HER2-targeted Tyrosine Kinase Inhibitors Research Articles

Clinical and structural insights into the rare but oncogenic HER2-activating missense mutations in non-small cell lung cancer: a retrospective ATLAS cohort study

BackgroundUnlike human epidermal growth factor receptor 2 (HER2) amplification or exon 20 insertions, missense mutations in the extracellular domain (ECD), transmembrane domain (TMD), and intracellular domain (ICD) of the HER2 protein have been implicated as oncogenic in non-small cell lung cancer (NSCLC). However, their molecular subtypes, structural disparities, and clinical responses to current medical treatments, particularly HER2-targeted tyrosine kinase inhibitors (TKIs), remain unclear in NSCLC and warrant investigation.MethodsA real-world observational ATLAS study was conducted to gather and analyze therapeutic outcomes of chemotherapy or TKIs for heterogeneous HER2 missense mutations in NSCLC. Computational models of typical ECD, TMD, and ICD mutations were utilized to explore their structural variances.ResultsWe screened 37 eligible patients with HER2-activating missense mutations, of which 35 patients who had received chemotherapy or HER2-targeted TKIs as first-line therapy were available for response assessment. The median progression-free survival (PFS) for chemotherapy was 4.43 months (95% confidence interval [CI], 3.77–5.10), with an objective response rate (ORR) of 26.1% (6/23) and a disease control rate (DCR) of 17/23 (73.9%). The administration of afatinib, dacomitinib, and pyrotinib, HER2-targeted TKIs, achieved a median PFS of 4.65 months, with an ORR of 33.3% (4/12) and a DCR of 83.3% (10/12). Molecular modeling and computational simulations of ECD, TMD, and ICD mutations revealed their distinct structural characteristics.ConclusionIn comparison to chemotherapy, HER2-targeted TKIs demonstrated similar activity and PFS benefits for HER2-activating missense mutations in NSCLC.

Tucatinib-trastuzumab-capecitabine for treatment of leptomeningeal metastasis in HER2+ breast cancer: TBCRC049 phase 2 study results.

2018 Background: Treatment options for patients with leptomeningeal metastasis (LM) are limited and prognosis is poor. Tucatinib is a potent, highly selective HER2-targeted tyrosine kinase inhibitor. The combination of tucatinib-trastuzumab-capecitabine is approved for patients with metastatic HER2+ breast cancer, with or without brain metastases, who have received ≥ 1 prior HER2-based regimens in the metastatic setting. Patients with LM were excluded from HER2CLIMB (NCT02614794). The aim of this study was to determine the benefit of this regimen in patients with HER2+ breast cancer and LM. We previously reported preliminary efficacy data, with a median OS of 10 months and a median time to CNS progression of 6.9 months. Here, we present additional data on LM objective response, provider-rated neurologic clinical exam, and patient-reported outcomes (PRO). Methods: TBCRC049 (NCT03501979) is an investigator-initiated phase 2 study evaluating a tucatinib-trastuzumab-capecitabine regimen in adults with HER2+ breast cancer and newly diagnosed LM. Eligible patients had a Karnofsky performance status > 50 and untreated LM (defined as positive CSF cytology and/or radiographic evidence of LM plus clinical signs/symptoms). In 21-day cycles, patients received PO tucatinib, PO capecitabine, and IV trastuzumab. The primary endpoint was OS. LM objective response was assessed using a composite of neuroaxis imaging, neurologic clinical exam, and CSF cytology, derived from RANO-LM. The clinical exam incorporated the NANO scoring tool and symptom evaluation using MDASI-BT. Up to 4 provider-rated baseline target neuro deficits were monitored. An imaging scorecard was used. PROs were assessed using the LASA and MDASI-BT tools. Results: Enrollment was planned for 30 patients but closed at 17 patients following FDA approval of tucatinib (April 2020). All patients (median age 53 years) had MRI evidence of LM, 15 (88%) were symptomatic, and 8 (47%) had abnormal CSF cytology. At data cutoff (7/20/21), 5 (38%) of 13 response-eligible patients achieved LM objective response per the composite criteria at first response assessment, and all 13 (100%) achieved clinical benefit (SD, PR, or CR). Notably, 7 (58%) of 12 evaluable patients with target neurologic deficits at baseline experienced improvement of deficits. All 17 completed ≥ 75% of LASA and MDASI-BT PRO questionnaires at pre-specified timepoints. The mean improvement in LASA score was 13.5, indicating improved QOL and the mean improvement in MDASI-BT score was 32, indicating improved symptom burden. Conclusions: This is the first prospective evidence of clinically meaningful benefit including objective responses, symptom improvement, and quality of life, along with extended survival, with a systemic regimen for LM from HER2+ BC. These data support the trend toward using systemic therapy as an initial approach in CNS metastases. Clinical trial information: NCT03501979 .

Tucatinib and stereotactic radiosurgery in the management of HER2 positive breast cancer brain metastases.

HER2-positive breast cancer has a high risk of brain metastasis. Stereotactic radiosurgery (SRS) is standard of care for limited brain metastases. Tucatinib, a HER2-targeted tyrosine kinase inhibitor, has demonstrated intracranial efficacy in the HER2-CLIMB Trial. However, it is unknown whether tucatinib with SRS is safe or effective. A retrospective analysis of HER2-positive breast cancer treated with SRS and tucatinib for brain metastases management was performed. All patients received tucatinib and SRS for the management of active brain metastases. The primary endpoint was local and distant brain tumor control. Secondary endpoints were intracranial progression free survival (CNS-PFS), systemic PFS, overall survival (OS), and neurotoxicity. A total of 135 lesions treated with SRS over 39 treatment sessions in 22 patients were identified. Median follow-up from tucatinib initiation was 20.8months. Local brain control was 94% at 12-months and 81% at 24-months. Distant brain control was 39% at 12-months and 26% at 24-months. Median survival was 21.2months, with 12- and 24-month OS rates of 84% and 50%, respectively. Median CNS-PFS was 11.3months, with 12- and 24-month CNS-PFS rates of 44.9% at both time points. Median systemic PFS was not reached, with 12- and 24-month systemic PFS rates of 86% and 57%, respectively. Symptomatic radiation necrosis occurred in 6 (4%) lesions. No additional unexpected toxicities were noted. SRS in combination with tucatinib, capecitabine, and trastuzumab appears to be a safe and feasible treatment for HER2 + brain metastases. Further prospective evaluation of potential synergistic effects is warranted.

