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Objectives: Targeted therapies have been shown to improve outcomes in metastatic non-small cell lung cancer (mNSCLC) with driver mutations. We evaluated the real-world prevalence of human epidermal growth factor receptor 2 (HER2; ERBB2) tumor gene mutations among patients with mNSCLC and described historical treatments and outcomes in patients with HER2-mutant mNSCLC, during a period when there was no approved targeted therapy for HER2-mutant mNSCLC., Materials and Methods: This retrospective observational study used a US nationwide de-identified NSCLC clinico-genomic database. Eligible patients were adults diagnosed with HER2-mutant mNSCLC from January 2014 to July 2021 without co-occuring epidermal growth factor receptor (EGFR) tumor mutations. Descriptive statistics were used to summarize prevalence, baseline characteristics and treatment patterns. Clinical outcomes were estimated with Kaplan-Meier analyses., Results: Among 9206 patients with mNSCLC, 164 (1.78%) met the eligibility criteria (mean age: 67.3 years, 63.4% White, 56.7% female, and 53.0% with a smoking history). 132/164 (80.5%) had at least one line of treatment. Platinum-based chemotherapy (45.5%) and immune checkpoint inhibitor (ICI) with chemotherapy (28.0%) were the most frequently used first-line treatments. The median (95% confidence interval [CI]) real-world (rw) progression-free survival in first-line was 5.5 (4.8, 6.2) months and 3.0 (2.3, 4.2) months in second-line. The median rw overall survival in first-line was 13.2 (10.6, 18.4) months and 8.2 (6.6, 13.2) months in second-line., Conclusion: During this study period, the most common regimens were platinum-based chemotherapy with or without ICI in first and second line, and median rwOS was 13.2 and 8.2 months, respectively. These results indicate the need for more effective targeted therapies in this patient population., (© 2024 AstraZeneca and The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

Introduction: No definitive answers currently exist regarding optimal first-line therapy for HER2-mutant NSCLC. Access to rapid tissue sequencing is a major barrier to precision drug development in the first-line setting. ctDNA analysis has the potential to overcome these obstacles and guide treatment., Methods: We retrospectively analyzed patients with metastatic HER2-mutant NSCLC who underwent prospective clinical ctDNA sequencing and received systemic therapy 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 LungTM assay. Primary endpoints were time to the next treatment (TTNT) and overall survival (OS)., Results: Sixty-three patients were included in the primary analysis. Chemoimmunotherapy (33/63, 52.4 %) was the predominant first-line treatment with a median TTNT of 5.1 months (95 %CI 4.1 - 6.1) whereas 55.0 % (22/40) of patients who received second-line T-DXd obtained a median TTNT of 9.2 m (95 % CI, 0-22.2). Plasma ctDNA was tested before first-line therapy in 40 patients with a median OS of 28.0 months (95 % CI 21-34), in whom 31 patients (78.0 %) had detectable ctDNA. HER2 mutations were detected on ctDNA with a median turnaround time of 13 days, occasionally co-occurred with EGFR and MET alterations and were tracked longitudinally