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HER2 activating mutations have emerged as oncogenic drivers and therapeutic targets in a variety of human tumors. In breast cancer, these deregulations occur at low frequency, and are mostly detected in HER2‐nonamplified, metastatic disease. Preclinical evidence has clarified the role of hotspot mutations in HER2 constitutive activation, defining them as an alternative mechanism to HER2 gene amplification. Furthermore, recent clinical studies have indicated the emergence of newly acquired HER2 deregulations in significant proportions of breast cancer patients who experience disease progression following both endocrine and HER2‐targeted therapies. As the involvement of HER2 mutation in therapy resistance may profoundly impact patient outcomes on successive therapies, several clinical trials are currently investigating the efficacy of various HER2‐targeted drugs in HER2‐mutant breast cancer. In this review, we firstly summarize the structural organization of the HER2 oncogene and its historical impact on breast cancer prognosis and therapeutic advancement. Then, we provide an overview of the frequencies and functional relevance of clinically recurrent HER2 mutations in breast cancer with a special focus on their role in therapeutic resistance. Finally, we provide a collection of the clinical trials that are currently exploring novel therapeutic approaches for this patient subset and discuss the related perspectives and challenges. [ABSTRACT FROM AUTHOR]

HER2 mutation and amplification have been identified as distinct molecular targets in lung cancer with different therapeutic and prognostic values. The coexistence of HER2 and EGFR mutations is extremely rare, and therefore, no data exist on the best treatment in these cases.

There remains an unmet need for targeted therapies against advanced non‐small‐cell lung cancer (NSCLC) with HER2 mutations. To improve the antitumor activity of single anti‐HER2 agent, this prospective, single‐arm clinical trial (NCT05016544) examined the safety profile and efficacy of anti‐HER2 antibody inetetamab and pan‐HER TKI pyrotinib in HER2‐posivite advanced NSCLC patients. Enrolled patients received inetetamab every 3 weeks and pyrotinib once per day (pyrotinib, dose‐escalation part, 240 mg, 320 mg; dose‐expansion part, 320 mg). Primary endpoints were dose‐limiting toxicity (DLT) dosage and safety. Secondary endpoints included progression‐free survival (PFS), objective response rate (ORR), and disease control rate (DCR). A total of 48 patients were enrolled. During the dose‐escalation period, no DLT occurred. Diarrhea was the most commonly reported treatment‐related adverse event (TRAE). Grade 3 TRAEs occurred in seven patients. The median PFS (mPFS) was 5.5 months [95% confidence interval (CI): 4.4–8.6 months]. The confirmed ORR and DCR reached 25% (11/44) and 84.1% (37/44), respectively. Responses were shown in patients with distinct HER2 aberrations. In summary, inetetamab in combination with pyrotinib demonstrated acceptable safety and antitumor activity among patients with advanced HER2‐mutant NSCLC. [ABSTRACT FROM AUTHOR]

Abstract There remains an unmet need for targeted therapies against advanced non‐small‐cell lung cancer (NSCLC) with HER2 mutations. To improve the antitumor activity of single anti‐HER2 agent, this prospective, single‐arm clinical trial (NCT05016544) examined the safety profile and efficacy of anti‐HER2 antibody inetetamab and pan‐HER TKI pyrotinib in HER2‐posivite advanced NSCLC patients. Enrolled patients received inetetamab every 3 weeks and pyrotinib once per day (pyrotinib, dose‐escalation part, 240 mg, 320 mg; dose‐expansion part, 320 mg). Primary endpoints were dose‐limiting toxicity (DLT) dosage and safety. Secondary endpoints included progression‐free survival (PFS), objective response rate (ORR), and disease control rate (DCR). A total of 48 patients were enrolled. During the dose‐escalation period, no DLT occurred. Diarrhea was the most commonly reported treatment‐related adverse event (TRAE). Grade 3 TRAEs occurred in seven patients. The median PFS (mPFS) was 5.5 months [95% confidence interval (CI): 4.4–8.6 months]. The confirmed ORR and DCR reached 25% (11/44) and 84.1% (37/44), respectively. Responses were shown in patients with distinct HER2 aberrations. In summary, inetetamab in combination with pyrotinib demonstrated acceptable safety and antitumor activity among patients with advanced HER2‐mutant NSCLC.

