Tukysa (tucatinib)

P1, N=25, Active, not recruiting, Merck Sharp & Dohme LLC | Trial primary completion date: Dec 2023 --> Jan 2025

P1/2, N=18, Recruiting, Jonsson Comprehensive Cancer Center | Phase classification: P1b --> P1/2 | Trial completion date: Apr 2025 --> Apr 2026 | Trial primary completion date: Apr 2024 --> Apr 2025

We postulate that telangiectasias may be a previously unreported dermatologic side effect of combination treatment with tucatinib and T-DM1. Electrocautery is a safe and effective procedure to reduce the appearance of telangiectasias and improve patient satisfaction during chemotherapy.

Little is known regarding the outcomes associated with tucatinib combined with trastuzumab and capecitabine (TTC) after trastuzumab-deruxtecan exposure among patients with ERBB2 (previously HER2)-positive metastatic breast cancer (MBC)...The median number of prior treatment lines for metastatic disease at TTC treatment initiation was 4 (range, 2-15), including 82 patients (81.2%) with previous trastuzumab and/or pertuzumab and 94 (93.1%) with previous ado-trastuzumab-emtansine) exposure...In this study, TTC therapy was associated with clinically meaningful outcomes in patients with ERBB2-positive MBC after previous trastuzumab-deruxtecan treatment, including those with brain metastases. Prospective data on optimal drug sequencing in this rapidly changing therapeutic landscape are needed.

At present, standard of care first-line treatment for those with HER2-positive mCRC remains chemotherapy in combination with epidermal growth factor receptor (EGFR) inhibitors or bevacizumab, depending on RAS/BRAF mutational status and tumor sidedness...While the choice of anti-HER2 therapy is empiric given lack of head-to-head comparisons, the combination of trastuzumab plus tucatinib has received FDA accelerated approval for use in this setting and is generally the authors' preference. Trastuzumab plus lapatinib, trastuzumab plus pertuzumab, and trastuzumab deruxtecan (T-DXd) also have evidence of efficacy in this setting...These include the optimal sequence of anti-HER2 therapies with chemotherapy and anti-EGFR therapies, the optimal combination partners for anti-HER2 therapies, and the incorporation of predictive biomarkers to guide use of anti-HER2 therapies. Results of ongoing studies may thus alter the treatment paradigm above in the coming years.

P1, N=41, Completed, Dana-Farber Cancer Institute | Active, not recruiting --> Completed

P3, N=565, Recruiting, Seagen Inc. | Trial completion date: Apr 2024 --> Oct 2027

P1/2; Phase classification: P2 --> P1/2

P2, N=30, Recruiting, Criterium, Inc. | Trial completion date: May 2025 --> Aug 2027 | Trial primary completion date: Nov 2023 --> Jun 2027

P2, N=252, Completed, Genentech, Inc. | Active, not recruiting --> Completed

P2, N=70, Active, not recruiting, Seagen Inc. | Trial primary completion date: Jan 2024 --> Jul 2024

We also found that ErbB2's nuclear localization signal was not essential for LCR activity, but rather the cellular ErbB2 protein level and activation status that were inhibited by tucatinib and CP-724714...Expanding our investigation to directly assess the impact of ErbB2 on viral gene expression, quantitative analysis of E6 and E7 transcript levels in HPV16 and HPV18 transformed cell lines unveiled a noteworthy decrease in oncogene expression following ErbB2 depletion, concomitant with the downregulation of Akt and ERK signaling pathways. In light of these findings, we propose that ErbB2 holds promise as potential target for treating HPV infections and HPV-associated malignancies by silencing viral gene expression.

L-JIMT-1 cells were resistant to all five tyrosine kinase inhibitors tested in vitro (afatinib, erlotinib, lapatinib, sapitinib, and tucatinib). In a mouse model, all three ADCs inhibited the growth of L-JIMT-1 lung metastases compared to a vehicle, but DV and T-DXd more strongly than T-DM1, and DV treatment led to the smallest tumor burden. The L-JIMT breast cancer lung metastasis model developed may be useful in the evaluation of anti-cancer agents for multiresistant HER2-positive advanced breast cancer.

P1/2, N=198, Recruiting, Seagen Inc. | Not yet recruiting --> Recruiting

P2, N=30, Recruiting, UNICANCER | Not yet recruiting --> Recruiting

P2, N=66, Recruiting, Institut Curie | Active, not recruiting --> Recruiting

We found that TH-4000E ([(E)-4-[[4-(3-bromo-4-chloroanilino)pyrido[3,4-d]pyrimidin-6-yl]amino]-4-oxobut-2-enyl]-dimethyl-[(3-methyl-5-nitroimidazol-4-yl)methyl]azanium) (1-1000 nM) had potent and highly selective toxic effects on HER2 breast cancer cells and inhibited the phosphorylation of HER family kinases at lower doses than that of Lapatinib and Tucatinib. The prodrug TH-4000 ([(E)-4-[[4-(3-bromo-4-chloroanilino)pyrido[3,4-d]pyrimidin-6-yl]amino]-4-oxobut-2-enyl]-dimethyl-[(3-methyl-5-nitroimidazol-4-yl)methyl]azanium;bromide) (50 mg/kg) effectively suppressed the tumor growth with less liver damage in mouse tumor models. This hypoxia-targeted strategy has possessed advantage in avoiding drug-induced liver damage, TH-4000 could be a promising drug candidate for the treatment of HER2 breast cancer.

