Exkivity (mobocertinib)

Our findings contribute to the evolving standard of care for this specific population and highlight the clinical benefits of targeted cancer therapies.

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.

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.

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..

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.

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.

Our study revealed EGFR-dependent and -independent mechanisms of mobocertinib resistance in patients with advanced EGFR Ex20ins-mutant NSCLC.

This review explores key therapeutic agents, such as Amivantamab, Mobocertinib, Poziotinib, Zipalertinib, and Sunvozertinib, which have shown promise in treating NSCLC with EGFR exon 20 insertions. Despite these advances, challenges in overcoming resistance mutations and improving central nervous system penetration remain. Future research should focus on optimizing first-line combination therapies and enhancing diagnostic strategies for comprehensive mutation profiling.

Amivantamab (JNJ-372) and mobocertinib (TAK-788) have been reported to have favorable therapeutic effect for non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) exon 20 insertion (ex20ins) mutations. NGS is more advantageous and strongly recommended for the detection of EGFR ex20ins mutations. Considering the fast and cost-effective ARMS detection method, it is suggested that the primers design should be updated according to the characteristics of EGFR ex20ins mutations in Chinese NSCLC patients.

As patients carrying EGFR exon20ins may be eligible for treatment with novel therapeutics-the bispecific antibody amivantamab, the TKI mobocertinib, or potential future innovations-they need to be identified reliably in clinical practice for which quality-based routine genetic testing is crucial. Most of these mutation-/allele-specific (q)PCR assays are not designed to detect the whole spectrum of EGFR exon20ins mutations leading to false negative results. These data suggest that NGS is a suitable method to detect EGFR exon20ins in various types of patient samples and is superior to the detection spectrum of commercially available assays.

A total of 1,418 EGFR E20ins mutations were collected from six studies (FoundationInsights, Geneseeq Technology Inc, mobocertinib phase I/II trial, poziotinib phase II trial, sunvozertinib phase I trial, and Samsung Medical Center) and reorganised according to Human Genome Variation Society (HGVS) nomenclature. To ensure comprehensive coverage in real-world settings, it is essential to standardise the annotations for each variant, for example using the HGVS nomenclature. The accurate classification and analysis of drug responsiveness in EGFR E20ins necessitate consideration of the nomenclature, particularly with respect to the locations where the actual mutations occur.

(Trial registration number ClinicalTrials.gov NCT03811834. Registration date January 22, 2019).

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

In 2021, two drugs, amivantamab and mobocertinib each received FDA accelerated approval for second line use after platinum based therapy. The PAPILLON regimen received subsequent FDA approval. In this commentary, we review the details of PAPILLON and also discuss why the rival trial, EXCLAIM2, may have failed.

We explored the mechanisms of resistance by analyzing postprogression biopsies, as well as cross-resistance to amivantamab. Potential mechanisms of resistance to mobocertinib included amplifications in MET, PIK3CA, and NRAS. Mobocertinib demonstrated meaningful efficacy in a real-world setting but was associated with considerable gastrointestinal and cutaneous toxicity.

P1, N=53, Active, not recruiting, Takeda | Trial completion date: Mar 2024 --> Mar 2025

Furthermore, in silico docking simulations were utilized to substantiate the binding of mobocertinib within the drug-binding pockets of both ABCB1 and ABCG2. We conclude that further testing of mobocertinib in combination therapy is warranted for patients with tumors expressing elevated levels of the ABC drug transporters ABCB1 and ABCG2.

EGFR-C797S in cis to all EGFR mutations evaluated generated dependent cells that were resistant to the covalent EGFR tyrosine kinase inhibitors mobocertinib, zipalertinib, furmonertinib, sunvozertinib, poziotinib, and osimertinib. This report highlights that poziotinib and mobocertinib are susceptible to on-target resistance mediated by EGFR-T790M or -C797S in the background of the most prevalent EGFR exon 20 insertion mutations. Furmonertinib, sunvozertinib, and to a less extent zipalertinib can overcome EGFR-T790M compound mutants, whereas EGFR-C797S leads to covalent inhibitor cross-resistance-robust data that support the limitations of mobocertinib and should further spawn the development of next-generation covalent and reversible EGFR exon 20 insertion mutation active inhibitors with favorable therapeutic windows that are less vulnerable to on-target resistance.