• ICIs plus chemotherapy prolonged the PFS in HER2 -mutant NSCLC. • TMB was higher in the tumors harboring HER2 mutations compared to EGFR mutations. • The relatively high TMB might be involved in the prolongation of the PFS. HER2 mutations are reported to occur in 2%–5% of all cases of non-small cell lung cancer (NSCLC). The clinical outcomes in patients with HER2 -mutant NSCLC treated with immune checkpoint inhibitors (ICIs) plus platinum-based chemotherapy as 1st line treatment still remain unclear. Using the large-scale clinico-genomic database of LC-SCRUM-Asia, the clinico-genomic characteristics and therapeutic outcomes of patients with HER2 -mutant NSCLC were investigated. Of the 15,251 patients with NSCLC enrolled in the LC-SCRUM-Asia database, tumor HER2 mutations were detected in 402 patients (2.6 %). The most common subtype of HER2 mutations was exon 20 in-frame insertions (79 %), followed in frequency by mutations in the tyrosine kinase domain other than Exon20ins (10 %) and mutations in extracellular domains (7 %). NSCLCs harboring HER2 mutations showed a higher tumor mutation burden (TMB) as compared with NSCLCs harboring EGFR mutations or ALK fusions (median: 4.22 vs. 2.54 and 2.52 mutation per megabase, respectively). Of the 402 patients, 268 patients had received platinum-based chemotherapy with ICIs (Chemo-ICI, n = 95) or without ICI (Chemo-alone, n = 173) as 1st line treatment. The progression-free survival (PFS) was significantly longer in the Chemo-ICI group as compared with the Chemo-alone group (median 8.5 vs. 6.3 months; HR [95 %CI]: 0.66 [0.50–0.88]; P < 0.005). Multivariate analysis identified use of ICIs in addition to platinum-based chemotherapy as an independent favorable prognostic factor for PFS. There was no significant difference in the overall survival between the patients of the Chemo-ICI and Chemo-alone groups (median 31.1 vs. 23.3 months; HR [95 %CI]: 0.80 [0.57–1.12], P = 0.20). Addition of ICIs to platinum-based chemotherapy in 1st line treatment may improve the PFS in patients with HER2 -mutant NSCLC. The relatively high TMB might be involved in the prolongation of the PFS in patients with HER2 -mutant NSCLC receiving platinum-based chemotherapy with ICIs. [ABSTRACT FROM AUTHOR]

Abstract Background There is currently a lack of effective treatments for non-small cell lung cancer (NSCLC) patients harboring HER2 mutations. We examined the efficacy and safety of, and potential resistance mechanism to, pyrotinib, a pan-HER inhibitor, in advanced NSCLC carrying HER2 mutations. Methods In this multicenter, single-arm, phase II trial, stage IIIB-IV NSCLC patients harboring HER2 mutations, as determined using next-generation sequencing, were enrolled and treated with pyrotinib at a dose of 400 mg/day. The primary endpoint was 6-month progression-free survival (PFS) rate, and secondary endpoints were objective response rate (ORR), PFS, overall survival (OS), disease control rate (DCR), and safety. The impact of different HER2 mutation types on sensitivity to pyrotinib and the potential of utilizing mutational profile derived from circulating tumor DNA (ctDNA) to predict disease progression were also explored. Results Seventy-eight patients were enrolled for efficacy and safety analysis. The 6-month PFS rate was 49.5% (95% confidence interval [CI], 39.2–60.8). Pyrotinib produced an ORR of 19.2% (95% CI, 11.2–30.0), with median PFS of 5.6 months (95% CI, 2.8–8.4), and median OS of 10.5 months (95% CI, 8.7–12.3). The median duration of response was 9.9 months (95% CI, 6.2–13.6). All treatment-related adverse events (TRAEs) were grade 1–3 (all, 91.0%; grade 3, 20.5%), and the most common TRAE was diarrhea (all, 85.9%; grade 3, 16.7%). Patients with exon 20 and non-exon 20 HER2 mutations had ORRs of 17.7% and 25.0%, respectively. Brain metastases at baseline and prior exposure to afatinib were not associated with ORR, PFS, or OS. Loss of HER2 mutations and appearance of amplification in HER2 and EGFR were detected upon disease progression. Conclusions Pyrotinib exhibited promising efficacy and acceptable safety in NSCLC patients carrying exon 20 and non-exon 20 HER2 mutations and is worth further investigation. Trial registration Chinese Clinical Trial Registry Identifier: ChiCTR1800020262

