Exkivity (mobocertinib) / Takeda - LARVOL DELTA

EXCLAIM-2: Phase III trial of first-line (1L) mobocertinib versus platinum-based chemotherapy in patients (pts) with epidermal growth factor receptor (EGFR) exon 20 insertion (ex20ins)+ locally advanced/metastatic NSCLC (ESMO Asia 2023) - P3 | "Methods This open-label, multicenter study (NCT04129502) randomized pts with untreated EGFR ex20ins+ locally advanced/metastatic NSCLC to (1:1) mobocertinib 160 mg PO daily or pemetrexed 500 mg/m2 plus cisplatin 75 mg/m2/carboplatin AUC 5 IV every 3 weeks for 4 cycles followed by maintenance pemetrexed. Conclusions At IA, mobocertinib efficacy was similar but not superior to 1L platinum-based chemotherapy. Safety profiles were similar to previous reports, with no new safety concerns identified."

Clinical • EGFR exon 20 • Metastases • P3 data • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR

On-Target Acquired Resistance to Zongertinib and Strategy to Overcome It - in Vitro Study usingHER2ex20 Insertion Models (IASLC-WCLC 2026) - "Methods : We examined efficacy of zongertinib, sevabertinib and other TKIs with HER2 inhibitory activity (erlotinib, afatinib, poziotinib, mobocertinib, and osimertinib) using murine pro-B-cell line (Ba/F3) models harboring one of three most common HER2 exon 20 insertions (A775_G776insYVMA (YVMA), G776delinsVC (VC) and P780_Y781insGSP (GSP)). Conclusions : These findings indicate that distinct compound mutations confer differential resistance to HER2-TKIs depending on the original HER2 exon 20 insertion. Zongertinib-resistant mutations, such as YVMA+S783A and GSP+G776C, remained sensitive to poziotinib, whereas compound mutations associated with poziotinib resistance, including YVMA+C805S and VC+C805S, were effectively inhibited by sevabertinib."

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

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

FDA Approval Summary: Mobocertinib for Metastatic Non-Small Cell Lung Cancer with EGFR Exon 20 Insertion Mutations. (PubMed, Clin Cancer Res) - P1/2 | "Product labeling includes a Boxed Warning for QTc prolongation and Torsades de Pointes. This is the first approval of an oral targeted therapy for patients with advanced EGFR exon 20 insertion mutation-positive NSCLC."

EGFR exon 20 • FDA event • Journal • Dental Disorders • Fatigue • Lung Cancer • Musculoskeletal Diseases • Musculoskeletal Pain • Non Small Cell Lung Cancer • Oncology • Pain • Solid Tumor • Stomatitis • EGFR

Emerging phase 1 data of BLU-451 in advanced NSCLC with EGFR exon 20 insertions. (ASCO 2023) - P1/2 | "Background: In patients (pts) with NSCLC harboring EGFR exon 20 insertions (ex20ins), treatment options are limited, with platinum-based chemotherapy with/without programmed death-ligand 1 inhibitors being the standard of care in first line, and recent accelerated approvals of mobocertinib and amivantamab in the USA for second-line treatment. As of the data cutoff, BLU-451 monotherapy was generally well tolerated, with early evidence of clinical activity in heavily pretreated pts with EGFR ex20ins–positive NSCLC. Early data at initial dose levels consisted of tumor reduction including responses, CNS activity, and ctDNA responses. The dose escalation is ongoing to determine the MTD and/or RP2D."

EGFR exon 20 • Metastases • P1 data • CNS Disorders • Cough • Fatigue • Gastrointestinal Disorder • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pruritus • Respiratory Diseases • Solid Tumor • EGFR • PD-L1

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

Amivantamab and Mobocertinib in Exon 20 insertions EGFR Mutant Lung Cancer, Challenge To The Current Guidelines. (PubMed, Transl Oncol) - "Our analysis has implications beyond patients with exon 20 insertion. In an era with growing identification of new and rarer molecular entities, misguided incorporation of new compounds into practice may obstruct trial enrollment in decisive clinical trials."

Journal • 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

Salidroside Alleviates Mobocertinib-Induced Cardiotoxicity by Improving Cardiac Electrophysiology. (PubMed, Cardiovasc Toxicol) - "Notably, Atp2b2 was upregulated in mobocertinib group but downregulated in salidroside combination group, whereas Agtr1b showed opposite pattern. Thus, salidroside mitigates mobocertinib-induced electrophysiological toxicity by modulating Atp2b2/Agtr1b-related signaling networks, providing a novel cardioprotective strategy against mobocertinib-associated cardiotoxicity."

