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No benefit to adding radiation to PD-L1/CTLA-4 therapy in resistant metastatic NSCLC

The Lancet Oncology
Reuters Health - 25/01/2022 - In patients with resistant metastatic non-small-cell lung cancer (NSCLC), adding radiation to PD-L1 and CTLA-4 inhibition alone or combination did not increase responses, researchers say. 

However, the findings suggest that combination PD-L1 plus CTLA-4 might be an option on its own for such patients, note Dr. Jonathan Schoenfeld of Dana-Farber Cancer Institute in Boston and colleagues in The Lancet Oncology. 

"Patients with higher numbers of infiltrating T-cell populations that expressed the PD-1 receptor at baseline were more likely to respond to treatment.," Dr. Schoenfeld told Reuters Health by email. 

"This immune cell infiltration is a potential biomarker that could be investigated further to better predict which patients might be good candidates for the combined checkpoint inhibitor approach." 

"Despite promising preclinical data, the addition of radiotherapy did not improve outcomes, suggesting future studies in this population should explore other combinations to try to improve response rates," he added. 

"Interestingly, we also found that a decrease in peripheral lymphocytes on treatment was associated with treatment resistance and this was seen more frequently in the patients that received radiotherapy," he noted. "This is one potential reason why the addition of radiotherapy might not have improved outcomes, and should be explored in more detail in subsequent investigations." 

The US-based open-label, randomized, multicenter, phase 2 trial included patients with metastatic NSCLC, an Eastern Cooperative Oncology Group performance status of 0 or 1, and progression during previous PD(L)-1 therapy. 

Seventy-eight patients (median age, 65; about 38% women; about 64% white) all received durvalumab (1,500 mg IV every 4 weeks for up to 13 cycles) plus tremelimumab (75 mg IV every 4 weeks for up to four cycles). Half were randomly assigned to also receive either low-dose radiotherapy (0.5 Gy twice daily for two days during each of the first four cycles of therapy) or hypofractionated radiotherapy (24 Gy total delivered in three 8-Gy fractions during the first cycle only). Radiotherapy began one week after initial durvalumab-tremelimumab administration. 

The trial was stopped due to futility assessed in an interim analysis. 

At a median follow-up of 12.4 months, no between-group differences were seen in overall response rates between the durvalumab-tremelimumab alone group (11.5%) and the low-dose radiotherapy group (7.7%) or the hypofractionated radiotherapy group (11.5%). 

The most common grade 3-4 adverse events were dyspnea (8% in the durvalumab-tremelimumab alone group; 12% in the low-dose radiotherapy group; and 12% in the hypofractionated radiotherapy group) and hyponatremia (4% vs. 8% vs. 12%, respectively). 

Treatment-related serious adverse events occurred in one patient in the durvalumab-tremelimumab alone group (maculopapular rash); five in the low-dose radiotherapy group (abdominal pain, diarrhea, dyspnea, hypokalemia, and respiratory failure), and four in the hypofractionated group (adrenal insufficiency, colitis, diarrhea, and hyponatremia). 

In the low-dose radiotherapy group, one death from respiratory failure occurred, potentially related to the study therapy. 

Dr. Michael MacManus of Peter MacCallum Cancer Centre in Melbourne, coauthor of a related editorial, commented in an email to Reuters Health, "The trial showed that combined immune checkpoint inhibitor (ICI) immunotherapy may overcome resistance to single-agent ICI and suggests that such immunotherapy combinations represent a promising area of future research for this important group of patients." 

"The relatively small sample size...and the inclusion of heavily pre-treated patients does not exclude the possibility that combinations of radiotherapy and ICIs might provide clinical benefits by cooperatively enhancing immunity in NSCLC," he said. "However, these particular combinations of radiotherapy and ICIs appear to be no more effective that combined ICI therapy in this clinical cohort." 

"This area of medicine is at a very exciting stage, with many promising early phase trials either in progress or reporting promising data," he added. "However, well conducted randomized trials, such as this one, are sorely needed to provide a rational basis for selecting treatments for patients in our communities." 

SOURCE: https://bit.ly/3qYKoQX and https://bit.ly/3IGBZYH The Lancet Oncology, online January 13, 2022. 

By Marilynn Larkin 

© 2023 The Author(s). Published by Medicom Medical Publishers.
User license: Creative Commons Attribution – NonCommercial (CC BY-NC 4.0)

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