Receptor tyrosine kinases (RTKs) play a crucial role in cellular signaling and oncogenic progression. Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) have become the standard treatment for advanced non-small cell lung cancer (NSCLC) patients with EGFR-sensitizing mutations, but resistance frequently emerges between 10 to 14 months. A significant factor in this resistance is the role of human EGFR 3 (HER3), an EGFR family member. Despite its significance, effective targeting of HER3 is still developing. This review aims to bridge this gap by deeply examining HER3’s pivotal contribution to EGFR TKI resistance and spotlighting emerging HER3-centered therapeutic avenues, including monoclonal antibodies (mAbs), TKIs, and antibody-drug conjugates (ADCs). Preliminary results indicate combining HER3-specific treatments with EGFR TKIs enhances antitumor effects, leading to an increased objective response rate (ORR) and prolonged overall survival (OS) in resistant cases. Embracing HER3-targeting therapies represents a transformative approach against EGFR TKI resistance and emphasizes the importance of further research to optimize patient stratification and understand resistance mechanisms.

Targeting HER3 to overcome EGFR TKI resistance in NSCLC

Epidermal growth factor receptor (EGFR) activating mutations are known oncogenic drivers in non-small-cell lung cancer (NSCLC), with 85% attributable to an exon 19 deletion or exon 21 L858R point substitution. The next most common is an exon 20 insertion mutation (Ex20Ins), which results in an altered active site that sterically interferes with tyrosine kinase inhibitor (TKI) binding, resulting in a poorer response rate to EGFR TKIs. Amivantamab (JNJ-61186372), a fully humanized EGFR- mesenchymal-epithelial transition receptor (MET) bispecific antibody has been approved for use in adults with locally advanced or metastatic NSCLC with EGFR Ex20Ins mutations, whose disease has progressed on or after platinum-based chemotherapy. To prepare this review, we searched various websites, including the European Medicines Agency Drug Manual, United States Food and Drug Administration, PubMed, Science Direct, and UpToDate using the search terms, “Amivantamab,” “NJ-61186372,” “amivantamab-vmjw,” and” “EGFRexon20ins.” We shortlisted 121 articles published between 2015 and 2023, of which 49 were included. This review discusses the clinical indications, adverse effects, safety, pharmacodynamics, pharmacokinetics, and the key research trials that investigated the use of amivantamab.

Amivantamab: A narrative drug review

Lung adenocarcinoma (LUAD), the most prevalent form of non-small cell lung cancer (NSCLC), remains a leading cause of cancer-related death globally, including in India, with a 5-year survival rate below 10%. Despite these grim statistics, recent advances in the use of next-generation sequencing (NGS) for identifying genetic alterations and the emergence of targeted therapies have opened new possibilities for personalized treatment based on distinct molecular signatures. To understand the molecular pattern of NSCLC, a retrospective study was conducted with 53 Indian LUAD patient samples, using a targeted NGS panel of 46 cancer-relevant oncogenes to identify clinically relevant variants. Pathogenic or likely pathogenic variants were detected in 94% of the 53 cases. Non-synonymous mutations, rearrangements, copy number alterations, insertions, and deletions of functional relevance were observed in 31 out of 46 genes. The most frequently mutated genes included TP53 (52.8%) and EGFR (50.9%), followed by RET, PIK3CA and ERBB2; some patients had multiple alterations in the same gene. Gender-based enrichment analysis indicated that ALK and IDH2 alterations were more prevalent in females, while TP53 and PTEN were more common in males. No significant correlation was found between mutations and other clinicopathological attributes, such as age, stage, and subtype. A higher prevalence of EGFR, RET, PIK3CA, ERBB2 and ALK mutations were observed compared to previous LUAD genetic studies coupled with a lower frequency of KRAS mutations. Clinically actionable variants were annotated using OncoKB and categorized into the four therapeutic levels based on their clinical evidence. Seventy-nine percent of cases had at least one clinically actionable alteration. Most patients (39.6%) had the highest level of actionability (Level 1) wherein an FDA-approved drug is available specifically for the observed mutation in lung cancer patients. EGFR Exon19 in-frame deletions and EGFR L858R were the most frequent among targetable variants (20.7%). These findings emphasize the importance of a selective NGS panel in enabling personalized medicine approaches by identifying actionable molecular alterations and informing the choice of targeted therapy for more effective treatment options in Indian NSCLC patients.

