On August 16, 2023 Vergent Bioscience, a clinical-stage biotechnology company developing tumor-targeted imaging agents, and its wholly owned subsidiary Vergent Bioscience Australia Pty Ltd, reported that new clinical data from a Phase 2 study of the company’s investigational agent VGT-309 will be presented at the 2023 World Conference on Lung Cancer (#WCLC23) hosted by the International Association for the Study of Lung Cancer (IASLC), taking place September 9-12, 2023, in Singapore (Press release, Vergent Bioscience, AUG 16, 2023, View Source [SID1234634459]).

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"We’ve steadily advanced the VGT-309 clinical program and look forward to sharing the latest results from our Phase 2 study evaluating the safety, efficacy, and dosing of this novel compound," said John Santini, Ph.D., president and chief executive officer at Vergent Bioscience. "VGT-309 has the potential to fill deficits in tumor visualization during surgery to optimize outcomes for patients."

Early Phase 1 and 2 clinical trials evaluating VGT-309 in lung cancer yielded compelling safety and efficacy data that support the agent’s ability to help surgeons see difficult-to-find or previously undetected tumors in real-time, ensuring all tumor tissue is removed during minimally invasive (MIS) and robotic-assisted surgical procedures.

Following are details about the VGT-309 presentation at the 2023 WCLC:

Title: Results from a Phase II trial of a Tumor-Activated Fluorescent Molecule for the Intra-Operative Identification of Lung Cancer
Presenter: Professor Gavin M. Wright, Ph.D., director of Surgical Oncology, St. Vincent’s Hospital, Melbourne, Australia
Abstract/Session: #844; MA11.06 – New Technology and Innovations in Early-Stage Lung Cancer
Date/Time: 2:30 – 3:30 PM Singapore/2:30 – 3:30 AM ET, September 11, 2023
Location: Suntec Singapore Convention & Exhibition Centre, Room 405C

About VGT-309

VGT-309 is a tumor-targeted imaging agent designed to enable a complete solution for optimal tumor visualization during open, MIS, and robotic-assisted surgical procedures. VGT-309 is delivered to patients via a short infusion several hours before surgery. Invented in Professor Matt Bogyo’s Lab at Stanford University School of Medicine, the molecule binds tightly (i.e., covalently) to cathepsins, a family of proteases that are overexpressed across a broad range of solid tumors. This approach provides distinct clinical advantages and positions VGT-309 as an ideal tumor imaging agent. VGT-309’s imaging component is the near infrared (NIR) dye indocyanine green (ICG), which is compatible with all commercially available NIR intraoperative imaging systems that support MIS technologies and is the preferred dye to minimize confounding background autofluorescence.

On August 16, 2023 IDEAYA Biosciences, Inc. (Nasdaq: IDYA), a precision medicine oncology company committed to the discovery and development of targeted therapeutics, reported the achievement of First-Patient-In for the company-sponsored Phase 2 clinical trial evaluating darovasertib as neoadjuvant and adjuvant therapy in primary uveal melanoma (UM) patients (Press release, Ideaya Biosciences, AUG 16, 2023, View Source [SID1234634458]).

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"We are excited to dose our first patient in this Phase 2 clinical trial. Our recently reported preliminary clinical data in the neoadjuvant setting showed compelling evidence of anti-tumor activity – with observed tumor shrinkage in 9 patients, including two patients who were able to avoid enucleation. These data support further clinical evaluation of darovasertib to determine its potential as a neoadjuvant and adjuvant therapy," said Dr. Darrin Beaupre, Chief Medical Officer, IDEAYA Biosciences.

"Treatment with darovasertib as a neoadjuvant therapy provides an opportunity to save the patient’s eye by avoiding enucleation or to reduce the tumor in the eye and enable treatment with less radiation to preserve vision. As an adjuvant therapy, the goal is to potentially extend recurrence free survival,", said Sreenivasa R. Chandana, M.D., Ph.D., Medical Oncologist at The Cancer & Hematology Centers in Grand Rapids, Michigan, and an investigator of the Phase 2 clinical trial.

