HER2 Mutations Research Articles

Prevalence and clinicopathological associations of HER2 expression in non-small cell lung cancer: a retrospective study in Jordanian patients

BackgroundHuman epidermal growth factor receptor 2 (HER2), a promising therapeutic target, can be mutated, amplified, or overexpressed in different malignancies, including non-small cell lung cancer (NSCLC). Although these alterations showed adverse prognostic effects in many cancers, their clinical significance in NSCLC is controversial. This study primarily assessed the prevalence of HER2 protein expression in NSCLC among Jordanian patients. In addition, the possible association between HER2 protein expression and clinicopathological variables was evaluated.MethodsA total of 100 surgically resected NSCLC cases treated at King Hussein Cancer Center (KHCC) between 2009 and 2021 were examined for HER2 protein expression using immunohistochemistry (IHC). The American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) guidelines for breast cancer were applied to interpret the results with a final score ranging from 0 to 3+, considering a score of 3 + as overexpression. Additionally, a separate subset of patients was tested for HER2 gene mutation. Fisher’s exact test was used to assess the association between HER2 scores and the other variables. Kaplan-Meier method was used to calculate survival.ResultsOf the 100 cases, Her2 overexpression (score 3+) was detected in 2 cases (2%), score 2 + in 10 cases (10%), score 1 + in 12 cases (12%), and score 0 in 76 cases (76%). The two positive cases were one adenocarcinoma and one squamous cell carcinoma; both patients were elderly male smokers. No significant association was identified between Her2 expression and age, gender, smoking, histological subtype, grade, stage, tumor size, and lymph node status. Our findings also showed no association between Her2 expression and survival; however, advanced tumor stages and positive lymph node metastasis were significantly associated with poor overall survival. All cases tested for the Her2 mutation were negative.ConclusionsHer2 overexpression is uncommon in NSCLC among the Jordanian population. However, when the same scoring criteria are used, the rates are similar to other results found in Asian cohorts. Due to our study’s relatively small sample size, a larger one is required to investigate the prognostic value and the molecular associations between the different Her2 alterations.

Molecular correlation of response to pyrotinib in advanced NSCLC with HER2 mutation: biomarker analysis from two phase II trials

BackgroundNon-small cell lung cancer (NSCLC) with HER2 mutation has entered into the era of targeted therapy. However, both anti-HER2 antibody–drug conjugates (ADCs) and tyrosine kinase inhibitors (TKIs) showed moderate objective response rate (ORR) and median progression-free survival (PFS). The aim of this study was to investigate the molecular features of responders to pyrotinib in advanced NSCLC with HER2 mutation.MethodsPatients from our two previous phase II trials were pooled analyzed. Their circulating tumor DNA (ctDNA) were detected by next-generation sequencing (NGS) panels, and the correlation with the efficacy of pyrotinib was investigated.ResultsThis pooled analysis included 75 patients, and 50 of them with baseline plasma samples were finally enrolled with a median age of 57 years old. The overall ORR and median PFS were 28% and 7.0 months respectively. Biomarker analysis showed that 5 patients were ctDNA nonshedding. Patients with TP53 wild type were significantly associated with higher disease control rate (97.1%vs. 68.8%, p = 0.010), PFS (median 8.4 vs. 2.8 months, p = 0.001) and overall survival (OS, median 26.7 vs. 10.4 months, p < 0.001) than those with mutations. ctDNA of nonshedding and clearance exhibited significantly longer PFS (median: 10.2 vs. 9.8 vs. 5.6 months, p = 0.036) and a trend of longer OS (median: 35.3 vs. 18.1 vs. 14.6 months, p = 0.357) than those not.ConclusionPatients with TP53 wild type, ctDNA nonshedding, or clearance showed superior efficacy of pyrotinib in patients with HER2-mutated advanced NSCLC, which might be helpful to guide the utility of pyrotinib in clinical setting.Trial registration: The patients were from two registered clinical trials (ClinicalTrials.gov: NCT02535507, NCT02834936).

Prognostic effects of TP53 variants co-occuring in patients with HER2-mutated non-small cell lung cancer (NSCLC).

e21065 Background: TP53 variants are common in NSCLC and have been reported as prognostic of poor outcome. The impact of TP53 variants in ERBB2/HER2-mutated NSCLC is unclear. Methods: A total of 40 patients with HER2-mutated NSCLC at Princess Margaret Cancer Centre were identified retrospectively; next generation sequencing results were reviewed for TP53 variant status. Associations between TP53 status with patient and tumor characteristics, and outcomes (overall survival [OS] and progression-free survival [PFS]), were investigated. Median survival was computed by Kaplan-Meier estimator; differences between groups were assessed via Cox proportional hazards regression. Results: Co-occurring TP53 variants and HER2 mutations were found in 19/40 patients (47.5%). Median age was 64.5 years and most patients were female (65%), never-smokers (74%), and had adenocarcinoma (90%; Table 1). Median OS was 39.3 months (95% CI:31 months – not reached [NR]) in the TP53 wildtype (WT) cohort compared to 20.5 months (95% CI:3.7 months - NR) in the TP53 variant cohort (HR 2.65 (95% CI: 1.09-6.43; p = 0.03). Median PFS was 30.9 months [16.7-59.8] vs 15.9 months [10.2-NR], although not statistically significant (HR 1.86, 95% CI 0.83-4.18; p = 0.13). There was a tendency for presence of brain metastases at any point for those with TP53 variants (38% versus 63%, p = 0.11). Of the 29 de novo stage IV patients, 10 (36%) had first line targeted treatment. The rest had chemoimmunotherapy (29%), chemotherapy (25%) or immunotherapy (11%). Overall response rates were similar to first line palliative treatment (33% vs 38%, p = 1.00). Conclusions: Co-occuring TP53 variants with HER2 mutations are prognostic of shorter OS and PFS in NSCLC, and may be associated with a higher incidence of brain metastases. Our larger validation dataset with ~75 patients will be presented.[Table: see text]

Characteristics and predictive modeling of HER2 mutation in patients with non-small cell lung cancer.

