HER-2 S310F

P2, N=102, Active, not recruiting, AstraZeneca | Trial completion date: Jan 2028 --> Jul 2026

Matched tumor samples from six patients identified the same mutations with an 83% concordance rate. In summary, our highly sensitive multiplex digital PCR assays are well suited for plasma-based monitoring of ERBB2 mutational status in patients with MBC.

Lastly, MTAP loss, an emerging biomarker for new synthetic lethality based anti-cancer drugs, was less frequent in ERBB2 ECD-mutated MPUC (11.1%) than non-MPUC (26.9%) (p = 0.018). Characterizing the genomic landscape of MPUC may not only improve our fundamental knowledge about this aggressive morphological variant of UBC, but also has the potential to identify possible prognostic and predictive biomarkers that may drive tumor progression and dictate treatment response to therapeutic approaches.

Neratinib resulted in durable responses and disease control in patients with HER2-mutant metastatic/recurrent cervical cancer in SUMMIT. These findings support next-generation sequencing and tailored therapy for select patients with advanced cervical cancer. All responses occurred in patients with endocervical adenocarcinoma. Further assessment of neratinib in this setting is warranted.

HER2 status did not influence ADFS for NMIBC; PFS and OS for MIBC regardless of neoadjuvant cisplatin chemotherapy (chemo); OS for 1st line (1L) MetBC treated with gemcitabine plus platinum (GC) chemo or 2nd line (2L) immune checkpoint inhibitor (ICI) therapy post 1L-chemo (table). We present one of the largest and comprehensive study of HER2 mutation in BC. Overall, HER2 amplification was significantly less frequent for NMIBC. HER2 alterations were not a prognostic marker for NMIBC or MIBC independent of neoadjuvant cisplatin-based chemo, MetBC- 1L GC-chemo and 2L ICI post GC-chemo.

Our data demonstrated the clinical benefit of anti-HER2 treatment in Chinese breast cancer patients harboring HER2 mutation and/or HER2 fusion. The value of immunotherapy and treatment selection among individual HER2 variants needs further study.

Novel therapeutic strategies for NMIBC are urgently needed. ERBB2 alterations are frequently observed in high grade NMIBC and are associated with enrichment of oncogenic co-alterations, especially in homologous recombination repair genes. Preclinical studies and early phase clinical trials are warranted to study anti-HER2 small molecule inhibitors and antibody-drug conjugates in NMIBC.

Here we describe the clinical and genomic characteristics of a large cohort of ERBB2/3-mut breast cancers. We identify a notable enrichment of ERBB2/3-mut in lobular histology and metastatic tumors and tendency for co-alteration with CDH1 and multiple transcription factors reflecting the unique biology of ERBB2/3-mut breast cancers. Further analyses on an expanded cohort (n >6000 pts), including outcomes on HER2-directed antibody-drug conjugates (T-DXd) and targeted therapies such as PI3K inhibitors, will be presented at the 2023 SABCS Annual Meeting.

We then used them to test neratinib and other TKIs with ADCs, including T-DXd and trastuzumab emtansine (T-DM1). Although the reason for the discrepancies in drug response between ILC cell lines and PDOs is not clear, we hypothesize that response in 3D PDOs might be more faithfully representing response seen in patients. We will generate additional ILC PDOs with knock-in ERBB2 mutations to validate our findings. Irreversible HER2 TKIs, such as neratinib and afatinib, showed synergy with T-DXd in ERBB2 mutant ILC PDOs.

MSI-high was observed in 15 samples. Conclusions Comprehensive ctDNA NGS can identify ERBB2m including complex insertions and co-alterations that may inform therapeutic decisions for patients with AC in AME.

Conclusions The study provided the landscape of ERBB2 alterations in UC that may benefit from anti-HER2 agents. Consideration should be given to developing trials inclusive of patients with UC harboring ERBB2 alterations.