Human epidermal growth factor receptor 2 (HER2) amplification or activating mutations are found in 1.6%–4% of non-small cell lung cancer (NSCLC). Pyrotinib has been reported to have better potency in NSCLC patients with HER2 exon 20 insertion (ex20ins) mutations; however, more clinical evidence is urgently needed to guide pyrotinib-based therapy in NSCLC with HER2 amplification or heterogeneous mutations. We retrospectively analyzed advanced NSCLC patients with HER2 amplification or mutations who were treated with pyrotinib-based therapy between September 25, 2018 and October 30, 2020 in our hospital. Molecular dynamics simulation was used to explore the bioactive conformation and binding mechanisms of pan-ErbB tyrosine kinase inhibitors (TKIs) including pyrotinib for different HER2 ex20ins variants. In this study, 79 eligible patients were included with 70 ex20ins variants, 6 missense mutations and 3 primary HER2 amplifications identified. A775_G776insYVMA insertion was the most common observed subtype. The median progression-free survival (mPFS) was 5.8 (95% CI: 4.1–7.4) months. Use of pyrotinib-based therapy in first-/second-line settings showed a significantly better prognosis than that observed in third-line settings or above (mPFS: 9.1 vs. 4.4 months; P = 0.0003). Compared with HER2 amplification and exon 20 non-YVMA insertion variants, patients with HER2 missense mutations had a visible mPFS benefit (12.2 vs. 6.8 vs. 5.2 months). Computational docking simulations revealed that pyrotinib failed to interact with the specific insertion variant P780_Y781insGSP. These results indicated that pyrotinib-based therapy exhibited good anti-tumor activity and acceptable safety profile in HER2-altered advanced NSCLC.

Colorectal cancer (CRC) represents a global health threat, standing as the second leading cause of cancer-related death worldwide. Targeted therapies brought new hope for the metastatic stage, which historically bore a very poor prognosis. Human epidermal growth receptor 2 (HER2) overexpression concerns about 5 % of the metastatic CRC (mCRC) patients, including both gene amplifications and point mutations. Albeit its controversial prognostic role, preclinical and clinical data indicate HER2 as a negative predictive biomarker of response to anti-EGFR therapies. Tissue and plasma-based NGS testing, could permit a precise identification of this resistance mechanism both at baseline and during treatment, thus guiding decision-making. Furthermore, promising results come from completed and ongoing randomized trials, testing HER2 as an actionable target. In this review, we discuss the available evidence on HER2 targeting in advanced CRC, analyzing its possible future role in the treatment algorithm., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: D.R. received honoraria from Amgen, MSD and Takeda. The other authors declare no competing interests, (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

HER2 mutation and amplification have been identified as distinct molecular targets in lung cancer with different therapeutic and prognostic values. The coexistence of HER2 and EGFR mutations is extremely rare, and therefore, no data exist on the best treatment in these cases., Competing Interests: The authors declare no conflict of interest., (© 2024 The Authors.)

With the increased use of low-dose computed tomography (LDCT), the detection of multifocal pulmonary ground-glass nodules (GGNs) has increased. According to the current clinical guidelines, multifocal GGNs tend to be treated as the multiple primary early-stage lung adenocarcinoma. However, studies have indicated that parts of multiple GGNs may originate from single nodules via intrapulmonary metastasis (IPM). Such IPM indicates the advanced stages even when the multiple GGNs are present as the early characteristics in pathological assessments. However, no gold standard exists for the differential diagnosis of multiple IPM GGNs. Here, we report two multifocal pulmonary GGNs cases where panel sequencing (672 driver mutation loci) showed that patient 1 (P1) shared two rare epidermal growth factor receptor (EGFR) mutations (primary L747_T751del and primary T790M) in the left upper lobe anterior segment and left lower lobe superior segment, respectively. Patient 2 (P2) shared a low-frequency human epidermal growth factor receptor 2 (HER2) mutation (primary Tyr772_Ala775dup) in two GGNs located in the apicoposterior and superior lingular segment of the left lower lobe (LLL). Oncogenic driver mutations were concordant between primary tumors and metastasis. Thus, shared low-frequency driver mutations in multiple GGNs strongly suggested that IPM existed with a high probability in these patients. Also, tumor cell spread through air spaces (STAS) was identified in pathological sections of the left upper lobe (LUL) nodule of P1, suggesting aerogenous spread may have been an effective pathway for IPM. Our report suggests that oncogenic driver mutations have prominent diagnostic value for IPM. Also, GGN IPM may occur in one lung lobe and between in different lung lobes.