P1, N=53, Active, not recruiting, Takeda | Phase classification: P1/2 --> P1

MAIC analysis showed that mobocertinib and amivantamab had similar efficacy in patients with NSCLC harboring EGFR ex20ins mutations whose disease progressed during or after platinum-based chemotherapy. These findings may benefit patients by supporting future treatment options.

A new modality of treatment for NSCLC patients with EGFRx20ins has been established with the approval of mobocertinib and amivantamab. There are also numerous novel targeted treatments for NSCLC with EGFRex20ins in development, which are anticipated to improve this patient population's survival even further. This review provides a reference for the clinical management of these patients by summarizing the most recent epidemiological, and clinicopathological characteristics, diagnostic techniques, and therapeutic advances of EGFRex20ins in NSCLC.

Sponsored by Takeda

As of August 23, 2023, the first generation EGFR-TKIs, gefitinib, icotinib, and erlotinib; the second generation EGFR-TKIs, afatinib and dacomitinib; and the third generation EGFR-TKIs, osimertinib, almonertinib, furmonertinib and befotertinib were all approved for marketing by China National Medical Products Administration (NMPA). In addition, multiple domestic third-generation EGFR-TKIs are undergoing clinical trials, such as rezivertinib (BPI-7711), limertinib (ASK120067), and oritinib (SH-1028). Meanwhile, mobocertinib and sunvozertinib, which targets EGFR 20ins mutations, were also approved by NMPA. With the increasing variety of EGFR-TKIs approved for marketing subsequently, it brings confusion to clinicians when choosing specific medications, and there is an urgent need to develop relevant treatment guidelines. Hence, the Medical Oncology Branch of China International Exchange and Promotive Association for Medical and Health Care and the Chinese Association for Clinical Oncologists convened experts to integrate the research results of various EGFR-TKIs, and proposed the "China clinical practice guideline for epidermal growth factor receptor tyrosine kinase inhibitors in stage Ⅳ non-small cell lung cancer (version 2023)", to provide reference for better clinical practice.

15 of 23 any-grade treatment-related adverse events reported for mobocertinib were significantly less common for amivantamab versus only two for mobocertinib. Results suggest that amivantamab has an improved response rate with similar survival and a more favorable safety profile versus mobocertinib in EGFR exon20ins non-small-cell lung cancer.

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.

P1/2, N=334, Active, not recruiting, Takeda | Recruiting --> Active, not recruiting

P=N/A, N=0, Withdrawn, Takeda | N=120 --> 0 | Not yet recruiting --> Withdrawn

In this review, we describe the structural, molecular characteristics, and detection strategies of EGFR ex20ins mutations and summarize the latest clinical data on approved treatments and emerging therapies for patients with NSCLC harboring EGFR ex20ins mutations. Further, we will discuss the response heterogeneity of ex20ins mutations to new drugs and acquired drug resistance mechanisms.

In total, 51 patients (48.6%) reported diarrhea (all grades) related to mobocertinib (treatment discontinuation due to diarrhea: 4 patients [7.8%]). Conclusions Patients had favorable RW outcomes suggesting clinical effectiveness of mobocertinib.

In the retrospective analysis, mPCR identified EGFR ex20ins in an estimated 79.0% (502/636) of pts. Conclusions The AmoyDx mPCR assay performed better than traditional PCR and effectively identified pts with EGFR ex20ins+ NSCLC who may benefit from mobocertinib therapy, providing a fast and effective diagnostic option to guide treatment.

P1/2, N=53, Active, not recruiting, Takeda | N=33 --> 53

The Flatiron Health electronic health record database was used to select three cohorts among patients diagnosed with NSCLC with EGFRex20ins (January 1, 2011-February 29, 2020): (1) first-line (1L) or patients receiving 1L therapy after documented EGFRex20ins; (2) second or later-line (≥2L) or patients receiving ≥2L therapy after documented EGFRex20ins; and (3) ≥2L postplatinum trial-aligned, or ≥2L patients previously treated with platinum chemotherapy whose baseline characteristics aligned with key eligibility criteria (initiating new treatment after documented EGFRex20ins and ≥1 previous treatment excluding mobocertinib or amivantamab) of the mobocertinib trial NCT02716116. The outcomes for patients with NSCLC with EGFRex20ins were poor. This real-world study provides a benchmark on treatment outcomes in this patient population and highlights the unmet need for improved therapeutic options.

