HER2 Tyrosine Kinase Inhibitor Research Articles

126TiP HER2CLIMB-02: Tucatinib or placebo with T-DM1 for unresectable locally-advanced or metastatic HER2+ breast cancer

Tucatinib (TUC), an oral tyrosine kinase inhibitor (TKI) highly selective for HER2 with minimal inhibition of EGFR, is approved in the US, Canada, Switzerland, Australia, and Singapore for combined treatment with trastuzumab (Tras) and capecitabine for patients with HER2+ metastatic breast cancer (MBC), including patients with brain metastases (BM) who received 1 or more prior anti-HER2-based regimens in the metastatic setting. Ado-Tras emtansine (T-DM1), approved for treatment of HER2+ MBC after Tras and a taxane, has improved progression-free survival (PFS) and overall survival (OS). Further improvements are needed, including in patients with active BM. A phase Ib trial evaluated TUC+T-DM1 in 50 patients with HER2+ MBC who received prior treatment with Tras and a taxane; 60% of patients had BM at baseline (Borges 2018). Common adverse events, mostly Grade 1/2, were nausea (72%), diarrhea (60%), and fatigue (56%). Median PFS was 8.2 months and objective response rate (ORR) in patients with measurable disease (n=34) was 47%. Brain specific response rate (RECIST v1.1) in patients with measurable BM (n=14) was 36%. This encouraging clinical activity, including in patients with BM, provides rationale to evaluate TUC+T-DM1. HER2CLIMB-02 is a randomized, double-blind, placebo-controlled, phase III study enrolling patients with centrally confirmed HER2+ unresectable locally-advanced or MBC previously treated with Tras and taxane. Patients must have ECOG ≤1. Approximately 460 patients will be randomized 1:1 for 21-day cycles of TUC (300 mg PO BID) or placebo with T-DM1 (3.6 mg/kg IV). Prior treatment with investigational anti-HER2 agent, anti-EGFR agent, or HER2 TKI is not permitted. Prior pertuzumab treatment is permitted. Baseline brain MRIs are required; patients with stable, progressing, or untreated BM may be eligible. Treatment response assessments per RECISTv1.1 occur every 6 weeks for the first 24 weeks, and then every 9 weeks. Primary endpoint is PFS per investigator assessment, with OS and ORR as key secondary endpoints. Enrollment is ongoing in the US, Canada, EU, Japan, South Korea, Australia, and Israel, and is planned for Singapore. NCT03975647. Editorial assistance was provided by Craig Bolte of MMS Holdings. Seagen Inc.

Treating Advanced Unresectable or Metastatic HER2-Positive Breast Cancer: A Spotlight on Tucatinib.

The management of HER2 positive breast cancer has been transformed by the development of targeted therapies. Dual blockade with the monoclonal antibodies, trastuzumab and pertuzumab, added to first-line taxane chemotherapy and second-line therapy with the antibody–drug conjugate, T-DM1, are internationally agreed standards of care for advanced HER2 positive breast cancer, where available. However, until recently, options for patients for third-line therapy and beyond were of modest efficacy or limited by toxicity. In 2019, the results of trials of two exciting new agents for this space were presented. A third-generation HER2 tyrosine kinase inhibitor, tucatinib, combines the efficacy of the second-generation drug, neratinib, with a more manageable toxicity profile and has become a new standard of care after T-DM1, in combination with capecitabine and trastuzumab. The antibody–drug conjugate, trastuzumab deruxtecan, demonstrated remarkable efficacy in heavily pre-treated patients and received accelerated approval in the United States, whilst confirmatory Phase 3 trials are completed. This review will discuss the available data for the post-T-DM1 setting, focusing on tyrosine kinase inhibitors including tucatinib.

Abstract PD3-08: Tucatinib vs placebo in combination with trastuzumab and capecitabine for patients with locally advanced unresectable or HER2-positive metastatic breast cancer (HER2CLIMB): Outcomes by hormone receptor status