e13559 Background: Recent advances in targeted therapies have increased the survival and quality of life for non-small cell lung cancer (NSCLC) patients. Understanding clinical characteristics and predicting HER2 status may facilitate efficient use of next-generation sequencing (NGS) testing and promote precision medicine/targeted therapies. Methods: NSCLC patients ≤65 years old, diagnosed between 01/2011 and 06/2021 who have NGS test results were identified in from two National Cancer Institute designated cancer centers in the Northeastern region of the United States. Demographics, behavioral, and clinical characteristics were extracted from electronic health record (EHR) data and EHR-linked cancer registry. Prevalence prediction modelling of HER2/ERBB2 mutation was performed using machine learning (ML) methods including logistic regression (LR), random forest (RF), naïve Bayes (NB), extreme gradient boosting (XGBoost) and multi-layer perceptron (MLP). 10- fold cross validation and k-nearest neighbor method were used to impute missing values. Under-sampling, oversampling and feature selection methods were tried. Results: Among 761 NSCLC patients with NGS reports available, 353 (46%) were ≤65 years old. Among 353 (mean age 57, 58% female, 88% non-Hispanic, 69% white, 57% had metastasis, 58% prescribed chemotherapy) 25 (7%) had a HER2 mutation. Based on univariate significance tests with LR on the complete data: cerebrovascular disease, BMI between 27.5-29.9, KRAS, EGFR and MET were significant with odds ratios (ORs) ranging from 0.2-3.9. In our prediction models, BMI, cerebrovascular disease, weight loss, hepatic metastases, diabetes, congestive heart failure, and KRAS, EGFR, MET and RET alteration status were significant predictors in multivariate analyses, suggesting the potential usefulness of these features in predicting HER2 mutation among patients with NSCLC. Area under the ROC curve (AUC) varied across different models from 70.9% (RF), 70% (XGB and MLP), 69.5% (LR) to 68.2% (Naïve Bayes). The best performing model with RF yielding an AUC ~71% can provide relative high specificity and acceptable sensitivity depending on the cut off. Conclusions: Our prediction models yielded AUC around 70% with the best performing model’s AUC being 71% in a subgroup aged ≤65. After further validation, our prediction model may be used to identify patients appropriate for repeat NGS testing who did not have HER2 testing in first molecular profiling. Future work is needed to predict status in repeat testing with previously test negative patients who relapse or have progression of disease. Random forest (RF) Model performance across different cutoff for the predicted probability. [Table: see text]

Characterization of diverse targetable alterations in ERBB2 and ERBB3 in 93,465 non-small cell lung cancers (NSCLC).

9094 Background: Recently, fam-trastuzumab deruxtecan-nxki was approved for NSCLC with selected activating ERBB2 (HER2) mutations. Patritumab deruxtecan, a novel HER3 directed antibody drug conjugate, exhibits in vitro activity against HER3 mutations. We present a comprehensive landscape of ERBB2/ ERBB3 alterations (alt) that may predict sensitivity to HER2/HER3 targeted therapies in development. Methods: We queried an institutional database (Foundation Medicine) of tissue or liquid comprehensive genomic profiling (CGP) results from 93,465 patients with NSCLC (85,704 tissue and 7,761 liquid samples). ERBB2 amp was defined as ≥ sample ploidy +3. Activating/likely activating alts were called using annotations including presence in COSMIC, functional knowledge of the gene affected, internal insights, and characterization in the literature. ctDNA tumor fraction (TF) on FoundationOneLiquid CDx was estimated using a composite algorithm. Results: Activating/likely activating alt in ERBB2 and ERBB3 were detected in 3.9% (n = 3337) and 0.8% (n = 696) of NSCLC tissue samples, respectively ( ERBB2: 2.0% amp, 1.7% mutations [mut; SNVs or indels], 0.001% rearrangements [RE], and 0.2% multiple; ERBB3: 0.5% amp, 0.3% mut, and 0.004% multiple). Age at diagnosis, sex, and predicted ancestry were similar among patients with ERBB2alt and ERBB2wt tumors. ERBB2 alt were more frequently observed in non-squamous NSCLC (4.3% vs 2.3% in SCC), largely driven by differential ERBB2 mut frequencies (2.0% vs 0.4%). ERBB2 mut were most common in the kinase domain (KD; 70%, 56% of which were exon 20 insertions [ex20ins]), followed by the extracellular domain (ECD; 20%) and transmembrane domain (TMD; 6%), while ERBB3 mut were most common in the ECD (88%, most commonly V104L/M and G284R). ERBB2 RE or splice mut affecting exon 16 were detected in 23 cases (0.03%). While ERBB2 alt were mutually exclusive with other oncogenic drivers ( KRAS, ALK, BRAF, EGFR, MET, ROS1, RET; each p &lt; 0.05), ERBB3 alt were found to co-occur with both ERBB2 (8.5% vs 3.9% ERBB2wt, p &lt; 0.001) and MET (8.6% vs 5.2% ERBB2wt, p &lt; 0.001) alt. A similar distribution of ERBB2 alt (1.6% amp, 2.4% mut, 0.4% multiple) was detected in liquid samples with elevated TF (≥10%; n = 1458); across all liquid samples, ERBB2 mut frequency was comparable to tissue (1.5%) but frequency of amp was 0.5%. In our study, 26% of ERBB2 mut tissue samples had activating/likely activating mut not included in the DESTINY-Lung01 trial, most notably 100% of both TMD mut (n = 99) and exon 16 alt (n = 25), as well as 35% of ECD mut (117/331) and 14% of KD mut (162/1145, including 6% of ex20ins). Conclusions: Diverse ERBB2 and ERBB3 alt in NSCLC may predict sensitivity to anti-HER2/3 therapies, but not all classes of alts are detected/reported by all profiling assays. Utilization of comprehensive testing to guide biomarker definitions, treatment selection, and clinical trial enrollment is imperative.

Phase I Beamion Lung 1 trial of BI 1810631, a HER2 tyrosine kinase inhibitor (TKI), as monotherapy in patients (pts) with advanced/metastatic solid tumors with HER2 aberrations: Updated data.