Abstract 4017: TAS2940 inhibits intracranial tumor growth and prolongs survival in HER2-aberrant and EGFR-amplified patient-derived xenograft models

Abstract Patients with brain tumors and metastases have poor prognosis and overall survival rates despite the advancements in neurosurgery, radiotherapy, and chemotherapy. Genomic alterations in HER2 are present in brain metastases of breast cancer (BC; ~20%) and non-small cell lung cancer (NSCLC; 13-20%), and EGFR alterations occur frequently in glioblastoma multiforme (GBM; >50%). Despite the advancements in standard of care options, optimal treatment management for these patients remains an unmet medical need. Recent evidence suggests activity of systemic therapy for immune and targeted therapies in the brain, including agents targeting HER2/EGFR. HER2-targeted tyrosine kinase inhibitors lapatinib, neratinib, and tucatinib and the HER2-targeted antibodies trastuzumab and pertuzumab, in combination with chemotherapy, have been shown to improve survival of patients with HER2 overexpressing BC in the presence of brain metastases. The limited penetration of these compounds into the CNS, however, limits their efficacy. TAS2940 is an irreversible pan-ErbB inhibitor with greater brain-penetrability than poziotinib, tucatinib, and neratinib. Here, we demonstrate that TAS2940 induces downregulation of phosphorylated HER2/EGFR, reduces tumor burden, and promotes a significant increase in survival in intracranial xenograft mouse models with HER2-amplification (BC), HER2-Exon20 insertion mutation (NSCLC), and EGFR-amplification (GBM). These promising preclinical data highlight potential novel therapeutic strategies for patients with EGFR-aberrant GBM and brain metastases harboring HER2/EGFR alterations, and may help support the advancement of the ongoing first-in-human clinical trial (NCT04982926) for TAS2940 in solid tumors with EGFR and/or HER2 alterations. Citation Format: Jing Han, Mikhila Mahendra, Poojabahen Gandhi, Joseph R. Daniele, Caroline C. Carrillo, Benjamin J. Bivona, Ningping Feng, John V. Heymach, Funda Meric-Bernstam, Kei Oguchi, Shinji Mizuarai, Timothy P. Heffernan, Christopher P. Vellano, Joseph R. Marszalek. TAS2940 inhibits intracranial tumor growth and prolongs survival in HER2-aberrant and EGFR-amplified patient-derived xenograft models. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4017.

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.

Abstract OT3-25-02: Inetetamab combined with pyrotinib and Chemotherapy in Pretreated Patients with HER2-positive metastatic breast cancer, a single arm, multicenter phase II clinical trial

Abstract Background: The HER2-targeted drugs selection after trastuzumab failure has become a challenging issue for HER2-positive metastatic breast cancer (MBC) patients. Inetetamab is a neotype of HER2-targeted monoclonal antibody with an engineered Fc segment that optimizes the antibody-dependent cell-mediated cytotoxicity (ADCC) effect, which was important for disease control. Moreover, HER2-targeted tyrosine kinase inhibitors, as pyrotinib, were found to further improve the ADCC effect of monoclonal antibodies in pre-clinical researches, indicating that the combination of pyrotinib and inetetamab could achieve complementarity and synergy effects in terms of short-term tumor killing effect and long-term immunotherapy benefits. Therefore, the combined treatment pattern of the two drugs has potential clinical benefits. Methods: This is a prospective, multi-center, single-arm clinical study designed to evaluate the efficacy and safety of pretreated patients with HER2-positive MBC. We recruited patients with pathologically confirmed HER2-positive MBC who had received 1-3 prior regimens for metastatic disease, which must include trastuzumab. The enrolled patients received 6 cycles of Inetetamab combined with pyrotinib and chemotherapy, subsequent maintenance therapy should be considered according to tolerability. The chemotherapy drugs were decided by physicians’ choice, and could be microtubules, anthracyclines, or antimetabolites. The primary endpoint was objective response rate (ORR) after 6 cycles of treatment, secondary endpoints included progression-free survival (PFS), overall survival (OS), and clinical benefit rate (CBR) and adverse events (AEs). Results: 57 patients were enrolled from October 2020 to July 2022. And 45 patients were available for response evaluation. The ORR and DCR were 53.5 % (24/45) and 86.7 % (39/45), respectively after 6 cycles treatment. The median PFS was 7.3 months. The incidence of grade Ⅲ-Ⅳ AEs was 15.8 %. The most common treatment-related AEs were diarrhea, anemia, neutropenia, leukopenia, hand and foot syndrome. No patient’ s left ventricle ejection fraction (LVEF) decreased to < 50% or decreased by >15%. And no significant decline in quality of life score was reported. Conclusion: Inetetamab combined with pyrotinib and chemotherapy showed a promising efficacy and a good tolerance in patients with HER2-positive metastatic breast cancer, confirming the synergistic effect between the ADCC optimized monoclonal antibodies and TKIs, which brings more treatment options for HER2-positive metastatic breast cancer. Citation Format: Jianli Zhao, Yangyang Cai, Linxiaoxiao Ding, Yaping Yang, Guorong Zou, Herui Yao, Ying Wang. Inetetamab combined with pyrotinib and Chemotherapy in Pretreated Patients with HER2-positive metastatic breast cancer, a single arm, multicenter phase II clinical trial [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 OT3-25-02.

