HER2 Alterations Research Articles

Efficacy of disitamab vedotin in non-small cell lung cancer with HER2 alterations: a multicenter, retrospective real-world study

BackgroundNon-small cell lung cancer (NSCLC) with human epidermal growth factor receptor 2 (HER2) alterations poses a substantial treatment challenge. Current HER2-targeted therapies offer limited efficacy. Antibody-drug conjugates (ADCs) targeting HER2 have emerged as a promising therapeutic strategy. This study aimed to evaluate the clinical response to a novel ADC drug Disitamab vedotin (RC48) in advanced NSCLC with HER2 alterations.MethodsThis study conducted a retrospective review of patients harboring HER2 alterations treated with RC48 in the real world. Clinical outcomes were evaluated in terms of objective response rate (ORR), disease control rate (DCR), and progression-free survival (PFS).ResultsOut of 22 patients, 21 (95.5%) received RC48 combination therapy, while one received RC48 monotherapy. The ORR of all patients reached 45.5%, and the DCR stood at 90.9%. The median PFS (mPFS) was 7.5 months. Among patients receiving RC48 combination therapy, the ORR was 47.7%, and the mPFS of 8.1 months. The combination of RC48 with platinum+/- bevacizumab resulted in the highest ORR of 71.4% (5 out of 7 patients), with HER2 TKI following at a 50.0% ORR (4 out of 8 patients). First-line (1L) treatment with RC48 showed an ORR of 62.5% (5 out of 8 patients), second-line (2L) treatments had a 57.1% ORR (4 out of 7 patients), and beyond second-line (>2L) treatments exhibited a 14.3% ORR (1 out of 7 patients). Patients with 1L, 2L, or >2L treatment had a mPFS of 8.1 months, 7.2 months, and 7.4 months, respectively. Patients with HER2 mutations or amplifications, and those with concurrent mutations and amplifications at baseline, showed mPFS of 8.1 months, 9.4 months, and 7.4 months, respectively. The mPFS was significantly longer in patients with HER2 amplification. The most common adverse events included hand-foot syndrome (54.5%), asthenia (50.0%), decreased white blood cell count (45.5%), and liver impairment (45.5%). Grade 3 adverse events occurred in one (4.5%) patient.ConclusionRC48, particularly in combination regimens, demonstrates promising efficacy in advanced NSCLC with HER2 alterations. These findings underscore the need for further research to validate RC48’s application in clinical practice.

Evaluating Biomarker Dynamics in Breast Cancer Post-Neoadjuvant Chemotherapy: A Retrospective Cross-sectional Study

Background: Neoadjuvant chemotherapy (NACT) is integral to breast cancer management, yet its influence on biomarkers, notably androgen receptor (AR), remains underexplored. This study examines post-NACT alterations in receptor status, including ER, PR AR, HER2 and Ki67 index in breast cancer patients. Methods: A cross-sectional study, spanning three years at a tertiary care center, enrolled patients with invasive breast cancer undergoing mastectomy post-NACT. Pre- and post-NACT specimens underwent histological grading and immunohistochemistry for hormone status, HER2 status, and Ki67 index. Discordance between pre- and post-NACT receptor statuses and expression levels of biomarkers was assessed using McNemar’s and Wilcoxon signed rank tests respectively. Results: Among 100 patients, 35 were assessed. Mean age was 43.83 years, with prevalent T1 tumors (34.3%) and N1 nodal involvement (37.1%). Post-NACT, 54.2% showed no histological grade change. Notable alterations included changes in ER (14.2%), PR (14.2%), and HER2 status (8.57%). AR expression showed a significant change following NACT (p=0.03), while ER expression exhibited a trend towards significance (p=0.06). Ki67 index decreased in only 5.7% of cases. Conclusion: This study unveils intricate biomarker dynamics following NACT in breast cancer, with particular emphasis on AR, hitherto not evaluated. Larger investigations are imperative to elucidate clinical implications and tailor treatment strategies for breast cancer patients undergoing NACT.

P2.10A.03 RESOLUTION: Phase II Study of Disitamab Vedotin in Combination with Tislelizumab and Bevacizumab in Patients with HER2 Alteration Advanced NSCLC

P2.10A.03 RESOLUTION: Phase II Study of Disitamab Vedotin in Combination with Tislelizumab and Bevacizumab in Patients with HER2 Alteration Advanced NSCLC

Prognostic and Predictive Roles of HER2 Status in Non-Breast and Non-Gastroesophageal Carcinomas.

