Exkivity (mobocertinib)

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.

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.

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: 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.

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.

The 52.7% (49) were treated with chemotherapy (CT), 21.5% (20) with 1st-generation tyrosine-kinase inhibitors (TKIs), 11.8% (11) with CT+Bevacizumab, 4.3% (04) with CT+Pembrolizumab, 3.2% (3) with osimertinib, 3.2% (3) with afatinib and 3.2% (3) with other regimens in 1st-line. Osimertinib, CT+Bevacizumab, and 1st-generation TKIs improved mPFS and mOS discreetly compared to chemotherapy in NSCLC Hispanic patients with EGFR exon20ins. Anti-EGFR exon20ins agents might be a better option to improve OS in this population representing a priority need for a subpopulation of NSCLC patients in Latin America.

However, a novel EGFR-TKI, mobocertinib, was approved by the US FDA for NSCLC patients with EGFR exon20 insertion. We examined efficacy of mobocertinib and other EGFR-TKIs (erlotinib, afatinib, poziotinib, CLN-081, sunvozertinib , osimertinib, and brigatinib) using murine pro-B-cell line (Ba/F3) models harboring one of five most common EGFR exon 20 insertions (A763_Y764insFQEA, V769_D770insASV, D770_N771insSVD, H773_V774insNPH and H773_V774insH). These findings indicate that T790M or C797S, depending on the original activating mutations, will cause acquired resistance to mobocertinib in NSCLCs with EGFR exon 20 mutations. Further analyses suggest that sunvozertinib will be effective against acquired resistant cells with T790M mutation. However, except for A763_Y764insFQEA plus C797S mutation that is sensitive to erlotinib, other treatment strategy, such as cytotoxic chemotherapy, should be considered for patients who develop C797S secondary mutation.

It is a structural analog of the third-generation TKI osimertinib, which targets EGFR T790M mutant non-small cell lung cancer (NSCLC); however, mobocertinib gains selectivity for EGFRex20ins mutants over wild type (WT) by interacting with the C790 gatekeeper residue of EGFR. In September 2021, the FDA granted accelerated approval for mobocertinib in the treatment of patients with locally advanced or metastatic NSCLC with EGFRex20ins mutation whose disease progressed while on platinum-based chemotherapy. The present review describes data that led to the approval of mobocertinib.

This is the largest preclinical/clinical report to highlight that EGFR-K745_E746insIPVAIK and other mutations with exon 19 XPVAIK amino-acid insertions are rare but sensitive to clinically available 1st, 2nd, and 3rd generation as well as EGFR exon 20 active TKIs; in a pattern that mostly resembles the outcomes of models with EGFR-L861Q and EGFR-A763_Y764insFQEA mutations. These data may help with the off-label selection of EGFR TKIs and clinical expectations of outcomes when targeted therapy is deployed for these EGFR mutated lung cancers.

US Food and Drug Administration has approved mobocertinib and amivantamab for targeting tumors with this aberration, but the number of comprehensive studies on ex20 ins/dup NSCLC is limited. NSCLCs harboring EGFR/ERBB2 ex20 ins/dup are rare and tend to be acinar predominant, negative for PD-L1, more frequent in non- or light smokers, and mutually exclusive with other driver mutations in NSCLC. The correlation of different EGFR/ERBB2 ex20 ins/dup variants and co-existing mutations with response to targeted therapy and the possibility of developing resistant mutations after mobocertinib treatment warrants further investigation.

"Foundation Medicine, Inc., today announced that the company and its collaborators will present 21 abstracts demonstrating the value of high-quality tumor profiling tests to inform cancer care at the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting from June 2-6 in Chicago."

No abstract available

P=N/A, N=120, Not yet recruiting, Takeda

For this, we combined the reversible methylindole-aminopyrimidine scaffold known from osimertinib with the affinity driving isopropyl ester of mobocertinib. By occupying the hydrophobic back pocket, we were able to generate reversible inhibitors with subnanomolar activity against EGFR-L858R/C797S and EGFR-L858R/T790M/C797S with cellular activity on EGFR-L858R/C797S dependent Ba/F3 cells. Additionally, we were able to resolve cocrystal structures of these reversible aminopyrimidines, which will guide further inhibitor design toward C797S-mutated EGFR.

This event is organized and accredited by Research to Practice and supported through educational grants provided by AstraZeneca Pharmaceuticals LP, Daiichi Sankyo Inc, Janssen Biotech Inc, administered by Janssen Scientific Affairs LLC, Lilly, Novocure Inc, Regeneron Pharmaceuticals Inc, and Takeda Pharmaceuticals USA Inc. Key efficacy and safety findings, including emerging overall survival data, from the Phase III ADAURA trial evaluating adjuvant osimertinib for patients with Stage IB to IIIA NSCLC with EGFR mutations; appropriate incorporation into clinical care Ongoing Phase III evaluation of osimertinib for nonmetastatic NSCLC, such as in the NeoADAURA and LAURA trials; nonresearch role, if any Optimal selection of first-line treatment for patients with metastatic NSCLC and EGFR tumor mutations, including those with CNS metastases Incidence, clinical relevance and spectrum of resistance mechanisms in patients receiving osimertinib Published findings (eg, from the SAVANNAH trial) with and ongoing studies (eg, the SAFFRON and ORCHARD trials) of osimertinib combined with other agents for patients experiencing disease progression on first-line osimertinib Mechanism of action of the novel HER3-directed antibody-drug conjugate patritumab deruxtecan; available data, ongoing evaluation and potential clinical role in metastatic EGFR tyrosine kinase inhibitor-resistant NSCLC Antitumor activity and tolerability of amivantamab/lazertinib in the CHRYSALIS-2 study for patients with progressive NSCLC with EGFR mutations Key efficacy and safety findings informing the FDA approvals of amivantamab and mobocertinib for patients with metastatic NSCLC and EGFR exon 20 mutations; appropriate selection and sequencing of these agents

Mobocertinib demonstrated clinically meaningful benefit in EGFR ex20ins+ mNSCLC in patients who had received prior platinum and anti-PD-(L)1 therapy. Among PPP, clinical benefit was observed in responders and in patients with SD.

"Foundation Medicine, Inc...today announced that it has received approval from the U.S. Food and Drug Administration (FDA) for FoundationOne®Liquid CDx to be used as a companion diagnostic for EXKIVITY® (mobocertinib), which is currently FDA-approved for adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 20 insertion mutations as detected by an FDA-approved test, whose disease has progressed on or after platinum-based chemotherapy."

Mobocertinib showed substantially improved outcomes versus an external control group using available therapies in platinum-pretreated patients with EGFR ex20ins-mutant NSCLC. In the absence of comparative evidence from randomized trials, these findings help elucidate potential benefits of mobocertinib in this rare population.