Tucatinib Research Articles

A Biophysical Study of Molecular Interaction of Tucatinib with Bovine Serum Albumin

AbstractA profound understanding of the binding dynamics of drugs with plasma proteins is highly important as it determines its therapeutical potential. Herein, we have investigated the molecular interaction of Tucatinib (TUC), a novel, primitive and highly selective drug for treatment of HER2+ advanced unresectable breast cancer, with bovine serum albumin (BSA) using multi‐pronged spectroscopic techniques and molecular docking. TUC considerably quenched the intrinsic fluorescence of BSA via static quenching mechanism, and it binds to the hydrophobic cleft of subdomain IIA of BSA with a moderate binding affinity. The thermodynamic analysis revealed the major interplay of van der Waals forces and hydrogen bonding interactions in stabilising the binding. The Förster distance ‘r’ signifies feasible energy transfer between BSA and TUC. The conformational analyses indicate some alterations in the protein secondary structure as a consequence of some changes in the protein polar environment due to complex formation. The experimental results are supported by docking analyses.

Tucatinib and trastuzumab for previously treated HER2−mutated metastatic breast cancer (SGNTUC−019): A phase 2 basket study.

1105 Background: Approximately 2-5% of breast cancers harbor HER2 mutations, often occurring in hormone receptor-positive (HR+) disease. There are currently no approved treatment options for patients (pts) with HER2-mutated metastatic breast cancer (HER2-mut MBC). Tucatinib (TUC) is a tyrosine kinase inhibitor highly selective for HER2 and is approved for previously treated HER2+ MBC with or without brain metastases in combination with trastuzumab (Tras) and capecitabine. Here, we report the efficacy and safety results of TUC combined with Tras in pts with previously treated HER2-mut MBC. Methods: SGNTUC-019 (NCT04579380) is an open-label phase 2 basket study evaluating efficacy, safety, and tolerability of TUC and Tras in pts with metastatic HER2-altered solid tumors. Pts in the HER2-mut MBC cohort must have HER2 mutations determined locally by tissue- or blood-based next-generation sequencing, not be HER2+ per local testing, been previously treated with ≥1 systemic therapy in the locally advanced, unresectable, or metastatic setting, and if HR+, have received a CDK4/6 inhibitor. Pts were treated in 21-day cycles with TUC (300 mg orally twice a day) and Tras (8 mg/kg IV followed by 6 mg/kg every 3 wks). Pts with HR+ disease also received fulvestrant (F; 500 mg IM once every 4 wks starting from cycle 1 day 1, and cycle 1 day 15). Disease status was determined based on RECIST v1.1 with assessments performed every 6 wks for 24 wks and every 12 wks thereafter. The primary endpoint is cORR per investigator assessment. Secondary endpoints include OS, DCR, DOR, PFS, and safety. Results: As of Nov 1, 2023, 31 pts were enrolled in the HER2-mut MBC cohort. The median duration of follow-up for OS was 15.0 months. Twenty-seven (87%) pts had HR+ disease and 18 (58%) had lobular histology. The pts received a median of 4 prior lines of systemic therapy in any setting. cORR was 41.9% (90% CI, 26.9-58.2) with 13 responses including 2 complete responses. Median DOR was 12.6 months (90% CI, 4.7, not estimable), DCR was 80.6% (n=25; 90% CI, 65.3-91.2), median PFS was 9.5 months (90% CI, 5.4-13.8), and median OS was 20.1 months (90% CI, 15.9 to not estimable). The most common treatment-emergent adverse events (TEAEs) reported were diarrhea (64.5%) and nausea (35.5%). The most common grade ≥3 TEAEs reported were diarrhea (13%), alanine aminotransferase increase (10%), and hypertension (10%). Two (6.5%) pts discontinued TUC due to TEAEs, but these pts continued Tras. No deaths were due to TEAEs. Additional biomarker analyses will be included in the presentation. Conclusions: The investigational combination of TUC and Tras, plus F in pts with HR+ disease, was well tolerated and had clinical activity in pts with previously treated HER2-mut MBC. The results support further evaluation of the combination of TUC and Tras as a potential treatment option for this pt population. Clinical trial information: NCT04579380 .

Final results of a phase 2 study of tucatinib and trastuzumab for HER2-positive mCRC (MOUNTAINEER).