The oncogene ERBB2, also known as HER2 or c-ERB2, is located on chromosome 17 (q12). It encodes a tyrosine kinase receptor, the human epidermal growth factor receptor 2 (HER2), involved in neoplastic proliferation, tumor angiogenesis, and invasiveness. Over the past years, the introduction of various anti-HER2 therapies has significantly improved outcomes for patients with HER2-positive breast and gastroesophageal carcinomas. More recently, the introduction of a new antibody-drug conjugate, that is trastuzumab deruxtecan, expanded the therapeutic options to low-HER2 breast and gastroesophageal tumors. HER2 protein overexpression is investigated using immunohistochemistry, gene amplification using fluorescence in situ hybridization, and gene mutation using next-generation sequencing. This review evaluated the predictive and prognostic role of HER2 status in various types of epithelial malignant cancers beyond breast and gastroesophageal cancers. We critically analyzed the key published studies, focusing on utilized scoring systems and assays used, and analyzed clinical parameters and therapeutic approaches. Although the evidence about prognostic and predictive roles of HER2 in carcinomas other than breast and gastroesophageal has been widely increasing over the last decade, it still remains investigational, revealing a tumor site-related prognostic and predictive value of the different types of HER2 alterations. However, standardized and validated scoring system assays have not been well-established for many organs.

Protein Expression, Amplification, and Mutation of HER2 Gene in Canine Primary Pulmonary Adenocarcinomas: Preliminary Results.

Recently, human epidermal growth factor receptor 2 (HER2) has emerged as a therapeutic target of interest for non-small-cell lung cancer in humans. The role of HER2 in canine pulmonary adenocarcinomas is poorly documented. To address this gap, this study employed three methodologies: immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), and next-generation sequencing (NGS) to investigate the protein expression, gene amplification, and mutation of HER2 in 19 canine primary pulmonary adenocarcinomas. By IHC, 3 out of 19 cases were overexpressed 3+, 6 were 2+, and 10 were negative. With FISH, 2 cases were amplified (12.5%), 3 were inadequate for the analyses, and the others were non-amplified. With NGS, seven cases were inadequate. All other cases were wild-type, except for one IHC 3+ case, which was amplified with FISH and with a specific mutation already described in human pulmonary adenocarcinoma, V659E. This mutation is probably sensitive to tyrosine kinase inhibitory drugs. These results are similar to those in human medicine and to the few data in the literature on canine lung carcinomas; the presence of 12.5% of amplified cases in dogs lays the foundation for future targeted drugs against HER2 alterations.

Muscle-invasive and metastatic urothelial carcinoma of the urinary bladder : Current state of histopathologic, molecular, and immunologic prognostic and predictive factors

Muscle-invasive and metastatic urothelial carcinoma (UC) represents aheterogeneous disease entity with numerous morphological, molecular, and immunological phenotypes. This article aims to provide an overview of current histopathological, molecular, and immunological prognostic and predictive factors in muscle-invasive and metastatic UC. Muscle-invasive and metastatic UC exhibits awide range of divergent differentiations and histological subtypes. The correct diagnosis of these morphological variants is essential, as they may determine the clinical course and may also present specific and potentially therapeutically targetable molecular alterations (e.g., HER2 alterations in micropapillary UC). The morphological subtypes largely correlate with the six molecular consensus subtypes. Furthermore, morphological and molecular subtypes are associated with immunological properties that are relevant for modern immunotherapies, such as the PD-L1 status. Numerous immunotherapy studies in the setting of curatively treatable muscle-invasive UC will be reported in 2024 and 2025, likely leading to an increasing number of PD-L1 testing indications.

HER2-targeted therapies beyond breast cancer - an update.

The receptor tyrosine-kinase HER2 (also known as ErbB2) is a well-established therapeutic target in patients with breast or gastric cancer selected on the basis of HER2 overexpression on immunohistochemistry and/or ERBB2 amplification on in situ hybridization. With advances in cancer molecular profiling and increased implementation of precision medicine approaches into oncology practice, actionable HER2 alterations in solid tumours have expanded to include ERBB2 mutations in addition to traditional HER2 overexpression and ERBB2 amplification. These various HER2 alterations can be found in solid tumour types beyond breast and gastric cancer, although few HER2-targeted therapeutic options have been established for the other tumour types. Nevertheless, during the 5 years since our previous Review on this topic was published in this journal, obvious and fruitful progress in the development of HER2-targeted therapies has been made, including new disease indications, innovative drugs with diverse mechanisms of action and novel frameworks for approval by regulatory authorities. These advances have culminated in the recent histology-agnostic approval of the anti-HER2 antibody-drug conjugate trastuzumab deruxtecan for patients with HER2-overexpressing solid tumours. In this new Review, we provide an update on the current development landscape of HER2-targeted therapies beyond breast cancer, as well as anticipated future HER2-directed treatment strategies to overcome resistance and thereby improve efficacy and patient outcomes.

HER2/PI3K/AKT pathway in HER2-positive breast cancer: A review.

