The addition of consolidative thoracic radiotherapy to atezolizumab maintenance increased serious toxic effects without improving survival in patients with extensive-stage small cell lung cancer (ES-SCLC), according to findings from the randomized phase 2 TREASURE trial.
Published in JAMA Oncology on July 9, 2026, the multicenter study found a markedly higher incidence of serious adverse events, including fatal infections and respiratory complications, among patients receiving thoracic radiotherapy alongside atezolizumab maintenance. Recruitment was stopped early because of the emerging safety signal.
The findings challenge the routine addition of consolidative thoracic radiotherapy in unselected patients receiving maintenance immunotherapy for ES-SCLC and raise important questions about radiation-induced lymphocyte depletion as a potential contributor to treatment-related toxicity.
Testing Thoracic Radiotherapy in the Immunotherapy Era
Atezolizumab combined with carboplatin and etoposide has become an established first-line treatment for ES-SCLC, followed by atezolizumab maintenance.
At the same time, thoracic radiotherapy has remained an area of clinical interest. Before the introduction of immunotherapy, the CREST trial demonstrated a modest survival benefit with thoracic radiotherapy following chemotherapy.
The TREASURE trial, formally known as AIO-TRK-0320, was designed to determine whether these approaches could be brought together: adding consolidative thoracic radiotherapy to atezolizumab maintenance after initial chemoimmunotherapy.
Investigators hypothesized that the combination could further improve outcomes. Instead, the randomized study uncovered a significant safety concern.
A Randomized Trial Stopped Before Full Enrollment
TREASURE was a multicenter, open-label, randomized phase 2 trial conducted across 20 sites in Germany and Austria.
Patients were eligible if they had ES-SCLC and achieved at least stable disease following induction therapy with carboplatin, etoposide, and atezolizumab.
Of 96 patients screened, 68 were randomized, with 34 allocated to each treatment arm.
Patients received either:
- Atezolizumab maintenance plus consolidative thoracic radiotherapy, delivered as 30 Gy in 10 fractions, or
- Atezolizumab maintenance alone.
The study originally planned to randomize 104 patients. However, recruitment was stopped after 68 participants because of an increased incidence of fatal serious adverse events in the radiotherapy arm.
Recruitment was initially paused in August 2022 and permanently discontinued in December 2022 after an unplanned preliminary survival analysis identified a disadvantage associated with the combination strategy.
No Survival Advantage From Adding Radiotherapy
The primary endpoint of the trial was overall survival.
Median overall survival was numerically shorter among patients receiving thoracic radiotherapy plus atezolizumab compared with those receiving atezolizumab alone:
6.7 months vs 13.4 months, respectively.
The hazard ratio was 1.55 (95% CI, 0.90-2.69; P = .34), meaning the difference did not reach statistical significance.
At one year, estimated overall survival was 30.3% in the combination group compared with 56.6% in the atezolizumab-only group.
At two years, the curves had crossed, with estimated survival rates of 24.2% and 15.7%, respectively. The investigators stressed that this observation requires cautious interpretation because relatively few patients remained at risk at this stage of follow-up.
An updated overall survival analysis conducted after an additional 19 months of follow-up produced similar findings.
Progression-Free Survival Remained Nearly Identical
The addition of thoracic radiotherapy also failed to improve progression-free survival.
Median progression-free survival was:
2.4 months with atezolizumab plus thoracic radiotherapy and 2.6 months with atezolizumab alone.
The hazard ratio was 0.92 (95% CI, 0.54-1.55; P = .85).
Investigators noted that the absence of a progression-free survival advantage provided no evidence of meaningful additional tumor control from consolidative thoracic radiotherapy in this setting.
At the same time, interpretation of the survival findings remains limited by the trial’s early termination and substantially reduced statistical power.
The Strongest Signal Came From Safety
The most striking difference between the two treatment groups was not disease progression. It was toxicity.
In the final safety analysis, adverse events occurred in 96.8% of patients receiving thoracic radiotherapy plus atezolizumab, compared with 75.8% receiving atezolizumab alone.
More importantly, serious adverse events were reported in:
61.3% vs 18.2% of patients, respectively (P < .001).
Treatment-related adverse events were also considerably more frequent with the combination, occurring in 71.0% of patients compared with 30.3% in the atezolizumab-only group.
Treatment-related serious adverse events occurred in 29.0% vs 6.1%, respectively.
The difference became particularly concerning when fatal events were examined.
Fatal adverse events occurred in 6 patients, or 19.4%, in the thoracic radiotherapy arm, compared with 1 patient, or 3.0%, in the atezolizumab-only arm (P = .04).
Infections and Respiratory Events Emerged as Key Concerns
Patients receiving thoracic radiotherapy experienced more microbial infections, including pulmonary and urinary tract infections, as well as gastrointestinal, respiratory, febrile, and skin-related adverse events.
Respiratory complications included pneumonitis, dyspnea, and cough, while gastrointestinal events included dysphagia and esophagitis.
Importantly, the trial’s initial safety monitoring had focused on severe pneumonitis.
