Adding Radiotherapy to Durvalumab/Tremelimumab Does Not Increase Responses in Refractory/Metastatic NSCLC

Article

Patients with PD-1/PD-L1–refractory metastatic non–small cell lung cancer did not achieve additional benefit when radiotherapy was added to durvalumab and tremelimumab.

Although the addition of radiotherapy did not increase responses vs durvalumab (Imfinzi) and tremelimumab alone for patients with PD-1/PD-L1–refractory metastatic non–small cell lung cancer (NSCLC), select patients may benefit from the PD-L1/CTLA-4 combination, according to findings from a phase 2 study (NCT02888743).

After a median follow up 12.4 months, investigators reported overall response rates (ORRs) of 11.5% (90% CI, 1.2%-21.8%), 7.7% (90% CI, 0.0%-16.3%; P = .64), and 11.5% (90% CI, 1.2%-21.8%; P = .99) in the durvalumab/tremelimumab alone, low-dose radiotherapy, and hypofractionated radiotherapy arms, respectively.

“We conducted a [randomized], phase 2 study testing the hypothesis that either repeated low-dose fractionated radiotherapy or hypofractionated radiation would increase the systemic overall response rate to durvalumab–tremelimumab in patients with NSCLC who had previously progressed on PD(L)-1–directed therapy. We did not identify any benefit in overall response rate for the addition of either radiation regimen to durvalumab–tremelimumab,” the investigators wrote. “There were also no differences in progression-free survival and overall survival between treatment groups,”.

Investigators recruited patients from outpatient oncology clinics who had histologically or cytologically confirmed disease for the open-label, multicenter, randomized study. To be eligible for the study, patients needed to be 18 years of age or older with an ECOG performance status of 0 or 1, a life expectancy of 6 months or more, and evidence of disease progression on systemic PD-1/PD-L1 therapy.

Patients were randomized 1:1:1 to receive either the durvalumab/tremelimumab combination alone or in combination with low-dose radiotherapy or hypofractionated radiotherapy. Both Durvalumab was given at a fixed dose of 1500 mg every 4 weeks for up to 13 cycles, and tremelimumab was given at a fixed-dose of 75 mg every 4 weeks for 4 cycles at most. Low-dose therapy was administered at 2 Gy in 4 fractions over 2 days for the first four 28-day cycles, and the hypofractionated group received 24 Gy in 3 fractions of 8 every other day in the first cycle.

The study’s primary end point was ORR, with key secondary outcomes including safety, investigator-assessed progression-free survival (PFS), and overall survival (OS).

A total of 90 patients were enrolled on the study from August 24, 201,7 to March 29, 2019, 78 of whom underwent their assigned treatment and were included in the safety and efficacy analysis. Baseline characteristics for the study were well balanced, with most patients previously undergoing treatment with chemotherapy (85%) and others receiving immunotherapy (35%). Common radiotherapy sites in both radiotherapy arms included lung (62%), lymph nodes (15%), liver (12%), and adrenal glands (10%).

Additional findings from the study indicated that the median durations of response in the durvalumab/tremelimumab, low-dose radiotherapy, and hypofractionated radiotherapy arms were not reached, 4.9 months, and not reached. Moreover, the median PFS across the 3 groups were 3.3 months, 4.6 months (HR, 0.83; 90% CI, 0.50-1.38; P = .55), and 4.0 months (HR, 0.81; 90% CI, 0.60-1.58; P = .92), respectively. Investigators also noted that differences in OS between the arms were not statistically significant.

However, investigators noted that certain subgroups of patients may still benefit from treatment durvalumab/tremelimumab.

“Data from our [randomized] trial suggest that durvalumab–tremelimumab should be further explored for its ability to benefit patients with NSCLC who have progressed on previous PD(L)-1-directed therapy. Improved patient selection by T cell-infiltrated [tumors] or other markers could be a worthy strategy to try to improve response rates and clinical benefit,” the investigators wrote.

Common grade 3 adverse effects (AEs) in the radiotherapy-free, low-dose radiotherapy, and hypofractionated radiotherapy arms, respectively, were dyspnea (8% vs 12% vs 12%), hyponatremia (4% vs 8% vs 12%), and increased gamma-glutamyl transferase (0% vs 4% vs 12%). In the overall population, 9% of patients discontinued due to treatment-related AEs (TRAEs), including 4% in the radiotherapy-free arm, 14% in the low dose group, and 8% in the hypofractionated group.

Serious TRAEs included 1 case each of maculopapular rash in the radiotherapy-free cohort; adrenal insufficiency, colitis, diarrhea and hyponatremia in the hypofractionated cohort; and abdominal pain, diarrhea, dyspnea, hypokalemia, and respiratory failure in the low-dose cohort.

Reference

Schoenfeld JD, Giobbie-Hurder A, Ranasinghe S, et al. Durvalumab plus tremelimumab alone or in combination with low-dose or hypofractionated radiotherapy in metastatic non-small-cell lung cancer refractory to previous PD(L)-1 therapy: an open-label, multicentre, randomised, phase 2 trial. Lancet Oncol. 2022;23(2):P279-291. doi:10.1016/S1470-2045(21)00658-6

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