Breast cancer is currently the most commonly occurring cancer globally. Among breast cancer cases, the human epidermal growth factor receptor 2 (HER2)-positive breast cancer accounts for 15% to 20% and is a crucial focus in the treatment of breast cancer. Common HER2-targeted drugs approved for treating early and/or advanced breast cancer include trastuzumab and pertuzumab, which effectively improve patient prognosis. However, despite treatment, most patients with terminal HER2-positive breast cancer ultimately suffer death from the disease due to primary or acquired drug resistance. The prevalence of aberrantly activated the protein kinase B (AKT) signaling in HER2-positive breast cancer was already observed in previous studies. It is well known that p-AKT expression is linked to an unfavorable prognosis, and the phosphatidylinositol-3-kinase (PI3K)/AKT pathway, as the most common mutated pathway in breast cancer, plays a major role in the mechanism of drug resistance. Therefore, in the current review, we summarize the molecular alterations present in HER2-positive breast cancer, elucidate the relationships between HER2 overexpression and alterations in the PI3K/AKT signaling pathway and the pathways of the alterations in breast cancer, and summarize the resistant mechanism of drugs targeting the HER2-AKT pathway, which will provide an adjunctive therapeutic rationale for subsequent resistance to directed therapy in the future.

Spectrum of HER2 alterations in NSCLC: Comparative analysis of tissue and liquid biopsies in lung cancer.

e20602 Background: Non-Small Cell Lung Cancer (NSCLC) exhibits a spectrum of molecular alterations that play a crucial role in understanding its heterogeneity and tailoring targeted therapies. Among these alterations, HER2 aberrations have gained significance as potential therapeutic targets. This study aims to explore the diversity of HER2 changes in NSCLC through tissue and liquid biopsies, providing valuable insights into the feasibility and accuracy of either method. Methods: Data from next generation sequencing of 799 tissues and 1380 liquid biopsy specimens was retrospectively analyzed. The study sought to elucidate the prevalence of HER2 alterations with these two methodologies, evaluating their respective strengths and limitations in detecting HER2 changes in NSCLC. Results: HER2 mutations were identified in 2.1% (17/799) of tissue, mirroring the prevalence observed in the TCGA cohort (2%). The liquid biopsy cohort identified Her2 mutations with similar prevalence and was positive for Her2 mutations in 2.2% (30/1380). Within Her2 mutations, HER2 exon 20 insertion mutations emerged as the predominant variant, accounting for all variants in tissue samples and 93.3% (28/30) in liquid biopsies. The most frequent HER2 exon 20 variant was p.Y772_A775dup variant (76.5% in tissue, 71.4% in liquid biopsy), followed by p.E770_A771insAYVM (17.6% in tissue and 7.1% in liquid). Less frequent HER2 mutations included p.G776delinsLC, p.G776delinsVC, p.V777_G778insGSP, p.A775_G776insYVMA. HER2 amplification was detected in 1.4% (5/352) of tissue and 1.3% (8/617) of liquid biopsy samples; concurrent HER2 mutation and Her2 amplification were detected in 3 liquid biopsy samples. 11/60 cases had concurrent targetable alterations in other targetable genes. Most common concurrent alterations were in EGFR followed by KRAS. Concurrent EGFR sensitizing alterations were observed in 7 patients ( 6 EGFR Exon 19 deletion and one EGFR L858R). Only 2/7 patients showed concurrent EGFR/HER2 alterations at baseline, the remaining 5/7 patients had received prior EGFR TKI therapy. Conclusions: Our results demonstrate equivalent Her2 alteration detection rate with liquid biopsy as compared to tissue molecular profiling in NSCLC. Our results support utility of liquid biopsy for Her2 profiling in the primary setting as well as to detect acquired Her2 alterations like in patients post EGFR-TKI therapy. It highlights that HER2mutations coexist with HER2 amplification in subset of advanced NSCLC patients. [Table: see text]

IAM1363-01: A phase 1/1b study of a selective and brain-penetrant HER2 inhibitor for HER2-driven solid tumors.

TPS3186 Background: HER2 activation promotes carcinogenesis, prompting the development of HER2-directed therapies in cancers with HER2 alterations. There is a critical need for novel agents to treat HER2-driven cancers, as current inhibitors display significant toxicity and lack efficacy against certain mutations. IAM1363 (formerly IAM-H1 and ENT-H1) is an irreversible and brain-penetrant small molecule inhibitor targeting both wildtype HER2 and oncogenic HER2 mutants, including the recalcitrant exon 20 mutations. IAM1363, discovered through Iambic Therapeutics' AI-driven discovery platform, represents the only example of a Type II HER2 inhibitor. It was designed to avoid off-target toxicities from EGFR inhibition thus expanding the therapeutic index over existing HER2 inhibitors. In preclinical studies, IAM1363 shows preferential tumor enrichment, a unique feature observed across tumor types and anatomic sites. The promising target specificity and pharmacokinetic profile of IAM1363 offers the potential to bridge gaps left by current standard of care HER2 targeted treatments. Methods: IAM1363-01 is a first-in-human, multicenter, open-label, Phase 1/1b dose escalation and expansion trial evaluating IAM1363 as monotherapy and in combination with trastuzumab. The study will enroll patients with relapsed/refractory malignancies that have documented HER2 gene alterations (amplification or tyrosine kinase domain mutations) or protein overexpression. Prior treatment with HER2 directed therapies is allowed after a washout period. Part 1, dose escalation, will enroll patients with any tumor type. Part 2 will optimize IAM1363 dosing as monotherapy and in combination with trastuzumab. Part 3 consists of a Simon 2-Stage evaluation of IAM1363 as monotherapy in patients with colorectal, non-small cell lung, and bladder cancer with or without brain metastases and in combination with trastuzumab in breast cancer patients with brain metastases. Key objectives are to establish the safety and tolerability of IAM1363, characterize PK/PD, and determine the recommended Phase 2 dose. Exploratory analysis will correlate HER2 expression level/mutation status with tumor response and tolerability. IAM1363 will be given orally once daily at a starting dose of 120 mg/day in up to 4 planned dose levels. Dose escalation employs an accelerated titration design that transitions to a standard 3 + 3 design based on protocol-specific criteria. Up to 287 patients will be enrolled at approximately 20 sites and treated until disease progression or unacceptable toxicity. The trial is designed to establish the safety profile of IAM1363 as a single agent and in combination with trastuzumab and to provide initial proof of antitumor activity in malignancies with HER2 overexpression, gene amplification, or tyrosine kinase mutations, including in patients with brain metastases. Clinical trial information: NCT06253871 .