Abstract Background Tucatinib (TUC) is a highly selective oral tyrosine kinase inhibitor of HER2 with minimal inhibition of EGFR. It was recently approved by the FDA for patients (pts) with HER2+ metastatic breast cancer (MBC), including pts with brain metastases (BM) whose cancers have progressed on at least 1 prior anti-HER2 regimen in the metastatic setting. In the HER2CLIMB (NCT02614794) pivotal trial, pts with HER2+ MBC previously treated with trastuzumab (T), pertuzumab, and trastuzumab emtansine (T-DM1) were randomized to receive TUC or placebo in combination with T and capecitabine (C). The addition of TUC resulted in clinically meaningful and statistically significant improvements in overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) in HER2+ MBC pts. Primary methods and outcomes have been reported previously (Murthy, NEJM 2019). Here we present an exploratory analysis describing the outcomes in the HER2CLIMB trial based on hormone receptor (HR) status. Methods Pts were randomized 2:1 to receive TUC or placebo in combination with T and C. All pts had a baseline brain MRI and randomization was stratified by presence of BM, ECOG status, and geographic region. All pts with HER2+ MBC who were positive for either or both estrogen receptor and progesterone receptor (> 1%) were assigned to the HR “positive” subgroup. Pts not meeting the above criteria were assigned to the HR “negative” subgroup. For the exploratory HR+/HR- efficacy analysis presented here, PFS per RECIST 1.1 by blinded independent central review was evaluated in the first 480 pts enrolled. OS, PFS in pts with baseline BM, and confirmed ORR in pts with measurable disease were evaluated in the total study population. P values presented for PFS are nominal. Results Overall, 612 pts were enrolled to HER2CLIMB; 370 pts (60%) had HR+ and 242 (40%) had HR- tumors. Baseline demographics and disease characteristics in HR+/HR- subgroups were generally balanced between treatment arms. In the HR+ group, there was a 42% reduction in the risk of progression or death in the TUC arm (hazard ratio: 0.58; 95% CI: 0.42, 0.80; P=0.0008); median (95% CI) PFS was 7.6 mo (7.4, 9.5) in the TUC arm vs 5.6 mo (4.3, 7.4) in the control arm. In the HR- group, there was a 46% reduction in the risk of progression or death in the TUC arm (hazard ratio: 0.54; 95% CI: 0.34, 0.86; P=0.008); median (95% CI) PFS was 8.1 mo (7.0, 11.6) in the TUC arm vs 4.2 mo (3.1, 8.6) in the control arm. In the total population, median OS was 21.7 mo vs 18.2 mo in HR+ in the TUC arm vs control arm, respectively; median OS in HR- was 31.1 mo in the TUC arm vs 14.1 mo in the control arm. In pts with BM in the HR+ group (n=166 [45%]), there was a 52% reduction in the risk of progression or death (hazard ratio: 0.48; 95% CI: 0.31, 0.75; P=0.0008); median (95% CI) PFS was 7.5 mo (5.6, 9.5) in the TUC arm vs 5.1 mo (4.1, 5.7) in the control arm, and median OS was 18.1 mo vs 12.8 mo, respectively. In pts with BM in the HR- group (n=125 [52%]), there was a 50% reduction in the risk of progression or death (hazard ratio: 0.50; 95% CI: 0.27, 0.95; P=0.03); median (95% CI) PFS was 7.8 mo (6.1, 11.6) in the TUC arm vs 5.4 mo (2.9, 8.6) in the control arm, and median OS was 18.5 mo vs 11.5 mo, respectively. In the total population, ORR was numerically higher in the TUC arm vs the control arm regardless of HR status (HR+: 37.4% [95% CI: 30.8, 44.5] vs 27.1% [95% CI: 19.0, 36.6], respectively and HR-: 45.3% [95% CI: 36.7, 54.0] vs 15.6% [95% CI: 7.8, 26.9], respectively). Conclusions Among pts with HER2+ MBC previously treated with T, pertuzumab, and T-DM1, the addition of TUC to T and C showed clinically meaningful improvements of PFS, OS, and ORR independent of HR status. Furthermore, pts with HR+ and HR- MBC with BM derived similar benefit from the addition of TUC to T and C. Citation Format: Erika Hamilton, Mattea Reinisch, Sherene Loi, Alicia Okines, Paula R. Pohlmann, Eva Harder Brix, Hugues Bourgeois, Belinda Yeo, Cheryl Aylesworth, Melody Cobleigh, Anthony Goncalves, Rebecca Moroose, Katherine H.R. Tkaczuk, Michaela Tsai, Christine Simmons, Michael Andersson, Hatem Soliman, Michelina Cairo, Lisa A. Carey, David Cameron, Jorge Ramos, Wentao Feng, Mafalda Oliveira. Tucatinib vs placebo in combination with trastuzumab and capecitabine for patients with locally advanced unresectable or HER2-positive metastatic breast cancer (HER2CLIMB): Outcomes by hormone receptor status [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD3-08.

Abstract OT-28-01: HER2CLIMB-02: A randomized, double-blind, phase 3 study of tucatinib or placebo with T-DM1 for unresectable locally-advanced or metastatic HER2+ breast cancer

Abstract Background - Tucatinib (TUC), an oral tyrosine kinase inhibitor (TKI) highly selective for HER2 with minimal inhibition of EGFR, is approved in the US for use in combination with trastuzumab (Tras) and capecitabine for treatment (tx) of adult patients (pts) with metastatic HER2+ breast cancer (MBC), including pts with brain metastases (BM), who have received 1 or more prior anti-HER2-based regimens in the metastatic setting. Ado-trastuzumab emtansine (T-DM1), approved for tx of pts with HER2+ MBC after Tras and a taxane, has led to significant improvements in progression-free survival (PFS) and overall survival (OS). Still, further improvements are needed, including pts with active BM. A phase 1b trial evaluated TUC (300 mg PO BID) with T-DM1 in 50 pts with HER2+ MBC who received prior tx with Tras and a taxane (Borges 2018). Common AEs included nausea (72%), diarrhea (60%), and fatigue (56%); mostly grade 1/2. Median PFS was 8.2 months and the objective response rate (ORR) in pts with measurable disease (n=34) was 47%. Sixty percent of pts treated with TUC + T-DM1 had BM at baseline and showed a brain specific response rate (RECISTv1.1) of 36% in pts with measurable BM. This encouraging clinical activity, including in pts with BM, provides rationale for a randomized trial to further evaluate this combination. Trial design - HER2CLIMB-02 is a randomized, double-blind, placebo-controlled phase 3 study to evaluate efficacy and safety of TUC + T-DM1 in pts with unresectable locally advanced or metastatic HER2+ breast cancer; ~460 pts will be randomized 1:1 to receive 21-day cycles of TUC (300 mg PO BID) or placebo with T-DM1 (3.6 mg/kg IV). Pts must have had prior tx with Tras and a taxane in any setting, be ≥18 yrs, with an ECOG ≤1 and histologically confirmed HER2+ MBC. Prior tx with any investigational antiHER2 or anti-EGFR agent or HER2 TKI is not permitted. Prior pertuzumab tx is allowed, but not required. Baseline brain MRIs are required for all pts; pts with stable, progressing, or untreated BM not requiring immediate local therapy are eligible. While on tx, radiographic disease evaluations (RECISTv1.1) will occur every 6 weeks for the first 24 weeks, and then every 9 weeks. The primary endpoint is PFS per investigator, with OS and ORR as key secondary endpoints. Enrollment is ongoing in the US (NCT03975647) and planned for Canada, the EU, and the Asia/Pacific region. Citation Format: Sara Hurvitz, Linda Vahdat, Nadia Harbeck, Antonio C. Wolff, Sara M. Tolaney, Sherene Loi, Norikazu Masuda, Joyce O’Shaughnessy, Cassie Dong, Luke Walker, Evelyn Rustia, Virginia F. Borges. HER2CLIMB-02: A randomized, double-blind, phase 3 study of tucatinib or placebo with T-DM1 for unresectable locally-advanced or metastatic HER2+ breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr OT-28-01.