3509 Background: HER2 overexpression/amplification (HER2+) occurs in ~3%-5% of pts with metastatic colorectal cancer (mCRC) and up to ~10% of pts with RAS/BRAF wild-type (WT) mCRC. The primary results of the MOUNTAINEER study (NCT03043313) demonstrated that the combination of tucatinib (TUC), a highly selective HER2-directed TKI, and trastuzumab (Tras) was well tolerated with clinically meaningful activity in pts with chemo-refractory HER2+ mCRC. Confirmed ORR was 38.1%, median DOR was 12.4 months, and median OS was 24.1 months. Here, we present results from the final analysis of MOUNTAINEER. Methods: MOUNTAINEER is a multi-center, open-label, randomized, phase 2 trial. Eligible pts had HER2+ and RAS WT mCRC with progression on or intolerance to last systemic therapy. Previous HER2-directed therapies were not permitted. The trial consisted of Cohort A, comprising pts treated with TUC (300 mg PO BID) + Tras (8 mg/kg IV then 6 mg/kg IV Q3W), as well as pts randomized 4:3 to receive TUC+Tras (Cohort B) or TUC monotherapy (Cohort C). Pts randomized to Cohort C were allowed to crossover and receive TUC+Tras on radiographic progression or if they did not achieve a complete or partial response by Week 12. Study endpoints evaluated at final analysis include DOR per BICR, PFS per BICR, OS, and safety. Results: The median duration of follow-up was 32.4 months (IQR, 25.1-46.7), with an additional 16.1 months of follow-up since the primary analysis (data cutoff, 02-Nov-2023). A total of 116 pts received at least 1 dose of study treatment (Cohorts A+B, N = 86; Cohort C, N = 30). In Cohorts A+B, median DOR per BICR was 15.2 months (95% CI, 8.9-20.5), median PFS per BICR was 8.1 months (95% CI, 4.2-10.2), and median OS was 23.9 months (95% CI, 18.7-28.3). In Cohort C post-crossover (N = 28), median DOR was not reached (95% CI, 2.8 months-NE). Median OS in Cohort C was 21.1 months (95% CI, 17.0-NE). The most common TEAEs in Cohorts A+B were diarrhea (66.3%), fatigue (44.2%), and nausea (34.9%). The majority of TEAEs were low grade, and rates were stable with longer follow-up. The most common grade ≥3 TEAE was hypertension (7.0%). TEAEs leading to TUC discontinuation in Cohorts A+B occurred in 5.8% of pts, which was unchanged from the primary analysis. In Cohort C, the most common TEAEs post-crossover were diarrhea (39.3%), back pain (21.4%), and pyrexia (21.4%); the most common grade ≥3 TEAE was AST increase (10.7%). No deaths resulted from TEAEs in any cohort and no new safety signals were identified. Conclusions: TUC+Tras continued to be well tolerated with sustained efficacy in pts with chemo-refractory RAS WT HER2+ mCRC, demonstrating clinically meaningful activity of the combination on longer follow-up. TUC+Tras is an important chemotherapy-free treatment option in HER2+ mCRC. TUC+Tras is being further evaluated in the first-line setting in combination with chemotherapy in the ongoing phase 3 MOUNTAINEER-03 trial (NCT05253651) for pts with HER2+ mCRC. Clinical trial information: NCT03043313 .

Exploring the molecular basis of tucatinib interaction with human serum albumin: A spectroscopic and computational analysis

This study delves into the kinetics of interaction among anticancer drug tucatinib (TCT) and human serum albumin (HSA), a pivotal protein that transports substances in the bloodstream of humans. Employing biophysical techniques alongside in-silico approaches, the TCT-HSA complex formation is substantiated. This binding interaction is unequivocally confirmed by the inverse relationship between temperature and Stern-Volmer constant (KSV) and the hyperchromicity in UV–visible spectra. The binding constant (Kb) value (5.34 x 104 M−1) indicates a moderate affinity between TCT and HSA, with thermodynamic analysis pointing towards stabilization through hydrogen bonds and hydrophobic and van der Waals interactions. Moreover, despite causing alterations in the vicinity of Tyr and Trp amino acids, the introduction of TCT to HSA confers a substantial protective effect against the thermal denaturation of the protein. Circular dichroism unveils a decrease in the content of alpha helices upon TCT binding. At the same time, CD thermal analysis hints at a marginal increase in the melting temperature of HSA, indicating heightened stability at elevated temperatures. Molecular docking and competitive displacement assays confirm that the preferred binding site for TCT is subdomain IIA (Sudlow's site I) of HSA. Molecular dynamics simulations emphasize the stability of the TCT-HSA complex. This work sheds light on a detailed characterization of the HSA-TCT interaction, elucidating binding mechanisms and their consequential impact on HSA structure and stability.

Results from the phase 1b/2 SGNTUC-024 study: Assessment of tucatinib, trastuzumab, and FOLFOX for HER2+ GI cancers.

