Dual Targeting Of HER2 Research Articles

Dual HER2 inhibition: Is two better than one?

Li etal. present data from a randomized frontline phase II trial in HER2+ gastroesophageal cancers exploring dual targeting of HER2 with HLX22 (a novel HER2-specific antibody) with HLX02 (a trastuzumab biosimilar) and capecitabine/oxaliplatin chemotherapy. While the objective response and progression-free survival are encouraging, the future development of the combination in a crowded HER2 space remains unclear.

Abstract LBO1-02: Pathologic complete response (pCR) of neoadjuvant therapy with or without atezolizumab in HER2-positive, early high-risk and locally advanced breast cancer: APTneo Michelangelo randomized trial

Abstract Background: Neoadjuvant dual targeting of HER2 with trastuzumab (H) and pertuzumab (P) plus chemotherapy is the standard of care for high-risk HER2-positive (HER2+) breast cancer (BC). Compelling data show the contribution of the immune system in prognosis and response/resistance to HER2 directed therapies, supporting combination of immune checkpoint inhibitors with anti HER2 antibodies. We designed APTneo to test the role of adding atezolizumab to neoadjuvant dual targeting of HER2 with chemotherapy, and the value of also using anthracyclines in this setting. Methods: In this multicenter open label phase III trial (NCT03595592), 661 patients (pts) with high-risk early and locally advanced (LA) centrally confirmed HER2+ BC were randomized to neoadjuvant HPCT (H and P d1, carboplatin and paclitaxel iv d1 and 8) given q3 wks for 6 cycles w/o (n=223, ARM A) or with atezolizumab 1200 mg iv d1 (n=438, ARM B). In Arm B pts were randomized to Arm B1 (n=218) to receive anthracycline and cyclophosphamide (AC) + atezolizumab iv d1 q3 wks for 3 cycles followed by HPCT + atezolizumab for 3 cycles, or to arm B2 (n=220) to receive HPCT + atezolizumab for 6 cycles. After surgery pts continued adjuvant HER2 directed therapies w/wo atezolizumab until completion of 1 year. Among intent-to-treat (ITT) pts, 44.8% were LABC, 35% hormonal receptor (HR) negative and 30.4% PD-L1 positive. Primary endpoint is event-free survival (EFS) of Arm B vs A. A key secondary endpoint is the rate of pCR (ypT0/Tis, ypN0) w/wo atezolizumab. Primary population for all efficacy endpoints is ITT. We also assessed baseline PD-L1 status (Ventana SP142) and stromal Tumor Infiltrating Lymphocytes (sTILs). Results: pCR rate in Arm B (57.8%) vs Arm A (52.0%) was not significantly increased (adjHR 1.33, 95% CI 0.95-1.86; p=0.091). Also, the difference in pCR rate in Arm B1 (61.9%) vs Arm B2 (53.6%) was not significant (adjHR 1.402, 95% CI 0.95-2.07; p=0.089). Compared to Arm A, Arm B1 had a 9.9% significantly higher pCR rate (multivariate analysis in Table). The different pCR rate in arms B1 and A was similar regardless of HR and PD-L1 status. High sTILs (≥30%) and PD-L1positive tumors had a higher likelihood of pCR in all arms. Serious adverse events (SAE) after start of therapy occurred in 6.8% pts in Arm A and 14.1% in Arm B (p=0.0064). SAE were numerically more frequent in Arm B1 than Arm B2 (16.7% and 11.6%, respectively), due to hematological toxicity with AC. Immune-related SAE were quite infrequent and similar in B1 (4.7%) and B2 (7.8%), respectively. No grade 5 AE did occur. Conclusions: Addition of atezolizumab to chemotherapy and HP did not significantly increase the rate of pCR in women with HER2+ BC. An exploratory analysis showed that adding atezolizumab to neoadjuvant AC followed by HPCT led to higher pCR rate compared to HPCT and atezolizumab. This could be because of anthracyclines themselves or to drug-drug enhancement of anthracyclines and immune modulation. Atezolizumab did not cause major tolerability issues. Molecular studies of collected biospecimens are ongoing. Patients will continue to be followed up for EFS and overall survival analyses. Table. Supported in part by unrestricted grant from Hoffman-La Roche, Ltd, Switzerland Citation Format: Luca Gianni, Elisabetta Munzone, Mauro Mansutti, Giampaolo Bianchini, Yann Izarzuzaga, Elena Rota Caremoli, Luc Dirix, Lucia Del Mastro, Santiago González-Santiago, Andreas Schneeweiss, Jose Ponce, Chiun-Shen Huang, Pauline Wimberger, Sevilay Altintas, Miguel Martín, Nicoleta Antone, Christian F. Singer, Ugo De Giorgi, Ana Godoy Ortiz, Hans-Joachim Lueck, Riccardo Spezia, Angelica Fasolo, Giuseppe Viale, Pinuccia Valagussa. Pathologic complete response (pCR) of neoadjuvant therapy with or without atezolizumab in HER2-positive, early high-risk and locally advanced breast cancer: APTneo Michelangelo randomized trial [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr LBO1-02.

Design, synthesis, and biological evaluation of novel quinoline-based EGFR/HER-2 dual-target inhibitors as potential anti-tumor agents.