8545 Background: There is an unmet need for effective TKIs against HER2 mutations in solid tumors, especially NSCLC. BI 1810631 is a highly potent and selective HER2 TKI that covalently binds to both wild-type and mutated HER2 receptors, including exon 20 insertions (ex20ins), while sparing EGFR. Beamion Lung 1 is an ongoing Phase Ia/Ib study to determine the safety, MTD, PK, PD, and preliminary efficacy of BI 1810631 in pts with HER2 aberration-positive solid tumors (NCT04886804). Preliminary results from Phase Ia are presented. Methods: In Phase Ia, pts with advanced/unresectable/metastatic solid tumors who were refractory or unsuitable for standard treatment (Tx) and had HER2 aberrations (e.g. overexpression, gene amplification, somatic mutation, or gene rearrangements) were enrolled. Pts received escalating doses of BI 1810631 BID starting from 15 mg or BI 1810631 QD starting from 60 mg via a Bayesian model. Phase Ib will initially include 30 pts with advanced HER2 tyrosine kinase domain mutation-positive, pre-treated NSCLC. Additional cohorts may be included. Primary endpoints: MTD based on DLTs; pts with DLTs (Phase Ia); ORR (Phase Ib). Secondary endpoints: number of pts with DLTs throughout entire Tx period and PK parameters (Phase Ia/Ib); DoR, DCR, duration of disease control, and PFS (Phase Ib). Results: As of 23 January 2023, 36 pts had been treated in the US, The Netherlands, Japan, and China. Pts had NSCLC (n = 22), colorectal cancer (n = 3), or other tumors (n = 11). Most pts (n = 26; ex20ins: n = 23) had a pathological HER2 mutation. Median (range) lines of prior systemic Tx: 2.5 (1–8). Prior HER2-targeted Tx: 12 (33%). Pts received BI 1810631 at 15, 30, 60, 100, 150 mg BID (n = 3/3/4/4/3) or 60, 120, 180, 240, 300 mg QD (n = 5/4/5/4/1). Median number of cycles was 4 (range 1–14). Tx is ongoing in 20 pts. To date, 3 DLTs have been observed (grade 2 edema [60 mg BID], grade 3 anemia [60 mg QD], grade 3 elevated ALT [180 mg QD]). The MTD has not been reached with either schedule. Tx-related adverse events (TRAEs) were reported in 25 pts (69%). The most common TRAEs were diarrhea (n = 10), anemia (n = 5), increased alkaline phosphatase, increased creatinine, increased ALT, hypoalbuminemia (all n = 4), hypocalcemia, increased AST, dry skin, increased GGT (all n = 3). Three pts had grade 3 TRAEs (anemia/increased GGT [n = 1], increased ALT [n = 2]). Strong preliminary efficacy signals were observed across all dose levels. Of 22 evaluable NSCLC patients, 10 responded (all PRs; all ex20ins) and 11 had SD. Two patients with other tumors (esophagus; cholangiocarcinoma) also achieved PR. Conclusions: These preliminary data indicate that BI 1810631 is well tolerated and shows encouraging anti-tumor activity in pts with HER2 aberration-positive solid tumors. Recruitment into Phase Ia is ongoing. Updated data, including durability endpoints, will be presented. Clinical trial information: NCT04886804 .

Safety and efficacy of inetetamab in combination with pyrotinib in HER2 mutant patients with non-small cell lung cancer (NSCLC): An open-label, phase Ib trial.

9105 Background: Currently, limited targeted therapies are available for HER2 mutant NSCLC patients. Previous studies have shown the antitumor activity of pyrotinib in advanced NSCLC patients with HER2 mutations. Inetetamab is a recombinant humanized anti-HER2 monoclonal antibody. Whether inetetamab combined with pyrotinib could show manageable safety and more active antitumor activity remains unknown. This study was designed to evaluate the safety and efficacy of inetetamab in combination with pyrotinib in HER2 mutant patients with advanced NSCLC. Methods: This study was an open-label, phase Ib study. The HER2 mutant patients with locally advanced or metastatic NSCLC were assigned to receive inetetamab combined with pyrotinib. The study consisted of dose-escalation part and dose-expansion part. During dose-escalation period, the parallel "3+3" dose-escalation design was used to determine the dose-limiting toxicity (DLT). Inetetamab was administered every 3 weeks (8 mg/kg loading dose for cycle 1, followed by 6 mg/kg in subsequent cycles) with pyrotinib (dose-escalation part, 240mg QD, 320mg QD; dose-expansion part, 320mg QD). Primary endpoint of the study was DLT dosage and safety. The DLT was assessed during the 21-day DLT evaluation period after the first dose. Secondary endpoints included objective response rate (ORR), disease control rate (DCR), progression free survival and overall survival. Results: Between August 6, 2021, and August 25, 2022, 48 patients were enrolled. No DLT occurred during pyrotinib 240mg and 320mg escalation period. Therefore, pyrotinib 320mg was chosen as expansion dose. The most common treatment-related adverse events (TRAEs) were diarrhea (66.7% [2/3] in pyrotinib 240mg group, 95.6% [43/45] in pyrotinib 320mg group), rash (66.7% [2/3] in pyrotinib 240mg group, 22.2% [10/45] in pyrotinib 320mg group) and vomiting (0 in pyrotinib 240mg group, 24.4% [11/45] in pyrotinib 320mg group). TRAEs were generally Grade (G) 1-2. Only 7 patients reported G3 TRAE (1 in pyrotinib 240mg group, 6 in pyrotinib 320mg group). The preliminary efficacy was shown in the table below. The ORR and DCR of group receiving inetetamab with pyrotinib 240mg were 0% and 66.7%, respectively. The ORR and DCR of inetetamab with pyrotinib 320mg group were 36.6% and 85.4% respectively. The relationship between different mutation subtypes or co-mutations and efficacy will be updated during the conference reports. Conclusions: The preliminary data of inetetamab in combination with pyrotinib showed manageable safety and compelling antitumor activity in advanced NSCLC patients harboring HER2 mutations. Clinical trial information: NCT05016544 . [Table: see text]

Prognostic and predictive implications of plasma ctDNA in guiding first-line targeted therapy for metastatic HER2-mutant non-small cell lung cancer (NSCLC).