IDEAYA’s Phase 2 clinical trial, designated as IDE196-009 (NCT05907954), is evaluating darovasertib as monotherapy in (neo)adjuvant uveal melanoma with potential near-term clinical neoadjuvant endpoints such as eye preservation for large ocular tumors and reduction in radiation dose and/or vision preservation for small or medium ocular tumors.

Pursuant to the clinical protocol, neoadjuvant treatment of primary UM patients will occur prior to a standard-of-care primary interventional treatment – typically enucleation or radiation therapy. One cohort of UM patients with large tumors will be treated with single-agent darovasertib until maximum benefit or six months, at which time they will undergo a primary interventional treatment. The neoadjuvant endpoint for this large-sized tumor cohort is eye preservation. For example, a patient who would otherwise have undergone enucleation would instead be eligible for radiation treatment. Another neoadjuvant cohort of UM patients with small or medium tumors will be treated with single-agent darovasertib until maximum benefit or six months, at which time they will undergo a primary interventional treatment such as radiation therapy. Neoadjuvant endpoints for this small- or medium-sized tumor cohort include reducing the radiation dose that the patient receives, relative to the radiation dose they would have otherwise received without the neoadjuvant treatment, and functional vision preservation.

In the adjuvant setting, each of the two neoadjuvant cohorts will be treated with single-agent darovasertib for up to six months as follow-up adjuvant therapy after the primary interventional treatment. The adjuvant endpoints for this portion of the clinical trial include recurrence free survival and useful vision.

IDEAYA plans to enroll patients in the company-sponsored Phase 2 clinical trial at clinical sites in the United States, Canada, , Europe and Australia. This clinical trial supplements and expands the scope of the ongoing investigator-sponsored Phase 1 clinical trial (IST) in Australia captioned as "Neoadjuvant / Adjuvant trial of Darovasertib in Ocular Melanoma" (NADOM). The NADOM trial is being led by principal investigator Professor Anthony Joshua, MBBS, PhD, FRACP, Head Department of Medical Oncology, Kinghorn Cancer Centre, St. Vincent’s Hospital in Sydney with participating sites of Alfred Health and the Royal Victorian Eye and Ear Hospital in Melbourne. IDEAYA plans to present an update of clinical data update in the fourth quarter of 2023 from the ongoing NADOM IST evaluating darovasertib as neoadjuvant therapy in primary UM.

Uveal melanoma is a rare, lethal form of melanoma that arises from melanocytes of the iris, the ciliary body, or most commonly the choroid, with an annual potential incidence of approximately 8,700 patients and an estimated prevalence of approximately 100,000 patients total in the U.S. and Europe. Current approaches for treatment of primary UM includes radiotherapy (plaque brachytherapy or stereotactic radiosurgery) and, for larger tumors, enucleation of the eye, with consequential patient impact including reduced vision, decreased depth perception, diminished social functioning and unsatisfactory cosmesis.

Darovasertib (IDE196) is a potent, selective small molecule inhibitor of protein kinase C (PKC). Mutations in GNAQ or GNA11 (GNAQ/11) have been identified in approximately 90% of patients with metastatic UM. These mutations are associated with activation of signaling pathways, including oncogenic RAS/RAF/MEK/ERK via PKC activation, driving tumor progression.

The FDA has designated darovasertib as an Orphan Drug in uveal melanoma, including primary and metastatic disease under 21 C.F.R Part 316. IDEAYA owns or controls all commercial rights in darovasertib in UM, subject to certain economic obligations pursuant to its exclusive, worldwide license with Novartis.

On August 16, 2023 AstraZeneca reported its robust lung cancer portfolio and pipeline at the International Association for the Study of Lung Cancer (IASLC) 2023 World Conference on Lung Cancer (WCLC), 9 to 12 September 2023 (Press release, AstraZeneca, AUG 16, 2023, View Source [SID1234634457]).

