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Legends for Supplementary Tables S1-S6

Supplementary Table S1. List of antibodies used in reverse phase protein array (RPPA). A table summarizing the antibodies used for RPPA in this study.

Best response to treatment. A table summarizing the best responses to study treatment in all patients. This table also compares responses in patients who received BRAF/MEK inhibitors prior to study enrollment with patients who did not.

Characteristics of patients who received prior treatment with BRAF and/or MEK inhibitors (N=10). A table summarizing the characteristics, PTEN status and best response in patients who previously received BRAF and/or MEK inhibitors (N=10).

Changes in protein expression in paired samples (n=3) obtained before and after treatment with PX-866. A table comparing protein expression levels between tumor biopsy specimens obtained at baseline and on C1D8.

Differences in baseline protein expression between patients who did (n=3) and did not (n=3) achieve disease control. A table summarizing the differences in baseline levels of protein expression between patients who achieved disease control and those who did not.

Patterns of progression. A table summarizing the patterns of progression for patients (N=14) who had progression of disease by RECIST v1.1 criteria while on this study.

Purpose: The objectives of the study were to evaluate the safety of daily oral PX-866 in combination with twice daily vemurafenib and to identify potential predictive biomarkers for this novel combination.Experimental Design: We conducted a phase I, open-label, dose-escalation study in patients with advanced BRAF V600–mutant solid tumors. PX-866 was administered on a continuous schedule in combination with vemurafenib. Patients underwent a baseline and on-treatment biopsy after 1-week of PX-866 monotherapy for biomarker assessment.Results: Twenty-four patients were enrolled. The most common treatment-related adverse events were gastrointestinal side effects. One dose-limiting toxicity (DLT) of grade 3 rash and one DLT of grade 3 pancreatitis were observed in cohort 2 (PX-866 6 mg daily; vemurafenib 960 mg twice daily) and cohort 3 (PX-866 8 mg daily; vemurafenib 960 mg twice daily), respectively. Of 23 response-evaluable patients, seven had confirmed partial responses (PR), 10 had stable disease, and six had disease progression. Decreases in intratumoral pAKT expression were observed following treatment with PX-866. Patients who achieved PRs had higher rates of PTEN loss by IHC (80% vs. 58%) and pathogenic PTEN mutations and/or deletions (57% vs. 25%). Two patients with durable PRs had an increase in intratumoral CD8+ T-cell infiltration following treatment with PX-866.Conclusions: PX-866 was well tolerated at its maximum tolerated single-agent dose when given in combination with a modified dose of vemurafenib (720 mg twice daily). Response to treatment appeared to be associated with PTEN loss and treatment with PX-866 seemed to increase CD8+ T-cell infiltration in some patients. Clin Cancer Res; 24(1); 22–32. ©2017 AACR.

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

Tucatinib is a potent tyrosine kinase inhibitor selective for human epidermal growth factor receptor 2 (HER2) approved by the US Food and Drug Administration for the treatment of HER2‐positive metastatic breast cancer and in development for other HER2‐positive solid tumors. Modest, reversible serum creatinine (SCr) elevations have been observed in tucatinib clinical trials. SCr is conveyed by the renal drug transporters organic cation transporter 2 (OCT2) and multidrug and toxin extrusion protein 1 (MATE1) and 2‐K (MATE2‐K) and can increase in the presence of inhibitors of these transporters. In vitro, tucatinib inhibited OCT2‐, MATE1‐, and MATE2‐K‐mediated transport of metformin, with IC50 values of 14.7, 0.340, and 0.135 µM, respectively. Tucatinib also inhibited OCT2‐ and MATE1‐mediated transport of creatinine, with IC50 values of 0.107 and 0.0855 µM, respectively. A phase 1 study with metformin administered orally in the absence and presence of tucatinib was conducted in 18 healthy subjects. Renal function was assessed by measuring glomerular filtration rate (GFR; based on iohexol plasma clearance) and endogenous markers (SCr, cystatin C‐based estimated glomerular filtration rate [eGFR]) with and without tucatinib. Metformin exposure increased (1.4‐fold) and renal clearance decreased (29.99‐17.64 L/h) with tucatinib, with no effect on metformin maximum concentration. Creatinine clearance transiently decreased 23% with tucatinib. GFR and eGFR, which are unaffected by OCT2 and/or MATE1/2‐K transport, were unchanged with tucatinib. These data demonstrate that tucatinib inhibits OCT2‐ and MATE1/2‐K‐mediated tubular secretion of creatinine, which may manifest as mild SCr elevations that are not indicative of renal impairment.

Background Brain metastases are frequent in HER2-positive breast cancer. ONT-380 (tucatinib) is a potent selective inhibitor of HER2 with intracranial activity in preclinical models. Patients and methods This was a phase I study of tucatinib with trastuzumab, without chemotherapy, in patients with progressive, measurable HER2-positive brain metastases. The study tested two schedules of tucatinib: cohort A was twice daily and cohort B was once daily. The primary objective was determination of the maximum tolerated dose (MTD). Secondary end points included objective response (intracranial and extracranial) using modified RECIST and clinical benefit rate (CBR). Results Overall, 41 patients were enrolled (cohort A, n = 22; cohort B, n = 19). Patients had a median of two prior treatments for metastatic breast cancer and 83% had progressed after prior brain radiation. The MTD of tucatinib for cohort A was 300 mg twice daily and for cohort B was 750 mg once daily. The most common dose-limiting toxicities included thrombocytopenia and aspartate transaminase/alanine aminotransferase elevation. Grade 3/4 aspartate transaminase/alanine aminotransferase elevation occurred in nine of 41 patients (22%). Intracranial responses were observed in two of 17 (12%) patients in cohort A and one of 17 (6%) patients in cohort B treated at the MTD. In cohort A, CBR at 16 weeks was 35% (n = 6). In cohort B, CBR at 16 weeks was 53% (n = 9). Of 15 patients overall who experienced clinical benefit, 12 (80%) had received prior neratinib and/or lapatinib. Median progression-free survival for cohorts A and B was 3.4 and 4.1 months, respectively. Conclusion The combination of tucatinib and trastuzumab is tolerable and demonstrated preliminary evidence of efficacy in patients with HER2-positive brain metastases. Clinical Trial Registration NCT01921335.