9052 Background: Trastuzumab deruxtecan (T-DXd) is the first HER2-targeted drug approved for NSCLC with human epidermal growth factor receptor 2 ( HER2, ERBB2) mutation in the second or later line settings. However, the optimal first-line treatment for these patients remains unclear. Access to rapid tissue sequencing is not always available, thus presenting challenges to first-line drug development. Circulating tumor DNA (ctDNA) analysis has the potential to overcome these obstacles to guide optimal first-line targeted therapy for patients with HER2-mutant NSCLC. Methods: We retrospectively analyzed patients with metastatic HER2-mutant NSCLC who underwent prospective clinical ctDNA sequencing at Memorial Sloan Kettering Cancer Center (MSK) from January 2016 to September 2022. HER2 mutations were identified by next-generation sequencing through MSK-IMPACT, MSK-ACCESS or Resolution ctDx Lung. Results: We identified 64 patients with metastatic HER2-mutant NSCLC who had received at least one line of systematic therapy. The median age was 63 years (range: 23–90), and there were more women (n = 38, 60%), and never-smokers (n = 38, 60%). The activating HER2 mutations included exon 20 insertions (73%), exon 8 (11%), 19 (11%), and 20 SNVs (5%). Plasma ctDNA was tested before initial therapy in 40 patients with a median overall survival (OS) of 28 months (95% CI 21-34), in whom 31 patients (78%) had at least one detectable ctDNA alteration by MSK-ACCESS and ctDx Lung. 55% (17/31) received chemoimmunotherapy with pembrolizumab as the first-line treatment. The median time to treatment discontinuation (TTD) was 6 months (95%CI 5.5-6.9). Additionally, 19% of patients (6/31) received a HER2-targeted antibody-drug conjugates (ADC) as first-line treatment with a median TTD of 6 months (95% CI 2-10), including 5 with T-DM1 and one who received first-line T-DXd treatment with a TTD of 9 months. Patients with baseline ctDNA alterations had significantly shorter OS (hazard ratio (HR), 5.25; 95% CI, 1–24; p = 0.019). Conclusions: Baseline plasma ctDNA has the potential to guide first-line targeted therapy for patients with HER2-mutant NSCLC. As an independent negative prognostic biomarker, detectable ctDNA at baseline would need to be taken into account for patient selection in future studies to avoid underestimating the effects of therapy.

Analytical and clinical validation of oncomine Dx target (ODxT) test and local testing for identifying patients with HER2 (ERBB2)-mutant (HER2m) non–small-cell lung cancer (NSCLC) for treatment with trastuzumab deruxtecan (T-DXd) in DESTINY-Lung01/02 (DL-01/02).

9033 Background: Based on the international DL-01 trial, the US Food and Drug Administration (FDA) approved the ODxT Test as a companion diagnostic (CDx) to identify patients (pts) with NSCLC harboring activating HER2 mutations who may benefit from T-DXd. The ODxT Test uses next-generation sequencing (NGS) to detect genomic alterations in formalin-fixed, paraffin-embedded tumor tissue. The accuracy of the ODxT Test by central testing and its agreement with clinical trial assays (CTAs; NGS, polymerase chain reaction, etc.) by local testing was evaluated using analytical and clinical validation data from DL-01 cohort 2 and DL-02 arm 1. Methods: ODxT Test and Illumina TruSight Tumor170 NGS assay results were compared for analytical accuracy in NSCLC samples from DL-01 and commercial vendors. Diagnostic agreement was assessed for DL-01/02 by concordance between the ODxT Test and CTAs. Clinical accuracy per objective response rate (ORR) and duration of response (DoR) to T-DXd were evaluated in all pts with HER2m NSCLC identified by ODxT Test vs CTA. Activating HER2 mutations included single nucleotide variants and exon 20 insertions. Pts received T-DXd 6.4 mg/kg in DL-01 or 5.4 mg/kg (FDA-approved dose) in DL-02 every 3 weeks. Results: NSCLC samples from DL-01 (n = 91), DL-02 (n = 102), and commercial vendors (n = 129) were individually assessed. The ODxT Test met requirements for analytical accuracy (≥90% agreement when excluding unknown results), with a positive percent agreement (PPA) of 100% and negative percent agreement (NPA) of 99.1% for detecting HER2 mutations. Clinical accuracy of the ODxT Test also met FDA requirements (excluding unknowns) for NPA (≥98%) and PPA (95% CI lower bound ≥85%). DL-01 PPA (95% CI) was 98.0% (89.2%-100%) and NPA was 100.0% (96.6%-100%); for DL-02, PPA was 96.7% (88.7%-99.6%) and NPA was 100% (96.6%-100%). In DL-01, confirmed ORR (95% CI) for pts with HER2m NSCLC identified by central ODxT Test was 58.3% (43.2%-72.4%) vs 54.9% (44.2%-65.4%) of pts identified by local CTA; median DoR (95% CI) was 12.0 mo (5.5 mo-18.2 mo) per the ODxT Test vs 9.3 mo (5.7 mo-14.7 mo) per CTA. In DL-02 (prespecified interim analysis early cohort), ORR (95% CI) was 53.6% (33.9%-72.5%) per ODxT Test vs 53.8% (39.5%-67.8%) per CTA; median DoR (95% CI) was not estimable (NE [NE-NE]) per the ODxT Test and NE (4.2 mo-NE) per CTA. Conclusions: This study demonstrates the analytical and clinical accuracy of the ODxT Test as a CDx for detecting activating HER2 mutations in NSCLC to identify pts who may benefit from T-DXd. A high level of agreement was also shown between the ODxT Test and CTAs. Clinical trials for HER2m NSCLC may successfully use a central testing assay as a CDx while allowing adequately validated local testing assays to expedite patient enrollment. Clinical trial information: NCT03505710 , NCT04644237 .

A phase 1, open-label, first-in-human study of TAS2940 in patients with advanced solid tumors.