Pyrotinib combined with apatinib for targeting metastatic non-small cell lung cancer with HER2 alterations: a prospective, open-label, single-arm phase 2 study (PATHER2)

BackgroundAlthough targeted agents have been gradually applied in the treatment of HER2-mutated non-small cell lung cancer (NSCLC) in recent years, patients’ therapeutic demands are far from being met. PATHER2 was the first phase 2 trial to explore the efficacy and safety of the HER2-targeted tyrosine kinase inhibitor (TKI) pyrotinib plus the antiangiogenic agent apatinib in previously treated HER2-altered metastatic NSCLC patients.MethodsHER2-mutated or HER2-amplified metastatic NSCLC patients who had failed at least first-line chemotherapy or HER2-targeted TKIs received oral pyrotinib 400 mg plus apatinib 250 mg once daily until disease progression, intolerable toxicity, or death. The primary endpoint was the investigator-assessed objective response rate (ORR).ResultsBetween March 2019 and December 2020, 33 patients were enrolled; 13 (39.4%) presented brain metastases, and 16 (48.5%) had received at least two lines of prior chemotherapy or HER2-targeted TKIs. As of September 20, 2021, the median follow-up duration was 11.3 (range, 3.5–26.0) months. The investigator-assessed ORR was 51.5% (17/33; 95% CI, 33.5 to 69.2%), and the disease control rate was 93.9% (31/33; 95% CI, 79.8 to 99.3%). The median duration of response, progression-free survival, and overall survival were 6.0 (95% CI, 4.4 to 8.6) months, 6.9 (95% CI, 5.8 to 8.5) months, and 14.8 (95% CI, 10.4 to 23.8) months, respectively. The most frequent grade ≥ 3 treatment-related adverse events included diarrhea (3.0%) and hypertension (9.1%). No treatment-related deaths were reported.ConclusionsPyrotinib plus apatinib demonstrated promising antitumor activity and a manageable safety profile in HER2-mutated or HER2-amplified metastatic NSCLC patients.Trial registrationChinese Clinical Trial Registry Identifier: ChiCTR1900021684.

53P ‘HER2-LOW’ breast cancer brain metastases: An opportunity for targeted systemic therapies in a high-need patient population

The landscape of systemic therapies available for treating BrM has recently expanded to include new HER2-targeted tyrosine kinase inhibitors and antibody-drug conjugates for patients with HER2-positive metastatic breast cancer (MBC). Given that HER2-targeted therapies are now being investigated among patients whose disease does not meet established cut points for HER2 expression, we examined the proportion of patients with “HER2-low” in breast cancer brain metastases BrM.

Specific HER2 Exon 20 Gly776 Deletion-Insertions in Non-Small Cell Lung Cancer: Structural Analysis and Sensitivity to HER2-Targeted Tyrosine Kinase Inhibitors.

Background: HER2 exon 20 insertions remain a subset heterogeneous alterations in lung cancer, with currently unmet need for precision targeted therapy. G776delinsVC, a typical HER2 exon 20 deletion-insertion at codon Gly776, was reported to respond discrepantly to afatinib compared with the predominant insertion A775_G776insYVMA (YVMA). However, it lacks structural evidence to illustrate the possible mechanism and predict the binding activities of its similar variants over YVMA insertion to HER2-targered tyrosine kinase inhibitors (TKIs). Methods: Real-world cohort study was performed to investigate clinical outcomes with HER2-targeted TKI afatinib and pyrotinib, and structural analysis for exon 20 Gly776 deletion-insertions G776delinsVC, G776delinsLC and G776delinsVV, and YVMA by molecular dynamics simulation and cellular kinase inhibition assay were provided for full exploration. Results: Afatinib revealed low objective response rate (ORR) of 0–9.5% and short median progression-free survival (mPFS) of 2.8–3.2 months for YVMA, but with higher ORR of 20–28.6% and longer mPFS of 4.3–7.1 months for G776delinsVC. Pyrotinib presented significantly improved PFS benefit than afatinib for G776delinsVC and YVMA as first-line (median, 6.8 vs. 3.4 months, p = 0.010) or second-line therapy (median, 5.8 vs. 2.8 months, p < 0.001). No significant difference was observed on drug binding pocket and TKI binding activity between G776delinsVC, G776delinsLC and G776delinsVV, and both afatinib and pyrotinib showed favorable binding activity. YVMA insertion significantly affected the loop region with altering HER2 protein secondary structure and forming steric hindrance to binding of afatinib. Pyrotinib showed the best selectivity to HER2, with more favorable activity to YVMA than afatinib indicated by cellular inhibition assay. Conclusion: Both afatinib and pyrotinib showed favorable activity for NSCLC patients with HER2 exon 20 Gly776 deletion-insertions. Pyrotinib revealed more potent activity to A775_G776insYVMA insertion than afatinib due to the steric binding hindrance induced by YVMA.

Abstract P2-13-36: Comparative time course analysis of the effects of neratinib, lapatinib and tucatinib in an in vitro HER2+ breast cancer model

