anti-HER2 Tyrosine Kinase Inhibitors Research Articles

Trastuzumab, pertuzumab and nab-paclitaxel plus pyrotinib or not in neoadjuvant treatment of HER2-positive breast cancer: A multi-center, randomized, open-label, phase II study.

e12634 Background: Trastuzumab plus pertuzumab (TP) combined with chemotherapy is the standard neoadjuvant treatment regimen for HER2+ breast cancer. Anti-HER2 tyrosine kinase inhibitor, pyrotinib, shows great efficacy in HER2+ metastatic breast cancer, but lacking efficacy data on the basis of TP and chemotherapy in the neoadjuvant setting. This study aims to evaluate the efficacy and safety of TP plus nab-paclitaxel with or without pyrotinib as neoadjuvant treatment in HER2+ breast cancer. Methods: Stage II-III HER2+ breast cancer patients, stratified by disease stage (II vs. III) and hormone receptor (HR) status (positive vs. negative), were randomized 1:1 into the pyrotinib group or the control group. Both groups received a combination of 3-weekly TP and weekly nab-paclitaxel for 12 weeks. The pyrotinib group was concurrent given 320mg pyrotinib once daily. Primary endpoint was the total pathological complete remission (tpCR), defined as no invasive cancer in the breast and axillary lymph node. Results: From Nov 2020 to Apr 2023, a total of 109 patients were enrolled, with 108 receiving treatment: 55 in the pyrotinib group and 53 in the control group.The tpCR rate was 65.5% (95% CI: 51.4%, 77.8%) in the pyrotinib group, which shows no significant difference with the control group [60.4% (95% CI: 46.0%,73.5), P = 0.585). The breast pathological complete response (bpCR) rates were 70.9% (95% CI: 57.1%,82.4%) and 64.2%(95% CI: 49.8%,76.9%) in the pyrotinib and control group, respectively (P = 0.453). In the pyrotinib group, 52 (94.5%), 31 (56.4%), and 23 (41.8%) patients experienced dose-interruption, dose-reduction, and discontinuation of pyrotinib, respectively. The most common grade ≥3 adverse events in the pyrotinib and control groups were diarrhea (58.1% vs. 0%), decreased neutrophil count (23.6% vs. 15.1%), and decreased white blood cell count (16.4% vs. 7.5%). Conclusions: Our study showed pyrotinib didn’t significantly improve tpCR rate with pyrotinib on the basis of TP and nab-paclitaxel neoadjuvant therapy of HER2+ breast cancer. Concurrent pyrotinib treatment with TP was associated with a high rate of severe diarrhea. Further biomarker analyses are needed to identify which population would receive great benefit with neoadjuvant pyrotinib therapy in HER2+ breast cancer. Clinical trial information: NCT04398914 .

Tucatinib promotes immune activation and synergizes with programmed cell death-1 and programmed cell death-ligand 1 inhibition in HER2-positive breast cancer.

Programmed cell death-1 (PD-1) and programmed cell death-ligand 1 (PD-L1) inhibitors have poor efficacy in patients with trastuzumab-resistant advanced HER2-positive breast cancer. Tucatinib is a potent, selective anti-HER2 tyrosine kinase inhibitor with proven clinical benefit in the advanced setting in patients with trastuzumab resistance. We investigated if tucatinib can alter the tumor microenvironment and if this could be harnessed for therapeutic efficacy. We investigated the antitumor efficacy and contribution of the immune response of tucatinib using 2 immunocompetent, HER2-positive murine breast cancer models (trastuzumab-sensitive H2N113; trastuzumab-resistant Fo5) and the efficacy of tucatinib with trastuzumab and PD-1 or PD-L1 checkpoint inhibitors. In both models, tucatinib statistically significantly inhibited tumor growth and demonstrated dose-dependent efficacy. Ex vivo analysis by flow cytometry of tumor-infiltrating lymphocytes in mice treated with tucatinib showed increased frequency, higher proliferation, and enhanced effector function of CD8+ effector memory T cells. Tucatinib treatment also increased frequency of CD8+PD-1+ and CD8+TIM3+ T cells, CD49+ natural killer cells, monocytes, and major histocompatibility complex II expression on dendritic cells and macrophages and a decrease in myeloid-derived suppressor cells. Gene expression analysis revealed statistically significant enrichment in pathways associated with immune activation, type I and II interferon response, adaptive immune response, and antigen receptor signaling. In vivo, tucatinib and α-PD-L1 or α-PD-1 demonstrated statistically significantly increased efficacy and improved survival of mice compared with tucatinib alone. Tucatinib modulates the immune microenvironment favorably, and combination treatment with α-PD-L1 or α-PD-1 demonstrated increased efficacy in preclinical HER2-positive tumor models. These findings provide a rationale for investigation of tucatinib and immune checkpoint inhibition in the clinic.

Abstract ED13-1: Beyond anthracyclines and trastuzumab: Cardiotoxicity of novel agents

Abstract Breast cancer treatment can have a diverse array of delayed and long-term effects, including cardiovascular events such as heart failure, valvular damage, coronary artery disease, arrythmias, and cardiac dysfunction. The adverse cardiovascular effects of anthracyclines and trastuzumab in the treatment of early and advanced breast cancer have been well elucidated withing the literature; however, there is less understanding of the potential cardiovascular impact of more recent novel breast cancer therapies. Dual HER2 targeted therapy (pertuzumab/trastuzumab) is now standard of care for neoadjuvant and adjuvant treatment, particularly in the setting of lymph node involvement, but is there a higher risk of cardiotoxicity? There is a limited understanding of the potential short- and long-term cardiovascular toxicity associated with antibody-drug conjugates, such as T-DM1 and fam-trastuzumab deruxtecan, and well as oral anti-HER2 tyrosine kinase inhibitors such as lapatinib, neratinib, and more recently tucatinib. CDK4/6 inhibitors (eg ribociclib) combined with endocrine therapy have significantly improved clinical outcomes for individuals with hormone receptor positive, HER-2 advanced breast cancer but are associated with an increased risk of QTc prolongation, which can be compounded by electrolyte abnormalities and drug-drug interactions. Immune checkpoint inhibitors (pembrolizumab) are approved in the neoadjuvant (high risk) and advanced setting (PDL-1 positive) for triple negative breast cancer but are associated with several toxicities including endocrinopathies and rarely fatal myocarditis. The goal of this session is to improve the awareness and understanding of the potential cardiovascular toxicities associated with modern anti-cancer therapies used in the treatment of breast cancer. Citation Format: Susan Dent. Beyond anthracyclines and trastuzumab: Cardiotoxicity of novel agents [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr ED13-1.

