Exkivity (mobocertinib) / Takeda - LARVOL DELTA

Resistance Mechanisms of Novel Targeted Therapies to EGFR Exon 20 Insertion Mutation-Positive Non-Small Cell Lung Cancer (IASLC-WCLC 2025) - "Two patients with p.A763_Y764insFQEA who received afatinib therapy developed EGFR T790M as the resistance mechanism. Among 10 patients who received mobocertinib (n = 7), sunvozertinib (n = 2) or furmonertinib (n = 1), baseline EGFR mutations preserved in post-treatment tissue samples in 9 (90%) patients, EGFR amplification was detected in 5 (50%) patients...Conclusions : EGFR amplification is the most common resistance mechanism of novel EGFR inhibitors targeted on EGFR exon 20 insertion mutation. The resistance mechanisms of amivantamab therapy warrant further study."

EGFR exon 20 • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • CDK4 • EGFR • MDM2 • MET • MYC

Advances in the management of lung & gastro-intestinal cancers: clinical studies review from ASCO 2022/2023 annual meetings. (PubMed, Cancer Treat Res Commun) - "Additionally, novel therapeutic options such as Mobocertinib and sotorasib were identified as offering new hope for patients with specific 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."

Journal • Review • Gastrointestinal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Solid Tumor

Exceptional Response to Immunotherapy-based Treatment in Compound EGFR-Mutated Oligometastatic Pulmonary Sarcomatoid Carcinoma: A Case Report. (PubMed, J Immunother Precis Oncol) - "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."

IO biomarker • Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Sarcoma • Solid Tumor • EGFR

Sunvozertinib (Zegfrovy) for NSCLC. (PubMed, Med Lett Drugs Ther) - No abstract available

Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

In silico drug repurposing targeting fusion and nucleoprotein of human metapneumovirus: A step toward pandemic preparedness. (PubMed, Indian J Pharmacol) - "The study highlights mobocertinib, rutin, and levetiracetam as promising repurposed drugs against HMPV. While mobocertinib exhibited the strongest predicted binding affinity, levetiracetam demonstrated the best pharmacokinetic profile, making it a particularly viable candidate for further experimental validation. These results validate the usefulness of in silico drug repurposing in addressing unmet antiviral needs and warrant preclinical studies to evaluate therapeutic efficacy."

Journal

Electrophysiological consequences of acute mobocertinib exposure in isolated rat and guinea-pig hearts and transfected cell lines. (PubMed, Biochem Biophys Res Commun) - "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."

Journal • Preclinical • Cardiovascular • Congestive Heart Failure • Heart Failure • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR • NAV1

Effects of antihypertensive drugs on the metabolism of mobocertinib in rats both in vitro and in vivo. (PubMed, Drug Metab Dispos) - "The inhibitory mechanism of mobocertinib was further investigated for nicardipine, irbesartan, telmisartan, carvedilol, prazosin hydrochloride, and spironolactone. In this study, the most common antihypertensive drugs were found to inhibit the metabolism of mobocertinib in vitro. We found that benidipine, nicardipine, telmisartan, and irbesartan inhibited the metabolism of mobocertinib in vitro and in vivo."

Journal • Preclinical

Real-world use of accelerated approval oncology drugs subsequently withdrawn in the United States. (ASCO 2025) - " Included AA drugs were mobocertinib (NSCLC), sacituzumab govitecan (bladder cancer), atezolizumab (breast cancer), nivolumab (SCLC), and pembrolizumab (SCLC). Findings indicate mixed real-world uptake of AA therapies and no consistent differences in patient characteristics. It appears care teams promptly follow regulatory guidance and cease initiating withdrawn AA drugs after IW. Pembrolizumab and nivolumab in SCLC indications that are retained in the clinical practice guidelines seem to be the exception to this trend."

Clinical • Real-world • Real-world evidence • Bladder Cancer • Breast Cancer • Genito-urinary Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor

Efficacy of zipalertinib in NSCLC patients with EGFR exon 20 insertion mutations who received prior platinum-based chemotherapy with or without amivantamab. (ASCO 2025) - P1/2 | "Of the 51 pts with prior ami, 30 had no other ex20ins-directed therapy, while 21 had also received other ex20ins drugs (such as mobocertinib, sunvozertinib, BLU-451, or poziotinib), the cORR was 30.0% and 14.3%, respectively. Zipalertinib demonstrated clinically meaningful efficacy with a manageable safety profile in pts with exon20ins NSCLC who have received prior platinum-based chemotherapy and for those who received prior amivantamab, a significant and growing unmet need. BICR assessed tumor responses per RECIST v1.1.CR=complete response, PR=partial response, SD=stable disease."