100 Background: HER2 is overexpressed in various GI tumors. Tucatinib (TUC), which is approved in combination with trastuzumab (Tras) in the US for previously treated RAS WT HER2+ metastatic colorectal cancer (mCRC), is a tyrosine kinase inhibitor highly selective for HER2. Preliminary safety and antitumor activity results of TUC + trastuzumab + FOLFOX in patients (pts) with HER2+ GI cancers are presented. Methods: The phase 1b/2 SGNTUC-024 (NCT04430738) study evaluated TUC + Tras + FOLFOX in pts with HER2+ metastatic GI cancers in Cohorts 1A, 1B, 1D (pts in Japan), and 2B. For Cohorts 1A, 1B, and 1D (enrolled sequentially), eligible pts had unresectable or metastatic HER2+ GI malignancies, including mCRC. Cohort 2B is still enrolling, and pts with HER2+ mCRC are eligible. Pts received a combination of TUC 150 mg orally twice a day (PO BID; Cohort 1A) or TUC 300 mg PO BID (Cohorts 1B, 1D, and 2B) + Tras + FOLFOX. Pts in Cohort 2B were enrolled to further assess the study regimen. Antidiarrheal prophylaxis was required for Cohort 1D. Results: As of July 10, 2023, 25 pts were treated (5, 11, 7, and 2 in Cohorts 1A, 1B, 1D, and 2B, respectively). In Cohort 1A (TUC 150 mg PO BID), the most common TEAEs were diarrhea, fatigue, nausea, and proteinuria (each in 60.0% [3/5]). For pts receiving TUC 300 mg PO BID, the most common TEAEs were diarrhea (90.0% [18/20]) and fatigue (65.0% [13/20]). Table 1 presents the overall summary of adverse events. In Cohort 1A, Treatment-emergent adverse events (TEAEs) leading to any treatment discontinuation were reported in 40.0% (2/5) pts, with 20.0% (1/5) discontinuing tucatinib. For pts treated with TUC 300 mg, TEAEs leading to treatment discontinuation were reported in 35.0% (7/20), with 15.0% (3/20) discontinuing tucatinib. One TEAE leading to death (aspiration) in Cohort 1A was unrelated to study treatment. Grade ≥3 diarrhea was observed in 45.5% (5/11) pts in Cohort 1B; most were observed in elderly pts or pts with gastric, gastroesophageal, or esophageal cancer or pts who were generally noncompliant with antidiarrheal treatment. No grade ≥3 diarrhea was observed in Cohort 1D. Among pts receiving TUC 300 mg, confirmed objective response rate was 83.3% (5/6) for mCRC, 40.0% (4/10) for gastroesophageal cancers, and 0% (0/4) for biliary tract cancer. Conclusions: TUC + Tras + FOLFOX showed manageable safety in the enrolled pt population and preliminary antitumor activity in pts with HER2+ mCRC and gastroesophageal cancer. This regimen will be compared with the standard of care (FOLFOX with or without bevacizumab/cetuximab) in the ongoing randomized, phase 3 study (MOUNTAINEER-03; NCT05253651) for pts with HER2+ RAS WT mCRC. Clinical trial information: NCT04430738 . [Table: see text]

Real-world patient characteristics and treatment patterns associated with tucatinib therapy in patients with HER2+ metastatic breast cancer.

1051 Background: Tucatinib (TUC) is an oral HER2-targeted therapy approved by the FDA in Apr 2020 for use in combination with trastuzumab and capecitabine (TRA+CAP) for patients with previously treated HER2+ metastatic breast cancer (MBC). In the randomized HER2CLIMB trial, median (95% CI) overall survival (mOS) and progression-free survival (PFS) for patients receiving TUC with TRA+CAP were 21.9 (18.3, 31.0) and 7.8 (7.5, 9.6) months, respectively. Median duration of therapy was 7.3 months. HER2CLIMB used a standard of care comparator arm and included patients with active and stable brain metastasis (BM). HER2CLIMB was conducted prior to approval of fam-trastuzumab deruxtecan (T-DXd) so did not assess the impact of TUC-based therapy following T-DXd. Objective: Describe patient characteristics, treatment patterns, and clinical outcomes for TUC-based treatment in the real-world setting. Methods: This retrospective study included patients in the Komodo Health dataset (aggregating data from patient administrative health claims in the United States) diagnosed with MBC between Jan 1, 2017 and Sep 3, 2022 and initiating TUC post- approval in Apr 2020. Patient characteristics were described in the baseline period (≤6 months from TUC initiation). Key outcomes were time to next treatment (TTNT; as a proxy for PFS), time to discontinuation (TTD), and persistence (proportion continuing treatment at each timepoint) in all TUC-treated patients, and in patients receiving TUC immediately following T-DXd. Results: Of 16,990 patients identified with HER2+ MBC, 528 received TUC-based treatment. Of these, 57 (11%), 164 (31%), 154 (29%), and 153 (29%) received TUC in first-line (1L), second-line (2L), third-line (3L), and fourth-line or later (4L+), respectively. Median follow-up from TUC initiation was 9 months. Overall, 400 patients (76%) had BM prior to initiating TUC (43 [75%], 138 [84%], 111 [72%], and 108 [71%] in 1L, 2L, 3L, and 4L+, respectively). Median (95% CI) TTNT was 10.7 (9.4, 13.1) months overall and 11.5 (9.6, 14.4) in patients receiving TUC in 2L or 3L. Median (95% CI) TTD was 8.5 (7.2, 9.3) months overall, and 9.1 (7.7, 9.9) in patients receiving TUC in 2L or 3L. TUC persistence in the overall cohort was 46% (91/200) at 12 months and 35% (40/115) at 18 months. Sixty-one patients (12%) received TUC immediately following T-DXd (median 4L; 12 in 2L/3L, 49 in 4L+); of whom 36 (59%) had BM prior to initiating TUC. TTNT and TTD for patients treated with TUC following T-DXd were 7.5 (5, 13.3) and 7.3 (3.2, 9.5) months, respectively. Conclusions: In the real-world setting, a higher proportion of patients receiving TUC had BM compared with the HER2CLIMB patient population. TUC-based treatment in the real world is used in multiple lines of therapy and is associated with a similar TTNT and TTD to PFS observed in HER2CLIMB, inclusive of a cohort of patients who received TUC following T-DXd therapy.

