Ex20ins Mutations Research Articles

Amivantamab: A narrative drug review

ABSTRACT Epidermal growth factor receptor (EGFR) activating mutations are known oncogenic drivers in non-small-cell lung cancer (NSCLC), with 85% attributable to an exon 19 deletion or exon 21 L858R point substitution. The next most common is an exon 20 insertion mutation (Ex20Ins), which results in an altered active site that sterically interferes with tyrosine kinase inhibitor (TKI) binding, resulting in a poorer response rate to EGFR TKIs. Amivantamab (JNJ-61186372), a fully humanized EGFR- mesenchymal-epithelial transition receptor (MET) bispecific antibody has been approved for use in adults with locally advanced or metastatic NSCLC with EGFR Ex20Ins mutations, whose disease has progressed on or after platinum-based chemotherapy. To prepare this review, we searched various websites, including the European Medicines Agency Drug Manual, United States Food and Drug Administration, PubMed, Science Direct, and UpToDate using the search terms, “Amivantamab,” “NJ-61186372,” “amivantamab-vmjw,” and” “EGFRexon20ins.” We shortlisted 121 articles published between 2015 and 2023, of which 49 were included. This review discusses the clinical indications, adverse effects, safety, pharmacodynamics, pharmacokinetics, and the key research trials that investigated the use of amivantamab.

Mobocertinib in non-small cell lung cancer

Tyrosine kinase inhibitors (TKIs) have provided great benefit for patients with EGFR-mutant non-small cell lung cancer (NSCLC). While prior TKIs have demonstrated limited efficacy against exon 20 insertion mutations of EGFR (EGFR Ex20Ins), mobocertinib (TAK-788) is designed to specifically inhibit these Ex20Ins mutations. In a phase I/II clinical trial, mobocertinib demonstrated meaningful benefits among a cohort of platinum-pretreated patients with EGFR Ex20Ins mutant NSCLC. For this cohort, the objective response rate was 28% (95% confidence interval [CI], 20%-37%). The median progression-free survival and duration of response were 7.3 months (95% CI, 5.5-9.2) and 17.5 months (95% CI, 7.4-20.3), respectively, both by independent review committee assessment. On the basis of these results, mobocertinib was granted accelerated approval as the first TKI for treatment of this indication by the U.S. Food and Drug Administration (FDA) in 2021. This review summarizes the preclinical development of mobocertinib and the early-phase clinical data leading to its approval and discusses potential directions for mobocertinib's development.

EP08.02-049 A Phase I Trial of the HER2 Exon 20 Inhibitor, BI 1810631, In Patients With Advanced Solid Tumors With HER2 Aberrations

HER2 mutations are present in 2-4% of NSCLC tumors; of these ∼50% are exon 20 insertion (ex20ins) mutations. There is an unmet need for effective targeted therapy against HER2 mutations in solid tumors, particularly in NSCLC. Historically, ex20ins mutations have responded poorly to TKIs. Moreover, TKIs that inhibit both mutant EGFR and HER2 are typically limited by toxicities associated with inhibition of wild-type EGFR. Despite the promise of trastuzumab deruxtecan and other agents in this setting, the development of orally available selective TKIs is important given the heterogeneity of HER2 aberrations, potential for combination regimens, and the risk of interstitial lung disease with ADCs.

Discovery of mobocertinib, a new irreversible tyrosine kinase inhibitor indicated for the treatment of non-small-cell lung cancer harboring EGFR exon 20 insertion mutations.

Epidermal growth factor receptor (EGFR) is essential for normal cellular functions. Mutations of EGFR’s kinase domain can cause dysregulation leading to non-small cell lung cancer (NSCLC). Exon 20 insertion (ex20ins) mutations in EGFR are one of the leading contributors to oncogenesis and confer insensitivity to most available therapeutics. Mobocertinib is a novel tyrosine kinase inhibitor (TKI) recently approved by the US FDA as a first-in-class small molecule therapeutic for EGFR ex20ins-positive NSCLC. When compared to osimertinib, a TKI indicated for the treatment of EGFR T790M-positive NSCLC, mobocertinib differs only by the presence of an additional C5-carboxylate isopropyl ester group on the middle pyrimidine core. Together with the acrylamide side chain that is responsible for irreversible inhibition, this additional C5-substituent affords mobocertinib high anticancer potency and specificity to EGFR ex20ins-positive lung cancer that is resistant to other EGFR TKIs. This review article provides an overview of the discovery of mobocertinib from osimertinib including their structure-activity relationships, mechanisms of action, preclinical pharmacology, pharmacokinetics, and clinical applications. The discovery and use of mobocertinib and other EGFR TKIs demonstrate the power of structure-based drug design and promising therapeutic outcomes of using precision medicine approaches in the management of molecularly defined tumors. Graphical abstract

