HER2 exon 20 insertions in non-small-cell lung cancer are sensitive to the irreversible pan-HER receptor tyrosine kinase inhibitor pyrotinib.
ABSTRACT: 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.
Project description:Abstract The clinical benefits of HER2 inhibitors in patients with non-small cell lung cancer (NSCLC) have been limited. There is a paucity of effective therapies in NSCLC after developing resistance to initial anti-HER2 therapy. Herein, we presented the clinical benefit of pyrotinib in a 53-year-old patient with advanced lung adenocarcinoma whose circulating tumor DNA (ctDNA) analysis of pleural effusion revealed the coexistence of HER2 exon 20 p.Y772_A775dup (mutation ratio: 38.86%) and HER2 amplification (copy number: 4.5) following failures of multiple therapies including afatinib and ado-trastuzumab emtansine (T-DM1). Notably, pyrotinib treatment induced rapid and marked improvement of clinical symptoms, and partial response was observed after 8 weeks. CtDNA monitoring during the treatment showed that the mutation ratio of HER2 decreased to 7.99%, and the amplification disappeared. The patient achieved a progression-free survival of 7.5 months after treatment with pyrotinib. Thus, pyrotinib may be a new treatment strategy for the subgroup of lung adenocarcinoma patients, with coexistence of HER2 exon 20 p.Y772_A775dup and HER2 amplification even after failures of multiple anti-HER2 therapies. It also indicated the value of capture-based next-generation sequencing to monitor and guide therapy.
Project description:<h4>Background</h4>Standard therapy for human epidermal growth factor receptor 2 (HER2)-mutant non-small-cell lung cancer (NSCLC) is lacking. The clinical benefits with pan-HER inhibitors (afatinib, neratinib, and dacomitinib), anti-HER2 antibody drug conjugate (ADC) trastuzumab emtansine, and an emerging irreversible tyrosine kinase inhibitor (TKI) poziotinib were modest. Another new ADC trastuzumab deruxtecan showed encouraging outcomes, but only phase I study was completed. Pyrotinib, another emerging irreversible epidermal growth factor receptor (EGFR)/HER2 dual TKI, has been approved in HER2-positive breast cancer in 2018 in China. It has shown promising antitumor activity against HER2-mutant NSCLC in phase II trials, but pyrotinib-related diarrhea remains an issue. The antiangiogenic and immunomodulatory drug thalidomide is a cereblon-based molecular glue that can induce the degradation of the IKAROS family transcription factors IKZF1 and IKZF3. The use of thalidomide can also decrease gastrointestinal toxicity induced by anti-cancer therapy.<h4>Methods</h4>This is an open-label, single-arm phase II trial. A total of 39 advanced NSCLC patients with HER2 exon 20 insertions and ≤ 2 lines of prior chemotherapy will be recruited, including treatment-naïve patients who refuse chemotherapy. Patients are allowed to have prior therapy with immune checkpoint inhibitors and/or antiangiogenic agents. Those who have prior HER2-targeting therapy or other gene alterations with available targeted drugs are excluded. Eligible patients will receive oral pyrotinib 400 mg once daily and oral thalidomide 200 mg once daily until disease progression or intolerable toxicity. The primary endpoint is objective response rate.<h4>Discussion</h4>The addition of thalidomide to pyrotinib is expected to increase the clinical benefit in advanced NSCLC patients with HER2 exon 20 insertions, and reduce the incidence of pyrotinib-related diarrhea. We believe thalidomide is the stone that can hit two birds.<h4>Trial registration</h4>ClinicalTrials.gov Identifier: NCT04382300 . Registered on May 11, 2020.
Project description:<h4>Background</h4> HER2 (or ERBB2) amplification is an important mechanism for acquired resistance to EGFR tyrosine kinase inhibitors (TKI). The benefits of HER2-targeted therapy have been limited. Herein, we investigated the molecular and clinical patterns of HER2 amplification in non-small cell lung cancer (NSCLC) patients during progression on EGFR-TKIs and the potential of combining EGFR-TKI and pyrotinib to overcome resistance. <h4>Methods</h4> In this study, 1,637 NSCLC cases from Geneseeq after progression of EGFR-TKIs were screened and analyzed by next generation sequencing (NGS), in which 48 patients with HER2 amplification were eligible and enrolled. A total of 403 patients from Sun Yat-sen University Cancer Center (SYSUCC) were screened and five patients with concomitant EGFR mutations and HER2 amplification were retrospectively collected to assess the effect of afatinib or combination of EGFR-TKI and pyrotinib. <h4>Results</h4> In the 48 patients from the Geneseeq cohort, 27 (56.2%) patients suffered from resistance of 1st/2nd generation EGFR-TKI, and 21 (43.8%) patients from 3rd generation. As for the five patients forming the SYSUCC cohort, three patients were treated with afatinib, one achieved partial response (PR) with progression-free survival (PFS) of 6 months and two quickly developed disease progression. Two patients were treated with EGFR-TKIs plus pyrotinib, one receiving gefitinib plus pyrotinib achieved PR with PFS of 8 months and benefited from osimertinib plus pyrotinib for 3 months till data-off; one receiving osimertinib plus pyrotinib achieved SD for 4 months till data-off. The most common co-occurring alteration was TP53 (91.7%) in the mutation profile of the 48 patients from the Geneseeq cohort, and four patients had TP53 co-mutations of the five patients from the SYSUCC cohort. <h4>Conclusion</h4> In this study, we detected 7% HER2 amplification present in EGFR-TKIs resistance. Patients with concomitant EGFR mutation and HER2 amplification may derive clinical benefit from therapies that target both EGFR and HER2.