Therapeutic landscape of advanced HER2-positive breast cancer in 2022.

HER2-positive breast cancer is an aggressive subtype of breast cancer with five-year survival rates of 30% for the advanced stage. The development of anti-HER2 treatments has led to a paradigm shift in the management and clinical outcomes of advanced HER2-positive breast cancer patients. The standard first-line treatment consists of taxane-based chemotherapy plus dual anti-HER2 therapies with trastuzumab and pertuzumab. The antibody-drug conjugate (ADC) ado-trastuzumab emtansine (T-DM1) has been a second-line therapeutic standard, but the second-line treatment approach is rapidly evolving. Given a substantial advantage of another ADC, Fam-trastuzumab deruxtecan (T-DXd), compared to T-DM1 in a recent randomized trial in the second-line setting, T-DXd is currently the preferred second-line option. Optimal third-line treatment strategies are still not established, and multiple approaches have been used including combinations based on capecitabine, trastuzumab, or both with oral anti-HER2 tyrosine kinase inhibitors. Tucatinib plus capecitabine and trastuzumab, lapatinib plus trastuzumab, neratinib or lapatinib plus capecitabine are some of the FDA approved combinations. Another newer agent approved for third- or later-line therapy in the metastatic setting ismargetuximab, an Fc-engineered anti-HER2 monoclonal antibody, in combination with chemotherapy. Other novel agents currently under clinical trials are the drugs that indirectly target HER2, including immune cell cycle inhibitors, PI3K/mTOR inhibitors, and immunotherapy agents.

Trends in anti-HER2 drugs consumption and influencing factors.

BackgroundHuman epidermal growth factor receptor 2 (HER2) inhibitors have been approved to treat various cancers with HER2 amplification. The Chinese government has made great efforts to improve the availability and affordability of these drugs. This study aimed to analyze the trends in anti-HER2 drug consumptions in Nanjing from 2012 to 2021, and explore influencing factors.MethodsData about use of anti-HER2 drugs in 2012–2021 were extracted from Jiangsu Medicine Information Institute. Six types of anti-HER2 drugs were included. Drug consumption was expressed as defined daily doses (DDDs) and expenditure. Time series analysis was adopted to find trends in consumption, while interrupted time series was used in analyzing the impact of policy on consumption. The correlation between DDDs and defined daily cost (DDC) was analyzed by Pearson's correlation test.ResultsThe DDC, DDDs, and expenditure of anti-HER2 drugs changed little from 2012 to 2016. The DDC decreased intermittently, while the DDDs and expenditure of these drugs grew continuously from 2017 to 2021. The anti-HER2 monoclonal antibodies contributed to the majority of total consumption in 2012–2019. The DDDs of anti-HER2 tyrosine kinase inhibitors surpassed the DDDs of monoclonal antibodies in 2020–2021. Trastuzumab was the predominantly prescribed drug in 2012–2019, but the DDDs of pyrotinib surpassed the DDDs of trastuzumab in 2020–2021. The ln value of DDC or self-paid DDC of trastuzumab was negatively correlated with the ln value of its DDDs. The national health insurance coverage (NHIC) and national drug price negotiation policy about anti-HER2 drugs were initiated in 2017. Low-price generics and biosimilar of trastuzumab came into the market in 2020 and 2021, separately. Interrupted time series analysis showed that the DDDs increased significantly after the implementation of NHIC, price negotiation or generic drug replacement.ConclusionThe consumption of anti-HER2 drugs has significantly increased and their DDC has decreased after the implementation of NHIC, price negotiation, or low-price generic drug replacement since 2017. Further efforts are needed to translate the high consumption into clinical benefits.

Thoughts on therapy strategy in the era of "after anti-HER2 TKI" in CSCO BC Guidelines 2022.

Treatment of breast cancer (BC) is becoming stratified on the basis of classified treatment. Different from trastuzumab emtansine (T-DM1) as 2nd-line anti-human epidermal growth factor receptor 2 (HER2) treatment is recommended by foreign guidelines and clinical practice, more patients in China are receiving anti-HER2 tyrosine kinase inhibitor (TKI) as 2nd-line anti-HER2 targeted therapy for metastatic BC, which raises the issue of subsequent targeted therapy after TKI failure, the preferred regimen and how to optimize it. Evidence from high-quality randomized controlled clinical trials is lacking up to now, but in clinical practice this stratified subgroup patients need to be treated. Failure to TKI treatment is first described in the Chinese Society of Clinical Oncology Breast Cancer (CSCO BC) Guidelines 2022, based on existing clinical trials data, real-world research data and expert opinions on HER2-positive metastatic BC, although there are no Level I recommendations and Level II options include anti-HER2 antibody-drug conjugate (ADC) (2A evidence), pertuzumab and trastuzumab plus other (non-taxane) chemotherapy (2A evidence), switching to another TKI plus chemotherapy (2A evidence) and entering strictly designed clinical trials. In the era of "after anti-HER2 TKI", there will be more results of randomized controlled clinical trials and real-world researches as evidences to guide the therapy in the future, and clinicians must ensure accurate classification and precise stratification of patients to deliver optimized, precise subsequent therapy.