EP08.02-018 Phase 1/2 Study of BLU-451, a Small Molecule Inhibitor of EGFR, in EGFR Exon 20 Insertion-Mutant Incurable Advanced Cancers

Oncogenic EGFR exon 20 insertion (ex20ins) mutations, found in ∼2% of non-small cell lung cancers (NSCLC) and a small percentage of other cancers, are generally not responsive to EGFR-targeted agents that have been approved for treatment of NSCLC with a common EGFR mutation, including L858R and exon 19 deletion. Similar to these more common types of EGFR-mutated NSCLC, central nervous system (CNS) metastases are a challenge with EGFR ex20ins mutant NSCLC and are associated with poor outcomes. While two EGFR ex20ins-targeting drugs were recently approved by the US Food and Drug Administration (amivantamab and mobocertinib), neither have established CNS activity.

MO29-3 A database of 1023 patients with NSCLC and uncommon EGFR mutations treated with afatinib: focus on Asian patients

We developed a database of 1023 pts with NSCLC and uncommon EGFR mutations treated with afatinib (afa) in clinical trials and real-world practice. Here, we focus on outcomes in Asian pts, pts with ex20ins mutations and pts with osimertinib (osi) resistance mutations.

EE153 Budget Impact Analysis of Introducing Mobocertinib for Locally Advanced or Metastatic Epidermal Growth Factor Receptor Exon 20 Insertion-Positive Non-Small-Cell Lung Cancer in the United States from the Payer Perspective

Amivantamab and mobocertinib received accelerated approval by the US FDA in May and September 2021, respectively, for the treatment of locally advanced or metastatic non-small-cell lung cancer (mNSCLC) harboring epidermal growth factor receptor (EGFR) exon 20 insertion (ex20ins) mutations previously treated with platinum-based chemotherapy (PBC). Before May 2021, there were no approved targeted treatments for this underserved population. This study quantifies the budget impact (BI) of introducing mobocertinib in a US payer health plan.

Abstract CT212: A phase I, open-label, dose escalation, confirmation, and expansion trial of BI 1810631 as monotherapy in patients with advanced or metastatic solid tumors with HER2 aberrations

Abstract Background: HER2 mutations are present in 2-4% of NSCLC tumors; of these ~50% are exon 20 insertion (ex20ins) mutations. There is an unmet need for effective targeted therapy against HER2 mutations in solid tumors, particularly in NSCLC. Historically, ex20ins mutations have responded poorly to TKIs. Moreover, EGFR-targeted agents that inhibit mutant HER2 are associated with off-target wild type-related toxicities. Despite the promise of trastuzumab deruxtecan and other agents in this setting, the development of orally available selective TKIs is important given the heterogeneity of HER2 aberrations, potential for combinations regimens, and the risk of ILD with ADCs. BI 1810631 is a HER2 selective TKI that covalently binds to both wild-type and mutated HER2 receptors, including ex20ins, whilst sparing EGFR signaling; preclinical data suggest good tolerability and efficacy. This Phase Ia/Ib, open-label, non-randomized study aims to determine the safety, MTD, PK, pharmacodynamics, and preliminary efficacy of BI 1810631 in pts with HER2+ solid tumors (NCT04886804). Methods: It is planned that ~96 pts from 3 sites in the US, Netherlands, and Japan will be recruited. In Phase Ia, consecutive cohorts of pts will receive BI 1810631 QD or BID at escalating doses. Starting dose level: 15 mg BID (~36 pts); QD schedule will begin after one dose level above estimated therapeutic dose of BI 1810631 is determined safe by the Dose Escalation Committee (expected starting dose: 60 mg [~30 pts]). BI 1810631 dose escalation will continue (guided by Bayesian Logistic Regression Model) until MTD and/or RP2D for each schedule is determined, as well as a preferred Phase Ib schedule. In Phase Ib an initial 30 pts with HER2 ex20ins mutation-positive, pre-treated NSCLC will be enrolled, with possible inclusion of additional cohorts in the future. Overall pt inclusion criteria (Phase Ia): ≥18 years of age; histologically/cytologically confirmed HER2+ (defined as overexpression, gene amplification, non-synonymous somatic mutation, or gene rearrangement involving HER2 or NRG1) advanced, unresectable and/or metastatic solid tumors refractory/not suitable for standard therapy; exhausted treatment options; measurable or evaluable lesions (according to RECIST v1.1); ECOG PS ≤1. Phase Ib criteria: HER2 ex20ins mutation-positive NSCLC; received ≥1 line of platinum-based combination chemotherapy in the advanced/metastatic setting. Primary endpoints: MTD based on the number of DLTs/number of pts with DLTs (Phase Ia); objective response (Phase Ib). Secondary endpoints: number of pts with DLTs throughout entire treatment period and PK parameters (Phase Ia/Ib); duration of response, PFS, disease control, and duration of disease control (Phase Ib). The trial is actively recruiting; 5 pts have been enrolled to date and 2 dose levels have been completed. Citation Format: John Heymach, Frans Opdam, Minal Barve, Neil Gibson, Behbood Sadrolhefazi, Josep Serra, Noboru Yamamoto. A phase I, open-label, dose escalation, confirmation, and expansion trial of BI 1810631 as monotherapy in patients with advanced or metastatic solid tumors with HER2 aberrations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT212.