Characterization of HER2 alterations in lung adenocarcinoma.

8534 Background: Mutations in the human epidermal growth factor receptor 2 (ERBB2; HER2) are oncogenic in lung adenocarcinoma (LUAD). An FDA-approved drug, trastuzumab deruxtecan, is now available as second line treatment (rx) of patients (pts) with HER2 mutated NSCLC. HER2 activation occurs via gene mutation (mt), gene amplification (amp), or protein overexpression. Further information is needed about HER2 alterations (alt) and the potential association with rx response. The purpose of this study is to describe the genomic landscape of a cohort of pts with HER2 alt LUAD in the American Association for Cancer Research (AACR) Project Genomics Evidence Neoplasia Information Exchange (GENIE) Biopharma Collaborative (BPC). Methods: In a cohort of 16,241 NSCLC LUAD pts available in GENIE v.13.0, we analyzed the association of HER2 alt (mt/amp) with alt in other driver genes. Also, we assessed the relationship between HER2 alt and expression levels using TCGA and CPTAC cohorts (566 and 110 pts), and prognosis using GENIE NSCLC BPC cohort (1,846 pts). Results: LUAD pts were classified as having KRASmt (K; 6426 pts; 31.9%), EGFRmt (E; 5256 pts; 26%) or EML4-ALK fusion (A; 102 pts; 0.5%). The remainder were classified as “KRAS/EGFR/ALK other (KEAother).” HER2mt (6.06%) and amp (2.06%) were more frequent in the KEAother cohort(p<0.001). HER2 amp were also found more frequently in the E deletion(del) mt cohort (1.63%), compared to KA cohorts (p<0.001). Additionally, there was significant co-occurrence of HER2 mt and HER2 amp (OR 6.49; p<0.001) in the KEAother cohort. HER2mt/amp had significant odds of co-occurrence with TP53 alt (OR 1.43; p<0.001), CDKN2A del (OR 2.15; p<0.001), TERT amp (OR 2.37; p<0.001), RB1 alt (OR 1.6; p<0.001). Additionally, HER2 amp co-occurred with TP53 alt (OR 4.0; p<0.001), CDKN2A del (OR 3.44; p<0.001), while HER2 mt co-occurred with CDKN2A del (OR 2.03; p<0.001), TERT amp (OR 2.43; p<0.001). BRAF mts were mutually exclusive with HER2 mt/amp (OR 2.31; p<0.001) and HER2 mt (OR 1.93; p<0.001). In the E cohort, there was a significant rate of HER2 mt or amp co-occurring with RB1 alt (OR 2.95; p<0.001). Despite limited survival data in the GENIE database, HER2 mt and amp had a trend toward inferior mOS (HER2mt 29.4 months vs HER2amp 27.8 months vs HER2wt 51.0 months), but this difference was not statistically significant. High HER2 mRNA expression is associated with increased age, while low expression is associated with stage IV disease. Pts with high HER2 expression that never smoked, have a trend toward inferior mOS (p=0.19), but this is based on a limited number of pts (n=18). Conclusions: HER2 mts are found in 1-4% of pts with NSCLC but can be identified in up to 6% of KEAother NSCLC. In contrast to prior reports, there was a significant rate of co-occurring HER2 mt and HER2 amp. BRAF mts were mutually exclusive with both HER2 mt and amp. Further analysis using the Caris database is planned to evaluate clinical outcomes by HER2 alt, co-mts, and prior rx received.

Characterization of diverse targetable ERBB2 alterations in 512,993 patients with solid tumors.

