HER-2 exon 23 mutation

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

EGFR/ERBB2-20ins is more common in early lung adenocarcinoma. EGFR-20ins had more variants. In both cohorts, the results for first-line systemic treatments showed no significant difference.

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

This study showed that platinum-based chemotherapy plus ICIs had limited efficiency compared to platinum-based chemotherapy for patients with EGFR/ERBB2 Ex20ins. Chemotherapy plus bevacizumab may be a potential scheme for these patients.

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

The liquid-first approach enhances the yield of rare mutations by tissue NGS which is resource-dependent. It benefits regions where tissue biopsy is a rate limiting factor and EGFR mutations are prevalent.

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.

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.

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.

No abstract available

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

Approved and investigational therapies for NSCLC patients with EGFR exon 20 insertion mutations have only demonstrated moderate clinical efficacy (28-52% ORR), compared to Osimertinib's significant 70-80% ORR activity in the more common EGFR mutant tumors. Here we disclose for the first time the structure and optimization efforts that led to the discovery of STX-721, a highly-differentiated EGFR/HER2 inhibitor that provides superior exon 20 insertion mutation vs. wild type selectivity relative to approved and clinical benchmarks across in vitro and in vivo model biological systems, including in vivo isogenic/matched human cancer cell line models. STX-721 has the potential to provide a best-in-class profile to improve outcomes in patients harboring cancers with EGFR/HER2 exon 20 mutations and has completed investigational new drug (IND)-enabling studies with a favorable risk/benefit profile supporting clinical development.

Combination P + T showed evidence of antitumor activity in heavily pretreated patients with non-small-cell lung cancer and ERBB2 mutation or amplification, particularly those with ERBB2 exon 20 insertion mutations.

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

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.

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.

Co-occuring TP53 variants with HER2 mutations are prognostic of shorter OS and PFS in NSCLC, and may be associated with a higher incidence of brain metastases. Our larger validation dataset with ~75 patients will be presented. >*Two patients had an unknown smoking status.