Abstract Introduction: Human epidermal growth factor 2 (HER2/ErbB2) is overexpressed in approximately 20% of breast cancers. The HER2-targeted tyrosine kinase inhibitors (TKIs) neratinib, lapatinib and tucatinib are all FDA-approved for the treatment of HER2-positive breast cancer. All three inhibit the HER2 kinase domain but differ in binding characteristics (the irreversible neratinib vs reversible lapatinib and tucatinib) and their affinity for other HER family members. The aim of this study was to carry out kinetic analysis of the effect of the three TKIs on HER family signalling, cellular proliferation, and apoptosis induction in a cell model of breast cancer. Methods: In this study, the anti-proliferative effects of the three TKIs were assessed in the HER2-amplified breast cancer cell line SKBR3 by acid phosphatase assay (5-day endpoint assay) and with the IncuCyte→ live-cell imaging system over 120 hours. TKI IC50 values were calculated using CalcuSyn software. Apoptotic cells were detected every 3 hours for 5 days using the Incucyte→ Caspase 3/7 dye. Western blotting was used to investigate the time course effects (15 min, 6 h, 24 h, 72 h) of the TKIs on the expression and phosphorylation of EGFR, HER2 and on their downstream effectors ERK1/2 and Akt. Results: All three TKIs displayed nanomolar activity against SKBR3 cells. Neratinib showed the greatest anti-proliferative effect (IC50 = 3.4 ± 1.1 nM), followed by tucatinib (IC50 = 37.5 ± 18.4 nM) and lapatinib (IC50 = 51.0 ± 23.0 nM). 50 nM neratinib induced higher activation of caspase 3/7 than 500 nM lapatinib or 500 nM tucatinib. Total levels of HER2 and EGFR were increased in the presence of lapatinib and tucatinib, but decreased in the presence of neratinib. The three drugs (500 nM) significantly inhibited the activation of EGFR and HER2 at 15 min. From 6 h to 72 h, treatment with 5 nM and 50 nM neratinib resulted in greater inhibition of phosphorylated HER2 and EGFR, compared to the equivalent concentration of lapatinib or tucatinib. All three TKIs (500 nM) inhibited the activity of phospho-Akt at the earliest timepoint (15 min), but a strong impact on downstream ERK1/2 phosphorylation was not observed until the 6h timepoint. 50 and 500 nM neratinib was more effective at preventing reactivation of ERK1/2 and Akt phosphorylation than either 500 nM lapatinib or tucatinib at 72 h. Conclusion: These data highlight the differences in in vitro efficacy of the three HER2-targeting TKIs currently approved for the treatment of HER2+ breast cancer in the clinic. Neratinib inhibits HER2 and EGFR at lower concentrations and for longer compared to lapatinib and tucatinib, resulting in increased apoptosis induction. This may be due to the irreversible nature of neratinib binding, as opposed to the reversible nature of lapatinib and tucatinib binding. Further comparative studies between neratinib, lapatinib and tucatinib are warranted to explore the impact of varied pre-clinical characteristics on the emergence of therapeutic resistance. Citation Format: Myra E Castel, Neil T Conlon, Naomi Walsh, Irmina Diala, Lisa Eli, John Crown, Denis M Collins. Comparative time course analysis of the effects of neratinib, lapatinib and tucatinib in an in vitro HER2+ breast cancer model [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 P2-13-36.

Abstract PD4-02: Safety and efficacy of a tucatinib-trastuzumab-capecitabine regimen for treatment of leptomeningeal metastasis (LM) in HER2-positive breast cancer: Results from TBCRC049, a phase 2 non-randomized study

Abstract Background: Treatment options for patients (pts) with leptomeningeal metastasis (LM) are limited, and the prognosis is poor (median overall survival (OS) ~ 4-5 months). Tucatinib is a potent and highly selective HER2-targeted tyrosine kinase inhibitor approved for use in combination with trastuzumab and capecitabine in pts with metastatic HER2+ breast cancer who have received ≥1 prior HER2-based regimen in the metastatic setting, including pts with brain metastases. TBCRC049 (NCT03501979) is an investigator-initiated, phase 2, single-arm study evaluating the safety and efficacy of tucatinib, trastuzumab and capecitabine in HER2+ breast cancer with newly diagnosed LM. We have previously demonstrated therapeutic levels of tucatinib in CSF in pts with HER2+ LM (Stringer-Reasor et al, ASCO 2021). We now report efficacy outcomes of the study. Methods: Eligible pts were adults with HER2+ metastatic breast cancer, Karnofsky performance status (KPS) &amp;gt; 50, and newly diagnosed, untreated LM (defined as positive CSF cytology and/or radiographic evidence of LM, plus clinical signs/symptoms). Pts with treated or concurrent/new brain metastases were allowed. Pts received tucatinib 300 mg orally twice daily starting with cycle 1, day 1 (C1D1); capecitabine 1000 mg/m2 orally twice daily on days 1-14 of a 21-day cycle, starting on C1D1; and trastuzumab loading dose of 8 mg/kg IV on C1D1, and then 6 mg/kg IV once every 21 days, starting with C2D1. The primary endpoint was OS. Planned enrollment was 30 pts; however, due to lack of accrual since the FDA approval of tucatinib (4/2020), the study was closed after 17 patients were enrolled. Results: Baseline disease characteristics at LM diagnosis are shown in Table 1. Eight pts (47%) had abnormal CSF cytology (positive or equivocal). All pts had MRI evidence of LM in the brain, and 14/17 (82%) had brain metastases, of which 11 (65%) had received prior treatment for brain metastases. Median age at study treatment initiation was 53 years. Median number of treatment cycles received was 5 (range: 2-27). Median OS time was 11.9 months (95% CI: 4.1, NR). At data cutoff (6/22/21), 7/17 pts (41%) remained alive and median followup was 17 months(8-26). Median time to CNS progression was 6.9 months (95% CI: 2.8, 13.8). Conclusions: In pts with LMD from HER2+ metastatic breast cancer who were treated with tucatinib, trastuzumab, and capecitabine, the median OS time was nearly 1 year. This is the first prospective evidence of clinical benefit with a systemic regimen for HER2+ LM. Further studies evaluating brain-penetrant oral drugs in this rare pt population are needed. Baseline Disease Characteristics (N=17)Number%Baseline CSF cytologyPositive529%Negative847%Equivocal318%None obtained1*6%Symptoms attributable to LMDYes1588%No212%MRI evidence of LMDBrain only1165%Brain and Spine635%History of brain metastasisYes1482%Prior treatment1165%New/concurrent diagnosis – no prior treatment318%No318%Extra-CNS DiseaseYes1165%No635%*One patient had VP shunt and difficulty sampling fluid; all CSF sent for research PK and non-PK studies Citation Format: Rashmi K Murthy, Barbara O'Brien, Donald A Berry, Akshara Singareeka-Raghavendra, Maria Gule Monroe, Jason Johnson, Jason White, Jennifer Childress, Justin Sanford, Jill Schwartz-Gomez, Michelle Melisko, Aki Morikawa, Sherise Ferguson, John F de Groot, Ian Krop, Vicente Valero, Mothaffar Rimawi, Antonio Wolff, Debu Tripathy, Nancy U Lin, Erica Stringer-Reasor. Safety and efficacy of a tucatinib-trastuzumab-capecitabine regimen for treatment of leptomeningeal metastasis (LM) in HER2-positive breast cancer: Results from TBCRC049, a phase 2 non-randomized study [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 PD4-02.