Dual targeting of EGFR and HER2 is a valid anti-cancer approach for treating solid tumors. We designed and synthesized a new series of EGFR/HER-2 dual-target inhibitors based on quinoline derivatives. The structure of the newly synthesized compounds was verified using 1H NMR, 13C NMR, and elemental analysis. The targeted compounds were tested for antiproliferative efficacy against four cancer cell lines. All the compounds had GI50s ranging from 25 to 82 nM, with breast (MCF-7) and lung (A-549) cancer cell lines being the most sensitive. Compound 5a demonstrated the most significant antiproliferative action. With inhibitory (IC50) values of 71 and 31 nM, respectively, compound 5a proved to be the most effective dual-target inhibitor of EGFR and HER-2, outperforming the reference erlotinib (IC50 = 80 nM) as an EGFR inhibitor but falling short of the clinically used agent lapatinib (IC50 = 26 nM) as a HER2 inhibitor. The apoptotic potential activity of 5a was examined, and the findings demonstrated that 5a promotes apoptosis by activating caspase-3, 8, and Bax while simultaneously reducing the expression of the anti-apoptotic protein Bcl-2. The docking studies provided valuable insights into the binding interactions of compounds 3e and 5a with EGFR, effectively rationalizing the observed SAR trends.

CD98 regulates the phosphorylation of HER2 and a bispecific anti-HER2/CD98 antibody inhibits the growth signal of human breast cancer cells.

Human epidermal growth factor receptor (HER) family proteins are currently major targets of therapeutic monoclonal antibodies against various epithelial cancers. However, the resistance of cancer cells to HER family-targeted therapies, which may be caused by cancer heterogeneity and persistent HER phosphorylation, often reduces overall therapeutic effects. We herein showed that a newly discovered molecular complex between CD98 and HER2 affected HER function and cancer cell growth. The immunoprecipitation of the HER2 or HER3 protein from lysates of SKBR3 breast cancer (BrCa) cells revealed the HER2-CD98 or HER3-CD98 complex. The knockdown of CD98 by small interfering RNAs inhibited the phosphorylation of HER2 in SKBR3 cells. A bispecific antibody (BsAb) that recognized the HER2 and CD98 proteins was constructed from a humanized anti-HER2 (SER4) IgG and an anti-CD98 (HBJ127) single chain variable fragment, and this BsAb significantly inhibited the cell growth of SKBR3 cells. Prior to the inhibition of AKT phosphorylation, BsAb inhibited the phosphorylation of HER2, however, significant inhibition of HER2 phosphorylation was not observed in anti-HER2 pertuzumab, trastuzumab, SER4 or anti-CD98 HBJ127 in SKBR3 cells. The dual targeting of HER2 and CD98 has potential as a new therapeutic strategy for BrCa.

Abstract P3-07-16: Pre-clinical study of amcenestrant and HER2-targeted therapies in HER2+/ER+ breast cancer cell line models

Abstract Background: Up to 70% of HER2 over-expressing (HER2+) breast cancers also express estrogen receptor (ER). Dual targeting of HER2 and ER has shown pre-clinical and clinical benefit in HER2+/ER+ breast cancer. Rationale for these combinations is based on circumvention of resistance mediated by crosstalk between HER2 and ER signalling pathways. Fulvestrant is the only selective estrogen receptor degrader (SERD) approved by the FDA for the treatment of ER+ breast cancer. Development of alternative orally available SERDs with improved bioavailability, such as amcenestrant, is underway. The HER2-targeted tyrosine kinase inhibitors (TKIs) lapatinib, neratinib and tucatinib and the antibody drug conjugate T-DM1 are approved for the treatment of HER2+ breast cancer. This pre-clinical study aims to investigate the potential of combining the oral SERD amcenestrant with HER2-targeted therapies for the treatment of HER2+/ER+ breast cancer through identification of synergistic combinations. Methods: ER and HER2 expression levels were assessed in the HER2+/ER+ BT-474 and MDA-MB-361 cell lines by western blot. 5-day acid phosphatase-based assays were used to assess cell viability following treatment with neratinib, lapatinib, tucatinib, and T-DM1; alone and in combination with amcenestrant. All TKIs were commercially sourced, T-DM1 was obtained from Saint Vincent’s University Hospital. Amcenestrant was supplied by Sanofi. IC50 values were determined using Calcusyn, while matrix combination assays of the HER2-targeted therapies combined with amcenestrant were analysed using Combenefit software employing the Loewe model (LM) to determine synergy (Score > 0) or antagonism (Score < 0). All data are the result of a minimum of three independent experiments. Results: HER2 and ER expression was confirmed in the MDA-MB-361 and BT-474 cell lines. MDA-MB-361 cells express higher levels of ER and lower levels of HER2 and phosphorylated HER2 than BT474 cells. MDA-MB-361 exhibited a higher sensitivity to 1 µM amcenestrant alone (% cell viability = 53.3 ± 2.3 %) than the BT-474 (% viability = 85.3 ± 5%). A comparison of IC50 values for each TKI alone or in combination with 1 µM amcenestrant showed amcenestrant significantly lowered the IC50 values for neratinib and tucatinib in BT-474, and all three TKIs in MDA-MB-361 (Table 1). In matrix combination assays, all TKIs exhibited synergistic combinations, with the combination of neratinib and amcenestrant demonstrating the highest synergy values in MDA-MB-361 (LM max value = 25 ± 7) and in BT-474 (LM max value = 19 ± 7). The combination of amcenestrant and T-DM1 displayed additivity (LM value = 0) rather than synergy in the BT-474 cell line, likely due to the high potency of T-DM1 as a single agent. Conclusions: The combination of amcenestrant and HER2-targeting therapies such as neratinib shows potential as a dual-target therapeutic strategy for the treatment of HER2+/ER+ breast cancer and warrants further investigation. Table 1. IC50 values for TKIs alone and with the addition of 1 µM amcenestrant. Significance of chance in IC50 point calculated by Student’s T test, ns = p > 0.05, * = p < 0.05, ** = p < 0.01, SD = standard deviation Citation Format: Amira F. Mahdi, Niall Ashfield, Neil T. Conlon, John Crown, Denis M. Collins. Pre-clinical study of amcenestrant and HER2-targeted therapies in HER2+/ER+ breast cancer cell line models [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 P3-07-16.