A deep learning approach to discover cyclin-dependent kinases 12 (CDK12) inhibitors in breast cancer.

e15086 Background: Although anti-HER2 tyrosine kinase inhibitors (TKIs) have significantly prolonged survival and improved prognosis in HER2-positive breast cancer patients, resistance is a constant obstacle leading to TKIs treatment failure and tumor progression. Our previous research shows dual inhibition of HER2/CDK12 will prominently benefit the outcomes of patients with HER2-positive breast cancer by sensitizing the tumors to anti-HER2 TKIs treatment. Unfortunately, there is no high selective CDK12 inhibitor in clinical. This study sought to accelerate the CDK12 inhibitor discovery by a deep learning approach. Methods: We developed a large-scale self-supervised graph neural network to learn 11 million unlabelled compounds for molecular representation. And the model was trained with 233,823 kinase domain sequences by drug-target interaction datasets from the BindingDB database. Then, this transformer architecture was used to predict potential CDK12 inhibitors. The candidate hits compounds with diverse skeletons were divided into 50 clusters by clustering analysis. The representative hits with high transform scores and rational binding mode in each cluster were detected in the homogeneous time-resolved fluorescence CDK12 kinase assay. Candidate clusters with half-maximal inhibitory concentrations (IC50) lower than 200 nM were selected into expanded validation and kinase selective panel detection. xCELLigence RTCA system was adopted to monitor cell growth and sensitivity of breast cancer cells to CDK12 inhibitors in a real-time manner. Results: Our predictive transfer learning model yielded satisfactory predictions on various targets including CDK12. We screened a total of 4,527,236 compounds and recommended 50 clusters of potential CDK12 inhibitors for further enzyme activity detection. The IC50 of seven cluster representative compounds is lower than 10 uM. Expanded screening of 500 compounds in these clusters discovered a lot of hits with highly CDK12 selective inhibition. Half of the new compounds are showed promising proliferation inhibition in breast cancer cell lines. Conclusions: Our study provides a highly efficient and end-to-end deep learning approach to discover highly selective CDK12 inhibitors in breast cancer.

Pyrotinib plus nab-paclitaxel in patients with HER2-positive advanced or metastatic breast cancer: A multicenter, single-arm, open-label phase 2 trial.

1035 Background: For human epidermal growth factor receptor 2 (HER2) positive advanced or metastatic breast cancer, the standard therapeutic strategy is HER2-targeted agents combined with a taxane. This multicenter, single-arm phase 2 trial was designed to assess the efficacy and safety of pyrotinib (a brand-new generation, irreversible anti-HER2 tyrosine kinase inhibitor) plus nab-paclitaxel in patients with HER2-positive advanced or metastatic breast cancer. Methods: This was a multicenter, single-arm, open-label phase 2 trial conducted at seven centers in China (ChiCTR1900023653). Women aged 18-75 years, with histologically or cytologically confirmed HER-2 positive (immunohistochemistry [IHC] 3+ or positive confirmed by fluorescence in situ hybridization) advanced or metastatic breast cancer and with Eastern Cooperative Oncology Group performance score (ECOG PS) of 0-1 were enrolled. Patients with primary resistance to trastuzumab and bone-only metastases were excluded. Eligible patients received pyrotinib (400 mg, po, qd) plus nab-paclitaxel (125 mg/m2, iv, day 1/8/15) for each 28-day cycle until disease progression, unacceptable toxicity, consent withdrawal or death. The primary endpoint was objective response rate (ORR), defined as the proportion of patients with complete response (CR) or partial response (PR) according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Secondary endpoints included progression-free survival (PFS), overall survival, safety and quality of life. Results: Between December 2019 and December 2021, 51 patients were enrolled. The median age was 55 years (range 35–72). Twenty-three patients (45.1%) had ECOG PS of 0. Ten patients (19.6%) with metastatic disease had previously received first-line treatment and 28 (54.9%) had received prior treatment with trastuzumab. More than half (29 of 51, 56.9%) had hormone receptor-positive disease. Visceral metastases occurred in 56.9% of the patients (29 of 51) and 26 patients (51.0%) were menopausal. The data cutoff for the present analysis was January 21, 2022. Among 38 evaluable patients, four patients (10.5%) had CR, 27 (71.1%) had PR, six (15.8%) had stable disease, and one (2.6%) had progressive disease. The confirmed ORR was 81.6% (95% CI 65.1-91.7%). The PFS data were still immature. The most common grade ≥3 treatment-emergent adverse events included neutropenia (14 of 51, 27.5%), diarrhea (10 of 51, 19.6%), fatigue (5 of 51, 9.8%) and peripheral neuropathy (4 of 51, 7.8%). Conclusions: Pyrotinib combined with nab-paclitaxel showed a promising antitumor activity with good tolerance in patients with HER2-positive advanced or metastatic breast cancer. Clinical trial information: ChiCTR1900023653.

Efficacy and safety of pan-ErbB inhibitor pyrotinib combined with antiangiogenic agent apatinib for HER2-mutant or amplified metastatic NSCLC: A phase II clinical study.

