Post-progression survival in advanced non-small cell lung cancer treated with anti-PD-1/PDL-1 monotherapy: progression after durable clinical benefit versus primary resistance.

ABSTRACT

Aims Anti-PD-1/PD-L1 can face the issue of tumor resistance in advanced non-small cell lung cancer (aNSCLC), mostly as primary resistance to the treatment. Still, disease progression (PD) also occurs after prior durable clinical benefit (DCB). Comparison of both situations and tools to evaluate residual benefit of PD-1/PD-L1 blockade are needed to understand and manage resistance.

Methods We reviewed aNSCLCs with anti-PD-1/PD-L1 monotherapy, and disease progression per RECIST 1.1 (PD) in our center. Primary objective was comparison of post-progression survival (PPS) in primary resistance versus PD after DCB. Secondary objectives were to characterize patterns of PD after DCB; assess the feasibility and relevance of Tumor Growth Rate (TGR) in PD after DCB.

Results 148 patients were included. Median PPS were 5.2months (95% CI: 2.6-6.5) and 21.3months (95% CI: 18.5-36.3) (p<0.0001) for primary resistance and PD after DCB respectively. Multivariable hazard ratio for death in PD after DCB versus primary resistance was 0.14 (95% CI: 0.07-0.30). 76.7% of PD after DCB occurred in ≤3 lesions; 72.1% occurred only in preexisting lesions. TGR suggested a persistent benefit of PD-1/PD-L1 blockade in at least 44.2% of cases.

Conclusions PD after DCB was an independent factor of longer post-progression survival, with specific patterns of progression. TGR is a promising tool to assess residual benefit of immunotherapy.

Highlights

Anti-PD-(L)1 immunotherapy still faces the problem of resistance in lung cancer

Resistance can be classified as primary or secondary (acquired)

Outcomes and mechanisms of both situations need to be characterized

This unique comparative study reveals diverging survival and progression patterns

Prior durable clinical benefit associates with longer post-progression survival

This data benefits our understanding and management of resistance to anti-PD-(L)1

Competing Interest Statement

Dr H. de Saint Basile reports grant from BMS. Dr M. Ung reports support for attending meetings and/or travel from Guerbet. Pr L. Fournier reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events, from Bayer, Novartis, Janssen, Sanofi, GE Healthcare; support for attending meetings and/or travel from Guerbet. Dr E. Fabre reports research grant from BMS; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from BMS, MSD, Roche; consulting fees from BMS, MSD; support for attending meetings and/or travel from MSD, advisory board for Roche. The remaining authors declare no conflict of interest.

Funding Statement

This study did not receive any funding

Author Declarations

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The present study has been accepted and registered to the relevant institutional research and ethical committee (European Georges Pompidou Hospital); it has been conducted in accordance with the Declaration of Helsinki. All patients provided informed consent under the European Georges Pompidou Hospital approved protocol allowing collection and analysis of data.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

Footnotes

Disclosure: Dr H. de Saint Basile reports grant from BMS. Dr M. Ung reports support for attending meetings and/or travel from Guerbet. Pr L. Fournier reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events, from Bayer, Novartis, Janssen, Sanofi, GE Healthcare; support for attending meetings and/or travel from Guerbet. Dr E. Fabre reports research grant from BMS; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from BMS, MSD, Roche; consulting fees from BMS, MSD; support for attending meetings and/or travel from MSD, advisory board for Roche. The remaining authors declare no conflict of interest.

Funding: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Data Availability

All data produced in the present study are available upon reasonable request to the authors

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