A phase 2 basket study of tucatinib and trastuzumab in previously treated solid tumors with HER2 alterations: Urothelial cancer cohort (SGNTUC-019).

TPS587 Background: Tucatinib, a highly selective human epidermal growth factor receptor 2 (HER2)-directed tyrosine kinase inhibitor approved in multiple regions for HER2-positive (HER2+) metastatic breast cancer, is being investigated as a novel therapy for metastatic colorectal cancer, gastric cancer, and other solid tumors. In xenograft models of HER2+ and HER2-mutated tumors, dual targeting of HER2 with tucatinib plus trastuzumab showed superior activity to either alone (Kulukian 2020; Peterson 2020). Despite development of several new therapies for metastatic urothelial cancer (UC), most patients are refractory to subsequent therapies and die from the disease, highlighting the need for additional therapeutic approaches. Given that 20%–30% of metastatic UCs have molecular alterations of the ErbB family, tucatinib plus trastuzumab warrants further evaluation. SGNTUC-019 (NCT04579380) is a multi-cohort, open-label, phase 2 study evaluating tucatinib plus trastuzumab in patients with previously treated solid tumors displaying HER2+ or HER2-mutated solid tumors, including a cohort with locally advanced or metastatic UC. Methods: Eligible patients in the UC cohort must have HER2+ locally advanced or metastatic disease, with progression during or after, or intolerance of, the most recent line of systemic therapy. Patients must have an ECOG PS ≤1; adequate hepatic, hematologic, renal, and cardiac function; and no prior exposure to HER2-directed therapy. HER2 alterations can be demonstrated by HER2 overexpression/amplification in tumor tissue by prior IHC/ISH or by HER2 amplification in prior or prescreening NGS assay of ctDNA or prior tissue NGS assay. The HER2 overexpression/amplification UC cohort will enroll 12 response-evaluable patients per RECIST 1.1. If ≥2 responses are observed, the cohort will be expanded to 30. The primary objective is antitumor activity, with confirmed ORR as the primary endpoint and DCR, duration of response, PFS, and OS as secondary efficacy endpoints. Confidence intervals (CIs) will be calculated for confirmed ORR and DCR. For time-to-event endpoints, median survival time will be estimated by the Kaplan-Meier method, and the associated 95% CI will be calculated using complementary log-log transformation. Safety endpoints will be assessed using descriptive statistics. Patients will receive tucatinib 300 mg orally twice daily and trastuzumab 8 mg/kg intravenously on Cycle 1 Day 1 and 6 mg/kg every 21 days from Cycle 2 Day 1. Disease assessments per RECIST 1.1 will occur every 6 weeks for 24 weeks, then every 12 weeks. Trough concentrations of tucatinib will be evaluated in Cycles 2–6, with peak concentration sampled in Cycle 3. Quality of life will be evaluated every second cycle using the EQ-5D-5L. Sites are currently enrolling within the US, EU, and Asia Pacific. Clinical trial information: NCT04579380 .

P-156 MOUNTAINEER-02: Phase 2/3 study of tucatinib, trastuzumab, ramucirumab, and paclitaxel in previously treated HER2+ gastric or gastroesophageal junction adenocarcinoma: Trial in progress

Tucatinib (TUC), a highly selective HER2-directed tyrosine kinase inhibitor (TKI) approved in multiple regions for HER2+ metastatic breast cancer, is being developed as a novel therapy for patients with GI tumors including gastric or gastroesophageal junction adenocarcinoma (GEC). While trastuzumab (Tras) with chemotherapy is standard in the first-line setting for metastatic HER2+ GEC, no anti-HER2 therapy has demonstrated an OS benefit over chemotherapy as second-line therapy, possibly due to loss of HER2 expression following Tras-based therapy. In GEC xenograft models, dual targeting of HER2 with TUC and Tras showed superior activity to either agent alone. (Kulukian 2020) Interim results from the MOUNTAINEER study have shown promising activity for TUC and Tras for HER2+ mCRC.(Strickler 2019) The MOUNTAINEER-02 study (NCT04499924) is evaluating the efficacy and safety of TUC with Tras, ramucirumab (Ram), and paclitaxel (Pac) in patients with HER2+ GEC in the second-line setting. MOUNTAINEER-02 is a phase 2/3 study evaluating TUC + Tras with Ram and Pac. Eligible patients have locally-advanced unresectable or metastatic HER2+ GEC and have received a HER2-directed antibody and 1 prior line of therapy for advanced disease. Patients are ≥18 years of age; have an ECOG ≤1; and have had no prior exposure to Ram, an anti-HER2 or anti-EGFR TKI, HER2-directed antibody-drug conjugates, or taxanes ≤12 months before enrollment. Patients receive TUC 300 mg or placebo PO BID and Tras or placebo (IV on Days 1 and 15 of each 28-day cycle) in combination with Pac (IV on Days 1, 8, and 15) and Ram (IV on Days 1 and 15). The study includes an initial Pac-dose optimization stage because of the potential impact of TUC on Pac metabolism. The open-label phase 2 part determines the recommended dose of Pac (60 or 80 mg/m2) combined with TUC, Tras, and Ram in 6–18 patients and evaluates safety and activity of the regimen in Cohorts 2A and 2B (30 patients each). The randomized, double-blind, phase 3 part compares the efficacy and safety of TUC and Tras (Arm 3A, ∼235 patients) vs placebo (Arm 3B, ∼235 patients), both in combination with Ram and Pac, and evaluates activity of TUC with Ram and Pac (Arm 3C, ∼30 patients). The coprimary phase 3 endpoints are OS and PFS per investigator, and secondary endpoints include DOR, confirmed ORR, and DCR. Secondary objectives include patient-reported outcomes. HER2 status is determined by blood-based NGS assay or IHC/ISH assay of a tumor tissue sample (IHC3+ or IHC2+/ISH+) at screening. In Cohort 2A and phase 3, patients must be HER2+ by blood-based NGS. In Cohort 2B, patients must be HER2+ by biopsy but HER2 negative by blood-based NGS after progression in first-line or subsequent therapy. Disease assessments per RECIST v1.1 occur q6 weeks for 36 weeks, then q9 weeks. The pharmacokinetics of TUC, Pac, and their metabolites are evaluated in a subset of patients, including a cohort with gastrectomies. Enrollment in phase 2 is ongoing. NCT04499924. The authors thank Joseph Giaconia of MMS Holdings, Michigan, USA for providing medical writing support/editorial support, which was funded by Seagen Inc., Bothell, WA, USA in accordance with Good Publication Practice (GPP3) guidelines. Seagen Inc.