Abstract PS10-08: Tucatinib potentiates the activity of the antibody-drug conjugate T-DM1 in preclinical models of HER2-positive breast cancer

Abstract Background: Tucatinib is an orally administered, reversible, highly specific HER2 tyrosine kinase inhibitor recently approved by the FDA in combination with trastuzumab and capecitabine for adult patients with advanced unresectable or metastatic HER2-positive breast cancer (mBC), including patients with brain metastases, that have failed at least one anti-HER2 regimen in the metastatic setting. In a phase IB clinical trial, tucatinib in combination with the HER2-targeted antibody-drug conjugate (ADC) ado-trastuzumab emtansine (T-DM1) was well tolerated and demonstrated activity in heavily pre-pretreated patients with HER2-positive mBC (NCT01983501; Borges VF et al., 2018). We previously presented preclinical data that tucatinib increases the activity of trastuzumab-derived ADCs in HER2-positive breast cancer models. Here, we provide mechanistic insight that tucatinib potentiates the activity of T-DM1 by modulating HER2 protein dynamics and facilitating increased cytotoxic maytansinoid drug delivery. Methods: To assess changes to HER2 protein levels upon treatment with tucatinib, HER2-amplified breast cancer cell lines were analyzed by Western blot and quantitative FACS (qFACS). To probe the dynamics of HER2 at the cell surface upon binding to antibody therapeutics, SK-BR-3 cells were incubated with fluorescently labeled trastuzumab to mark HER2 at the cell surface. Cells were imaged over 72 hours to observe the internalization of surface-bound antibody. Concurrent experiments were conducted with trastuzumab labeled with QF01, a quenched fluor which fluoresces only upon lysosomal processing and can serve as a proxy for antibody catabolism. To directly measure the rates of ADC catabolism, lysates were generated from BT-474 cells treated with T-DM1 in the presence or absence of tucatinib over a 72 hour time course, and were analyzed by mass spectrometry for the T-DM1 adduct, Lys-MCC-DM1. Results: In HER2-amplified breast cancer cell lines, treatment with tucatinib increased overall and cell membrane-localized HER2 levels. As demonstrated by internalization assays, tucatinib had an initial effect that increased the dwell time of HER2 at the cell surface of SK-BR-3 cells. At later timepoints, HER2 bound to trastuzumab was internalized and directed towards lysosomes. These data were supported by parallel intracellular Lys-MCC-DM1 measurements, which demonstrated increased concentration of the adduct when TDM-1 was administered in combination with tucatinib. These data provide a mechanistic rationale as to why the co-administration of tucatinib with T-DM1 in vitro was synergistic by isobologram analysis, and why the combination of tucatinib with T-DM1 was more effective in vivo than either single agent alone in BT-474 xenografts and in PDX models tested, producing a higher proportion of partial or complete tumor regressions. Conclusions: The described preclinical in vitro and in vivo data of simultaneous dual HER2 inhibition with tucatinib and T-DM1, along with the results of the phase IB/2 clinical trial demonstrating preliminary safety and efficacy of the combination, warrant further clinical development of tucatinib in combination with T-DM1. These results also support the evaluation of tucatinib in combination with other HER2-targeted ADCs in patients with HER2-positive mBC. Citation Format: Anita Kulukian, Janelle Taylor, Nishi Jain, Devra Olson, Margo Zaval, Robert Thurman, Shawna Hengel, Lauren Farr, Thomas Pires, Scott R. Peterson. Tucatinib potentiates the activity of the antibody-drug conjugate T-DM1 in preclinical models of HER2-positive breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS10-08.

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.

Current management and future prospect of HER-2 mutant non-small cell lung cancer

Since Erb-B2 receptor tyrosine kinase 2 (HER-2) was regarded as oncogenic driver gene for malignancies, HER-2 targeted therapy has benefited many patients with breast cancer and gastric cancer. However, as a member of the epidermal growth factor receptor (EGFR) family, HER-2 has failed to respond well to both traditional anti-HER-2 and anti-EGFR targeted agents when compared to EGFR in non-small cell lung cancer (NSCLC). It is reported that unlike gene copy number variation in breast cancer, HER-2 intragenic kinase domain mutations (the exon 20 in-frame insertions are dominant, and missense mutations in kinase domain are also observed) in NSCLC might account for the poor response to traditional HER-2 or EGFR tyrosine kinase inhibitors (TKIs). In this review, we summarize the pathogenesis, molecular variations, clinical features and current therapeutic strategies for HER-2 mutated NSCLC to discuss the challenges and perspectives for this population.

Abstract 3016: Tucatinib inhibits CYP3A, CYP2C8 and P-gp-mediated elimination and is impacted by CYP2C8 inhibition in healthy volunteers

Abstract Background: Tucatinib is a potent, highly selective HER2 tyrosine kinase inhibitor in development for the treatment of patients with HER2+ metastatic breast cancer. In vitro metabolism studies suggest that drug metabolizing enzymes CYP2C8 and CYP3A play a role in tucatinib metabolism. Tucatinib exhibits competitive inhibition of CYP2C8, CYP2C9, CYP3A, and P-gp, and metabolism-dependent inactivation of CYP3A in vitro. ONT-380-012 was a clinical drug interaction study conducted to evaluate the magnitude of potential enzyme and transporter interactions for tucatinib (both as a victim and perpetrator), and the safety of healthy subjects when administered tucatinib doses at therapeutic levels (300 mg BID). Methods: Healthy volunteers (n=116) at multiple centers were enrolled in the study. Parts A-C evaluated the effects of a strong CYP2C8 inhibitor (gemfibrozil), a strong CYP3A inhibitor (itraconazole), and a CYP3A/CYP2C8 inducer (rifampin) on single-dose tucatinib (300 mg) PK. Parts D and E assessed the effects of steady-state tucatinib (300 mg BID) on single-dose PK of substrate probes for CYP2C8 (repaglinide), CYP2C9 (tolbutamide), CYP3A (midazolam), and P-gp (digoxin). Plasma samples were collected for PK analysis and drug concentrations were measured using validated LC-MS/MS methods. Results: A strong CYP3A inhibitor (itraconazole) increased tucatinib AUCinf and Cmax 1.3-fold. A CYP3A/CYP2C8 inducer (rifampin) decreased tucatinib AUCinf and Cmax 48% and 37%, respectively. A strong CYP2C8 inhibitor (gemfibrozil) increased tucatinib AUCinf and Cmax 3.1- and 1.6-fold, respectively. Tucatinib increased the AUCinf and Cmax of the CYP3A substrate (midazolam) 5.7- and 3.0-fold, respectively, the AUCinf and Cmax of the CYP2C8 substrate (repaglinide) 1.7-fold, and the AUCinf of the P-gp substrate (digoxin) 1.5-fold. Tucatinib had no impact on the PK of the CYP2C9 substrate (tolbutamide). Overall, tucatinib was well tolerated in healthy volunteers when administered 300 mg BID. Conclusions: Together, these data indicate tucatinib is metabolized primarily by CYP2C8 and to a lesser extent via CYP3A. Tucatinib was found to be a strong inhibitor of CYP3A, a weak inhibitor of CYP2C8 and P-gp, and had no impact on CYP2C9-mediated metabolism in vivo. Citation Format: Ariel R. Topletz-Erickson, Anthony Lee, Hao Sun, JoAl Mayor, Luke Walker, Christopher J. Endres. Tucatinib inhibits CYP3A, CYP2C8 and P-gp-mediated elimination and is impacted by CYP2C8 inhibition in healthy volunteers [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3016.