Abstract PD4-05: Preclinical and clinical efficacy of trastuzumab deruxtecan in breast cancer brain metastases (BCBM)

Abstract Purpose: Up to half of patients (pts) with HER2+ metastatic breast cancer (MBC) will develop BCBM. Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate (ADC) with demonstrated efficacy in previously treated pts with HER2+ MBC. However, few pts with stable/treated brain metastases, and no pts with active (untreated or progressive) brain metastases, were included in completed clinical trials of T-DXd. Thus, central nervous system (CNS) efficacy of T-DXd is not well-characterized. Methods: We tested T-DXd in orthotopic pt BCBM-derived xenograft (PDX) models of HER2+, and HER2-low, BCBMs. To further validate T-DXd single agent CNS activity, we described clinical outcomes of T-DXd in a multi-institutional retrospective cohort of 16 patients with BCBM. Consecutive pts who initiated T-DXd between 1 Jan 2020 - 1 Nov 2020 (Duke) or 1 Jan 2020 - 15 June 2020 (Dana-Farber Cancer Institute) were included. Data cut-off date was 31 Dec 2020. CNS response was measured by via central radiology review at each participating institution. Up to 5 CNS target lesions were included. CNS partial response (PR) required &amp;gt;30% reduction in sum of CNS target lesions. Results: Treatment with 10 mg/kg T-DXd significantly prolonged survival in HER2+ BCBM PDX models DFBM-354 (67 vs 154 days, p=0.0018) and DFBM-355 (78 vs 156 days, p=0.0067) vs. vehicle control. We then tested TDX-d in a HER2 low BCBM PDX model (IHC 2+/FISH ratio &amp;lt;2) and found that c.f. vehicle, TDX-d significantly prolonged survival (72 v 141 days, p = 0.02). Finally, we treated DFBM-355 with trastuzumab emtansine (T-DM1) to generate resistance followed by treatment with T-DXd. We found that c.f. vehicle or continued T-DM1, T-DXd significantly prolonged survival in a T-DM1 resistant BCBM PDX model (63 vs 99 vs 215 days, p=0.01). In the retrospective cohort, median age was 44 (33-69 years). 15/16 pts had confirmed HER2 IHC 3+ or FISH-positive primary or metastatic tissue. 9/16 (56%) pts had either progressive or untreated HER2+ BCBMs on initiation of T-DXd. Median number of prior metastatic therapies was 4 (0-10). 14/16 (88%) had received previous T-DM1; 11/16 (69%) had received previous HER2-targeted tyrosine kinase inhibitor. Median time from previous CNS radiation was 15.1 months (1.3 - 45.2). At the time of data cutoff, 7 pts remained on T-DXd. Median number of cycles was 7 (2-17+). Responses are shown in Table 1. The overall intracranial clinical benefit rate (CR/PR or stable disease) was 75%, including 89% (8/9) of those with progressive or untreated BCBM at baseline. Conclusions: In a multi-institution cohort of 16 pts with HER2+ BCBMs treated with T-DXd, we find preliminary evidence of CNS efficacy, including in pts with progressive or untreated BCBMs. Additional pt data and further follow up will be presented at the meeting. Using BCBM PDX models we find that T-DXd prolongs survival in untreated HER2+ BCBM PDX models as well as in T-DM1 treated models. We also demonstrate efficacy of T-DXd in a HER2 low BCBM PDX model. Together, these data suggest that T-DXd has intracranial efficacy against HER2+ BCBMs. Prospective clinical trials in this pt population are warranted. Table 1.Best CNS Response of study cohortOverall population (n=16)Pts with progressive or untreated CNS disease at baseline (N=9)Pts with stable/treated CNS disease at baseline (N=7)Complete response (CR)0 (0)00 (0)Partial response (PR)10 (63)6 (67)#4 (57)+Stable disease (SD)2 (13)2 (22)0 (0)Progressive disease (PD)1 (6)0 (0)1 (14)No measurable CNS disease at baseline2 (13)0 (0)2 (29)Lost to follow-up1 (6)1 (11)0 (0).#Among these 6 pts, interval between most recent radiation and T-DXd initiation was 14.3 months, 12.4 months, 17 months, 18.2 months, and 8.2 months (one pt was radiation-naïve). +Among these 4 pts, interval between most recent radiation and T-DXd initiation was 19.1 months, 15.1 months, 1.5 months, and 16.9 months, respectively. Citation Format: Sheheryar Kabraji, Jing Ni, Sarah Sammons, Amanda ED Van Swearingen, Yanzhi Wang, Alyssa M Pereslete, Liangge Hsu, Chris Lascola, Heather Moore, Melissa Hughes, Akshara S Raghavendra, Maria Gule-Monroe, Rashmi K Murthy, Eric P Winer, Carey K Anders, Jean J Zhao, Nancy U Lin. Preclinical and clinical efficacy of trastuzumab deruxtecan in breast cancer brain metastases (BCBM) [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 PD4-05.

276P Dalpiciclib, a novel CDK4/6 inhibitor, combined with pyrotinib for HER2+ advanced breast cancer: Interim results of a phase II trial

Given nearly all patients (pts) with human epidermal growth factor receptor 2-positive (HER2+) breast cancer (BC) developed resistance to trastuzumab eventually, novel approaches were urgently needed. This study aimed to evaluate the efficacy and safety of a novel CDK4/6 inhibitor dalpiciclib combined with pyrotinib, a HER2-targeted tyrosine kinase inhibitor (TKI), in HER2+ advanced BC.