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More than 40 abstracts will feature eight approved and potential new medicines from AstraZeneca, including nine oral presentations and a late-breaking plenary Presidential Symposium presentation of results from the FLAURA2 Phase III trial of Tagrisso (osimertinib) in combination with chemotherapy for patients with locally advanced or metastatic epidermal growth factor receptor-mutated (EGFRm) lung cancer.

Dave Fredrickson, Executive Vice President, Oncology Business Unit, AstraZeneca, said: "Our data at WCLC support our ambition to have the right AstraZeneca medicine for more than half of all patients treated for lung cancer by 2030, and underscore the need to increase screening and early diagnosis to improve patient outcomes. The strong results from FLAURA2 will further establish Tagrisso as the backbone therapy in EGFR-mutated non-small cell lung cancer, and the recent Breakthrough Therapy Designation in the US is a significant validation of the potential we see for this regimen."

Susan Galbraith, Executive Vice President, Oncology R&D, AstraZeneca, said: "Following last year’s accelerated approval of Enhertu as the first HER2-directed therapy for patients with previously treated HER2-mutant metastatic lung cancer, new data at WCLC will reinforce its potential benefit to patients in need of targeted options. In addition, data for datopotamab deruxtecan will further support the potential to combine this agent with immune checkpoint inhibitors and the continued investigation of these combinations in first-line settings."

Improving outcomes across early- and late-stage EGFRm lung cancer
A late-breaking plenary Presidential Symposium presentation will showcase progression-free survival (PFS) data from the FLAURA2 Phase III trial evaluating Tagrisso in combination with chemotherapy for patients with locally advanced (Stage IIIB-IIIC) or metastatic (Stage IV) EGFRm non-small cell lung cancer (NSCLC). In May, high-level results showed the Tagrisso combination demonstrated a statistically significant and clinically meaningful improvement in PFS compared to standard-of-care Tagrisso monotherapy. In August, Tagrisso plus chemotherapy was granted Breakthrough Therapy Designation in the US for advanced EGFRm NSCLC.

An oral presentation of results from a Phase IIIb trial will show the potential of Orpathys (savolitinib) as a 1st-line treatment for advanced or metastatic NSCLC harbouring MET exon 14 mutations. Orpathys is approved for this indication in China.

In addition, an e-poster on a computational pathology analysis of MET expression in patients treated with a combination of Orpathys and Tagrisso in the SAVANNAH Phase II trial will showcase the Company’s progress in developing transformational technology solutions to identify patients who are most likely to respond to treatment. Encouraging efficacy for the combination has been previously reported in the same study in patients with high levels of MET overexpression and/or amplification whose disease progressed on treatment with Tagrisso.

Realising the potential of antibody drug conjugates (ADCs) in advanced lung cancer
A late-breaking oral presentation of first results from the TROPION-Lung04 Phase Ib trial will highlight the safety and efficacy of datopotamab deruxtecan (Dato-DXd) plus Imfinzi (durvalumab) with and without carboplatin in patients with previously treated or untreated, advanced or metastatic NSCLC without actionable genomic alterations. There are currently no TROP2-directed ADCs approved for the treatment of patients with lung cancer.

A mini-oral presentation of primary results from the DESTINY-Lung02 Phase II trial will share the first overall survival and PFS data for Enhertu (trastuzumab deruxtecan) in patients with previously treated HER2-mutant metastatic NSCLC. Enhertu is approved for this indication in a number of countries, including in the US, where it was granted accelerated approval based on interim results from the trial.