3129 Background: Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate (ADC) that has demonstrated activity against a range of HER2-expressing and HER2-mutant (mut) solid tumors. We present an extensive landscape of ERBB2 alterations (alt) that may predict sensitivity to HER2-targeted therapies in development with a focus on mutations and cancer types without approved indications. Methods: We queried institutional databases (MSKCC and Foundation Medicine, Inc.) of comprehensive genomic profiling (CGP) performed on solid tumor tissue samples using either MSK-IMPACT (N=83,332; MSK) or FoundationOne/FoundationOne CDx (N=429,661; FMI) and on patient-matched liquid biopsies using FoundationOne Liquid CDx (N=1,922). ctDNA tumor fraction (ctDNA TF) on FoundationOne Liquid CDx was estimated using a composite algorithm. Clinicopathological characteristics and treatment outcomes were annotated for MSK-IMPACT samples. Results: ERBB2 activating alt were detected in 6.6% (n=28,508) and 5.0% (n=4,133) of tumors in the FMI and MSK cohorts, respectively. In FMI tissue samples, ERBB2 alt were most prevalent in gastroesophageal (GEC; 18.1%), bladder (18.0%), salivary gland (14.1%), breast (12.7%), and uterine (12.1%) cancers. The cancer types with the largest number of ERBB2mut tumors, specifically, included NSCLC (n=1,618, 1.9%), breast (n=1,565, 3.5%), colorectal (CRC; n=1,221, 2.3%), bladder (n=855, 8.8%), and GEC (n=660, 3.4%). Across these 5 cancers, ERBB2 mut were most commonly located in the kinase domain (KD; 58%), followed by the extracellular domain (ECD; 28%) and transmembrane domain (TMD; 2%). Rare splice site mut and in-frame deletions resulting in exon 16 loss (Ex16Alt) were also observed (n=76, <0.1%). ERBB2 mut were found to be mutually exclusive with other RTK/MAPK driver oncogenes including: EGFR, KRAS, ALK, MET, BRAF, and RET in NSCLC; FGFR1 in breast cancer; BRAF in CRC; and FGFR3 in bladder cancer. In patient-matched liquid biopsy samples, sensitivity for detecting ERBB2 amplifications (amp; 33.3%, 43/129) was lower than for detecting ERBB2 mut (72.3%, 47/65) across select cancers. However, sensitivity for detection of both alts was improved in liquid samples with elevated ctDNA TF (≥1%), increasing to 52.6% (40/76) for amp and 97.3% (36/37) for mut. In the MSK cohort, 110 of 986 (11.2%) patients with ERBB2 mut non-NSCLC tumors received one or more HER2-targeted therapies, including ADCs. Clinical responses to HER2-targeted therapies were observed in patients harboring KD mut (n=10), ECD mut (n=6), TMD mut (V659E, n=1), and in 1 patient with a V697L mut. Conclusions: CGP detects diverse ERBB2activating alt at a high incidence in solid tumor types beyond NSCLC. These represent patient populations who may benefit from HER2-directed therapies. Trials of novel HER2-targeted agents are necessary to refine our understanding of the biological dependency of HER2 alterations.

RAS/RAF mutations and microsatellite instability status in primary colorectal cancers according to HER2 amplification.

HER2 amplification-associated molecular alterations and clinicopathologic features in colorectal cancers (CRCs) have not been well established. In this study, we assessed the prevalence of HER2 amplification and microsatellite instability (MSI) status of 992 patients with primary CRC. In addition, molecular alterations of HER2 amplified and unamplified CRCs were examined and compared by next-generation sequencing. HER2 amplifications were found in 41 (4.1%) of 992 primary CRCs. HER2 amplification was identified in 1.0% of the right colonic tumors, 5.1% of the left colonic tumors, and 4.8% of the rectal tumors. Approximately 95% of HER2 amplification was observed in the left colon and rectum. Seven (87.5%) of eight metastatic tumors showed HER2 amplification. Most clinicopathologic features were unrelated to HER2 amplification except tumor size and MSI status. All 41 HER2 amplified CRCs were microsatellite stable. In a molecular analysis of frequently identified somatic mutations in CRCs, HER2 amplified CRCs showed a lower rate of KRAS mutations (24.4%) but a higher rate of TP53 mutations (83%) than unamplified CRCs. No BRAF and NRAS mutations were identified in HER2 amplified CRCs. Our study suggests that HER2 amplified CRCs are mutually exclusive of MSI and harbor less frequent KRAS/NRAS/BRAF mutations but frequent T53 mutations.

Investigation of efficacy of two different chemotherapy protocols used in neoadjuvant chemotherapy in clinical stages II-IV canine malignant mammary tumours.

The first aim of this study is to demonstrate the clinical efficacy and reliability of two different neoadjuvant chemotherapy (NAC) protocols consisting of doxorubicin/cyclophosphamide (AC) and paclitaxel in dogs with clinical stages II-IV canine malignant mammary tumours (CMTs). Secondly, to determine the Luminal A, Luminal B, HER2-positive and triple-negative molecular subtypes and their value in predicting clinical response to NAC in biopsy samples, and thirdly, to reveal the changes in Ki-67, human epidermal growth factor receptor type 2 (HER2), oestrogen receptor (ER), and progesterone receptor (PgR) expression levels induced by NAC. Thirty dogs with clinical stages II-IV CMTs (T1-3N0-1M0) according to the modified TNM system were included in the study. Dogs in group-1 (n = 15) AC combination and dogs in group-2 (n = 15) were administered paclitaxel. Partial response (PR) was the most common clinical response in both treatment groups (66.66% and 86.66%, respectively). There was no difference between the groups regarding clinical response parameters (p = .001). The rate of treatment responders was higher than the rate of non-responders in both groups (p < .001). The adverse effects observed in both groups were mostly limited to grades 1 and 2 and all were easy to manage. The most frequently detected molecular subtype was Luminal A (59.25%). Complete response (CR) was achieved in 33.33% of dogs with triple-negative CMT in the AC group and 14.29% of the Luminal A subtype in the paclitaxel group. Alterations in Ki-67, HER2, ER, and PgR expressions after chemotherapy were not statistically significant (p > .05). As a result, we have shown that these neoadjuvant chemotherapy protocols are effective and safe alternative treatment options for CMTs.