Clinical • EGFR exon 20 • IO biomarker • Anemia • Dental Disorders • Hematological Disorders • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Stomatitis • EGFR

Orally effective FDA-approved protein kinase targeted covalent inhibitors (TCIs): A 2025 update. (PubMed, Pharmacol Res) - "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..."

FDA event • Journal • Review • Alopecia • Biliary Cancer • Breast Cancer • Cholangiocarcinoma • Hematological Malignancies • HER2 Breast Cancer • HER2 Positive Breast Cancer • Immunology • Lung Cancer • Lymphoma • Mantle Cell Lymphoma • Non Small Cell Lung Cancer • Oncology • Solid Tumor • BTK • EGFR • FGFR

Real-world treatment patterns of patients with EGFR exon 20 insertion-mutated advanced NSCLC treated with amivantamab or mobocertinib after platinum-based chemotherapy: A multi-database cohort study. (PubMed, Cancer Treat Res Commun) - "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."

HEOR • Journal • Real-world evidence • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR

An insight into the in vivo antitumor therapeutic potential of indole-(fused) pyri(mi)dine hybrids. (PubMed, Future Med Chem) - "Moreover, numerous indole hybrids exemplified by mobocertinib (indole-pyrimidine hybrid) and osimertinib (indole-quinazoline hybrid) have already been utilized in clinical cancer treatment. Therefore, indole hybrids have emerged as valuable scaffolds for the treatment and eradication of cancer. This review aims to elucidate the current landscape of indole-(fused) pyri(mi)dine hybrids, including indole-quinolines/quinolinones, indole-pyridines, indole-pyrimidines, and indole-fused pyrimidines, with in vivo antitumor therapeutic potential, offering effective candidates for in-depth preclinical evaluations, encompassing articles published from 2021 onward."

Journal • Preclinical • Review • Oncology

A Study of Mobocertinib in Japanese Adults With Non-Small Cell Lung Cancer (clinicaltrials.gov) - P1 | N=53 | Active, not recruiting | Sponsor: Takeda | Trial completion date: Mar 2025 ➔ Sep 2026

Trial completion date • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR • HER-2

Antitumor activity of YH42946, a potent tyrosine kinase inhibitor, in NSCLC harboring EGFR exon 20 insertion mutations (AACR 2025) - "It demonstrated superior activity compared to Mobocertinib (IC50 < 30 nM for ASV and IC50 < 30 nM for SVD), Furmonertinib (IC50 < 100 nM for ASV and IC50 < 100 nM for SVD), and Zipalertinib (IC50 < 100 nM for ASV and IC50 < 100 nM for SVD), and was comparable to Poziotinib (IC50 < 10 nM for ASV and IC50 < 10 nM for SVD). YH42946 is a potent small-molecule inhibitor that selectively targets EGFR ex20ins while sparing EGFR WT in preclinical models, offering potential therapeutic benefits for NSCLC patients with EGFR ex20ins mutations. Additionally, YH42946 has demonstrated effective inhibition of the EGFR pathway. Given these robust activities against EGFR ex20ins, YH42946 is anticipated to provide a significant therapeutic option for NSCLC patients harboring EGFR ex20ins mutations."

EGFR exon 20 • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR

Elucidating mechanisms of acquired resistance to mobocertinib in non-small cell lung cancer harboring EGFR exon 20 insertion mutations (AACR 2025) - "In conclusion, we found that genomic or transcriptomic alterations of MAPK/RAS signaling mediate mobocertinib resistance. Further validation and exploration are needed to improve the therapy of EGFR ex20insmutant NSCLC."

EGFR exon 20 • Preclinical • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR • KRAS

A highly potent and selective small molecule TY-4028 for the targeted therapy of non-small cell lung cancer with EGFR exon 20 or HER2 exon20 insertion mutations (AACR 2025) - "Furthermore, Antibody such as Amivantamab has difficulty penetrating the BBB, brain metastases presents a significant clinical challenge in lung cancer with EGFR exon20ins mutations...The data showed that the efficacy of TY-4028 was similar to that of Mobocertinib(TAK-788)and better than that of Sunvozertinib (DZD9008), whereas the tolerance of TY-4028 was better than that of Mobocertinib in CDX mouse models... TY-4028 is a novel, potent, and orally available inhibitor targeting EGFR and Her2 exon20ins mutations. It is a highly potent covalent inhibitor with rapid absorption and clearance, which contributes to the decreased toxicity of covalent drugs. Preclinical studies have shown a good PK profile and manageable toxicity with TY-4028."