correlating with treatment response. Patients with detectable baseline ctDNA had significantly shorter OS (hazard ratio (HR), 5.25; 95 % CI, 1.2-23.9; p = 0.019)., Conclusion: Chemoimmunotherapy remains a major treatment option for metastatic HER2-mutant NSCLC. ctDNA can rapidly detect HER2 and co-mutations, and it has the potential to guide and monitor optimal first-line therapy. As a negative prognostic biomarker, detectable ctDNA at baseline would need to be taken into account for patient selection in future studies., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Bob T. Li has served as an uncompensated advisor and consultant to Amgen, AstraZeneca, Boehringer Ingelheim, Bolt Biotherapeutics, Daiichi Sankyo, Genentech, and Lilly. He has received research grants to his institution from Amgen, AstraZeneca, Bolt Biotherapeutics, Daiichi Sankyo, Genentech, Jiangsu Hengrui Pharmaceuticals, Lilly, Nuvalent, and Revolution Medicines. He has received academic travel support from Amgen. He is an inventor on three institutional patents at MSK (US62/685,057, US62/514,661, US63/424,813) and has intellectual property rights as a book author at Karger Publishers and Shanghai Jiao Tong University Press. Alexander Drilon declared as follows: Honoraria: 14ner/Elevation Oncology, Amgen, Abbvie, ArcherDX, AstraZeneca, Beigene, BergenBio, Blueprint Medicines, Bristol Myers Squibb, Chugai Pharmaceutical, EcoR1, EMD Serono, Entos, Exelixis, Helsinn, Hengrui Therapeutics, Ignyta/Genentech/Roche, Janssen, Loxo/Bayer/Lilly, Merus, Monopteros, MonteRosa, Novartis, Nuvalent, Pfizer, Prelude, Regeneron, Repare RX, Springer Healthcare, Takeda/Ariad/Millenium, Treeline Bio, TP Therapeutics, Tyra Biosciences, Verastem. Advisory Boards: Bayer, MonteRosa, Abbvie, EcoR1 Capital, LLC, Amgen, Helsinn, Novartis, Lilly, AnHeart Therapeutics. Consulting: MonteRosa, Innocare, Boundless Bio, Treeline Bio, Nuvalent, 14ner/Elevation Oncology, Entos, Prelude. Associated Research Paid to Institution: Foundatin Medicine, GlaxoSmithKlein, Teva, Taiho, PharmaMar. Equity: mBrace. Copyright: Selpercatinib-Osimertinib (filed/pending). Royalties: Wolters Kluwer; Other (Food/Beverage): Merck, Puma, Merus, Boehringer Ingelheim; CME Honoraria: Answers in CME, Applied Pharmaceutical Science, Inc, AXIS, Clinical Care Options, Doc Congress, EPG Health, Harborside Nexus, I3 Health, Imedex, Liberum, Medendi, Medscape, Med Learning, MedTalks, MJH Life Sciences, MORE Health, Ology, OncLive, Paradigm, Peerview Institute, PeerVoice, Physicians Education, Projects in Knowledge, Resources, Remedica Ltd, Research to Practice, RV More, Targeted Oncology, TouchIME, WebMD. Sarat Chandarlapaty has received institutional grant/funding from Daiichi-Sankyo, AstraZeneca, and Lilly, Shares/Ownership interests in Odyssey Biosciences, Effector Therapeutics, and Totus Medicines, and consultation/Ad board/Honoraria from AstraZeneca, Daiichi-Sankyo, Novartis, Neogenomics, Nuvalent, Blueprint, SAGA Diagnostics, and Effector Therapeutics. Jiannan Guo is a former employee of Resolution Bioscience. Eric Gagne, Kavita Garg and Frederick Baehner are employees of Exact Sciences. All remaining authors have declared no conflict of interest., (Copyright © 2024. Published by Elsevier Ltd.)