Tucatinib is approved for treatment of human epidermal growth factor receptor 2-positive metastatic breast cancer. Understanding potential drug-drug interactions (DDIs) informs proper dosing when co-administering tucatinib with other therapies. The aim of this study was to evaluate DDIs between tucatinib and metabolizing enzymes and transporters in healthy volunteers.Parts A-C assessed the impact of itraconazole (cytochrome P450 [CYP] 3A4 inhibitor), rifampin (CYP3A4/CYP2C8 inducer), or gemfibrozil (CYP2C8 inhibitor) on the pharmacokinetics of a single 300 mg dose of tucatinib administered orally and its primary metabolite, ONT-993. Parts D and E assessed the effect of steady-state tucatinib on the pharmacokinetics of repaglinide (CYP2C8 substrate), tolbutamide (CYP2C9 substrate), midazolam (CYP3A4 substrate), and digoxin (P-glycoprotein substrate).Tucatinib area under the concentration-time curve from time 0 extrapolated to infinity (AUCThe potential DDIs identified here may be mitigated by avoiding concomitant use of tucatinib with strong CYP3A inducers, moderate CYP2C8 inducers, CYP3A substrates with a narrow therapeutic window (modifying substrate dose where concomitant use is unavoidable), and strong CYP2C8 inhibitors (decreasing tucatinib dose where concomitant use is unavoidable), or by reducing the dose of P-glycoprotein substrates with a narrow therapeutic window.This trial (NCT03723395) was registered on October 29, 2018.

We seem to be living in a golden age of scholarship on Blake’s reception, and Linda Freedman’s William Blake and the Myth of America is a welcome addition to this critical canon. As Freedman notes, the recent scholarly antecedents of her study include the collections Blake 2.0: William Blake in Twentieth-Century Art, Music and Culture (ed. Steve Clark, Tristanne Connolly, and Jason Whittaker, 2012), Blake, Modernity and Popular Culture (ed. Clark and Whittaker, 2007), and The Reception of Blake in the Orient (ed. Clark and Masashi Suzuki, 2006), as well as Colin Trodd’s monograph Visions of Blake: William Blake in the Art World, 1830–1930 (2012) and Edward Larrissy’s Blake and Modern Literature (2006). Freedman’s book, which benefits from sixteen color illustrations embedded throughout the text, also follows hot on the heels of the even more lavishly illustrated William Blake and the Age of Aquarius (ed. Stephen F. Eisenman, 2017). Yet, as she acknowledges, the contents of William Blake and the Myth of America connect it more specifically to William Blake and the Moderns, the 1982 collection edited by Robert J. Bertholf and Annette S. Levitt, which prepared the ground for the current crop of Blakean reception studies; figures from that book who reappear in Freedman’s monograph include Walt Whitman, Hart Crane, T. S. Eliot, Theodore Roethke, Robert Duncan, and Allen Ginsberg.

Introduction/Background* Tucatinib, a highly selective HER2-directed tyrosine kinase inhibitor with minimal EGFR inhibition, is approved for use in combination with trastuzumab and capecitabine in patients with breast cancer who have received anti-HER2–based regimens in the metastatic setting. In xenograft models of HER2-overexpressed/amplified (HER2+) and HER2-mutated tumors, dual targeting with tucatinib and trastuzumab showed superior activity to either agent alone. The prognosis of locally-advanced unresectable or metastatic (LAUM) cervical and uterine cancer remains poor. HER2 amplification/overexpression and mutations occur in up to 21% and 80% of cervical and uterine cancers, respectively. Methodology SGNTUC-019 (NCT04579380) is an open-label, international Phase 2 basket study evaluating tucatinib and trastuzumab in adult patients with LAUM HER2+ or HER2-mutated solid tumors. Multiple disease- and HER2 alteration-specific cohorts are being enrolled, including HER2+ cervical and uterine cancer cohorts. Patients will receive tucatinib 300 mg orally twice daily and trastuzumab 8 mg/kg IV on Cycle 1 Day 1 and 6 mg/kg q21 days from Cycle 2 Day 1 HER2+ cervical and uterine cancer cohorts will enroll 12 patients each. If ≥2 responses are observed in a cohort, it will be expanded to 30 patients. Patients with HER2-mutated cervical and uterine cancers will enroll in a cohort of 30 patients for all solid tumor types. Eligible patients must have progressed on or after the last systemic therapy, with platinum-based therapy ± bevacizumab required in patients with metastatic cervical cancer. Patients must have ECOG PS ≤1, adequate organ function, and have not received HER2-directed therapy; patients with uterine serous carcinoma may have received trastuzumab. HER2 alterations can be demonstrated by HER2 overexpression/amplification in tumor tissue by prior IHC/ISH, or by HER2 amplification/mutation in a prior or on-study NGS assay of ctDNA or prior tissue NGS assay. The primary endpoint is confirmed ORR per investigator. Disease control rate, duration of response, PFS, and OS are the secondary endpoints. Disease assessments per RECIST 1.1 will occur q6 weeks for 24 weeks, then q12 weeks. QoL will be evaluated q2 cycles using EQ-5D-5L. Result(s)* Not applicable. Conclusion* Enrollment in US began in Dec 2020; EU and Asia sites will be opened.