EGFR exon 20 • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR • HER-2

Development of indole hybrids for potential lung cancer treatment - part II. (PubMed, Future Med Chem) - "Moreover, indole hybrids osimertinib, mobocertinib, cediranib, and vizimpro are currently applied in clinics for lung cancer therapy, demonstrating that indole hybrids are valuable scaffolds in the treatment and eradication of lung cancer. This review provides a comprehensive overview of the evolving landscape of indole hybrids with the in vitro and in vivo efficacy against lung cancer, and the structure-activity relationships as well as mechanisms of action are also discussed, covering articles published from 2021 onward."

Journal • Review • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

EXCLAIM-2: TAK-788 as First-Line Treatment Versus Platinum-Based Chemotherapy for Non-Small Cell Lung Cancer (NSCLC) With EGFR Exon 20 Insertion Mutations (clinicaltrials.gov) - P3 | N=354 | Active, not recruiting | Sponsor: Takeda | Trial completion date: Jul 2025 ➔ Sep 2026 | Trial primary completion date: Dec 2024 ➔ Sep 2026

Trial completion date • Trial primary completion date • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • HER-2

EXCLAIM: A Study of TAK-788 in Adults With Non-Small Cell Lung Cancer (clinicaltrials.gov) - P1/2 | N=334 | Active, not recruiting | Sponsor: Takeda | Trial completion date: Mar 2025 ➔ Oct 2026 | Trial primary completion date: Mar 2025 ➔ Oct 2026

Trial completion date • Trial primary completion date • Biliary Tract Cancer • Breast Cancer • Esophageal Cancer • Head and Neck Cancer • HER2 Breast Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • HER-2

A real-world multicenter study of furmonertinib in EGFRex20ins mutant advanced NSCLC patients and related structural insights (ESMO-TAT 2025) - "Furthermore, based on the computational model findings, rather than erlotinib (GlideScore: -5.564; MM/GBSA: -52.8044), gefitinib (-7.68; -47.317), afatinib (-5.075; -44.64), mobocertinib (-7.213; -38.38) and sunvozertinib (-8.95; -57.03), furmonertinib (-11.085; -68.1575) and osimertinib (-10.031; -63.87) revealed favorable binding activity to EGFRex20ins, with furmonertinib being the most significant. Advanced NSCLC patients with ex20ins mutation benefit from furmonertinib targeted therapy."

Clinical • EGFR exon 20 • Metastases • Real-world • Real-world evidence • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • JAK1

Mobocertinib in the Treatment of EGFR Exon 20 Insertion-Positive NSCLC: A Systematic Review (JSMO 2025) - No abstract available

EGFR exon 20 • Review • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR

Phase Ia/Ib trial on the safety and efficacy of mobocertinib and T-DM1 for patients with HER2-mutant solid tumors (JSMO 2025) - No abstract available

Clinical • P1 data • Oncology • Solid Tumor • HER-2

First-Line Mobocertinib Versus Platinum-Based Chemotherapy in Patients With EGFR Exon 20 Insertion-Positive Metastatic Non-Small Cell Lung Cancer in the Phase III EXCLAIM-2 Trial. (PubMed, J Clin Oncol) - P3 | "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."

Journal • P3 data • Constipation • Gastroenterology • Gastrointestinal Disorder • Hematological Disorders • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR

Fist-Line Mobocertinib Versus Platinum-Based Chemotherapy in Patients With EGFR Exon 20 Insertion–Positive Metastatic Non–Small Cell Lung Cancer in the Phase III EXCLAIM-2 Trial (J Clin Oncol) - P3 | N=354 | EXCLAIM-2 (NCT04129502) | Sponsor: Takeda | "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."

EGFR exon 20 • P3 data • Non Small Cell Lung Cancer

Evaluation of the safety profile of amivantamab based on real-world evidence: a call to vigilance. (PubMed, Expert Opin Drug Saf) - "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."

HEOR • Journal • Real-world evidence • Cardiovascular • Hematological Disorders • Infectious Disease • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pneumonia • Solid Tumor • Thrombosis • EGFR