2257P - Stereotactic body radiation therapy and atezolizumab combination: Results of the international multi-centre SABR-PDL1 phase II trial colorectal cohort

Background

Immunoradiotherapy may improve outcomes for patients with advanced solid tumors, although optimized combination modalities remain unclear. Here, we report the analysis of the colorectal (CRC) cohort of the SABR-PDL1 trial that evaluated the PD-L1 inhibitor atezolizumab in combination with stereotactic body radiation therapy (SBRT) in advanced cancer patients.

Methods

Eligible patients received atezolizumab 1200 mg (IV) every 3 weeks until progression or unmanageable toxicity, together with ablative SBRT delivered concurrently with the 2^nd cycle (recommended 45 Gy in 3 fractions, adapted upon normal tissue tolerance constraint). SBRT was delivered to at least one tumor site, with at least one additional measurable lesion being kept from the radiation field. The primary efficacy endpoint was one-year progression-free survival (PFS) rate from the start of atezolizumab. Sequential tumor biopsies were collected for deep multi-feature immune profiling.

Results

60 heavily pretreated advanced CRC patients (38 men [63%]; median age, 59 years [range, 20-81 years]) were enrolled in five centers (France: n=4, Spain: n=1) from 11/2016 to 04/2019. All but one (98%) received atezolizumab and 54/60 (90%) received SBRT. The most frequently irradiated site was lung (n=30/54; 56.3 %). Treatment-related G3 (no higher grade observed) toxicity was observed in 3 (5%) patients. Median OS and PFS rates were respectively 8.4 [95%CI:5.9-11.6] and 1.4 months [95%CI:1.2-2.6]. Immune-centric multiplex IHC and RNAseq suggested that SBRT redirected immune cells towards tumor lesions even in the case of radio-induced lymphopenia. Tumor PD-L1 was more expressed in responding patients vs progressive disease (PD) patients at baseline (P=0.0087). IRF1 nuclear expression was higher in responding patients at baseline in CD3+ T cells (P=0.0043) and in CD68+ cells (P=0.0498). Upregulation of CCL19, BHLHE41, CXCL9, GZMB and SLAMF1 in bulk RNA samples correlated with improved outcome.

Conclusions

Despite low PFS, this study provides new data on the feasibility, efficacy, and immune context of tumors that may help better identify advanced CRC patients most likely to respond to immunoradiotherapy.

Clinical trial identification

EudraCT N°: 2015-005464-42; NCT02992912.

Editorial acknowledgement

Legal entity responsible for the study

Gustave Roussy.

Funding

Roche.

Disclosure

A. Levy: Financial Interests, Institutional, Invited Speaker: PharmaMar; Financial Interests, Institutional, Funding: AstraZeneca; Financial Interests, Institutional, Coordinating PI: Beigene. A. Hollebecque: Financial Interests, Personal, Invited Speaker: Servier, Incyte, Eisai; Financial Interests, Personal, Advisory Board: Basilea, Tahio, Relay Therapeutics, QED Therapeutics, Debiopharm, MSD, Boehringer Ingelheim; Financial Interests, Institutional, Funding: Incyte; Financial Interests, Institutional, Research Grant: AstraZeneca; Non-Financial Interests, Principal Investigator, M19-345: AbbVie; Non-Financial Interests, Principal Investigator, CO42216; WP42627; CO40939: Roche; Non-Financial Interests, Principal Investigator, MCLA-158: Merus; Non-Financial Interests, Principal Investigator, SGNB6A: Seattle Genetics; Non-Financial Interests, Principal Investigator, TAS-120-202: Tahio; Non-Financial Interests, Principal Investigator, Krystal-10: Mirati; Non-Financial Interests, Principal Investigator, ADP-0033: Adaptimmune; Non-Financial Interests, Principal Investigator, ACT16902: Sanofi; Non-Financial Interests, Principal Investigator, C4201002: Pfizer; Non-Financial Interests, Principal Investigator, RLY-4008: Relay Therapeutics; Non-Financial Interests, Principal Investigator, CC-90011: Celgene/BMS; Non-Financial Interests, Principal Investigator, Loxo-IDH: Loxo/Lilly; Non-Financial Interests, Principal Investigator: AstraZeneca; Non-Financial Interests, Principal Investigator, SN-201 study: SOTIO; Non-Financial Interests, Principal Investigator, Tropics-03: Gilead; Non-Financial Interests, Principal Investigator, BI1403: Boehringer Ingelheim. E. Deutsch: Financial Interests, Personal, Other, Clinical Research Seminar: Roche Genentech; Financial Interests, Institutional, Other, Drug Radiotherapy programs: Boehringer Ingelheim, AstraZeneca; Financial Interests, Personal, Advisory Board, Drug Radiotherapy advice: Merck Serono, BMS; Financial Interests, Personal, Advisory Board, Drug RT advice: MSD; Non-Financial Interests, Advisory Role: TheraPanacea. All other authors have declared no conflicts of interest.