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Addition of Radiotherapy to Durvalumab Plus Tremelimumab in Patients With Metastatic NSCLC Refractory to PD-1/PD-L1 Inhibitor Therapy


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In a phase II trial reported in The Lancet Oncology, Jonathan Schoenfeld, MD, and colleagues found that the addition of low-dose or hypofractionated radiotherapy to durvalumab plus tremelimumab did not improve objective response rates in patients with metastatic non–small cell lung cancer (NSCLC) refractory to prior PD-1/PD-L1 inhibitor therapy.

As stated by the investigators, “Patients with NSCLC that is resistant to PD-1– and PD-L1–targeted therapy have poor outcomes. Studies suggest that radiotherapy could enhance antitumor immunity. Therefore, we investigated the potential benefit of PD-L1 (durvalumab) and CTLA-4 (tremelimumab) inhibition alone or combined with radiotherapy.”


Radiotherapy did not increase responses to combined PD-L1 plus CTLA-4 inhibition in patients with NSCLC resistant to PD-1/PD-L1 therapy. However, PD-L1 plus CTLA-4 therapy could be a treatment option for some patients. Future studies should refine predictive biomarkers in this setting.
— Jonathan Schoenfeld, MD, and colleagues

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Study Details

In the open-label study—performed by the National Cancer Institute Experimental Therapeutics Clinical Trials Network at 18 U.S. sites—76 eligible patients were randomly assigned 1:1:1 between August 2017 and March 2019 to receive durvalumab at 1,500 mg every 4 weeks for a maximum of 13 cycles plus tremelimumab at 75 mg every 4 weeks for a maximum of four cycles alone (n = 26) or with low-dose (n = 26) or hypofractionated radiotherapy (n = 26). Low-dose radiotherapy was given at 0.5 Gy twice daily, repeated for 2 days during each of the first four cycles of therapy; hypofractionated radiotherapy was given at 24 Gy in three 8-Gy fractions during the first cycle only 1 week after initial durvalumab/tremelimumab administration.

Treatment continued until 1 year or disease progression. The primary endpoint was objective response rate.

Responses

The trial was stopped due to futility determined at interim analysis. At a median follow-up of 12.4 months (interquartile range = 7.8–15.1 months), objective response was observed in three patients (11.5%, 90% confidence interval [CI] = 1.2%–21.8%) in the durvalumab/tremelimumab–alone group, two (7.7%, 90% CI = 0.0%–16.3%) in the low-dose radiotherapy group (P = .64), and three (11.5%, 90% CI = 1.2%–21.8%) in the hypofractionated radiotherapy group (P = .99). Disease control rates were 30.8%, 23.1%, and 34.6%, respectively.

In post hoc analysis, median response duration was not reached (90% CI = 10.3 months–not estimable) in the durvalumab/tremelimumab–alone group, 4.9 months (90% CI = 4.3–5.5 months) in the low-dose radiotherapy group and not reached (90% CI = 2.5 months–not estimable) in the hypofractionated radiotherapy group. Median progression-free survival was 3.3 months (90% CI = 1.8–5.5 months), 4.6 months (90% CI = 2.1–7.2 months, P = .55), and 4.0 months (90% CI = 2.1–7.0 months, P = .92), respectively. Median overall survival was not reached (90% CI = 4.9 months–not reached), 9.1 months (90% CI = 3.8–23.9 months, P = .24), and 9.7 months (90% CI = 5.1 months–not reached, P = .44), respectively.

KEY POINTS

  • The trial was stopped due to futility at interim analysis.
  • Objective response rates ranged from 7.7% to 11.5%.

Adverse Events

The most common grade 3 or 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%, 8%, and 12%). Treatment-related serious adverse events occurred in one patient (4%) in the durvalumab/tremelimumab alone group (maculopapular rash), five (19%) in the low-dose radiotherapy group (abdominal pain, diarrhea, dyspnea, hypokalemia, and respiratory failure), and four (15%) in the hypofractionated radiotherapy group (adrenal insufficiency, colitis, diarrhea, and hyponatremia). One death considered potentially related to treatment was observed (respiratory failure in a patient in the low-dose radiotherapy group).

The investigators concluded, “Radiotherapy did not increase responses to combined PD-L1 plus CTLA-4 inhibition in patients with NSCLC resistant to PD-1/PD-L1 therapy. However, PD-L1 plus CTLA-4 therapy could be a treatment option for some patients. Future studies should refine predictive biomarkers in this setting.”

Dr. Schoenfeld, of the Department of Radiation Oncology, Dana-Farber Cancer Institute, is the corresponding author for The Lancet Oncology article.

Disclosure: The study was funded by the National Institutes of Health and Dana-Farber Cancer Institute. For full disclosures of the study authors, visit thelancet.com.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
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