P-74 SGNTUC-019: Phase 2 basket study of tucatinib and trastuzumab in previously treated solid tumors with HER2 alterations: Biliary tract cancer cohort (trial in progress)

Tucatinib (TUC), a highly selective HER2-directed tyrosine kinase inhibitor approved in multiple regions for HER2+ metastatic breast cancer, is being investigated as a novel therapy for patients with metastatic colorectal cancer, gastric cancer, and other GI tumors. In xenograft models of HER2+ and HER2-mutated tumors, dual targeting of HER2 with TUC + trastuzumab (Tras) showed superior activity to either agent alone. (Kulukian 2020) Interim results from the MOUNTAINEER study have shown promising activity for TUC + Tras in HER2+ colorectal cancer.

SGNTUC-019: Phase 2 basket study of tucatinib and trastuzumab in previously treated solid tumors with HER2 alterations—Urothelial cancer cohort (trial in progress).

TPS586 Background: Tucatinib, a highly selective HER2-directed tyrosine kinase inhibitor approved in multiple regions for HER2+ metastatic breast cancer, is being investigated as a novel therapy for metastatic colorectal cancer, gastric cancer, and other GI tumors. In xenograft models of HER2+ and HER2-mutated tumors, dual targeting of HER2 with tucatinib and trastuzumab showed superior activity to either alone (Kulukian 2020; Peterson 2020 ). Despite development of several new therapies for metastatic urothelial cancer, most patients do not respond to subsequent therapies, and majority of patients succumb to the disease, highlighting the need for additional therapeutic approaches. Given 20%-30% of metastatic urothelial cancers have molecular alterations of the ErbB family, tucatinib + trastuzumab warrants further evaluation. SGNTUC-019 (NCT04579380) is a multi-cohort, open-label, international Phase 2 study evaluating tucatinib + trastuzumab in patients with previously treated solid tumors displaying HER2+ or HER2-mutated solid tumors, including a cohort with locally advanced or metastatic urothelial cancer (UC). Methods: Eligible patients must have HER2+ or HER2-mutated locally advanced or metastatic solid tumors, with progression on or after the last systemic therapy for advanced disease. Additionally, patients must have an ECOG PS ≤1, adequate hepatic, hematologic, renal, and cardiac function, and no prior exposure to HER2-directed therapy in the UC cohort. For eligibility, HER2 alterations can be demonstrated by HER2 overexpression/amplification in tumor tissue by prior IHC/ISH, or by HER2 amplification/mutation in prior or pre-screening NGS assay of ctDNA or prior tissue NGS assay. The HER2 overexpression/amplification UC cohort will enroll 12 response-evaluable patients per RECIST 1.1. If ≥2 responses are observed, the cohort will be expanded to 30. Patients with HER2-mutated UC will be enrolled into a cohort of 30 patients with HER2-mutated solid tumors (except breast and non-squamous non-small cell lung cancers). The primary objective is antitumor activity, with confirmed ORR as the primary endpoint, and disease control rate, duration of response, PFS, and OS as secondary efficacy endpoints. Patients will receive tucatinib 300 mg orally twice daily and trastuzumab 8 mg/kg intravenous on Cycle 1 Day 1 and 6 mg/kg q21 days from Cycle 2 Day 1. Disease assessments per RECIST 1.1 will occur q6 weeks for 24 weeks, then q12 weeks. Trough concentrations of tucatinib will be evaluated in Cycles 2-6, with a peak concentration sampled in Cycle 3. Quality of life will be evaluated q2 cycle using EQ-5D-5L. Sites are currently enrolling within the US, EU, and Asia Pacific. Clinical trial information: NCT04579380.