Two posters will feature AZD9592, an EGFR/cMET bispecific ADC designed to deliver targeted chemotherapy to cancer cells expressing both EGFR and cMET with a topoisomerase inhibitor 1 warhead using the Company’s proprietary linker technology. A trial-in-progress poster will describe the EGRET Phase I trial, a first-in-human study evaluating AZD9592 in patients with advanced solid tumours including in combination with Tagrisso in metastatic EGFRm NSCLC. In addition, a poster on translational results for AZD9592 suggests it may provide clinical benefit in areas of unmet need, including in patients with NSCLC previously treated with chemotherapy or targeted agents. This is the Company’s first bispecific ADC to enter the clinic.

Reinforcing Imfinzi benefits alone and in novel combinations across lung cancer settings
Two late-breaking oral presentations will share new data from the AEGEAN Phase III trial of Imfinzi in combination with neoadjuvant chemotherapy before surgery and as adjuvant monotherapy after surgery in patients with resectable NSCLC, including key surgical outcomes and exploratory analyses of clinical outcomes in a subset of patients with EGFRm disease. Previously presented primary results from AEGEAN demonstrated statistically significant and clinically meaningful improvement in event-free survival and pathologic complete response with this Imfinzi-based regimen versus neoadjuvant chemotherapy alone followed by surgery.

Another oral presentation of data from a planned subset analysis of the PACIFIC-R observational study of Imfinzi in a real-world population of patients with EGFRm disease will explore the long-term clinical outcomes of Imfinzi in patients with unresectable, Stage III NSCLC.

Data will also be shared from new exploratory subgroup analyses of the POSEIDON Phase III trial describing patients deriving long-term benefit from the combination of Imfinzi, Imjudo (tremelimumab) and chemotherapy in the metastatic NSCLC setting.

Advancing our commitment to increase lung cancer screening and early diagnosis
An oral presentation will describe a framework to support government implementation of high-quality and impactful lung cancer screening programmes. Screening is essential to early detection and reducing lung cancer mortality. Published in March 2023, the framework was developed by the Lung Cancer Policy Network, an initiative of the Lung Ambition Alliance aimed at elevating lung cancer as a policy priority worldwide. AstraZeneca is a founding member of the Lung Ambition Alliance, a global coalition working to accelerate innovation and deliver meaningful improvements for people with lung cancer, including and beyond treatment.

Collaboration in the scientific community is critical to improving outcomes for patients. AstraZeneca is collaborating with Daiichi Sankyo Company Limited to develop and commercialise Enhertu and datopotamab deruxtecan, and with HUTCHMED to develop and commercialise Orpathys.

Key AstraZeneca presentations during WCLC 2023

Lead Author

Abstract Title

Presentation details (SGT)

Tumour drivers and resistance

Janne, PA

Osimertinib With/Without Platinum-Based Chemotherapy as First-line Treatment in Patients with EGFRm Advanced NSCLC (FLAURA2)

Abstract #PL03.13

Plenary Session 3: Presidential Symposium

11 September 2023

9:40 AM

Lu, S

A Phase 3b Study of 1L Savolitinib in Patients with Locally Advanced or Metastatic NSCLC Harboring MET Exon 14 Mutation

Abstract #OA21.03

Oral Session MET Matters in NSCLC

12 September 2023

2:32 PM

Soo, R

TARGET: A Phase II Study of 5-year Adjuvant Osimertinib in Completely Resected EGFR-mutated Stage II-IIIB NSCLC

Abstract #P1.25-09

Poster Session Early-Stage Non-small Cell Lung Cancer

10 September 2023

5:30 PM

Tan, DSW

OSTARA: A Phase II Study of First-line Osimertinib Combined with Amivantamab in EGFRm Advanced Non-Small Cell Lung Cancer

Abstract #P2.09-17

Poster Session Metastatic Non-small Cell Lung Cancer – Targeted Therapy

11 September 2023 6:00 PM

Christ, S

Computational Pathology-Based Assessment of cMET IHC Expression for Patient Selection in the Treatment of MET Overexpressing NSCLC