9035 Background: Tumor angiogenesis could be induced by activation of HER2 receptor, and currently, there is lack of clinical evidence of anti-HER2 tyrosine kinase inhibitors (TKIs) combined with antiangiogenic therapy for HER2-mutant or amplified non-small cell lung cancer (NSCLC). We conducted a study to explore the efficacy and safety of a pan-ErbB inhibitor pyrotinib combined with apatinib for metastatic NSCLC patients harboring HER2 amplification or activating mutations. Methods: This was a single-center, single-arm phase II study with Simon’s optimal two-stage design. Metastatic NSCLC patients with ECOG scores of 0-1 and harboring primary HER2 amplification, exon 20 insertion or activating missense mutations who had failed to prior chemotherapies or anti-HER2 TKIs were eligible to be enrolled. All patients received oral pyrotinib (400mg once daily) combined with apatinib (250mg once daily) therapy. The primary endpoint was objective response rate (ORR), and second endpoints included progression-free survival (PFS), duration of response (DoR), disease control rate (DCR), overall survival (OS) and safety. Results: Between March 5, 2019, and December 1, 2020, 33 metastatic NSCLC patients with HER2 alterations were enrolled, including exon 20 insertions (A775_G776insYVMA, 20/33; P780_Y781insGSP, 6/33; other variants, 2/33), missense mutations (3/33), and primary HER2 amplification (2/33). Seventeen patients (51.5%) were pretreated with first-line platinum-based chemotherapies or anti-HER2 TKIs, and the remaining had received at least 2 lines of prior therapies (range, 2-6). At the last follow-up time January 23, 2021, the overall ORR and DCR were 45.5% (15/33) and 93.9% (31/33), respectively. The median PFS was 6.8 (95%CI: 5.4-8.2) months. The median DoR and OS were 5.3 (95%CI: 0-11.8) and 12.9 (95%CI: 8.6-17.2) months, respectively. The mPFS was significantly longer in patients who received second-line pyrotinib combined with apatinib therapy than those in third- or above-line settings (9.8 vs. 5.3 months, P = 0.018, HR = 0.281 [95%CI: 0.098-0.807]). Although pyrotinib combined with apatinib therapy showed similar ORRs in patients with presence (46.2%, 6/13) or absence (45.0%, 9/20) of brain metastases, and those in second-line (47.1%, 8/17) or above-line settings (43.8%, 7/16). Common treatment-related adverse events (AEs) were grade 1-2, mainly including diarrhea (90.9%), hypertension (72.7%), asthenia (63.6%), anorexia (54.5%) and nausea (51.5%). Grade 3 AEs were diarrhea (3.0%) and hypertension (9.1%). No grade 4 or 5 AE or treatment-related deaths were reported. Conclusions: Pyrotinib combined with apatinib showed potent anti-tumor activity and acceptable safety profile in metastatic NSCLC with HER2 amplification or activating mutations. Clinical trial information: ChiCTR1900021684.

CDK12 inhibition enhances sensitivity of HER2+ breast cancers to HER2-tyrosine kinase inhibitor via suppressing PI3K/AKT

BackgroundAlhtough anti-HER2 tyrosine kinase inhibitors (TKIs) have radically prolonged survival and improved prognosis in HER2-positive breast cancer patients, resistance to these therapies is a constant obstacle leading to TKIs treatment failure and tumour progression. MethodsTo develop new strategies to enhance TKIs efficiency by combining synergistic gene targets, we performed panel library screening using the CRISPR/Cas9 knockout technique based on data mining across TCGA data sets and verified the candidate target in preclinical models and breast cancer high-throughput sequencing data sets. ResultsWe identified that CDK12, co-amplified with HER2 in a high frequency, is powerful to sensitise or resensitise HER2-positive breast cancer to anti-HER2 TKIs lapatinib, evidenced by patient-derived organoids in vitro and cell-derived xenograft or patient-derived xenograft in vivo. Exploring mechanisms, we found that inhibition of CDK12 attenuated PI3K/AKT signal, which usually serves as an oncogenic driver and is reactivated when HER2-positive breast cancers develop resistance to lapatinib. Combining CDK12 inhibition exerted additional suppression on p-AKT activation induced by anti-HER2 TKIs lapatinib treatment. Clinically, via DNA sequencing data for tumour tissue and peripheral blood ctDNA, we found that HER2-positive breast cancer patients with CDK12 amplification responded more insensitively to anti-HER2 treatment than those without accompanying CDK12 amplification by harbouring a markedly shortened progression-free survival (PFS) (median PFS: 4.3 months versus 6.9 months; hazards ratio [HR] = 2.26 [95% confidence interval [CI] = 1.32–3.86]; P = 0.0028). ConclusionsDual inhibition of HER2/CDK12 will prominently benefit the outcomes of patients with HER2-positive breast cancer by sensitising or resensitising the tumours to anti-HER2 TKIs treatment.

Abstract PD4-06: Early clinical development of RC48-ADC in patients with HER2 positive metastatic breast cancer