Abstract 3015: Tucatinib inhibits creatinine and metformin renal tubule secretion but has no effect on renal function (GFR)

Abstract Background: Tucatinib (TUC) is a potent, highly selective investigational HER2 tyrosine kinase inhibitor in development for treatment of patients with HER2+ metastatic breast cancer (MBC). In HER2CLIMB (H2C), a pivotal study of patients with HER2+ MBC, a modest transient, reversible increase in serum creatinine (SCr) levels was observed in patients who received TUC. Similarly, in a study with healthy volunteers, SCr increased after 300 mg BID TUC and returned to baseline levels after TUC discontinuation. Clinically, SCr is used as a biomarker for glomerular filtration rate (GFR) and is routinely measured to monitor for potential renal injury. However, SCr renal elimination also depends on the kidney transporters OCT2 (uptake), MATE1 (efflux) and MATE2-K (efflux). Inhibition of OCT2 and MATE1/2-K has been associated with SCr increases in the absence of kidney damage (e.g., abemaciclib). In vitro assessments and a clinical study were performed to assess the impact of TUC on OCT2 and MATE1/2-K-mediated transport. Methods: Inhibition of OCT2, MATE1, and MATE2-K-mediated transport by TUC was estimated in transfected MDCK-II cells using creatinine and metformin (MF), a sensitive OCT2 and MATE1/2-K substrate used to quantify transport inhibition in vivo, as probe substrates. Subsequently, a single-arm drug-drug interaction study was performed in 17 healthy volunteers to evaluate the effects of TUC on MF PK. MF (850 mg, PO) was administered in the absence and presence of TUC (300 mg BID, PO). Iohexol was administered to calculate actual GFR (aGFR) in the absence and presence of TUC. Plasma (iohexol, MF and TUC) and urine (MF) samples were collected for PK analysis; drug concentrations were measured using validated LC-MS/MS methods. Serum and urine creatinine levels were also measured. Results: In MDCK II cells, TUC inhibited creatinine transport by OCT2 (IC50 = 0.107 µM) and MATE1 (IC50 = 0.086 µM) and MF transport by MATE1 (IC50 = 0.340 µM) and MATE2-K (IC50 = 0.135 µM), but not by OCT2 (IC50 = 14.7 µM). Using these IC50 values, physiologically-based pharmacokinetic (PBPK) model simulations predicted a 1.16 to 1.35-fold increase of MF exposure in the presence of TUC. Consistent with the PBPK prediction, in healthy volunteers MF exposure (AUCinf) increased ~1.4-fold and renal clearance decreased from 29.99 L/h to 17.64 L/h in the presence of TUC with no effect on MF Cmax. Iohexol clearance was unaffected in the presence of TUC indicating no change in aGFR. SCr increased in the presence of TUC and returned to baseline 8 days after TUC discontinuation. Conclusions: Together, these data demonstrate that the observed SCr increase in clinical studies with TUC is due to inhibition of tubular secretion of creatinine via OCT2 and MATE1 and not due to an effect on kidney function. An alternative, non-creatinine-based measure of renal function should be considered for tucatinib. Citation Format: Ariel R. Topletz-Erickson, Anthony Lee, JoAl Mayor, Evelyn Rustia, Layth Abdulrasool, Luke Walker, Christopher J. Endres. Tucatinib inhibits creatinine and metformin renal tubule secretion but has no effect on renal function (GFR) [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3015.

New Therapeutics in HER2-Positive Advanced Breast Cancer: Towards a Change in Clinical Practices?pi.

Over the last few decades, improved knowledge of oncogenic activation mechanisms of HER2 protein has led to the development of HER2 targeted therapies that are currently commonly used in HER2-positive advanced breast cancer, such as trastuzumab, lapatinib, pertuzumab, and ado-trastuzumab emtansine. The management of this breast cancer subgroup has thus been revolutionized and its prognosis has changed dramatically. Nevertheless, HER2-positive advanced breast cancer remains an incurable disease and resistance to conventional anti-HER2 drugs is almost unavoidable. Nowadays, biochemical and pharmaceutical advances are meeting the challenge of developing increasingly sophisticated therapies directed against HER2, including novel anti HER2 antibodies with increased affinity. New antibody-drug conjugates (ADC) with more advanced pharmacological properties, and dual targeting of epitopes via bispecific monoclonal antibodies are also emerging. In addition, more potent and more specific HER2 tyrosine kinase inhibitors have shown interesting outcomes and are under development. Finally, researchers’ interest in tumor microenvironment, particularly tumor-infiltrating lymphocytes, and the major role that signaling pathways, such as the PI3K/AKT/mTOR pathway, play in the development of resistance to anti-HER2 therapies have spurred the development of clinical trials evaluating innovative combinations of anti-HER2 with PD-1/PDL-1, CDK4/6 and PI3K inhibitors. However, several questions remain unresolved, like the optimal management of HER2-positive/HR-positive advanced breast cancer and the identification of predictive biomarkers to better define populations that can benefit most from these new therapies and approaches.