The heterogeneous relationship between protein expression, amplification, and mutations in human epidermal growth factor receptor 2 (HER2) in non-small cell lung cancer (NSCLC) and the optimal methods for detecting these alterations remain unclear. We aimed to elucidate the clinicopathological and molecular characteristics of HER2-altered NSCLC and investigate practical approaches for identifying patients who might benefit from HER2-targeted therapies. Using next-generation sequencing data from 1680 individuals, we searched for patients with HER2-altered NSCLCs, including amplifications and mutations. Clinicopathological data and tissue slides were reviewed. Immunohistochemistry (IHC) and silver in situ hybridization were performed according to the American Society of Clinical Oncology/College of American Pathologists guidelines. Our analysis identified 89 (5.3%) patients with HER2-altered NSCLCs, comprising 30 (1.8%) with amplification and 59 (3.6%) mutations, and they were compared with 165 control patients. Of the 59 HER2-mutated cases, 52 harbored tyrosine kinase domain (TKD) mutations, primarily HER2 exon 20 insertions. HER2 TKD alterations were associated with younger age, female sex, nonsmoking status, adenocarcinoma with a micropapillary pattern, lung-to-lung metastasis, and poor overall survival. The 33 patients with TKD mutations and 3 with non-TKD point mutations showed incomplete or complete membranous HER2 immunoreactivity (1+ and 2+, 61.07%). Six patients exhibiting amplifications had an IHC score of ≤2+ despite their high copy numbers and concomitantly displayed other actionable EGFR, KRAS, SMARCA4, and other HER2 mutations. These HER2-altered NSCLCs with molecular coalterations showed heterogeneous patterns through HER2 IHC and silver in situ hybridization. Therefore, next-generation sequencing should be used to identify HER2 mutations in patients with NSCLC who present with concomitant alterations. In addition, the above clinicopathological characteristics and HER2 IHC results can be valuable determinants for identifying patients with HER2-altered NSCLC. These insights hold promise for the development of more effective diagnostic and therapeutic strategies for this complex subset of NSCLC patients., (Copyright © 2024. Published by Elsevier Inc.)

Background: HER2 alteration (mutation and/or amplification) is associated with poor survival in NSCLC and can mediate resistance to EGFR tyrosine kinase inhibitors., Methods: We retrospectively analyzed de-identified molecular information from 12,946 NSCLC samples that underwent next-generation sequencing (NGS) with Caris Life Sciences. The objectives were to determine the prevalence and type of HER2 alterations with and without EGFR as a co-mutation. Insurance claims were utilized to obtain outcomes data., Results: Three hundred and twenty-one patients (2.5%) had HER2 alteration: mutation in 197 patients and amplification in 134. Median age was 65 years and 62% were female. A total of 84% were adenocarcinoma. HER2 exon 20 insertion was most common (69%). A total of 1551 (12%) patients had EGFR mutations. Among samples with EGFR mutations, 24 (1.5%) had concurrent HER2 alteration (8 with HER2 mutation and 16 with amplification). Among 8 patients who had both EGFR and HER2 mutations, 3 had EGFR exon 19 deletions and exon 8 HER2 mutation (S310F). One-third of the patients (7/21) with HER2 extracellular domain (ECD) mutation had co-occurring EGFR mutations. All 7 were S310. Patients with concurrent EGFR mutation and HER2 amplification had longer median time on treatment with EGFR TKI(s) than those with EGFR mutation without HER2 amplification (HR 2.284, P =.004)., Conclusion: A minority of NSCLC samples with EGFR mutations had HER2 alterations. In patients with both mutations, exon 21 mutations for EGFR and exon 8 mutations for HER2 were common. It will be critical to continue to accumulate valuable clinical data for further real-world outcomes analysis., (Copyright © 2021. Published by Elsevier Inc.)