Abstract Background: RC48-ADC is a novel HER2-targeting antibody-drug conjugate (ADC) that selectively delivers anticancer agent MMAE into HER2 overexpression tumor cells. We report the clinical outcomes of RC48-ADC in the HER2 positive metastatic breast cancer (MBC) which consist of phase 1 study (C001 CANCER, NCT02881138) and phase 1b study (C003 CANCER, NCT03052634). Methods: Patients with HER2 positive (IHC 3+ or IHC 2+ & FISH amplification) locally advanced or metastatic breast cancer were enrolled in both studies. C001 CANCER was a dose-escalation study (0.5, 1.0, 1.5, 2.0 and 2.5 mg/kg) with 3+3 design aiming to evaluate the maximum tolerated dose (MTD). C003 CANCER was an open-label, parallel design with 3 dose cohorts (1.5, 2.0 and 2.5 mg/kg, Q2W) aiming to determine the recommended phase 2 dose. Pooled analysis of two studies was conducted for the efficacy and safety profile. Results: In C001 CANCER, 3 (0.5 mg/kg), 3 (1.0 mg/kg), 3 (1.5 mg/kg), 6 (2.0 mg/kg) and 9 patients (2.5 mg/kg) were enrolled in each dose cohort respectively. In C003 CANCER, 46 patients were enrolled in 1.5 mg/kg (15 patients), 2.0 mg/kg (15 patients) and 2.5 mg/kg (16 patients) cohorts. All of the 70 patients were included in the pooled analysis. At baseline, most patients had visceral metastasis (87.1%) and received no less than 2 lines of chemotherapy (78.6%) for MBC. Forty-seven patients (67.1%) had previously received trastuzumab for (neo)adjuvant or MBC treatment previously. About half of patients (42.9%) had previously received anti-HER2 tyrosine kinase inhibitor therapy and 24 patients (34.3%) had received ≥ 2 lines of anti-HER2 therapy. In C001 CANCER, MTD was not reached. No response was observed in 0.5 mg/kg and 1.0 mg/kg cohorts. As reported, the most common treatment-related adverse events (TRAEs) were AST increased (62.9%), ALT increased (61.4%), leukopenia (51.4%), hypoesthesia (51.4%) and neutropenia (51.4%), which were mostly classified as grade 1 or 2. Grade 3 or 4 TRAEs were reported in 29 patients (41.4%,), mainly neutropenia (21.4%), asthenia (15.7%), and leukopenia (10.0%). Adverse events of special interest (AESI), consisting of varied AEs under the categories of liver function abnormal, hematologic toxicities, neurotoxicity and gastrointestinal disorders, were reported in 50 patients (71.4%), 47 patients (67.1%), 40 patients (57.1%), and 31 patients (44.3%), respectively. TRAEs leading to dose reduction or interruption were more frequent in 2.5 mg/kg cohort. Treatment-related serious adverse events (SAEs) occurred in 4 patients (5.7%), and the most common treatment-related SAE was ileus (in 2 patients, 2.9%). The confirmed overall response rate (cORR) was 31.4% (22/70). The clinical benefit rate (CBR) was 38.6%. The median progression-free survival (mPFS) was 5.8 months. For the 64 patients who received ≥ 1.5 mg/kg treatment, the cORR was 34.4% (22/64); the median PFS was 6.2 months. Specifically, for the dose levels of 1.5 mg/kg, 2.0 mg/kg and 2.5 mg/kg, the cORR was 22.2%, 42.9% and 36.0%, respectively; the mPFS was 6.2 months, 6.0 months, and 6.3 months, respectively. Conclusion: RC48-ADC was demonstrated good tolerability and promising efficacy when administrated Q2W in the patients with HER2-positive MBC. Comparing with the other dose levels, 2.0 mg/kg Q2W was proved to be a more favorable option for MBC in terms of benefit/risk balance. Accordingly, the phase 2 study which evaluates the efficacy of RC48-ADC 2.0 mg/kg Q2W versus capecitabine + lapatinib in the HER2 positive MBC was underway (clinicaltrials.gov: NCT03500380). What’s more, an additional cohort of C003 CANCER exploring preliminary efficacy of 2.0 mg/kg Q2W on low HER2-expression MBC, and a phase 3 study for low HER2-expression MBC are also in the plan. Citation Format: Binhe Xu, Jiayu Wang, Jianmin Fang, Xuelian Chen, Yiqun Han, Qing Li, Pin Zhang, Peng Yuan, Fei Ma, Yang Luo, Ying Fan, Ruigang Cai, Shanshan Chen, Qiao Li. Early clinical development of RC48-ADC in patients with HER2 positive metastatic breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr PD4-06.

Glucose-6-phosphate dehydrogenase blockade potentiates tyrosine kinase inhibitor effect on breast cancer cells through autophagy perturbation

BackgroundGlucose-6-phospate dehydrogenase (G6PD) is the limiting enzyme of the pentose phosphate pathway (PPP) correlated to cancer progression and drug resistance. We previously showed that G6PD inhibition leads to Endoplasmic Reticulum (ER) stress often associated to autophagy deregulation. The latter can be induced by target-based agents such as Lapatinib, an anti-HER2 tyrosine kinase inhibitor (TKI) largely used in breast cancer treatment.MethodsHere we investigate whether G6PD inhibition causes autophagy alteration, which can potentiate Lapatinib effect on cancer cells. Immunofluorescence and flow cytometry for LC3B and lysosomes tracker were used to study autophagy in cells treated with lapatinib and/or G6PD inhibitors (polydatin). Immunoblots for LC3B and p62 were performed to confirm autophagy flux analyses together with puncta and colocalization studies. We generated a cell line overexpressing G6PD and performed synergism studies on cell growth inhibition induced by Lapatinib and Polydatin using the median effect by Chou-Talay. Synergism studies were additionally validated with apoptosis analysis by annexin V/PI staining in the presence or absence of autophagy blockers.ResultsWe found that the inhibition of G6PD induced endoplasmic reticulum stress, which was responsible for the deregulation of autophagy flux. Indeed, G6PD blockade caused a consistent increase of autophagosomes formation independently from mTOR status. Cells engineered to overexpress G6PD became resilient to autophagy and resistant to lapatinib. On the other hand, G6PD inhibition synergistically increased lapatinib-induced cytotoxic effect on cancer cells, while autophagy blockade abolished this effect. Finally, in silico studies showed a significant correlation between G6PD expression and tumour relapse/resistance in patients.ConclusionsThese results point out that autophagy and PPP are crucial players in TKI resistance, and highlight a peculiar vulnerability of breast cancer cells, where impairment of metabolic pathways and autophagy could be used to reinforce TKI efficacy in cancer treatment.