P1, N=30, Recruiting, National Cancer Institute (NCI) | N=18 --> 30

Background Given the early promising data with afatinib in advanced UC and the recent approval in NSCLC for anti-HER2 targeted therapy for activating kinase domain exon 20 ERBB2 insertion mutations, there is considerable interest in targeting additional locations in the ERBB2 gene in other tumor types...Conclusions ERBB2 ECD mutation-driven UBC represents a distinct subtype of UBC featuring an enrichment of MPUC histology from 1-2% to 28% incidence in ERBB2 ECD mutated UBC, and unique clinical and molecular characteristics, including differences in mutational signatures and genetic ancestry. Further exploration of anti-HER2 targeted therapy for non-amp sequence mutations in ERBB2 in UBC appears warranted.

In heavily pretreated pts with limited Tx options, T-DXd demonstrated encouraging anticancer activity and long DoR across multiple tumor types with HER2m and a range of HER2 expression levels, with a known safety profile. Translational research will help characterize pts who may derive greatest benefit from T-DXd.

Due to this unusual ligand mediated interaction, cancer cells were found susceptible to EGFR targeted therapeutics i.e. Gefitinib and Erlotinib. Further, in TCGA analysis, BC patients harbouring HER3-D297Y mutation showed increased p-EGFR levels as compared to the patients harbouring HER3-WT and HER3-G284R mutations. For the first time, this comprehensive study showed the importance of specific hotspot mutations in HER3 dimerization domain can defy the Trastuzumab therapy, rather cells become susceptible to the EGFR inhibitors.

Patients with oncogenic ERBB4 mutations (n=3) harbored also TP53 alterations, which may contribute to the lack of response to neratinib, as has been suggested for ERBB2-mutant patients.ConclusionMany of the recurrent ERBB4 mutations are oncogenic. Further investigation into potential utility of clinically used pan-ERBB inhibitors, such as neratinib, for patients whose tumors harbor these ERBB4 mutations is warranted.

This targeted NGS study revealed critical mutations involved in the carcinogenetic progression of flat lesions with putative pathobiological pathways. Importantly, KRAS G12C and ERBB2 S310F/Y mutations were identified as potential prognostic and therapeutic biomarkers for urothelial carcinoma.

Long-term survivors with EGFRm mNSCLC treated before the osimertinib era were more likely to be nonsmokers and have no baseline brain metastases. This highlights a subset of EGFRm patients who had excellent outcomes with older treatment strategies and may not benefit as much from intensification approaches. Additional baseline mutational data will be presented at the conference.

"Of 21 pts with paired plasma samples, 17 (81%) had ≥1 acquired genomic alteration. RTK alterations and secondary (2°) RAS alterations were most common; each occurred in 57% of pts (Table). KRAS amplification was the most common single alteration (43%)."

In two large independent cohorts, Chinese and Western, ERBB2 mutation and co-mutation patterns were similar. ERBB2 exon 20 insertions/mutations were dominant at over 80% with Y772_A775dupYVMA being the most common driver mutation; TP53 and EGFR were the most frequently co-occurred genes. ERBB2 mutation lung cancers had low TMB and PDL1, as expected in female dominant lung adenocarcinomas, similar to EGFR exon 20 NSCLC.

The overall variation rate of ERBB2 is 5.4% in Chinese patients with CRC, which is accompanied by significantly different molecular pathological characteristics compared to patients with wild-type ERBB2, and different mutation types (CNV or SNV) display different molecular pathological characteristics.

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.

Diarrhoea is the most common adverse event, with any-grade diarrhoea in 14 patients (56%). Although neratinib demonstrates antitumour activity in patients with refractory BTC harbouring HER2 mutations, the primary endpoint was not met and combinations may be explored.

P2, N=25, Completed, City of Hope Medical Center | Active, not recruiting --> Completed | Trial completion date: Dec 2022 --> Sep 2022

ERBB2 ECD mutation driven UBC is a unique form of UBC featuring enrichment of MPUC histology and a unique clinical and genomic landscape including genomic signatures and ancestry.

