Amivantamab is a fully human bispecific monoclonal antibody indicated for treating patients with specifically large cell lung cancer. Its dosage is based on the patient\'s initial body weight and is administered via intravenous infusion after dilution. Therefore, this drug is given as a strategy due to the great need for a molecule targeting epidermal growth factor receptor (EGFR) and the mesenchymal-epithelial transition factor (MET), as acquired resistance to tyrosine kinase inhibitors (TKIs) was observed in the treatment of large cell lung cancer. This article encompasses a review of the benefits of amivantamab for patients with non-small cell lung cancer (NSCLC). This drug is the first therapy directed against this specific mutation, and unlike others, it could bind to two genetic receptors, whereas antibodies, in general, are directed toward a single receptor.

UNASSIGNED: In non-small cell lung cancer (NSCLC), the epidermal growth factor receptor (EGFR) mutation is a representative oncogenic driver mutation. Only about 12% of EGFR mutation patients have the exon 20 insertion mutation, which is the third most frequent mutation among EGFR mutation NSCLC. Amivantamab, an EGFR and MET proto-oncogene, receptor tyrosine kinase (MET) bispecific antibody, was approved for NSCLC patients with the EGFR exon 20 insertion (E20I) mutation. In this study, we described the real-world, single-center efficacy and safety data of amivantamab in E20I mutation patients.
UNASSIGNED: This study included metastatic NSCLC patients with EGFR E20I mutations. From January 2018 to June 2022, patients with EGFR E20I mutations who were treated with amivantamab were analyzed at Samsung Medical Center as part of the clinical trial or the early access program (EAP). We collected the patients\' characteristics [age, sex, smoking history, location of mutation, sites of metastasis, programmed death-ligand 1 (PD-L1) expression status, etc.] and analyzed progression-free survival (PFS) and overall survival (OS) stratified by PD-L1 expression status, co-mutation such as tumor protein p53 (TP53), and metastasis sites.
UNASSIGNED: A total of 42 patients were analyzed, of which 16 patients were enrolled in the phase 1 study, and 26 patients received amivantamab through EAP. There were 14 (33%) patients with partial remission, 18 (43%) patients with stable disease, and 10 (24%) patients with disease progression. The objective response rate (ORR) was 33%, and the disease control rate (DCR) was 76%. PFS was analyzed by dividing the near and far loop for 31 patients whose mutation location was known. The two groups had no statistically significant difference in PFS [median (range): 11.8 (2.3-21.3) vs. 11.3 (3.4-19.2) months, P=0.69]. For 29 patients with TP53 mutation data, there was no significant difference in PFS between the two groups [median (range): 5.9 (0-18.0) vs. 12.6 (6.9-18.3) months, P=0.11]. When analyzing PFS in 37 patients with PD-L1 expression data, PD-L1 (+) patients showed a poor prognosis [median (range): 11.3 (5.0-17.6) vs. 19.5 (5.3-33.7) months, P=0.04; hazard ratio (HR), 0.44; 95% confidence interval (CI): 0.20-0.98].
UNASSIGNED: The efficacy of amivantamab was confirmed for the real-world population for EGFR E20I-mutated NSCLC. PD-L1 status could be a poor predictive factor, which should be further validated.

EGFR mutations comprise a sizeable portion of non-small cell lung cancers. While the most common EGFR mutation consists of exon 19 in-frame deletions and exon 21 point mutations, rare EGFR mutations have become a more frequent occurrence. Currently, no clinical guidelines exist for the treatment of such mutations. In this case, we see a 68-year-old non-small cell lung cancer male patient with a history of smoking presenting with a rare exon 20 R776H EGFR mutation who demonstrates a response to Osimertinib, further exploring potential standard treatments for patients with rare EGFR mutations.

A non-small-cell-lung-cancer patient with cerebral metastasis presenting an atypical exon 20 mutation in the EGFR gene had a long-lasting tumor cotrol on mulimodal treatment with osimertinib and stereotaxic radiotherapy on oligoprogressing lesions. Most exon-20 mutations are resistant to first, second and third generation EGFR-directed TKI. This case was discussed on our molecular tumour board. As the more specific exon-20 targeted therapies were not yet available and as sporadic short responses on the third generation EGFR-directed TKI, osimertinib had been described, the patient started osimertinib. She had a prolonged tumoral response on Osimertinib. The patient is still asymptomatic up to 32 months after initiating the medication. This case confirms that not all exon20 EGFR mutations are equal to osimertinib and that the localization of the exon 20 insertion mutation is probably important to consider when treating EGFR mutated NSCLC. The long-term clinical benefit can be maintained through stereotactic radiotherapy on focal progressive lesions.

