Sensitivity to Immune Checkpoint Blockade in Advanced Non-Small Cell Lung Cancer Patients with EGFR Exon 20 Insertion Mutations.

Giulio Metro,Miriam Garaffa,Angelo Sidoni,Martina Mandarano,Monica Sassi,Marco Gunnellini,Francesca Romana Tofanetti,Francesca Marasciulo,Annalisa Guida,Maria Sole Reda,Vincenzo Minotti,Bruna Di Girolamo,Carmen Molica,Marco Toraldo,Alessio Gili,Guido Bellezza,Sara Baglivo,Vienna Ludovini,Enrico Prosperi,Fausto Roila,Annamaria Siggillino,A Giglietti ,Giovanni M Marchetti

doi:10.3390/genes12050679

Abstract

Besides platinum-based chemotherapy, no established treatment option exists for advanced non-small-cell lung cancer (NSCLC) patients with EGFR exon 20 (Ex20ins) insertion mutations. We sought to determine the clinical outcome of patients with this EGFR mutation subtype in the immunotherapy era. Thirty NSCLCs with EGFR Ex20ins mutations were identified, of whom 15 had received immune checkpoint blockade (ICB) treatment as monotherapy (N = 12), in combination with chemotherapy (N = 2) or with another immunotherapeutic agent (N = 1). The response rate was observed in 1 out of 15 patients (6.7%), median progression-free survival (PFS) was 2.0 months and median overall survival (OS) was 5.3 months. A trend towards an inferior outcome in terms of PFS and OS was observed for patients receiving ICB treatment in the first versus second line setting (PFS: 1.6 months versus 2.7 months, respectively, p = 0.16—OS: 2.0 months versus 8.1 months, respectively, p = 0.09). Median OS from the time of diagnosis of advanced disease was shorter for patients treated with ICB versus those who did not receive immunotherapy (12.9 months versus 25.2 months, respectively, p = 0.08), which difference remained associated with a worse survival outcome at multivariate analysis (p = 0.04). Treatment with ICB is poorly effective in NSCLCs with EGFR Ex20ins mutations, especially when given in the first-line setting. This information is crucial in order to select the optimal treatment strategy for patients with this subtype of EGFR mutation.

Highlights

Two major treatment paradigms have been recently established for the management of advanced non-small-cell lung cancer (NSCLC), either targeted therapies based on the inhibition of aberrant oncogenic drivers or immunotherapy based on the blocking of immunosuppressive checkpoints [1]
From August 2008 until October 2020, 30 patients harboring an epidermal growth factor receptor (EGFR) exon 20 insertion mutations (Ex20ins) mutation were eligible for inclusion in the study
In all cases the histological subtype consisted of adenocarcinoma

Summary

Introduction

Two major treatment paradigms have been recently established for the management of advanced non-small-cell lung cancer (NSCLC), either targeted therapies based on the inhibition of aberrant oncogenic drivers or immunotherapy based on the blocking of immunosuppressive checkpoints [1]. 19 (deletions) or 21 (L858R point mutations), which comprise approximately 90% of all EGFR mutations [2]. Some uncommon EGFR mutations may still respond to treatment with an EGFR-TKI (i.e., G719, L861Q and S861Q), to a less extent compared with common EGFR exon 19 deletion/L858R point mutations. EGFR exon 20 insertion mutations (Ex20ins), which constitute a heterogeneous group of genetic in-frame insertions in exon 20 of EGFR, are generally insensitive (with very few exceptions) to EGFR-TKI targeted treatment [3]. Platinum-based chemotherapy is to be considered the standard first-line treatment for NSCLCs with EGFR Ex20ins mutations; this results in a dismal prognosis as no other validated options are available at the time of disease progression.

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