The landscape of actionable genomic alterations in lung adenocarcinomas in India

Mechanism of morusin on breast cancer via network pharmacology and in vitro experiments

Background: Accurate molecular testing in non-small-cell lung cancer (NSCLC) is of paramount importance for treatment, prediction, and prognostication. Objectives: We aimed to comprehensively describe the clinicopathological and molecular profile of Indian patients with NSCLC with regard to alterations in the epidermal growth factor receptor ( EGFR), anaplastic lymphoma kinase ( ALK), and c-ros oncogene 1 ( ROS1 ). Materials and Methods: We conducted a retrospective analysis of lung tissue samples tested between January 2015 and December 2021 at the Metropolis Healthcare Limited global referral laboratory facility in Mumbai, Maharashtra, India. Testing was conducted for EGFR by real time reverse transcriptase polymerase chain reaction (RT-PCR) and Sanger sequencing , ALK by immunohistochemistry (IHC), ALK by fluorescence in situ hybridization (FISH), and c-ros oncogene 1 (ROS1) by FISH. We analyzed the positivity status and determined the trends in the results of the molecular targets in NSCLC cases. Results: Out of 3220 samples with malignancy, 1750 (54.3%) were tested for EGFR , out of which 510 (29.1%) were positive. The most common mutation detected was in exon 19 of EGFR (334/510, 65.5%), followed by exon 21 (164/510, 32.2%). A total of 1548 (48.1%) cases were tested for ALK by IHC, of which 125/1548 (8.1%) showed positivity, while among the 372/3220 (11.6%) cases tested for ALK by FISH, 29/372 (7.8%) were positive. In patients with squamous cell carcinoma, the ALK positivity rate by IHC was 5.3%. Of the 372 cases tested for ALK by FISH, 353 (94.9%) cases were tested for ALK by IHC as well; 98.9% concordance was observed for the positive cases. ROS1 testing was conducted in 370/3220 (11.5%) samples and showed a low positivity rate of 13/370 (3.5%). Conclusions: Indian patients with NSCLC have 29% EGFR positivity, 8.1% ALK positivity, and 3.5% ROS1 positivity, when tested with RT-PCR, IHC, and FISH, respectively. A detailed molecular analysis using next-generation sequencing (NGS) may help detect a higher number of molecular targets amenable to therapy. 

Molecular analysis for EGFR, ALK, and ROS1 alterations in over 3000 Indian patients with non-small-cell lung cancer: A retrospective observational study

Lung cancer is the world’s leading cause of cancer-related deaths. Epidermal growth factor receptor (EGFR) is one of the critical oncogenes and plays a significant role in tumor proliferation and metastasis. Patients with sensitizing mutations in the EGFR gene have better clinical outcomes when treated with tyrosine kinase inhibitors (TKI). This study expands our knowledge of the spectrum of EGFR mutations among lung cancer patients in the Indian scenario. This is a retrospective descriptive study of all newly diagnosed patients with lung cancer in tertiary care hospital in India. All the samples were subjected to real-time PCR (q-PCR) analysis and confirmation of rare novel mutations was done using Sanger sequencing. Clinicopathological characteristics, mutational EGFR status, and location on the exon and metastatic sites were evaluated. An analysis of total 212 samples showed mutations in 38.67% of cases. Among these, five (5.9%) samples had mutations in exon 18, 41 (48.8%) samples had mutations in exon 19, 12 (14.28%) samples had mutations in exon 20, and 26 (30.95%) samples had mutations in exon 21. Eleven (13.41%) were found to be uncommon EGFR mutations. Additionally, six (21.4%) samples that had EGFR mutations were also positive for brain metastasis. Future testing on bigger panels will help to characterize the incidence of genetic mutations and to determine the appropriate targeted treatment choices for NSCLC patients.

/pdf/mutational-analysis-of-egfr-mutations-in-non-small-cell-lung-16a19mel.pdf

Mutational Analysis of EGFR Mutations in Non-Small Cell Lung Carcinoma—An Indian Perspective of 212 Patients

Acute myeloid leukemia with nucleophosmin 1 mutation: Clonal hematopoiesis with indeterminate potential or oncogenic potential?

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Mutational Analysis of EGFR Mutations in Non-Small Cell Lung Carcinoma—An Indian Perspective of 212 Patients

Acute myeloid leukemia with nucleophosmin 1 mutation: Clonal hematopoiesis with indeterminate potential or oncogenic potential?