Abstract OT1-15-01: SGNTUC-019: Phase 2 basket study of tucatinib and trastuzumab in previously treated solid tumors with HER2 alterations: HER2-mutated breast cancer cohort (ongoing clinical trial)

Abstract Background: Tucatinib (TUC), approved in multiple regions for HER2+ metastatic breast cancer, is a highly selective HER2-directed tyrosine kinase inhibitor with minimal EGFR inhibition. TUC is being developed as a novel therapy for patients with HER2+ metastatic breast cancer, colorectal cancer, and gastric cancer. In xenograft models of HER2+ and HER2-mutated tumors, dual targeting of HER2 with TUC and trastuzumab showed superior activity to either agent alone. Somatic HER2 mutations occur in approximately 3% of breast cancers, mostly in patients with hormone receptor-positive disease and the lobular sub-type. HER2 mutations lead to enhanced tyrosine kinase activity and tumorigenesis in preclinical models and have been postulated as a mechanism of endocrine therapy resistance. The SGNTUC-019 basket study (NCT04579380) is evaluating TUC in combination with trastuzumab in patients with HER2+ or HER2-mutated solid tumors, including a cohort of patients with locally advanced unresectable or metastatic breast cancer that is HER2-mutated and not overexpressed/amplified. Trial Design: SGNTUC-019 is a multi-cohort, open-label, international Phase 2 study evaluating patients with previously treated solid tumors displaying HER2 overexpression/amplification or activating mutations. Eligible breast cancer patients must have HER2-mutated, locally advanced unresectable or metastatic disease with progression on or after ≥1 prior line of therapy (chemotherapy, endocrine or targeted therapy) in the locally advanced or metastatic disease setting. Additionally, an ECOG Performance Status of ≤1; adequate hepatic, hematological, renal, and cardiac functions; and no previous HER2-directed therapy are required for enrollment. For eligibility, HER2 mutations can be demonstrated in a previous or on-study next-generation sequencing (NGS) assay of circulating tumor DNA or a previous tissue NGS assay. The breast cancer cohort will enroll 30 response-evaluable patients with HER2-mutated disease. Patients with HER2+ (overexpression/amplification) breast cancer will not be enrolled. The primary objective in each cohort is antitumor activity. The primary endpoint is a confirmed objective response rate, and secondary endpoints are the disease control rate, duration of response, progression-free survival, and overall survival. Safety and efficacy endpoints will be summarized descriptively. For response rates, the 2-sided exact interval using the Clopper-Pearson method will be calculated. Patients will receive TUC 300 mg orally twice a day and trastuzumab 8 mg/kg intravenously on Cycle 1 Day 1 and 6 mg/kg every 21 days from Cycle 2 Day 1. Hormone receptor-positive HER2-mutated breast cancer patients will also receive fulvestrant 500 mg intramuscularly every 4 weeks and on Cycle 1 Day 15. Disease assessments per RECIST v1.1 are every 6 weeks for 24 weeks, then every 12 weeks. Patients in the breast cancer cohort will undergo baseline brain magnetic resonance imaging, and those patients with brain metastases may be eligible for the study. Quality of life will be evaluated using EQ-5D-5L every 2 cycles. Enrollment began in December 2020 and is ongoing globally. Citation Format: Alicia Okines, Paula R. Pohlmann, Jorge Ramos, Luke Walker, Erika Hamilton. SGNTUC-019: Phase 2 basket study of tucatinib and trastuzumab in previously treated solid tumors with HER2 alterations: HER2-mutated breast cancer cohort (ongoing clinical trial) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT1-15-01.

SGNTUC-019: Phase 2 basket study of tucatinib and trastuzumab in previously treated solid tumors with HER2 alterations—Biliary tract cancer cohort.

TPS489 Background: Tucatinib (TUC), a highly selective HER2-directed TKI approved in multiple regions for HER2+ metastatic breast cancer, is being investigated as a novel therapy for patients (pts) with metastatic colorectal cancer, gastric cancer, and other GI tumors. Preclinical and clinical data have shown HER2-targeted agents may improve clinical outcomes. In xenograft models of HER2+ and HER2-mutated tumors, dual targeting of HER2 with TUC + trastuzumab (Tras) showed superior activity to either agent alone (Kulukian 2020). Interim results from the MOUNTAINEER study have shown promising activity for TUC + Tras in HER2+ colorectal cancer. In 23 response-evaluable pts, an objective response rate (ORR) of 52% was observed with a median progression-free survival (PFS) of 8.1 months (mo) (Strickler 2019). The prognosis for pts with biliary tract cancers (BTCs) remain poor, and treatment options are limited. Given that approximately 12%-15% of BTC pts are HER2+, and 1%-8% have HER2 mutations, TUC + Tras warrants further evaluation in this patient population. The SGNTUC-019 basket study (NCT04579380) is evaluating TUC + Tras in pts with previously treated, locally advanced, unresectable or metastatic solid tumors including BTC that display HER2 overexpression/amplification or activating mutations. We describe the design of the BTC cohort. Methods: SGNTUC-019 is a multi-cohort, open-label, international Phase 2 study. Pts must be ≥18 years old; have an ECOG PS of ≤1; have adequate hepatic, hematological, renal, and cardiac functions; and have no previous exposure to HER2-directed therapy. BTC pts must have progressed on or after ≥1 previous line of treatment. The HER2+ BTC cohort will enroll 12 response-evaluable pts. If >2 responses are observed, the cohort will be expanded to 30 pts. HER2-mutated BTC patients may also be enrolled in a 30 pts cohort for other HER2-mutated solid tumors. The primary objective is antitumor activity with confirmed ORR as the primary endpoint. Secondary efficacy endpoints include disease control rate, duration of response, PFS, and OS. For eligibility, HER2 alterations can be demonstrated by HER2 overexpression/amplification in tumor tissue by prior IHC/ISH, or by HER2 amplification/mutation in a prior or on-study NGS assay of ctDNA or prior tissue NGS assay. Pts will receive TUC 300 mg orally twice a day and Tras 8 mg/kg intravenously on Cycle 1 Day 1 then 6 mg/kg every 21 days from Cycle 2 Day 1. Disease assessments per RECIST 1.1 are every 6 weeks for the first 24 weeks, then every 12 weeks. Quality of life will be evaluated every 2 cycles using EQ-5D-5L. Sites are currently enrolling within the US, EU and Asia-Pacific. Clinical trial information: NCT04579380.