Abstract 5838: The landscape of EGFR exon 20 insertion mutations in Chinese patients with non-small cell lung cancer

Abstract Background: The epidermal growth factor receptor (EGFR) is one of the most commonly altered genes in non-small cell lung cancer(NSCLC). Of these, insertion mutation in 20 exon (Ex20ins) of the EGFR occurs less frequently. In comparison with the common EGFR mutations (19Del/L858R), the NSCLC patients with Ex20ins have a worse prognosis. Recently, the FDA approved targeted oral therapeutic agent for NSCLC patients with EX20ins mutation, which has markedly improved their survival. Here we carry out a complete analysis of the frequency and types of EGFR 20 Exon insertion mutations in the large-scale NSCLC cohort of the Chinese population. Methods: From January 2020 to October 2021, a total of 4,091 patients were confirmed as NSCLC were included in the study. The Next-generation sequencing was utilized for detecting genetic mutations. Results: Among the 4,091 NSCLC patients, 2,411 (58.9%) experienced EGFR mutations. In which we identified 90 patients(2.2%) with Ex20ins. All of the Ex20ins were localized between amino acids S767-V774, and after C-helix of the EGFR kinase domain. Different from the exon 19 deletion, we found that Ex20ins exhibits various types of mutations. A total of 34 Ex20ins types were detected, with the most common A767_V769dupASV and S768_D770dupSVD mutations, accounting for 26% and 22.2% respectively. In addition, H773dupH (6.67%), H773_V774dupHV(5.56%), H773_V774insAH (2.22%), D770_N771insG (2.22%), and N771_P772insG(2.22%) were also observed in the NSCLC patients. Conclusions: We described the landscape of EGFR Ex20ins in Chinese NSCLC patients cohort. Based on the large sample size, the frequency of the Ex20ins mutation in Chinese NSCLC patients was 2.2%, and the types of EGFR Ex20ins mutation were highly heterogeneous. Citation Format: shun xu, Zhichao Fu. The landscape of EGFR exon 20 insertion mutations in Chinese patients with non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5838.

Abstract 3332: LNG-451 is a potent, CNS-penetrant, wild-type EGFR sparing inhibitor of EGFR exon 20 insertion mutations

Abstract Exon 20 insertion mutations (Ex20ins) are the third most common type of EGFR oncogenic mutation in lung cancer patients. While several small molecules have been approved (mobocertinib) or are in clinical development (e.g. CLN-081, BDTX-189) none have demonstrated meaningful CNS activity and they can be associated with treatment-limiting adverse events, including wild-type (WT) EGFR-mediated toxicities. LNG-451 is a CNS-penetrant, wild-type EGFR-sparing, covalent inhibitor of EGFR Ex20ins. In cell viability assays dependent on five EGFR Ex20ins mutations, LNG-451 was a potent inhibitor (IC50 7 - 78 nM) including the three most prevalent insertions (V769_D770insASV IC50 = 78 nM, D770_N771insSVD IC50 = 53 nM, H773_V774insNPH IC50 = 75 nM). LNG-451 had low potency in WT EGFR dependent cell assays (WT EGFR Ba/F3 IC50=1,960 nM, cell panel IC50 = 1630 nM). LNG-451 was 21-fold selective for its least potent Ex20ins (V769_D770insASV) relative to WT EGFR. LNG-451 potently inhibited cells dependent on EGFR L861Q (IC50 = 6 nM), EGFR G719S (IC50 = 8 nM), and EGFR G719S/T263P (IC50 = 11 nM). LNG-451 is a highly selective kinase inhibitor (1 μM LNG-451, >90% inhibition for 7 of 409 WT kinases) with screening hits having a similarly positioned cysteine as EGFR. In a Ba/F3 cell-derived xenograft model harboring an EGFR V769_D770insASV exon 20 insertion mutation (EGFR V769_D770insASV CDX), 10 and 50 mg/kg LNG-451 QD PO dosing for 15 days was well-tolerated and resulted in tumor growth inhibition (TGI) of 75.7% and 105.4%, respectively. LNG-451 was efficacious and well-tolerated in the EGFR Ex20ins HuPrime® LU0387 H773-V774insNPH patient-derived xenograft tumor model: 10 mg/kg LNG-451 QD, 67% TGI; 50 mg/kg LNG-451 QD, 91% tumor regression. LNG-451 was highly active in the intracranial PC9-luc xenograft mouse model. In a single dose PK/PD study using the EGFR V769_D770insASV CDX, similar LNG-451 concentrations were observed in tumor, large intestine, and skin tissues (e.g. 50 mg/kg LNG-451 3h post dose: tumor, 8387 ng/mL; large intestine tissue, 14483 ng/mL; skin, 4623 ng/mL). LNG-451 potently suppressed EGFR phosphorylation in tumor tissue (e.g. 99%, 3 h post 50 mg/kg dose) but had minimal-to modest suppression of phospho-EGFR in large intestine tissue (e.g. 4.2%, 3h post 50 mg/kg dose) and skin tissue (e.g 1.9%, 3h post 50 mg/kg dose). Taken together, LNG-451 is a wild-type EGFR-sparing, CNS-penetrant EGFR Ex20ins inhibitor that is expected to provide strong anti-tumor efficacy for patients with advanced/metastatic solid cancers harboring oncogenic EGFR exon 20 insertions with reduced WT EGFR-driven toxicities. Citation Format: Brion W. Murray, Anjali Pandey, Bruce Roth, Tracy Saxton, Daniel J. Estes, Himanshu Agrawal, Santosh Vishwakarma, Gurulingappa Hallur, Ishtiyaque Ahmad, Ravi Trivedi, Helen Jenkins, Paul G. Pearson. LNG-451 is a potent, CNS-penetrant, wild-type EGFR sparing inhibitor of EGFR exon 20 insertion mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3332.