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

Drug-induced paronychia: a disproportionality and time-to-onset pharmacovigilance study using FAERS and JADER. (PubMed, Cutan Ocul Toxicol) - "The ten drugs with the strongest disproportionality signals (ranked by ROR) were Dacomitinib [ROR 374.77; 95% CI 276.31-508.31], Selumetinib [304.66; 228.55-406.10], Afatinib [296.98; 264.27-333.74], Panitumumab [204.37; 183.10-228.11], Amivantamab [167.61; 124.71-225.26], Necitumumab [151.38; 67.14-341.35], Mobocertinib [117.03; 71.21-192.34], Erdafitinib [59.36; 33.57-104.99], Lapatinib [48.09; 39.71-58.24], and Gefitinib [47.28; 37.09-60.27]...Time-to-onset analysis of 30 drugs with valid TTO data revealed that median onset times ranged from 4 days (Necitumumab) to 575.5 days (Alendronate), with several of the most frequently reported EGFR and MEK inhibitors exhibiting an early-failure pattern (Weibull β < 1), supporting concentrated monitoring during the first weeks of therapy...These findings, derived from spontaneous reporting data, indicate associations rather than causal risk and require further clinical and epidemiologic evaluation. The signals identified may..."

Adverse events • Journal • Oncology • Pain

Paired ctDNA analysis reveals diverse resistance mechanisms to mobocertinib in EGFR exon 20 insertion NSCLC. (PubMed, Front Oncol) - "Mobocertinib demonstrated clinically meaningful activity, regardless of previous exposure to amivantamab, in EGFR exon 20 insertion-positive NSCLC subjects. Acquired resistance mechanisms to mobocertinib were diverse, which poses challenges to sustained efficacy, emphasizing the need for development of a tailored subsequent therapeutic strategy."

Circulating tumor DNA • Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ATM • EGFR

OB-001 boost the brain penetration of multiple TKIs (AACR 2026) - "OB-001 selectively boosts brain exposure without substantially increasing systemic exposure. These data demonstrate that theoretically a pharmacokinetic window can be achevied with OB-001 whereby enhanced brain metatsases efficacy could be acheived for numerous kinase inhibitors without effecting systemic toxicity. These findings support OB-001 as a first-in-class CNS-targeted efflux modulating adjunct capable of elevating brain drug exposure beyond what is achievable by existing kinase inhibitors alone."

Oncology • Solid Tumor • ABCB1 • ABCG2

A newly developed patient-derived culture panel identifies precision therapies and pan-effective agents for head and neck squamous cell carcinoma (AACR 2024) - "Subsequent high-content imaging cell death assay further demonstrates a dose-dependent tipifarnib-induced cell death in HRASp.G13R-mutated PDC, but not in SNU-899; 2) TP53-EP300 co-mutated HNSCC-PDCs are most sensitive to cisplatin with ~340 nM sensitivity (mean IC50) among all PDCs tested, which is 22 times more sensitive than that reported in Genomics of Drug Sensitivity in Cancer (GDSC) HNSCC cell lines; 3) EGFR-AS1 (c.2361G>A)-germline mutated PDCs, and MAPK1-mutated PDCs, are both hypersensitive to EGFR inhibitors (EGFRi: erlotinib and mobocertinib), which independently credentialed gene-drug sensitivity relationships reported in exceptional responders in HNSCC clinical trials. These include 3 FDA-approved agents, TAK-981, Selinexor (a novel XPO1 inhibitor), and trametinib, as well as the preclinical agent JQ1. In conclusion, our pilot HNSCC-PDC drug screen identifies new gene-drug sensitivity relationships for HNSCC PM development and new pan-effective agents..."

IO biomarker • Late-breaking abstract • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • CASP8 • EP300 • HRAS • MAPK1 • PIK3CA • SHH

VEGFA mediates traditional EGFR-TKI resistance in non-small cell lung cancer with EGFR exon 20 insertions (AACR 2024) - "Our study highlights the potential of VEGFA as a mechanism of resistance to EGFR-TKIs and induces immunosuppression microenvironment in NSCLC with Ex20ins. Furthermore, the findings suggested that antiangiogenetic therapy could be a promising therapeutic approach."

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

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) - "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

Strategic characterization of active pharmaceutical ingredients co-eluting impurities: Identification, enrichment and structural elucidation of an oxidized impurity from mobocertinib drug substance. (PubMed, J Pharm Biomed Anal) - "Following isolation by prep-HPLC, 1D and 2D NMR studies and HRMS characterization assigned the isolate as Mobocertinib-N-oxide. In addition, NMR-based reaction monitoring was conducted to trace its formation, allowing a plausible mechanism of formation to be proposed."