A phase II basket study of MCLA-128, a bispecific antibody targeting the HER3 pathway, in NRG1 fusion-positive advanced solid tumors.

TPS3654 Background: NRG1 fusions are oncogenic drivers across various cancers. NRG1 fusion proteins bind to HER3, leading to HER2/HER3 heterodimerization, increased downstream signaling, and tumor growth. Clinical responses to anti-HER3 antibodies or HER2 tyrosine kinase inhibitors have been reported. In contrast to these agents, MCLA-128 is a HER2/HER3 bispecific antibody that blocks both NRG1 binding and HER2/3 dimerization. Two patients with chemotherapy-resistant ATP1B1-NRG1-positive pancreatic KRAS-wild-type adenocarcinomas who received MCLA-128 through FDA-approved single-patient Investigational New Drug (IND) applications showed significant tumor shrinkage and durable tumor marker (CA-19-9) response. These data support the evaluation of MCLA-128 in NRG1 fusion-positive tumors using a basket approach. Methods: This is a global, open-label, multicenter phase 2 basket trial of MCLA-128 in patients with solid tumors harboring NRG1 gene fusions. Main eligibility criteria are locally advanced unresectable or metastatic cancers harboring an NRG1 fusion, and failure under prior standard therapy appropriate for the tumor type and disease stage. Genomic screening of tumor tissue is done at a local laboratory (with post-hoc central confirmation) or central laboratory (RNA sequencing). Three NRG1 fusion-positive tumor cohorts are being evaluated: pancreatic cancer, NSCLC, and other solid tumors. The sample size for the first two cohorts is up to 25 patients; the basket group may enroll up to 40 patients. The primary endpoint for all cohorts is investigator-assessed objective response rate (RECIST v1.1). The key secondary endpoint is duration of response. Other secondary endpoints include progression-free and overall survival. Eligible patients receive a bi-weekly dosing regimen of 750 mg of MCLA-128 (2-hour infusion), every 2 weeks, in 4-week cycles. The study is actively accruing patients in North America, Europe, and Asia. Previously presented at ESMO 2019, 685TiP, Schram et al.-Reused with permission. Clinical trial information: NCT02912949 .

Masterkey-01: Phase I/II, open-label multicenter study to assess safety, tolerability, pharmacokinetics, and antitumor activity of BDTX-189, an inhibitor of allosteric ErbB mutations, in patients with advanced solid malignancies.

TPS3665 Background: A significant unmet need exists for drugs targeting allosteric ErbB mutations (non-canonical mutations outside the ATP binding site). Current EGFR and HER2 tyrosine kinase inhibitors or mAbs have limited antitumor activity against allosteric mutations, resulting in toxicity before adequate drug exposure (Connell and Doherty, 2017). BDTX-189 is a potent and selective orally available irreversible inhibitor targeting unique oncogenic driver mutations of ErbB kinases in EGFR and HER2, while sparing WT EGFR. Preclinical studies demonstrated antitumor activity across a range of allosteric ErbB mutants, including extracellular domain allosteric mutations of HER2 as well as EGFR and HER2 kinase domain exon 20 insertions (Buck, 2019). This first-in-human trial (NCT04209465) is aimed to determine the recommended phase 2 dose (RP2) and schedule (Phase 1, P1), and evaluate the efficacy (Phase 2, P2) of BDTX-189. P1 primary objective is to determine the RP2 dose and schedule of monotherapy BDTX-189. Secondary objectives include assessment of safety, tolerability, pharmacokinetics (PK), pharmacodynamic (PD) effects in tumor, and preliminary efficacy. The P2 primary objective is to assess antitumor activity of monotherapy BDTX-189. Methods: The study will enroll patients (pts) ≥18 yrs with histologically or cytologically confirmed locally advanced or metastatic solid tumors with no standard therapy available or for whom standard therapy is unsuitable or intolerable. P1 dose-escalation will use a BOIN design (Yuan, 2016) and will enroll ≤ 88 pts with allosteric HER2 or HER3 mutation; EGFR or HER2 exon 20 insertion mutation; HER2 amplified or overexpressing tumor; or EGFR exon 19 deletion or L858R mutation. BDTX-189 will be dosed orally (PO) initially QD in 3 wk cycles. Regimen optimization will use PK, PD and safety data and may explore a BID schedule. An expansion cohort of ≤12 pts will further evaluate safety and preliminary efficacy of BDTX-189 prior to P2. P2, utilizing a Simon 2-stage design, will enroll ≤100 pts with NSCLC with EGFR or HER2 exon 20 insertion mutations (cohort 1); breast cancer with an allosteric ErbB mutation (cohort 2); tumors (except breast) with S310F/Y mutation (cohort 3); and other allosteric ErbB mutations not defined in cohorts 1-3 (cohort 4). Assessments include safety, tolerability, DLTs, evaluation of MTD, PK, PD, and preliminary antitumor activity. Enrollment began 1/2020. Clinical trial information: NCT04209465 .

Tolerability of neratinib in older adults with HER2 positive or HER2 mutated metastatic breast cancer.