HER2 testing in the MOUNTAINEER trial: Analysis of treatment response based on central HER2 assessment using IHC/ISH and NGS.

3528 Background: Tucatinib (TUC) is a highly selective HER2-directed TKI approved by the FDA in combination w/trastuzumab (Tras) for treatment (tx) of pts w/ RAS wild-type HER2+ unresectable or metastatic colorectal cancer (mCRC) that has progressed following tx w/ fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy. There are currently no established best practices for HER2 testing/interpretation in mCRC. Here we present results of central HER2 testing across multiple platforms and response to tx for MOUNTAINEER pts treated w/ TUC + Tras based on central HER2 status. Methods: MOUNTAINEER (NCT03043313) enrolled pts w/ local HER2+ mCRC using ≥1 method: IHC, ISH, and/or NGS testing; retrospective central assessment of HER2 status was performed on multiple platforms. Pts in cohorts A+B were treated w/ TUC + Tras; pts in cohort C were treated w/ TUC monotherapy. Confirmed objective response rates (cORRs) using RECIST v1.1 per BICR, DOR, and PFS were calculated for pts treated w/ TUC + Tras based on each central testing method. Results: 114 pts were enrolled in cohorts A (n = 45), B (n = 39), and C (n = 30) w/ HER2+ tumors per ≥1 local testing method. Of samples submitted for central testing for Cohorts A and B, 70 per IHC/FISH, 50 per tissue NGS, and 71 per blood NGS had evaluable results. In all cohorts, there was 81.0% (95% CI, 68.6-90.1) agreement between blood and tissue NGS, 92.6% (95% CI, 83.7-97.6) between IHC/FISH and tissue NGS, and 79.5% (95% CI, 69.2-87.6) between IHC/FISH and blood NGS. In cohorts A and B, pts w/ HER2+ tumors by central IHC/ISH had a mDOR of 16.4 months (95% CI: 10.6-25.5) and mPFS of 10.1 months (95% CI: 4.2-15.2). cORR was 41.1% to 47.7% for the 3 assays. Detailed HER2 results are presented in the Table. Conclusions: Percent agreement of HER2 status was highest w/ tissue-based platforms. Detection of HER2 amplification by ctNDA NGS is useful; however, pts w/o HER2 amplification should be confirmed w/ a tissue-based assay. HER2 status by all 3 platforms predicted tx response to TUC + Tras. cORR in IHC2+/ISH+ was numerically lower but remained clinically relevant. These data support use of the above methods to identify HER2+ mCRC patients that may benefit from TUC + Tras. Clinical trial information: NCT03043313 . [Table: see text]

MOUNTAINEER-03: Phase 3 study of tucatinib, trastuzumab, and modified FOLFOX6 as first line treatment in HER2+ metastatic colorectal cancer.