Introduction: HER2 mutations occur in 1-3% of lung adenocarcinomas. With increasing use of next-generation sequencing at diagnosis, more patients with HER2-mutant tumours present for treatment. Few data are available to describe the clinical course and outcomes of these patients when treated with afatinib, a pan-HER inhibitor., Methods: We identified patients with metastatic or recurrent HER2-mutant lung adenocarcinomas treated with afatinib among seven institutions across Europe, Australia, and North America between 2009 and 2017. We determined the partial response rate to afatinib, types of HER2 mutations, duration of response, time on treatment, and survival., Results: We collected information on 27 patients with stage IV or recurrent HER2-mutant lung adenocarcinomas treated with afatinib. Of 23 patients evaluable for response, three partial responses were noted (13%, 95% confidence interval [CI] 4-33%). In addition, 57% of patients (13/23) had stable disease, and 30% (7/23) had progressive disease. We documented partial responses in patients with HER2 exon 20 insertions, including two with YVMA insertion and one with VAG insertion. Two patients with partial responses were previously treated with trastuzumab and pertuzumab. Median duration of response to afatinib was 6 months (range 5-10); median time on treatment was 3 months (range 1-30) and median overall survival from the date of diagnosis of metastatic or recurrent disease was 23 months (95% CI 18-53 months)., Conclusions: Afatinib is modestly active in patients with HER2-mutant lung adenocarcinomas, including responses after progression on prior HER2-targeted therapies. However, investigations into the biology of HER2-mutant lung adenocarcinomas and development of better HER2-directed therapies are warranted., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

HER2 mutations are a rare group of driving genes that respond to HER2 targeted therapy, particularly afatinib. No more than 20 such cases have been reported, but afatinib was used after first-line chemotherapy. We present the case of a never-smoking female patient diagnosed with stage IV lung adenocarcinoma harboring a Her2 exon 20 inserted mutation who achieved a durable response (12 months) to first-line afatinib treatment. We review the literature concerning afatinib therapy in this rare cohort of mutated lung cancer patients., (© 2018 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Acquired resistance inevitably occurs after initial treatment with first-generation EGFR-tyrosine kinase inhibitors (TKIs). Several mechanisms have been identified, including EGFR T790M mutation and HER2 amplification. Herein, we present the case of a patient who progressed on first-generation EGFR-TKIs and developed EGFR T790M mutation, HER2 amplification, and HER2 mutation. The administration of single-agent osimertinib yielded an inconsistent response, with worsened pleural effusion and a reduction to lung metastases, but remarkably, a partial response was achieved after four weeks of treatment with combined osimertinib and afatinib, with grade 1 rash and grade 2 diarrhea. Our findings indicate an overlap of T790M, HER2 amplification, and HER2 mutation, which is rarely reported. Moreover, HER2 mutation was identified during the development of resistance, suggesting that HER2 mutation may cause resistance to first-generation EGFR-TKIs., (© 2018 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Objectives: Oncogenic HER2 mutations are present in 2-4% of lung adenocarcinomas, but the relevant clinical trials are unsatisfactory. The novel HER2 inhibitor poziotinib was recently developed and clinical trials are ongoing. We compared poziotinib with nine tyrosine kinase inhibitors (TKIs), and derived poziotinib-resistant clones to investigate the resistant mechanism., Materials and Methods: We introduced three common HER2 mutations A775_G776insYVMA (YVMA), G776delinsVC (VC) and P780_Y781insGSP (GSP), which account for 94% of HER2 exon 20 insertions in the literature, into Ba/F3 cells. We then compared the activity of poziotinib with that of nine TKIs (erlotinib, afatinib, dacomitinib, neratinib, osimertinib, AZ5104, pyrotinib, lapatinib, and irbinitinib), determined the 90% inhibitory concentration (IC 90 ) through a growth inhibition assay, and defined a sensitivity index (SI) as IC 90 divided by the trough concentration at the recommended dose as a surrogate for drug activity in humans. We also generated resistant clones by exposure to poziotinib in the presence of N-ethyl-N-nitrosourea, and HER2 secondary mutations that might serve as a resistance mechanism were searched., Results: YVMA showed resistance to all tested drugs except neratinib, poziotinib and pyrotinib. Poziotinib was the only drug with an SI less than 10 for YVMA, the most common HER2 exon 20 insertion. We established 62 poziotinib-resistant clones, and among these, only C805S of HER2, which is homologous to C797S of the EGFR, was identified as a secondary mutation in 19 clones. We also revealed that heat shock protein (HSP) 90 inhibitors show potent anti-growth activity to the C805S secondary mutant clone., Conclusions: Poziotinib showed the most potent activity against HER2 exon 20 mutations. We identified the secondary C805S at the covalent binding