Among the first 23 patients receiving thoracic radiotherapy, only one case of grade 3 or higher pneumonitis occurred, meaning the predefined safety threshold was initially satisfied.
The broader safety problem became evident later, when investigators observed an excess of fatal serious adverse events that were not limited to pneumonitis.
Could Lymphocyte Depletion Explain the Toxicity?
One of the most notable findings from TREASURE emerged from the analysis of immune cell counts.
Lymphocyte levels were initially similar between treatment groups. After thoracic radiotherapy, however, patients in the combination arm developed pronounced and persistent lymphocyte depletion.
By the second cycle of atezolizumab maintenance, low lymphocyte counts were observed in 91.7% of evaluated patients in the radiotherapy group, compared with 13.6% in the atezolizumab-only group.
The difference persisted during subsequent treatment cycles.
At cycle 3, low lymphocyte counts were reported in 77.8% vs 26.7% of patients, and at cycle 4 in 69.2% vs 8.3%, respectively.
This effect appeared specific to lymphocytes. Leukocyte and neutrophil counts were not similarly affected.
The persistent lymphocyte depletion occurred alongside an accumulation of adverse events, particularly infections and respiratory disorders, leading investigators to identify radiation-induced lymphopenia as a potential contributor to the toxicity observed with the combination.
The association remains exploratory and requires further investigation.
Baseline Lung Function May Also Matter
Investigators examined whether differences in baseline characteristics could explain the higher rate of serious adverse events.
No substantial differences between treatment groups were identified in ECOG performance status, comorbidity, pulmonary function, thoracic tumor burden, or tumor location.
Similarly, no clear clinical or dosimetric factor was associated with the overall occurrence of serious adverse events in the radiotherapy arm.
One potential signal did emerge among patients who experienced fatal adverse events.
Mean baseline single-breath diffusing capacity of the lungs for carbon monoxide, or DLCO SB, was significantly lower among patients with fatal events than among other patients receiving thoracic radiotherapy:
45.3 vs 56.7, respectively (P = .04).
Investigators emphasized that the finding requires caution because of the small sample size.
Radiotherapy Exposure Was Associated With Higher Adverse-Event Risk
In a time-to-event analysis, thoracic radiotherapy was positively associated with the risk of adverse events, with a hazard ratio of 2.47 (95% CI, 1.15-5.32; P = .01).
Longer exposure to atezolizumab without radiotherapy was not significantly associated with increased adverse-event risk.
The timing of radiotherapy also did not appear to explain the findings. Whether thoracic radiotherapy was delivered concurrently with atezolizumab or sequentially was not associated with the occurrence of adverse events.
Radiation doses and treated volumes were within typical clinical ranges and below established organ-at-risk thresholds.
A Cautionary Result for Combining Two Modalities
The TREASURE findings are particularly notable because previous prospective single-arm studies evaluating thoracic radiotherapy alongside immunotherapy in ES-SCLC had not demonstrated the same increase in toxicity.
The investigators also placed the findings in the context of randomized studies in non-small cell lung cancer, including PACIFIC-2 and CheckMate 73L, where simultaneous thoracic chemoradiotherapy and immunotherapy were also associated with increased fatal infections and toxic effects in experimental treatment groups.
Taken together, the TREASURE investigators suggested that combining thoracic radiotherapy with immunotherapy may create clinically important toxicity without a corresponding efficacy advantage in some settings.
Early Termination Limits the Final Interpretation
The trial’s principal limitation is its premature termination.
Because recruitment stopped after 68 patients rather than the planned 104, the study had substantially less statistical power than originally intended. The efficacy analyses therefore remain exploratory and descriptive.
Nevertheless, the magnitude of the safety signal was sufficient for the Safety Monitoring Committee to recommend stopping recruitment, a decision that the investigators concluded was supported by the final risk-benefit findings.
TREASURE Calls for Greater Caution in Patient Selection
TREASURE represents the first reported randomized phase 2 trial examining consolidative thoracic radiotherapy during immunotherapy maintenance in ES-SCLC.
Its results do not support routine addition of thoracic radiotherapy to atezolizumab maintenance in unselected patients following chemoimmunotherapy.
Instead of improving survival, the combination was associated with substantially more serious toxicity, including fatal infections and pulmonary complications, alongside persistent radiation-associated lymphocyte depletion.
The investigators concluded that consolidative thoracic radiotherapy cannot currently be recommended outside clinical trials for unselected patients in this setting.
Future studies will need to determine whether particular patient subgroups can receive this approach safely and whether treatment strategies that reduce radiation exposure to highly perfused organs, optimize the timing of radiotherapy relative to immunotherapy, or incorporate predefined safety stopping rules can improve the risk-benefit balance.
Ongoing biomarker analyses from TREASURE could also help identify patients with either heightened vulnerability to toxicity or a greater likelihood of therapeutic benefit.
Source: Bozorgmehr F, Chung I, Behnisch R, et al. Consolidative Thoracic Radiotherapy With Atezolizumab Maintenance in Extensive-Stage Small Cell Lung Cancer: The Phase 2 TREASURE Randomized Clinical Trial (AIO-TRK-0320). JAMA Oncology.
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