P1, N=30, Recruiting, The Netherlands Cancer Institute | Not yet recruiting --> Recruiting

P2, N=30, Recruiting, Sunnybrook Health Sciences Centre | Not yet recruiting --> Recruiting

This activity is supported by educational grants from Natera Inc and Pfizer Inc. Frequency and clinical relevance of HER2 aberrations among patients with mCRC Published data from the pivotal Phase II MOUNTAINEER trial evaluating tucatinib/trastuzumab for previously treated HER2-positive mCRC; recent FDA approval and optimal incorporation into practice Available efficacy and safety findings with trastuzumab deruxtecan (T-DXd) for patients with HER2-expressing mCRC (eg, from the DESTINY-CRC01 and DESTINY-CRC02 trials); current and potential nonresearch role Incidence of KRAS G12C mutations in patients with mCRC; early data with sotorasib and adagrasib monotherapy Biological rationale for combining KRAS G12C inhibitors with EGFR antibodies Recently presented results from the Phase III CodeBreaK 300 study evaluating sotorasib with panitumumab versus standard therapy for chemorefractory mCRC with KRAS G12C mutations; implications for clinical practice Early data with and ongoing evaluations of other targeted strategies for mCRC

Even though data were collected before the wide availability of tucatinib, neratinib and trastuzumab deruxtecan in Canada, the PMT cohort revealed the emergence of new therapeutic combinations and a shift from lapatinib usage to T-DM1 choice was observed. The absence of a consensus on post-second-line treatment highlights the pressing need for more efficient therapeutic alternatives beyond the currently available options. This study not only offers valuable insights into the present landscape of third-line treatment in Canada but validates the significance and effectiveness of the PMT registry as a tool for generating pan-Canadian real-world evidence in oncology and its capacity to provide information on evolution of therapeutic practices.

P2, N=477, Recruiting, Gruppo Oncologico del Nord-Ovest | N=300 --> 477

P2, N=66, Active, not recruiting, Institut Curie | Not yet recruiting --> Active, not recruiting

Systemic therapies under investigation for LMD in breast cancer include tucatinib, trastuzumab deruxtecan, and paclitaxel trevatide; trastuzumab is the main intrathecal agent currently under investigation. Large retrospective cohorts with various inclusion criteria and treatment regimens provide some real-world data. However, there remains an urgent need for randomised clinical trials which include patients with LMD across all breast cancer subtypes.

The average monthly cost for the treatment of neoplastic diseases was $17,900 with a price of $44,000 for futibatinib (used to treat cholangiocarcinomas with FGFR2 fusions) and minimum of $5100 for binimetinib (melanoma). The average monthly cost for the treatment of non-neoplastic diseases was $6800 with a maximum of $17,000 for belumosudil (graft vs. host disease) and a minimum of $200 for netarsudil eye drops (glaucoma). There is a negative correlation of the cost of the drugs and the incidence of the targeted disease. Many of these agents are or were designated as orphan drugs meaning that there are fewer than 200,000 potential patients in the United States.

P1/2, N=120, Recruiting, Seagen Inc. | Phase classification: P1b/2 --> P1/2

P1, N=30, Not yet recruiting, The Netherlands Cancer Institute

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.

P1/2, N=198, Not yet recruiting, Seagen Inc.

P1/2, N=245, Active, not recruiting, AstraZeneca | Phase classification: P1b/2 --> P1/2

In vitro and in vivo patient-derived xenograft experiments revealed that pretreatment of the TKR subgroup with a tyrosine kinase inhibitor (lapatinib or tucatinib) could inhibit HER2 signaling and induce accumulated expression of nonfunctional HER2, resulting in increased sensitivity to the sequential HER2-targeting, Ab-drug conjugate DS-8201. Our findings identify clinically relevant subgroups and provide potential therapeutic strategies for HER2-low TNBC subtypes.

We ultimately propose an evidence-based treatment algorithm for clinicians treating HER2 + BCs patients with BMs.

Tucatinib had no clinically relevant effects on studied ECG parameters. This study constitutes a clearly negative TQT study per ICH E14 guidance.