e13018 Background: The tolerability and efficacy of targeted therapy in older adults with cancer have not been adequately studied. Neratinib is an oral pan-HER1, HER2, and HER4 tyrosine kinase inhibitor that has been FDA approved for early stage HER 2+ breast cancer. This phase II trial is designed to evaluate the safety of neratinib in older adults (≥60 years) who have HER2 amplified or HER2 mutated metastatic breast cancer (MBC). Methods: Older adults with HER2+ or HER2 mutated MBC with any number of previous lines of therapy received neratinib at 240 mg daily in 28-day cycles. Loperamide was used for diarrhea prophylaxis: 4mg tid x 14 days followed by 4mg bid for days 15-28, and as needed after first cycle. Participants completed a pre-treatment geriatric assessment (GA) including measures of function, comorbidity, cognition, nutrition, and psychosocial status at cycle 1, cycle 4, and end of the study. Relationships between tolerability (dose reductions and number of completed courses) and log2 risk score were assessed using t-test and linear regression. Response rate (RR), progression free survival (PFS) and overall survival (OS) were evaluated. Results: Twenty-five patients (mean age 68 [60-79]) were enrolled from 12/2016 to 03/2019, and 36% of patients (pts) were >70 years old. Median number of cycles completed was 3 (0-13): 1/25 (4%) pts had a partial response, 11/25 (44%) had stable disease, 12/25 (48%) had progression of disease, and 1/25 (4%) was not evaluable for response. PFS was 2.6 months (95% CI [2.56-5.26]). The median OS was 17.4 months (95% CI [10.3, NA]). A total of 9/25 pts (36%) had dose modification. Of these, 3/9 had at least one dose hold, and all 9 had at least one dose reduction (diarrhea, n = 6). 20/25 participants (80%, 95% CI [59%, 93%]) had grade ≥2 toxicities, and 9/25 pts (36%, 95% CI [18%, 57%]) had grade 3 toxicities that were attributable to treatment: diarrhea (n = 5), abdominal pain (n = 2), and vomiting (n = 2). There were no grade 4 or 5 toxicities. Two pts (8%) were hospitalized due to neratinib toxicity, and two pts went off treatment due to toxicity attributed to neratinib (diarrhea and nausea). There was a trend in the difference in toxicity risk scores by whether a participant had a dose reduction (t-test: p-value = 0.054) with participants with higher risk scores being more likely to require a dose reduction; however, toxicity risk score did not predict number of cycles completed based on linear regression (slope = -1.29, se = 1.44, p = .39). Conclusions: Neratinib is safe in older adults with HER2 positive or HER2 mutated MBC. Clinical trial information: NCT02673398 .

Utilization of Flavonoid Compounds as HER2 Tyrosine Kinase Inhibitor in Breast Cancer Using Fragment-Based Drug Design

Breast cancer has become one of the leading cause of women’s death around the world. Breast cancer can be caused by genetic or environmental factors. Human epidermal growth factor receptor 2 (HER2) is one of the main causes of breast cancer. The HER2 tyrosine kinase plays a significant role in the dimerization reaction which causes auto-phosphorylation of tyrosine residues in the cytoplasmic domain that triggers growth of the cancer cells. Inhibition of HER2 protein activity can be a potential alternative for breast cancer treatment. Flavonoids have become an important scaffold in medicinal chemistry due to its bioactivity and availability. Therefore, flavonoids were used as the database on this in silico research. Fragment-based drug design was applied to determine novel drug candidates. Three potential candidates were obtained in this research. VC-962 was selected as the best inhibitor candidates for HER2 tyrosine kinase.

Monitoring the Crosstalk Between the Estrogen Receptor and Human Epidermal Growth Factor Receptor 2 with PET

PurposeOvarian cancer (OC) leads to poor survival rates mainly due to late stage detection and innate or acquired resistance to chemotherapy. Thus, efforts have been made to exploit the estrogen receptor (ER) and human epidermal growth factor receptor 2 (HER2) to treat OC. However, patients eventually become resistant to these treatments as well. HER2 overexpression contributes to the acquired resistance to ER-targeted treatment. Trastuzumab treatment, on the other hand, can result in increased expression of ER, which, in turn, increases the sensitivity of the tumors towards anti-estrogen therapy. More insight into the crosstalk between ER and HER2 signaling could improve our knowledge about acquired resistance in ovarian cancer. The aim of this study was to evaluate whether PET could be used to detect changes in ER expression induced by HER2-targeted treatment in vivo.ProceduresMale athymic nude mice were subcutaneously (sc) inoculated with 106 SKOV3 human ovarian cancer cells (HER2+/ER+). Two weeks after inoculation, tumor-bearing mice were treated intraperitoneally with either vehicle, the HER2 antibody trastuzumab (20 mg/kg, 2×/week), or the HER2-tyrosine kinase inhibitor lapatinib (40 mg/kg, 5 days/week) for 2 weeks. Thereafter, ER expression in the tumor was assessed by PET imaging with 16α-[18F]-fluoro-17β-estradiol ([18F]FES). Tumors were excised for ex vivo ER and HER2 measurement with Western blotting and immunohistochemistry.ResultsAll treatments led to smaller tumors than vehicle-treated tumors. Higher [18F]FES maximum standardize tumor uptake (SUVmax) was observed in animals treated with trastuzumab (+ 29 %, P = 0.002) or lapatinib (+ 20 %, P = 0.096) than in vehicle-treated controls. PET results were in agreement with ex vivo analyses.ConclusionFES-PET imaging can detect changes in ER expression induced by HER2-targeted treatment and therefore can be used to investigate the crosstalk between ER and HER2 in a noninvasive manner.

Abstract GS6-04: Co-occurring gain-of-function mutations in HER2 and HER3 modulate HER2/HER3 activation, breast cancer progression, and HER2 inhibitor sensitivity