Background: This study evaluated outcomes among patients with advanced/metastatic non-small-cell lung cancer (NSCLC) treated at Asian centers participating in the global named-patient-use (NPU) program for afatinib. Methods: Patients had progressed after initial benefit with erlotinib or gefitinib, and/or had an EGFR or HER2 mutation, had no other treatment options, and were ineligible for afatinib trials. The recommended starting dose of afatinib was 50 mg/day. Dose modifications were allowed, and afatinib was continued as long as deemed beneficial. Response and survival information was provided voluntarily. Safety reporting was mandatory. Results: 2242 patients (26% aged ≥ 70 years, 96% with adenocarcinoma) received afatinib at centers in 10 Asian countries. Most were heavily pre-treated, including prior treatment with erlotinib or gefitinib. Of 1281 patients tested, 1240 had EGFR mutations (common: 1034/1101; uncommon: 117/1101). There were no new safety signals, the most common adverse events being rash and diarrhea. Objective response rate (ORR) was 24% overall (n = 431 with data available), 27% for patients with common EGFR mutations (n = 230) and 28% for those with uncommon mutations (n = 32); median time to treatment failure (TTF) in these groups was 7.6 months (n = 1550), 6.4 months (n = 692) and 8.4 months (n = 83), respectively. In patients with EGFR exon 20 insertions (n = 23) and HER2 mutations (n = 12), median TTF exceeded 12 months. Conclusions: Patient outcomes in this study were similar to those reported in the analysis of the global NPU. Afatinib achieved clinical benefits in patients with refractory NSCLC. ORR and TTF were similar between patients with tumors harboring uncommon and common EGFR mutations. [ABSTRACT FROM AUTHOR]

HER2 activating mutations act as oncogenic drivers in various cancer types. In the clinic, they can be identified by next generation sequencing (NGS) in either tumor biopsies or circulating cell-free DNA (cfDNA). Preclinical data indicate that HER2 "hot spot" mutations are constitutively active, have transforming capacity in vitro and in vivo and show variable sensitivity to anti-HER2 based therapies. Recent clinical trials also revealed activity of HER2-targeted drugs against a variety of tumors harboring HER2 mutations. Here, we review the prevalence and type of HER2 mutations identified in different human cancers, their biochemical and biological characterization, and their sensitivity to anti HER2-based therapies in both preclinical and clinical settings. [ABSTRACT FROM AUTHOR]

Background Effective targeted therapy for non-small-cell lung cancer (NSCLC) patients with human epidermal growth factor receptor 2 (HER2) mutations remains an unmet need. This study investigated the antitumor effect of an irreversible pan-HER receptor tyrosine kinase inhibitor, pyrotinib. Patients and methods Using patient-derived organoids and xenografts established from an HER2-A775_G776YVMA-inserted advanced lung adenocarcinoma patient sample, we investigated the antitumor activity of pyrotinib. Preliminary safety and efficacy of pyrotinib in 15 HER2-mutant NSCLC patients in a phase II clinical trial are also presented. Results Pyrotinib showed significant growth inhibition of organoids relative to afatinib in vitro (P  =   0.0038). In the PDX model, pyrotinib showed a superior antitumor effect than afatinib (P  =   0.0471) and T-DM1 (P  =   0.0138). Mice treated with pyrotinib displayed significant tumor burden reduction (mean tumor volume, −52.2%). In contrast, afatinib (25.4%) and T-DM1 (10.9%) showed no obvious reduction. Moreover, pyrotinib showed a robust ability to inhibit pHER2, pERK and pAkt. In the phase II cohort of 15 patients with HER2 - mutant NSCLC, pyrotinib 400 mg resulted in a objective response rate of 53.3% and a median progression-free survival of 6.4 months. Conclusion Pyrotinib showed activity against NSCLC with HER2 exon 20 mutations in both patient-derived organoids and a PDX model. In the clinical trial, pyrotinib showed promising efficacy. Clinical trial registration NCT02535507. [ABSTRACT FROM AUTHOR]