Abstract #EP06.05-09

E-Poster Session Pathology and Biomarkers

On-Demand

Antibody drug conjugates

Papadopoulos, KP

Datopotamab Deruxtecan (Dato-DXd) + Durvalumab ± Carboplatin in Advanced/mNSCLC: Initial Results from Phase 1b TROPION-Lung04

Abstract #OA05.06

Oral Session Antibody Drug Conjugates: The Next Tsunami

10 September 2023 3:32 PM

Janne, P

Trastuzumab Deruxtecan in Patients with HER2-Mutant Metastatic Non-Small Cell Lung Cancer: Primary Results of DESTINY-Lung02

Abstract #MA13.10

Mini Oral Session Targeted Therapy: EGFR and Her2

11 September 2023 4:25 PM

McGrath, L

In Vivo Efficacy of AZD9592, an EGFR-cMET Bispecific ADC, in a Broad Panel of NSCLC Patient-Derived Xenograft Models

Abstract #P1.12-04

Poster Session Tumour Biology – Translational Biology

10 September 2023 5:30 PM

Aggarwal, C

AVANZAR: Phase III Study of Datopotamab Deruxtecan (Dato-DXd) + Durvalumab + Carboplatin as 1L Treatment of Advanced/mNSCLC

Abstract #P2.04-02

Poster Session Metastatic Non-small Cell Lung Cancer – Cytotoxic Therapy

11 September 2023 6:00 PM

Aggarwal, C

EGRET: First-in-human Study of the Novel Antibody-drug Conjugate AZD9592 ± Anti-cancer Agents in Advanced Solid Tumours

Abstract #P2.04-03

Poster Session Metastatic Non-small Cell Lung Cancer – Cytotoxic Therapy

11 September 2023 6:00 PM

Zhou, C

TROPION-Lung08: Datopotamab deruxtecan plus pembrolizumab in untreated advanced/metastatic non-small cell lung cancer (NSCLC)

Abstract #P2.08-01

Poster Session Metastatic Non-small Cell Lung Cancer – Immunotherapy

11 September 2023 6:00 PM

Immuno-Oncology

Mitsudomi, T

Surgical outcomes with neoadjuvant durvalumab + chemotherapy followed by adjuvant durvalumab in resectable NSCLC (AEGEAN)

Abstract #OA12.05

Oral Session Pushing the Boundaries: Adjuvant and Neoadjuvant Approaches in Early Stage Non-small Cell Lung Cancer

11 September 2023

12:22 PM

He, J

Neoadjuvant Durvalumab + Chemotherapy Followed by Adjuvant Durvalumab in Resectable EGFR-mutated NSCLC (AEGEAN)

Abstract #OA12.06

Oral Session Pushing the Boundaries: Adjuvant and Neoadjuvant Approaches in Early Stage Non-small Cell Lung Cancer

11 September 2023 12:32 PM

Peters, S

Real-World Outcomes with Durvalumab After Chemoradiotherapy in Unresectable Stage III EGFR-Mutated NSCLC (PACIFIC-R)

Abstract #OA17.03

Oral Session Next Steps in Locally Advanced NSCLC: Optimizing Techniques & Choosing Populations That Benefit

11 September 2023 3:47 PM

Cho, BC

Durvalumab ± Tremelimumab + Chemotherapy in 1L Metastatic NSCLC: Characterisation of patients with PFS ≥12 months in POSEIDON

Abstract #P2.06-05

Poster Session Metastatic Non-small Cell Lung Cancer – Immunotherapy

11 September 2023 6:00 PM

Advancing lung cancer screening

Lam, SC

Taking A Health Systems Approach to Low-Dose CT Lung Cancer Screening: A Bespoke Framework to Support Implementation

Abstract #OA16.03

Oral Session

Expanding the Scope of Lung Cancer Screening Initiatives Worldwide

11 September 2023 3:47 PM

On August 16, 2023, Synlogic Operating Company, Inc. ("Synlogic OpCo"), a wholly-owned subsidiary of Synlogic, Inc. (the "Company"), F. Hoffmann-La Roche Ltd ("Roche Basel") and Hoffmann-La Roche Inc. ("Roche US", and together with Roche Basel, "Roche") reported to have entered into an amendment (the "Amendment") to the Pilot Collaboration and Option Agreement (the "Roche Collaboration and Option Agreement"), effective as of June 16, 2021, by and between Synlogic OpCo and Roche (Filing, 8-K, Synlogic, AUG 16, 2023, View Source [SID1234634455]).

