Mobocertinib 40mg capsules

Background and objectiveThis review will provide an overview of EGFR and ERBB2 mutations in non-small-cell lung cancer (NSCLC) with a focus on recent clinical approvals.MethodsWe obtained data from the literature in accordance with narrative review reporting guidelines.Key content and findingsEGFR mutations are present in up to 15-20% of all NSCLCs; amongst these, 10% correspond to kinase domain insertions in exon 20. Structurally similar, ERBB2 (HER2) mutations occurs in 1-4% of NSCLCs, mostly consisting of insertions or point mutations. The majority of EGFR exon 20 insertions occur within the loop following the regulatory C-helix and activate the kinase domain of EGFR without generating a therapeutic window to gefitinib, erlotinib, afatinib, dacomitinib or osimertinib. Mobocertinib represents a novel class of covalent EGFR inhibitors with a modest therapeutic window to these mutants and induces anti-tumor responses in a portion of patients [at 160 mg/day: response rate of 17 months and progression-free survival (PFS) of >7 months] albeit with mucocutaneous and gastrointestinal toxicities. The bi-specific EGFR-MET antibody amivantamab-vmjw has modest but broad preclinical activity in EGFR-driven cancers and specifically for EGFR exon 20 insertion-mutated NSCLC has response rates ERBB2-mutated NSCLC has been thwarted by mucocutaneous/gastrointestinal toxicities that preclude a pathway for drug approval, as the case of poziotinib. However, the activation of ERBB2 has allowed for repurposing of antibody-drug conjugates (ADCs) that target ERBB2 with cytotoxic payloads. The FDA approved fam-trastuzumab deruxtecan-nxki in 2022 for NSCLC based on response rate of >55%, DoR >9 months, PFS >8 months and manageable adverse events (including cytopenias, nausea and less commonly pneumonitis). Other therapies in clinical development include sunvozertinib and zipalertinib, among others. In addition, traditional cytotoxic chemotherapy has some activity in these tumors.ConclusionsThe approvals of mobocertinib, amivantamab, and trastuzumab deruxtecan represent the first examples of precision oncology for EGFR exon 20 insertion-mutated and ERBB2-mutated NSCLCs.

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Epidermal growth factor receptor exon 20 insertion mutations (EGFRex20ins) are a unique molecular subtype of non-small cell lung cancer (NSCLC) linked to resistance to EGFR tyrosine kinase inhibitors of the first and second generations. Until recently, these patients had few and frequently ineffective treatment options. Amivantamab, a bispecific antibody targeting both EGFR and mesenchymal-epithelial transition factor, has become a novel therapeutic strategy for this population. This review explores the mechanism of action of Amivantamab and its clinical efficacy and safety as demonstrated in clinical trials. Additionally, the clinical development of the subcutaneous formulation of amivantamab, real-world evidence and its regulatory status were evaluated. Lastly, we contextualise Amivantamab in the current treatment landscape by contrasting it with mobocertinib and highlighting current studies that aim to improve central nervous system activity and overcome resistance mechanisms. This review highlights the therapeutic benefit of Amivantamab in EGFRex20ins-mutated NSCLC and offers guidance for future research in this quickly developing area.

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Advancements in cancer research play a pivotal role in enhancing prevention, diagnosis, and treatment strategies. The American Society of Clinical Oncology (ASCO) convenes major annual meetings, gathering experts worldwide to discuss the latest discoveries and trends in the field. In this study, we conducted a comprehensive bibliographic analysis of ASCO presentations and publications from 2022 to 2023 to identify dominant themes in cancer research. Our research methodology involved targeted searches in bibliographic databases and ASCO meeting archives, utilizing specific keywords related to various cancer types. Subsequently, we rigorously selected studies based on predefined criteria, with a particular focus on lung and gastrointestinal cancers due to their prevalence and significant public health impact. Among notable studies, evaluations of immune checkpoint inhibitors in advanced gastrointestinal cancers revealed promising response rates, while precision medicine approaches showed significant improvements in clinical outcomes. Studies like PARADIGM and PRODIGE demonstrated the efficacy of novel therapeutic combinations, while the NEO-PAN trial explored new avenues in locally advanced pancreatic cancer treatment. Additionally, novel therapeutic options such as Mobocertinib and sotorasib were identified as offering new hope for patients with specific lung cancers. Studies KEYNOTE-799 and SKYSCRAPER also demonstrated significant survival improvements in patients with stomach, esophageal, and non-small cell lung cancers. Furthermore, the PROTECT study underscored the crucial importance of efforts to reduce severe chemotherapy-related side effects, potentially enhancing patients' quality of life. These findings highlight the significance of ASCO meetings as a vital source of information and collaboration in the fight against cancer, providing valuable insights for the clinical management of this complex disease.

