1050P - Sensitization to immunotherapy through manipulation of tumor transcription by lurbinectedin

Background

Despite recent advances in the use of immunotherapy only a minority of cancers respond to immune checkpoint blockade (ICB). Current cytotoxic drug treatments for small cell lung cancer (SCLC) have been known to act by induction of DNA damage. These notable results can be explained by high number of genomic aberrations observed in SCLC combined with rapid cellular proliferation resulting in accumulation of DNA damage and genomic instability. SCLC cells are reliant on DNA damage repair pathways and transcription proficiency. Recent preclinical data have shown that the DDR influences multiple aspects of tumor immunogenicity. We propose the sensitizing of ICB resistant tumors through transcriptional stress by exposure to the RNA Pol II inhibitor lurbinectedin (LUR). 2SMALL is a two-part phase 1/2 study assessing the safety, tolerability and efficacy of LUR in combination with atezolizumab (ATZ) as second line treatment for ES-SCLC.

Methods

2SMALL phase I was an open-label, single arm, dose exploration trial. ES-SCLC patients received increasing doses of LUR plus a fixed dose of ATZ every 3 weeks following a standard 3+3 dose escalation design. Study endpoints included the definition of the safety profile and the recommended dose. Additional objectives included efficacy (ORR and PFS). A syngeneic immunocompetent mice model for SCLC (Rb-/-p53-/-) has been used to identify the efficacy of LUR in combination with an anti PD-L1 mAb. The role of LUR at inducing DNA sensing pathways was evaluated in several cell lines, PDX derived organoids and ex vivo.

Results

Objective responses were observed in 15 pts (ORR: 57.69%), including complete responses in 2 pts (7.69%), partial response in 13 pts (50%). 6 pts had stable disease (26.92%) and 3 pts progressive disease (11.54%). Disease control rate was 84.61 %, median PFS was 4.93 months (range 3.37 - 7.67 months). Type I IFN pathway, proinflammatory cytokines, chemokines and PD-L1 were upregulated by LUR in SCLC models.

Conclusions

Combination of LUR plus ATZ was well tolerated, with no unexpected toxicities. Preliminary anti-tumor activity is remarkable. Our results show effective tumor-activating IFN type 1, which increases immunity against tumors and provides the rationale to combine DDR inhibitors with ICBs.

Clinical trial identification

NCT04253145.

Editorial acknowledgement

Legal entity responsible for the study

Oncosur Foundation & Luis Paz-Ares.

Funding

Oncosur Foundation.

Disclosure

A.F. Navarro Mendivil: Financial Interests, Personal, Advisory Board: Boehringer Ingelheim, Oryzon Genomics, Amgen, Hengenix Biotech, MedSIR, BMS; Financial Interests, Personal, Invited Speaker: Roche, AstraZeneca, Pfizer, Takeda; Non-Financial Interests, Principal Investigator: BMS, PharmaMar, MSD, Amgen, Novartis, Debiopharm, Daiichi Sankyo, Roche, AstraZeneca. L. Paz-Ares: Financial Interests, Personal, Advisory Board, Speaker fees: Roche, MSD, BMS, AZ, Lilly, PharmaMar, BeiGene, Daichii, Medscape, PER; Financial Interests, Personal, Advisory Board: Merck Serono, Pfizer, Bayer, Amgen, Janssen, GSK, Novartis, Takeda, Sanofi, Mirati; Financial Interests, Personal, Other, Board member: Genomica, Altum sequencing; Financial Interests, Institutional, Coordinating PI: Daiichi Sankyo, AstraZeneca, Merck Sharp & Dohme corp, BMS, Janssen-cilag international NV, Novartis, Roche, Sanofi, Tesaro, Alkermes, Lilly, Takeda, Pfizer, PharmaMar; Financial Interests, Personal, Coordinating PI: Amgen; Financial Interests, Other, Member: AACR, ASCO, ESMO; Financial Interests, Other, Foundation Board Member: AECC; Financial Interests, Other, President.ASEICA (Spanish Association of Cancer Research): ASEICA; Financial Interests, Other, Foundation president: ONCOSUR; Financial Interests, Other, member: Small Lung Cancer Group. All other authors have declared no conflicts of interest.