Response to Lapatinib-Capecitabine combination in a young patient with recurrent HER2-positive breast cancer refractory to two lines of therapy with anti-HER2 drugs

HER2-positive breast cancer is an aggressive tumour that affects approximately one in five breast cancer women. Clinical studies have shown that HER2-positive cancer have different characteristics from other mammary tumors: a more rapid progression of the disease, an earlier age of onset (women of childbearing age between 30 and 45 are also affected to a large extent), a different response to chemotherapyand, in general, an unfavorable prognosis. Breast cancer with overexpression of the HER2 protein may benefit from the latest generation of target treatments (monoclonal antibodies and anti-HER2 tyrosine kinase inhibitors). Not all HER2-positive tumors, however, respond to therapies, and some responders may later become resistant. We report the case of a young woman with HER2-positive mammary carcinoma who presented resistance to the first two treatment lines with anti-HER2 drugs (trastuzumab-pertuzumab and TDM1) and responded to the combination lapatinib-capecitabine in third line (Oncology).

HER-targeted tyrosine kinase inhibitors enhance response to trastuzumab and pertuzumab in HER2-positive breast cancer.

Despite trastuzumab and pertuzumab improving outcome for patients with HER2-positive metastatic breast cancer, the disease remains fatal for the majority of patients. This study evaluated the anti-proliferative effects of adding anti-HER2 tyrosine kinase inhibitors (TKIs) to trastuzumab and pertuzumab in HER2-positive breast cancer cells. Afatinib was tested alone and in combination with trastuzumab in HER2-positive breast cancer cell lines. TKIs (lapatinib, neratinib, afatinib) combined with trastuzumab and/or pertuzumab were tested in 3 cell lines, with/without amphiregulin and heregulin-1β. Seven of 11 HER2-positive cell lines tested were sensitive to afatinib (IC50 < 80nM). Afatinib plus trastuzumab produced synergistic growth inhibition in eight cell lines. In trastuzumab-sensitive SKBR3 cells, the TKIs enhanced response to trastuzumab. Pertuzumab alone did not inhibit growth and did not enhance trastuzumab-induced growth inhibition or antibody-dependent cellular cytotoxicity. Pertuzumab enhanced response to trastuzumab when combined with lapatinib but not neratinib or afatinib. In two trastuzumab-resistant cell lines, the TKIs inhibited growth but adding trastuzumab and/or pertuzumab did not improve response compared to TKIs alone. Amphiregulin plus heregulin-1β stimulated proliferation of SKBR3 and MDA-MB-453 cells. In the presence of the growth factors, neither antibody inhibited growth and the TKIs showed significantly reduced activity. The triple combination of trastuzumab, pertuzumab and a TKI showed the strongest anti-proliferative activity in all three cell lines, in the presence of exogenous growth factors. In summary, addition of anti-HER2 TKIs to combined anti-HER2 monoclonal antibody therapy results in enhanced anticancer activity. These data contribute to the rationale for studying maximum HER2 blockade in the clinic.

Molecular sequencing and gene fusion detection in non-small cell lung cancer (NSCLC) patients: Impact of co-existing alterations.

e23103 Background: There is a growing need for accurate molecular diagnostics for proper targeted therapeutics selection in NSCLC patients (pts). We assess whether next generation techniques increase the identification of alterations in a prospective cohort of NSCLC pts, and evaluate prognostic value of different molecular alterations. Methods: Next generation sequencing (Amplicon-seq, 60 genes) and NanoString Gene fusion (20 genes) testing were conducted in NSCLC pts treated in a single center from November 2014 to May 2016. Overall survival (OS) according to the molecular profile was analysed by Kaplan-Meier method and Cox models. Results: Molecular tests were performed in 73advanced NSCLC pts.Median age was 54 year, 50% were women. Histology: 73% adenocarcinoma; 7% squamous, 20% others (Neuroendocrine, NOS). Tests were performed in biopsies from metastatic sites in 55% of pts.These techniques identified molecular alterations in 89% of cases: TP53 mutation (mut) 37/73 (51%); KRASmut 21/73 (29%); EGFRmut 11/73 (15%) ; CDKN2mut 7/73 (9%); BRAFmut (pG469R), ERBB2mut and METexon14mut in (1/73) 1.3%, respectively; ALKfusion (fus) 2/73 (2.7%); ROS1fus 1/73 (1.3%) , and RET fus 3/73 (4%). Concomitant mutations were identified in 32% of pts mainly with TP53 (TP53/EGFR: (5/11) 45% and TP53/KRAS: (7/21) 33%). Matched targeted treatment was offered in 17/73 (23%), mostly tyrosine kinase inhibitors (TKI); anti-EGFR in 11/17 (65%) and ALK/ROS TKI in 3/17 (17.5%). Three pts (17.5%) received anti-MET or anti-HER2 TKI. OS in this whole population treated with target therapies (n = 17) was 45.7 months (m) (CI95% 26.8-NA). The KRASmut group had median OS of 10 m (CI95% 7.5-NA), while the remaining population with wild type (WT) for all driver alterations had median OS of 23 m (CI95% 20-NA), (HR 1.71 for KRASmut vs WT pts, p = 0.18). The presence of coexisting TP53mut did not negatively impact on OS in the cohorts with EGFRmut and KRASmut (p &gt; 0.1) in a multivariate model. Conclusions: Combined next generation techniques for molecular profile in NSCLC pts identifies molecular alterations that have clinically relevant impact in survival. Coexisting TP53mut alteration shows no detrimental effect in OS.