MOUNTAINEER-02: Phase 2/3 study of tucatinib, trastuzumab, ramucirumab, and paclitaxel in previously treated HER2+ gastric or gastroesophageal junction adenocarcinoma—Trial in progress.

TPS371 Background: Tucatinib (TUC), a highly selective HER2-directed tyrosine kinase inhibitor (TKI) approved in multiple regions for HER2+ metastatic breast cancer, is being developed as a novel therapy for patients (pts) with GI tumors including gastric or gastroesophageal junction adenocarcinoma (GEC). While trastuzumab (Tras) with chemotherapy is standard in the 1st-line setting for metastatic HER2+ GEC, no anti-HER2 therapy has demonstrated an OS benefit over chemotherapy as 2nd-line therapy, possibly due to loss of HER2 expression following Tras-based therapy. In GEC xenograft models, dual targeting of HER2 with TUC and Tras showed superior activity to either agent alone.(Kulukian 2020) Interim results from the MOUNTAINEER study have shown promising activity for TUC and Tras for HER2+ mCRC.(Strickler 2019) The MOUNTAINEER-02 study is evaluating the efficacy and safety of TUC with Tras, ramucirumab (Ram), and paclitaxel (Pac) in pts with HER2+ GEC in the 2nd-line setting. Methods: MOUNTAINEER-02 (NCT04499924) is a phase 2/3 study evaluating TUC + Tras with Ram and Pac. Pts receive TUC 300 mg or placebo PO BID, Tras (6 then 4 mg/kg) or placebo (IV on Days 1 and 15 of each 28-day cycle), Pac (IV on Days 1, 8, 15), and Ram (IV on Days 1 and 15). Eligible pts have locally-advanced unresectable or metastatic HER2+ GEC and have received a HER2-directed antibody and 1 prior line of therapy for advanced disease. Pts must be ≥18 years of age, with an ECOG ≤1, and have had no prior exposure to Ram, anti-HER2 or anti-EGFR TKI, HER2-directed antibody-drug conjugates, or taxanes ≤12 months before enrollment. Due to the potential impact of TUC on Pac metabolism, the study will include an initial Pac dose optimization stage. The open-label phase 2 part will determine the recommended dose of Pac (60 or 80 mg/m²) combined with TUC, Tras, and Ram in 6-18 pts, and evaluate safety and activity of the regimen in Cohorts 2A and 2B (30 pts each). The randomized, double-blind, phase 3 part will compare the efficacy and safety of TUC and Tras (Arm 3A; ̃235 pts) vs. placebo (Arm 3B; ̃235 pts), both in combination with Ram and Pac, and also evaluate activity of TUC with Ram and Pac (Arm 3C; ̃30 pts). The dual primary phase 3 endpoints are OS and PFS per investigator, with confirmed ORR as a key secondary endpoint. HER2 status is determined at baseline using a blood-based NGS assay, and IHC/ISH of fresh or archival tumor biopsies, if available. Pts must be HER2+ by blood-based NGS in Cohort 2A and phase 3; in Cohort 2B, pts must be HER2+ in a biopsy taken post-progression during/after 1st-line therapy, but HER2-negative by blood-based NGS. Disease assessments per RECISTv1.1 will occur q6 weeks for 36 weeks, then q9 weeks. The pharmacokinetics of TUC, Pac, and their metabolites will be evaluated in a subset of pts, including a cohort with gastrectomies. Enrollment in phase 2 is ongoing. Clinical trial information: NCT04499924.

P47.01 SGNTUC-019: Phase 2 Study of Tucatinib and Trastuzumab in Solid Tumors: Lung Cancer Cohorts (Clinical Trial in Progress)

Tucatinib, a highly selective human epidermal growth factor receptor 2 (HER2)-directed tyrosine kinase inhibitor recently approved in multiple regions for overexpressed/amplified (HER2+) metastatic breast cancer, is also being developed as a novel therapy for patients with metastatic colorectal, gastric, and gastroesophageal cancers. In xenograft models of HER2 overexpression and HER2-mutated tumors, dual targeting of HER2 with tucatinib and trastuzumab showed superior activity to either agent alone.

1434TiP MOUNTAINEER-02: Phase II/III study of tucatinib, trastuzumab, ramucirumab, and paclitaxel in previously treated HER2+ gastric or gastroesophageal junction adenocarcinoma (GEC): Trial in progress

Tucatinib (TUC), a highly selective HER2-directed TKI with minimal EGFR inhibition approved for HER2+ metastatic breast cancer, is being developed for patients (pts) with metastatic colorectal cancer (mCRC) and other GI tumors. In GEC xenograft models, dual targeting of HER2 with TUC and trastuzumab (Tras) showed superior activity to either agent alone. Interim results from the MOUNTAINEER study have shown promising activity for TUC and Tras in HER2+ mCRC.

557TiP SGNTUC-019: Phase II basket study of tucatinib and trastuzumab in previously treated solid tumors with HER2 alterations

Tucatinib (TUC), a highly selective HER2-directed TKI with minimal EGFR inhibition, is approved in combination with trastuzumab (Tras) and capecitabine for adult patients (pts) with HER2 overexpressed/amplified (HER2+) locally-advanced unresectable or metastatic (LAUM) breast cancer (BC). Dual targeting of HER2 with TUC and Tras showed superior activity to either agent alone in HER2+ and HER2-mutated (HER2-mut) xenograft models. Currently, HER2-directed therapies are approved only in HER2+ BC and gastric cancer.