Short-term efficacy of furmonertinib in treatment of NSCLC patients with EGFR exon20 insertion.

e21063 Background: EGFR is a key driver gene of lung cancer, in which exon 20 insertion (Ex20ins) mutation accounts for about 1-5%. However, the first- and second-generation EGFR-TKI had poor efficacy on patients with Ex20ins mutation (ORR = 6.9%, mPFS = 1.9 months, mOS = 12.9 months, DCR = 44.8%). Our study retrospectively observed the short-term efficacy and safety of furmonertinib in Chinese NSCLC patients with EGFR Ex20ins mutation. Methods: The study retrospectively collected 15 NSCLC patients with EGFR Ex20ins mutant who were treated in two medical institutions in Changzhou City, Jiangsu Province from April 2021 to December 2021. All patients received targeted therapy with furmonertinib. The last follow-up time was December 30, 2021. All patients received 160 mg furmonertinib orally until disease progression, drug intolerance, patient refusal or death. EGFR Ex20ins mutation was confirmed by ARMS or next generation sequencing (NGS). The patient's gender, age, score of Eastern Cooperative Oncology Group (ECOG), smoking history, pathological type, tumor stage, gene status and other basic clinical characteristics and adverse events (AES) were collected. The clinical efficacy was evaluated according to RECIST version 1.1, and the adverse events were evaluated according to the NCI-CTCAE version 5.0. SPSS 25.0 software was used to record and analyze the data. Results: All 15 patients had received ≥2 lines of therapy. The median age was 62 (25-80) years old, and there were 8 male patients (53.3%). Most patients had no smoking history (13 cases, 86.7%). ECOG score was mostly 1 (13 cases, 86.7%). In 15 patients, we found 10 different EGFR Ex20ins variants, among which p.A767_V769dup (n = 3) and p.A767_V769dup (n = 4) were more common. By the end of follow-up, 15 patients had completed at least one efficacy evaluation, and all had different degrees of tumor regression. No patient reached CR, 8 patients had PR and 7 patients had SD. This preliminary efficacy data showed that the overall ORR was 53.5% and DCR was 100%. No grade 3 or above adverse events were observed. The 3-months PFS rate was 100%. Conclusions: The results of this study in ≥2 lines patients treated with twice the conventional dose had a good curative effect (compared with 3 times of conventional dosage in FAVOUR study), which provided more treatment options for NSCLC patients in multiple lines of treatment and could alleviate part of their economic pressure, but the PFS and OS data still need further follow-up and verification of a larger sample size. The overall findings suggested that furmonertinib is a third generation EGFR-TKI with good efficacy and acceptable safety. Given the heterogeneity of EGFR Ex20ins mutation, the efficacy of targeted therapy may vary in different mutation types and requires further investigation.

A phase I, open-label, dose escalation, confirmation, and expansion trial of BI 1810631 as monotherapy in patients with advanced/metastatic solid tumors with HER2 aberrations.