Purpose of Review: HER2 activating mutations are a new, druggable mutation identified by next-generation DNA sequencing (NGS) of breast cancer. Here, we review the recent data on the diagnosis and treatment of HER2 mutated, metastatic breast cancer.Recent Findings: Pre-clinical studies have shown that HER2 activating mutations accelerate tumor growth and can be inhibited by HER2 targeted drugs, including trastuzumab and the second-generation, pan-HER tyrosine kinase inhibitor, neratinib. HER2 mutations can be diagnosed by NGS testing on either a tumor biopsy or circulating tumor DNA obtained from peripheral blood. Case reports provided initial evidence that HER2 targeted therapies can effectively treat patients with HER2 mutated, metastatic breast cancer. Two phase II clinical trials, MutHER and SUMMIT, both demonstrate that neratinib monotherapy has clinical efficacy for these patients, with clinical benefit rate of 31-40%.Summary: HER2 targeted therapies are effective for HER2 mutated breast cancer but emergence of drug resistance remains a problem. Clinical trials are now testing neratinib-containing drug combination regimens for HER2 mutated, metastatic breast cancer patients. [ABSTRACT FROM AUTHOR]

The development of precision medicine in oncology is entirely dependent on the ability to obtain accurate molecular information that can assist physicians in selecting targeted treatments for cancer patients. To date, most clinical studies and companion diagnostic efforts utilizing this approach have relied heavily upon genomic information as the sole determinant for patient selection. Unfortunately, many of these genomic alterations are infrequent, occurring in 1 to 5% of cancers, which generates a frustrating dynamic in patient accrual and the powering of clinical outcome correlations. Moreover, while these rare events can be readily identified by genomic profiling, it is impossible to know ahead of time which genomic alterations are true driving events for any individual patient's tumor. Analysis of the functional proteome may provide a synergistic solution, since these genetic derangements ultimately lead to aberrant protein synthesis and activation of signaling networks responsible for sustaining tumor growth and progression. Because changes within the signaling architecture--and, particularly in kinase activity, are the ultimate causal event of cancer, the signaling network, itself, has become the direct target of the new generation of therapeutic agents. For these reasons, high-throughput proteomic platforms able to capture changes within these signaling networks have received increasing attention in recent years. Among others, the Reverse Phase Protein Microarray (RPPA), a widely used proteomic platform for signaling network mapping of biological samples, is currently used as a companion diagnostic for patient stratification to personalized treatment. This platform generates high-throughput, multiplex, quantitative information starting from a relatively low amount of biological material such as a fine needle biopsy. In this article, two clinical case studies are presented that illustrate the clinical potential for utilizing functional proteomics data into the precision medicine workflow. [ABSTRACT FROM AUTHOR]

Background: HER2 mutations and amplifications have been identified as oncogenic drivers in lung cancers. Dacomitinib, an irreversible inhibitor of HER2, EGFR (HER1), and HER4 tyrosine kinases, has demonstrated activity in cell-line models with HER2 exon 20 insertions or amplifications. Here, we studied dacomitinib in patients with HER2- mutant or amplified lung cancers. Patients and methods: As a prespecified cohort of a phase II study, we included patients with stage IIIB/IV lung cancers with HER2 mutations or amplification. We gave oral dacomitinib at 30-45 mg daily in 28-day cycles. End points included partial response rate, overall survival, and toxicity. Results: We enrolled 30 patients with HER2-mutant (n = 26, all in exon 20 including 25 insertions and 1 missense mutation) or HER2-amplified lung cancers (n = 4). Three of 26 patients with tumors harboring HER2 exon 20 mutations [12%; 95% confidence interval (CI) 2% to 30%] had partial responses lasting 3+, 11, and 14 months. No partial responses occurred in four patients with tumors with HER2 amplifications. The median overall survival was 9 months from the start of dacomitinib (95% CI 7-21 months) for patients with HER2 mutations and ranged from 5 to 22 months with amplifications. Treatment-related toxicities included diarrhea (90%; grade 3/4: 20%/3%), dermatitis (73%; grade 3/4: 3%/0%), and fatigue (57%; grade 3/4: 3%/0%). One patient died on study likely due to an interaction of dacomitinib with mirtazapine. Conclusions: Dacomitinib produced objective responses in patients with lung cancers with specific HER2 exon 20 insertions. This observation validates HER2 exon 20 insertions as actionable targets and justifies further study of HER2- targeted agents in specific HER2-driven lung cancers. [ABSTRACT FROM AUTHOR]