Abstract CT159: Phase I trial of trastuzumab deruxtecan in combination with neratinib in solid tumors with HER2 alterations (NCI 10495)

Abstract Background: Human epidermal growth factor receptor 2 (HER2) overexpression, amplification, or mutation occurs across a variety of solid tumors. Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate (ADC) that has been approved by the FDA for HER2-overexpressed advanced breast, gastroesophageal cancers, HER2-low breast cancer, and HER2-mutated non-small cell lung cancer. However, some patients do not derive clinical benefit from T-DXd, and drug resistance is inevitable. Preclinical studies demonstrated that neratinib, an oral irreversible pan-HER tyrosine kinase inhibitor, can increase uptake of HER2-targeting ADCs, including ado-trastuzumab emtansine and T-DXd, in vivo. Enhanced uptake of ADC is postulated to be secondary to hindering HSP90 binding to the HER2 receptor, thereby inducing receptor ubiquitination and internalization. This finding was further confirmed in patient-derived xenograft models from two patients with HER2-mutated, but non-amplified, low-expressing advanced breast cancer. Therefore, we hypothesized that the combination of T-DXd and neratinib in patients with advanced solid tumors with a HER2 alteration will enhance the efficacy of T-DXd. As T-DXd and neratinib may have overlapping toxicities in patients, a phase I study to establish the safety of the combination is warranted. Methods: This is a multi-center, phase I clinical trial (NCT05372614, NCI 10495) with a 3+3 design to study the safety and tolerability of T-DXd and neratinib. The trial is supported by the National Cancer Institute Experimental Therapeutics Clinical Trials Network. Eligible patients have advanced solid tumors with HER2 overexpression, amplification by ISH/NGS, or an activating HER2 mutation. Up to 18 evaluable patients will be enrolled in the dose escalation portion (Part 1), and 12 patients will be enrolled in the pharmacodynamic cohort (Part 2). During Part 1, the maximum tolerated dose and recommended phase 2 dose will be determined for neratinib. The dose of T-DXd is fixed at 5.4 mg/kg. We are actively enrolling patients in Part 1. The primary endpoint is dose-limiting toxicities of the combination during the first 2 cycles of treatment (42 days). Key secondary objectives of the study include T-DXd payload (DXd/MAAA-1181a) in tumor tissue obtained before and after co-treatment with neratinib to assess the potential enhanced payload concentration with the combination and quantitative HER2 assessed by mass spectrometry using multiplex reaction monitoring. Citation Format: Andrew A. Davis, Ecaterina E. Dumbrava, Aparna Kalyan, Nataliya V. Uboha, Haider S. Mahdi, Reema A. Patel, Farshid Dayyani, Jessica Porzel, Whitney L. Hensing, Cynthia X. Ma, Ron Bose, Haeseong Park. Phase I trial of trastuzumab deruxtecan in combination with neratinib in solid tumors with HER2 alterations (NCI 10495) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT159.

Prognostic and predictive biomarkers with therapeutic targets in nonsmall-cell lung cancer: A 2023 update on current development, evidence, and recommendation.

Since the publication of the original work in 2014, significant progress has been made in the characterization of genomic alterations that drive oncogenic addiction of nonsmall cell lung cancer (NSCLC) and how the immune system can leverage non-oncogenic pathways to modulate therapeutic outcomes. This update evaluates and validates the recent and emerging data for prognostic and predictive biomarkers with therapeutic targets in NSCLC. We performed a literature search from January 2015 to October 2023 using the keywords non-small cell lung cancer, clinical practice guidelines, gene mutations, genomic assay, immune cancer therapy, circulating tumor DNA, predictive and prognostic biomarkers, and targeted therapies. We identified, reviewed, and evaluated relevant clinical trials, meta-analyses, seminal articles, and published clinical practice guidelines in the English language. Regulatory-approved targeted therapies include those somatic gene alterations of EGFR ("classic" mutations, exon 20 insertion, and rare EGFR mutations), ALK, ROS1, BRAF V600, RET, MET, NTRK, HER2, and KRAS G12C. Data for immunotherapy and circulating tumor DNA in next-generation sequencing are considered emerging, whereas the predictive role for PIK3CA gene mutation is insufficient. Advances in sequencing and other genomic technologies have led to identifying novel oncogenic drivers, novel resistance mechanisms, and co-occurring mutations that characterize NSCLC, creating further therapeutic opportunities. The benefits associated with immunotherapy in the perioperative setting hold initial promise, with their long-term results awaiting.

