Exkivity (mobocertinib) / Takeda - LARVOL DELTA

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

Patterns of Treatment and Real-World Outcomes of Patients With Non-small Cell Lung Cancer With EGFR Exon 20 Insertion Mutations Receiving Mobocertinib: The EXTRACT Study. (PubMed, Cancer Med) - P=N/A | "These data illustrate the real-world effectiveness of mobocertinib."

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

A Drug-Drug Interaction Study of Mobocertinib and Midazolam, a Cytochrome P450 3A Substrate, in Patients With Advanced Non-Small Cell Lung Cancer. (PubMed, Clin Pharmacol Drug Dev) - "Two of 16 patients with EGFR exon 20 insertion mutations were confirmed responders per investigator. Coadministration of mobocertinib decreased the area under the plasma concentration-time curve from time zero to infinity of oral and intravenous midazolam by approximately 32% and 16%, respectively (geometric least-squares mean ratios of 0.676 and 0.837, respectively)."

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

AYVM to AYMM transition on HER2 exon 20 insertion induces TKI resistance in NSCLC. (PubMed, J Thorac Oncol) - "Drug screening indicated that mobocertinib and dacomitinib could effectively restrain the growth of tumors bearing the HER2 p.E770_A771insAYMM mutation. In summary, our findings unveil a new form of resistance-a secondary mutation superimposed on the original mutation-and offer insights into a potentially sequential strategy for overcoming resistance to pyrotinib."

Journal • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • HER-2

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: Dec 2024 ➔ Jul 2025

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

A real‑world study of clinical characteristics, treatment sequence and outcomes of patients with non-small cell lung cancer and EGFR exon 20 insertion mutations. (PubMed, Clin Transl Oncol) - "Our findings contribute to the evolving standard of care for this specific population and highlight the clinical benefits of targeted cancer therapies."

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

Mobocertinib antagonizes multidrug resistance in ABCB1- and ABCG2-overexpressing cancer cells: in vitro and in vivo studies. (PubMed, Cancer Lett) - "In the tumor-bearing mouse model, mobocertinib boosted the antitumor effect of paclitaxel and topotecan, resulting in tumor regression. In summary, our study uncovers a novel potential for repurposing mobocertinib as a dual inhibitor of ABCB1 and ABCG2, and suggests the combination of mobocertinib with substrate drugs as a strategy to counteract MDR."

Journal • Preclinical • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ABCB1 • ABCG2

Biochemical analysis of EGFR exon20 insertion variants insASV and insSVD and their inhibitor sensitivity. (PubMed, Proc Natl Acad Sci U S A) - "Biochemical, structural, and cellular studies of a diverse panel of EGFR inhibitors revealed that the more recently developed compounds BAY-568, TAS6417, and TAK-788 inhibit EGFR insASV and insSVD in a mutant-selective manner, with BAY-568 being the most potent and selective versus wild-type (WT) EGFR. Cocrystal structures with WT EGFR reveal the binding modes of each of these inhibitors and of poziotinib, a potent but not mutantselective inhibitor, and together they define interactions shared by the mutant-selective agents. Collectively, our results show that these exon20 insertion variants are not inherently inhibitor resistant, rather they differ in their drug sensitivity from WT EGFR. However, they are similar to each other, indicating that a single inhibitor should be effective for several of the diverse exon 20 insertion variants."

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

Activity and safety of Mobocertinib (TAK-788) in previously treated non-small cell lung cancer with EGFR Exon 20 insertion mutations (KSMO 2024) - No abstract available

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

EGFR Exon 20 Insertion Mutation: Research Status and New Treatment Strategies (PubMed, Zhongguo Fei Ai Za Zhi) - "Firstly Mobocertinib and Amivantamab obtained approval from U.S. Food and Drug Administration (FDA) for EGFR ex20ins mutant NSCLC patients, then other drugs, such as Sunvozertinib, made breakthroughs and combination therapies also obtained gains. As mentioned above, it's definitely important to gain deeper understanding of molecular mechanism of EGFR ex20ins and assess effect and difference between novel drugs. This review is devoted to make a summary about newest achievement so to provide valuable reference about precise therapy for patients with EGFR ex20ins.."

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

Mobocertinib in Patients with EGFR Exon 20 Insertion-Positive Non-Small Cell Lung Cancer (MOON): An International Real-World Safety and Efficacy Analysis (OGP-OGTC 2024) - "We explored the mechanisms of resistance by analyzing postprogression biopsies, as well as cross-resistance to amivantamab. Mobocertinib demonstrated meaningful efficacy in a real-world setting but was associated with considerable gastrointestinal and cutaneous toxicity."

Clinical • EGFR exon 20 • Real-world • Real-world evidence • Gastrointestinal Disorder • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR • MET • NRAS • PIK3CA

Modeling the Relationship of Clinical Safety Profile of EGFR Inhibitors with Wild-Type EGFR Inhibition in Cellular Model (IASLC-WCLC 2024) - "The EGFR inhibitors include commercially available proxy compounds of gefitinib, afatinib, osimertinib, mobocertinib, sunvozertinib, zipalertinib, BLU-945, BDTX-1535, etc. Clinical safety data are obtained from drug labels or publications, including all grades AEs and Grades ≥3 rash and diarrhea. The potency of inhibition of WT EGFR in a uniform nonclinical assay strongly correlated with overall rates and severity of rash and diarrhea observed in the clinical setting. These results may be useful in enhancing the understanding of the potential clinical safety profile of novel EGFR targeted therapies at the nonclinical development stage."

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

Efficacy of EGFR-Tyrosine Kinase Inhibitors in Patients with NSCLC Harboring EGFR Exon 19 Insertions: A Report from the LC-SCRUM-Asia (IASLC-WCLC 2024) - "We also studied preclinical Ba/F3 models expressing EGFR -K745_E746insIPVAIK (Ba/F3-IPVAIK) and EGFR -delE746_A750 (Ba/F3-Del19) to investigate the sensitivity to 1st-generation (gen) (gefitinib and erlotinib), 2nd-gen (afatinib, dacomitinib, and poziotinib), 3rd-gen (osimertinib), and EGFR exon 20 insertion active TKIs (mobocertinib, sunvozertinib, and zipalertinib). The preclinical therapeutic window of Ba/F3-IPVAIK and Ba/F3-Del19 for all the 2nd generation TKIs were similarly favorable, whereas Ba/F3-IPVAIK had much unfavorable therapeutic windows to other EGFR-TKIs compared to Ba/F3-Del19. Conclusions : Our clinical and preclinical findings indicate 2nd-gen EGFR-TKIs are more effective than 1st and 3rd-gen EGFR-TKIs in patients with EGFR exon 19 insertions."

Clinical • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • CDKN2B • EGFR • FGFR • PIK3CA • TP53

A phase 2 study of mobocertinib as first-line treatment in Japanese patients with non-small cell lung cancer harboring EGFR exon 20 insertion mutations. (PubMed, Int J Clin Oncol) - "Although study enrollment was terminated early owing to futility, our results showed modest activity of mobocertinib in Japanese patients with NSCLC with EGFR ex20ins mutations with no additional safety concerns."

EGFR exon 20 • Journal • P2 data • Dental Disorders • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Stomatitis • EGFR