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Cetuximab in Patients with Non-Small Cell Lung Cancer and EGFR Exon 20 Insertion Alterations.

ABSTRACT: Epidermal Growth Factor Receptor (EGFR) exon 20 insertion alterations represent 4%-10% of all EGFR mutations in Non-Small Cell Lung Cancer (NSCLC) and result in resistance to standard EGFR-directed therapies. EGFR exon 20 insertions restrict the size of the kinase pocket, prohibiting the entry of approved EGFR kinase inhibitor drugs. Structural In Silico modeling also predicts that EGFR exon 20 insertion anomalies increase attractive electrostatic dimerization, hence stabilizing the activating dimer configuration. EGFR antibodies such as cetuximab that interfere with dimerization may lead to responses. We identified three non-smoking patients with NSCLC and EGFR exon 20 insertions treated with cetuximab-based therapy. All three patients demonstrated clinical benefit. A 58-year-old woman achieved prolonged stable disease lasting 9 months, while a 76-year-old woman and 38-year-old man maintained a partial response with progression-free survivals of 13 months and 32 months, respectively. In conclusion, cetuximab merits further investigation as it appears to be an additional promising therapy for overcoming EGFR exon 20 insertion-related resistance.

SUBMITTER: Nikanjam M

PROVIDER: S-EPMC8994415 | biostudies-literature | 2022 Jan

REPOSITORIES: biostudies-literature

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Cetuximab in Patients with Non-Small Cell Lung Cancer and EGFR Exon 20 Insertion Alterations.

Nikanjam Mina M Kato Shumei S Adashek Jacob J JJ Kurzrock Razelle R

Clinical oncology, case reports 20211215 1

Epidermal Growth Factor Receptor (EGFR) exon 20 insertion alterations represent 4%-10% of all EGFR mutations in Non-Small Cell Lung Cancer (NSCLC) and result in resistance to standard EGFR-directed therapies. EGFR exon 20 insertions restrict the size of the kinase pocket, prohibiting the entry of approved EGFR kinase inhibitor drugs. Structural In Silico modeling also predicts that EGFR exon 20 insertion anomalies increase attractive electrostatic dimerization, hence stabilizing the activating d ...[more]

PMID: 35403176

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Project description:BackgroundEpidermal growth factor receptor exon 20 insertion (EGFRex20ins) mutations represent approximately 4-12% of EGFR mutations and are generally refractory to the 1st and 2nd generation EGFR tyrosine kinase inhibitors (TKIs). Development of effective therapies for patients with EGFRex20ins mutant non-small-cell lung carcinoma (NSCLC) represents a great unmet need. Preclinical models have shown that osimertinib is active in NSCLC harboring EGFRex20ins, while the antitumor activity of osimertinib remains to be evaluated in patients with EGFRex20ins mutations.MethodsTumor genotyping was performed in 2316 Chinese NSCLC cases with targeted next generation sequencing (NGS) covering the whole exons of EGFR gene. The frequency and genetic characteristics of EGFRexon20ins mutations were analyzed. Furthermore, six patients with specific EGFRexon20ins mutations and receiving osimertinib 80 mg once daily were retrospectively included to assess the antitumor activity and safety of monotherapy osimertinib.ResultsEGFRex20ins mutations were identified in 4.8% (53/1095) of EGFR mutant NSCLC and 2.3% (53/2316) of all NSCLC cases. The most frequently identified EGFRexon20ins is A767_V769dup (17/53,32.1%). We found that the genetic characteristics of EGFRex20ins mutations in Chinese patients with NSCLC were comparable to those reported in Caucasian patients. Four patients with osimertinib therapy achieved partial response and the rest stable disease. Median progression free survival (PFS) was 6.2 months (95% confidence interval 5.0-12.9 months; range 4.9-14.6 months). The most common adverse events (AEs) were diarrhea (2/6), pruritis (2/6), stomatitis (1/6) and nausea (1/6). No grade 3 or more AEs were documented.ConclusionsThis study revealed that the genetic characteristics of EGFRex20ins mutations in Chinese patients with NSCLC were comparable to those reported in Caucasian patients. Furthermore, our study firstly demonstrated promising antitumor activity of osimertinib in certain EGFRex20ins mutant advanced NSCLC patients, indicating that osimertinib treatment for EGFRex20ins positive patients deserves further study.

Project description:BackgroundEpidermal growth factor receptor (EGFR) exon 20 insertion (EGFR ex20ins) is a common mutation in non-small cell lung cancer (NSCLC). Patients with EGFR ex20ins generally respond poor to EGFR-tyrosine kinase inhibitors (EGFR-TKIs). EGFR ex20ins are often co-occurring with EGFR amplification. However, the impact of EGFR amplification on the survival of patients with EGFR ex20ins mutations has not been determined.MethodsThis is an observational longitudinal cohort study. A prospectively managed database included consecutive treatment-naïve adult patients with advanced NSCLC and EGFR ex20ins confirmed by next-generation sequencing (NGS) at Guangdong Provincial People's Hospital between November 2017 and February 2019. The participants were enrolled from the database and extracted their clinical characteristics, treatment and clinical outcomes. NGS was used to establish whether EGFR amplification was present in tumor tissue. Overall survival (OS) and progression-free survival (PFS) were compared between EGFR amplification and non-EGFR amplification groups using the Kaplan-Meier method and log-rank test. Subgroup analyses were performed based on the treatment used (EGFR-TKI or chemotherapy).ResultsFifteen different EGFR ex20ins mutation subtypes were identified in the 39 patients included in the analysis, and the most common subtypes were p.A767_D770dup (25.6%), p.S768_D770dup (23.1%) and p.N771_H773dup (10.3%). Among 31 patients with EGFR ex20ins mutations and NGS data for tumor tissue, EGFR amplification was identified in 12 patients (38.7%) and there were no significant differences in clinical characteristics. Among 26 patients, there were no significant differences between the EGFR amplification (n=11) and non-EGFR amplification (n=15) groups in median OS (715 vs. 452 days, P=0.912). Among 20 patients administered chemotherapy, there were no significant differences between the EGFR amplification and non-EGFR amplification groups in median PFS (206 vs. 112 days, P=0.425). Among 24 patients administered an EGFR-TKI, median PFS was longer in the non-EGFR amplification group than in the EGFR amplification group (110 vs. 31 days, P=0.030).ConclusionsThere is a tendency that EGFR amplification might be a poor predictor in EGFR ex20ins-positive NSCLC patients treated with EGFR-TKIs.

Dataset Information

Cetuximab in Patients with Non-Small Cell Lung Cancer and EGFR Exon 20 Insertion Alterations.

Publications

Cetuximab in Patients with Non-Small Cell Lung Cancer and EGFR Exon 20 Insertion Alterations.

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