TPS3631 Background: The current standard of care (SOC) for the treatment of metastatic colorectal cancer (mCRC) is multi-agent chemotherapy, with or without a VEGF or EGFR inhibitor. Human epidermal growth factor receptor-2 (HER2) is a validated clinical target in breast and gastric cancers. HER2 amplification occurs in 3%–5% of patients with mCRC; the rate of HER2 amplification can increase to approximately 10% in patients with RAS/BRAF wild-type mCRC tumors. Tucatinib (TUC)—a highly selective, HER2-directed tyrosine kinase inhibitor—is approved in multiple regions for HER2-positive (HER2+) metastatic breast cancer, approved in the US for HER2+ metastatic colorectal cancer, and under investigation in gastrointestinal cancers. MOUNTAINEER (NCT03043313) evaluated the safety and efficacy of TUC and trastuzumab (Tras) in patients with treatment-refractory RAS wild-type, HER2+ mCRC. Results from the primary endpoint analysis showed clinically meaningful activity, with a confirmed objective response rate (ORR) per blinded independent central review (BICR) of 38.1% (95% confidence interval [CI] 27.7, 49.3) and median duration of response per BICR of 12.4 months (95% CI 8.5, 20.5). Results also demonstrated TUC + Tras was well tolerated, with a low discontinuation rate (5.8%) and no deaths due to adverse events. MOUNTAINEER-03 will further investigate TUC in combination with modified FOLFOX (mFOLFOX) and Tras in patients with RAS wild-type HER2+ mCRC. Methods: MOUNTAINEER-03 (NCT05253651) is a global, open-label, randomized, phase III study for first-line treatment of HER2+ and RAS wild-type mCRC. Approximately 400 patients will be randomized 1:1 to the TUC experimental arm (TUC [300 mg orally twice daily] + Tras + mFOLFOX) or the SOC arm (mFOLFOX alone or in combination with either bevacizumab or cetuximab). HER2 status is determined centrally with tissue-based HER2 immunohistochemistry and in situ hybridization assays. Eligible patients must not have received prior treatment in the metastatic setting but may have received adjuvant treatment if completed > 6 months prior to enrollment. Patients must be ≥18 years old with an Eastern Cooperative Oncology Group Performance Status of ≤1 and RAS wild-type mCRC. Patients with treated stable central nervous system metastases are eligible. Randomization is stratified by primary tumor location (left-sided vs other) and liver metastases (presence/absence). The primary endpoint is progression-free survival per RECIST v1.1 assessed by BICR. Key secondary endpoints are overall survival and confirmed ORR per RECIST v1.1 assessed by BICR. Enrollment is ongoing in North America, Asia, Australia, and Europe. Clinical trial information: NCT05253651 .

Tucatinib and trastuzumab for previously treated HER2-positive metastatic biliary tract cancer (SGNTUC-019): A phase 2 basket study.

4007 Background: Biliary tract cancer (BTC) is an aggressive malignancy with a poor prognosis, and current treatment options for advanced BTC are limited, with second-line therapy, FOLFOX and S-1 offering an objective response rate (ORR) of 5.0% and 7.5%, respectively. Up to 20% of BTCs overexpress human epidermal growth factor receptor 2 (HER2). Tucatinib (TUC) is a highly selective HER2-directed TKI approved for HER2-positive (HER2+) metastatic breast and colorectal cancer. Discussed here are the efficacy and safety results of TUC combined with Trastuzumab (Tras) in pts with previously treated HER2+ metastatic BTC. Methods: SGNTUC-019 (NCT04579380) is an open-label phase 2 basket study evaluating efficacy, safety, and tolerability of TUC and Tras in pts with HER2-altered solid tumors. Pts in the BTC cohort had been previously treated with and progressed after ≥1 line of systemic therapy for metastatic disease. Eligible pts had locally determined HER2+ (defined as HER2 overexpression determined by immunohistochemistry [IHC] 3+ or HER2 amplification determined by in situ hybridization assay or next-generation sequencing) metastatic BTC. Pts were treated on a 21-day cycle with TUC (300 mg orally twice a day) and Tras (8 mg/kg IV followed by 6 mg/kg every 3 wks). Disease status was determined based on RECIST v1.1 with assessments performed every 6 wks for 24 wks and every 12 wks thereafter. The primary endpoint is confirmed objective response rate (cORR) per investigator assessment. Secondary endpoints include overall survival (OS), disease control rate (DCR), duration of response (DOR), progression-free survival (PFS), and safety. Results: Thirty pts were enrolled in the BTC cohort as of data cutoff date of 30 Nov 2022. The median duration of follow-up was 8.3 months. cORR was 46.7% (90% CI, 30.8, 63.0), with 14 responses including 1 complete and 13 partial responses. Median DOR was 6.0 months (90% CI, 5.5, not estimable). DCR was 76.7% (n=23; 90% CI, 60.6, 88.5), and median PFS was 5.5 months (90% CI, 3.9, 8.1). At data cutoff, 13 (43.3%) patients had died, and the 12-months OS rate was 53.8% (90% CI, 35.2, 69.1%). Overall, the most common treatment-emergent adverse events (TEAEs) reported were pyrexia (43.3%) and diarrhea (40.0%). Grade ≥3 TEAEs were reported in 18 (60.0%) of 30 pts; however, only 6 (20.0%) and 2 (6.7%) of these pts had Grade ≥3 TEAEs related to TUC and Tras, respectively. Two (6.7%) pts discontinued TUC due to TEAEs, cholangitis and liver disorder. No deaths were due to TEAEs. Conclusions: The combination of TUC and Tras was well tolerated in pts with previously treated HER2+ metastatic BTC. The observed antitumor activity supports the combination of TUC and Tras as a future chemotherapy-free treatment option for this population with historically poor outcomes. Clinical trial information: NCT04579380 .