TPS9143 Background: HER2 mutations are present in 2–4% of NSCLC tumors; of these ̃50% are exon 20 insertion (ex20ins) mutations. There is an unmet need for effective targeted therapy against HER2 mutations in solid tumors, particularly in NSCLC. Historically, ex20ins mutations have responded poorly to TKIs. Moreover, TKIs that inhibit both mutant EGFR and HER2 are typically limited by toxicities associated with inhibition of wild-type EGFR. Despite the promise of trastuzumab deruxtecan and other agents in this setting, the development of orally available selective TKIs is important given the heterogeneity of HER2 aberrations, potential for combination regimens, and the risk of ILD with ADCs. BI 1810631 is a HER2 selective TKI that covalently binds to both wild-type and mutated HER2 receptors, including ex20ins, whilst sparing EGFR signaling; preclinical data suggest good tolerability and efficacy. This Phase Ia/Ib, open-label, non-randomized study aims to determine the safety, MTD, PK, pharmacodynamics, and preliminary efficacy of BI 1810631 in pts with HER2+ solid tumors (NCT04886804). Methods: ̃96 pts from 5–7 sites in the US, Netherlands, Japan, and China will be recruited. Phase Ia: consecutive cohorts of pts will receive BI 1810631 QD or BID at escalating doses. Starting dose level: 15 mg BID (̃36 pts); QD schedule will begin after one dose level above estimated therapeutic dose of BI 1810631 is determined safe by the Dose Escalation Committee (expected starting dose: 60 mg [̃30 pts]). BI 1810631 dose escalation will continue until MTD/RP2D for each schedule is determined, as well as a preferred Phase Ib schedule. Phase Ib: an initial 30 pts with HER2 ex20ins mutation-positive, pre-treated NSCLC will be enrolled, with possible inclusion of additional cohorts in the future. Overall pt inclusion criteria (Phase Ia): ≥18 years of age; histologically/cytologically confirmed HER2+ (defined as overexpression, gene amplification, non-synonymous somatic mutation, or gene rearrangement involving HER2 or NRG1) advanced/unresectable/metastatic solid tumor refractory/not suitable for standard therapy; exhausted treatment options; measurable/evaluable lesions (per RECIST v1.1); ECOG PS ≤1. Phase Ib criteria: HER2 ex20ins mutation-positive NSCLC; received ≥1 line of platinum-based combination chemotherapy in the advanced/metastatic setting. Primary endpoints: MTD based on number of DLTs/number of pts with DLTs (Phase Ia); objective response (Phase Ib). Secondary endpoints: number of pts with DLTs throughout entire treatment period and PK parameters (Phase Ia/Ib); duration of response, disease control, duration of disease control, and PFS (Phase Ib). The trial is actively recruiting with 6 pts enrolled to date. More patients may be recruited depending on whether 2 dose levels have been completed and the MTD/RP2D determined. Clinical trial information: NCT04886804.

Molecular analysis of circulating tumor DNA (ctDNA) in patients (pts) with EGFR exon 20 insertion-positive (ex20ins+) advanced NSCLC treated with mobocertinib.

9108 Background: ctDNA is an important tool to diagnose and monitor mutations in pts with non–small cell lung cancer (NSCLC). We evaluated epidermal growth factor receptor gene ( EGFR) ex20ins mutations in tumor vs plasma samples, assessed changes in EGFR ex20ins variant allele frequency (VAF) with mobocertinib treatment and correlation with response, and identified potential emerging variants of acquired resistance. Methods: Tumor tissue samples were collected at baseline (BL) from pts with EGFR ex20ins+ advanced NSCLC receiving mobocertinib 160 mg QD in a phase 1/2 study (NCT02716116); plasma samples were collected at BL, after 2 treatment cycles (Cycle 3, Day 1 [C3D1]) and at disease progression/end of treatment (DP/EOT). ctDNA samples were analyzed by next-generation sequencing for EGFR ex20ins to determine concordance rate detection between tissue and plasma ctDNA at BL. Changes in VAF for EGFR ex20ins from BL were analyzed at C3D1 and DP/EOT by confirmed response (RECIST v1.1) to mobocertinib per independent review committee. Emerging variants at DP/EOT were evaluated by elimination of germline variants seen in healthy populations (gnomAD databases and 1000 Genomes) and nonharmful variants predicted by PolyPhen and SIFT tools or annotated as benign in ClinVar database. Results: BL EGFR ex20ins mutations were detected by ctDNA sequencing in 29 of 38 pts (76%) with tissue-confirmed EGFR ex20ins+ NSCLC. VAFs for EGFR ex20ins significantly decreased at C3D1 in mobocertinib-treated pts with confirmed partial response (PR; P=0.0057) or stable disease (SD; P=0.0016), but not in pts with progressive disease (PD; P=0.14) (Table). ctDNA at EOT/DP analysis identified numerous genetic variants; EGFR, TP53, and DNMT3A were the most common genes with emerging variants. Twelve emerging missense mutations were identified in EGFR in 9 pts, including mutations located in the exon 20 loop following the C-helix (6), T790M (5), and D379E (1). Conclusions: Concordance between tissue and plasma ctDNA for EGFR ex20ins mutations at BL was 76%. EGFR ex20ins VAF decreased significantly after 2 treatment cycles in mobocertinib-treated patients with PR and SD. Plasma ctDNA longitudinal monitoring may be useful to assess mutation status and disease progression in pts with NSCLC treated with mobocertinib. Clinical trial information: NCT02716116. [Table: see text]

Phase 1/2 study of BLU-451, a central nervous system (CNS) penetrant, small molecule inhibitor of EGFR, in incurable advanced cancers with EGFR exon 20 insertion (ex20ins) mutations.