Press-hardened boron steels with ultrahigh strength (above 1500 MPa) are widely used in crash-sensitive safety components in automobiles. Joining such steels to aluminum alloys is challenging due to various factors including the steel’s tenacious Al-Si coating. A novel application of ultrasonic plus resistance spot welding was developed for such dissimilar metal joining. The nugget formation and the interface microstructure especially intermetallics formed were correlated to the joint strength, ductility and failure behavior.

Ultrasonic interlayered resistance spot welding (Ulti-RSW) is a recently developed method for dissimilar metal joining of aluminum alloy to advanced high strength steel. It makes use of a thin insert (or interlayer) which is first ultrasonic spot welded to one of the two sheets. The second sheet is then resistance spot welded to the insert side of the first sheet. In the present study, two inserts were tested, 0.3-mm-thick AA3003-H14 and 0.25-mm-thick stainless steel 316, for joining 0.8-mm-thick Zn-coated (galvannealed) dual phase steel 590 to 1.2-mm-thinck aluminum AA6022-T4. The joint with the aluminum insert achieved a peak tensile-shear strength of 4.1kN and a fracture energy of 1.7J, while the joint with the stainless steel insert achieved a peak strength of 4.5kN and a fracture energy of 2.6J. Both welds were much stronger than a direct resistance spot weld between the two sheets which had a strength of 3.3kN and an inferior fracture energy of 0.87J. The increase in strength and fracture energy achieved using stainless steel insert over aluminum insert was discussed based on the nugget diameter and the interface microstructure.

This abstract was withdrawn by the authors. Citation Format: Paplomata E, Borges V, Loi S, Abramson V, Hamilton E, Hurvitz S, Lin N, Walker L, Murthy RK. Withdrawn [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 OT2-07-08.

This article analyses how jihadist ideology groups discursively represent “the West” and “non-believers” in their online propagandamagazines. In doing so, it contributes to the field of Critical Te...

BACKGROUND: Patients with human epidermal growth factor receptor 2 (HER2)–positive metastatic breast cancer who have disease progression after therapy with multiple HER2-targeted agents have limited treatment options. Tucatinib is an investigational, oral, highly selective inhibitor of the HER2 tyrosine kinase.METHODS: We randomly assigned patients with HER2-positive metastatic breast cancer previously treated with trastuzumab, pertuzumab, and trastuzumab emtansine, who had or did not have brain metastases, to receive either tucatinib or placebo, in combination with trastuzumab and capecitabine. The primary end point was progression-free survival among the first 480 patients who underwent randomization. Secondary end points, assessed in the total population (612 patients), included overall survival, progression-free survival among patients with brain metastases, confirmed objective response rate, and safety.RESULTS: Progression-free survival at 1 year was 33.1% in the tucatinib-combination group and 12.3% in the placebo-combination group (hazard ratio for disease progression or death, 0.54; 95% confidence interval [CI], 0.42 to 0.71; PCONCLUSIONS: In heavily pretreated patients with HER2-positive metastatic breast cancer, including those with brain metastases, adding tucatinib to trastuzumab and capecitabine resulted in better progression-free survival and overall survival outcomes than adding placebo; the risks of diarrhea and elevated aminotransferase levels were higher with tucatinib. (Funded by Seattle Genetics; HER2CLIMB ClinicalTrials.gov number, NCT02614794. opens in new tab.)

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.

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

Background: Brain metastases remain an important cause of death for pts with advanced HER2+ BC. ONT-380 is an oral, potent and selective inhibitor of HER2 capable of penetrating the blood brain barrier in pre-clinical models. We evaluated the safety and preliminary efficacy of ONT-380 in combination with trastuzumab. Methods: Open-label, dose finding, Phase I study to estimate the MTD(s) of ONT-380 + trastuzumab in pts with HER2+ BCBM. The study was conducted in parallel cohorts testing two schedules of ONT-380 (once-daily or twice-daily). The primary endpoint was determination of the MTD. A total of 15 pts were to be treated at the MTD of each schedule in order to select the best regimen for future phase 2 studies. Response was assessed by RECIST 1.1 (extracranial) and modified RECIST 1.1 (intracranial). Results: Between Aug 2013 and March 2016, 41 pts were enrolled. Median age was 49 (range 29-65); ECOG performance status 0-1 (85%), 2 (15%). 34 (83%) patients had progressed after prior WBRT and/or SRS. Patients had a median of 2 prior treatments for metastatic breast cancer prior to enrollment. As of June 7, 2016, median number of cycles was 4 (range 1-32); 4 patients remain on active protocol therapy. 2 DLTs were observed among 5 pts treated at 450 mg BID (G3 thrombocytopenia and G3 thrombocytopenia and G3 ALT). The dose was de-escalated to 300 mg BID, and with 0/3 patients experiencing a DLT. 300mg BID was identified as the MTD and an additional 14 patients were enrolled at this dose level. 1/7 pts experienced a DLT at 750 mg QD (G3 ALT). At 900 mg QD, 2/2 pts experienced a DLT (2 patients had G3 ALT/AST). An additional 10 pts were enrolled at the MTD of 750 mg QD. The most common AEs, regardless of relationship, were fatigue, diarrhea, AST/ALT elevation, nausea, headache. Gr 3/4 AST/ALT elevation has occurred in 9/41 pts (22%), though has been reversible with dose interruption and reduction. One Gr 3 diarrhea has occurred at 450 mg BID, and 1 Gr 3 diarrhea has occurred at 750 mg QD. PK assessments showed similar exposure of ONT-380 for QD and BID regimens. Preliminary assessment CNS response is available for 19 pts in the QD cohort (5% PR, 89% SD, 5% PD) and 17 pts in the BID cohort (12% PR, 59% SD, 12% PD, 18% unknown). Preliminary non-CNS assessment for the same population is as follows: QD cohort (100% SD); BID cohort (6% PR, 71% SD and 23% unknown). Conclusions: The combination of ONT-380 and trastuzumab is feasible. The combination has an acceptable safety profile with low incidence and severity of diarrhea and rash. Transaminase elevation was asymptomatic for all pts and resolved with drug interruption/delay. Preliminary evidence of activity was observed in CNS and non-CNS disease. Citation Format: Metzger O, Barry W, Krop I, Guo H, Younger J, Lawler E, Walker L, Freedman R, Tolaney S, Winer E, Lin N. Phase I dose-escalation trial of ONT-380 in combination with trastuzumab in patients (pts) with HER2+ breast cancer brain metastases [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-12-04.

