25P - Platinum-based chemotherapy (PCT) addition to 1st-line PD-1/PD-L1 inhibitors (ICI) prevent hyperprogressive disease (HPD) in non-small cell lung cancer (NSCLC) patients (pts) by reducing circulating immature neutrophils

Background

HPD has been described in ≃14-25% of pretreated NSCLC pts upon single-agent (SA) ICI and has not been reported upon PCT-ICI. So far, no predictive biomarkers are available for HPD early detection.

Methods

NSCLC pts treated with 1^st line SA-ICI or PCT-ICI were assessed for HPD and circulating neutrophils. HPD was defined as delta tumor growth rate (TGR) >50% and/or TGR ratio ≥2. Circulating low density neutrophils (LDNs) were assessed by flow cytometry on peripheral blood mononuclear cells (PMBCs). LDNs were defined as CD66b⁺CD15⁺ cells among CD11b⁺ PBMCs and immature subtypes as CD10^- LDNs. The LDNs predictive role was assessed by penalized model-based tests. LDNs’ survival and sensitivity to cisplatin induced cell death were tested in-vitro.

Results

144 NSCLC pts were included: 75 treated with SA-ICI, 69 with PCT-ICI. In the SA-ICI cohort, HPD occurred in 8 (11%) pts. Baseline immature circulating CD10^- LDNs were significantly higher (p <0.01) in HPD [median (ME): 39.3, interquartile range (IQR): 28.7] vs pts with progression [ME: 7.4, IQR: 14.9] or response/stable disease [ME: 3.7, IQR: 12.6]. CD10^- LDNs were associated with HPD [odds ratio (OR): 1.17, 95% CI: 1.06; 1.29], with a good prediction capability [cross-validated AUC 0.97 (95%CI: 0.94;1.00)]. A 30.5% cut-off value was identified by Youden index to discriminate HPD from others. In the PCT-ICI cohort, 14 pts had CD10^- LDNs ≥30.5% being at high HPD risk. However, no HPD was observed in PCT-ICI cohort and dynamic LDNs evaluation in high HPD risk pts showed a 52.3% median reduction in CD10^- LDNs upon PCT-ICI, vs only an 8.9% reduction in HPD pts upon SA-ICI, suggesting that PCT prevents HPD by reducing immature LDNs. In vitro experiments showed that immature CD10^- LDNs had prolonged survival compared to mature CD10⁺ LDNs (alive cells after 5-days: 18.7% vs 0%), however, they were more sensitive to cisplatin induced necrotic cell death, confirming the role of PCT in killing preferentially immature LDNs.

Conclusions

Baseline immature CD10^- LDNs is a circulating easy to measure biomarker to early detect HPD upon 1^st line SA-ICI and could select NSCLC pts to be addressed to PCT-ICI.

Legal entity responsible for the study

Istituto Nazionale dei Tumori di Milano.

Funding

International Association for the Study of Lung Cancer (IASLC).

Disclosure

R. Ferrara: Financial Interests, Personal, Advisory Board: MSD, Beigene. All other authors have declared no conflicts of interest.