site of HER2 to poziotinib as a potential mechanism of acquired resistance. HSP90 inhibitors might be a therapeutic strategy for the C805S secondary mutation., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Introduction: HER2 mutations are found in 2% to 4% of non-small-cell lung cancer cases and are usually mutually exclusive with other genetic alterations. We screened a large cohort of patients from multiple institutions in Korea, described the characteristics of HER2-mutant cases, and reported on several patients who were treated with pan-HER inhibitors., Patients and Methods: The study population consisted of 360 patients diagnosed with adenocarcinoma from 4 institutions in Korea from June 2015 to September 2016. Tissue specimens from all participants were screened by direct sequencing, and next-generation sequencing was conducted only on specimens that were positive in direct sequencing. HER2-targeted therapy, either poziotinib or afatinib, was orally administrated., Results: Next-generation sequencing was conducted in 129 patients, and finally 29 (8.1%) patients with HER2 mutation were identified. Most patients were female (58.6%), had never smoked (70.0%), and had stage IV non-small-cell lung cancer (55.2%). For all patients, the histologic type was adenocarcinoma, with no coexisting EGFR or ALK alterations. The most common type of HER2 mutation (48.3%) was c.2326_2327insTGT in exon 20. A partial response was observed in 2 patients who received poziotinib and 1 patient who received afatinib. The main toxicities of the pan-HER inhibitors were nausea, diarrhea, and mucositis., Conclusion: HER2 mutation was estimated at a frequency of approximately 8.1% in Korean patients with adenocarcinoma in the absence of known driver mutations. Because some of the HER2-mutant cases responded to poziotinib or afatinib, further studies are warranted., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: HER2 mutation has been found to be an oncogenic driver gene in non-small cell lung cancers(NSCLC) and HER2-directed therapies have shown promising results in this unique population, while little is known about its association with outcomes of chemotherapy. The aim of this study was to investigate the efficacy of first line chemotherapy in patients with advanced HER2-mutant lung adenocarcinomas., Methods: Patients with advanced NSCLC(N = 1714) initially underwent testing for EGFR, KRAS, BRAF mutations and ALK, ROS1 rearrangements, and negative cases were then assessed for HER2 mutations using the method of amplification refractory mutation system(ARMS). The efficacy of first line pemetrexed-based chemotherapy was investigated in patients with HER2-mutant and those with EGFR-mutant, ALK/ROS1-rearranged and KRAS-mutant advanced adenocarcinomas., Results: HER2 mutations were detected in 29 of 572(5.1%) specimens from a selected population of EGFR/KRAS/BRAF/ALK/ROS1 negative patients. All of them are adenocarcinomas. Among patients with HER2-mutant lung cancers, 25 received pemetrexed-based first line chemotherapy. The objective response rate(ORR) was 36.0%. Their median progression free survival(PFS) was 5.1 months, which was similar with that of KRAS-mutant group (n = 40,5.0 months, p = 0.971), numerically shorter than that of EGFR-mutant group(n = 74, 6.5 months, p = 0.247) and statistically significantly shorter than that of ALK/ROS1-rearranged group (n = 39,9.2 months, p = 0.004). Furthermore, HER2 variants subgroup analysis showed that PFS was inferior in A775_G776insYVMA group compared with other variants (4.2 vs 7.2 months, p = 0.085)., Conclusions: Patients with advanced HER2-mutant lung adenocarcinomas showed an inferior outcome of first line pemetrexed-based chemotherapy compared to those with ALK/ROS1 rearrangements, which strengthen the need for effective HER2-targeted drugs in clinical practice.

Background: ERBB2 (HER2) is a driver gene identified in non-small cell lung cancer (NSCLC). The prevalence, clinicopathology, genetic variability and treatment of HER2-positive NSCLC in Chinese population are unclear., Patients and Methods: Eight hundred and fifty-nine patients with pathologically confirmed NSCLC were screened for HER2 mutations using Sanger sequencing. Next-generation sequencing (NGS) was performed in positive cases. HER2 amplification was detected with FISH. Overall survival (OS) was evaluated using Kaplan-Meier methods and compared with log-rank tests., Results: Twenty-one cases carrying HER2 mutations were identified with a prevalence of 2.4%. HER2 mutations were more frequently encountered in females, non-smokers and adenocarcinoma. NGS was performed in 19 out of 21 patients, The results showed 16 cases with additional genetic aberrations, most commonly associated with TP53 (n = 6), followed by EGFR (n = 3), NF1 (n = 3), KRAS (n = 2) and other mutations. One patient harbored HER2 amplification. Four patients with stage IV received afatinib treatment, and three showed stable disease with a median progression-free survival of 4 months and one patient was diagnosed with progressive disease., Conclusion: HER2 mutations represent a distinct subset of NSCLC. NGS showed that HER2 mutations commonly co-existed with other driver genes. Afatinib treatment displayed moderate efficacy in patients with HER2 mutations.