Background: ONT-380, a potent, highly selective, orally available small molecule inhibitor of HER2, has been associated with clinical benefit and minimal EGFR-type toxicities in single agent and combination studies of pts with HER2+ MBC, including pts with brain mets. In this Phase 1b study, ONT-380 was evaluated in combination with C and/or T in pts with HER2+ MBC who had been treated with T, a taxane, and ado-trastuzumab emtansine (T-DM1). During doublet dose escalation, ONT-380 300 mg PO BID was well tolerated and responses were seen in combination with either C or T alone; no maximum tolerated dose (MTD) was reached. ONT-380 300 mg PO BID was then studied in combination with both C and T as triplet therapy in order to provide dual blockade of HER2 in combination with cytotoxic chemotherapy. Safety and efficacy results of the triplet cohort are reported here. Methods: ONT-380 300 mg PO BID was administered with C (1000 mg/m2 PO BID 14 days of a 21-day cycle), and T (8 mg/kg IV loading; then 6 mg/kg IV once every 21 days). Prior treatment with T, a taxane, and T-DM1 were required; prior pertuzumab, lapatinib, or neratinib were permitted; prior capecitabine exposure was prohibited. Pts with asymptomatic brain mets (treated or untreated) were also eligible. Assessments included safety and tumor response by RECIST 1.1 and Modified CNS RECIST 1.1. Results: Enrollment was complete as of December 2015. Interim safety and efficacy results as of May 27, 2016 are reported here, with mature data to be presented at the meeting. 27 pts were treated with ONT-380 + C + T: median age 50 y, 56% ER/PR+, 44% ER/PR, 47% PS 0, 53% PS 1. Pts received a median of 3 prior HER2 agents: 100% prior T and TDM-1, 74% prior pertuzumab, 37% prior lapatinib. 11 pts had brain mets at baseline, including 7 patients with untreated or progressive brain mets. Most toxicities were Gr 1. The most common adverse events (>40%) were diarrhea, nausea, palmar-plantar erythrodysaesthesia (PPE), vomiting, and fatigue. Gr 3 events included PPE (11%), diarrhea (11%), fatigue (11%), and reversible increase in AST/ALT (7%). Dose reductions of ONT-380 were required in 6 pts, with 4 of these patients having continued disease control >6 months at the reduced dose. In 24 pts with measurable disease at baseline, ORR was 58%, with best responses of 1 CR, 13 PR, 6 SD, and 4 PD, and clinical benefit rate (SD ≥ 6 mos, PR, CR) in all 27 pts was 67%. Median PFS as of this data cut was 6.3 m (95% CI: 4.1-n/a). Median time on treatment for all 27 pts was 6.2 mo (range 1.4-21.4 mo), with 12 pts still active. Conclusion: ONT-380 in combination with C and T exhibits an acceptable well tolerated safety profile and shows evidence of responses and long-term disease control in pts who have received contemporary standard of care treatment for HER2+ MBC with both pertuzumab and T-DM1, including pts with brain mets. Based on these encouraging data, a randomized placebo-controlled Phase 2 study (HER2CLIMB) is now enrolling to further evaluate the activity of ONT-380 in this population, including pts with brain mets.Background: ONT-380, a potent, highly selective, orally available small molecule inhibitor of HER2, has been associated with clinical benefit and minimal EGFR-type toxicities in single agent and combination studies of pts with HER2+ MBC, including pts with brain mets. In this Phase 1b study, ONT-380 was evaluated in combination with C and/or T in pts with HER2+ MBC who had been treated with T, a taxane, and ado-trastuzumab emtansine (T-DM1). During doublet dose escalation, ONT-380 300 mg PO BID was well tolerated and responses were seen in combination with either C or T alone; no maximum tolerated dose (MTD) was reached. ONT-380 300 mg PO BID was then studied in combination with both C and T as triplet therapy in order to provide dual blockade of HER2 in combination with cytotoxic chemotherapy. Safety and efficacy results of the triplet cohort are reported here. Methods: ONT-380 300 mg PO BID was administered with C (1000 mg/m2 PO BID 14 days of a 21-day cycle), and T (8 mg/kg IV loading; then 6 mg/kg IV once every 21 days). Prior treatment with T, a taxane, and T-DM1 were required; prior pertuzumab, lapatinib, or neratinib were permitted; prior capecitabine exposure was prohibited. Pts with asymptomatic brain mets (treated or untreated) were also eligible. Assessments included safety and tumor response by RECIST 1.1 and Modified CNS RECIST 1.1. Results: Enrollment was complete as of December 2015. Interim safety and efficacy results as of May 27, 2016 are reported here, with mature data to be presented at the meeting. 27 pts were treated with ONT-380 + C + T: median age 50 y, 56% ER/PR+, 44% ER/PR, 47% PS 0, 53% PS 1. Pts received a median of 3 prior HER2 agents: 100% prior T and TDM-1, 74% prior pertuzumab, 37% prior lapatinib. 11 pts had brain mets at baseline, including 7 patients with untreated or progressive brain mets. Most toxicities were Gr 1. The most common adverse events (>40%) were diarrhea, nausea, palmar-plantar erythrodysaesthesia (PPE), vomiting, and fatigue. Gr 3 events included PPE (11%), diarrhea (11%), fatigue (11%), and reversible increase in AST/ALT (7%). Dose reductions of ONT-380 were required in 6 pts, with 4 of these patients having continued disease control >6 months at the reduced dose. In 24 pts with measurable disease at baseline, ORR was 58%, with best responses of 1 CR, 13 PR, 6 SD, and 4 PD, and clinical benefit rate (SD ≥ 6 mos, PR, CR) in all 27 pts was 67%. Median PFS as of this data cut was 6.3 m (95% CI: 4.1-n/a). Median time on treatment for all 27 pts was 6.2 mo (range 1.4-21.4 mo), with 12 pts still active. Conclusion: ONT-380 in combination with C and T exhibits an acceptable well tolerated safety profile and shows evidence of responses and long-term disease control in pts who have received contemporary standard of care treatment for HER2+ MBC with both pertuzumab and T-DM1, including pts with brain mets. Based on these encouraging data, a randomized placebo-controlled Phase 2 study (HER2CLIMB) is now enrolling to further evaluate the activity of ONT-380 in this population, including pts with brain mets. Citation Format: Hamilton E, Borges V, Conlin A, Walker L, Moulder S. Efficacy results of a phase 1b study of ONT-380, an oral HER2-specific inhibitor, in combination with capecitabine (C) and trastuzumab (T) in HER2+ metastatic breast cancer (MBC), including patients (pts) with brain metastases (mets) [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-21-01.