TPS9155 Background: Oncogenic EGFR ex20ins mutations, found in ̃2% of non-small cell lung cancers (NSCLC) and a small percentage of other cancers, are generally not responsive to EGFR-targeted agents that have been approved for treatment of NSCLC with a common EGFR mutation, including L858R and exon 19 deletion. Similar to these more common types of EGFR-mutated NSCLC, CNS metastases are a challenge with EGFR ex20ins NSCLC and are associated with poor outcomes. While two EGFR ex20ins-targeting drugs were recently approved by the FDA (amivantamab and mobocertinib), neither have established CNS activity. BLU-451 is a CNS penetrant, wild type-sparing, covalent small molecule inhibitor of EGFR ex20ins as well as atypical (G719C, G719S, L861Q) and common EGFR mutants. Preclinical data have shown BLU-451 to have potent antitumor activity, including in an intracranial xenograft model, which has led to its clinical development in EGFR-mutant NSCLC. Methods: BLU-451-1101 (NCT05241873) is a phase 1/2, global, open-label study designed to evaluate single-agent BLU-451 in patients with NSCLC harboring EGFR ex20ins that has progressed following prior treatment for incurable recurrent or metastatic disease. Patients with Eastern Cooperative Oncology Group performance status 0–1 and EGFR ex20ins, exon 18 G719X or exon 21 L861Q mutant NSCLC (phases 1 and 2) or other cancers except primary CNS tumors (phase 1 only) are eligible. Patients with known ROS, RAF, ALK, or EGFR C797S mutations will be excluded. Stable, asymptomatic brain metastases are permitted, and active asymptomatic brain metastases are permitted in specific cohorts. Primary endpoints are determination of maximum tolerated dose (MTD), recommended phase 2 dose (RP2D), safety and tolerability (phase 1), in addition to evaluation of antitumor activity at the RP2D by RECIST v1.1 (phase 2). Secondary endpoints are evaluation of pharmacokinetics (PK) and antitumor activity by RECIST v1.1.(phase 1) and PK, safety, tolerability, and CNS antitumor activity (phase 2). Dose escalation will utilize a 3+3 design with up to 6 patients per cohort in phase 1 dose escalation and up to 12 per cohort in phase 1 dose expansion. Phase 2 will enroll patients in 3 cohorts (n = 18 each): patients with prior platinum-based chemotherapy and an EGFR ex20ins-targeted agent; patients with prior platinum but no EGFR ex20ins-targeted agent; and patients with active asymptomatic brain metastases with prior platinum with or without an EGFR ex20ins-targeted agent. The study is planned for approximately 40 centers in North America, the Asia-Pacific region, and/or Europe. Clinical trial information: NCT05241873.

Mobocertinib Dose Rationale in Patients with Metastatic NSCLC with EGFR Exon 20 Insertions: Exposure–Response Analyses of a Pivotal Phase I/II Study

Mobocertinib is an oral tyrosine kinase inhibitor approved for treatment of patients with locally advanced or metastatic non‐small cell lung cancer (mNSCLC) with epidermal growth factor receptor gene (EGFR) exon 20 insertion (ex20ins) mutations previously treated with platinum‐based chemotherapy. These exposure–response analyses assessed potential relationships between exposure and efficacy or safety outcomes in platinum‐pretreated patients with EGFRex20ins‐positive mNSCLC who received mobocertinib 160 mg once daily (q.d.) in a pivotal phase I/II study. A statistically significant relationship between the independent review committee‐assessed objective response rate and molar sum exposure to mobocertinib and its active metabolites (AP32960 and AP32914) was not discernable using a longitudinal model of clinical response driven by normalized dynamic molar sum exposure or a static model of best clinical response based on time‐averaged molar sum exposure. However, the longitudinal model suggested a trend for decreased probability of response with the change in mobocertinib molar sum exposure between the 160‐ and 120‐mg doses (odds ratio: 0.78; 95% confidence interval: 0.55–1.10; P = 0.156). Time‐averaged molar sum exposure was a significant predictor of the rate of grade ≥ 3 treatment‐emergent adverse events (AEs). Taken together, these exposure–efficacy and exposure–safety results support a favorable benefit‐risk profile for the approved mobocertinib 160‐mg q.d. dose and dose modification guidelines for patients experiencing AEs.