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

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

Discovery of TRX-211-399, a potent, CNS-penetrant, highly selective inhibitor of EGFR exon 20 insertion mutations (AACR 2024) - "Recently, as mobocertinib (EXKIVITY®) failed to improve progression-free survival in Phase 3 clinical trial, there remains a high unmet medical need to develop new drugs with wider therapeutic window to treat NSCLC harboring EGFR ex20ins mutations. Furthermore, in a PC-9-luc cell intracranial xenograft model, TRX-211-399 induced substantial anti-tumor effects and prolonged survival without body weight loss. TRX-211-399 is currently undergoing further preclinical evaluation as a potential candidate for clinical development for patients with EGFR exon20ins mutations."

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

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

Phase Ia/Ib trial of the safety and efficacy of mobocertinib in combination with T-DM1 for patients with HER2-mutant solid tumors (WJOG16022M). (PubMed, Eur J Cancer) - P1a/1b | "The combination of mobocertinib at 80 mg and T-DM1 at 3.6 mg/kg was found feasible and demonstrated potential efficacy for HER2-mutant solid tumors."

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

Characterizing dermatologic toxicities of novel agents for patients with EGFR exon 20 insertion mutations in NSCLC (AAD 2026) - "Introduction: Epidermal growth factor receptor (EGFR) mutations are key oncogenic drivers in non-small-cell-lung cancer (NSCLC).1 Patients with exon 20 insertion mutations have historically been resistant to standard EGFR tyrosine kinase inhibitors (TKIs), however, emerging therapies for these patients include amivantamab, mobocertinib, and investigational TKIs.2 These therapies have unique dermatologic adverse events (dAEs) in severity and distribution compared to standard EGFR TKIs and have not been thoroughly documented.3 We queried our health system’s EHR for patients receiving these three therapy classes for EGFR exon 20 insertion mutations in NSCLC from December 1, 2015 to July 31, 2025... Among 27 patients, 18 (66.7%) experienced a dAE. The median time to dAE was 11 days (range of 2-62 days). The most common toxicity was acneiform rash, with 14/27 patients (51.9%)."

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

Sunvozertinib A Next-Generation EGFR Exon 20 Insertion Inhibitor Transforming NSCLC Therapy. (PubMed, Zhongguo Ying Yong Sheng Li Xue Za Zhi) - "Recently developed agents such as amivantamab and mobocertinib have improved response rates, yet challenges related to tolerability, CNS penetration, and durability of benefit persist. Early-phase clinical trials, including the WU-KONG series, have reported promising clinical efficacy, including objective response rates ranging from 44-60% in previously treated patients and meaningful activity in treatment-naïve cohorts. The tolerability profile of the drug seems manageable, with diarrhea, rash, and stomatitis among the most commonly observed adverse events; these, however, tend to be milder compared with other agents targeting EGFR Ex20ins."

Journal • Review • Dental Disorders • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Stomatitis • EGFR

Evolving treatment strategies for EGFRex20ins-mutated NSCLC: a comprehensive review of Amivantamab's role and future directions. (PubMed, Ecancermedicalscience) - "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."

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

Efficacy and safety of later-line targeted therapies in advanced non-small cell lung cancer with EGFR exon 20 insertion mutations: a systematic review. (PubMed, Front Pharmacol) - "Recent developments in targeted therapies, including agents such as amivantamab, mobocertinib, and sunvozertinib, have shown promise in patients with pretreated ex20ins-positive NSCLC. No amendments were made to the registered protocol after commencement of the review. The full review protocol can be accessed on the PROSPERO database (Registration number: CRD420251056825)."

IO biomarker • Journal • Review • Hematological Disorders • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR

Comparing the effect of traditional and novel tyrosine kinase inhibitors for epidermal growth factor receptor exon 20 insertions by molecular dynamics simulation. (PubMed, J Int Med Res) - "When binding to osimertinib, ASV- and SVD-EGFR still revealed two energy minima on their free energy landscapes, but with considerably less conformational probability distribution at collective variable 2 >1.00 Å. In contrast, mobocertinib eliminated the energy minima at collective variable 2 >1.00 Å while decreasing the K745-E762 salt bridge formation rates.ConclusionsMobocertinib outperforms osimertinib in targeting specific subtypes of EGFR exon 20 insertions, highlighting its ability to restore the inactive state of this protein."

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