Lapatinib versus lapatinib plus capecitabine as second-line treatment in human epidermal growth factor receptor 2-amplified metastatic gastro-oesophageal cancer: A randomised phase II trial of the Arbeitsgemeinschaft Internistische Onkologie

IntroductionHuman epidermal growth factor receptor 2 (HER2) amplification is present in a subgroup of gastroo-esophageal cancers (GCs). HER2 inhibition with trastuzumab has shown to improve outcomes in advanced disease. Lapatinib ditosylate (LAP), a dual anti-epidermal growth factor receptor (EGFR) and anti-HER2 tyrosine kinase inhibitor with preclinical activity against GC, has been approved in HER2-positive breast cancer. We aimed to study the activity of LAP in HER2-amplified GC. Materials and methodsPatients (pts) with HER2-positive (gene amplification or increased copy numbers based on predefined criteria) advanced GC were randomly allocated 1:1 to receive LAP 1250mg per day 1–21 plus capecitabine (CAP) 2000mg/m2 on days 1–14 of a 21-day cycle or LAP 1500mg monotherapy day 1–21 after having failed on a platinum-based first-line therapy. HER2 status was assessed centrally. The primary end-point was the objective response rate (ORR) as assessed by the investigator using Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1). We aimed to include 38 pts per arm to show an interesting response rate of ⩾20% in either of the two arms. Results37 pts were enrolled (18 to LAP+CAP, 19 to LAP). Pts had received a median of three prior treatment lines. 12 pts in the LAP+CAP group (67%) and 12 pts in the LAP group (63%) had received prior trastuzumab. Only two pts (11.1%; 95% confidence interval (CI): 1.37–34.7), both in the LAP+CAP arm, achieved an objective response. The study was closed prematurely for futility. Median time to progression was 42 (95% CI: 38–61) days in the LAP group and 83 (95% CI: 42–86) days in the LAP+CAP group. Other secondary efficacy end-points (progression-free and overall survival) were comparable in the two treatment groups. Rates of diarrhoea were higher with LAP+CAP (61%; 95% CI: 35–83) compared to 26% (95% CI 9–51) with LAP mono, whereas other adverse events were mostly similar between the groups (18 [100%] versus 17 [90%]). DiscussionLapatinib showed insufficient activity in HER2-amplified pretreated advanced GC. The safety profile of LAP or LAP+CAP was as expected with some more toxicity in the combination arm. (ClinicalTrials.gov Identifier, NCT01145404).

Lapatinib versus lapatinib plus capecitabine as second-line treatment in HER-2-overexpressing metastatic gastro-esophageal cancer (GC): A randomized phase II trial of the Arbeitsgemeinschaft Internistische Onkologie (AIO).

112 Background: HER2 amplification is present in a subgroup of gastroesophageal cancers (GCs). HER2 inhibition with trastuzumab has shown to improve outcomes in advanced disease. Lapatinib ditosylate (LAP), a dual anti-EGFR and anti-HER2 tyrosine kinase inhibitor with preclinical activity against GC, has been approved in HER2-positive breast cancer. We aimed to study the activity of LAP in HER2-amplified GC. Methods: Patients (pts) with HER2-positive (gene amplification or increased copy numbers based on predefined criteria) advanced GC were randomly allocated 1:1 to receive LAP 1250 mg per day 1-21 plus capecitabine (CAP) 2000mg/m² on days 1-14 of a 21-day cycle or LAP 1500 mg monotherapy day 1-21 after having failed on a platinum-based first-line therapy. HER2 status was assessed centrally. The primary endpoint was the objective response rate (ORR) as assessed by the investigator using RECIST 1.1 criteria. We aimed to include 38 pts per arm to show a response rate of &gt;20% in either of the two arms. Results: 37 pts were enrolled (18 to LAP+CAP, 19 to LAP). Pts had received a median of three prior treatment lines, however, the treatment was intended to be tested as a second-line treatment. 12 pts in the LAP+CAP group (67%) and 12 pts in the LAP group (63%) had received prior trastuzumab. Only two pts (11.1%; 95% CI: 1.37 – 34.7), both in the LAP+CAP arm, achieved an objective response. The study was closed prematurely for futility. Median time to progression was 42 (95% CI: 38 to 61) days in the LAP group and 83 (95% CI: 42 to 86) days in the LAP+CAP group. Other secondary efficacy endpoints (progression-free and overall survival) were comparable in the two treatment groups. Rates of diarrhea were higher with LAP+CAP (61%; 95% CI: 35 to 83) compared to 26% (95%CI 9 to 51) with LAP mono, whereas other adverse events were mostly similar between the groups (18 [100%] vs. 17 [90%]). Conclusions: Lapatinib showed insufficient activity in HER2-amplified pretreated advanced GC. The safety profile of LAP or LAP+CAP was as expected with some more toxicity in the combination arm. Clinical trial information: NCT01145404.

629P - Lapatinib Versus Lapatinib Plus Capecitabine As Second-Line Treatment in Her2-Overexpressing Metastatic Gastro-Esophageal Cancer (Gc): a Randomized Phase Ii Trial of the Arbeitsgemeinschaft Internistische Onkologie (Aio)

ABSTRACT Aim: Her2 amplification is present in a subgroup of gastroesophageal cancers (GCs). Her2 inhibition with Trastuzumab has shown to improve clinical outcomes in metastatic disease. Lapatinib ditosylate (LAP), a dual anti EGFR and anti Her2 tyrosine kinase inhibitor with preclinical activity against GC, has been approved in Her2 positive breast cancer. We aimed to study the activity of LAP in HER2 amplified GC. Methods: Patients (pts) with Her2 positive (FISH ratio ≥2.0 or IHC3+ if ratio was between 1.8 and 20% in either of the two arms. Results: 37 pts were enrolled (18 to LAP + CAP, 19 to LAP mono). Pts received a median of three treatment cycles. 10 pts in the LAP + CAP group (56%) and 7 pts in the LAP mono group (37%) had received prior Trastuzumab. Only two pts (11.1%; 95% CI: 1.37 – 34.7), both in the LAP + CAP arm, achieved an objective response. Therefore, the study was closed prematurely. Median time to progression was 42 (95% CI: 38 to 61) days in the LAP group and 83 (95% CI: 42 to 86) days in the LAP + CAP group (p = 0.07). The other secondary efficacy endpoints (progression-free [median 41 and 47 days] and overall survival [median values not yet mature]) were comparable in the two treatment groups. Rates of diarrhea (all grades) were higher with LAP + CAP (61%; 95% CI: 35 to 83) compared to 26% (95%CI 9 to 51) with LAP mono, while other adverse events were mostly similar between the groups (18[100%] vs. 17[90%]). Slightly more pts in the LAP-CAP group experienced serious adverse events (44 vs. 32%). Conclusions: Lapatinib showed insufficient activity, especially as monotherapy, in HER2 amplified pretreated advanced GC. This led to premature study termination. The safety profile of LAP or LAP + CAP was as expected with some more toxicity in the combination arm. Disclosure: P.C. Thuss-Patience: Research support by GSK; F. Lordick: GSK. All other authors have declared no conflicts of interest.

