Timing of immunotherapy influences benefit in limited-stage small cell lung cancer
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Concurrent administration of chemoradiation and immunotherapy did not improve survival for patients with limited-stage small cell lung cancer, according to a study presented at American Society for Radiation Oncology Annual Meeting.
The findings follow those of the randomized phase 3 ADRIATIC trial, which showed durvalumab (Imfinzi, AstraZeneca) — a monoclonal antibody that binds to PD-L1 — administered after chemoradiation extended OS for this same patient population.
The disparate results suggest the timing of immunotherapy greatly influences its benefit, researchers concluded.
“Our trial shows us very clearly that, in small cell lung cancer, we should not give immunotherapy concurrently,” Kristin Higgins, MD, radiation oncologist, professor and chief clinical officer at City of Hope Cancer Center Atlanta, told Healio. “It needs to be after the completion of chemoradiation.”
Higgins and colleagues conducted the randomized phase 3 NRG Oncology/Alliance LU005 trial to assess whether concurrent delivery of immunotherapy and chemoradiation may confer benefit comparable to the sequential approach assessed in the ADRIATIC trial.
The analysis included 544 patients with limited-stage small cell lung cancer treated at centers in the United States (n = 500) or Japan (n = 44).
Researchers randomly assigned patients to standard chemoradiation alone or with the anti-PD-L1 antibody atezolizumab (Tecentriq, Genentech).
Chemoradiation consisted of radiation therapy administered twice daily at a total dose of 45 Gy or once daily at a dose of 66 Gy, plus four cycles of concomitant chemotherapy.
Trial participants assigned atezolizumab received the agent every 3 weeks beginning at the start of radiation and continuing for a maximum of 1 year.
The addition of concurrent atezolizumab to chemoradiation did not improve survival (1-year OS, 80.2% vs. 82.6%; median OS, 33.1 months vs. 39.5 months; HR = 1.1; 95% CI, 0.85-1.45).
Healio spoke with Higgins about the importance of the insights gleaned from this study and how the findings can help optimize the use of chemoradiation and immunotherapy for treatment of small cell lung cancer.
Healio: Prior to your study, what did the evidence suggest about the optimal timing of chemoradiation and immunotherapy?
Higgins: Some studies suggested a benefit to combining chemoradiation and immunotherapy, but nothing had been determined about the timing. If we extrapolate from non-small cell lung cancer, we had the PACIFIC trial, which showed that adding immunotherapy after chemoradiation confers a benefit. Interestingly, recently released results of the PACIFIC II trial showed that giving immunotherapy at the same time as chemoradiation did not work.
Healio: Why did you conduct the NRG LU005 study?
Higgins: Limited-stage small cell lung cancer is difficult to treat. Patients have high rates of metastatic disease. We give chemoradiation, but often the cancer recurs in other parts of the body. We are trying to reduce the likelihood that the cancer metastasizes and becomes incurable. There have been advances in metastatic small cell lung cancer when immunotherapy is added to chemoradiation. This has been seen both with atezolizumab and durvalumab. Atezolizumab gained FDA approval in combination with chemoradiation for extensive-stage or metastatic small cell lung cancer in 2019, and durvalumab received approval for this indication in 2020. Our rationale was to see if there’s benefit to moving immunotherapy into earlier stages of disease.
Healio: What did you find?
Higgins: Adding immunotherapy concurrently to chemoradiation does not improve OS or PFS. An interesting secondary finding is that patients who received radiation twice daily achieved longer survival. The best way to give thoracic radiation for these patients has been a hot debate for a long time. Our finding indicates that the twice-daily radiation — although perhaps onerous — gives a patient the best chance for favorable outcomes.
Healio: Do you have a theory why concurrent administration of chemoradiation and immunotherapy did not improve outcomes?
Higgins: Small cell lung cancer often consists of big, bulky tumors that are centrally located next to the heart. When you give radiation, you are giving radiation to that tumor. However, there is a lot of blood volume in that radiation field, and that’s where the lymphocytes live. You’re killing lymphocytes with radiation, and they need time to recover to gain the maximum benefit from the chemoradiation-immunotherapy combination. I believe that’s why the benefit is better when we give immunotherapy after chemoradiation, because this allows time for the body to recover.
Healio: Do you plan to study this further?
Higgins: I will definitely continue to study this because, even though we had positive results from the ADRIATIC trial, we can still do better. We’re probably going to need to look for other combinations of immunotherapeutic agents, or different bispecific T-cell engagers. We want to know how we can logically combine those and continue to improve cure rates for limited-stage small cell lung cancer. That is the way I believe the field will go.
References:
- ASTRO. Timing matters when adding immunotherapy to chemoradiation for patients with limited-stage small cell lung cancer (press release). Available at https://www.astro.org/news-and-publications/news-and-media-center/news-releases/2024/astro24higgins. Published Sept. 30, 2024. Accessed Oct. 4, 2024.
- Higgins KA, et al. Abstract LBA 02. Presented at: ASTRO Annual Meeting; Sept. 29-Oct. 2, 2024; Washington, D.C.
For more information:
Kristin Higgins, MD, can be reached at khiggins@coh.org.
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