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Under the Roche Collaboration and Option Agreement, Roche holds an exclusive option right (the "Option") to negotiate a definitive collaboration and license agreement for the further development of a Synthetic Biotic medicine for the treatment of inflammatory bowel disease. The Amendment extends the deadline for Roche to exercise the Option until the later of (i) January 15, 2024 or (ii) ninety (90) days after Synlogic OpCo has (A) delivered certain research data to Roche and (B) does not plan to conduct further experiments under the Roche Collaboration and Option Agreement. A copy of the Roche Collaboration and Option Agreement is attached as Exhibit 10.29 to the Company’s Annual Report on Form 10-K for the year ended December 31, 2022.

This summary of the Amendment is qualified in its entirety by reference to the full text of the Amendment, a copy of which will be attached as an exhibit to the Company’s 10-Q for the quarter ended September 30, 2023.

On August 16, 2023 Seagen Inc. (Nasdaq: SGEN) reported that the Phase 3 HER2CLIMB-02 clinical trial of TUKYSA (tucatinib) in combination with the antibody-drug conjugate ado-trastuzumab emtansine (Kadcyla) met its primary endpoint of progression-free survival (PFS) (Press release, Seagen, AUG 16, 2023, View Source [SID1234634454]). Patients in the trial had unresectable locally advanced or metastatic human epidermal growth factor receptor 2-positive (HER2-positive) breast cancer and had received previous treatment with a taxane and trastuzumab.​ Overall survival (OS) data, a secondary endpoint, are not yet mature. Discontinuations due to adverse events were more common in the combination arm of the trial, but no new safety signals emerged for the combination.

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"We are encouraged by these results for TUKYSA in combination with Kadcylain metastatic HER2-positive breast cancer, including in patients with brain metastases," said Roger Dansey, President of Research and Development and Chief Medical Officer at Seagen. "We plan to present the HER2CLIMB-02 data at an upcoming medical meeting and discuss the results with the FDA."

About HER2CLIMB-02

HER2CLIMB-02 is a global, multicenter, randomized, double-blind, placebo-controlled, Phase 3 clinical trial of tucatinib in combination with ado-trastuzumab emtansine (T-DM1) in patients with HER2-positive metastatic or unresectable breast cancer (MBC) who have had prior treatment with a taxane and trastuzumab in any setting. Trial enrollment began in 2019. The primary endpoint of the trial is PFS per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 by investigator assessment. OS, PFS by blinded independent committee review (BICR), objective response rate, duration of response, PFS and OS in patients with brain metastases at baseline, and safety and tolerability of the combination regimen are secondary objectives.

About the TUKYSA Breast Cancer Development Program

TUKYSA is currently approved in the U.S. in combination with trastuzumab and capecitabine for adult patients with advanced unresectable or metastatic HER2-positive breast cancer, including patients with brain metastases, who have received one or more prior anti-HER2-based regimens in the metastatic setting. Seagen has a robust development program for TUKYSA, including a study with registrational intent in first-line maintenance with trastuzumab and pertuzumab (HER2CLIMB-05). Seagen is also supporting a cooperative group study in adjuvant high-risk HER2-positive breast cancer in combination with T-DM1.

