Efficacy of chemotherapy plus immune checkpoint inhibitors in patients with non-small cell lung cancer who have rare oncogenic driver mutations: a retrospective analysis

Abstract

Background: Targeted therapy is now the standard of care in driver-oncogene-positive non-small cell lung cancer (NSCLC). Its initial clinical effects are remarkable. However, almost all patients experience treatment resistance to targeted therapy. Hence, chemotherapy is considered a subsequent treatment option. In patients with driver-oncogene-negative NSCLC, combined immune checkpoint inhibitors (ICIs) and chemotherapy as the first-line therapy has been found to be beneficial. However, the efficacy of ICI plus chemotherapy against driver-oncogene-positive NSCLC other than epidermal growth factor receptor mutation and anaplastic lymphoma kinase fusion is unclear.

Methods: Using the hospital medical records, we retrospectively reviewed advanced or recurrent NSCLC patients who were treated with chemotherapy with or without ICIs at Aichi Cancer Center Hospital between January 2014 and January 2023. Patients with druggable rare mutations such as KRAS-G12C, MET exon 14 skipping, HER2 20 insertion, BRAF-V600E mutations, and ROS1 and RET rearrangements were analyzed.

Results: In total, 61 patients were included in this analysis. ICI plus chemotherapy was administered in 36 patients (the ICI-chemo group) and chemotherapy in 25 patients (the chemo group). The median progression-free survival (PFS) rates were 14.0 months in the ICI-chemo group and 4.8 months in the chemo group (hazard ratio [HR] = 0.54, 95% confidence interval [CI] = 0.28-1.01). The median overall survival rates were 31.3 and 21.7 months in the ICI-chemo and chemo groups, respectively (HR = 0.70, 95% CI = 0.33-1.50). Multivariate Cox regression analysis of PFS revealed that HER2 exon 20 insertion mutation was significantly associated with a poorer PFS (HR: 2.39, 95% CI: 1.19-4.77, P = 0.014). Further, ICI-chemo treatment was significantly associated with a better PFS (HR: 0.48, 95% CI: 0.25-0.91, P = 0.025).

Conclusion: ICI plus chemotherapy improves treatment efficacy in rare driver-oncogene-positive NSCLC.

Keywords: Driver mutation; Immune checkpoint inhibitors; Immunotherapy; Non-small cell lung cancer.

Fig. 1

Patient flowchart NSCLC: non-small cell lung cancer; ICI: immune checkpoint inhibitor

Fig. 2

Kaplan–Meier survival curves of progression-free survival and overall survival in all patients (A and B) Chemo: chemotherapy; ICI: immune checkpoint inhibitor; CI: confidence interval

Fig. 3

Swimmer plots of 61 patients who received chemotherapy with or without immune checkpoint inhibitors Individual swimmer plots displayed the mutation types and treatment duration. Chemo: chemotherapy; ICI: immune checkpoint inhibitor; ex20-ins: exon 20 insertion; ex14: exon 14 skipping; CR: complete response; PR: partial response; SD: stable disease; PD: progressive disease

Fig. 4

Progression-free survival in patients who received platinum combination chemotherapy with or without immune checkpoint inhibitors (A) PD-L1 of < 1% and (B) PD-L1 of ≥ 1%. Chemo: chemotherapy; ICI: immune checkpoint inhibitor; CI: confidence interval; PD-L1: programmed cell death-ligand 1