Consolidative radiotherapy shows no survival benefit, added risk in SCLC

The phase 2 TREASURE trial, which tested whether combining atezolizumab maintenance with consolidative thoracic radiotherapy could improve outcomes for patients with extensive-stage small cell lung cancer (ES-SCLC), was stopped early after a safety monitoring committee flagged a rise in fatal adverse events in the combination arm, according to results published in JAMA Oncology.

Atezolizumab plus carboplatin-etoposide became the standard first-line regimen for ES-SCLC based on the IMpower133 trial, which showed an overall survival benefit over chemotherapy alone, the authors explained. Thoracic radiotherapy (TRT) had shown a modest survival benefit when added after chemotherapy in the earlier CREST trial, before immunotherapy became standard, but its role alongside immunotherapy maintenance had remained undefined.

TREASURE, a multicenter, open-label trial run at 20 sites in Germany and Austria, set out to test whether adding TRT to atezolizumab maintenance could build on both results.

Researchers randomized 68 patients with at least stable disease after induction chemoimmunotherapy to atezolizumab maintenance combined with consolidative TRT or to atezolizumab maintenance alone. Toxic effects occurred in 96.8% of patients on combination therapy versus 75.8% on atezolizumab alone. Serious adverse events were more than three times as common in the combination arm (61.3% versus 18.2%), and fatal adverse events were roughly six times as common (19.4% versus 3.0%), with infections and respiratory disorders, including pneumonitis, driving most of the excess.

Despite the added toxicity, the combination did not translate into better outcomes. Median overall survival was numerically shorter with combined treatment than with atezolizumab alone, although the difference did not reach statistical significance given the trial's reduced size. Progression-free survival was similar between arms (2.4 months versus 2.6 months), which the authors said points to treatment-related toxic effects, rather than faster tumor progression, as the likely driver of the survival gap.

Enrollment, originally planned for 104 patients, was paused after 68 when the safety monitoring committee saw the pattern of fatal events, then stopped altogether after an unplanned interim survival analysis confirmed the disadvantage in the combination arm.

The authors linked the excess toxicity to a specific, persistent drop in lymphocyte counts among patients who received radiotherapy, a pattern not seen in white blood cell or neutrophil counts. No baseline differences in performance status, comorbidity burden, or pulmonary function distinguished patients who had serious adverse events from those who didn't, though patients who died of treatment-related causes tended to have lower baseline lung diffusing capacity going into treatment.

“In this randomized clinical trial, combining consolidative TRT with atezolizumab maintenance resulted in an unexpected increase of toxic effects, including partially fatal infections and pulmonary disorders, associated with a reduced baseline DLCO SB and protracted radiation-induced lymphopenia,” the authors concluded.

TREASURE is the latest randomized trial to find that pairing thoracic radiotherapy with immune checkpoint inhibitors raises safety concerns without a clear efficacy payoff. In an accompanying editor's note, Charles R. Thomas Jr., M.D., of Dartmouth-Hitchcock Medical Center, pointed to similar results from the PACIFIC-2 trial in non-small cell lung cancer (NSCLC), where adding durvalumab to concurrent chemoradiotherapy also failed to improve progression-free survival.

“The aforementioned trials and other results of larger fields that encompass draining nodes and conventional radiotherapy (RT) multifractionation might suggest that concurrent ICI and RT is a suboptimal strategy to use,” Thomas wrote. “However, there is evidence that further adjusting the sequencing by initiating ICIs alone much earlier than definitive RT may have promise for nasopharyngeal cancer. As such, future study designs will need to consider the myriad factors affecting the complex interaction between ICIs and RT.”