P-37 SGNTUC-019: Phase 2 basket study of tucatinib and trastuzumab in previously treated solid tumors with HER2 alterations: Biliary tract cancer cohort (trial in progress)

Tucatinib, a highly selective human epidermal growth factor receptor 2 (HER2)-directed tyrosine kinase inhibitor, recently approved in multiple regions for overexpressed/amplified (HER2+) metastatic breast cancer, is also being developed as a novel therapy for patients with metastatic colorectal, gastric, and gastroesophageal cancers. In xenograft models of HER2+ and HER2-mutated tumors, dual targeting of HER2 with tucatinib and trastuzumab showed superior activity to either agent alone. Interim results from the MOUNTAINEER study have shown promising activity for tucatinib and trastuzumab in HER2+ colorectal cancer.

SGNTUC-019: Phase 2 basket study of tucatinib and trastuzumab in previously treated solid tumors with HER2 alterations (trial in progress).

TPS3151 Background: Tucatinib (TUC) is a highly selective HER2-directed TKI approved in combination with trastuzumab (Tras) and capecitabine (Cape) for HER2 overexpressed/amplified (HER2+) metastatic breast cancer (BC), based on a statistically significant and clinically meaningful PFS, OS, and ORR benefit over Tras and Cape. In xenograft models of HER2+ and HER2-mutated (HER2-mut) tumors, dual targeting of HER2 with TUC and Tras showed superior activity to either agent alone. While various HER2-directed agents have been evaluated in HER2+ and HER2-mut tumors, there are no approved HER2 therapies outside of breast and gastric cancers. The SGNTUC-019 basket study is evaluating TUC combined with Tras in patients (pts) with HER2+ or HER2-mut locally-advanced unresectable or metastatic solid tumors. Methods: SGNTUC-019 (NCT04579380) is a multi-cohort, open-label, international phase 2 study. Eligible pts must have progressed on or after the last systemic therapy for advanced disease. Metastatic cervical cancer: must have received platinum-based chemotherapy ± bevacizumab; hormone receptor positive (HR+) HER2-mut BC: must have received a prior CDK4/6 inhibitor. Pts must be ≥18 years old, with ECOG PS ≤1, adequate hepatic, hematological, renal, coagulation, and cardiac function, and no prior HER2-directed therapy (except Tras for uterine serous carcinoma). For eligibility, HER2 alterations can be demonstrated by HER2+ in tumor tissue by prior IHC/ISH (IHC 3+/signal ratio ≥2.0 or gene copy number >6), or by HER2 amplification/mutation in a prior or on-study NGS assay of ctDNA or prior tissue NGS assay. Pts with HER2+ disease will be enrolled in cohorts for cervical, uterine, biliary tract, and urothelial cancers, non-squamous NSCLC, and other solid tumors (except GEC, BC, and CRC). Pts with HER2-mut disease will be enrolled in cohorts for non-squamous NSCLC, BC, and other solid tumors. Except for solid tumor and BC cohorts, 12 RECIST 1.1 evaluable pts will be enrolled in each cohort. If ≥2 responses are observed, the cohort will be expanded to a total of 30 pts. Other solid tumor and BC cohorts will enroll 30 pts in a single stage. If justified, additional HER2+ or HER2-mut disease-specific cohorts may be opened. Approximately 162-270 pts are planned. The primary objective is antitumor activity in each cohort, with confirmed ORR per investigator as primary endpoint, and disease control rate, duration of response, PFS, and OS as secondary endpoints. Pts will receive TUC 300 mg orally twice daily and Tras 8 mg/kg IV on Cycle 1 Day 1 and 6 mg/kg q21 days from Cycle 2 Day 1. HR+ BC pts will also receive fulvestrant 500 mg IM every 4 weeks and C1 D15. Disease assessments per RECIST 1.1 will occur q6 weeks for 24 weeks, then q12 weeks. TUC PK will be evaluated in all pts in Cycles 2-6. QoL is evaluated q2 cycle using EQ-5D-5L. Sites are open in the US; EU and Asia will be opened. Enrollment began in Dec 2020. Clinical trial information: NCT04579380.

125TiP SGNTUC-019: Phase II basket study of tucatinib and trastuzumab in previously treated solid tumours with HER2 alterations: HER2-mutated breast cancer cohort

Tucatinib (TUC), a highly selective HER2-directed TKI recently approved for HER2 overexpressed/amplified (HER2+) metastatic breast cancer (BC), on the basis of a statistically significant and clinically meaningful PFS, OS, and ORR benefit for the addition of TUC to trastuzumab (Tras) and capecitabine. TUC is being developed as a novel therapy for patients (pts) with metastatic BC, CRC, and gastric cancer. In xenograft models of HER2+ and HER2-mutated (HER2-mut) tumors, dual targeting of HER2 with TUC and Tras showed superior activity to either agent alone.

SGNTUC-019: Phase II basket study of tucatinib (TUC) and trastuzumab (Tras) in previously treated solid tumors with HER2 alterations: Urothelial cancer cohort (trial in progress).

