HER-2 V777L

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

Zongertinib potently and selectively blocks HER2, while sparing EGFR, and inhibits the growth of cells dependent on HER2 oncogenic driver events, including HER2-dependent human cancer cells resistant to trastuzumab deruxtecan. Zongertinib displays potent anti-tumor activity in HER2-dependent human NSCLC xenograft models and enhances the activities of antibody-drug conjugates and KRASG12C inhibitors, without causing obvious toxicities. The preclinical efficacy of zongertinib translates in objective responses in patients with HER2-dependent tumors, including cholangiocarcinoma (SDC4-NRG1 fusion) and breast cancer (V777L HER2 mutation) thus supporting the ongoing clinical development of zongertinib.

P2; Trial completion date: Feb 2024 --> Feb 2025 | Trial primary completion date: Feb 2024 --> Feb 2025

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

Our results strongly suggest that metastatic driver mutations are sequentially acquired and selected within the same clonal lineage both before, but more commonly after, dissemination from the primary tumor, and that these mutations are biologically consequential. Despite inherent limitations in sampling archival primary tumors, our findings indicate that tumor cells in most patients continue to undergo clinically relevant genomic evolution after their dissemination from the primary tumor. This provides further evidence that metastatic recurrence is a multi-step, mutation-driven process that extends beyond primary tumor dissemination and underscores the importance of longitudinal tumor assessment to help guide clinical decisions.

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.

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.

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.

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

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.

Herein, we describe a case in which a patient with estrogen receptor-positive/HER2-negative metastatic ILC with 2 activating HER2 mutations (D769H and V777L) exhibited a significant and durable response to anti-HER2 treatment with pyrotinib (an irreversible TKI) in combination with ado-trastuzumab emtansine, which was administered after multiple lines of therapy that had resulted in disease progression. Further, based on the evidence from the present case, TKI plus ADC seems to be a promising combination anti-HER2 regimen for patients with HER2-negative/HER2-mutated advanced BC, although further rigorous studies are warranted to confirm these findings.

We validated both the neratinib plus trastuzumab deruxtecan and neratinib plus palbociclib combinations using a human breast cancer patient-derived xenograft with very similar HER2 and PIK3CA mutations. Further, these two drug combinations effectively treated spontaneous lung metastasis in syngeneic mice transplanted with HP breast cancer organoids. Both of these drug combinations are being tested in phase 1 clinical trials and this study provides valuable preclinical evidence for them.

Among patients with any ERBB2 mutations, 7 received a combination of chemotherapy plus anti-EGFR, either cetuximab or panitumumab, 6 had PR and 1 SD as best response. In this consecutive real-world series, ERBB2 activating mutation prevalence was 3.1%. We found an addition 4.4% ERBB2 VUS prevalence, with a ERBB2 mutation prevalence of 7.5% as a whole. Pathogenetic mutations can co-occur with other driver molecular alterations.

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

P2; Trial completion date: Mar 2023 --> Mar 2024 | Trial primary completion date: Mar 2023 --> Mar 2024

P2; Recruiting --> Active, not recruiting | N=80 --> 116

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

HER2 mutations are most common in EC among gynecologic cancers, with R678Q most frequent in our cohort, and T862A in cBioportal. While no HER2 -mutated tumors had a 3+ IHC score, increased HER2 expression (2+) was seen in tumors with L313V, R678Q, and T862A mutations, and HER2 rearrangement. Targeted therapy has already been applied in other tumor types with these HER2 mutations; however, further studies are necessary to explore the prognostic and therapeutic implications of these findings in gynecologic cancers.

Collectively, these data suggest that HOXA5 suppresses malignancy in breast epithelial cells by blunting NF-κB action via stabilization of its inhibitor IκBα. Loss of HOXA5 reduces IκBα stability and increases NF-κB signaling to exacerbate breast cancer aggressiveness, providing new insights into the tumor suppressor functions of HOXA5.

P1/2, N=91, Terminated, Black Diamond Therapeutics, Inc. | Completed --> Terminated; The development of BDTX-189 was discontinued by the sponsor.

P1/2, N=91, Completed, Black Diamond Therapeutics, Inc. | Active, not recruiting --> Completed | Trial completion date: Dec 2023 --> Sep 2022 | Trial primary completion date: Jun 2023 --> Sep 2022

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.

In March 2019, AstraZeneca entered into a global development and commercialization collaboration agreement with Daiichi Sankyo for trastuzumab deruxtecan (T-DXd; DS-8201)... Detection of rare mutations require sensitive and specific diagnostic assays. AmoyDx HER2 Mutation Detection Kit demonstrated robust performance in detecting representa-tive HER2 indel and single nucleotide variant mutations at low frequencies. The AmoyDx Pan Lung Cancer PCR assay showed similarly robust and sensitive detection of the common HER2 A775_G776insYVMA indel in addition to detecting clinically relevant EGFR mutations.

P2; Trial primary completion date: Mar 2022 --> Mar 2023

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

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

P1/2, N=91, Active, not recruiting, Black Diamond Therapeutics, Inc. | Recruiting --> Active, not recruiting | N=200 --> 91

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.

Neratinib is tolerable with modest antitumor activity in patients with BTC harboring HER2 mutations. Although the primary endpoint was met, future studies should evaluate rational combinations to augment and/or prolong responses.

Of the entire cohort, we observed five activating PIK3CA mutations (R108H; G364R; E542K; E545K, n = 2) which may be sensitive to FDA-approved PIK3CA inhibitor alpelisib. Additionally, patients with loss-of-function mutation in NF1 (n = 2), STK11 (n = 1) and PTEN (n = 1) can be targeted with MEK inhibitor selumetinib and mTOR inhibitor everolimus, respectively. Except for one V600E mutation, all mutations in BRAF are either type 2 (L597R, n = 1) or type 3 (N581S, n = 1; D594N, n = 4) which were sensitive to MEK inhibitor trametinib...Interestingly, one IDH1 mutation (R132C) carrier in our cohort might benefit from ivosidenib... Through comprehensive genomic characterization of Chinese SBA patients, we identified actionable variants of multiple signaling pathways in plenty. NGS profiling results can guide physicians to enroll a significant portion of SBA patients in genomically-matched clinical trials.

Pts received N+F+T (oral N 240 mg/d with loperamide prophylaxis, im F 500 mg d1&15 of cycle 1 then q4w, iv T 8 mg/kg initially then 6 mg/kg q3w). N+F+T is a promising combination for HR+, HER2-mutated MBC with prior exposure to CDK4/6i, across a range of activating HER2 mutations. Results from the upcoming Apr 2022 data cut, including biomarkers, safety, mechanisms of acquired resistance, and preclinical mechanism of N+T, will be presented.

P2, N=25, Active, not recruiting, City of Hope Medical Center | N=40 --> 25 | Trial completion date: Oct 2021 --> Dec 2022

P2; Trial completion date: Feb 2022 --> Feb 2024 | Trial primary completion date: Feb 2022 --> Feb 2024