In this article, I explore Paul Goodman’s ambivalent relationship with Allen Ginsberg as a fellow elder statesman of the sixties, and argue that his conflicted attitude towards the Beats is reflective of broader tensions within the radical cultures of the period. Finally, I also suggest that by exploring points in common between Goodman and the Beats, we can gain a better understanding of the links between 1960s counterculture and its precursor and successor movements, from Romanticism to Green politics.

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

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.

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.

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.

There are several reasons why this 2017 album release represents a significant moment for anyone interested in the role played by William Blake in shaping the counterculture of the sixties (and the role of that counterculture in shaping academic and popular understandings of Blake). The most basic is that the original 1970 album, Songs of Innocence and Experience [sic] by William Blake, Tuned by Allen Ginsberg, has never previously been made available as a CD or digital download. However, it is a credit to Pat Thomas, who produced this expanded reissue for Omnivore Recordings, that there are other, more important, reasons to celebrate. The double-CD Complete Songs of Innocence and Experience is not just a rerelease of the album in a new format with a few alternative takes added as filler; rather, at over twice the length, it aims for the first time to fulfill Ginsberg’s original intentions for his extensive Blake recording project, to which he devoted much of his creative energy between 1968 and 1971.

TPS1107Background: Tucatinib (ONT-380) is a highly selective small molecule inhibitor of HER2 kinase with nanomolar potency. Unlike dual HER2/EGFR agents, it does not inhibit EGFR at clinically relevant concentrations, decreasing the potential for EGFR-related toxicities (severe skin rash and diarrhea). In preclinical studies, tucatinib demonstrated synergistic activity with Tz, and was active in HER2+ models of brain metastases (mets). In a Phase 1b study, tucatinib was combined with C and Tz in pts with HER2+ MBC previously treated with trastuzumab emtansine (T-DM1) and Tz. Objective responses were seen, including in pts with brain mets. The combination was well tolerated, with low rates of Gr 3 diarrhea at the recommended dose (300 mg PO BID, equivalent to the single agent MTD). Based on these data, tucatinib is now being evaluated in a study in combination with C and Tz (HER2CLIMB). Methods: The primary study objective is to assess the effect of tucatinib vs. placebo given with C + Tz on progression-f...

Background: The risk of CNS involvement in patients with HER2+ metastatic breast cancer (MBC) is high. The natural history of HER2+ CNS metastases (mets) is different from other breast cancer subtypes; there is a longer time from metastatic diagnosis to CNS relapse, greater control of extracranial disease at the time of CNS relapse, and longer median overall survival from the time of CNS relapse. Local treatments, i.e., surgery and/or radiation, remain the mainstay of treatment for HER2+ CNS disease as standard systemic therapy options have limited efficacy. ONT-380, a potent HER2 selective tyrosine kinase inhibitor with minimal EGFR-like side effects, has been associated with increased survival compared to lapatinib or neratinib in an animal model of HER2+ CNS disease. Here, we describe 24 pts from two studies with response-evaluable CNS mets treated with ONT-380 in combination with other systemic therapies. Methods: Pts with asymptomatic untreated or post-treatment progressive CNS mets were enrolled in ongoing phase 1b studies of ONT-380 + ado-trastuzumab emtansine (T-DM1) or ONT-380 ± trastuzumab (T) ±capecitabine (C). All pts received treatment in 21 day cycles including ONT-380 300 mg PO BID and approved doses of either T-DM1, T or C alone, or T+C. Eligibility criteria for all pts included prior treatment with T and a taxane, and for pts receiving T and/or C, prior T-DM1. Prior lapatinib was allowed. Assessments included safety, systemic tumor response per RECIST 1.1, and CNS tumor response by MRI every 2 cycles per modified RECIST 1.1. Results: 24 pts (10 with untreated CNS mets and 14 with progressive CNS mets after local therapy) received ONT-380 plus T-DM1 (n =14), C (n=1), T (n = 5) or T+C (n = 4) for 1-8 cycles. Of these 24 pts, 14 are evaluable for response in the CNS (at least one follow-up MRI); 7 pts have not yet been rescanned, and 3 are non-evaluable. In the 14 response-evaluable pts, best CNS response has been: 1 CNS CR (T-DM1), 4 CNS PR (T-DM1 n = 2; T+C n = 1; C n=1) and 9 CNS SD (T-DM1 n = 5; T n = 3; T+C n=1). Pts with CR or PR (prior lapatinib n=2; prior pertuzumab n=2; prior T-DM1 n=2) all had > 50% decrease in CNS target lesions. One CNS non-evaluable pt (T) had a 15% increase in their target lesion and underwent surgical resection; pathology, however, revealed no viable tumor with only necrotic tissue present. Two additional CNS non-evaluable pts (T-DM1 n=1; C+T n=1) were taken off study due to systemic PD after treatment was held for AEs (Gr 3 AST/ALT elevation [n=1]; Gr 4 edema in thalamic lesion [n=1]). No other ≥ Gr 3 ONT-380 related events were reported. Systemic disease control was also seen, with a best response in 17 evaluable pts of 6 PR, 9 SD, and 2 PD. Conclusions: This case series demonstrates early clinical signs of activity of ONT-380 against HER2+ CNS mets in combination with other systemic agents. Further study of the CNS activity of ONT-380 is ongoing and further studies are being planned. Updated results will be reported. Clinical trial information: NCT01983501, NCT02025192. Citation Format: Murthy RK, Hamilton E, Borges VF, Moulder S, Aucoin N, Welch S, Chaves J, Falkson CI, Walker L, Ferrario C. ONT-380 in the treatment of HER2+ breast cancer central nervous system (CNS) metastases (mets). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-14-19.

