LBA8 - Precision immuno-oncology for advanced non-small cell lung cancer (NSCLC) patients with PD-(L)1 inhibitors resistance (PIONeeR): A phase Ib/IIa clinical trial targeting identified resistance pathways

Background

Anti-PD-(L)1 are approved for the treatment of advanced NSCLC. However, most patients (pts) progress during treatment with limited options after anti-PD-(L)1. The aim of PIONeeR trial was to overcome resistance to anti-PD(L)-1 by targeting 4 major pathways.

Methods

This open-label, multicenter, controlled randomized study used a Bayesian adaptive design. Advanced NSCLC pts with disease progression after sequential or concomitant PD-(L)1 and platinum-based chemotherapy were eligible. Pts were randomly allocated to Arm A: Durvalumab (Du) + Monalizumab, Arm B: Du + Oleclumab, Arm C: Du + Ceralasertib, Arm E: Du + Savolitinib or Arm D (control): Docetaxel. Primary endpoint was the 12-week Disease Control Rate (12-w DCR) by RECIST1.1. Main secondary endpoints were Duration of Response (DoR), Overall Response Rate (ORR), Progression-Free Survival (PFS), Overall Survival (OS) and safety. Interim analyses used a futility boundary of 30%. A combination arm was considered effective if there was a high probability (P ≥ 90%) for 12-w DCR to be ≥ 12-w DCR of arm D.

Results

114 pts were randomized in arms A, n=28; B, n=3; C, n=32; D, n=31 & E, n=20. Arms B and E were prematurely closed due to lack of efficacy. 11 pts enrolled in arm D withdrew prior to treatment. The 12-w DCR was 54.5% (95%CI [34.0%; 74.3%]) in the control arm vs 24.1% [10.7%; 41.0%] in arm A, 0% in arm B, 50% [33.1%; 66.9%] in arm C and 13.6% [3.0%; 30.4%] in arm E; P was 1.2%, and 36.8%, in arm A and C respectively. No significant PFS or OS benefit was seen in experimental arms compared to arm D. However, 5 pts achieved PR by RECIST in arm C with a median DoR of 5.6 months [2.1; 9.7]. No unexpected safety signal was seen. Preliminary biomarker analyses will be presented during the meeting.

Conclusions

With its innovative and adaptive design, the PIONeeR trial was able to explore several options to overcome resistance to ICIs. Although no experimental arm performed better than outcomes observed with docetaxel, some pts had long DoR, suggesting durvalumab combinations can be highly effective. Biomarker work is ongoing to identify patients most likely to benefit from combination treatment.

Clinical trial identification

NCT03833440.

Editorial acknowledgement

Legal entity responsible for the study

Assistance Publique - Hôpitaux de Marseille (APHM).

Funding

French National Research Agency (ANR).

Disclosure

P. Tomasini: Financial Interests, Personal, Invited Speaker: Roche, AstraZeneca, BMS, Lilly, Janssen, Amgen, Takeda; Financial Interests, Institutional, Local PI: Roche, AstraZeneca, Amgen, Lilly, Takeda; Financial Interests, Institutional, Coordinating PI: Janssen. M. Pérol: Financial Interests, Personal, Advisory Board: Roche, AstraZeneca, MSD, BMS, Lilly, Novartis, Takeda, Gritstone, Sanofi, Pfizer, Amgen, Janssen, GSK, Eisai, Ipsen, AstraZeneca, AbbVie, Anheart Therapeutics, Daiichi Sankyo; Financial Interests, Personal, Invited Speaker: Roche, AstraZeneca, MSD, BMS, Boehringer Ingelheim, Takeda, Illumina, Pfizer, Medscape; Financial Interests, Personal, Advisory Board, Advisory board: Novocure; Financial Interests, Institutional, Research Grant: AstraZeneca, Roche, Takeda, Boehringer Ingelheim; Financial Interests, Personal, Steering Committee Member: Roche, Sophia Genetics, PharmaMar, Anheart Therapeutics; Financial Interests, Personal, Other, DMSB: Roche; Financial Interests, Institutional, Local PI: AstraZeneca, Amgen, Roche, AbbVie, Apollomics, Anheart Therapeutics, Innate Pharma, Boehringer Ingelheim, Arrivent Biopharma, Daiichi Sankyo, Bayer; Financial Interests, Steering Committee Member: Lilly. L. Greillier: Financial Interests, Personal, Advisory Board: AbbVie, AstraZeneca, BMS, MSD, Novartis, Sanofi, Takeda, Roche; Financial Interests, Personal, Invited Speaker: Lilly, Pfizer; Financial Interests, Institutional, Local PI: AstraZeneca, AbbVie, BMS, MSD, Novartis, Takeda, Pfizer, Roche, PharmaMar; Financial Interests, Institutional, Coordinating PI: Sanofi. F. Monville: Financial Interests, Institutional, Full or part-time Employment: Veracyte SAS. E. Vivier: Other, Institutional, Full or part-time Employment: Innate Pharma. D. Perol: Financial Interests, Personal, Invited Speaker: AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Eli-Lilly, Gilead, Ipsen, Pfizer, Novartis, Merck Sharp And Dohme, Roche, Takeda; Financial Interests, Personal, Advisory Board: Brenus Pharma; Other, Travel expenses (ESMO annual meeting Madrid 2023): Novartis; Other, Travel expenses (ESMO annual meeting Paris 2022): Roche. F. Barlesi: Financial Interests, Institutional, Advisory Board: AstraZeneca, Bayer, Bristol Myers Squibb, Boehringer Ingelheim, Eli Lilly Oncology, F. Hoffmann–La Roche Ltd, Novartis, Merck, Mirati, MSD, Pierre Fabre, Pfizer, Sanofi Aventis, Seattle Genetics, Takeda, AbbVie, Acea, Amgen, Eisai, Ignyta; Non-Financial Interests, Principal Investigator: AstraZeneca, BMS, Merck, Pierre Fabre, F. Hoffmann-La Roche Ltd., Innate Pharma, Mirati. All other authors have declared no conflicts of interest.