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Adding immunotherapy to chemoradiation therapy (CRT) for limited-stage small cell lung cancer (SCLC) failed to improve survival in a randomized trial.

As compared with CRT alone, concurrent atezolizumab (Tecentriq) did not improve overall survival (OS), progression-free survival (PFS), distant metastasis-free survival (DMFS), or time to local failure (TTLF). Interestingly, patients who received radiation therapy on a twice-daily schedule had significantly better OS, reported Kristin A. Higgins, MD, of City of Hope Cancer Center in Atlanta, at the American Society for Radiation Oncology (ASTRO) meeting in Washington, D.C.

"We looked at patient subsets ... and the hazard ratios, the 95% confidence intervals [for OS] cross 1 for every subset," said Higgins. "We observed similar results for progression-free survival in patient subsets. We looked at radiation fractionation, and there was no difference in survival for atezolizumab versus the control arm for patients who received twice-daily versus once-daily radiation."

"But when we considered the radiation schedule alone, with twice daily as the reference, the hazard ratio for once-daily was 1.45 for overall survival," she added. "There was better survival for patients who received twice-daily radiation to 45 Gy versus once daily to 60 Gy."

The results with atezolizumab are "eerily reminiscent" of those from the recent randomized trial that showed no survival benefit in locally advanced non-small cell lung cancer (NSCLC) when durvalumab (Imfinzi) was added to CRT, said ASTRO discussant Robert Samstein, MD, PhD, of the Icahn School of Medicine at Mount Sinai in New York City. The original PACIFIC study established consolidative durvalumab after CRT as a standard of care for locally advanced NSCLC.

In contrast to this trial, the recent ADRIATIC study in limited-stage SCLC showed significant improvement in median OS and median PFS with durvalumab consolidation after CRT. Several differences between the trials might help explain the disparate outcomes, said Samstein.

The control arm of this study performed better, with a median OS of 39.5 months versus 33.4 months in ADRIATIC. Patients who received durvalumab in ADRIATIC had achieved stable disease or better response with CRT prior to starting immunotherapy, whereas all patients assigned to the experimental arm of this study received atezolizumab. The patient populations also differed, with ADRIATIC enrolling patients from Asia, Europe, and South America versus North America and Japan in the current study.

"Of course, the major distinction between the studies is the inherent design, with the immunotherapy started concurrently [NRG-LU005] or only as consolidation [ADRIATIC]," said Samstein.

With a few exceptions, other studies across different disease sites have shown a similar lack of benefit for concurrent CRT and immunotherapy. The accumulation of negative results begs the question of whether concurrent radiation therapy limits immunotherapy activity.

"The obvious concern is that lymphocytes are known to be highly sensitive to radiation, and especially in small cell lung cancer with central disease, high doses of radiation to draining lymph nodes, where immune responses are orchestrated, may prevent immunotherapy-driven T-cell proliferation," said Samstein. "There have been several elegant preclinical studies ... that have demonstrated and confirmed this hypothesis."

"The start of immunotherapy is a critical time period," he noted. "Radiation to the nodal basins, or perhaps blood volume, can ultimately restrain this acute response that's necessary, but giving immunotherapy soon after radiation can potentially harness the benefits of radiation on immune response without the potential harm."

A subset analysis of ADRIATIC supported the importance of timing, as patients who derived the greatest benefit from durvalumab started the PD-L1 inhibitor within 14 days of completing radiation therapy.

The finding that patients had better survival with twice-daily RT also has a precedent in ADRIATIC. A subgroup analysis reported last month at the congress showed significantly better OS with once-daily radiation regardless of whether patients received durvalumab.

"Consolidative durvalumab after chemoradiation, based on the ADRIATIC study, likely remains the new standard of care for limited small cell lung cancer," said Samstein. "We need to strongly reconsider approaches with concurrent immunotherapy and radiation, particularly in the setting of significant lymph node or blood volume dose. [Twice-daily] fractionation remains the standard of care and should be preferred when feasible."

For this study, Higgins and colleagues enrolled 544 patients with limited-stage SCLC in the U.S. and Japan and randomized them to CRT with or without atezolizumab. The primary outcome was OS, and secondary outcomes included PFS, overall response rate, local control, and DMFS.

After a median follow-up of 21 months, the results showed a median OS of 33.1 months with atezolizumab versus 39.5 months with CRT alone, which translated into a hazard ratio of 1.11. Additional calculations yielded hazard ratios of 1.00 for PFS, 0.95 for DMFS, and 0.95 for TTLF.

With regard to the superiority of once- versus twice-daily radiation therapy, Higgins noted that "patients may have received twice-daily radiation over once daily for a number of reasons, including better performance status."

Adverse events (AEs) occurred in a similar proportion of patients in both treatment arms. Grade 3/4 AEs occurred in 92.5% of the CRT-only group and 86.5% of the atezolizumab arm. Rates of fatal AEs were 9% in the atezolizumab arm and 1.6% in the CRT-alone arm, and fatal treatment-related AE rates were 1% with CRT alone and 3% with the addition of atezolizumab.

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