About HER2-positive Breast Cancer

An estimated 300,590 people will be diagnosed with breast cancer in the United States this year.1 Between 15 and 20 percent of breast cancer cases are HER2-positive, which means tumors have high levels of a protein called HER2 that promotes the growth of cancer cells.2 Up to 50 percent of patients with HER2-positive MBC develop brain metastases over time.3

About TUKYSA (tucatinib)

TUKYSA (tucatinib) is an oral medicine that is a tyrosine kinase inhibitor of the HER2 protein. It is approved in more than 40 countries. Merck, known as MSD outside the U.S. and Canada, has exclusive rights to commercialize TUKYSA in regions outside of the U.S., Canada and Europe.

TUKYSA is approved in the U.S.:

in combination with trastuzumab and capecitabine for adult patients with advanced unresectable or metastatic HER2-positive breast cancer, including patients with brain metastases, who have received one or more prior anti-HER2-based regimens in the metastatic setting.

in combination with trastuzumab for adult patients with RAS wild-type, HER2-positive unresectable or metastatic colorectal cancer that has progressed following treatment with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.
Important U.S. Safety Information

Warnings and Precautions

Diarrhea: TUKYSA can cause severe diarrhea including dehydration, hypotension, acute kidney injury, and death. If diarrhea occurs, administer antidiarrheal treatment as clinically indicated. Perform diagnostic tests as clinically indicated to exclude other causes of diarrhea. Based on the severity of the diarrhea, interrupt dose, then dose reduce or permanently discontinue TUKYSA.

In HER2CLIMB, when TUKYSA was given in combination with trastuzumab and capecitabine, 81% of patients who received TUKYSA experienced diarrhea, including 0.5% with Grade 4 and 12% with Grade 3. Both patients who developed Grade 4 diarrhea subsequently died, with diarrhea as a contributor to death. Median time to onset of the first episode of diarrhea was 12 days and the median time to resolution was 8 days. Diarrhea led to TUKYSA dose reductions in 6% of patients and TUKYSA discontinuation in 1% of patients. Prophylactic use of antidiarrheal treatment was not required on HER2CLIMB.

In MOUNTAINEER, when TUKYSA was given in combination with trastuzumab, diarrhea occurred in 64% of patients, including Grade 3 (3.5%), Grade 2 (10%) and Grade 1 (50%).
Hepatotoxicity: TUKYSA can cause severe hepatotoxicity. Monitor ALT, AST, and bilirubin prior to starting TUKYSA, every 3 weeks during treatment, and as clinically indicated. Based on the severity of hepatotoxicity, interrupt dose, then dose reduce or permanently discontinue TUKYSA.

In HER2CLIMB, 8% of patients who received TUKYSA had an ALT increase >5 × ULN, 6% had an AST increase >5 × ULN, and 1.5% had a bilirubin increase >3 × ULN (Grade ≥3). Hepatotoxicity led to TUKYSA dose reductions in 8% of patients and TUKYSA discontinuation in 1.5% of patients.

In MOUNTAINEER, 6% of patients had a bilirubin increase > 3 × ULN (Grade ≥3), 6% had an AST increase > 5 × ULN, and 4.7% had an ALT increase > 5 × ULN. Hepatotoxicity led to dose reduction of TUKYSA in 3.5% of patients and discontinuation of TUKYSA in 2.3% of patients.
Embryo-Fetal Toxicity: TUKYSA can cause fetal harm. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential, and male patients with female partners of reproductive potential, to use effective contraception during TUKYSA treatment and for 1 week after the last dose.
Adverse Reactions

In HER2CLIMB, serious adverse reactions occurred in 26% of patients; the most common (in ≥2% of patients) were diarrhea (4%), vomiting (2.5%), nausea (2%), abdominal pain (2%), and seizure (2%). Fatal adverse reactions occurred in 2% of patients who received TUKYSA including sudden death, sepsis, dehydration, and cardiogenic shock. Adverse reactions led to treatment discontinuation in 6% of patients who received TUKYSA; the most common (in ≥1% of patients) were hepatotoxicity (1.5%) and diarrhea (1%). Adverse reactions led to dose reduction in 21% of patients who received TUKYSA; the most common (in ≥2% of patients) were hepatotoxicity (8%) and diarrhea (6%). The most common adverse reactions in patients who received TUKYSA (≥20%) were diarrhea, palmar-plantar erythrodysesthesia, nausea, hepatotoxicity, vomiting, stomatitis, decreased appetite, anemia and rash.

