HER-2 L755S

P2, N=45, Completed, IFCT

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.

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

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.

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

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

HER2 mutations drive the growth of a subset of breast cancers and are targeted with HER2 tyrosine kinase inhibitors (TKI) such as neratinib...Cells expressing double HER2 mutations exhibited resistance to most HER2 TKIs but retained sensitivity to mobocertinib and poziotinib...Double-mutant cells showed enhanced MEK/ERK signaling, which was blocked by combined inhibition of HER2 and MEK. Together, these findings reveal the driver function of secondary HER2 mutations in resistance to HER2 inhibition and provide a potential treatment strategy to overcome acquired resistance to HER2 TKIs in HER2-mutant breast cancer.

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.

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

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.

Dual GFP-Luc tagged HER2+ BT474 naïve parental cells and their acquired lapatinib (LapR), neratinib (NeraR), and tucatinib (TucaR) resistant (Res) derivatives harboring acquired HER2 L755S, HER2 L755S and a pathogenic PIK3CA mutation, or EGFR amplification, respectively were used. Additional studies to investigate the organ-specific metastatic tropism of each acquired resistant model are currently ongoing. Molecular and functional characterization of our established metastatic cultures will guide future in vivo studies, including testing the efficacy of new targeted treatment regimens to treat organ-specific metastasis, and expanding such studies to additional relevant cell and patient-derived xenograft/organoid models.

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

We analyzed cfDNA from 39 Japanese patients with MBC. The tumor subtypes were as follows; 18 cases of luminal, 7 cases of luminal-HER2, 6 cases of HER2, and 8 cases of triple-negative. Median turnaround time of the assay was 8 days (6–26 days).

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

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.

Eight ongoing clinical trials are underway to test different anti-HER2 treatments in ERBB2 mutant mCRC. Several reports documented the emergence of ERBB2 mutations in the circulating tumor DNA (ctDNA) of ERBB2 amplified mCRC progressing to anti-HER2 agents, thus hinting a role in acquired resistance.

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.

The most highly recurrent HER2 mutant, L755S, was particularly resistant to neratinib but sensitive to the pan-HER TKI poziotinib, alone or in combination with fulvestrant. Similar therapeutic effects of poziotinib were observed in both an engineered HER2L755S MCF7 model and a patient-derived xenograft harboring a HER2G778_P780dup mutation. Overall, these findings support the need for clinical evaluation of poziotinib for the treatment of HER2 mutant metastatic breast cancer.

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.

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.

ERBB2mts& fusions were observed in all breast cancer subtypes - more commonly in HER2+, metastatic, & lobular histology tumors - & did not influence prognosis. These alterations may reflect response to treatment pressures in HER2+ disease to reactivate HER2-mediated growth pathways following anti-HER2 therapy & may represent a targetable upregulated oncogenic pathway in HER2- disease. Ongoing identification of ERBB2 alterations may augment treatment options for breast cancer pts & clinical outcomes from this approach are under investigation.

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

P2, N=46, Active, not recruiting, Intergroupe Francophone de Cancerologie Thoracique | Trial completion date: Jul 2022 --> Jul 2023 | Trial primary completion date: Jul 2021 --> Jul 2022

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

Background : With recent approval of the irreversible pan-HER tyrosine kinase inhibitor (TKI) neratinib (N) and the HER2-specific TKI tucatinib (T) in the advanced setting and their edging towards the early setting in HER2+ BC, resistance will likely emerge as a challenge, as illustrated by the HER2CLIMB study, where only one patient with brain metastasis remained progression free after 2 years on T. We set out to define the mechanisms of resistance to T and treatment strategies to overcome it. Materials and Methods : Our previously characterized HER2+ BT474 models with acquired resistance to lapatinib (L; LapR) or N (NrbR) (SABCS20-PD3-09), and our recently developed models of BT474 and SKBR3 with acquired resistance to T (TucaR) developed through long-term exposure to increasing doses of T (up to 200nM) and their naïve parental (P) were used...Further, the elevated pEGFR, pHER2, pHER3, pAKT, and pS6 levels in TucaR models were substantially suppressed by the EGFR-specific TKI gefitinib (G) (50, 500nM) or even further when combined with T (500 nM G+200nM T)...Whilst we previously reported that the LapR and NrbR cells were cross-resistant to T, the TucaR cells remained highly sensitive to the pan-HER TKIs N, poziotinib, and pyrotinib...Further, while resistance to L and N confers cross-resistance to T, resistance to T may be overcome using pan-HER TKIs or the combination of potent EGFR and HER2 inhibitors. Together, our findings hold crucial implications in light of the current treatment landscape of HER2+ BC, with a particular emphasis on the considerations to strategize the treatment sequence of currently available TKIs.

Effects of estrogen (E2), fulvestrant, or neratinib on cell growth and HER2 signaling were examined on ER+/ILC cells (MM134) stably expressing HER2/WT, HER2/S310F, and HER2/L755S. We demonstrate that clinically associated HER2 mutations drive endocrine therapy or neratinib resistance and poor patient outcome in ER+ patients. Our data propose the use of the irreversible pan-HER TKI poziotinib for treating endocrine therapy or neratinib refractory ER+ HER2-mutant metastatic breast cancer.

P2; Trial completion date: Mar 2021 --> Mar 2023 | Trial primary completion date: Mar 2021 --> Mar 2022