79TiP A phase I, open-label, dose escalation, confirmation, and expansion trial of BI 1810631 as monotherapy in patients with advanced or metastatic solid tumors with HER2 aberrations

HER2 mutations are present in 2–4% of NSCLC tumors; of these ∼50% are exon 20 insertion (ex20ins) mutations. There is an unmet need for effective targeted therapy against HER2 mutations in solid tumors, particularly in NSCLC. BI 1810631 is a HER2 selective TKI that covalently binds to both wild-type/mutated HER2 receptors, including ex20ins, whilst sparing EGFR signaling; preclinical data suggest good tolerability and efficacy. This phase Ia/Ib, open-label, non-randomized study aims to determine safety, MTD, PK, pharmacodynamics, and preliminary efficacy of BI 1810631 in pts with HER2+ solid tumors (NCT04886804). ∼96 pts from 3 sites in the US, Netherlands, and Japan will be recruited. Phase Ia: consecutive cohorts of pts will receive BI 1810631 QD or BID at escalating doses. Starting dose level: 15 mg BID; QD schedule will begin after one dose level above estimated therapeutic dose of BI 1810631 is determined safe by the Dose Escalation Committee (expected starting dose: 60 mg). BI 1810631 dose escalation will continue until MTD and/or RP2D is determined, as well as preferred phase Ib schedule. Phase Ib: an initial 30 pts with HER2 ex20ins mutation-positive, pre-treated NSCLC will be enrolled, with possible inclusion of additional cohorts in the future. Inclusion criteria (Phase Ia): ≥18 years of age; histologically/cytologically confirmed HER2+ advanced, unresectable and/or metastatic solid tumors refractory/not suitable for standard therapy; exhausted treatment options; measurable or evaluable lesions (according to RECIST v1.1); ECOG PS ≤1. Phase Ib criteria: HER2 ex20ins mutation-positive NSCLC; received ≥1 line of platinum-based combination chemotherapy in the advanced/metastatic setting. Primary endpoints: MTD based on the number of DLTs/number of pts with DLTs (Phase Ia); objective response (Phase Ib). Secondary endpoints: number of pts with DLTs throughout entire treatment period and PK parameters (Phase Ia/Ib); duration of response, PFS, disease control, and duration of disease control (Phase Ib). The trial is actively recruiting; 5 pts have been enrolled to date and 2 dose levels have been completed. NCT04886804. Medical writing assistance, supported financially by Boehringer Ingelheim, was provided by Rick Burgon, of Ashfield MedComms, an Ashfield Health Company, during the development of this abstract. Boehringer Ingelheim.

26MO Efficacy and safety of poziotinib in treatment-naïve HER2 exon 20 insertion (ex20ins) mutated non-small cell lung cancer (NSCLC): ZENITH20-4

Patients (pts) with advanced NSCLC harboring HER2 ex20ins mutations have a poor prognosis with no approved targeted therapy. Poziotinib is a potent tyrosine kinase inhibitor (TKI) able to target the inaccessible binding pocket of ex20ins. Cohort 4 of the ZENITH20 phase 2 study aims to evaluate the clinical efficacy of poziotinib in treatment-naïve pts with advanced HER2 ex20ins NSCLC. Preliminary efficacy and safety of QD dosing in this cohort were presented previously. Here, we present the primary efficacy analysis of the full cohort of 70 patients. ZENITH20-4 enrolled pts with locally advanced or metastatic treatment-naïve advanced HER2 ex20ins NSCLC. Poziotinib was administered orally 16 mg QD or 8 mg BID, with optional dose interruptions/reductions for toxicity. The primary endpoint was objective response rate (ORR) by independent review (RECIST 1.1). Secondary endpoints included disease control rate (DCR), duration of response (DOR), progression-free survival (PFS), and safety. In total, 70 pts (QD, n = 48; BID, n = 22) were treated; 14 remain on study (n = 3 and n = 11, respectively). Demographics were representative of this population. Among those treated with QD and BID dosing, 90% and 68% had dose interruptions, and 79% and 64% required dose reductions, respectively. Treatment-related AEs of any grade occurred in all pts treated with QD and 86% (n = 19) of pts treated with BID dosing. Among grade 3 AEs, the most common were rash (n = 17 [35%]; n = 4 [18%]), stomatitis/mucosal inflammation (n = 10 [21%]; n = 3 [14%]), and diarrhea (n = 7 [15%]; n = 3 [14%]). Combined ORR was 41% (95% CI: 30%, 54%), and 4 pts had unconfirmed responses (uORR = 47%). DCR was 73%, median DoR was 5.7 months (range: 1.2, >19.1), with 34% of pts having a DOR of >6 months, and median PFS was 5.6 months (range: 0, >20.2). For both QD and BID dosing regimens, poziotinib therapy demonstrated statistically significant clinically meaningful efficacy in pts receiving front-line treatment for HER2 ex20ins NSCLC. Tolerability was improved with BID dosing, and overall AEs were manageable with dose modifications.

Clinicopathologic and molecular characteristics of Chinese lung adenocarcinoma patients with EGFR exon 20 insertion mutations.

