Seagen Announces Results from Pivotal MOUNTAINEER Trial Demonstrating Clinically Meaningful Antitumor Activity of TUKYSA® (tucatinib) in Combination with Trastuzumab in Previously Treated HER2-Positive Metastatic Colorectal Cancer

–Phase 2 trial showed chemotherapy-free TUKYSA combination resulted in clinically meaningful and durable tumor responses–

–Results presented in late-breaking oral session at the ESMO World Congress on Gastrointestinal Cancer–

Seagen Inc. (Nasdaq:SGEN) today announced full results from the pivotal phase 2 MOUNTAINEER trial, which showed TUKYSA^® (tucatinib) in combination with trastuzumab was well-tolerated with durable responses in patients with previously treated HER2-positive metastatic colorectal cancer (mCRC). These late-breaking data were presented in an oral session at the European Society for Medical Oncology (ESMO) World Congress on Gastrointestinal Cancer on July 2 in Barcelona, Spain.

“Patients with chemotherapy-refractory HER2-positive metastatic colorectal cancer receive limited clinical benefit with currently available therapies,” said John H. Strickler, M.D., Associate Professor of Medicine, Duke University School of Medicine and lead trial investigator. “With sustained responses and favorable tolerability in heavily pretreated patients, tucatinib in combination with trastuzumab has the potential to be a new treatment option for previously treated HER2-positive mCRC.”

“This study has shown the benefits of dual-HER2 inhibition with tucatinib and trastuzumab in patients with HER2-positive metastatic colorectal cancer, including many whose cancer had spread to the liver or lungs before joining the trial,” said Roger Dansey, M.D., interim CEO and Chief Medical Officer, Seagen. “We believe this chemotherapy-free combination may play an important role in addressing the unmet needs of patients with this disease.”

At a median duration of follow-up of 20.7 months (interquartile range: 11.7, 39.0), results of the MOUNTAINEER trial showed a 38.1% confirmed objective response rate (cORR) (95% Confidence Interval [CI]: 27.7, 49.3) per blinded independent central review (BICR) in the HER2-positive patients who were assigned to receive tucatinib in combination with trastuzumab (n=84 with a median age of 55.0 years [range 24 to 77]). In these patients, the median duration of response (DoR) per BICR was 12.4 months (95% CI: 8.5, 20.5). Median progression-free survival per BICR was 8.2 months (95% CI: 4.2, 10.3), and median overall survival was 24.1 months (95% CI: 20.3, 36.7). At study entry, 64.3% and 70.2% of these patients had liver or lung metastases, respectively, and had received a median of 3.0 (1, 6) prior lines of systemic therapy.

In a cohort of patients who received tucatinib monotherapy (n=30), the ORR per BICR by 12 weeks was 3.3% (95% CI: 0.1, 17.2) and the disease control rate was 80.0%. Participants who did not respond to tucatinib monotherapy by 12 weeks or progressed at any time had the option to receive the combination of tucatinib and trastuzumab.

The most common (greater than or equal to 20%) treatment-emergent adverse events (AEs) in patients assigned to receive tucatinib and trastuzumab (n=86) were diarrhea (Grade 1 or 2: 60.5%, Grade 3: 3.5%), fatigue (Grade 1 or 2: 41.9%, Grade 3: 2.3%), nausea (Grade 1 or 2: 34.9%) and infusion-related reaction (Grade 1 or 2: 20.9%). The most common Grade ≥3 AE was hypertension (Grade 3: 7.0%). AEs leading to discontinuation of any treatment occurred in 5.8% of patients. No deaths due to AEs were reported. Please see Important Safety Information at the end of this press release for further safety information regarding tucatinib.

Data from this trial will form the basis of a planned supplemental New Drug Application to the U.S. Food and Drug Administration under the Accelerated Approval Program. 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 and plans to discuss these results with certain global health authorities.

About MOUNTAINEER

MOUNTAINEER is a U.S. and European multicenter, open-label, randomized phase 2 clinical trial of tucatinib in combination with trastuzumab or as a single agent that enrolled 117 patients with HER2-positive metastatic or unresectable colorectal cancer following previous standard-of-care therapies. MOUNTAINEER began as a U.S. investigator-sponsored trial and initially consisted of a single cohort (Cohort A) of patients who 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 trial was then expanded globally to include patients who were randomized to receive tucatinib plus trastuzumab (Cohort B) or tucatinib monotherapy (Cohort C).

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 in patients receiving the combination of tucatinib and trastuzumab (Cohorts A and B). Duration of response, progression-free survival, overall survival and safety and tolerability of the combination regimen are secondary objectives.

About Colorectal Cancer

Globally, more than 1.9 million new colorectal cancer cases and 935,000 deaths were estimated to occur in 2020, representing about one in 10 cancer cases and deaths.¹ Colorectal cancer is the third leading cause of cancer-related deaths in the U.S. and is anticipated to lead to about 52,580 deaths in 2022.² Approximately 22% of U.S. patients with colorectal cancer are diagnosed at the advanced stage.³ Human epidermal growth factor receptor 2 (HER2) is overexpressed in 3-5% of patients with metastatic colorectal cancer.^4,5 There are currently no FDA-approved therapies that specifically target HER2 in colorectal cancer.

About TUKYSA

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 36 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. Merck, known as MSD outside the U.S. and Canada, has exclusive rights to commercialize TUKYSA in Asia, the Middle East and Latin America and other regions outside of the U.S., Canada and Europe.

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.

Adverse Reactions

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.

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.

Drug Interactions

• 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.

About Seagen

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.

Forward-Looking Statements

Certain of the statements made in this press release are forward looking, such as those, among others, relating to the planned submission of a supplemental New Drug Application to the FDA under the FDA’s Accelerated Approval Program, discussions with global health authorities, the therapeutic potential of TUKYSA, its possible efficacy, safety and therapeutic uses, 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 the possibility that the data from the MOUNTAINEER trial may not be sufficient to support accelerated approval or expansion of the labeled indications of use for TUKYSA in the U.S; the possibility of impediments or delays in the submission of a supplemental New Drug Application to the FDA; the risk of adverse events, including the potential for newly-emerging safety signals; 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 quarter ended March 31, 2022, and subsequent periodic reports, 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.

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¹ American Cancer Society Journal: Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. https://acsjournals.onlinelibrary.wiley.com/doi/10.3322/caac.21660. Accessed June 2022.

² American Cancer Society: Key Statistics for Colorectal Cancer-2022. https://www.cancer.org/cancer/colon-rectal-cancer/about/key-statistics.html. Accessed March 2022.

³ 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.

⁴ Takegawa N and Yonesaka K (2017). HER2 as an emerging oncotarget for colorectal cancer treatment after failure of anti-epidermal growth factor receptor therapy. Clin Colorectal Cancer 16: 247-51.

⁵ Valtorta E., et al. Assessment of a HER2 scoring system for colorectal cancer: results from a validation study. Mod Pathol 28: 1481-91 2015.

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