Project description:Human epidermal growth factor receptor 2 (HER2) is a member of the HER family of proteins containing four receptor tyrosine kinases. It plays an important role in the pathogenesis of certain human cancers. In non-small-cell lung cancer (NSCLC), HER2 amplification or mutations have been reported. However, little is known about the benefit of HER2-targeted therapy for NSCLCs harboring HER2 alterations. In this study, we investigated the antitumor effect of afatinib, an irreversible epidermal growth factor receptor (EGFR)-HER2 dual inhibitor, in lung cancers harboring HER2 oncogene alterations, including novel HER2 mutations in the transmembrane domain, which we recently identified. Normal bronchial epithelial cells, BEAS-2B, ectopically overexpressing wild-type HER2 or mutants (A775insYVMA, G776VC, G776LC, P780insGSP, V659E, and G660D) showed constitutive autophosphorylation of HER2 and activation of downstream signaling. They were sensitive to afatinib, but insensitive to gefitinib. Furthermore, we examined the antitumor activity of afatinib and gefitinib in several NSCLC cell lines, and investigated the association between their genetic alterations and sensitivity to afatinib treatment. In HER2-altered NSCLC cells (H2170, Calu-3, and H1781), afatinib downregulated the phosphorylation of HER2 and EGFR as well as their downstream signaling, and induced an antiproliferative effect through G1 arrest and apoptotic cell death. In contrast, HER2- or EGFR-non-dependent NSCLC cells were insensitive to afatinib. In addition, these effects were confirmed in vivo by using a xenograft mouse model of HER2-altered lung cancer cells. Our results suggest that afatinib is a therapeutic option as a HER2-targeted therapy for NSCLC harboring HER2 amplification or mutations.
Project description:Anti-human epidermal growth factor receptor 2 (HER2) therapy is an effective treatment for HER2-positive gastric and breast malignancies. However, the efficacy of HER2-targeted therapy in non-small cell lung cancer (NSCLC) patients with HER2 alterations remains controversial. We searched studies on HER2-targeted therapy in NSCLC patients that reported objective response rate (ORR), disease control rate (DCR) and progressionfree survival (PFS) published from database inception to 30 May 2021. A total of 32 trials involving 958 patients were included. The ORRs of HER2-TKIs targeted therapy, humanised monoclonal antibody, trastuzumab-based treatment and antibody-drug conjugate (ADC) (T-DM1) were 22% (95% CI 11-31), 23% (95% CI 20-65), 26% (95% CI 14-39) and 16% (95% CI _6-37), while that of ADC (DS-8201) was 60% (95% CI 35-85). The DCRs of these groups were 59% (95% CI 49-69), 39% (95% CI _9-88), 63% (95% CI 37-89), 31% (95% CI 4-58) and 87% (95% CI 62-112), respectively. In the subgroup analysis, numerically higher ORRs and DCRs were observed in the poziotinib (38%; 75%) and pyrotinib (35%; 83%) groups. The median PFSs of these groups were 5.51 months, 3.09 months, 4.61 months, 2.65 months and 12.04 months, respectively. HER2-targeted therapy can be considered an acceptable treatment strategy for NSCLC patients with HER2 alterations. In particular, ADC (DS-8201), pyrotinib and poziotinib demonstrated promising anti-tumour activity in HER2-positive NSCLC.