TPS3165 Background: Aberrant expression and signaling of the ERBB family of receptor tyrosine kinases, including epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2), has a role in the pathogenesis of solid tumors such as breast cancer (BC), non–small cell lung cancer (NSCLC), and glioblastoma (GBM). Although therapies that target HER2 are effective in early and advanced HER2-overexpressing BC, many patients develop resistance despite tumor dependence on HER2 at the time of progression. Approximately 4% of patients with NSCLC have HER2 mutations, mostly presenting as exon 20 insertions (ex20ins); however, approved HER2/EGFR tyrosine kinase inhibitors (TKIs) have limited efficacy in patients with NSCLC and HER2 ex20ins. Many patients with NSCLC or BC develop brain metastases, and EGFR alterations, including EGFRvIII mutations, are common in GBM. There is therefore a need for a brain-penetrable TKI with activity against tumors harboring HER2/EGFR alterations. TAS2940 is a potent, selective, and orally bioavailable pan-ERBB inhibitor that has shown promising preclinical efficacy against cancers with a variety of HER2/EGFR mutations and amplifications. Further, TAS2940 inhibited tumor growth and induced tumor regression in a dose-dependent manner in nude mice intracranially implanted with NCI-N87, a HER2-overexpressing human gastric cancer cell line. Methods: TAS2940-101 (NCT04982926) is an open-label, phase 1, first-in-human trial to evaluate the safety, tolerability, pharmacokinetics (PK), and preliminary antitumor activity of TAS2940 in patients with advanced solid tumors and HER2/ EGFR aberrations. Eligible patients are aged ≥18 years, have non-measurable (Part 1) or measurable (Part 1 and 2) disease per RECIST 1.1 or RANO criteria, ECOG performance status 0/1, and adequate organ function. Patients with non-stable brain metastases are excluded. Part 1 (dose escalation) will use a Bayesian optimal interval design with a starting dose of 15 mg/kg orally QD (planned dose levels: 15, 30, 60, 120, 240 and 480 mg). Once the recommended phase 2 dose is determined, Part 2 (dose expansion) will enroll patients with NSCLC (Cohort A), HER2+ BC (Cohort B), recurrent/refractory GBM (Cohort C), or other solid tumors with EGFR/ HER2 aberrations (Cohort D). The primary objectives are the maximum tolerated dose of TAS2940 in Part 1 and antitumor activity in Part 2. Secondary objectives include antitumor activity in Part 1. The safety and PK profile of TAS2940 will be assessed in both parts. Approximately 142 patients will be enrolled, comprising ~42 in Part 1 and ~100 in Part 2. As of January 24, 2023, 15 patients have been enrolled. No dose-limiting toxicities have been reported with dose escalation up to 240 mg QD. Recruitment is ongoing. Clinical trial information: NCT04982926 .

A comparative analysis of next-generation sequencing based on plasma cfDNA and tumor tissue DNA in patients with advanced lung cancer.

e21021 Background: Although liquid biopsy based on plasma cell-free DNA (cfDNA) provides a non-invasive detection method for cancer patients, tissue biopsy is still the gold standard for molecular subtyping. The concordance of these two techniques has been evaluated in certain cohorts. The comparison of plasma cfDNA and tissue DNA NGS ina large Chinese cancer cohort is yet to be analyzed. Methods: We retrospectively reviewed HaploX's genomic sequencing data from July 2021 to December 2022 to assess the concordance between plasma cfDNA and cancer tissue DNA. A total of 589 advanced lung cancer patients with matched tissue and plasma sample were included in the study. Tissue and peripheral blood was collected at the same time during surgical operation or biopsy. Tissue DNA and plasma cfDNA were isolated and prepared for the NGS with commercially available kits. The positive percent agreement (PPA) between plasma cfDNA sequencing and tissue sequencing, the negative percent agreement (NPA), positive predictive value (PPV), negative predictive value (NPV), and overall percent agreement (OPA) were calculated and compared. Results: The positive percent agreement (PPA) of plasma cfDNA sequencing compared with tissue sequencing were 78% (EGFR, 82%; KRAS, 71%; HER2 mutation, 76%; BRAF V600E mutation, 75%; ALK fusion, 74%; RET fusion, 60%; ROS1 fusion,33.3%; MET exon14 skipping, 50%). EGFR mutations included EGFR p.L858R,19del, p.C797S, p.L861Q, p.T790M, KRAS mutations included p.G12X and p.Q61X.， HER2 mutations included gain-of-function mutations；NPA was 92.4%，PPV was 93.8%，NPV was 74.4%，OPA was 84%. Conclusions: The positive mutation detection consistency of plasma cfDNA sequencing and tissue sequencing in advanced lung cancer patients is 78%, indicating that liquid biopsy based on plasma cfDNA is reliable in most advanced lung cancer patients, but there are some limitations in gene fusion and MET exon 14 jumping detection. Liquid biopsy based on plasma cfDNA can meet most clinical genomic testing needs in general, especially when tissue is not available, but physicians need to be more cautious with negative results. Keywords: Liquid biopsy, Next-generation sequencing (NGS), Concordance Analysis, Lung Cancer.

Biomarkers to predict the efficacy of immune checkpoint inhibitors in patients with non-small-cell lung cancer with actionable genetic alterations.

e21175 Background: Although the efficacy of immune checkpoint inhibitors (ICI) in patients with actionable genetic alterations (AGAs) in non-small-cell lung cancer (NSCLC) has been known to be modest, some patients demonstrated improved survival. Thus, this study aimed to find predictive biomarkers for ICI in patients with NSCLC with various AGAs and to identify the predictive biomarkers for ICI efficacy. Methods: We compared the progression-free survival (PFS) of 324 advanced NSCLC patients who received ICI monotherapy (as over second-line therapy) by different AGAs from January 2018 and July 2022 at the Samsung Medical Center. To identify predictive markers of ICI, we adjusted the impacts on PFS of ICI in smoking status, PD-L1 expression, TP53, KEAP, STK11 mutation status, and steroid use during ICI monotherapy. Results: The median age was 63.1 years (range, 27.8–84.8) and 53.1% of patients was male, and 46.3% of patients was an ex-/or current smoker. A total of 324 patients were included with the following AGAs: EGFR mutation (n = 149, 46.0%), ALK rearrangement, (n = 12, 3.7%), KRAS mutation (n = 72, 22.2%), HER2 mutation or amplification (n = 34, 10.5%), and MET ex14 skipping or amplification (n = 32, 9.9%), ROS1 rearrangement (n = 9, 2.8%), BRAF V600E (n = 9, 2.8%), and RET rearrangement (n = 7, 2.2%). The median PFS was 2.0 months (95% confidence interval, 1.8–2.2) in the total AGA group. The 6-month PFS rate was 25.8% (19.5–34.3) in the group with KRAS/ BRAF V600E/ MET/ HER2 and 12.8% (8.6–19.1) in the group with EGFR/ ALK/ ROS1/ RET (P &lt; 0.01). In the group with KRAS/ BRAF V600E/ MET/ HER2, KEAP, or STK11 wild-type (P = 0.03), PD-L1 (≥1%) (P &lt; 0.01) and steroid use during ICI monotherapy due to immune-related adverse events (IRAE) (P &lt; 0.01) were related to a favorable PFS of ICI; however, no statistical significance was found for TP53 mutation and smoking status for PFS of ICI. In the group with EGFR/ ALK/ ROS1/ RET, PD-L1(≥ 50%) was the only factor that was related to a favorable PFS, and not TP53 mutation status, KEAP, or STK11. Conclusions: This study showed a difference in PFS among each type of AGAs. Although there are limitations due to the small number of patients, the KRAS/ BRAF V600E/ MET/ HER2 group had a favorable PFS compared with the EGFR/ ALK/ ROS1/ RET group . KEAP/STK11/PD-L1 status and steroid use due to IRAE predicted favorable PFS of ICI in the KRAS/ BRAF V600E/ MET/ HER2 group .