Background: ONT 380 is a potent HER2 selective tyrosine kinase inhibitor with minimal EGFR-like side effects. Preclinical studies demonstrate synergism with trastuzumab (T) and chemotherapy, as well as activity in models of HER2+ CNS disease. Based on the potential for increased clinical activity of dual HER2 blockade in the context of a targeted cytotoxic agent, we evaluated the safety, tolerability, and anti-tumor activity of ONT-380 in combination with T-DM1 in patients (pts) with MBC with and without CNS metastases (mets). Methods: 3+3 dose escalation with MTD expansion cohorts in pts with/without CNS mets evaluating ONT-380 (300 or 350 mg PO BID) combined with T-DM1 3.6 mg/kg IV q 21 days. Prior treatment with T and taxane was required; prior lapatinib and asymptomatic brain mets (treated or untreated) were allowed. Assessments included safety, PK, and systemic (RECIST 1.1) and CNS (modified RECIST) tumor response, with brain MRI at baseline and q 6 wks in pts with CNS mets at baseline. DLT was defined as the occurrence of protocol-specified events during the 1st treatment cycle. Results: As of 01 June 2015, 51 pts have been enrolled and have received between 1 and 22 cycles, with safety data available for 43 pts (n=36 at 300 mg BID; n=7 at 350 mg BID). Pts had a median of 2 prior treatments for MBC, including T (n=43); pertuzumab (n=15) and lapatinib (n=7). The MTD for ONT-380 was 300 mg BID with 5/36 pts (14%) with DLT (Gr 3 AST/ALT [n=4]; Gr 2 vomiting/Gr1 diarrhea [n=1]) vs. 3/7 pts (43%) with DLT at 350 mg BID (Gr 3 vomiting [n=1]; Gr 3 hypersensitivity [n=1]; Gr 3 fatigue [n=1]). Overall, the majority of AEs have been Gr 1 or 2. The most common AEs, regardless of relationship, were nausea, fatigue, diarrhea, vomiting, thrombocytopenia, AST/ALT elevation, headache, decreased appetite, epistaxis, constipation, and hypokalemia. Gr 3 AST/ALT elevation has occurred in 7/43 pts (16%), with no events meeting Hy's law, and has been reversible with dose interruption and reduction except in 2 pts found to have progressive liver mets. No Gr 3 diarrhea has occurred at any dose. ONT-380 PK was dose proportional, and no drug-drug interaction was observed with T-DM1. In 33 of 43 pts with data available from at least one follow-up scan to evaluate response, best systemic response regardless of dose was 11 PR, 16 SD, and 6 PD, with clinical benefit rate (CBR= CR, PR, or SD >6 mos) of 19/33 (58%). The most common reason for treatment discontinuation was PD, with 3 pts coming off study for AEs (n=1 each of Gr 3 hypersensitivity, Gr 2 vomiting, Gr 3 AST/ALT). Eight pts to date have been evaluable for CNS response (untreated or progressive CNS mets with ≥1 follow-up MRI), with best CNS response of 1 CNS CR, 2 CNS PR, and 5 CNS SD, with a CNS CBR of 5/8 (63%). All pts with CNS response are still active. Conclusion: Treatment with ONT-380 300 mg BID and T-DM1 3.6 mg/kg has been tolerable. Early evidence of anti-tumor activity has been seen, including clinical benefit in patients with CNS mets. Updated results will be presented. Citation Format: Ferrario C, Hamilton E, Aucoin N, Falkson CI, Khan Q, Krop IE, Welch S, Bedard PL, Conlin A, Chaves J, Vo A, Walker L, Borges V. A phase 1b study of ONT 380, an oral HER2-specific inhibitor, combined with ado trastuzumab emtansine (T DM1), in HER2+ metastatic breast cancer (MBC). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-14-20.

