Exkivity (mobocertinib)

Imp-A, a novel compound, demonstrated promising anticancer activity in vitro. However, further in vivo studies are required to fully assess its therapeutic potential, which may hold promise for clinical applications in cancer treatment.

In vitro studies show that afatinib, poziotinib, and zipalertinib more potently inhibited near-loop than far-loop insertions, whereas mobocertinib has similar IC50 in both groups. In comparison, in the previously published EXCLAIM trial (NCT02716116), mobocertinib demonstrates similar activities across both groups in tumor size reduction (-38.5% vs. -34.1%, p = 0.59) and PFS (12.0 vs. 13.0 months, p = 0.99). Therefore, EGFRex20ins location differentially impacts the sensitivity of TKIs.

The patient exhibited disease progression despite sequential treatment with EGFR TKIs, including osimertinib, afatinib, and mobocertinib, in combination with chemotherapy. The treatment strategy was then shifted to immunotherapy with pembrolizumab alongside carboplatin and paclitaxel, leading to a remarkable response...This case challenges the conventional paradigm that EGFR-mutated NSCLC does not benefit from immunotherapy, highlighting the potential for an alternative treatment approach in rare subtypes such as PSC. Our findings emphasize the importance of comprehensive molecular profiling and a personalized treatment strategy to optimize outcomes in aggressive and refractory lung cancers.

These data suggest that mobocertinib exerts acute, direct cardiac electrophysiological effects-predominantly via hERG and Cav1.2 inhibition-providing a mechanistic basis for observed QT prolongation and conduction delay in patients.

The clinical efficacy of ibrutinib, a Bruton tyrosine kinase blocker, in the treatment of mantle cell lymphoma following its 2013 approval helped to overcome a general bias against the development of irreversible drug inhibitors. Other approved targeted covalent inhibitors include acalabrutinib and zanubrutinib, which also block Bruton tyrosine kinase. Afatinib, dacomitinib, lazertinib, mobocertinib, and osimertinib inhibit members of the epidermal growth factor receptor family (ErbB1/2/3/4) and are used in the treatment of non-small cell lung cancers. Neratinib inhibits ErbB2 and is used in the management of ErbB2/HER2-positive breast cancer. Futibatinib blocks the fibroblast growth factor receptor family and is prescribed for the treatment of cholangiocarcinoma while ritlecitinib, which inhibits JAK3, is used in the management of alopecia areata. The eleven drugs considered in this review have a common mechanism of action involving the addition of a protein cysteine thiolate anion (proteinS:) to an acrylamide or an acrylamide-like derivative producing a thioether. The development of targeted covalent inhibitors is gaining acceptance as a valuable component of the medicinal chemist's toolbox and has made a significant impact on the development of protein kinase antagonists and receptor modulators.

This retrospective study described patient characteristics, treatment patterns, and outcomes in patients with EGFR exon20ins-mutated advanced or metastatic NSCLC who received amivantamab or mobocertinib monotherapy after platinum-based chemotherapy. Real-world patients treated with amivantamab experienced TTNTD and TTD consistent with the median progression-free survival observed in its registrational trial, while patients treated with mobocertinib exhibited faster disease progression and a higher frequency of treatment discontinuation.

P1, N=53, Active, not recruiting, Takeda | Trial completion date: Mar 2025 --> Sep 2026

P3, N=354, Active, not recruiting, Takeda | Trial completion date: Jul 2025 --> Sep 2026 | Trial primary completion date: Dec 2024 --> Sep 2026

P1/2, N=334, Active, not recruiting, Takeda | Trial completion date: Mar 2025 --> Oct 2026 | Trial primary completion date: Mar 2025 --> Oct 2026

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.

These data illustrate the real-world effectiveness of mobocertinib.

Mobocertinib, an agent with similar properties to amivantamab, served as a control for comparison. Moreover, amivantamab was associated with higher risks of thrombosis events, bone marrow suppression, skin and soft tissue infection, deterioration of respiratory symptoms, and noninfectious pneumonitis. The safety profile of amivantamab requires attention; particularly, monitoring of the adverse drug events described above is necessary during its administration.