De novo metastatic Her2+ breast cancer in a diverse population of women under age 40.

e13045 Background: Breast cancer (BC) is the most common malignancy among women. Her2 mutation has historically been associated with more aggressive disease and worse prognosis, however this paradigm is changing with Her2-directed therapies. Her2 positive BC presents with de novo metastatic disease more often than other subtypes. Young women are more likely to be diagnosed with Her2 positive BC, however previous studies have not had adequate representation of Black/African American women. We evaluated a diverse group of young women under the age of 40 to determine if Her2+ disease was more likely to present with de novo metastatic disease. Methods: We performed a retrospective chart review and collected data on 746 women diagnosed with BC under the age of 40 from 2012 to 2022. We collected age at diagnosis, Her2 receptor status, self-identified race, and stage at diagnosis. 187 of these patients were Her2 positive, and 276 patients were Black. We stratified patients as Black versus White, and as stage IV at diagnosis versus stages I to III at diagnosis. We performed Fisher's exact test to determine if Her2 positive BC was more or less likely to present as de novo metastatic disease compared to Her2 negative BC. Results: In our population of 746 young women under the age of 40 presenting to our health system in a 10-year period, 48 (6.4%) presented with de novo metastatic BC, and 19 (39.6%) of these were Her2 positive. 36% of our study population was Black, which is representative of the demographics of our region. We performed Fisher's exact test, and found that Her2 positive BC was more likely to present as de novo metastatic disease compared to Her2 negative BC. This was statistically significant (p = 0.024). When divided for race, this was not statistically significant for White patients alone (p = 0.052) or Black patients alone (p = 0.234). Conclusions: Our data shows that Her2 positive BC in women under the age of 40 is statistically more likely to present with de novo metastatic disease. Previous research in this area has not been inclusive of Black patients. Current guidelines only recommend staging imaging among patients with systemic symptoms. Based on this data, consideration should be made for staging scans for young women presenting with new HER2+ breast cancer diagnoses. There is limited data available for breast cancer subtype incidence and prognosis among Black patients, and this study underscores the need for more inclusive study populations.[Table: see text]

Trastuzumab (T) plus gemcitabine-cisplatin (GC) for treatment naïve HER2 positive biliary tract adenocarcinomas (BTC): A multicentre open-label, phase II study (TAB).

4089 Background: HER2 over-expression or amplification is seen in 4%-16% of BTCs and is a therapeutic target of interest. Gemcitabine-cisplatin (GC) is one of the standard regimens of choice in advanced BTCs. We aimed to evaluate the clinical activity of GC plus anti-HER2 antibody trastuzumab as initial treatment in HER2-positive BTC. Methods: This study was an investigator-initiated, open-label, single-arm, multi institutional, phase II trial in patients (pts) aged 18 years or older with HER2-positive (defined as IHC 3+ or IHC 2+ and FISH positive), treatment naïve BTCs. Patients received GC (Gem 1000 mg/m2 IV and Cisplatin 25mg/m2 IV on day 1 and 8, q 3 weeks) combined with Trastuzumab at 8mg/kg as initial dose followed by 6mg/kg q 3 -weekly till disease progression (PD) or unacceptable toxicities. The primary end-point of the study was an improvement in 6-month progression free survival (PFS) from 40% (historical cohort) to 60% in the study arm. Next generation sequencing to evaluate HER2 and other mutations was conducted on the tissue samples of the patients screened for this study. Results: From March 2020 to August 2022, of the 876 patients were screened for HER2 status, 118 (13.4%) were found to have HER2 positive status and 90 of them were enrolled into the study. A majority of patients had GBC (95.6%) and at-least 2 sites of metastatic disease beyond primary (77.8%). With a median follow up of 8.5 months, 72 patients had PD and the median PFS was 7.95 months (95% CI: 6.84 -9.06; median overall survival (OS) was 9.95 months (95% CI: 9.25 – 10.66). Partial responses (PR) were seen in 8 patients (8.9%) and 61 had stable disease (67.7%) for a disease control rate of 76.6%. Common chemotherapy-related grade 3 or 4 adverse events were anemia [26 (28.9%)], neutropenia [18(20%)] and thrombocytopenia [8(8.9%)] while one patient has Trastuzumab related asymptomatic fall in cardiac ejection fraction (&gt;=10%). The presence of isolated TP53 mutations predicted for inferior PFS compared to patients with other mutations (TERT promoter, HER2, PIK3CA etc) or no detected mutations (6.51 months vs. 12.02 months vs. 10.58 months; p&lt;0.001). Conclusions: The combination of GC and trastuzumab shows near doubling of survival in treatment naive HER2 positive BTC in a prospective manner for the first time and sets the stage for a larger phase III trial with the combination. Evaluating mutations like TP53, HER2, TERT promoter and PIK3CA along with HER2 testing could be considered as a preferred modality to select these patients for anti HER2 therapy. Clinical trial information: CTRI/2019/11/021955 . [Table: see text]

A phase 1, first-in-human, open label, escalation and expansion study of ORM-5029, a highly potent GSPT1 degrader targeting HER2, in patients with HER2-expressing advanced solid tumors.

