- FDA Has Set Action Date of January 19, 2023 -
Seagen Inc. (Nasdaq: SGEN) today announced that the U.S. Food and Drug Administration (FDA) has accepted for Priority Review the supplemental New Drug Application (sNDA) seeking accelerated approval for TUKYSA® (tucatinib) in combination with trastuzumab for adult patients with HER2-positive colorectal cancer who have received at least one prior treatment regimen for unresectable or metastatic disease.
The sNDA submission is based on the results of the pivotal phase 2 MOUNTAINEER trial. These data were presented at the European Society for Medical Oncology (ESMO) World Congress on Gastrointestinal Cancer in July 2022.
“There are currently no FDA-approved therapies for metastatic colorectal cancer that specifically target HER2,” said Marjorie Green, M.D., Senior Vice President and Head of Late-Stage Development, Seagen. “The FDA’s prioritization of our application for tucatinib in combination with trastuzumab supports our belief in its significant potential to benefit people with previously treated HER2-positive metastatic colorectal cancer.”
The FDA grants Priority Review to applications for medicines that, if approved, would provide significant improvements in safety or effectiveness of the treatment, diagnosis or prevention of serious diseases. Under the Prescription Drug User Fee Act (PDUFA), the FDA has set a target action date of January 19, 2023. In July 2022, the FDA granted Breakthrough Therapy Designation for tucatinib in combination with trastuzumab for the treatment of adult patients with unresectable or metastatic HER2-positive colorectal cancer who have previously received fluoropyrimidine-, oxaliplatin- and irinotecan-containing chemotherapy based on results from the MOUNTAINEER trial.
In February 2022, Seagen initiated the randomized, global phase 3 MOUNTAINEER-03 clinical trial, which is evaluating tucatinib in combination with trastuzumab and standard chemotherapy versus chemotherapy given with or without cetuximab or bevacizumab in first-line HER2-positive metastatic colorectal cancer. MOUNTAINEER-03 is intended to serve as a confirmatory trial in the U.S. and to support global filings. Merck, known as MSD outside of the U.S. and Canada, is commercializing TUKYSA in regions outside of the U.S., Canada and Europe.
MOUNTAINEER is a U.S. and European open-label, multicenter phase 2 clinical trial of tucatinib in combination with trastuzumab or as a single agent that enrolled 117 patients with HER2-positive unresectable or metastatic colorectal cancer following previous standard-of-care therapies. Patients evaluated in MOUNTAINEER had not received prior anti-HER2 therapy. Patients received tucatinib (300 mg) twice per day orally in combination with trastuzumab intravenously (8 mg/kg loading dose, then 6 mg/kg every three weeks thereafter). The primary endpoint of the trial is confirmed objective response rate by RECIST (Response Evaluation Criteria in Solid Tumors) version 1.1 criteria per blinded independent central review. Duration of response, progression-free survival, overall survival and safety and tolerability of the combination regimen are secondary objectives.
About Colorectal Cancer
In the U.S., approximately 151,000 people will be diagnosed with colorectal cancer in 2022, and the rate of the disease is increasing in younger adults. Approximately 22% of U.S. patients with colorectal cancer are diagnosed at the advanced stage. Human epidermal growth factor receptor 2 (HER2) is overexpressed in 3-5% of patients with metastatic colorectal cancer. In 2022, colorectal cancer is anticipated to lead to about 52,500 deaths in the U.S., where it is the third-leading cause of cancer-related deaths.
About TUKYSA (tucatinib)
TUKYSA is an oral medicine that is a tyrosine kinase inhibitor of the HER2 protein. In vitro (in lab studies), TUKYSA inhibited phosphorylation of HER2 and HER3, resulting in inhibition of downstream MAPK and AKT signaling and cell growth (proliferation), and showed anti-tumor activity in HER2-expressing tumor cells. In vivo (in living organisms), TUKYSA inhibited the growth of HER2-expressing tumors. The combination of TUKYSA and the anti-HER2 antibody trastuzumab showed increased anti-tumor activity in vitro and in vivo compared to either medicine alone.
TUKYSA is approved in 38 countries. It was approved by the U.S. FDA in April 2020 and by the European Medicines Agency and the UK Medicines and Healthcare Products Regulatory Agency in February 2021.