HER2 overexpression and anti-HER2 agents represent probably the best story of success of individualized therapy in breast cancer. Due to the important therapeutic implications, the issue under the spotlight has been, since ever, the correct identification of true HER2 positivity on tissue specimens. Eligibility to anti-HER2 agents is strictly dependent on the demonstration of HER2 overexpression (by immunohistochemistry) or of HER2 gene amplification by in situ techniques (fluorescence in situ hybridization, FISH), however there are controversial issues involving cases with "equivocal" HER2 status based on conven-tional techniques (about 20% of specimens). In terms of HER2 expression a major debate is the presence of full-length and truncated forms of the protein and controversial clinical data have been reported on the therapeutic implications of these HER2 fragments. In terms of HER2 gene assessment, the occurrence of amplification of the chromosome 17 centromeric region (CEP17) has been proven responsible for misleading HER2 FISH results, precluding anti-HER2 based therapy to some patients. Finally HER2 activating mutations have been recently described as a biological mechanisms alternative to HER2 gene amplification. In this review we will focus on the controversies that pathologists and oncologists routinely face in the attempt to design the most tailored treatment for breast cancer patients. We will focus on the HER2 gene and on the protein, both at technical and interpretational levels. [ABSTRACT FROM AUTHOR]

Simple Summary: The use of novel therapeutic drugs in lung cancer has changed the paradigm of the diagnosis and treatment of lung cancer. Due to the development of advanced diagnostic procedures (e.g., next generation sequencing (NGS)) around half of non-small-cell lung cancer (NSCLC) patients can be identified with genetic aberrations. The presence of activating mutations of EGFR, ALK and ROS-1 have already been well explored. New targets that can be successfully targeted include NTRK, MET, RET and HER 2 genes. Some particles have already received FDA approval, whereas many more are in the late stages of clinical trials. Considering rapid changes in thoracic oncology, an up-to-date summary is needed. In this review, we present the current landscape of approved therapeutic drugs, as well as important ongoing clinical trials. Lung cancer is the most common cause of cancer-related death worldwide, and the prognosis for stage IV remains poor. The presence of genetic alterations in tumor cells, such as EGFR and BRAF gene mutations, as well as ALK and ROS1 gene rearrangements, are indications for targeted therapies. Many such treatments are already registered and used on a wide scale. In comparison to standard chemotherapy, they can prolong not only progression-free survival but also overall survival. Moreover, they are able to provide excellent quality of life and rapid improvement of cancer-related symptoms such as dyspnea, cough and pain. Recent years have witnessed great advances in both molecular diagnostics and new molecular therapies for non-small-cell lung cancer. This review presents new therapeutic targets in NSCLC, as well as drugs of which the activity against NTRK, RET, MET or HER2 gene alterations (including EGFR exon 20 insertions) has either been confirmed or is currently being evaluated. Although these particular genetic alterations in NSCLC are generally rare, each accounting for 1–2% of patients, in total about half of all patients have molecular alterations and may ultimately receive targeted therapies. [ABSTRACT FROM AUTHOR]

Human epidermal growth factor receptor 2 ( HER2 ) amplification or activating mutations are found in 1.6%-4% of non-small cell lung cancer (NSCLC). Pyrotinib has been reported to have better potency in NSCLC patients with HER2 exon 20 insertion (ex20ins) mutations; however, more clinical evidence is urgently needed to guide pyrotinib-based therapy in NSCLC with HER2 amplification or heterogeneous mutations. We retrospectively analyzed advanced NSCLC patients with HER2 amplification or mutations who were treated with pyrotinib-based therapy between September 25, 2018 and October 30, 2020 in our hospital. Molecular dynamics simulation was used to explore the bioactive conformation and binding mechanisms of pan- ErbB tyrosine kinase inhibitors (TKIs) including pyrotinib for different HER2 ex20ins variants. In this study, 79 eligible patients were included with 70 ex20ins variants, 6 missense mutations and 3 primary HER2 amplifications identified. A775&#95;G776insYVMA insertion was the most common observed subtype. The median progression-free survival (mPFS) was 5.8 (95% CI: 4.1-7.4) months. Use of pyrotinib-based therapy in first-/second-line settings showed a significantly better prognosis than that observed in third-line settings or above (mPFS: 9.1 vs. 4.4 months; P  = 0.0003). Compared with HER2 amplification and exon 20 non-YVMA insertion variants, patients with HER2 missense mutations had a visible mPFS benefit (12.2 vs. 6.8 vs. 5.2 months). Computational docking simulations revealed that pyrotinib failed to interact with the specific insertion variant P780&#95;Y781insGSP. These results indicated that pyrotinib-based therapy exhibited good anti-tumor activity and acceptable safety profile in HER2 -altered advanced NSCLC., (© 2021 Chinese National Cancer Center. Published by Elsevier B.V.)

