Federico Cappuzzo, MD

Invited discussant Federico Cappuzzo, MD, Director of Medical Oncology at the National Cancer Institute Regina Elena in Rome, said the study reported by Peters et al is “important” and “provocative,” but he raised some concerns. “From this study, we cannot answer from a scientific point of view whether there really is a difference between first-line single-agent immunotherapy and immunotherapy plus chemotherapy in PD-L1–high NSCLC, but it gives an important message: We should choose the best treatment for a given patient, because there’s no difference in overall survival,” Dr. Cappuzzo said.

Although immunotherapy outperforms chemotherapy in patients with NSCLC with high PD-L1 expression, about 30% of patients in phase III clinical trials have better survival outcomes with chemotherapy than with single-agent checkpoint inhibitors. This suggests that chemotherapy plus immunotherapy might be superior to single-agent immunotherapy in this population, he said.

Survival Benefit Has a Cost

“An indirect comparison of the most relevant trials shows that, in high PD-L1 expressors, median overall survival with the single agent is less than 2 years, but more than 2 years with the combination of chemotherapy and immunotherapy,” he continued. “However, the potential survival benefit has a cost: toxicity.” He noted that grade 3 to 5 toxicity is experienced by approximately 60% of patients receiving combinations, as compared with 20% of those treated with single agents. This is relevant to daily clinical practice, he pointed out, because of the preference for the combination in the setting of aggressive disease, at least in patients who can tolerate it. In contrast, monotherapy is often preferred for more indolent disease or when aggressive therapy is contraindicated.

The study showed the two approaches to yield comparable overall survival and real- world progression-free survival, except in never-smokers, who benefited more from the combination. However, Dr. Cappuzzo questioned whether these data are “enough to spare chemotherapy for the majority of PD-L1–high nonsquamous cell cancers?” His concerns were that, even though the study was adjusted, the treatment cohorts in this nonrandomized study included patients whose prognoses differed and patients who were not fully representative of daily practice (since patients with poor performance status and squamous histology, for example, were excluded). Furthermore, the study lacked information on how the data were generated, how patients were dosed, how well patients adhered to treatment, and how they responded to it.

“We know this information is important,” he said. “In trials, response to treatment is higher with chemotherapy plus immunotherapy (60% or more) compared with single agents (40%), and we know that response to treatment has an impact on long-term survival.”

Subgroup Considerations

In never-smokers, the study found combination therapy to be more effective. Dr. Cappuzzo suggested the question to ask is perhaps not whether chemotherapy should be added to immunotherapy, but whether immunotherapy is needed at all in this patient population. “In clinical practice, certainly chemotherapy plus immunotherapy is recommended even in never-smokers. But we have data showing immunotherapy is less effective in these patients, so the real question may be whether chemotherapy alone is enough…. We need to explore not only for which patients immunotherapy is more effective, but for which patients it is not completely useful.”

Finally, he said, “not all patients with PD-L1–high disease are equal.” Patients with PDL1 ≥ 90% are “extremely sensitive to immunotherapy and are probably the only group for whom monotherapy would be the optimal option.”

Dr. Cappuzzo concluded he would “still be generally in favor” of combination chemotherapy and immunotherapy “if it can be given safely.” However, he added: “Particularly in strongly PD-L1–positive patients, we need to consider patient characteristics and other factors…. If I have toxicity concerns, I go for single-agent immunotherapy.” ■

DISCLOSURE: Dr. Cappuzzo has received honoraria from AstraZeneca, Lilly, MSD Oncology, Pfizer, and Roche/Genentech; and has served as a consultant or advisor to AstraZeneca/MedImmune, Bristol Myers Squibb, Eli Lilly, MSD Oncology, Pfizer, Roche/Genentech, and Takeda.