HER2 mutations drive the growth of a subset of breast cancers and are targeted with HER2 tyrosine kinase inhibitors (TKI) such as neratinib...Cells expressing double HER2 mutations exhibited resistance to most HER2 TKIs but retained sensitivity to mobocertinib and poziotinib...Double-mutant cells showed enhanced MEK/ERK signaling, which was blocked by combined inhibition of HER2 and MEK. Together, these findings reveal the driver function of secondary HER2 mutations in resistance to HER2 inhibition and provide a potential treatment strategy to overcome acquired resistance to HER2 TKIs in HER2-mutant breast cancer.

No abstract available

This clinical need remained unmet until recently, when the EGFR Ex20ins mutation inhibitor mobocertinib was approved by the FDA...Herein, we analyze the structural mechanisms for ligand binding and resistance and summarize recent developments for the reported inhibitors of EGFR Ex20ins mutations. Furthermore, this Perspective aims to provide insights for the design of the next generation of EGFR Ex20ins inhibitors.

T790M or C797S, depending on the original X20ins mutations, conferred acquired resistance to mobocertinib. Sunvozertinib may be the treatment of choice for patients with tumors resistant to mobocertinib because of T790M.

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...The clinical development of kinase inhibitors for ERBB2-mutated NSCLC has been thwarted by mucocutaneous/gastrointestinal toxicities that preclude a pathway for drug approval, as the case of poziotinib...Other therapies in clinical development include sunvozertinib and zipalertinib, among others. In addition, traditional cytotoxic chemotherapy has some activity in these tumors. The approvals of mobocertinib, amivantamab, and trastuzumab deruxtecan represent the first examples of precision oncology for EGFR exon 20 insertion-mutated and ERBB2-mutated NSCLCs.

Results In vitro testing with different EGFRex20ins indicated a favorable IC50 for afatinib, CLN-081, and poziotinib in near-loop (A767-P772) versus far-loop (H773-R776) insertions, whereas mobocertinib had similar IC50 values in near- and far-loop insertions. Conclusions Preclinical and clinical data indicated that near- vs far-loop EGFRex20 insertions differentially impact sensitivity to individual TKIs. Thus, knowledge of insertion location may allow for more effectively tailored TKI therapy.

Recently, novel therapies (amivantamab and mobocertinib) have demonstrated modest clinical activity and received regulatory approval. The incidence of EGFR exon 20 insertion mutations is 4.6% in Asian non-squamous NSCLC. In a large real-world dataset, responses to standard therapies (chemotherapy, EGFR TKI, immunotherapy) were limited. Genomic characterization showed comparable features to EGFR ex19del/L858R mutated NSCLC.

Introduction: Mobocertinib is an oral tyrosine kinase inhibitor that received accelerated approval as a single agent to treat adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 20 insertion (ex20ins) mutations who received prior platinum-based chemotherapy... Patients who were negative for EGFR ex20ins ctDNA at baseline had a better outcome than patients who had detectable EGFR ex20ins ctDNA at baseline. Similarly, patients with ctDNA-negative status for EGFR ex20ins at C3D1 achieved a better outcome than patients with positive or increased EGFR ex20ins VAF at C3D1. These results warrant further testing of ctDNA as a prognostic biomarker in patients with EGFR ex20ins+ NSCLC.

The combination of mobocertinib with amivantamab displayed synergetic efficacy in 2 independent EGFR ex20ins+ NSCLC PDX models; unique resistant molecular profiles to single-agent or combination treatments were identified. These results warrant further testing of this combination to potentially improve patient outcomes.

Introduction: Treatments for advanced/metastatic non-small cell lung cancer (NSCLC) with EGFR exon 20 insertions (EGFRex20ins) are evolving and include two newly approved targeted therapies (amivantamab and mobocertinib). Patients with NSCLC with EGFRex20ins emphasized overall survival and response to treatment as important treatment benefits. Participants were less concerned about the risk of mild/moderate AEs or AEs that could be managed with medication.