Lung cancer is the foremost reason for cancer-related mortality among men and women. The ultimate goal of patient supervision post-diagnosis for advanced cases is to improve survival and quality of life with minimal treatment-associated side effects. With advancements in genomic medicine and a better understanding of cell signaling pathways, many actionable gene mutations have been identified in lung carcinoma, which drastically improve survival outcomes. Mutations in human epidermal growth factor receptor 2 (HER2) and epidermal growth factor receptor together are observed in nearly 1-3% of cases and act as an oncogenic driver. In the case of HER2-mutant lung cancers, there are limited approved agents, and the treatment represents a critical unmet medical need because of the poorer survival outcomes compared to patients with additional oncogenic drivers. The recent standard of care of treatment is chemotherapy, but reports suggest that compared with cytotoxic chemotherapy, patients receiving HER2-directed therapies have relatively longer median survival duration. Here, we report a case of HER2 exon 20-mutated metastatic lung adenocarcinoma patient who received trastuzumab emtansine in the third-line setting and achieved durable disease control.

OBJECTIVE: This study is a comprehensive review of the clinical pharmacology, pharmacokinetics, efficacy, safety, and clinical applicability of amivantamab-vmjw for metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 20 insertion (exon20ins) mutation.
RESULTS: The literature search to identify clinical trials returned only the CHRYSALIS phase 1 study. In a phase I trial, amivantamab-vmjw was associated with an overall response rate (ORR) of 40% (95% CI, 29-51) in the EGFR exon20ins NSCLC patient population (n = 81) after platinum-based chemotherapy. There were 3 complete responses (CRs) and 29 partial responses (PRs). The median duration of response (DOR) was 11.1 months (95% CI, 6.9-not reached; NR). The median progression-free survival (PFS) was 8.3 months (95% CI, 6.5-10.9), and overall survival (OS) was 22.8 months (95% CI, 14.6-NR).
CONCLUSIONS: This review summarizes the pharmacology, clinical evidence, and use of amivantamab-vmjw for patients with locally advanced or metastatic NSCLC with EGFR exon20ins mutation.
CONCLUSIONS: The FDA approval of amivantamab-vmjw, the first bispecific antibody to target the exon20ins mutation, represents an important advancement in the treatment of patients with NSCLC with limited effective treatment options. The initial findings of the CHRYSALIS trial demonstrate an overall tumor response benefit with an acceptable safety profile.

UNASSIGNED: Real-world evidence regarding molecular epidemiology and management patterns of patients with EGFR exon-20 mutated, advanced NSCLC outside the context of clinical trials is lacking.
UNASSIGNED: We created a European registry for patients with advanced EGFR exon 20-mutant NSCLC diagnosed from January 2019 to December 2021. Patients enrolled in clinical trials were excluded. Clinicopathologic and molecular epidemiology data were collected, and treatment patterns were recorded. Clinical end points according to treatment assignment were assessed using Kaplan-Meier curves and Cox regression models.
UNASSIGNED: Data on 175 patients from 33 centers across nine countries were included in the final analysis. Median age was 64.0 (range: 29.7-87.8) years. Main features included female sex (56.3%), never or past smokers (76.0%), adenocarcinoma (95.4%), and tropism for bone (47.4%) and brain (32.0%) metastases. Mean programmed death-ligand 1 tumor proportional score was 15.8% (range: 0%-95%) and mean tumor mutational burden was 7.06 (range: 0-18.8) mutations per megabase. Exon 20 was detected in the tissue (90.7%), plasma (8.7%), or both (0.6%), using mostly targeted next-generation sequencing (64.0%) or polymerase chain reaction (26.0%). Mutations were mainly insertions (59.3%), followed by duplications (28.1%), deletions-insertions (7.7%), and the T790M (4.5%). Insertions and duplications were located mainly in the near loop (codons 767-771, 83.1%) and the far loop (codons 771-775, 13%) and only in 3.9% within the C helix (codons 761-766). Main co-alterations included mutations in TP53 (61.8%) and MET amplifications (9.4%). Treatment on mutation identification included chemotherapy (CT) (33.8%), CT-immunotherapy (IO) (18.2%), osimertinib (22.1%), poziotinib (9.1%), mobocertinib (6.5%), mono-IO (3.9%), and amivantamab (1.3%). Disease control rates were 66.2% with CT plus or minus IO, 55.8% with osimertinib, 64.8% with poziotinib, and 76.9% with mobocertinib. Corresponding median overall survival was 19.7, 15.9, 9.2, and 22.4 months, respectively. In multivariate analysis, type of treatment (new targeted agents versus CT ± IO) affected progression-free survival (p = 0.051) and overall survival (p = 0.03).
UNASSIGNED: EXOTIC represents the largest academic real-world evidence data set on EGFR exon 20-mutant NSCLC in Europe. Indirectly compared, treatment with new exon 20-targeting agents is likely to confer survival benefit than CT plus or minus IO.