Abstract 5060: Tucatinib does not alter oxaliplatin PK or associated renal function: An OCT2 and MATE transport inhibition study

Abstract Background: Oxaliplatin (OX)-containing regimens are frequently utilized to treat gastrointestinal (GI) cancers. OX is eliminated predominately via urinary excretion (GFR and active tubular secretion). The contribution of active transport via OCT2 and MATE1/2-K to OX clearance is not fully understood. Tyrosine kinase inhibitors (TKIs) are frequently found to interact with OCT2/MATE transporters; however, a gap in knowledge remains between their clinical potential to impact OX pharmacokinetics (PK) and in turn, impact renal function. Tucatinib (TUC) is a highly selective human epidermal growth factor receptor 2 (HER2)-directed TKI approved in multiple regions in combination with trastuzumab and capecitabine for adult patients with metastatic HER2+ breast cancer and is currently being investigated in other HER2+ tumors. TUC inhibits OCT2/MATE-mediated transport of metformin and creatinine in vitro and in vivo. In this study, we investigated the impact of TUC on OX plasma PK, OX renal clearance (Clr), and renal function. Methods: In vitro inhibition of OCT2/MATE-mediated transport of OX by TUC was assessed in OCT2, MATE1, or MATE2-K-expressing MDCK-II cells. SGNTUC-024 (NCT04430738) is a Ph1b/2 clinical study in patients with HER2+ GI cancers evaluating the impact of TUC on the safety and PK of OX. Patients received TUC 150 mg (Cohort 1A) or 300 mg (Cohort 1B) BID starting on C1D8 of a 2-week cycle in combination with modified FOLFOX6/7. Intensive PK was collected in plasma and urine for OX alone (C1D1) or with steady-state TUC (C2D1). Total plasma platinum (Pt, analyzed as a surrogate for OX and catabolites), plasma Pt ultrafiltrate (PUF, unbound), and urine Pt were quantitatively analyzed via ICP-MS. Serum Cystatin C (CysC) was measured as a pharmacodynamic (PD) renal function marker in Cohorts 1A and 1B. Results: TUC inhibited in vitro OX transport by MATE1 (IC50 = 0.0639 µM), MATE2-K (IC50 = 0.0382 µM), and OCT2 (IC50 = 0.491 µM). In 11 patients, total Pt and PUF AUC0-8h geometric mean ratio (GMR) and 90% confidence intervals (CI) between patients who received OX alone compared to in combination were 1.1 (0.98, 1.3) and 1.0 (0.78, 1.4) in Cohort 1A (n=4) and 1.1 (0.96, 1.2) and 1.0 (0.98, 1.1) in Cohort 1B (n=7), respectively. OX GM (%CV) renal clearance (Clr,0-8h in mL/min) and fraction excreted 24h post-dose (fe,0-24h) were similar with and without TUC in both Cohort 1A (C1D1 Clr0-8h = 277 (33), fe,0-24h = 22% (17); C2D1 Clr0-8h = 249 (78), fe,0-24h = 21% (15)) and Cohort 1B (C1D1 Clr0-8h = 189 (37), fe,0-24h = 17.7% (16); C2D1 Clr0-8h = 177 (40), fe,0-24h = 16.6% (35)). Reversible slight increases in CysC (normalized to baseline) on day 3 of each cycle, irrespective of tucatinib, were observed. Conclusions: This investigation of in vitro and in vivo determinants of OX PK demonstrates that TUC does not alter the renal clearance of oxaliplatin nor renal function when OX is administered in combination with TUC. Citation Format: Ariel R. Topletz-Erickson, Anthony Lee, Vineet Kumar, Michelle Ubowski, JoAl G. Mayor, Layth I. Abdulrasool, Clark M. Henderson, Joseph A. Ware, Christopher J. Endres. Tucatinib does not alter oxaliplatin PK or associated renal function: An OCT2 and MATE transport inhibition study. [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 5060.

MOUNTAINEER-03: Phase 3 study of tucatinib, trastuzumab, and mFOLFOX6 as first-line treatment in HER2+ metastatic colorectal cancer—Trial in progress.