Abstract 1371: Pharmacokinetics of tucatinib in healthy and hepatically-impaired volunteers

Abstract Background: Tucatinib (TUKYSA®) is a selective HER2-targeted tyrosine kinase inhibitor indicated in combination with trastuzumab and capecitabine for adult patients with metastatic HER2+ breast cancer who have received ≥1 prior HER2-based regimen, including patients with brain metastases. Tucatinib is cleared via CYP2C8-mediated metabolism, to a lesser extent by CYP3A, and biliary excretion. Impaired hepatic function (HI) can cause alterations in drug disposition and pharmacokinetics (PK), thus characterizing PK in subjects with HI was necessary to inform dosing recommendations. ONT-380-009 was a clinical study conducted to evaluate the PK of tucatinib in volunteers with HI based on Child-Pugh (CP) score compared to matched healthy subject controls. Methods: Volunteers (N=37) at 4 centers were enrolled in the study. Subjects with mild (CP Class A; n=8), moderate (CP Class B; n=8) or severe (CP Class C; n=6) HI were matched to subjects with normal hepatic function (n=15) by age, BMI and sex. Tucatinib was administered as a single 300 mg oral dose. Plasma samples were collected for PK analysis and tucatinib concentrations measured using validated LC-MS/MS methods. The PK and safety profiles between each HI group and matched controls were compared. Results: Tucatinib single dose PK was similar between subjects with mild HI and matched controls (AUCinf and Cmax geometric mean ratios (GMR) [90% CI] were 99.0% [76.3%, 128%] and 104% [61.6%, 175%], respectively). Tucatinib plasma exposures were generally higher in subjects with moderate or severe HI compared to matched controls (AUCinf GMR [90% CI] were 115% [65.3%, 202%] and 161% [67.3%, 385%], respectively; Cmax GMR [90% CI] were 88.5% [42.1%, 186%] and 117% [36.6%, 377%], respectively). Changes were highly variable, and ratios crossed 1.0 (or 100%). The observed trend of increased plasma exposure for tucatinib by degree of HI did not reach statistical significance due to high inter-subject variability. Three subjects experienced a total of two Grade 1 (nausea, dermatitis) and one Grade 2 (increased transaminases) treatment-emergent adverse events (TEAEs) in the study, two of which were considered tucatinib-related. All three TEAEs recovered. No TEAEs were observed in patients with moderate or severe hepatic impairment. Conclusions: Subjects with mild HI had similar tucatinib exposures compared to subjects with normal hepatic function. Tucatinib exposure was generally increased in subjects with moderate and severe HI, however GMR values were less than 2-fold and exhibited large inter-subject variability. Overall, a single 300 mg oral dose of tucatinib was considered safe and well tolerated in this study for subjects with normal hepatic function or with mild, moderate, or severe HI. The 1.6-fold GMR AUCinf increase in severe HI subjects support dose reduction from 300 mg BID to 200 mg BID in those subjects; no dose adjustment is recommended for subjects with mild or moderate HI. Citation Format: Ariel R. Topletz-Erickson, Anthony Lee, JoAl G. Mayor, Hao Sun, Layth I. Abdulrasool, Evelyn L. Rustia, Luke Walker, Christopher J. Endres. Pharmacokinetics of tucatinib in healthy and hepatically-impaired volunteers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1371.

Brain metastases: new systemic treatment approaches

Summary Background Brain metastases (BM) still present a clinical challenge in oncology. Treatment of BM was mainly based on local approaches including neurosurgery and radiation. However, the fraction of patients with asymptomatic BM has risen over the last decade. Recent clinical trials on immune- and targeted therapies showed promising intracranial responses—especially in neurological asymptomatic status. Therefore, systemic treatment presents an emerging therapy approach specifically in patients with asymptomatic BM. Methods The present review highlights the recent advances in systemic therapeutic and preventive approaches in BM focusing on the main BM causing tumors: non-small cell lung cancer (NSCLC), melanoma and breast cancer. Results Remarkable intracranial efficacies were presented for several next-generation tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors, especially in asymptomatic BM patients. In NSCLC, osimertinib and afatinib presented intracranial response rates over 80%. Osimertinib showed even a potential for primary BM prevention. Considerable intracranial response rates were observed for the combination of dabrafenib and trametinib in BRAF mutated melanoma BM. Combined ipilimumab and nivolumab treatment in asymptomatic melanoma BM even presented with similar intra- and extracranial response rates. In breast cancer, HER2-targeted TKIs like lapatinib in combination with chemotherapy, or trastuzumab deruxtecan monotherapy presented also notable intracranial response rates. Conclusion New developments in targeted and immune-modulating therapies have postulated high intracranial efficacies in patients with BM from different solid tumors. However, more BM-specific studies and BM-specific endpoints in registration trials are warranted to underscore the role of systemic treatment in patients with BM.

Pharmacokinetic (PK) analyses in CSF and plasma from TBCRC049, an ongoing trial to assess the safety and efficacy of the combination of tucatinib, trastuzumab and capecitabine for the treatment of leptomeningeal metastasis (LM) in HER2 positive breast cancer.