We developed neratinib-resistant HER2 -mutant cancer cells by gradual dose escalation. RNA sequencing identified TORC1 signaling as an actionable mechanism of drug resistance. Primary and acquired neratinib resistance in HER2 -mutant breast cancer patient-derived xenografts (PDXs) was also associated with TORC1 hyperactivity. Genetic suppression of RAPTOR or RHEB ablated P-S6 and restored sensitivity to the tyrosine kinase inhibitor. The combination of the TORC1 inhibitor everolimus and neratinib potently arrested the growth of neratinib-resistant xenografts and organoids established from neratinib-resistant PDXs. RNA and whole-exome sequencing revealed RAS-mediated TORC1 activation in a subset of neratinib-resistant models. DNA sequencing of HER2- mutant tumors clinically refractory to neratinib, as well as circulating tumor DNA profiling of patients who progressed on neratinib, showed enrichment of genomic alterations that converge to activate the mTOR pathway. • Neratinib resistance in HER2 -mutant cancers is associated with TORC1 hyperactivation • Multiple mechanisms converge on TORC1 signaling to promote neratinib resistance • Combination with TORC1 inhibitor everolimus restores sensitivity to neratinib In brief, Sudhan et al. identify that hyperactivation of TORC1 restores HER2 downstream signaling to drive neratinib resistance across histologically distinct HER2 -mutant cancers. The combination of TORC1 inhibitor everolimus and neratinib arrests the growth of neratinib-resistant cells, organoids, and xenografts. [ABSTRACT FROM AUTHOR]

The treatment outcome has been unsatisfactory for patients with non-small-cell lung cancer (NSCLC) refractory to standard first-line chemotherapy. Trastuzumab emtansine (T-DM1), an anti-HER2 antibody conjugated with a vinca alkaloid, has been approved for clinical use in HER2+ breast cancer in many countries. Approximately 5% of NSCLC tumors possess HER2 alterations, and T-DM1 has shown excellent antitumor effects against HER2+ lung cancer cell lines in preclinical models. Therefore, we hypothesized that T-DM1 could significantly inhibit the growth of HER2+ lung cancers. We have launched a nonrandomized phase II trial of T-DM1 monotherapy for patients with HER2+ lung cancers. The major eligibility criteria are as follows: age ≥ 20 years, pathologically diagnosed NSCLC with documented HER2 positivity (immunohistochemistry 3+, both immunohistochemistry 2+ and fluorescence in situ hybridization positive, or exon 20 insertion mutation), and previous chemotherapy. Thirty patients will receive T-DM1 3.6 mg/kg every 3 weeks. The primary endpoint is the overall response rate. This trial will provide information on whether T-DM1 monotherapy is effective against HER2+ lung cancer., (Copyright © 2016 Elsevier Inc. All rights reserved.)

HER2 mutations, largely exon 20 in-frame insertions, have been described as an oncogenic driver alteration in 1% to 4% of NSCLC, exclusively in adenocarcinoma histology. The prognostic implication of these alterations is not known. Phase I and II trial data suggest that afatinib, neratinib and dacomitinib have some activity in this molecular subgroup. No comparative data, or any data regarding the activity of pertuzumab or trastuzumab-emtansine is available. HER2 deregulation either by protein overexpression or gene amplification, has little clinical relevance to date, as trials investigating trastuzumab activity merely suggest a benefit in the very small minority of patients whose tumor highly overexpresses HER2, a subpopulation that amounts to 2% to 6% of mostly adenocarcinomas.