HER-2 exon 20 insertion

Addition of ICIs to platinum-based chemotherapy in 1st line treatment may improve the PFS in patients with HER2-mutant NSCLC. The relatively high TMB might be involved in the prolongation of the PFS in patients with HER2-mutant NSCLC receiving platinum-based chemotherapy with ICIs.

Finally, phase II clinical trials involving HER2-altered NSCLC patients demonstrated promising treatment outcomes with trastuzumab deruxtecan, trastuzumab emtansine, pyrotinib, pyrotinib + apatinib and trastuzumab + pertuzumab + docetaxel. In conclusion, the prevalence of HER2 alteration among Malaysian NSCLC patients falls within the global range. A systematic review of clinical trials revealed promising treatment outcomes and Malaysian NSCLC patients with HER2 alterations are anticipated to similarly benefit from HER2-targeted therapies.

In addition, the above clinicopathological characteristics and HER2 IHC results can be valuable determinants for identifying patients with HER2-altered NSCLC. These insights hold promise for the development of more effective diagnostic and therapeutic strategies for this complex subset of NSCLC patients.

For patients with EGFR20ins mutation, compared to chemotherapy, ICI+Chemo prolongs PFS, and after chemotherapy progression, bevacizumab combined with chemotherapy seems better than Furmonertinib-based targeted therapy on PFS. For HER2-20ins mutation, Beva+Chemo may be a better choice.

P2, N=45, Completed, IFCT

The anti-PD-1 inhibitor-based combinational therapy elicited exciting anti-tumor efficacy and prolonged patient survival with manageable adverse effects in NSCLC patients harboring oncogenic alterations. The PD-L1 status and LIPI could be used as a biomarker predicting response to anti-PD-1 inhibitor-based combinational treatment in these patients.

Identification of EGFR and HER2 E20ins is more important as their targeted therapies improved outcomes. Upfront NGS test as a comprehensive molecular approach is strongly warranted.

P2, N=648, Terminated, Spectrum Pharmaceuticals, Inc | Trial completion date: Dec 2023 --> Apr 2023 | Active, not recruiting --> Terminated; Strategic business decision (unrelated to safety)

P1/2, N=26, Not yet recruiting, RemeGen Co., Ltd.

P2, N=46, Completed, Intergroupe Francophone de Cancerologie Thoracique | Active, not recruiting --> Completed

P1, N=170, Recruiting, ArriVent BioPharma, Inc.

P1/2, N=280, Recruiting, ORIC Pharmaceuticals | Phase classification: P1 --> P1/2 | N=42 --> 280 | Trial completion date: Mar 2025 --> Mar 2026

P1, N=170, Recruiting, ArriVent BioPharma, Inc. | Phase classification: P1b --> P1

In this study, pyrotinib plus antiangiogenic agents demonstrated promising efficacy and were tolerable in HER2-altered NSCLC patients.

MET alterations in NSCLC typically occur in the absence of other oncogenic driver mutations and are associated with poor survival outcomes. Notably, METi therapies are associated with improved survival outcomes in patients with MET-dysregulated NSCLC.

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

P1, N=36, Not yet recruiting, Jonathan Riess

P2, N=46, Active, not recruiting, Intergroupe Francophone de Cancerologie Thoracique | Trial completion date: Jul 2023 --> Feb 2024

(4) Overall survival was significantly longer among ex20ins patients who received any systemic therapy vs. those who did not. Overall survival was significantly better among HER2 ex20ins patients who received ex20ins-specific TKIs.

After treatment with T-DXd, the tumor significantly regressed and bone metastasis improved, maintaining a state of no progression for 21 months. This case report evidences the use of T-DXd in the treatment of NSCLC with HER2 exon 20 insertion mutation.

Conclusions In comparison to patients with classical EGFR alterations, those with HER2 alterations and advanced NSCLC have similar poor outcomes to treatment with ICI therapy. A comprehensive analysis of the tumor immune microenvironment may provide insight into future biomarkers of response.

In pts with HER2 ex20ins mutant disease, BAY 2927088 showed encouraging preliminary anti-tumour activity. These results warrant further investigation of BAY 2927088 in pts with NSCLC.

Of these, 35 patients (25 16 mg QD; 10 8 mg BID) had prior HER2 therapy such as trastuzumab, TDM1, and T-DXd...ORRs were 30% with PLT+any systemic therapy; 30% with PLT+docetaxel and 43% with PLT+TKI...Conclusions Poziotinib demonstrated clinically meaningful efficacy in patients who received prior 2+ lines of therapy including HER2 therapy. ZENITH20 study provides a large dataset in the 3rd or later line setting of HER2 exon 20 mutations in NSCLC who have very limited treatment options.

For patients with EGFR20ins mutation, ICI+Chemo significantly prolonged PFS, and after chemotherapy progression, bevacizumab combined with chemotherapy is markedly better than Furmonertinib-based targeted therapy. For HER2-20ins mutation, Beva+Chemo is a better choice.

Introduction: HER2 mutation is a newly established actionable target in non-small cell lung cancer (NSCLC) with trastuzumab-deruxtecan (T-DXd) as the only approved targeted therapy for patients as 2nd line therapy...ORRs were 31.3% with platinum+any systemic therapy; 30.8% with platinum+docetaxel; 24.0% with platinum+HER2 antibody-based therapy; 54.5% with platinum+TKI... Poziotinib demonstrated clinically meaningful efficacy in patients who received and progressed on prior 2+ lines of therapy regardless of types and sequence of treatment. ZENITH20 study provides a large dataset in the 3rd or later line setting of HER2 exon 20 mutations NSCLC patients who have very limited treatment options. No new safety signal was detected in this patient population.