Lapatinib in combination with capecitabine plus oxaliplatin (CapeOx) in HER2-positive advanced or metastatic gastric, esophageal, or gastroesophageal adenocarcinoma (AC): The TRIO-013/LOGiC Trial.

LBA4001 Background: HER2 amplification is common in upper GI tract (UGIT) adenocarcinomas and inhibition improves clinical outcomes. Lapatinib ditosylate (L), a dual anti EGFR and anti HER2 tyrosine kinase inhibitor with preclinical activity against these cancers, was investigated in a phase III, randomized, double blind trial evaluating efficacy and safety in combination with CapeOx as first-line treatment of advanced or metastatic HER2+ UGIT ACs. Methods: Subjects had measurable and/or non-measurable disease with overexpression or amplification of HER2 (IHC2+ and FISH amplified, or IHC 3+, or FISH, CISH, or SISH amplified). HER2 status was reviewed by the central lab. Subjects were randomized 1:1 to CapeOx q3w (oxaliplatin 130mg/m2 day 1; capecitabine 850mg/m2/BID days 1 – 14), and daily L (1250mg) (CapeOx+L) or placebo (CapeOx+P). The primary efficacy population (PEP) comprised all subjects whose tumors were centrally confirmed to be FISH amplified. The primary endpoint was overall survival (OS) of the PEP. Secondary endpoints included progression free survival (PFS), overall response rate (ORR) and safety. Results: 545 pts were randomized and 487 had HER2+ centrally confirmed. The primary endpoint was not reached with a hazard ratio (HR) for OS of CapeOx+L compared to CapeOx+P of 0.91 (95% CI 0.73, 1.12, p=0.35); median 12.2 vs. 10.5 months, respectively. HR for uncensored PFS was 0.86 (95% CI 0.71 - 1.04, p=0.10); median 6.0 vs. 5.4 months. The analysis of PFS censored by the time of subsequent anticancer therapy as per protocol showed a HR of 0.82 (95% CI 0.68, 1.00, p=0.04). ORR was 53% in the CapeOx+L arm and 40% in the CapeOx+P arm. Pre-specified subgroup analyses showed significant improvements in OS in Asian pts (HR= 0.68) and those under 60 years (HR=0.69). There was no association between IHC and OS. Toxicity profiles were similar except for increased overall diarrhea, and skin toxicity and grade 3+ diarrhea (12 vs 3%) with CapeOx+L. Conclusions: The addition of L to CapeOx did not reach its primary endpoint, though certain subgroups showed improvement. Further clinical and molecular analyses will be presented. Clinical trial information: NCT00680901.

Indirect comparison of the cost-effectiveness of letrozole plus lapatinib (LET+LAP) versus anastrozole plus trastuzumab (ANA+TZ) as first-line treatment for postmenopausal women with HER2+ and HR+ metastatic breast cancer (MBC) from the U.K. National Health Service (NHS) perspective.

1035 Background: The EGF30008 trial assessed the efficacy of the combination of the anti-HER2 tyrosine kinase inhibitor LAP and the aromatase inhibitor (LET) compared with LET plus placebo in postmenopausal women with HER2+ and HR+ MBC. The TAnDEM study evaluated the benefits of adding TZ to the AI ANA in postmenopausal women with advanced HER2+ and HR+ MBC. Both studies demonstrated statistically significant improvements in progression-free survival (PFS) with the addition of anti-HER2 therapy. Methods: An economic model was used to evaluate the incremental cost per quality-adjusted life year (QALY) gained with LET+LAP versus ANA+TZ as first-line treatment in postmenopausal women with HR+ and HER2+ MBC from the U.K. NHS perspective. Expected PFS and overall survival (OS) with LET+LAP and ANA+TZ were based on adjusted indirect comparison using data from the TAnDEM and EGF30008 trials as well as the P025 trial of LET versus tamoxifen (TAM) and the TARGET and North American trials of ANA versus TAM. Costs and utility values were obtained from the literature. Results: Shown in the Table (all results are discounted). LET+LAP yields more progression-free life years (PFLYs), life years (LYs), and QALYs than ANA+TZ. Medication costs are greater with LET+LAP, partly due to longer PFS. These higher costs are offset by savings in costs of drug administration. LAP+LET is therefore dominant (less costly and more QALYs) versus ANA+TZ. Conclusions: Letrozole plus lapatinib has greater effectiveness and lower cost from the U.K. NHS perspective when indirectly compared with anastrozole plus trastuzumab. Measure LET+LAP ANA+TZ Difference Effectiveness PFLY 1.181 1.042 0.139 LY 3.399 3.021 0.378 QALYs 2.434 2.162 0.272 Costs (in £) Medication 29,568 21,031 8,537 Drug administration 520 13,753 -13,232 Other preprogression 8,285 7,307 978 Other postprogression 20,105 17,943 2,162 Total 58,479 60,033 -1,554 Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration GlaxoSmithKline GlaxoSmithKline GlaxoSmithKline GlaxoSmithKline GlaxoSmithKline, Royal Marsden NHS Foundation Trust & Institute of Cancer Research Research Fund