Background: ONT-380 (also known as ARRY-380) is a potent, selective small molecule inhibitor of HER2 with 500-fold selectivity compared to EGFR. Preclinical studies have demonstrated synergistic activity with ONT-380 and chemotherapy or trastuzumab, as well as superior activity compared to lapatinib and neratinib in models of HER2+ CNS metastases. In a Phase 1 single agent study in HER2+ MBC, ONT-380 was well tolerated and provided clinical benefit with minimal EGFR-type toxicities, with an MTD of 600 mg BID using an API-in-capsule formulation. Based on the potential for dual blockade of HER2 to lead to clinical benefit, ONT-380 is being evaluated in combination with T-DM1 in patients previously treated with a taxane and trastuzumab for metastatic disease. Methods: This 3+3 dose escalation study evaluates escalating doses of ONT-380 in a new tablet formulation combined with T-DM1 at 3.6 mg/kg IV once every 21 days. Prior treatment with trastuzumab and a taxane are required. Prior lapatinib or neratinib therapy and asymptomatic brain metastases (treated or untreated) are allowed. Previous T-DM1 is not permitted. Normal left ventricular ejection fraction and anthracycline exposure ≤ 360 mg/m2 is required. Study assessments include safety, ONT-380 and T-DM1 PK, tumor response by RECIST 1.1, and CNS response by both modified RECIST and volumetric criteria. Dose escalation will be followed by enrollment of expansion cohorts in patients with and without CNS disease. Results: As of 21 May 2014, 7 patients have been treated with ONT-380 at 300 mg BID for 1–5 cycles. One dose limiting toxicity (DLT) of Grade 3 ALT/AST elevation was seen in the ONT-380 300 mg BID cohort, requiring a dose reduction for both agents with subsequent cohort expansion to 6 patients. No further DLTs have been seen in this cohort, and no other dose reductions have been required. Most toxicities have been Grade 1 or 2, with the most common regardless of attribution being nausea, fatigue, diarrhea, and thrombocytopenia. Two Grade 3 AEs have been reported, including the DLT of ALT/AST elevation, and one event of thrombocytopenia, considered related to T-DM1 but not ONT-380. There has been no Grade 3 diarrhea and no SAEs. In the four patients evaluable for response to date, best response has been 1PR, 2 SD, and 1 PD. Three patients with prior CNS radiation have had continued reduction in CNS lesions on study. Initial PK data indicate greater ONT-380 exposure is achieved with the new tablet formulation compared to the earlier capsule formulation with no evidence of drug interaction with T-DM1. Conclusions: Treatment with ONT-380 and T-DM1 has been associated with an acceptable safety profile, with only one DLT and minimal Grade 3 toxicity, including no Grade 3 diarrhea or rash. Early evidence of disease control has been seen, including in patients with CNS metastases. Dose escalation continues, and updated results will be presented for additional cohorts. Citation Format: Virginia F Borges, Erika Hamilton, Denise A Yardley, Jorge Chaves, Nathalie Aucoin, Cristiano Ferrario, Luke Walker, Ian Krop. A phase 1b study of ONT-380, an oral HER2-specific inhibitor, combined with ado-trastuzumab emtansine (T-DM1), in HER2+ metastatic breast cancer (MBC) [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P4-15-08.

Summary Introduction The phosphotidylinositol-3 kinase (PI3K)/serine–threonine kinase (AKT)/mammalian target of rapamycin (mTOR) signaling pathway is frequently altered in head and neck squamous cell cancer (HNSCC). PX-866 is an oral, irreversible, pan-isoform inhibitor of PI3K. Preclinical models revealed synergy with docetaxel and a phase 1 trial demonstrated tolerability of this combination. This randomized phase 2 study evaluated PX-866 combined with docetaxel in patients with advanced, refractory HNSCC. Methods Patients with locally advanced, recurrent or metastatic HNSCC who had received at least one and no more than two prior systemic treatment regimens were randomized (1:1) to a combination of docetaxel (75 mg/m2 IV every 21 days) with or without PX-866 (8 mg PO daily; Arms A and B, respectively). The primary endpoint was progression free survival (PFS). Secondary endpoints included objective response rate (RR), overall survival (OS), toxicity, and correlation of biomarker analyses with efficacy outcomes. Results 85 patients were enrolled. There was a non-significant improvement in response rate in the combination arm (14% vs. 5%; P = 0.13). Median PFS was 92 days in Arm A and 82 days in Arm B (P = 0.42). There was no difference in OS between the two arms (263 vs. 195 days; P = 0.62). Grade 3 or higher adverse events were infrequent, but more common in the combination arm with respect to diarrhea (17% vs. 2%), nausea (7% vs. 0%), and febrile neutropenia (21% vs. 5%); grade 3 or higher anemia was more frequent in arm B (7% vs. 27%). PIK3CA mutations or PTEN loss were infrequently observed. Conclusion The addition of PX-866 to docetaxel did not improve PFS, RR, or OS in patients with advanced, refractory HNSCC without molecular pre-selection.