Project description:<b>Purpose:</b> Different second-line treatments of patients with trastuzumab-resistant human epidermal growth factor receptor 2 (HER2) positive breast cancer were examined in randomized controlled trials (RCTs). A network meta-analysis is helpful to evaluate the comparative survival benefits of different options. <b>Methods:</b> We performed a bayesian network meta-analysis using R-4.0.0 software and fixed consistency model to compare the progression free survival (PFS) and overall survival (OS) benefits of different second-line regimens. <b>Results:</b> 13 RCTs (19 publications, 4313 patients) remained for qualitative synthesis and 12 RCTs (17 publications, 4022 patients) were deemed eligible for network meta-analysis. For PFS, we divided network analysis into two parts owing to insufficient connections among treatments. The first part involved 8 treatments in 9 studies and we referred it as PFS (#1). Amid the following 8 interventions: pyrotinib + capecitabine, T-DM1 + atezolizumab, pertuzumab + trastuzumab + capecitabine, T-DM1, trastuzumab + capecitabine, lapatinib + capecitabine, neratinib, and capecitabine, we found consistent benefits between the first three interventions; moreover, pyrotinib + capecitabine was most likely to be associated with the best benefits; capecitabine monotherapy was associated with the worst PFS. The second part included 3 treatments in 2 studies and we referred it as PFS (#2): everolimus + trastuzumab + vinorelbine had better PFS benefits versus trastuzumab + vinorelbine and afatinib + vinorelbine. For OS, we analyzed 7 treatments in 7 studies, and observed T-DM1 + atezolizumab, pertuzumab + trastuzumab + capecitabine, and T-DM1 had similar effectiveness, and the first had the highest probability to yield the longest OS; capecitabine or neratinib alone yielded the worst OS benefits. <b>Conclusions:</b> Our work comprehensively summarized and analyzed current available RCT-based evidence of the second-line treatments for trastuzumab-treated, HER2-positive, advanced breast cancer. These results provide clinicians and oncologists meaningful references for clinical drug administration and the development of novel effective therapies.
Project description:<h4>Background</h4>Several human epidermal growth factor receptor 2 (HER2)-targeted regimens (anti-HER2 target agent combined chemotherapy) have been introduced for the treatment of HER2-positive locally advanced or metastatic breast cancer progressed after trastuzumab. We therefore conducted a network meta-analysis to compare and rank HER2-targeted regimens in this population after trastuzumab therapy.<h4>Methods</h4>The electronic databases of PubMed, EmBase, Cochrane Central Register of Controlled Trials, and the websites of http://clinicaltrials.gov/ (US NIH) were systematically searched for published and unpublished randomized controlled trials (RCTs) from their inception to October, 2020. Nine treatment regimens were eligible to be included in this analysis. The primary outcomes were overall response rate (ORR), progression-free survival (PFS) and overall survival (OS), while the secondary outcomes were grade ≥3 adverse events.<h4>Results</h4>A total of 2,104 citations were identified and 12 RCTs comprising 3,769 patients were selected for final analysis. For HER2 positive unresectable, locally advanced or metastatic patients progressed after trastuzumab therapy pyrotinib plus capecitabine ranked the highest surface under the cumulative ranking area (SUCRA) in PFS, ORR and its SUCRA in OS was higher than Trastuzumab emtansine (T-DM1). T-DM1 plus atezolizumab, pyrotinib plus capecitabine, and pertuzumab plus trastuzumab plus capecitabine had comparable SUCRA in OS (76.1% <i>vs.</i> 74.5% <i>vs.</i> 71.2%). Six of included studies reported any grade ≥3 adverse events, the prevalence of any grade ≥3 adverse events in lapatinib plus capecitabine (353/683), T-DM1 (213/558), trastuzumab plus capecitabine (130/218), pertuzumab plus trastuzumab plus capecitabine (118/228), pyrotinib plus capecitabine (220/384), T-DM1 plus atezolizumab (43/132) and capecitabine (24/94) were 51.7%, 38.2%, 59.6%, 51.8%, 57.3%, 32.6% and 25.5%, respectively. Specific adverse event characteristics related to different HER2-targeted regimens need to be well known ahead and managed during the therapy.<h4>Conclusions</h4>The results indicated that for HER2 positive breast cancer with previous trastuzumab therapy pyrotinib plus capecitabine was probably more efficacious in PFS and ORR. T-DM1 plus atezolizumab, pyrotinib plus capecitabine and pertuzumab plus trastuzumab plus capecitabine have comparable effect on OS improvement and all of them were likely better than T-DM1. The risk of grade ≥3 adverse events for specific treatment regimens were also provided.