This validation study supports the feasibility of applying NGS testing to leftover fixed urine cytology specimens. In addition, the potential utility of urine NGS testing as an adjunct to urine cytology in the early detection of HGUC for cases in which cytology is negative and/or atypical/suspicious should be investigated further.

These results provide valuable insight into the differential molecular markers among the categories of cervical cancer, which helps our ability to classify these cancers and for targeted therapy.

Next generation ErbB2 inhibitors that are active against ErbB2 mutations, yet spare WT EGFR, would provide improved target coverage with fewer off target side effects compared to current therapies and have the potential to exhibit superior clinical efficacy. Herein, we describe the pre-clinical in vitro and in vivo activity of a novel ErbB2 inhibitor which has potency against prevalent mutations while sparing WT EGFR.

Patients with ERBB2 amplifications or mutations had higher TMB compared with patients with non-ERBB2 alterations. The study provided the landscape of ERBB2 alterations across a variety of solid tumors that may benefit from anti-HER2 agents.

Prior treatments included platinum-based chemotherapy (100%), bevacizumab (73%), and pembrolizumab (18%). No patients discontinued treatment due to diarrhea. Table: 559P CBR, CR + PR + SD ≥16 weeks; CR, complete response; DoR, duration of response; NE, not estimable; ORR, objective response rate; PFS, progression-free survival; PR, partial response; SD, stable disease Conclusions These encouraging results support the clinical benefit of neratinib in this patient population and warrant further investigation following platinum failure.

Receptor switching to other HER family members in Lapatinib resistance and HER2 receptor tyrosine kinase domain mutations have been elaborated in promoting resistance. BC cells over-expressing HER2-WT or S305C were found sensitive to Trastuzumab (P>0.001) or Neratinib (P>0.001), whereas cells with G309A, S310Y or P523S mutation were non-responder to those drugs as revealed by short-term, long-term viability, anchorage-independent growth and Immunoblot assessments. Conclusion The structural changes ensued after HER2 interaction domain mutations alters the downstream signalling cascades and impacts the therapy response to HER2 targeted medicines.

P1, N=18, Recruiting, National Cancer Institute (NCI) | Not yet recruiting --> Recruiting

P2, N=1, Terminated, Spectrum Pharmaceuticals, Inc | N=150 --> 1 | Trial completion date: Dec 2023 --> Mar 2022 | Recruiting --> Terminated | Trial primary completion date: Jun 2023 --> Mar 2022; Strategic business decision (unrelated to safety)

P1, N=18, Not yet recruiting, National Cancer Institute (NCI) | Trial completion date: Aug 2023 --> Jun 2024 | Trial primary completion date: Aug 2023 --> Jun 2024

P1, N=18, Not yet recruiting, National Cancer Institute (NCI)

We observed that two patients bearing HER2 mutations (Patient #1 bearing S310F and V777L mutations, Patient #2 bearing 778insGSP mutation) achieved a durable partial response to Trastuzumab combined with Everolimus. In vitro experiments showed that T47D and MCF7 cells overexpressing these HER2 mutants (S310F, V777L, 778insGSP and L755S) were sensitive to HER2-targeted therapies combined with the mTOR inhibitor Everolimus. These findings provide a treatment option for patients with HER2 mutations by combining HER2-targeted therapies with Everolimus.

ERBB2 S310F mutation up-regulated aerobic glycolysis and promoted gallbladder carcinoma growth. Our study reveals the roles of ERBB2 S310F mutation, which is beneficial to ERBB2 S310F mutant gallbladder carcinoma therapy.

We report mutational landscape and characteristics of ERBB2 in Chinese NSCLC patients.The prevalence of activating ERBB2 mutations was 3.1% in Chinese NSCLC patients. 80.1% of ERBB2 activating mutations were in TKD and 19.9% were in the non-TKD. The non-TKD mutations might also be used as a therapeutic target in ERBB2-directed target therapy.