This manuscript reports on a prospective, randomized study of cetuximab plus/minus a small molecule PI3K inhibitor (PX-866) targeting the protein product of PIK3CA, the gene with the highest rate of activating mutations in head and neck squamous cell cancer (HNSCC). The combination of PX-866 and cetuximab failed to improve outcomes compared with cetuximab alone in patients with advanced HNSCC. Background The phosphotidylinositol-3 kinase (PI3K)/serine–threonine kinase/mammalian target of rapamycin signaling pathway is frequently altered in head and neck squamous cell cancer (HNSCC). PX-866 is an oral, irreversible, pan-isoform inhibitor of PI3K. A phase I trial demonstrated tolerability of this combination. This randomized phase II study evaluated PX-866 combined with cetuximab in patients with advanced, refractory HNSCC. Methods Patients with recurrent or metastatic HNSCC who had received at least one and no more than two prior systemic treatment regimens were randomized (1 : 1) to cetuximab with or without PX-866 (8 mg p.o. daily; arms A and B, respectively). The primary end point was progression-free survival (PFS). Secondary end points included objective response rate (ORR), overall survival (OS), toxicity, and correlation of key biomarkers with efficacy outcomes. Results Eighty-three patients were enrolled. There was a similar response rate between arms (10% versus 7%). Of patients for whom tissue was assessable, 57% were human papillomavirus (HPV) positive. Median PFS was 80 days in both arms and there was no difference in OS between the two arms (211 versus 256 days). Overall toxicity was higher in arm A compared with arm B, especially in terms of nausea (53% versus 23%), vomiting (45% versus 15%), fatigue (43% versus 23%), diarrhea (40% versus 21%), and hypokalemia (25% versus 10%). Grade 3 or higher adverse events were infrequent, but more common in the combination arm although without a specific pattern.PIK3CA mutations were observed in 17% of the cases assessed, andPTEN loss was infrequently observed. Conclusion The addition of PX-866 to cetuximab did not improve PFS, RR, or OS in patients with advanced, refractory HNSCC enrolled without molecular preselection. In this contemporary cohort, HPV-positive patients comprised the majority, and neither HPV-positive nor HPV-negative patients derived clinical benefit for the addition of cetuximab plus PX-866.

Purpose: The objectives of the study were to evaluate the safety of daily oral PX-866 in combination with twice daily vemurafenib and to identify potential predictive biomarkers for this novel combination. Experimental Design: We conducted a phase I, open-label, dose-escalation study in patients with advanced BRAF V600–mutant solid tumors. PX-866 was administered on a continuous schedule in combination with vemurafenib. Patients underwent a baseline and on-treatment biopsy after 1-week of PX-866 monotherapy for biomarker assessment. Results: Twenty-four patients were enrolled. The most common treatment-related adverse events were gastrointestinal side effects. One dose-limiting toxicity (DLT) of grade 3 rash and one DLT of grade 3 pancreatitis were observed in cohort 2 (PX-866 6 mg daily; vemurafenib 960 mg twice daily) and cohort 3 (PX-866 8 mg daily; vemurafenib 960 mg twice daily), respectively. Of 23 response-evaluable patients, seven had confirmed partial responses (PR), 10 had stable disease, and six had disease progression. Decreases in intratumoral pAKT expression were observed following treatment with PX-866. Patients who achieved PRs had higher rates of PTEN loss by IHC (80% vs. 58%) and pathogenic PTEN mutations and/or deletions (57% vs. 25%). Two patients with durable PRs had an increase in intratumoral CD8+ T-cell infiltration following treatment with PX-866. Conclusions: PX-866 was well tolerated at its maximum tolerated single-agent dose when given in combination with a modified dose of vemurafenib (720 mg twice daily). Response to treatment appeared to be associated with PTEN loss and treatment with PX-866 seemed to increase CD8+ T-cell infiltration in some patients. Clin Cancer Res; 24(1); 22–32. ©2017 AACR.

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.

Introduction: The phosphotidylinositol-3 kinase/serine-threonine kinase (AKT)/mammalian target of rapamycin signaling pathway is frequently altered in non–small-cell lung cancer (NSCLC). PX-866 is an oral, irreversible, pan-isoform inhibitor of phosphotidylinositol-3 kinase. Preclinical models revealed synergy with docetaxel and a phase 1 trial demonstrated tolerability of this combination. This randomized phase 2 study evaluated PX-866 combined with docetaxel in patients with advanced, refractory NSCLC. Methods: Patients with locally advanced, recurrent, or metastatic NSCLC who had received at least one and no more than two prior systemic treatment regimens were randomized (1:1) to a combination of docetaxel (75 mg/m 2 intravenous every 21 days) with or without PX-866 (8 mg orally daily; arms A and B, respectively). The primary end point was progression-free survival (PFS). Secondary end points included objective response rate, overall survival (OS), toxicity, and correlation of biomarker analyses with efficacy outcomes. Results: A total of 95 patients were enrolled. Median PFS was 2 months in arm A and 2.9 months in arm B ( p = 0.65). Objective response rates were 6% and 0% in arms A and B, respectively ( p = 0.4). There was no difference in OS between the two arms (7.0 versus 9.2 months; p = 0.9). Grade 3 or higher adverse events were infrequent, but more common in the combination arm with respect to diarrhea (7% versus 2%), nausea (4% versus 0%), and vomiting (7% versus 0%). PIK3CA mutations or PTEN loss were infrequently observed. Conclusion: The addition of PX-866 to docetaxel did not improve PFS, response rate, or OS in patients with advanced, refractory NSCLC without molecular preselection.

Background This phase I, dose-finding study determined the safety, maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D), and antitumor activity of PX-866, a phosphatidylinositol 3-kinase inhibitor, combined with cetuximab in patients with incurable colorectal cancer or squamous cell carcinoma of the head and neck. Methods PX-866 was administered at escalating doses (6–8 mg daily) combined with cetuximab given at a 400 mg/m2 loading dose followed by 250 mg/m2 weekly. A “3 + 3” study design was used. Prior therapy with anti-EGFR therapies, including cetuximab, was allowed. Results Eleven patients were enrolled. The most frequent treatment-emergent adverse event was diarrhea (90.1 %), followed by hypomagnesemia (72.2 %), vomiting (72.2 %), fatigue (54.5 %), nausea (54.5 %), rash (45.5 %) and peripheral edema (40 %). No dose limiting toxicities were observed. The RP2D was 8 mg, the same as the single-agent PX-866 MTD. Best responses in 9 evaluable patients were: 4 partial responses (44.4 %), 4 stable disease (44.4 %), and 1 disease progression (11.1 %). The median progression free survival was 106 days (range: 1–271). Conclusion Treatment with PX-866 and cetuximab was tolerated with signs of anti-tumor activity. Further development of this combination is warranted.