Project description:<b>Background:</b> Purpose of this study was to evaluate the contribution of the Extracellular-regulated protein kinase (ERK)-1/2 pathway to oncogenic signaling elicited by the tyrosine kinase receptor HER2 in Non-Small Cell Lung Cancer (NSCLC) and to assess the prognostic value of these oncoproteins in NSCLC patients. <b>Methods:</b> Immunohistochemistry was performed to determine expression and activation of HER2 and ERK1/2 (detected by phosphorylation of Y1248 and T202/Y204, respectively) using Tissue Micro Arrays (TMA) containing matched normal and neoplastic tissues from 132 NSCLC patients. Survival analysis was carried out using the Kaplan-Meier method. Univariate and multivariate analysis were used to evaluate the prognostic value of pERK1/2, pHER2 and a combination thereof with clinical-pathological parameters such as age, lymph node status (N), size (T), stage (TNM) and grade. <b>Results:</b> We found that HER2 was overexpressed in 33/120 (27%) and activated in 41/114 (36%) cases; ERK1/2 was activated in 44/102 (43%) cases. A direct association was found between pERK1/2 and pHER2 (23/41; p=0.038). In addition, patients positive for pERK1/2 and for both pHER2 and pERK1/2 showed significantly worse overall survival (OS) and disease-free survival (DFS) compared with negative patients. Univariate and multivariate analysis of patients' survival revealed that positivity for pHER2-pERK1/2 and for pERK1/2 alone were independent prognostic factors of poor survival in NSCLC patients. In particular, this association was significantly important for DFS in stage I+II patients. <b>Conclusion:</b> This study provides evidence that activated ERK1/2 and/or the combined activation of HER2 and ERK1/2 are good indicators of poor prognosis in NSCLC patients, not only in unselected patients but also in early stage disease.
Project description:No targeted treatments are currently approved for HER2 exon 20 insertion-mutant lung adenocarcinoma patients. Mobocertinib (TAK-788) is a potent irreversible tyrosine kinase inhibitor (TKI) designed to target human epidermal growth factor receptor 2 (HER2/ERBB2) exon 20 insertion mutations. However, the function of mobocertinib on HER2 exon 20 insertion-mutant lung cancer is still unclear. Here we conducted systematic characterization of preclinical models to understand the activity profile of mobocertinib against HER2 exon 20 insertions. In HER2 exon 20 insertion-mutant cell lines, the IC50 of mobocertinib was higher than poziotinib and comparable with or slightly lower than afatinib, neratinib, and pyrotinib. Mobocertinib had the lowest HER2 exon 20 insertion IC50/wild-type (WT) EGFR IC50 ratio, indicating that mobocertinib displayed the best selectivity profile in these models. Also, mobocertinib showed strong inhibitory activity in HER2 exon 20YVMA allograft and patient-derived xenograft models. In genetically engineered mouse models, HER2 exon 20G776>VC lung tumors exhibited a sustained complete response to mobocertinib, whereas HER2 exon 20YVMA tumors showed only partial and transient response. Combined treatment with a second antibody-drug conjugate (ADC) against HER2, ado-trastuzumab emtansine (T-DM1), synergized with mobocertinib in HER2 exon 20YVMA tumors. In addition to the tumor cell autonomous effect, sustained tumor growth control derived from M1 macrophage infiltration and CD4+ T-cell activation. These findings support the ongoing clinical development of mobocertinib (NCT02716116) and provide a rationale for future clinical evaluation of T-DM1 combinational therapy in HER2 exon 20YVMA insertion-mutant lung adenocarcinoma patients. SIGNIFICANCE: This study elucidates the potent inhibitory activity of mobocertinib against HER2 exon 20 insertion-mutant lung cancer and the synergic effect of combined mobocertinib and T-DM1, providing a strong rationale for clinical investigation. Overall design: RNA sequencing on HER2 exon 20YVMA tumor nodules treated
Project description:<h4>Background</h4>Recently, progress has been made in the development of targeted therapies for human epidermal growth factor receptor 2 (HER2)-positive gastric cancer (GC). However, drug resistance has severely limited the efficacy of anti-HER2 therapies. Pyrotinib is a novel pan-HER inhibitor. Although it is effective in HER2-positive GC treatment, its efficacy in combination with apatinib and associated resistance mechanisms in HER2-positive GC remains unclear.<h4>Methods</h4>In this study, the combination effects of pyrotinib and apatinib were examined in two pyrotinib-sensitive GC cells and xenografts. The RNA sequencing was used to determine the underlying mechanisms of acquired pyrotinib resistance. The role of imatinib and apatinib in reversing pyrotinib resistance was tested in pyrotinib-resistant cells and xenografts.<h4>Results</h4>Here, we reported that a combination of pyrotinib and apatinib exhibits synergistic effect in HER2-positive NCI-N87 xenografts, and showed enhanced antitumor efficacy in HER2-positive GC, both in vitro and in vivo. Moreover, up-regulation of the stem cell factor (SCF) levels, and the PI3K/AKT and MAPK pathways was associated with acquired pyrotinib resistance in HER2-positive GC. Mechanistically, we demonstrated that the activation of the SCF/c-kit signaling and its downstream PI3K/AKT and MAPK pathways mediated pyrotinib resistance by promoting cell survival and proliferation. Imatinib and apatinib augmented the sensitivity of pyrotinib-resistant cells and xenografts to pyrotinib, by blocking SCF/c-kit signaling.<h4>Conclusion</h4>These results highlight the effectiveness of pyrotinib combined with apatinib in HER2-positive GC and acquired pyrotinib resistance, thus providing a theoretical basis for new treatment methods.