U.S. Indication and Important Safety Information
TUKYSA is indicated in combination with trastuzumab and capecitabine for treatment of 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.
Warnings and Precautions
Diarrhea – TUKYSA can cause severe diarrhea including dehydration, hypotension, acute kidney injury, and death. In HER2CLIMB, 81% of patients who received TUKYSA experienced diarrhea, including 12% with Grade 3 diarrhea and 0.5% with Grade 4 diarrhea. Both patients who developed Grade 4 diarrhea subsequently died, with diarrhea as a contributor to death. The 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 dose reductions of TUKYSA in 6% of patients and discontinuation of TUKYSA in 1% of patients. Prophylactic use of antidiarrheal treatment was not required on HER2CLIMB.
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.
Hepatotoxicity – TUKYSA can cause severe hepatotoxicity. 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 dose reduction of TUKYSA in 8% of patients and discontinuation of TUKYSA in 1.5% of patients.
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.
- Embryo-Fetal Toxicity – TUKYSA can cause fetal harm. Advise pregnant women and females of reproductive 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 at least 1 week after the last dose.
Serious adverse reactions occurred in 26% of patients who received TUKYSA. Serious adverse reactions in ≥2% of patients who received TUKYSA 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; those occurring in ≥1% of patients were hepatotoxicity (1.5%) and diarrhea (1%). Adverse reactions led to dose reduction in 21% of patients who received TUKYSA; those occurring 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, fatigue, hepatotoxicity, vomiting, stomatitis, decreased appetite, abdominal pain, headache, anemia, and rash.
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.
- Strong CYP3A or 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 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 toxicity.
Use in Specific Populations
- Lactation: Advise women not to breastfeed while taking TUKYSA and for at least 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.
Seagen is a global biotechnology company that discovers, develops and commercializes transformative cancer medicines to make a meaningful difference in people’s lives. Seagen is headquartered in the Seattle, Washington area, and has locations in California, Canada, Switzerland and the European Union. For more information on the company’s marketed products and robust pipeline, visit www.seagen.com and follow @SeagenGlobal on Twitter.
Certain of the statements made in this press release are forward looking, such as those, among others, relating to the potential for FDA approval of TUKYSA in the referenced indication, the timing of any potential FDA approval, the therapeutic potential of TUKYSA, its possible efficacy, safety and therapeutic uses, the MOUNTAINEER-03 trial, potential future regulatory submissions and the TUKYSA development program. Actual results or developments may differ materially from those projected or implied in these forward-looking statements. Factors that may cause such a difference include without limitation the possibility that the sNDA submission based on data from the MOUNTAINEER trial may not ultimately be approved by the FDA in a timely manner or at all or with the requested label; the risk that subsequent clinical trials may fail to establish sufficient efficacy; the risk of adverse events, including the potential for newly-emerging safety signals; the risk that adverse regulatory actions may occur; and the risk of delays, setbacks or failures in clinical development and regulatory activities for a variety of reasons, including the difficulty and uncertainty of pharmaceutical product development, adverse regulatory action, possible required modifications to clinical trials, failure to properly conduct or manage clinical trials and failure of clinical results to support continued development or regulatory approvals. More information about the risks and uncertainties faced by Seagen is contained under the caption “Risk Factors” included in the company’s Quarterly Report on Form 10-Q for the year ended June 30, 2022 filed with the Securities and Exchange Commission. Seagen disclaims any intention or obligation to update or revise any forward-looking statements, whether as a result of new information, future events or otherwise, except as required by law.
 American Cancer Society: Key Statistics for Colorectal Cancer-2022. https://www.cancer.org/cancer/colon-rectal-cancer/about/key-statistics.html. Accessed July 2022.
 Wang J., et al. Metastatic patterns and survival outcomes in patients with stage IV colon cancer: A population‐based analysis. Cancer Med. 2020 Jan; 9(1): 361–373.
 Ahcene Djaballah S, Daniel F, Milani A, Ricagno G, Lonardi S. HER2 in Colorectal Cancer: The Long and Winding Road From Negative Predictive Factor to Positive Actionable Target. Am Soc Clin Oncol Educ Book. 2022;42:1-14. doi:10.1200/EDBK_351354.
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Douglas Maffei, Ph.D.