medwireNews: Adding low-dose or hypofractionated radiotherapy to durvalumab plus tremelimumab offers no significant benefit to people with non-small-cell lung cancer (NSCLC) that is resistant to PD-1 or PD-L1 inhibition, US study findings indicate.
The multicenter phase 2 study, involving 78 patients with metastatic NSCLC that had progressed during anti-PD-1 or PD-L1 therapy, was stopped due to futility at the interim analysis.
Jonathan Schoenfeld (Dana-Farber Cancer Institute, Boston, Massachusetts) and co-investigators report that, after a median 12.4 months of follow-up, the overall response rate (ORR) was 11.5% among the 26 patients who were randomly assigned to receive durvalumab 1500 mg every 4 weeks for a maximum of 13 cycles plus tremelimumab 75 mg every 4 weeks for a maximum of four cycles.
By comparison, the ORRs were 7.7% and 11.5% among the participants given the PD-L1 and CTLA-4 inhibitors in combination with low-dose radiotherapy (0.5 Gy twice daily to a total of 8 Gy during each of the first four cycles of therapy; n=26) or hypofractionated radiotherapy (24 Gy in three fractions of 8 Gy fractions during the first cycle only; n=26), respectively.
There were no significant differences among the three arms for ORRs, nor for the corresponding disease control rates (30.8 vs 23.1 and 34.6%) and median progression-free survival durations (3.3 vs 4.6 months and 4.0 months).
Median overall survival was not reached in the durvalumab plus tremelimumab alone arm, compared with 9.1 months in the low-dose radiotherapy group and 9.7 months in the hypofractionated radiotherapy group. Again, nonsignificant differences.
In post-hoc correlative exploratory studies, the researchers found that pretreatment levels of three different types of tumor-infiltrating T cells (CD8+PD-1+, CD8+PD-1+Ki67+, and CD4+PD-1+Ki67+) were significantly higher in responders across all treatments than in nonresponders, but there was no difference in tumor PD-L1 expression between the two groups.
Schoenfeld and team say that the combination of durvalumab plus tremelimumab “was relatively well tolerated in this setting.”
Dyspnea was the most common grade 3 or 4 adverse event, occurring in 8% of the durvalumab plus tremelimumab alone group and 12% in each of the low-dose and hypofractionated radiotherapy groups. Hyponatremia occurred in a corresponding 4%, 8%, and 12%.
There was one death – in the low-dose radiotherapy group – from respiratory failure that was considered to be potentially related to study therapy.
Writing in The Lancet Oncology, Schoenfeld and colleagues say that although “[r]adiotherapy did not increase responses to combined PD-L1 plus CTLA-4 inhibition in patients with NSCLC resistant to PD(L)-1 therapy,” there were some patients with prolonged responses and disease control.
They therefore believe “[f]urther studies are warranted to identify the clinical and molecular features associated with benefit in this setting.”
The authors suggest: “Improved patient selection by T cell-infiltrated tumours or other markers could be a worthy strategy to try to improve response rates and clinical benefit.”
In an accompanying comment, Michael MacManus and Fiona Hegi-Johnson, both from the University of Melbourne in Victoria, Australia, note that the cohort was heavily pretreated (median three prior lines of therapy) and that the lack of benefit from radiotherapy could reflect “a reduced capacity to respond to immunotherapy.”
They say: “The immunomodulatory effects of radiotherapy could also be specific to tumour histology, metastatic site, and therapeutic drug. Hence, this trial does not exclude the possibility that other combinations of immunotherapy and radiotherapy might be efficacious in this clinical scenario.”
Indeed, the commentators believe that the findings “should stimulate further research in this area.”
medwireNews is an independent medical news service provided by Springer Healthcare Ltd. © 2022 Springer Healthcare Ltd, part of the Springer Nature Group
Lancet Oncol 2022; doi:10.1016/S1470-2045(21)00658-6
Lancet Oncol 2022; doi:10.1016/S1470-2045(21)00711-7