSCLC and a TPS of at least 50% should, in most cases, be single-agent pembrolizumab,” Dr. Doroshow commented. 

DISCLOSURE: Dr. Fan reported no conflicts of interest. Dr. Doroshow has served as a consultant or advisor to Atheneum Partners, Boston Healthcare Associates, Dedham Group, Guidepoint Global, and Ipsen; and has been reimbursed for travel, accommodations, or other expenses by Ipsen.

REFERENCES

1. Boyer M, Sendur MAN, Rodríguez-Abreu D, et al: Pembrolizumab plus ipilimumab vs pembrolizumab plus placebo as 1L therapy for metastatic NSCLC of PD-L1 TPS ≥ 50%: KEYNOTE-598. 2021 World Lung Cancer Conference. Abstract PS01.09. Presented January 30, 2021.

2. Peters S, Ramalingam SS, Paz-Ares L, et al: Nivolumab plus low-dose ipilimumab vs platinum-doublet chemotherapy as first-line treatment for advanced non-small cell lung cancer: CheckMate 227 Part 1 final analysis. ESMO 2019 Congress. Abstract 7128. Presented September 28, 2019.


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