Abstract Activating mutations in HER2 (ERBB2) drive the growth of a subset of breast cancers. The HER2 tyrosine kinase inhibitor (TKI) neratinib has shown clinical activity against cancers harboring HER2 activating mutations. Co-occurring HER2 and HER3 (ERBB3) mutations have been reported to co-occur in patients with breast cancer, suggesting the possibility of cooperativity of both oncogenes. Interrogation of the Project GENIE database revealed that gain-of-function missense mutations in HER2 and HER3 exhibit statistically significant co-occurence [q value=0.006 (breast cancer); q=1.01x10−26 (all cancer types)]. On the other hand, HER3 mutations were nearly absent in cancers harboring HER2 in-frame insertions and cancers with HER2 amplification. In breast cancer, co-occurring HER3 mutations were mutually exclusive with PIK3CA mutations, suggestive of potential functional redundancy. Sixty-eight unique breast cancers from cBioPortal, GENIE, and Foundation Medicine were found to harbor co-occurring mutations in HER2 and HER3, the most common of which were L755S, V777L, L869R/Q, and S310F, each with HER3E928G. Computational structural modeling suggested that the E928G substitution in HER3 enhances the interface energy between HER2 and HER3 kinase domains. This was confirmed by co-immunoprecipitation assays in HEK293 cells transfected with wild-type (WT) or mutant HER2 and HER3. This binding was further enhanced between HER3E928G and HER2 missense mutants. Further, structural modeling of L755S, V777L, and L869R/Q in HER2 revealed that each of these mutations increase HER2 kinase activation. Accordingly, each of these HER2 mutants, as well has HER2S310F in the extracellular domain, increased ligand-independent P-HER2 and P-HER3 in HEK293 cells. P-HER3 levels were the highest HEK293 in cells co-expressing HER2 and HER3 mutations. Similar results were observed in MCF10A breast epithelial cells stably expressing mutant HER2 and mutant HER3. Enhanced activation of the PI3K pathway (P-AKT and P-S6) was observed in cells expressing both mutations compared to cells expressing mutant HER2 with HER3WT or vice-versa. MCF10A HER2WT/HER3E982G cells did not form colonies in ligand-free 3D Matrigel assays, whereas cells expressing HER2L755S/HER3WT formed organized acini. In contrast, HER2L755S/HER3E928G acini were highly invasive. Addition of the HER3 ligand neuregulin (NRG) to HER2L755S/HER3WT cells phenocopied the effect of HER3E928G. Interestingly, MCF10A cells expressing the HER2Y772_A775 (YVMA) insertion together with HER3WT also formed invasive acini in the absence of NRG, suggesting that this HER2 insertion mutation is more transforming than HER2 missense mutations. Similar results were obtained with invasion assays using Matrigel-coated chambers. Finally, we examined the effects of HER2/HER3 co-mutations on sensitivity to HER2 inhibitors. Structural analysis was performed of the HER3/HER2 kinase domain complex docked with neratinib. HER3E928G, when bound to HER2, is located close to the neratinib-binding pocket of HER2 and was predicted to reduce HER2/neratinib binding affinity. Similarly, co-expression of HER3E928G reduced the ability of neratinib to inhibit P-HER3, P-AKT, P-S6, and growth of MCF10A cells expressing HER2/HER3 co-mutations. The PI3Kα inhibitor alpelisib restored neratinib sensitivity. Conclusions: Co-expression of mutant HER2 and mutant HER3 promotes ligand-independent HER2/HER association, HER3 phosphorylation, and cancer cell invasion via enhanced activation of the PI3K pathway; this enhanced signaling output is incompletely blocked by neratinib. Therefore, breast cancers expressing co-occurring HER2 and HER3 mutations may require the addition of a PI3Kα inhibitor to a HER2 TKI. Citation Format: Ariella B. Hanker, Harikrishna Sekar Jayanthan, Dan Ye, Chang-Ching Lin, Hiroaki Akamatsu, Jonathan H. Sheehan, James P. Koch, Dhivya R. Sudhan, Monica Red Brewer, Alberto Servetto, Jie He, Vincent A. Miller, Alshad S. Lalani, Jens Meiler, Carlos L. Arteaga. Co-occurring gain-of-function mutations in HER2 and HER3 modulate HER2/HER3 activation, breast cancer progression, and HER2 inhibitor sensitivity [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 GS6-04.

Abstract P1-19-07: Results from plasmaMATCH trial treatment cohort B: A phase II trial of neratinib plus fulvestrant in ER positive breast cancer or neratinib alone in ER negative breast cancer in patients with a HER2 mutation identified via ctDNA screening (CRUK/15/010)

Abstract Background: HER2 mutations occur in approximately 3% of HER2 non-amplified cancers and include missense substitutions and indels within the tyrosine kinase domain resulting in oncogenic HER2 activation. Neratinib, an irreversible EGFR, HER2 and ERBB4 tyrosine kinase inhibitor, has demonstrated activity in pre-clinical HER2 mutant models, and in a prior phase I trial with HER2 mutations identified through tumour testing. The plasmaMATCH trial Cohort B assessed the efficacy of neratinib in BC patients with a HER2 mutation identified in ctDNA testing. Methods: The plasmaMATCH trial was an open-label, multi-centre, multi-cohort platform trial, consisting of ctDNA testing in ~1000 patients with advanced BC. Patients with a HER2 mutation identified via ctDNA testing were registered to Cohort B. Patients were treated with 240mg neratinib once daily. Patients with ER positive BC were also treated with fulvestrant 500mg intramuscularly on Cycle 1 Days 1 and 15, and Cycle 2 onwards every 28 days. The primary endpoint for Cohort B was confirmed objective response rate as defined by RECIST v1.1. Using a single stage A’Hern design with a target response rate of 25%, unacceptable response rate of 5%, alpha=5% and power=80%, at least 3 responses out of 16 evaluable patients were required to infer efficacy. Results: Following ctDNA testing, 21 patients enrolled in Cohort B (58% of patients with HER2 mutations identified in ctDNA testing). Eighteen (86%) were ER positive, 2 (10%) were HER2 amplified, and 18 (86%) had visceral metastases. The most common HER2 mutations detected in baseline plasma were L755S (47.6%), V777L (19%), and S310F (14.3%). In the 20 evaluable patients, confirmed response rate was 25.0% (95%CI 8.7-49.1%, 5/20) (first 16 evaluable patients: 4/16, 25.0% (95%CI 7.3-52.4)). One patient had a complete response, ongoing at 29 months duration, and three additional patients had unconfirmed partial responses. Median progression free survival was 5.4 months (IQR 3.4-9.1) and median duration of response was 5.7 months (IQR 3.7-9.7 months) with 3 patients continuing on treatment. The most common clinically significant grade 3 or 4 adverse events were diarrhoea (20%) and hypertension (15%). Conclusions: Neratinib, with or without fulvestrant, was active in advanced BC patients with HER2 mutations identified in ctDNA testing, meeting the pre-specified threshold for efficacy. Citation Format: Andrew M Wardley, Lucy Kilburn, Sarah Kernaghan, Iain Macpherson, Richard D Baird, Rebecca Roylance, Peter Stephens, Olga Oikonomidou, Jeremy P Braybrooke, Mark Tuthill, Jacinta Abraham, Matthew C Winter, Belinda Kingston, Katie Wilkinson, Judith M Bliss, Alistair Ring, Nicholas Turner, on behalf of the plasmaMATCH Trial Management Group. Results from plasmaMATCH trial treatment cohort B: A phase II trial of neratinib plus fulvestrant in ER positive breast cancer or neratinib alone in ER negative breast cancer in patients with a HER2 mutation identified via ctDNA screening (CRUK/15/010) [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 P1-19-07.