Abstract 5857: Trastuzumab deruxtecan resistance can be mediated by payload resistance or secondary extracellular ERBB2 mutations but sensitivity to HER2 tyrosine kinase inhibitors is maintained

Abstract Among NSCLC patients, the most common HER2 mutation is the exon 20 insertion mutation, Y772dupYVMA, which accounts for over 40% of all HER2 mutations in lung cancer. Trastuzumab deruxtecan (T-DXd), a HER2 antibody-drug conjugate (ADC), received FDA approval for the treatment of HER2 mutant NSCLC yielding a confirmed objective response of 52% and a median duration of response of greater than 9 months. Unfortunately, patients that initially respond to T-DXd will eventually acquire resistance, and the mechanisms of resistance as well as effective targeting strategies to overcome resistance are not yet elucidated. We generated Ba/F3 cells expressing the HER2 YVMA insertion mutation with acquired resistance to T-DXd by culturing cells in T-DXd until resistance occurred. T-DXd resistant cells retained expression of HER2, but were resistant to the payload, deruxtecan, as well as other topoisomerase inhibitors. T-DXd resistant cells exhibited loss of topoisomerase I, a previously reported mechanism of topoisomerase inhibitor resistance. In parallel, we generated a PDX model of acquired T-DXd resistance and observed sustained expression of HER2 but loss of TOP1 in resistant tumors. T-DXd resistant cell lines were sensitive to payloads with alternate mechanisms of action including maytansine and likewise retained sensitivity to the HER2 ADC trastuzumab emtansine (T-DM1) which utilizes DM1 as a payload. Given that T-DXd resistant cells retained HER2 expression, we assessed whether they were sensitive to HER2 tyrosine kinase inhibitors (TKI). T-DXd resistant cells remained highly sensitive to HER2 TKIs including poziotinib, afatinib, BI-4142, and BI-1622. To investigate whether genomic alterations of HER2 could facilitate HER2 ADC resistance, we utilized the LentiMutate approach which employs an error-prone HIV-1 reverse transcriptase to produce a high frequency of mutations to identify resistance-associated mutations in cells treated with a HER2 ADC. Sequencing analysis revealed that resistant cells had an enrichment in point mutations within HER2 domain IV (D582N, F595C/S, E580K, C623Y), which includes the binding site of trastuzumab. To validate the impact of these mutations on HER2 ADC resistance, we generated cells expressing a HER2 exon 20 insertion in combination with the observed domain IV mutations. D582N and F695C/S co-mutations conferred resistance to T-DXd and T-DM1 but not to HER2 TKIs. These data demonstrate that resistance to T-DXd can be mediated by loss of sensitivity to the ADC payload in which case ADCs bearing payloads with alternate mechanisms of action as well as HER2 TKIs retain anti-tumor cell activity. Moreover, resistance to trastuzumab-based ADCs can also be mediated by secondary mutations within domain IV of HER2. However, these resistance mutations do not diminish HER2 TKI activity. Citation Format: Monique B. Nilsson, Xiuning Le, Junqin He, Xiaoxing Yu, Xiaofang Huo, Ashwani Kumar, Alissa Poteete, Qian Huang, Ralf Kittler, John Heymach. Trastuzumab deruxtecan resistance can be mediated by payload resistance or secondary extracellular ERBB2 mutations but sensitivity to HER2 tyrosine kinase inhibitors is maintained [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5857.

Abstract 1970: Discovery and characterization of potent and selective HER2 exon20 insertion mutant inhibitors

Abstract Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, accounting for over 85% of all cases. Among NSCLC, approximately 2-4% of patients have mutations in the HER2, a member of the ErbB family of receptor tyrosine kinases and key proliferation driver, with exon 20 insertions making up about 90% of these mutations. HER2 exon mutations can have various alterations, and among them, the most common HER2 mutation is in-frame insertions in exon 20, especially the A775_G776insYVMA insertion/duplication. These mutations can affect the structure and function of the HER2 protein and may contribute to tumor development and growth. HER2 mutations have often shown resistance to EGFR tyrosine kinase inhibitors (TKIs), further highlighting the need for HER2-specific treatments. Also, inhibitors targeting HER2 mutations are selective, meaning they specifically target HER2 alterations without causing toxicities or affecting EGFRWT. Therefore, there is a need for the development of selective HER2 exon20 insertion mutant inhibitors. Herein, Hanmi has identified selective HER2 exon20 insertion mutant small molecule inhibitors, designed based on affinity and binding mode starting from a known crystal structure using GLIDE (Schrödinger), and the screening for the viability of cell lines including HER2A775_G776insYVMA, HER2G776delinsVC , HER2WT and EGFRWT was investigated. Hanmi's HER2 exon20 insertion mutant inhibitors selectively target mutant HER2 receptor tyrosine domains through shared binding, sparing EGFRWT and minimizing EGFR-related toxicities. With highly selectivity against EGFRWT and desirable pharmacokinetic properties, the Hanmi compounds inhibit HER2 mutant cells and HER2 mutant enzymes. Additionally, the compounds have an oral administration-compatible DMPK profile and demonstrated anti-tumor activity in HER2 mutant and HER2WT tumor xenograft mice. In conclusion, based on our study, Hanmi compounds, a novel HER2 exon20 insertion mutant inhibitors could be suggested as an appropriate therapeutic agent for inhibitory activity against HER2 exon20 insertion mutant NSCLC. Citation Format: Ho Yeon Nam, Sun Young Jang, Jiyoung Jeon, HyungSeok Yoo, Jooyun Byun, Gunwoo Lee, Youngjoo Lee, Yu-Yon Kim, Soye Jeon, Young Gil Ahn. Discovery and characterization of potent and selective HER2 exon20 insertion mutant inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1970.

