1343P - Adding histology-driven chemotherapy (ChT) to overcome primary resistance to first-line immunotherapy (ICI) in patients (pts) with advanced non-small cell lung cancer (aNSCLC) with PD-L1 ≥50%

Background

ICIs as single-agent are the standard of care first-line treatment for pts with non-oncogene addicted aNSCLC with PD-L1≥ 50%. However, 30-40% of tumors are primarily resistant to ICIs (progressive disease, PD, or stable disease lasting <6 months as the best response).

Methods

This is a retrospective study among 5 European centers to assess the efficacy of the combination of histology-driven platinum-based ChT and ICI (ChT-ICI) with respect to standard platinum-based ChT alone for patients affected by aNSCLC with PD-L1 ≥50% primarily resistant to upfront ICI. The primary endpoint is progression-free survival 2 (PFS2). Overall survival (OS) and overall response rate (ORR) are secondary endpoints.

Results

380 pts received upfront ICI from 2016 to 2024; of them, 132 (34.7%) were primary resistant. 56 (42%) pts were treated with a second-line platinum-based ChT with (n=18) or without (n=38) ICI beyond progression. The median (m) age was 62.9 (IQR 55.2-70.3); 28 pts (50%) were male, 51 (91%) had a smoking history, 41 (73.2%) had adenocarcinoma histology, 29 (51.7%) had KRAS-mutant tumors, 32 (57.1%) had an ECOG PS 0-1, 14 (25%) had >3 metastatic sites, 17 (30.3%) had brain and 3 had liver (10.9%) metastasis before second line. No imbalances according to these features were observed between ChT-ICI and ChT groups. Overall, mOS was 14.5 months (95% CI, 10.1-17.7), and mPFS2 was 9.2 months (95% CI, 7.4-12.0). The mPFS2 was 12.2 (95% CI 8.3-NR) in the ChT-ICI group vs. 7.5 (95% CI 7.0-11.7) in the ChT group (p= 0.02). The mOS was 21.8 months (95% CI 13.8-NR) in the ChT-ICI group vs. 10.1 months (95% CI 8.3-17.0) in the ChT group (p=0.01). The ORR was 70% with ChT-ICI vs. 42% with ChT (p=0.10) but with numerically lower PD as the best response with ChT-ICI (2 vs.12 pts).

Conclusions

Our study suggests that adding histology-driven ChT to ICI may improve survival outcomes compared to standard platinum-doublets ChT as second-line treatment for pts with a PD-L1 ≥ 50% NSCLC with primary resistance to first-line single-agent ICI. These results need to be prospectively validated in a larger population.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