Abstract OT2-01-01: Randomized, double-blind, phase 3 study of tucatinib or placebo in combination with T-DM1 for subjects with unresectable locally-advanced or metastatic HER2+ breast cancer

Abstract Background: Tucatinib is an orally-available, reversible HER2 small molecule tyrosine kinase inhibitor (TKI) being developed as a novel treatment for patients with HER2+ metastatic breast cancer (mBC), including patients with brain metastases. Two key features of tucatinib are its potency and selectivity for HER2, compared to the epidermal growth factor receptor (EGFR). Ado-trastuzumab emtansine (T-DM1) is approved for the treatment of patients with HER2+ mBC after prior treatment with trastuzumab and a taxane. While treatment with T-DM1 has led to significant improvements in progression-free survival (PFS) and overall survival, further improvements in therapy are needed, especially for patients with active brain metastases. Based upon evidence that dual targeting of HER2 may lead to further improvements in efficacy in mBC, a phase 1b trial enrolled subjects with HER2+ mBC, previously treated with trastuzumab and taxane, to receive tucatinib (300 mg orally [PO] twice a day [BID]) with T-DM1 (Borges et al, 2018). Forty-six percent of these subjects had received prior pertuzumab. The combination of tucatinib with T-DM1 demonstrated a median PFS of 8.2 months (95% CI, 4.8-10.3) and an objective response rate of 47% in subjects with measurable disease. Sixty percent of subjects treated with this combination had baseline brain metastases and showed a brain-specific response rate (using modified RECIST v1.1 criteria) of 36% in subjects with measurable central nervous system disease. Tucatinib with T-DM1 was found to have a tolerable safety profile, the most common adverse events were nausea (72%), diarrhea (60%), and fatigue (56%), with the majority of events being grade 1 or 2. This encouraging clinical activity, including in subjects with brain metastases, provides rationale for a randomized trial to further evaluate this combination. Study Design: This is a randomized, double-blind, placebo-controlled, international, multicenter, phase 3 study designed to evaluate the efficacy and safety of tucatinib in combination with T-DM1 in subjects with unresectable locally-advanced or metastatic HER2+ breast cancer. Subjects must have had prior treatment with a taxane and trastuzumab in any setting (adjuvant, neoadjuvant, or metastatic). The primary objective of the study is to compare PFS between the treatment arms per investigator assessment, with overall survival as a key secondary endpoint. In this study, subjects must be ≥18 years, with an ECOG of ≤1 and have histologically confirmed HER2+ mBC. Prior treatment with any investigational anti-HER2 or anti-EGFR agent or HER2 TKI agent is not permitted. Prior pertuzumab therapy is allowed, but not required. Subjects with stable, progressing, or untreated brain metastases not requiring immediate local therapy, are eligible for inclusion in the trial. Approximately 460 subjects will be randomized 1:1 to receive 21-day cycles of either tucatinib (300 mg PO BID) or placebo in combination with T-DM1 (3.6 mg/kg intravenously). Disease response and progression will be assessed using RECIST v1.1. While on study treatment, radiographic disease evaluations will be performed every 6 weeks for the first 24 weeks, and every 9 weeks thereafter. A subset of subjects will participate in a pharmacokinetic substudy. Citation Format: Sara Hurvitz, Linda Vahdat, Nadia Harbeck, Antonio C Wolff, Sara M Tolaney, Sherene Loi, Norikazu Masuda, Cassie Dong, Luke Walker, Evelyn Rustia, Virginia Borges. Randomized, double-blind, phase 3 study of tucatinib or placebo in combination with T-DM1 for subjects with unresectable locally-advanced or metastatic HER2+ 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 OT2-01-01.

HER2 Tyrosine Kinase Inhibitors in the Sensitization to Cancers Resistant to HER2 Antibodies.

Human epidermal growth factor receptor (HER2) is a well-established histopathological marker. It is aberrantly expressed in various cancers, predominantly in breast cancer. HER2 protein overexpression and/or HER2 gene amplification induces HER2 dimerization, tyrosine kinase (TK) phosphorylation, activation of different signaling pathways including the mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) pathways, and hence, carcinogenesis. HER2 antibodies like trastuzumab and pertuzumab act on the extracellular domain (ECD) of the HER2 receptor. These were developed to treat HER2-overexpressing or amplified cancers. These effectively inhibit HER2 dimerization and, hence, further signaling. However, antibody resistance and, thereby, disease relapse have emerged as serious concerns. HER2 splicing, cross-signaling, and intracellular alterations are the most common factors causing HER2-antibody resistance. To overcome the therapeutic resistance associated with trastuzumab, TK inhibitors (TKIs) were developed. These bind to the intracellular TK domain and inhibit TK phosphorylation and, therefore, signaling. Though less selective, TKIs have been reported to show activity against HER2 spliced variants and inhibit breast cancers resistant to HER2 antibodies. However, these have not really been established as monotherapeutic agents and have remained as alternative therapeutics only on the account of resistance, toxicity, and poor pharmacokinetic profile. These issues can be resolved by employing combination treatment regimens including HER2-antibody and HER2 TKI. The HER2 TKI in conjunction with HER2 antibody sensitize the refractory HER2-positive cancers towards HER2-anti-body therapy. In addition, these act synergistically with the HER2-antibody resulting in an additive clinical response in patients. This chapter will explore various HER2 TKIs- lapatinib, neratinib, afatinib, sapitinib, CP-724,714, dacomitinib, tucatinib, pyrotinib, and poziotinib as promising clinical tools in sensitizing resistant cancers to HER2 antibodies.

685TiP - A phase II basket study of MCLA-128, a bispecific antibody targeting the HER3 pathway, in NRG1 fusion-positive advanced solid tumours

685TiP - A phase II basket study of MCLA-128, a bispecific antibody targeting the HER3 pathway, in NRG1 fusion-positive advanced solid tumours