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Multicenter Study
. 2023 Nov;18(6):927-939.
doi: 10.1007/s11523-023-01009-w. Epub 2023 Nov 3.

Histo-Molecular Factors of Response to Combined Chemotherapy and Immunotherapy in Non-Small Cell Lung Cancers

Marine Marchal  1 , Vincent Leroy  2 , Hélène Behal  3 , Eric Dansin  4 , Nicolas Paris  5 , Soraya Bordier  6 , Sarah Humez  7   8 , Fabienne Escande  9 , Clément Gauvain  10 , Alexis B Cortot  10   8
Affiliations
Multicenter Study

Histo-Molecular Factors of Response to Combined Chemotherapy and Immunotherapy in Non-Small Cell Lung Cancers

Marine Marchal et al. Target Oncol. 2023 Nov.

Abstract

Background: Chemo-immunotherapy (CIT) is the standard of care for advanced non-small cell lung cancer (NSCLC), but the impact of routinely available histo-molecular biomarkers on its efficacy has not yet been fully assessed.

Objective: The purpose of this multicenter study was to evaluate the clinical activity of CIT according to oncogenic drivers, STK11 and TP53 mutations, and MET overexpression.

Patients and methods: Patients receiving CIT for advanced NSCLC with available comprehensive molecular profile were included. The primary endpoint was progression-free survival (PFS), adjusted on main confounding factors, and secondary endpoints were overall survival (OS) and objective response rate.

Results: Among the 195 patients included between September 2018 and October 2021, 88 (41%) had a KRAS mutation, 16 (8.2%) an EGFR mutation or an ALK, ROS1, or RET rearrangement, 11 (5.6%) a BRAF mutation, 6 (3.1%) a MET exon 14 mutation or MET amplification, and 5 (2.6%) a HER2 mutation. Seventy-seven patients (39.5%) had none of these alterations. The median PFS was 6.4 months (95% CI 5.3-7.3). Per subgroup, the median PFS was 7.1 months (5.4-8.9) for KRAS, 5.5 months (2.5-15.3) for EGFR/ALK/ROS1/RET, 12.9 months (2.6-not reached [NR]) for BRAF, 1.5 months (0.6-NR) for MET, 3.9 months (2.6-NR) for HER2, and 5.6 months (4.7-7.8) for patients without any oncogenic alteration. No difference in PFS was observed between the KRAS, BRAF, EGFR/ALK/ROS1/RET, and no-driver subgroups. STK11 mutations were associated with poor PFS (HR 1.59 [95% CI 1.01-2.51]) whereas TP53 mutations had no impact. MET overexpression was associated with longer PFS (HR 0.59 [95% CI 0.35-0.99]).

Conclusion: This study suggests that the efficacy of combining pembrolizumab with pemetrexed and platinum-based chemotherapy differs according to the histo-molecular biomarkers, which may help to identify patients liable to benefit from CIT.

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Conflict of interest statement

A.B.C. has received research grants (paid to institution) from Merck; consulting fees from Novartis and Roche; a speaker honorarium from Astra-Zeneca, BMS, MSD, Pfizer, Novartis, Takeda, Janssen, Roche, Abbvie, Amgen, and Exeliom; support from Pfizer, Novartis, and MSD to attend meetings; and has served on advisory boards for Novartis and InhaTarget. V.L. has received a speaker honorarium from Novartis, Astra-Zeneca and MSD. E.D. has received a speaker honorarium from Novartis. M.M., H.B., N.P., S.B., S.H., F.E., and G.C. declare that they have no conflicts of interest that might be relevant to the contents of this manuscript.

Figures

Fig. 1
Fig. 1
Kaplan-Meier curves of progression-free survival in each oncogenic driver subgroup. Shown are Kaplan–Meier estimates of progression-free survival in patients without oncogenic alteration, with KRAS mutations, with EGFR mutations or ALK, ROS1 or RET rearrangements, with BRAF mutations, with MET exon 14 skipping mutations or MET amplifications and with HER2 mutations. Tick marks indicate censoring of data.
Fig. 2
Fig. 2
Kaplan-Meier curves of progression-free survival and overall survival according to SK11 mutational status in the overall population (A, B) and in the KRAS sub-group (C, D). Shown are Kaplan–Meier estimates of progression-free survival and overall survival in patients with inactivating STK11 mutations and in patients without inactivating STK11 mutation in the overall population (A, B) and in KRAS-mutated patients (C, D). Tick marks indicate censoring of data. HR hazard ratio, KRASm KRAS mutation, KRASwt KRAS wild-type, mOS median overall survival, mPFS median progression-free survival, STK11m STK11 mutation, STK11wt STK11 wild-type, 95% CI 95% confidence interval
Fig. 3
Fig. 3
Kaplan-Meier curves of progression-free survival (A) and overall survival (B) according to MET expression score. Shown are Kaplan–Meier estimates of progression-free survival and overall survival in patients harboring MET overexpression (immunohistochemistry staining scores of 2+ or 3+) and in patients without MET overexpression (immunohistochemistry staining scores of 0+ or 1+). Tick marks indicate censoring of data. HR hazard ratio, mOS median overall survival, mPFS median progression-free survival, NR not reached, 95% CI 95% confidence interval
Fig. 4
Fig. 4
Best response to chemotherapy plus immunotherapy according to RECIST 1.1 criteria in each oncogenic driver subgroup
See this image and copyright information in PMC

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