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Background and objectiveEpidermal growth factor receptor (EGFR) exon 20 insertion mutations (ex20ins) are uncommon in non-small cell lung cancer (NSCLC). These mutations are generally resistant to first-generation EGFR tyrosine kinase inhibitors, unlike common EGFR mutations, including exon 19 deletions or exon 21 L858R point mutation. The development of effective targeted therapies for NSCLC harboring EGFR ex20ins has been eagerly anticipated over the years. Recently, the therapeutic landscape of this subgroup of EGFR-mutant NSCLC patients has rapidly evolved due to the emergence of new drugs. In 2021, several novel agents, such as amivantamab and mobocertinib, have been approved by the US Food and Drug Administration for patients with advanced platinum-resistant NSCLC harboring EGFR ex20ins. In this review, we mainly focus on emerging therapies targeting NSCLC with EGFR ex20ins, as well as important ongoing clinical trials.MethodsSearches were conducted in PubMed and supplemented with recent conference proceedings in November 30th, 2021.Key content and findingsSeveral novel emerging therapies showed favorable safety profile and promising anti-tumor activity in NSCLC patients with EGFR ex20ins in recent several clinical trials.ConclusionsThere is still room for improvement in the treatment results of NSCLC harboring EGFR ex20ins. Future research should focus on the molecular heterogeneity in the size and location of distinct EGFR ex20ins, the mechanisms of acquired resistance to novel EGFR inhibitors, effective treatment that have good central nervous system penetrance, and the potential role of combination strategy.

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PURPOSE Mobocertinib is an oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor that targets EGFR exon 20 insertion (ex20ins) mutations in non–small cell lung cancer (NSCLC). This open-label, phase III trial (EXCLAIM-2, ClinicalTrials.gov identifier: NCT04129502 ) compared mobocertinib versus platinum-based chemotherapy as first-line treatment of EGFR ex20ins+ advanced/metastatic NSCLC. METHODS Patients with treatment-naive EGFR ex20ins+ locally advanced/metastatic NSCLC were randomly assigned 1:1 to mobocertinib 160 mg once daily or pemetrexed plus cisplatin or carboplatin every 3 weeks for four cycles followed by maintenance pemetrexed. The primary end point was progression-free survival (PFS) by blinded independent central review (BICR), with planned interim analysis (IA) after approximately 70% of 227 expected PFS events. RESULTS A total of 354 patients were randomly assigned (mobocertinib: n = 179; chemotherapy: n = 175). Baseline characteristics were balanced between arms. At IA (cutoff: April 4, 2023), the median PFS per BICR was 9.6 months in each treatment arm (hazard ratio [HR], 1.04 [95% CI, 0.77 to 1.39]; P = .803). The primary end point crossed the prespecified futility boundary (HR > 1). The confirmed objective response rate (95% CI) per BICR was 32% (26 to 40) with mobocertinib versus 30% (24 to 38) with chemotherapy; the median duration of response was 12.0 versus 8.4 months. Quality-of-life assessments indicated clinically meaningful delays in time to deterioration of lung cancer symptoms, cognitive function, and constipation with mobocertinib versus chemotherapy. Grade ≥3 adverse events in >5% of patients (mobocertinib, chemotherapy) were diarrhea (20%, 1%), anemia (6%, 10%), increased lipase (6%, 0%), and decreased neutrophil count (1%, 7%). CONCLUSION The EXCLAIM-2 trial did not meet its primary end point. The efficacy of mobocertinib was not superior to platinum-based chemotherapy for first-line treatment of patients with EGFR ex20ins+ advanced/metastatic NSCLC.

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