Without any doubt, the best data come from trastuzumab deruxtecan (TDXd), a third-generation antibody-drug conjugate that had shown in 2021 an impressive improvement in progression-free survival (PFS) compared with TDM1...However, because these studies were not randomized, whether TDXd is a better option compared to tucatinib-based treatment in this setting remains a matter of debate...In the PHOEBE study, pyrotinib and capecitabine were compared with the combination of lapatinib and capecitabine...In addition, the Phila study showed an impressive improvement in PFS when pyrotinib was added to the docetaxel and trastuzumab combination, compared with placebo, trastuzumab and docetaxel. However, since the control arm did not include pertuzumab, this strategy is unlikely to change the standard of care in many countries...However, based on the latest results achieved by TDXd in patients with these cancers, HER2-low expressing tumours have become a new standard terminology. TDXd has shown to improve PFS and OS in patients with HER2-low mBC in the second/ third line treatment compared to the best chemotherapeutic agents (DB04 trial).

The drug combinations were performed using proliferation and colony formation assays on TNBC cell lines that were sensitive or resistant to EPZ015938, a PRMT5 inhibitor that has been evaluated in clinical trials. The chemotherapies analyzed were cisplatin, doxorubicin, camptothecin, and paclitaxel. The targeted therapies tested were erlotinib (EGFR inhibitor), neratinib (EGFR/HER2/HER4 inhibitor) and tucatinib (HER2 inhibitor)...We noticed that synergy can be obtained in TNBC cell lines that were resistant to PRMT5 inhibition alone. Altogether, our data highlight the therapeutic potential of targeting PRMT5 using combinatorial strategies for the treatment of subsets of TNBC patients.

P2, N=117, Completed, Seagen Inc. | Active, not recruiting --> Completed

More recently, two monoclonal antibodies have demonstrated their efficacy in combination with oxaliplatin-based first-line chemotherapy, nivolumab (anti-PD1) for PD-L1 CPS ≥5 tumors, and zolbetuximab for tumors overexpressing Claudin 18.2. Recent years have seen the emergence of new drugs that have improved patient survival, such as trastuzumab in first-line for HER2-positive tumors, ramucirumab alone or in combination with paclitaxel in second-line, and trifluridine-tipiracil beyond the second-line treatment. Advanced gastric adenocarcinoma is a common disease with a poor prognosis whose treatment has for decades been based on cytotoxic chemotherapy, including platinum salts in first-line, and taxane or irinotecan in second or later line. In addition, regorafenib has been also showed effective in phase 3 trial for heavily pretreated patients. Based on phase 2 studies, trastuzumab-deruxtecan was approved in 2022 by the EMA for HER2-positive pretreated patients. This agent is currently evaluated in phase 3 study (DESTINY-Gastric04 trial), as are several other anti-HER2 (zanidatamab, margetuximab, tucatinib), immune checkpoint inhibitors, or targeted therapies (anti-FGFR2b).

The trial started enrollment in February 2023. Trial Information: NCT05553522.

On January 19, the Food and Drug Administration (FDA) granted accelerated approval to the combination of two targeted drugs, tucatinib (Tukysa) and trastuzumab (Herceptin) for people with HER2-positive colorectal cancer that is metastatic or that cannot be treated with surgery. The FDA can grant accelerated approval for new treatments that fill unmet needs for patients with serious medical conditions.

Tucatinib, a brain-penetrable HER2-targeting tyrosine kinase inhibitor, when added to trastuzumab and capecitabine improves intracranial progression free survival (PFS) and overall survival (OS) in patients with stable or active HER2+ BrMs. An additional 4 sites are pending opening. Those interested in this trial can reach out to the study Principal Investigators, Carey Anders, MD (carey.anders@duke.edu) or Sarah Sammons, MD (sarahl_sammons@dfci.harvard.edu).

Although targeting PI3Kα in cancer is a therapeutically proven strategy, with the currently approved drug alpelisib showing clinical efficacy alone or in combination with other therapies, treatment with non-mutant selective PI3Kα inhibitors such as alpelisib is associated with significant toxicities such as hyperglycemia, due to on-target inhibition of the wild-type enzyme...Moreover, OKI-219 dosed in combination with the selective estrogen receptor degraders (SERDs) fulvestrant, elacestrant or camizestrant showed significant combination benefit leading to tumor regressions of up to 100% in the ER+ H1047R mutant breast cancer model xxT47D, at doses where no regressions were observed with single agent treatment. Dosing OKI-219 in combination with HER2-inhibitors, such as tucatinib, led to tumor regressions in the ER-HER2+ and H1047R mutant breast cancer CDX model HCC1954, also at doses where no regressions were observed with single agent treatment. These data indicate that OKI-219 offers improved efficacy and a wider therapeutic window compared to non-mutant selective PI3Kα inhibitors. OKI-219 is advancing into clinical trials.