In MOUNTAINEER, serious adverse reactions occurred in 22% of patients; the most common (in ≥2% of patients) were intestinal obstruction (7%), urinary tract infection (3.5%), pneumonia, abdominal pain and rectal perforation (2.3% each). Adverse reactions leading to permanent discontinuation of TUKYSA occurred in 6% of patients; the most common (in ≥2% of patients) was increased ALT (2.3%). Adverse reactions leading to dosage interruption occurred in 23% of patients; the most common (in ≥3% of patients) were increased ALT and diarrhea (3.5% each). Adverse reactions leading to dose reduction occurred in 9% of patients; the most common (in ≥2% of patients) were increased ALT and diarrhea (2.3% each). The most common adverse reactions (≥20%) in patients treated with TUKYSA and trastuzumab were diarrhea, fatigue, rash, nausea, abdominal pain, infusion-related reactions and pyrexia. Other adverse reactions (<10%) include epistaxis (7%), weight decreased (7%), oropharyngeal pain (5%), oral dysesthesia (1%) and stomatitis (1%).

Lab Abnormalities

In HER2CLIMB, Grade ≥3 laboratory abnormalities reported in ≥5% of patients who received TUKYSA were decreased phosphate, increased ALT, decreased potassium, and increased AST. The mean increase in serum creatinine was 32% within the first 21 days of treatment with TUKYSA. The serum creatinine increases persisted throughout treatment and were reversible upon treatment completion. Consider alternative markers of renal function if persistent elevations in serum creatinine are observed.

In MOUNTAINEER, Grade ≥3 laboratory abnormalities reported in ≥5% of patients who received TUKYSA were decreased lymphocytes, decreased sodium, increased AST, and increased bilirubin. The mean increase in serum creatinine was 32% within the first 21 days of treatment with TUKYSA. The serum creatinine increases persisted throughout treatment and were reversible in 87% of patients with values outside normal lab limits upon treatment completion. Consider alternative markers of renal function if persistent elevations in serum creatinine are observed.

Drug Interactions

Strong CYP3A/Moderate CYP2C8 Inducers: Concomitant use may decrease TUKYSA activity. Avoid concomitant use of TUKYSA.
Strong or Moderate CYP2C8 Inhibitors: Concomitant use of TUKYSA with a strong CYP2C8 inhibitor may increase the risk of TUKYSA toxicity; avoid concomitant use. Increase monitoring for TUKYSA toxicity with moderate CYP2C8 inhibitors.
CYP3A Substrates: Concomitant use may increase the toxicity associated with a CYP3A substrate. Avoid concomitant use of TUKYSA with a CYP3A substrate, where minimal concentration changes may lead to serious or life-threatening toxicities. If concomitant use is unavoidable, decrease the CYP3A substrate dosage.
P-gp Substrates: Concomitant use may increase the toxicity associated with a P-gp substrate. Consider reducing the dosage of P-gp substrates where minimal concentration changes may lead to serious or life-threatening toxicities.
Use in Specific Populations

Lactation: Advise women not to breastfeed while taking TUKYSA and for 1 week after the last dose.
Renal Impairment: Use of TUKYSA in combination with capecitabine and trastuzumab is not recommended in patients with severe renal impairment (CLcr < 30 mL/min), because capecitabine is contraindicated in patients with severe renal impairment.
Hepatic Impairment: Reduce the dose of TUKYSA for patients with severe (Child-Pugh C) hepatic impairment.
For more information, please see the full Prescribing Information for TUKYSA here .