This study outlines the clinical management and outcomes of patients with HER1/HER2 exon 20 insertion in the era preceding the availability of molecularly targeted therapies. Our findings contribute to a body of evidence which demonstrates the ineffectiveness of conventional EGFR-TKI in both EGFR-exon20ins and ERBB2-exon20ins, and suggests a potential effectiveness of ICI-based therapy for ERBB2-exon20ins for PD-L1 TPS 50%. Future prospective studies are required to quantify the relative benefits and determine any risks inherent in the use of ICI-based therapies among a patient population which also has increasing availability to novel targeted therapies.

P1/2, N=42, Terminated, Spectrum Pharmaceuticals, Inc | N=76 --> 42 | Trial completion date: Mar 2025 --> May 2023 | Active, not recruiting --> Terminated | Trial primary completion date: Jan 2025 --> Feb 2023; Business decision, not related to safety.

P2, N=240, Recruiting, German Cancer Research Center | Not yet recruiting --> Recruiting

P2, N=240, Not yet recruiting, German Cancer Research Center | Trial completion date: Dec 2029 --> Dec 2030 | Trial primary completion date: Apr 2029 --> Mar 2030

One patient discontinued treatment due to a grade 3 rash after three cycles of ICI plus anlotinib treatment. The results showed that immunotherapy combined with chemotherapy may play a role in the first-line treatment of NSCLC patients with ex20ins mutations. This finding requires further investigation for application.

This study aimed to assess the effectiveness and safety of pyrotinib plus antiangiogenic agents, including apatinib, anlotinib, and bevacizumab in previously treated patients with HER2-altered advanced NSCLC. Pyrotinib plus antiangiogenic agents demonstrated promising antitumor activity and a manageable safety profile in HER2-altered NSCLC patients.

P1/2, N=334, Recruiting, Takeda | Trial completion date: Mar 2023 --> Mar 2025 | Trial primary completion date: Mar 2023 --> Mar 2025

P2; Trial completion date: Mar 2024 --> Sep 2024 | Trial primary completion date: Mar 2024 --> Sep 2024

This was an important case since it exerted effective response to DS-8201. Meanwhile, myelosuppression is also found in the patient, which requires attention to pulmonary symptoms and careful monitoring.

Poziotinib demonstrated clinically meaningful efficacy with a manageable toxicity profile for treatment-naïve NSCLC patients harboring HER2 exon 20 mutations.

With the recent approval of fam-trastuzumab deruxtecan-nxki, the first targeted treatment option became available for HER2 mutant NSCLC patients. In addition, the compound was active in a subset of endogenously HER2 mutant cancer cell lines. The in vitro activity of BAY 2927088 was validated in vivo in a patient-derived xenograft model carrying the HER2 exon20 insertion mutation A775insYVMA.The strong preclinical activity of BAY 2927088 in HER2 mutant NSCLC supports clinical evaluation in this indication and might offer a novel targeted therapy option for NSCLC patients that carry HER2 mutations.

In addition, trastuzumab and EGFR-TKIs have limited effectiveness for NSCLC patients with HER2 exon 20ins mutation. TAK-788 (mobocertinib) and JNJ6372 (amivantamab-vmjw) are the FDA approvals for NSCLC driven by EGFR exon 20ins mutations. Only T-Dxd is used as a second-line treatment for NSCLC patients with HER2 mutation...In EGFR-related tumor cells and genetically engineered Ba/F3 cell lines, TY-4028 showed similar or better antitumor effects than TAK-788, and better antitumor effects than DZD9008...#Jun Li and Chengshan Niu contributed equally to this work. *They are the correspondent authors.

HER2-targeted tyrosine kinase inhibitors lapatinib, neratinib, and tucatinib and the HER2-targeted antibodies trastuzumab and pertuzumab, in combination with chemotherapy, have been shown to improve survival of patients with HER2 overexpressing BC in the presence of brain metastases...TAS2940 is an irreversible pan-ErbB inhibitor with greater brain-penetrability than poziotinib, tucatinib, and neratinib. Here, we demonstrate that TAS2940 induces downregulation of phosphorylated HER2/EGFR, reduces tumor burden, and promotes a significant increase in survival in intracranial xenograft mouse models with HER2-amplification (BC), HER2-Exon20 insertion mutation (NSCLC), and EGFR-amplification (GBM). These promising preclinical data highlight potential novel therapeutic strategies for patients with EGFR-aberrant GBM and brain metastases harboring HER2/EGFR alterations, and may help support the advancement of the ongoing first-in-human clinical trial (NCT04982926) for TAS2940 in solid tumors with EGFR and/or HER2 alterations.

It was superior to Mobocertinib (IC50 = 27.1 nM for YVMA and IC50 = 3.3 nM for GSP) and comparable with Poziotinib (IC50 = 3.4 nM for YVMA and IC50 = 0.4 nM for GSP). JIN-A04 is highly potent against HER2 exon 20 insertion mutations including YVMA and GSP, while largely sparing HER2 WT activity. Also, JIN-A04 demonstrated effective HER2 pathway inhibition. Based on these robust activities for HER2 exon 20 insertion, JIN-A04 is expected to provide a potent therapeutic opportunity for NSCLC patients with HER2 exon20 insertion mutations.