Seagen recently presented positive pivotal Phase II data from its trial of Tukysa (tucatinib) in combination with trastuzumab in HER2-positive metastatic colorectal cancer.
As Seagen preens in the window for potential acquirer Merck, its pipeline is helping to strengthen the case. Over the long weekend, the Seattle-based company announced positive results from its pivotal Phase II MOUNTAINEER trial evaluating Tukysa (tucatinib) in combination with trastuzumab, a biologic, for the treatment of previously treated patients with HER2-positive metastatic colorectal cancer (mCRC). The data readout demonstrated the drug’s ability to enact clinically meaningful antitumor activity.
In patients with colorectal cancer, the disease typically begins as a polyp inside the colon or rectum. Unfortunately, it is usually diagnosed at an advanced stage, making it difficult to halt progression of the malignancies. Colorectal cancer is the third leading cause of cancer-related deaths in the U.S. and is estimated to have impacted 1.9 million individuals in 2020 globally.
Seagen is hoping to make a difference for patients who have already run the gauntlet of standard care options.
Tukysa Combo Shines in Metastatic Colorectal Cancer
The Phase II MOUNTAINEER trial included 117 patients with HER2-positive mCRC who had previously received standard of care therapies. Cohort A of the trial received Tukysa twice per day in combination with trastuzumab. The trial was then expanded globally to include Cohorts B and C in which patients were given either the combinatorial therapy or Tukysa alone.
The complete data readout, which was presented at the European Society for Medical Oncology World Congress, showed promising results from the combination therapy. At a median follow-up of 20.7 months, trial participants experienced a 38.1% confirmed objective response rate and the median progression-free survival rate was 8.2 months. The median overall survival rate was 24.1 months.
Patients who were treated with Tukysa alone demonstrated a disease control rate of 80%. Additionally, the chemotherapy-free therapy resulted in clinically meaningful and durable tumor responses.
The Value of a Chemo-free Approach in mCRC
“The non-chemotherapeutic approach offers patients the opportunity to receive meaningful clinical benefit without the toxicity of traditional cytotoxic chemotherapy,” John Strickler, M.D., associate professor of medicine at Duke University School of Medicine and lead investigator of the MOUNTAINEER trial, told BioSpace in an email.
Chemotherapy-free treatments are often very important to patients as chemotherapeutics can cause undesirable side effects such as severe fatigue, nausea, anemia, cognitive dysfunction and susceptibility to infection. Researchers have suggested that in the case of mCRC, incorporating chemo-free therapy intervals can help to prolong survival and maintain the best quality of life.
“Patients with HER2-positive mCRC who progress on early lines of chemotherapy regimens receive limited clinical benefit from current standard-of-care treatments. There are currently no approved therapies for patients with HER2+ RAS wild-type metastatic colorectal cancer. Tucatinib (Tukysa) in combination with trastuzumab has the potential to become a new standard of care for this patient population,” Strickler said.
In addition to demonstrating efficacy, Tukysa in combination with trastuzumab was generally well-tolerated among patients with the most common treatment-emergent adverse events including diarrhea, fatigue, nausea and infusion-related reaction.
“These results provide rationale for continued investigation of tucatinib in combination with trastuzumab in [the] first-line treatment of HER2-positive mCRC,” Strickler said, adding that Seagen’s MOUNTAINEER-03 trial is evaluating the drug in combination with trastuzumab and chemotherapy regimen mFOLFOX6 versus standard of care treatment in first-line HER2+ mCRC.
The results of the Phase II trial will form the basis of a supplemental New Drug Application submission which Seagen will submit to the FDA under the Accelerated Approval Program. Merck, which is partnered with Seagen on Tukysa, retains the rights to commercialize the therapeutic outside of the U.S., Canada and Europe. Previously, Merck purchased Tukysa for $125 million upfront.
Tukysa was approved by the U.S. Food and Drug Administration in 2020 for the treatment of adult patients with advanced unresectable or metastatic HER2-positive breast cancer in combination with trastuzumab and capecitabine. The approval also covered patients with brain metastases who have received one or more prior anti-HER2 based regimens in the metastatic setting. Tukysa is additionally approved in 36 countries worldwide.
Tukysa’s Unique Mechanism of Action
Tukysa inhibits the HER2 protein, which has been found to be overexpressed in 3-5% of patients with mCRC. HER2 protein overexpression has been associated with tumor cell proliferation and survival pathways, making it an important target for cancer therapeutics. By inhibiting the phosphorylation of HER2, Tukysa has been shown to inhibit the growth of HER2-expressing tumors.
Strickler explained the unique qualities of the drug.
“Tukysa is highly selective for HER2, which allows more complete blockade of HER2 signaling without some of the side effects (rash and diarrhea) that occur due to off-target activity,” he said.
Currently, there are no FDA-approved therapies that specifically target HER2 in mCRC, prompting hope that Tukysa in conjunction with tratstuzumab could be a promising new type of care for patients.
Seagen is also investigating the drug in combinatorial therapies for metastatic breast cancer, gastroesophageal cancer, metastatic solid tumors with HER2 alterations and metastatic gastrointestinal cancers.
The company is developing a wide array of other chemotherapy-free treatments for a broad spectrum of oncological targets including large B-cell lymphoma, Hodgkin Lymphoma, urothelial cancer, bladder cancer and cervical cancer. In April, Seagen presented 26 abstracts at the American Society of Clinical Oncology meeting highlighting its expansive portfolio.