L. Zullo: Financial Interests, Institutional, Research Grant: Owkin. A. Di Federico: Financial Interests, Personal, Advisory Board: Hanson-Wade; Financial Interests, Personal, Other, Honoraria: SITC. L.E. Hendriks: Financial Interests, Institutional, Advisory Board: Amgen, Boehringer Ingelheim, Lilly, Novartis, Pfizer, Takeda, Merck, Janssen, MSD, AnHeart; Financial Interests, Institutional, Invited Speaker, for educational webinar: AstraZeneca, Lilly; Financial Interests, Institutional, Invited Speaker, educational webinar/interview: Bayer; Financial Interests, Institutional, Invited Speaker, educationals: MSD; Financial Interests, Personal, Invited Speaker, for webinars: Medtalks; Financial Interests, Personal, Invited Speaker, payment for post ASCO round table discussion: VJOncology; Financial Interests, Personal, Invited Speaker, payment for post ASCO/ESMO/WCLC presentations, educational committee member: Benecke; Financial Interests, Institutional, Invited Speaker, payment for post ESMO/ASCO discussion: high5oncology; Financial Interests, Institutional, Other, podcast on brain metastases: Takeda; Financial Interests, Institutional, Other, educational webinar: Janssen; Financial Interests, Institutional, Invited Speaker, satellite symposium at conference: GSK, Sanofi; Financial Interests, Personal, Invited Speaker, presentation guideline: Medimix; Financial Interests, Institutional, Invited Speaker, podcast and educational: Pfizer; Financial Interests, Personal, Other, member of the committee that revised these guidelines: Dutch guidelines NSCLC, brain metastases and leptomeningeal metastases; Financial Interests, Institutional, Research Grant, for IIS: Roche, Boehringer Ingelheim, AstraZeneca, takeda, Novartis; Financial Interests, Institutional, Research Grant, donation for health care improvement project: Merck; Financial Interests, Institutional, Research Grant, funding for healthcare improvement project: Pfizer; Financial Interests, Institutional, Research Grant, for IIS, under negotiation: gilead; Financial Interests, Institutional, Local PI: AstraZeneca, GSK, Novartis, Merck Serono, Roche, Takeda, Blueprint Medicines, Mirati, AbbVie, MSD, Gilead; Non-Financial Interests, Other, Chair metastatic NSCLC for lung cancer group: EORTC; Non-Financial Interests, Other, secretary NVALT studies foundation: NVALT; Non-Financial Interests, Other, vice chair scientific committee: Dutch Thoracic Group. L. Mezquita: Financial Interests, Personal, Advisory Board: Takeda, Roche, AstraZeneca, MSD, Janssen; Financial Interests, Personal, Invited Speaker: Takeda, Roche, BMS, AstraZeneca, Janssen; Financial Interests, Personal, Research Grant, SEOM Beca Retorno 2019: BI; Financial Interests, Personal, Research Grant, ESMO TR Research Fellowship 2019: BMS; Financial Interests, Institutional, Research Grant, COVID research Grant: AMGEN; Financial Interests, Institutional, Coordinating PI, Cover cost of molecular test.: INIVATA; Financial Interests, Institutional, Coordinating PI: GILEAD; Financial Interests, Institutional, Coordinating PI, Beca SEOM Grupo Emergente 2022: AstraZeneca. S. Novello: Financial Interests, Personal, Invited Speaker: AZ, MSD, Eli Lilly, Novartis, BeiGene, Amgen, Thermo Fisher; Financial Interests, Personal, Advisory Board: BI, BMS, Pfizer, Takeda, Roche, Sanofi, Amgen, J&J; Financial Interests, Institutional, Coordinating PI, IIT: MSD, BI; Financial Interests, Institutional, Coordinating PI: AZ, AMG, Eli Lilly, Sanofi, J&J, Roche; Non-Financial Interests, Leadership Role, president of this European advocacy: WALCE; Non-Financial Interests, Member: IASLC, AIOM, ASCO. A. Ardizzoni: Financial Interests, Personal, Advisory Board: BMS, Eli Lilly, MSD, AZ, Takeda, Roche, Janssen, Sanofi, Novartis, AbbVie, Daiichi Sankyo. B. Besse: Financial Interests, Institutional, Advisory Board: Amgen, AstraZeneca, BeiGene, Blueprint Medicine, Cergentis, Chugai pharmaceutical, Daiichi Sankyo, F. Hoffmann-La Roche, Inivata, Pfizer, PharmaMar, Sanofi Aventis, Springer Healthcare Ltd., 4D Pharma, AbbVie, Da Voltera, Eli Lilly, Ellipse Pharma Ltd., F-Star, GSK, Janssen, Onxeo, Ose Immunotherapeutics, Socar research, Taiho oncology, Turning Point Therapeutics; Financial Interests, Institutional, Invited Speaker: Genzyme Corporation, Hedera Dx, Medscape, MSD; Financial Interests, Institutional, Local PI: AbbVie, Amgen, Blueprint Medicines, Daiichi Sankyo, Pfizer, Roche-Genentech, Turning Point Therapeutics, Nuvalent, Enliven, Prelude therapeutics; Financial Interests, Institutional, Coordinating PI: AstraZeneca, Ose Immunotherapeutics, Sanofi, Taiho; Financial Interests, Institutional, Steering Committee Member: BeiGene, GSK, Janssen, Takeda, Genmab; Financial Interests, Institutional, Funding: Cristal Therapeutics. F. Gelsomino: Financial Interests, Personal, Advisory Board: Eli Lilly, Novartis, AstraZeneca, MSD. All other authors have declared no conflicts of interest.