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

Background

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.

Methods

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.

Results

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).

Conclusions

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.

Clinical trial identification

NCT04462276.

Editorial acknowledgement

Legal entity responsible for the study

Institut für Klinische Krebsforschung IKF GmbH at Krankenhaus Nordwest.

Funding

Roche.

Disclosure

F. Bozorgmehr: Financial Interests, Personal, Advisory Board: AMGEN, Janssen, Novartis, AstraZeneca, Novocure; Financial Interests, Personal, Invited Speaker: Novocure, AstraZeneca, MSD, Janssen; Financial Interests, Institutional, Research Grant: Roche, AstraZeneca; Non-Financial Interests, Principal Investigator: AstraZeneca, GSK, Janssen, Amgen. F. Weykamp: Financial Interests, Personal, Speaker, Consultant, Advisor: AstraZeneca, Merck Sharp & Dohme. E.L. Buchmeier: Financial Interests, Personal, Invited Speaker, and congress sponsoring: Takeda; Financial Interests, Personal, Advisory Board: Ipsen; Financial Interests, Institutional, Local PI: BMS, AstraZeneca, Novartis, MSD, Janssen Cilag, PDC Line Pharma, Roche, GSK, Novartis; Non-Financial Interests, Member: Political Party FDP. T.C. Gauler: Financial Interests, Advisory Role: Roche, MSD, BMS, AstraZeneca, Merck Serono. M. Ulmer: Financial Interests, Advisory Board: AstraZeneca, Roche, Novartis, Amgen, Lilly, Teva, Chugai, Pfizer, MSD, BMS, Merck, Mediolanum Biosciences, Servier, Eisai, Takeda, Boehringer Ingelheim. A. Mueller: Financial Interests, Speaker, Consultant, Advisor: AstraZeneca; Financial Interests, Local PI: SAKK; Financial Interests, Research Funding: DFG; Financial Interests, Writing Engagement: Servier. P. Christopoulos: Financial Interests, Personal, Advisory Board: AstraZeneca, Boehringer Ingelheim, Chugai, Pfizer, Novartis, MSD, Takeda, Roche, Daiichi Sankyo; Financial Interests, Personal, Writing Engagement: Gilead; Financial Interests, Personal, Invited Speaker: Thermo Fisher; Financial Interests, Institutional, Funding: AstraZeneca, Boehringer Ingelheim, Amgen, Novartis, Roche; Financial Interests, Personal, Funding: Takeda. M. Thomas: Financial Interests, Personal, Advisory Board: Sanofi, Lilly, BMS, MSD, Roche, Boehringer Ingelheim, Janssen, AstraZeneca, Amgen, Novartis; Financial Interests, Personal, Invited Speaker: Sanofi, Lilly, MSD, Roche, GSK, Pfizer, Janssen, AstraZeneca, Amgen, Novartis; Financial Interests, Institutional, Advisory Board: Takeda; Financial Interests, Institutional, Invited Speaker: Takeda; Financial Interests, Institutional, Funding: Roche, Takeda, BMS, AstraZeneca, Amgen. All other authors have declared no conflicts of interest.