In women with metastatic breast cancer (MBC), introduction of the anti-HER2 (human epidermal growth factor receptor-2) directed therapies including trastuzumab, pertuzumab, lapatinib, and/or trastuzumab-DM1 has markedly improved overall survival. However, not all cases of HER2-positive breast tumours derive similar benefit from HER2-directed therapy, and a significant number of patients experience disease progression because of primary or acquired resistance to anti-HER2-directed therapies. We integrated genomic and clinicopathological analyses in a cohort of patients with refractory breast cancer to anti-HER2 therapies to identify the molecular basis for clinical heterogeneity. To study the molecular basis underlying refractory MBC, we obtained 36 MBC tumours tissues and used next-generation sequencing to investigate the mutational and transcriptional profiles of 83 genes. We focused on HER2 mutational sites and HER2 pathways to identify the roles of HER2 mutations and the HER2 pathway in the refractoriness to anti-HER2 therapies. Analysis using massively parallel sequencing platform, CancerSCAN™, revealed that HER2 mutations were found in six of 36 patients (16.7%). One patient was ER (estrogen receptor)-positive and HER2-negative and the other five HER2 mutated patients were HER2-positive and HR (hormone receptor)-negative. Most importantly, four of these five patients did not show any durable clinical response to HER2-directed therapies. The HER2 pathway score obtained through transcriptional analyses identified that Growth Receptor Biding protein 2 (GRB2) was the most significantly down regulated gene in the HER2 mutated samples. Detection of HER2 mutations using higher deep DNA sequencing may identify a predictive biomarker of resistance to HER2-directed therapy. Functional validation is warranted.

Background: Dysregulation of HER2 signaling pathways results in tumor progression in several types of carcinomas. The aim of the current study is to identify clinicopathological characteristics of HER2-mutated non-small cell lung carcinomas (NSCLCs) in conjunction with HER2 protein expression, gene amplification, and phosphorylation., Patients and Methods: We investigated 1275 patients including 1055 adenocarcinomas (ADCs), 146 squamous cell carcinomas, 2 large cell carcinomas, 8 sarcomatoid carcinomas, and 64 adenosquamous carcinomas. High-resolution melting analysis of HER2 hot spot inflame deletion mutations, chromogenic in situ hybridization for HER2 amplification, and immunostaining of wild-type and phosphorylated HER2 was performed., Results: HER2 mutations were detected in 46 (3.6%) of the NSCLCs, with mutations only present in the ADC. When analyzing ADC cases alone, the incidence of HER2 mutation was increased to 4.3%. All HER2-mutated tumors were negative for other driver gene alterations. HER2 mutation status correlated with never-smoker status and patients with smaller tumor size. HER2 amplifications were also identified in approximately half of the tumors with HER2 mutations. The overall survival rate was not significantly different between patients without and with HER2 mutations. When analyzing only invasive ADCs, HER2 mutation status was an independent factor for an unfavorable outcome. Amongst the 46 patients harboring HER2 mutations, univariate and multivariate analysis revealed that HER2 amplification was an unfavorable prognostic factor, while HER2 phosphorylation was a favorable prognostic factor., Conclusions: HER2 mutations were observed in 3.6% of NSCLCs, particularly in younger patients, those with no history of smoking, and those with small tumors. Amongst the patients with HER2 mutations, HER2 amplification and phosphorylation were independent prognostic factors., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)