TPS1114 Background: Targeted protein degradation (TPD) molecules have expanded the therapeutic options through their catalytic mechanism of action (MOA) and ability to degrade “undruggable” proteins. To increase the efficacy versus tolerability window of protein degradation and improve drug delivery, ORM-5029 uses a Dual-Precision TPD (TPD2) approach combining the catalytic mechanism of TPDs with the precision of tumor-targeting therapeutic antibodies. ORM-5029 is a first-in-class human epidermal growth factor receptor 2 (HER2)-targeted antibody-drug conjugate (ADC) comprised of SMol006, a highly potent GSPT1 degrader, conjugated to pertuzumab, a clinically validated antibody. HER2 is overexpressed in cancers such as breast, ovarian and gastric, and associated with early-onset aggressive disease. ORM-5029 is in development for treatment of HER2-expressing solid tumors. The MOA is mediated by targeted uptake of the ADC, release of the TPD payload, and cell death by GSPT1 degradation. ORM-5029 showed robust in vitro and in vivo efficacy in multiple HER2-expressing models with comparable activity to trastuzumab deruxtecan and strong activity in trastuzumab emtansine-refractory models. Methods: This phase 1 first-in-human study evaluates the safety, tolerability, and efficacy of ORM-5029 administered by intravenous infusion in patients (pts) with HER2-expressing advanced solid tumors (NCT05511844). The escalation, guided by the Bayesian Optimal Interval design, explores cohorts of ORM-5029 to identify the maximum tolerated dose (MTD) and/or expansion dose level (EDL). Each cohort will enroll ≥3 breast cancer pts with at least HER2 1+ (HER2 low) or greater by immunohistochemistry or positive by in situ hybridization. Expansion cohort A (HER2+ breast cancer) may enroll in parallel to escalation evaluating doses showing pharmacodynamic activity or efficacy. Up to 10 pts may be enrolled at each dose explored in cohort A. Enrollment into expansion cohort B (up to 21 pts) and cohort C (up to 22 pts) will begin once the EDL has been determined to further assess the safety, tolerability and efficacy of ORM-5029 using a Simon’s optimal 2-stage design. Cohort B will enroll pts with HER2+ breast cancer refractory or intolerant to standard treatment after ≥2 HER2 therapies in the metastatic setting. Cohort C will enroll pts with advanced solid tumors that are refractory or intolerable to standard treatment or for which no standard treatment is available, including HER2+ gastric or gastroesophageal junction adenocarcinoma or tumors with HER2 expression, amplification or mutations (e.g., colorectal, bile duct, ovarian, bladder, non-small cell lung). Study enrollment began in October 2022 in the United States. Escalation cohort 1 was completed without DLT; enrollment in cohort 2 began as of December 2022. Clinical trial information: NCT05511844 .

Negative selection of patients (pts) with HER2-positive and RAS wild-type (wt) metastatic colorectal cancer (mCRC) receiving dual HER2 blockade.

e15164 Background: Refining the selection of pts with HER2-positive mCRC for dual HER2 blockade is a challenge for precision oncology. Alterations in receptor tyrosin-kinase (RTK)/MAPK pathway and HER2 gene copy number (GCN) are promising predictive biomarkers for primary resistance or sensitivity, respectively. Methods: We conducted a multicentric case-control study to evaluate the negative predictive impact of a panel of candidate genomic alterations of primary resistance (PRESSING-HER panel) in pts with HER2-positive, RAS wt mCRC treated with trastuzumab-based dual HER2 blockade. Comprehensive genomic profiling was performed on archival pre-treatment tumor samples and screening sources were: the TRIUMPH trial (Oncomine Comprehensive Assay), the Italian-Spanish observational cohort (Foundation One CDx) and the MSKCC cohort (MSK-IMPACT). The panel grouped resistance alterations with a solid biological rationale as on-target, i.e. HER2 pathogenic mutations or rearrangements or off-target, i.e. mutations/amplifications in RTK/MAPK genes. Primary resistance was defined by PFS &lt; 4 months (mos), sensitivity was defined by PFS ≥4 mos. Hypothesizing a prevalence of PRESSING-HER alterations equal to 5% and 30% among controls and cases, respectively, 35 cases and 35 controls were needed to reject the null hypothesis of equally prevalent alterations, with α and β errors of 0.05 and 0.20. HER2 GCN was derived from NGS and the cut-off was calculated by ROC curve analyses using 4-month PFS rate as endpoint. Results: Sixty-eight pts were evaluable (33 resistant and 35 sensitive). In the overall population, PRESSING-HER alterations were found in 14 (20.6%) pts and included HER2 mutations in 7 (50%), HER2 rearrangements in 4 (29%), BRAF class 1 mutations in 2 (14%) and EGFR amplification in 1 (7%). PRESSING-HER alterations were significantly more frequent in pts with primary resistant (12/21, 57%) versus (vs) sensitive tumors (2/35, 6%; P= 0.004). HER2 GCN had a median value of 34.5 (IQR: 18.7-78.5) and an optimal cut-off of 33. In multivariable analyses including the main baseline clinical prognostic features, PRESSING-HER alterations were independently associated with inferior PFS (median PFS 2.0 vs 5.4 mos; adjusted HR 3.5, 95%CI 1.7-7.0; P&lt; 0.001) and OS (median OS 3.7 vs 14.8 mos; adjusted HR 3.9, 95%CI 1.8-8.3; P&lt; 0.001). HER2 GCN &lt; 33 was associated with significantly inferior median PFS (2.6 vs 5.4 mos; adjusted HR 1.8, 95%CI 1.0-3.1; P= 0.038) and numerically inferior OS (median OS 9.1 vs 15.4 mos; adjusted HR 1.3, 95%CI 0.7-2.5; P= 0.356). The predictive accuracy of PRESSING-HER was 66% and it was increased to 77% when combined with HER2 GCN. Conclusions: The combined assessment of HER2 on/off-target alterations and HER2 GCN stratifies patient outcomes to HER2 dual blockade.