TPS499 Background: Tucatinib (TUC), a highly selective HER2-directed TKI recently approved for HER2 overexpressed/amplified (HER2+) metastatic breast cancer, is being developed as a novel therapy for patients (pts) with metastatic CRC, gastric cancer, and other GI tumors. In xenograft models of HER2+ and HER2-mutated (HER2-mut) tumors, dual targeting of HER2 with TUC and trastuzumab (Tras) showed superior activity to either agent alone. Despite the development of several new therapies for metastatic urothelial cancer, response durations generally remain short and the great majority of pts succumb to the disease, highlighting the need for therapeutic approaches. Given that 20-30% of urothelial cancers have molecular alterations of the ErbB family, TUC in combination with Tras warrants further evaluation in this population. The SGNTUC-019 basket study is evaluating TUC in combination with Tras in pts with HER2+ or HER2-mut solid tumors, including a cohort of pts with locally advanced or metastatic (LAUM) urothelial cancer. Methods: SGNTUC-019 (NCT04579380) is a multi-cohort, open-label, international phase II study evaluating pts with previously treated solid tumors displaying HER2 overexpression/amplification or activating mutations. Eligible pts must have HER2+ or HER2-mut LAUM solid tumors, with progression on or after the last systemic therapy for advanced disease. Pts must be ≥18 years old, with ECOG PS ≤1, adequate hepatic, hematological, renal, coagulatory, and cardiac function, and no prior exposure to HER2-directed therapy. For eligibility, HER2 alterations can be demonstrated by HER2 overexpression/amplification in tumor tissue by prior IHC/ISH (IHC 3+/signal ratio ≥2.0 or gene copy number >6), or by HER2 amplification/mutation in a prior or on-study NGS assay of ctDNA or prior tissue NGS assay. The HER2 overexpression/amplification urothelial cancer cohort will enroll 12 RECIST 1.1 response-evaluable pts. If ≥2 responses are observed, the cohort will be expanded to a total of 30 pts. Pts with HER2-mut urothelial cancer will be enrolled in a cohort of 30 pts for all solid tumor types except breast cancer and non-squamous NSCLC. If justified, a separate cohort for HER2-mut urothelial cancer may be opened. The primary objective is antitumor activity in each cohort, with confirmed ORR as primary endpoint, and disease control rate, duration of response, PFS, and OS as secondary endpoints. Pts will receive TUC 300 mg orally twice daily and Tras 8 mg/kg IV on Cycle 1 Day 1 and 6 mg/kg q21 days from Cycle 2 Day 1. Disease assessments per RECIST 1.1 will occur q6 weeks for 24 weeks, then q12 weeks. Trough concentrations of TUC will be evaluated in all pts in Cycles 2-6, with a peak concentration sampled in Cycle 3. Quality of life will be evaluated q2 cycle using EQ-5D-5L. Sites will open in the US, EU, and Asia; enrollment is anticipated to begin in Dec 2020. Clinical trial information: NCT04579380.

MOUNTAINEER-02: Phase II/III study of tucatinib, trastuzumab, ramucirumab, and paclitaxel in previously treated HER2+ gastric or gastroesophageal junction adenocarcinoma—Trial in Progress.

TPS252 Background: Tucatinib (TUC), a highly selective HER2-directed TKI recently approved for HER2+ metastatic breast cancer (MBC), is being developed as a novel therapy for patients (pts) with metastatic colorectal cancer (mCRC) and other GI tumors. While trastuzumab (Tras) with chemotherapy is standard in the 1st-line setting for metastatic HER2+ gastric or gastroesophageal junction adenocarcinoma (GEC), no anti-HER2 therapy has demonstrated an OS benefit over chemotherapy in 2nd-line, possibly due to loss of HER2 expression following Tras-based therapy. In GEC xenograft models, dual targeting of HER2 with TUC and Tras showed superior activity to either agent alone. Interim results from the MOUNTAINEER study have shown promising activity for TUC and Tras in HER2+ mCRC. The MOUNTAINEER-02 study is evaluating the efficacy and safety of TUC in combination with Tras, ramucirumab (Ram), and paclitaxel (Pac) in pts with HER2+ GEC. Methods: MOUNTAINEER-02 (NCT04499924) is a phase 2/3 study evaluating TUC and Tras with the 2nd-line standard of care, Ram and Pac. Pts receive TUC 300 mg or placebo PO BID, Tras (6 then 4 mg/kg) or placebo (IV on Days 1 and 15 of each 28-day cycle), Pac (IV on Days 1, 8, 15), and Ram (IV on Days 1 and 15). Eligible pts have locally-advanced unresectable or metastatic HER2+ GEC, have received a HER2-directed antibody, and 1 prior line of therapy for advanced disease. Pts must be ≥18 years of age, with an ECOG ≤1, and have had no prior exposure to Ram, anti-HER2 or anti-EGFR TKI, HER2-directed antibody-drug conjugates, or taxanes ≤12 months before enrollment. Due to the potential impact of TUC on Pac metabolism, the study will include an initial Pac dose finding stage. The open-label phase 2 part will determine the recommended dose of Pac (60 or 80 mg/m²) combined with TUC, Tras, and Ram in 6-12 patients, and evaluate the safety and activity of the regimen in Cohorts 2A and 2B (30 patients each). The randomized, double-blind, phase 3 part will compare the efficacy and safety of TUC and Tras (Arm 3A; ~235 patients) vs. placebo (Arm 3B; ~235 patients), both in combination with Ram and Pac, and also evaluate activity of TUC with Ram and Pac (Arm 3C; ~30 patients). The dual primary phase 3 endpoints are OS and PFS per investigator, with confirmed ORR as a key secondary endpoint. HER2 status is determined at baseline using a blood-based NGS assay, and IHC/ISH of fresh or archival tumor biopsies, if available. Pts must be HER2+ by blood-based NGS in Cohort 2A and phase 3; in Cohort 2B, pts must be HER2+ in a biopsy taken post-progression during/after 1st-line therapy, but HER2-negative by blood-based NGS. Disease assessments per RECISTv1.1 will occur q6 weeks for 36 weeks, then q9 weeks. The pharmacokinetics of TUC, Pac, and their metabolites will be evaluated in a subset of pts, including a cohort with gastrectomies. Enrollment is ongoing in the U.S. Clinical trial information: NCT04499924.