TPS261 Background: Current standard of care (SOC) for treatment (tx) of metastatic colorectal cancer (mCRC) is multi-agent chemotherapy, w/ or w/o a VEGF- or EGFR-inhibitor. HER2 is a validated clinical target in breast and gastric cancers. HER2 amplification occurs in 3%-5% of patients (pts) w/ mCRC; the rate of HER2 amplification can increase to ~10% in pts w/ RAS/BRAF wild-type mCRC tumors. Tucatinib (TUC), a highly selective, HER2-directed tyrosine kinase inhibitor, is approved in multiple regions for HER2+ metastatic breast cancer and is being investigated in gastrointestinal cancers. MOUNTAINEER (NCT03043313) evaluated the safety and efficacy of TUC and trastuzumab (Tras) in pts w/ tx refractory RAS wild-type, HER2+ mCRC. Results from the primary endpoint analysis showed clinically meaningful activity (confirmed ORR of 38.1% and median DOR of 12.4 months) and demonstrated TUC + Tras was well tolerated with a low discontinuation rate (5.8%) and no deaths due to AEs. MOUNTAINEER-03 will further investigate TUC in combo w/ mFOLFOX and Tras in pts w/ RAS wild-type, HER2+ mCRC. Methods: MOUNTAINEER-03 (NCT05253651) is a global, open label, randomized, phase 3 study for 1L tx of HER2+ and RAS wild-type mCRC. Approximately 400 pts will be randomized 1:1 to the TUC experimental arm (TUC [300 mg PO BID] + Tras + mFOLFOX) or the SOC arm (mFOLFOX alone or in combo w/ either bevacizumab or cetuximab). HER2 status is determined centrally w/ tissue based HER2 immunohistochemistry and in situ hybridization assays. Eligible pts must not have received prior tx in the metastatic setting but may have received adjuvant tx if completed > 6 months prior to enrollment. Pts must be ≥18 years of age w/ an ECOG performance status of ≤1 and RAS wild-type mCRC. Pts w/ treated stable central nervous system metastases are eligible. Randomization is stratified by primary tumor location (left-sided vs other) and liver metastases (presence/absence). Primary endpoint is progression-free survival per RECIST v1.1, assessed by blinded independent central review (BICR). Key secondary endpoints are overall survival and confirmed objective response rate per RECIST v1.1 assessed by BICR. Enrollment is ongoing in the US, w/ global sites planned. Clinical trial information: NCT05253651 .

LBA27 Additional analyses of MOUNTAINEER: A phase II study of tucatinib and trastuzumab for HER2-positive mCRC

HER2 amplification/overexpression (HER2+) occurs in ∼3-5% of patients (pts) with metastatic colorectal cancer (mCRC). The primary analysis of MOUNTAINEER (NCT03043313) in cohorts A+B treated with tucatinib (TUC) + trastuzumab (Tras) was previously reported and showed tolerability and a confirmed objective response rate (cORR) per blinded independent central review (BICR) of 38.1%. Here, additional results of TUC monotherapy (cohort C) are reported. have been reported in a prior presentation (Strickler et al. ESMO-WCGI 2022 abstract no. LBA-2). Eligible pts had HER2+ (per local IHC, ISH, or NGS testing) RAS WT mCRC refractory to standard of care. Pts who initially received TUC monotherapy could cross over and receive TUC + Tras for radiographic progression or stable disease by 12 weeks. Prespecified analyses for cohort C include ORR by 12 weeks and disease control rate (DCR) by BICR; cORR by BICR for crossover pts, and safety for monotherapy and crossover pts. As of 28 Mar 2022, 86 pts received ≥1 dose of study treatment in cohorts A+B and 30 pts in cohort C. The ORR by week 12 in cohort C was 3.3% (95% CI, 0.1, 17.2) with DCR of 80.0%. Twenty-eight of 30 pts (93.0%) crossed over to received TUC + Tras, with cORR of 17.9% (95% CI, 6.1, 36.9). The most common AEs with TUC monotherapy were diarrhoea (33.3%), abdominal pain (20.0%), and fatigue (20.0%), which were grade (gr) 1 or 2; the most common gr ≥3 events were ALT/AST increase (6.7% for both). The most common AE for post-crossover pts was diarrhoea (35.7%) which was gr 1 or 2; the most common gr ≥3 events were ALT/AST increase (7.1% and 10.7%, respectively). There were no fatal AEs with TUC monotherapy or TUC + Tras. TUC monotherapy and TUC + Tras after crossover were well tolerated, consistent with the primary analysis. Disease stabilization was observed in most pts on TUC monotherapy; radiographic responses increased slightly after Tras addition. Monotherapy, crossover, and response data from the primary analysis show that concurrent initiation of dual HER2 blockade with TUC + Tras achieves optimal clinical benefit.

361P Tucatinib plus trastuzumab in patients (Pts) with HER2-positive metastatic colorectal cancer (mCRC): Patient-reported outcomes (PROs) from ph II study MOUNTAINEER

