1988MO Recruitment discontinuation in TREASURE trial (thoracic radiotherapy with atezolizumab in small cell lung cancer extensive disease) due to unexpected safety data

Carboplatin/etoposide + atezolizumab (IMpower133) is now 1L standard-of-care for patients with extensive disease small cell lung cancer (ED SCLC). Thoracic radiotherapy (TRT) after induction chemotherapy has been shown to increase 2-year overall survival rates. Alongside, evidence for synergistic immunostimulatory effects of radiotherapy and immunotherapy (IO) is increasing. Combining these results, the TREASURE trial attempted to improve response to chemo-IO by adding TRT. The phase II, multicenter TREASURE trial (NCT04462276) randomized patients with ED SCLC, ECOG≤1, and response to IMpower133 induction to receive atezolizumab maintenance therapy (1200mg, Q3W, until progression/toxicity) either with TRT (10x30 Gy, arm A) or without TRT (arm B). Safety interim analysis was planned once 23 patients in arm A had been observed for 3 months after TRT ended, with the safety signal being ≥2 patients with grade ≥3 pneumonitis. In 04/22, interim safety analysis showed only 1/23 patients with grade ≥3 pneumonitis in arm A. However, routine safety monitoring committee (SMC) review in 08/22 identified a potential imbalance in grade 5 severe adverse events (SAEs) between the arms (n=5 in A, n=1 in B), and thus recruitment was paused. Data review 3 months later revealed more SAEs in arm A (28 any, 16 grade 3/4, 6 grade 5) vs. B (9 any, 4 grade 3/4, 1 grade 5). Along with evaluation of further parameters, this prompted Coordinating Investigator and SMC to permanently stop recruitment. Of note, neither differences in clinical measures of comorbidity nor functional status were detected between arms. At the time of recruitment stop (12/22), 68 patients were included in the trial (n=34 in each arm). Although TRT-IO combinations have not been the source of safety concerns in other trials, it was associated with more SAEs in TREASURE. SAE analysis did not indicate any new safety signal of atezolizumab or TRT. Observed SAEs were either known adverse effects or confounded, and not clearly tied to either IO or TRT. Thus, the factors underlying this unexpected outcome remain to be identified and will be focus of the final analysis of this trial.