HER-2 V842I

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

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

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.

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.

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.

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

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.

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

P1/2, 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)

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.

Our results are emphasizing that SP individuals with ERBB2 mutants are at higher risks of subsequent colorectal neoplasms. ERBB2 mutants might work as facilitated markers for prediction of high-risk SPs and might implicate a potential mechanism in the serrated pathway to colorectal carcinoma (CRC).

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

We also observed one activating PIK3CA mutations (D549N) which may be sensitive to mTOR inhibitors and one targetable gene mutation of EGFR T790M which can be targeted by the third-generation EGFR-TKI osimertinib... The mutational landscape of our wild-type GIST cohort provided evidence that many driver mutations in these pathways are targetable. Our findings indicated that wild-type GIST patients should be tested for alternative driver mutations and receive the corresponding targeted therapies.

We also found two MAP2K1 activating mutations (K57E and K57N) which can be targeted by trametinib...We also observed two activating PIK3CA mutations (R108H and G364R) which may be sensitive to PIK3CA inhibitor alpelisib... The mutational landscape of our SBA cohort provided compelling evidence that multiple signaling pathways play a role in the pathogenesis of SBA and many driver mutations in these pathways are targetable. Our findings indicated that SBA patients should participate in matched clinical trials for better management of this disease.

P2, N=40, Active, not recruiting, City of Hope Medical Center | Trial completion date: Oct 2020 --> Oct 2021 | Trial primary completion date: Oct 2020 --> Oct 2021

68% of patients received =2 systemic regimens (96% received prior gemcitabine-based regimens). Neratinib is safe and tolerable in patients with advanced BTC patients and somatic HER2 mutations. The antitumor activity of neratinib appears comparable to current standards of care, with similar PFS and OS in heavily pretreated patients. Analysis of co-occurring oncogenic mutations and response is ongoing, and consideration is being given to neratinib-based combination regimens to further improve outcomes in this setting.

Drugs such as trastuzumab, pertuzumab, lapatinib, neratinib, and the more recent afatinib target the deregulation of HER2 expression. These data suggest that exploring HER2 SNPs in each patient could help individualize anti-HER2 therapies. Advances in our understanding of the genetics of the HER2 gene and its relations with the efficacy of anti-HER2 treatments are needed to improve the outcomes of patients with this aggressive breast cancer.

The in vitro and in vivo models of SBA developed here provide a valuable resource for understanding targetable mutations in this disease. Our findings support clinical efforts to target activating ERBB2 mutations in patients with SBA that harbors these alterations.

P2, N=150, Recruiting, Spectrum Pharmaceuticals, Inc | Not yet recruiting --> Recruiting