HER2 and PD-L1 immunohistochemistry (IHC) expression, and HER2 genomic alterations: Associations and clinical outcomes for advanced bladder cancer.

538 Background: Bladder cancer (BC) has a relatively high rate of human epidermal growth factor receptor 2 (HER2) alterations. The association between HER2 mutation/amplification, HER2, and PD-L1 immunohistochemistry (IHC) expression and associations with clinical outcomes for advanced bladder cancer (BC) has not been studied. Methods: We retrospectively analyzed BC samples for PD-L1 and HER2 IHC expression and compared HER2 alterations from genomic profiling with the MSK IMPACT platform. HER2 IHC expression was defined as 0, 1+, 2+, 3+, and PD-L1 IHC was the combined tumor and immune cell PD-L1 expression score (CPS). HER2 alteration was defined as either pathogenic mutation and/or amplification. We studied pairwise associations between HER2 alteration, PD-L1, and HER2 IHC expression in all patients and their associations with progression-free survival (PFS) and overall survival (OS) for muscle-invasive bladder cancer (MIBC) pts. Association analyses were performed using the Wilcoxon rank-sum test or Fisher’s exact test. Kaplan-Meier method and Cox proportional hazard models were used for time-to-event analyses. Results: Among 202 pts with HER2 IHC, 188 had MSK IMPACT, and 168 had PD-L1 CPS. The overall incidence of HER2 alteration was 22.3%; 48.2% had CPS ³10, and HER2 IHC distribution was 0:18.8%, 1+:29.7%, 2+:33.7%, and 3+:17.8%. The CPS score was inversely associated with HER2 IHC expression (p&lt;0.001). No association was noted between CPS score and HER2 alteration (p=0.735). HER2 altered tumors were strongly correlated with high-level HER2 IHC expression (p&lt;0.001). However, 41% (n=14/34) of HER2 IHC 3+ samples did not have HER2 alterations, and 17% (n=7/36) of HER2 altered samples had HER2 IHC expression of 0. In patients with MIBC, HER2 alteration and HER2 IHC expression (0/1+ vs. 2+/3+) were not associated with PFS (p=0.5 and p=0.4, respectively) or OS for MIBC pts (p=0.84 and p=0.94, respectively). A higher PD-L1 CPS score (&gt;=10 vs &lt;10) was associated with improved PFS for MIBC pts (p=0.03). Conclusions: Our study is the first to describe an inverse correlation between HER2 IHC expression and PD-L1 CPS score. Furthermore, HER2 IHC overexpression is strongly associated with HER2 amplification, but a subset of patients with high HER2 protein expression are potentially missed by genomic profiling alone. HER2 expression by IHC or HER2 genomic alteration is not a prognostic marker for MIBC pts in this cohort. This data provides the foundation for further HER2-directed advanced BC studies. [Table: see text]

Upfront Multiplex Gene Test Helps Prolong Survival in Advanced Non-small Cell Lung Cancer.

Detection of genetic abnormalities is crucial for selecting an appropriate therapy to effectively treat advanced non-small cell lung cancer (NSCLC). Multiplex genetic testing aids the selection of appropriate therapy and tailored treatments; however, its impact on survival remains unexplored. Using data from 112 patients with advanced or recurrent NSCLC between February 2020 and April 2023, we investigated the impact of multiplex genetic tests, conducted before the initiation of systemic therapy, on survival. Multiplex genetic test was performed on 72 patients (MPL group). Among the remaining 40 patients (non-MPL group), 18 underwent ≥1 single-plex genetic test, including tests for EGFR (18), ALK (14), and ROS1 (8). The frequency of EGFR mutations in the MPL and non-MPL groups was similar (28% and 25%, respectively), whereas alterations in KRAS, ALK, MET, HER2, and RET levels (5, 4, 4, 4, and 1, respectively) were exclusively detected in the MPL group. The MPL group exhibited a significantly improved survival rate compared to the non-MPL group (median survival time 20.6 vs. 9.3 months, p=0.009). Multiplex genetic testing, before the initiation of systemic treatment, could potentially enhance prognosis by uncovering a wide range of non-EGFR gene abnormalities. Multiplex genetic tests could be crucial for the effective application of modern anticancer therapeutic strategies.