1044 Background: Tucatinib is a potent and highly selective HER2-targeted tyrosine kinase inhibitor approved for use in combination with trastuzumab and capecitabine for patients with metastatic HER2+ breast cancer (MBC) who have received ≥1 prior HER2-based regimen in the metastatic setting, including patients with brain metastases (BM). TBCRC049 (NCT03501979) is an investigator-initiated phase 2 single-arm study currently enrolling to evaluate the safety and efficacy of tucatinib, trastuzumab and capecitabine in HER2+ BC with newly diagnosed LM. Here, we report the pre-specified pharmacokinetic (PK) analysis for the first 15 patients to determine bioavailability of tucatinib and its predominant metabolite, ONT-993, in the CSF. Methods: Eligible patients included adults with HER2+ MBC, KPS &gt; 50, and newly diagnosed, untreated LM (defined as positive CSF cytology and/or radiographic evidence of LM, plus clinical signs/symptoms). Patients with treated or concurrent/new BM were allowed. The primary endpoint is overall survival with an accrual goal of 30 pts. Parallel PK samples were collected in plasma and CSF via Ommaya reservoir on day 1 of cycles 1 and 2 at 0h (baseline), 2-3h, 5-7h and 24h (optional) following initiation of tucatinib 300 mg BID. Tucatinib and ONT-993 were quantified in plasma (n=15) and CSF (n=13) using validated liquid chromatography-mass spectrometry methods. Results: Tucatinib and ONT-993 plasma concentrations were consistent with previous studies and exhibited high interindividual variability. Tucatinib and ONT-993 were detectable in the CSF within 2 hours post tucatinib administration; concentrations ranged from 0.57 to 25 ng/mL for tucatinib (IC50 for tucatinib against HER2 is 3.3 ng/mL) and 0.28 to 4.7 ng/mL for ONT-993. Tucatinib concentrations in the CSF per timepoint were in a similar range to unbound plasma (plasmaub) tucatinib. CSF to plasmaub ratios were generally consistent over time; the steady-state (cycle 2) median tucatinib CSF to plasmaub ratio was 0.83 (0.19 to 2.1). ONT-993 CSF to plasmaub ratios were similar to tucatinib CSF to plasmaub ratios. Conclusions: In patients with LM from HER2+MBC who were treated with tucatinib, trastuzumab, and capecitabine, tucatinib and ONT-993 were detectable in the CSF of all patients at median levels similar to plasmaub tucatinib. This is the first documented evidence of tucatinib distributing into the CSF in patients with HER2+MBC. Efficacy and safety of tucatinib, trastuzumab, and capecitabine in patients with HER2+ LM will be reported upon completion of TBCRC 049 accrual. Clinical trial information: NCT03501979 .

Abstract PS10-06: Comparative analysis of anti-proliferative effects and gene profiling of lapatinib, neratinib, and tucatinib

Abstract Introduction: Human epidermal growth factor 2 (HER2/ERBB2) is frequently amplified or mutated across various cancer types. The tyrosine kinase inhibitors (TKIs) lapatinib, neratinib, and tucatinib are FDA-approved for the treatment of HER2-positive breast cancer. All three TKIs bind and inhibit the kinase domain of HER2 but differ both in the mechanism of binding and in specificity for other HER family members. Direct comparisons to differentiate the pre-clinical efficacy of the three TKIs have been limited to small-scale studies and novel biomarkers of response to further define appropriate patient populations are required. Methods: In this study, the anti-proliferative effects of the three TKIs were compared using a 115-cancer cell line panel, including 12 breast cancer cell lines and 22 cell lines harbouring point mutations or amplifications of EGFR, HER2, or HER3. Hierarchical clustering analysis was carried out to compare the IC50 “fingerprint” of the three TKIs to 168 other anti-cancer agents. Novel markers of TKI sensitivity and resistance were identified through cross-analysis of each drug response profile with mutation, copy number variation, and gene expression data. Results: All three TKIs were effective against HER2-positive breast cancer models; neratinib showed the most potent activity, followed by tucatinib and lapatinib respectively (Table 1). Neratinib displayed the greatest anti-proliferative activity in HER2-mutant and EGFR-mutant cell lines. Clustering analysis revealed that the anti-proliferative profile of tucatinib was most similar to trastuzumab, while neratinib and lapatinib were most like other HER family inhibitors. Mutation and gene expression analysis identified potential markers of response for each TKI. High expression of four genes (HER2, VTCN1, CDK12, and RAC1) correlated with response to all three TKIs. DNA damage repair genes were significantly associated with resistance to the HER2-targeted TKIs. BRCA2 mutation was correlated with neratinib and tucatinib response, and high gene expression of ATM, BRCA2, and BRCA1 were all associated with neratinib resistance. Conclusions: Neratinib was the most effective HER2-targeted TKI against HER2-amplified, -mutant, and EGFR-mutant cell lines. This analysis revealed possible mechanisms that may be exploited using combinatorial strategies involving CDK inhibitors, immunotherapies, and targeting DNA repair pathways. Table: IC50 values for neratinib, lapatinib, and tucatinib in the HER2+ breast cancer cell linesIC50 values (nM)Cell linesNeratinibLapatinibTucatinibAU-56520294125BT-4745926229HCC195413814262122MDA-MB-453306228445928SKBR3715222 Citation Format: Neil T Conlon, Jeffrey J Kooijman, Suzanne JC van Gerwen, Winfried R Mulder, Guido JR Zaman, Irmina Diala, Lisa D Eli, Alshad S Lalani, John Crown, Denis Collins. Comparative analysis of anti-proliferative effects and gene profiling of lapatinib, neratinib, and tucatinib [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 PS10-06.

Comparative analysis of drug response and gene profiling of HER2-targeted tyrosine kinase inhibitors

BackgroundHuman epidermal growth factor 2 (HER2/ERBB2) is frequently amplified/mutated in cancer. The tyrosine kinase inhibitors (TKIs) lapatinib, neratinib, and tucatinib are FDA-approved for the treatment of HER2-positive breast cancer. Direct comparisons of the preclinical efficacy of the TKIs have been limited to small-scale studies. Novel biomarkers are required to define beneficial patient populations.MethodsIn this study, the anti-proliferative effects of the three TKIs were directly compared using a 115 cancer cell line panel. Novel TKI response/resistance markers were identified through cross-analysis of drug response profiles with mutation, gene copy number and expression data.ResultsAll three TKIs were effective against HER2-amplified breast cancer models; neratinib showing the most potent activity, followed by tucatinib then lapatinib. Neratinib displayed the greatest activity in HER2-mutant and EGFR-mutant cells. High expression of HER2, VTCN1, CDK12, and RAC1 correlated with response to all three TKIs. DNA damage repair genes were associated with TKI resistance. BRCA2 mutations were correlated with neratinib and tucatinib response, and high expression of ATM, BRCA2, and BRCA1 were associated with neratinib resistance.ConclusionsNeratinib was the most effective HER2-targeted TKI against HER2-amplified, -mutant, and EGFR-mutant cell lines. This analysis revealed novel resistance mechanisms that may be exploited using combinatorial strategies.

