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. 2022 Mar 2:14:17588359221082339.
doi: 10.1177/17588359221082339. eCollection 2022.

First-line immunotherapy or angiogenesis inhibitor plus chemotherapy for HER2-altered NSCLC: a retrospective real-world POLISH study

Guangjian Yang  1 , Yaning Yang  1 , Runze Liu  2 , Weihua Li  3 , Haiyan Xu  4 , Xuezhi Hao  1 , Junling Li  1 , Puyuan Xing  1 , Shuyang Zhang  1 , Xin Ai  1 , Fei Xu  1 , Yan Wang  5
Affiliations

First-line immunotherapy or angiogenesis inhibitor plus chemotherapy for HER2-altered NSCLC: a retrospective real-world POLISH study

Guangjian Yang et al. Ther Adv Med Oncol. .

Abstract

Background: There have been no comprehensive large-scale studies that have evaluated the benefits of chemotherapy-based regimens in addressing HER2-altered advanced non-small-cell lung cancer (NSCLC) in a first-line setting. Data on HER2 alteration subtypes and concomitant alterations are also limited. Accordingly, our retrospective, real-world POLISH study assesses the efficacy of first-line chemotherapy alone (C) as well as combinations with immune checkpoint inhibitors (C + I) or angiogenesis inhibitors (C + A) for HER2-altered NSCLC; molecular features are also reported.

Methods: HER2-altered NSCLC patients who received a first-line treatment between November 2015 and September 2021 were screened. Patients treated with C, C + I, or C + A were included in our final efficacy analysis. Progression-free survival (PFS) was compared between the subgroups. A Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis was performed to evaluate concomitant alterations.

Results: A total of 293 patients were screened, with an identification of HER2 amplification and 37 distinct HER2 mutations, and 210 cases treated with C, C + I, or C + A were ultimately included. C + A achieved longer PFS than C (5.63 vs 4.03 months, hazard ratio: 0.64, 95% confidence interval [CI]: 0.46-0.88, p = 0.006). C + I did not improve median PFS compared to C + A or C (both p > 0.05), despite the programmed cell death ligand-1 (PD-L1) expression or tumor mutational burden. KEGG analysis revealed that concomitant upregulation of PI3 K/AKT pathway signaling was common in HER2-altered NSCLC.

Conclusion: Chemotherapy plus angiogenesis inhibitors may yield a greater survival benefit than chemotherapy alone in a first-line setting for HER2-altered NSCLC, whereas an immune-based combination therapy may not be superior to a sole chemotherapy regimen. Activation of PI3 K/AKT signaling may mediate immunosuppression in HER2-altered NSCLC.

Keywords: HER2 alteration; angiogenesis inhibitor; chemotherapy; immunotherapy; non-small-cell lung cancer; real-world study.

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Conflict of interest statement

Conflict of interest statement: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Figures

Figure 1.
Figure 1.
Proportion and detailed molecular landscape of NSCLC patients with distinct HER2-activating alterations. LUAD, lung adenocarcinoma.
Figure 2.
Figure 2.
(a) Top 10 concomitant altered genes together in NSCLC patients with HER2 alterations detected using next-generation sequencing among patients at primary diagnosis as per Venn plot and (b) Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis of concomitant signaling pathways in patients with HER2 mutations and HER2 amplification.
Figure 3.
Figure 3.
(a) Kaplan–Meier curves of PFS in patients harboring HER2-activating alterations with chemotherapy alone (C) vs chemotherapy plus angiogenesis inhibitors (C + A) vs chemotherapy plus ICIs (C + I) in a first-line setting and (b) PFS outcomes among subgroups with different programmed cell death ligand 1 (PD-L1) tumor proportion score. HR, hazard ratio.
Figure 4.
Figure 4.
Possible mechanism for immunosuppression in HER2-altered NSCLC mediated by the PI3 K/AKT signaling pathway.
See this image and copyright information in PMC

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