BACKGROUND: EGFR mutations widely exists in NSCLC patients, which are involved in cancer development.
OBJECTIVE: The function of EGFR mutations in the resistance to TKI treatments of NSCLC was evaluated to provide theoretical support for the clinical management of NSCLC patients.
METHODS: A total of 150 NSCLC patients including 118 patients with EGFR mutation and 32 without, were included in this study. The EGFR mutation status and subtypes were analyzed in recruited patients. The distribution of EGFR mutation subtypes and their association with clinicopathological features were also assessed. The prognostic value of EGFR mutation was evaluated by the overall survival of recruited patients. The function of EGFR mutation was estimated, in vitro, in the TKI resistant NSCLC cells with different subtypes of EGFR mutation.
RESULTS: The exon 19 deletion was the most common subtype of EGFR mutation in the enrolled patients followed by the exon 21 L858R point mutation. The EGFR mutations were closely associated with the differentiation degree and the histological types of NSCLC cases. EGFR mutation was an independent prognostic factor of NSCLC with a close relationship with the overall survival of patients. The exon 20 T790M mutation results in the erlotinib resistance through the PI3K/Akt signaling pathway.
CONCLUSIONS: The EGFR mutation is a critical factor in the prognosis and for the resistance to TKI treatment in NSCLC. The exon 20 T790M mutation was involved in the erlotinib resistance through PI3K/Akt signaling pathway.

OBJECTIVE: To compare the survival of first- and second-generation tyrosine kinase inhibitors (TKIs) in patients with rare EGFR exon 18 and exon 20 mutation-positive non-small cell lung cancer (NSCLC).
METHODS: We retrospectively evaluated survival characteristics of 125 patients with EGFR exon 18 and exon 20 mutated NSCLC who received erlotinib or afatinib as first line treatment between 2012 and 2021 from 34 oncology centres. Since exon 20 insertion is associated with TKI resistance, these 18 patients were excluded from the study.
RESULTS: EGFR exon 18 mutations were seen in 60%, exon 20 mutations in 16%, and complex mutations in 24% of the patients with NSCLC who were evaluated for the study. There were 75 patients in erlotinib treated arm and 50 patients in afatinib arm. Patients treated with erlotinib had progression-free survival time (PFS) of 8.0 months and PFS was 7.0 months in the afatinib arm (p = 0.869), while overall survival time (OS) was 20.0 vs 24.8 months, respectively (p = 0.190). PFS of exon 18 mutated arm was 7.0 months, exon 20 mutated arm was 4.3 months, and complex mutation positive group was 17.3 months, and this was statistically significant (p = 0.036). The longest OS was 32.5 months, seen in the complex mutations group, which was not statistically different than exon 18 and in exon 20 mutated groups (21.0 and 21.2 months, respectively) (p = 0.323).
CONCLUSIONS: In this patient group, especially patients with complex mutations are as sensitive to EGFR TKI treatment similar to classical mutations, and in patients with rare exon 18 and exon 20 EGFR mutation both first- and second-generation EGFR-TKIs should be considered, especially as first- and second-line options.

Epidermal growth factor receptor (EGFR) gene mutations play an important role in the treatment management of non-small cell lung cancer (NSCLC) patients. After a first- or second-generation EGFR tyrosine kinase inhibitor (TKI) therapy, the most common resistance mechanism involves the selection of a resistant clone carrying the exon 20 p.T790M point mutation. However, also for these patients, treated with a third-generation TKI (osimertinib) several mechanisms of acquired resistance are described. Here we report the case of a 68-year-old man with an EGFR exon 19 deletion treated with gefitinib in first line and osimertinib in second line besides on the presence of a p.T790M mutation, who developed an uncommon EGFR exon 20 p.L792Q point mutation at the progression to osimertinib, with the concomitant modification of the original sensitizing EGFR exon 19 deletion and the loss of p.T790M mutation.