Abstract 395: Aberrant HER2 signaling is a therapeutic target in a subset of castration-resistant prostate cancer

Abstract Background: Aberrant HER2 signaling promotes androgen receptor activity and is associated with 18-25% of castration-resistant prostate cancer (CRPC). We present preclinical and clinical data supporting signaling by canonical HER3/HER2 interaction and a constitutively active splice variant of HER2 (d16HER2) as potential oncogenic drivers of CRPC. Further, we provide preclinical evidence that increased HER2 signaling may be targeted with irreversible HER2-targeted tyrosine kinase inhibitors (TKIs) to block tumor growth. Methods: Human-derived VCaP prostate cancer xenografts were serially biopsied prior to castration, at castration-resistance, and after resistance to abiraterone + enzalutamide (Abi/Enza). Biopsies were submitted for RNA sequencing and RT-PCR, immunohistochemistry (IHC), and reverse-phase protein array (RPPA) for validation of gene/protein expression changes. Castration-resistant VCaP and LuCaP-70CR xenografts were treated with reversible EGFR/HER2 TKI lapatinib (100 mg/kg) or irreversible pan-HER TKIs afatinib (20 mg/kg) or neratinib (20 mg/kg). Transcript levels of total HER2 and d16HER2 variant were determined for TCGA and SU2C prostate cancer (PCa) datasets. IHC for phospho-HER2 (Tyr1221/1222) and phospho-HER3 (Tyr1289) were performed on tumor samples from 49 heavily-treated metastatic CRPC (mCRPC) patients and compared to 18 hormone-naïve prostatectomy samples. Results: VCaP xenografts exhibit increased activation of HER3/HER2 signaling and increased expression of d16HER2 with progression through castration and Abi/Enza therapy. Increases in pHER2 and pHER3 were observed by IHC and RPPA in serial biopsies of individual tumors, and increases in total HER2, wtHER2, and d16HER2 transcripts were observed by RT-PCR. Castration-resistant VCaP and LuCaP-70CR xenografts rapidly become resistant to lapatinib within 5 days, while the irreversible pan-HER TKIs inhibited tumor growth for at least 15 days. Analysis of TCGA (mostly hormone-naïve PCa) and SU2C (mCRPC) RNAseq datasets shows enrichment of tumors expressing d16HER2 in mCRPC. pHER3/pHER2 IHC in patient tumor specimens showed 9/49 (18%) mCRPC tumors exhibited concurrent pHER3/pHER2 staining compared to 1/18 (6%) of hormone-naïve PCa. An additional 4/49 (8%) mCRPC tumors stained positive for pHER2 alone, possibly representing d16HER2 activity. Conclusions: HER2 overexpression and d16HER2 expression are associated with PCa progression, castration-resistance, and resistance to second-line hormonal therapy. HER2-targeted therapy with irreversible TKIs is more effective at inhibiting CRPC growth than the reversible TKI lapatinib. Our data indicate a subset of CRPC with aberrant HER2 signaling may be clinically actionable, and further studies to investigate potential treatment with an irreversible pan-HER TKI such as neratinib in biomarker-selected metastatic CRPC patients is warranted. Citation Format: Joshua W. Russo, Xin Gao, David J. Einstein, Glenn J. Bubley, Steven P. Balk. Aberrant HER2 signaling is a therapeutic target in a subset of castration-resistant prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 395.

Abstract ES3-3: Systemic therapy for breast cancer brain metastases

Abstract Brain metastases occur in up to half of patients with HER2-positive metastatic breast cancer, 25-45% of patients with metastatic triple-negative breast cancer, and 10-15% of patients with metastatic ER-positive breast cancer. While local approaches such as surgery and radiotherapy can be effective, they do not address extracranial disease, and can be associated with short- and long-term toxicity. As some subsets of patients live longer after a diagnosis of brain metastasis, there is increasing interest in systemic approaches in lieu of repetitive rounds of local therapy. To date, no systemic therapy has gained an indication for the specific treatment of breast cancer brain metastases; however, a number of regimens have been associated with efficacy in the central nervous system (CNS) in non-randomized studies. For patients with HER2-positive breast cancer, the combination of lapatinib and capecitabine has been associated with CNS response rates of 66% in the upfront setting, and 18-38% in patients whose disease has progressed after prior radiotherapy. Several investigational HER2-targeted tyrosine kinase inhibitors have shown promise. The combination of tucatinib, capecitabine and trastuzumab was associated with a CNS response rate of 42% in a small number of patients with brain metastases treated on the phase 1 trial. Notably, patients with brain metastases (either stable or progressive) are allowed on the current tucatinib registration trial (NCT02614794). The combination of neratinib and capecitabine led to a CNS response rate = 49% in a prospective phase 2 trial. Finally, trastuzumab-emtansine has been reported to lead to CNS regressions in up to 40% of patients, based upon case series from several institutions. For patients with ER-positive breast cancer, endocrine therapies such as tamoxifen and aromatase inhibitors have been reported to induce CNS responses in case reports and small case series. Recently, there has been interest in exploring the role of CDK4/6 inhibitors in patients with brain metastases. Preliminary results of the JPBO study support potential CNS efficacy of abemaciclib in patients with ER+ breast cancer; final results are awaited. To date, no commercially available targeted agents have demonstrated efficacy against brain metastases from triple-negative breast cancer. Trials of immunotherapy approaches in breast cancer have almost completely excluded patients with active/progressive brain metastases and thus, the safety/efficacy profile of immunotherapy in this setting is unknown, though promising data in melanoma and lung cancer would support its exploration in patients with brain metastases from breast cancer. Despite the fact that most chemotherapeutic agents do not cross the intact blood brain barrier, it appears empirically that the blood-tumor barrier can be sufficiently disrupted to allow for CNS efficacy in the case of established brain metastases. Diverse agents including anthracyclines, capecitabine, platinum salts, and irinotecan have been reported to be associated with CNS response in breast cancer patients. Newer compounds which have been engineered to improve upon CNS penetration and/or CNS residence time are in clinical development and testing. Citation Format: Lin N. Systemic therapy for breast cancer brain metastases [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr ES3-3.