Early detection and Advanced Targeted Drug Therapies for HER2 positive breast cancer

HER 2 positive breast cancers are the aggressive subtype of breast cancer which can be treated completely if early detected. According to the National Cancer Institute, localized or stage 1 female breast cancer patients have a relative survival rate of 99% and they can survive for more than 5 years after diagnosis but only 63.1% cases are diagnosed at this stage. In later stages when it's diagnosed, the relative survival rate becomes 29%. The overexpression of HER2 proteins can be detected by early diagnosis and screening through advanced technologies like 3D mammography, Positron Emission Mammography, Molecular breast imaging, Contrast-enhanced mammography. The specific diagnosis can be done by Immunohistochemistry (IHC) and Fluorescence in situ hybridization (FISH) for confirmation of this type of breast cancer. Biomarkers such as Her2 heterogenicity, Her2 expression, Her2 mutations, Hormone receptor (ER positivity, PR positivity), PIK3CA mutation, PTEN, PD-L1, TIL, BRCA, miRNA can be used for detection of breast cancer. With successful early detection, which will be used to diagnose early and start the treatment as early as possible. Recently FDA has approved various individual and combination medications for treating the HER2 positive breast cancer and there are further research studies and clinical trials are going on to get more impactful treatment for providing complete cure of the deadly disease.

A Comprehensive Review on the Role of Human Epidermal Growth Factor Receptor 2 (HER2) as a Biomarker in Extra-Mammary and Extra-Gastric Cancers

The human epidermal growth factor receptors (HERs) are expressed abundantly in the human body. The tumorigenic potential of HER2/neu is linked to its overexpression, amplification or somatic mutation. The HER2 gene amplification leading to protein overexpression has been reported in 25–30% of breast cancers and 10–30% of gastric/gastroesophageal cancers. While HER2 is a well-documented predictive, prognostic, and therapeutic marker in breast and gastric/gastroesophageal cancers, its relevance has also been demonstrated in multiple other malignancies. In this article, we will conduct an extensive review of current data pertaining to HER2 amplification, overexpression, or mutation in cancers other than breast and gastric cancers.

BRCA 1/BRCA 2 Pathogenic/Likely Pathogenic Variant Patients with Breast, Ovarian, and Other Cancers.

The demographic and clinical characteristics of patients who have BRCA 1/BRCA 2 pathogenic/likely pathogenic variants may differ from their relatives who had BRCA-related cancer. In this study, we aimed to demonstrate the clinical and demographic findings of patients who had BRCA-related cancer and to assess the differences comparing their relatives who had BRCA-related cancer with breast, genital tract, prostate, and pancreas cancers as well. The results of sequencing analysis of 200 cancer patients (190 women, 10 men) who have been directed to genetic counseling with an indication of BRCA1/BRCA2 testing from different regions across 9 medical oncology centers were retrospectively analyzed. A total of 200 consecutive cancer patients who harbored the BRCA1/BRCA2 pathogenic/likely pathogenic variant (130 (65%) patients harbored BRCA 1 pathogenic/likely pathogenic variant, and 70 harbored BRCA 2 pathogenic/likely pathogenic variant) were included. Of these, 64.0% had breast cancer (43.8% of them had the triple-negative disease, and about 2.3% had only the HER-2 mutant), 31.5% had genital cancers (92.1% of them had ovarian cancer, 3.2% had endometrium, and 1.6% had peritoneum cancer as the primary site and mostly serous adenocarcinoma was the most common histopathology and 14.3% of the patients had endometrioid adenocarcinoma), 3.5% had prostate (median time from metastasis to castration-resistant status was 28 months) and 1.0% had pancreas cancer. Newly diagnosed cancer (breast and ovary) patients who had BRCA 1/BRCA 2 pathogenic/ likely pathogenic variant were younger than their previous cancer diagnosed (breast, ovary, and pancreas) parents who harbored BRCA pathogenic/likely pathogenic variant. We suggest that the genetic screening of BRCA 1/ BRCA 2 pathogenic/likely pathogenic variant is needed as a routine screening for those with a personal or family history of breast, ovarian, tubal, or peritoneal cancer. In addition, once BRCA 1 or BRCA 2 germline pathogenic variant has been identified in a family, testing of at-risk next-generation relatives earlier can identify those family members who also have the familial pathogenic variant, and thus need increased surveillance.

Efficacy of anti-HER2 drugs in the treatment of patients with HER2-mutated cancers: a systematic review and meta-analysis.

Anti-human epidermal growth factor receptor-2 (anti-HER2) therapy has shown excellent efficacy in patients with HER2 overexpression and amplification. Although HER2 mutations are rarely expressed in several cancers, when they occur, they can activate the HER2 signaling pathway. In recent years, studies have shown that anti-HER2 drugs have promising efficacy in patients with HER2 mutations. Based on keywords, we searched databases, such as PubMed, Embase, and Cochrane Library, and the main conference abstracts. We extracted data on objective response rate (ORR), clinical benefit rate (CBR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS) from studies on the efficacy of anti-HER2 therapies in patients with HER2-mutated cancers, and analyzed grade 3 or higher adverse events (AEs). We included 19 single-arm clinical studies and 3 randomized controlled trials (RCTs), containing a total of 1017 patients with HER2 mutations, involving seven drugs and nine cancers, and 18 studies enrolled a high proportion of heavily pretreated patients who had received multiple lines of therapy. Our results showed pooled ORR and CBR of 25.0% (range, 3.8-72.7%; 95% CI, 18-32%) and 36.0% (range, 8.3-63.0%; 95% CI, 31-42%) for anti-HER2 therapy in HER2-mutated cancers. The pooled median PFS, OS, DOR were 4.89 (95% CI, 4.16-5.62), 12.78 (95% CI, 10.24-15.32), and 8.12 (95% CI, 6.48-9.75) months, respectively. In a subgroup analysis, we analyzed the ORR for different cancers, showing 27.0, 25.0, 23.0, and 16.0% for breast, lung, cervical, and biliary tract cancers, respectively. ORR analyses were performed for different drugs as monotherapy or in combination, showing 60.0% for trastuzumab deruxtecan (T-DXd), 31.0% for pyrotinib, 26.0% for neratinib combined with trastuzumab, 25.0% for neratinib combined with fulvestrant, 19.0% for trastuzumab combined with pertuzumab, and 16.0% for neratinib. In addition, we found that diarrhoea, neutropenia, and thrombocytopenia were the most common grade ≥ 3 AEs associated with anti-HER2 therapeutic agents. In this meta-analysis of heavily pretreated patients with HER2 mutations, anti-HER2 therapies, DS-8201 and trastuzumab emtansine, showed promising efficacy and activity. Anti-HER2 therapies showed different efficacies in different or the same cancer settings and all had a tolerable safety profile.