HER2 amplification/overexpression (HER2-positive [HER2+]) is reported in ∼3-5% of all pts with mCRC. Treatment strategies for mCRC focus on prolonging survival, delaying tumor progression, and maintaining health-related quality of life (HRQoL). Tucatinib (TUC) is a highly selective, HER2-directed, tyrosine kinase inhibitor. Results from the MOUNTAINEER (NCT03043313) study demonstrated that dual HER2 inhibition with TUC and trastuzumab (T) in pts with HER2+ RAS WT mCRC is well tolerated with durable clinical benefit. Here we report the impact of TUC + T on HRQoL in pts from MOUNTAINEER. MOUNTAINEER is a global, multi-center, open-label, phase 2 trial that enrolled pts with HER2+ RAS WT mCRC previously treated with fluoropyrimidine, oxaliplatin, irinotecan, and anti-VEGF mAb. Overall, 117 pts were enrolled or randomized to receive TUC + T (cohorts A [n=45] and B [n=41]) or TUC monotherapy (cohort C [n=31]). HRQoL was assessed with EQ-5D-5L and EORTC QLQ-C30 for cohorts B and C. Cohort A was not assessed for HRQoL. Questionnaires were administered at predose on Cycle 1 Day 1 (C1 D1), C1 D8, C1 D15, then every D1 of C2-4 and every 3 following cycles until end of treatment. HRQoL data for cohorts B and C were analyzed using descriptive statistics. Thirty-seven pts in cohort B and 28 pts in cohort C had ≥1 dose of study treatment and completed baseline and at least 1 follow-up HRQoL assessment. For both cohorts, the mean changes from baseline during the treatment period for EORTC QLQ-C30 generally remained stable across all scales, including global health status/QoL and functional domains. Descriptive analyses showed some fluctuations in observed individual domain scores; however, global health status/QoL remained stable over time. EQ-5D-5L VAS scores also remained similar over time. HRQoL was maintained for pts treated with TUC + T or TUC monotherapy throughout the treatment period. These results, together with the primary efficacy and safety data from MOUNTAINEER, further support the overall tolerability profile of TUC + T and suggest this regimen may be an important treatment option for pts with HER2+ mCRC.

MO31-4 Phase 1b/2 trial of tucatinib+trastuzumab+/-chemotherapy or pembrolizumab in patients with metastatic HER2+ GI cancers

Human epidermal growth factor receptor 2 (HER2) gene amplification or protein overexpression (HER2+) occurs in many gastrointestinal (GI) cancers. Tucatinib (TUC) is a highly selective HER2-directed tyrosine kinase inhibitor with minimal EGFR inhibition, approved for HER2+ metastatic breast cancer. In patient-derived xenograft models of HER2+ GI tumors, TUC+trastuzumab (T) showed superior anti-tumor activity compared with either agent alone (Kulukian 2020). In the MOUNTAINEER study, TUC+T in HER2+ metastatic colorectal cancer (CRC) resulted in an objective response rate of 52% (interim results, Strickler 2019).

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

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

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

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

Safety and efficacy of monoclonal antibodies and tyrosine kinase inhibitors in advanced breast carcinoma.

e13017 Background: Novel drugs that target HER2 receptors have shown promise in the treatment of Advanced breast carcinoma (BC). We study here the safety and efficacy of select monoclonal drugs (Mab) and tyrosine kinase inhibitors (TKIs) in the treatment of advanced BC. Methods: Following the PRISMA guidelines, we searched the literature on PubMed, Cochrane, Embase & clinicaltrials.gov. A total of 1054 articles were screened, and 6 studies were included. Results: In a phase III trial comparing Margetuximab (MAR) vs Trastuzumab (TRA), the overall survival (OS) and Progression free survival (PFS) was superior for MAR (21.6m Vs 19.8m & 5.7m Vs 4.4m respectively). However, the side effect profile is comparable for both drugs.Neutropenia (50 %) was a key problem in an ongoing trial including Zenocutuzumab (ZENO), resulting in dosage reduction. Similarly, phase III trials incorporating TKIs such as Neratinib (NER) and Tucatinib (TUC), there was improved OS (21m Vs 18.7, 24.7m Vs 19.2m respectively) as compared to Standard of care and chemotherapy. Regarding safety profile, these therapies are generally well tolerated with manageable side effects as listed in the table. Conclusions: Both monoclonal antibodies and tyrosine kinase inhibitors show clinically significant benefits in advanced HER2 positive breast carcinoma. However, more evidence and randomized clinical trials are needed to further establish their role in this rapidly evolving field.[Table: see text]

19TiP SGNTUC-019 phase II basket study of tucatinib and trastuzumab in solid tumors with human epidermal growth factor receptor 2 alterations: Uterine and cervical cancer cohorts

The prognosis of locally-advanced unresectable or metastatic (LA/M) cervical and uterine cancer remains poor, with HER2 alterations occurring in 0.5-21% of cervical cancers and 2-80% of uterine cancers, respectively. Tucatinib (TUC), a highly selective HER2 directed TKI, is approved in combination with trastuzumab (Tras) and capecitabine in multiple regions for HER2+ metastatic breast cancer and is being investigated in other HER2+ cancers, including LA/M cervical and uterine cancer. SGNTUC-019 (NCT04579380) is an open-label, international phase II basket study evaluating TUC and Tras in adult patients (pts) with LA/M HER2+ or HER2-mutated solid tumors.

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

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

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

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