BackgroundEpidermal growth factor receptor exon 20 insertions (EGFR ex20ins) occur in about 4–14% of lung adenocarcinoma (LUAD) patients with EGFR mutations. Recently some targeted drugs have been approved for the treatment of LUAD patients with EGFR ex20ins. However, the heterogeneity of EGFR ex20ins mutations and resultant challenges in identifying them have led to the underestimation of their frequency.MethodsWe investigated the molecular and clinicopathologic features of EGFR ex20ins in 3,892 Chinese LUAD patients using next-generation sequencing (NGS). The frequency and distribution of EGFR ex20ins mutations between Chinese and Western LUAD patients were also compared by integrating the data of this study and the data of previous studies.ResultsA total of 23 unique EGFR ex20ins were identified in 77 LUAD patients, accounting for 1.98% of all LUAD patients and 3.49% of EGFR mutant LUDA patients. The 2 most common EGFR ex20ins subtypes were S768_D770dup and A767_V769dup, which together accounted for 55.84% of the EGFR ex20ins cases. About 61% (14/23) of the EGFR ex20ins subtypes occurred only once. Additionally, 8 of the EGFR ex20ins subtypes were not recorded in the COSMIC database. These results showed that the EGFR ex20ins mutations were highly heterogeneous. There was no significant difference in the frequency and distribution of EGFR ex20ins mutations between Chinese and Western LUAD patients, but the frequency of EGFR ex20ins mutations was significantly lower in EGFR-mutant Chinese LUAD patients than Western LUAD patients. The co-mutation analysis showed that EGFR ex20ins occurred significantly and exclusively with certain driver genes in LUAD, including ALK fusion (χ2=7.133, P=0.008), KRAS (χ2=8.468, P=0.004), and PIK3CA (χ2=5.792, P=0.016). No gene was observed to be significantly co-mutated with EGFR ex20ins. In general, patients with EGFR ex20ins shared a similar age and gender to patients with other EGFR mutations or without EGFR ex20ins.ConclusionsOverall, our results revealed the molecular and clinicopathologic features of EGFR ex20ins in Chinese LUAD patients, which will be helpful for drug development and in clinical trials targeting EGFR ex20ins.

EGFR Exon 20 Insertion Mutations in Sinonasal Squamous Cell Carcinoma.

Simple SummaryThe majority of patients with sinonasal squamous cell carcinoma (SNSCC) associated with inverted sinonasal papilloma carry an exon 20 insertion activating mutation in the epidermal growth factor receptor (EGFR). The aim of this review is to document the various features of EGFR mutations in SNSCC and other cancers, and to assess what we can learn from the study of these mutations in lung cancer, with a special focus on new therapeutic opportunities for SNSCC patients carrying EGFR exon 20 insertions mutations.Recurrent epidermal growth factor receptor (EGFR)-activating mutations have been identified in a rare form of head and neck cancer known as sinonasal squamous cell carcinoma (SNSCC), a malignant disease with a 5-year mortality rate of ~40%. Interestingly, the majority of EGFR mutations identified in patients with primary SNSCC are exon 20 insertions (Ex20ins), which is in contrast to non-small-cell lung cancer (NSCLC), where the EGFR exon 19 deletion and L858R mutations predominate. These studies demonstrate that EGFR Ex20ins mutations are not exclusive to lung cancer as previously believed, but are also involved in driving SNSCC pathogenesis. Here we review the landscape of EGFR mutations in SNSCC, with a particular focus on SNSCC associated with inverted sinonasal papilloma (ISP), a benign epithelial neoplasm. Taking lessons from NSCLC, we also discuss potential new treatment options for ISP-associated SNSCC harbouring EGFR Ex20ins in the context of targeted therapies, drug resistance and precision cancer medicine. Moving forward, further basic and translational work is needed to delineate the biology of EGFR Ex20ins in SNSCC in order to develop more effective treatments for patients with this rare disease.

Therapeutic exploration of uncommon EGFR exon 20 insertion mutations in advanced non-small cell lung cancer: breaking through brambles and thorns.

EGFR exon 20 insertion (EGFR ex20ins) mutations account for about 10-12% of all EGFR-mutated tumors, which are usually associated with primary drug resistance to conventional EGFR-TKI therapy and worse survival outcomes, and are currently a major problem for clinicians in clinical management. In recent years, with the rapid improvement of sequencing technology and careful review of clinical data, investigators have gained a deeper understanding and clearer cognition of the clinicopathological features and molecular mechanisms of these EGFR ex20ins mutations. The aim of this study was to systemically review the molecular structure and clinical characteristics of EGFR ex20ins mutations, and focus on summarizing the latest data of emerging therapies (including novel small-molecule EGFR-TKI drugs, specific monoclonal antibodies, novel drugs targeting other mechanisms, and immunotherapy) for those patients. Advances in overcoming these systemic challenges have greatly accelerated the development of new drugs targeting EGFR ex20ins, and are committed to designing more rational combination therapies to overcome or delay the emergence of drug resistance, ultimately improve the prognosis of such uncommon mutant populations.