The US Food and Drug Administration (FDA) has granted Seagen Inc. Accelerated Approval for TUKYSA (tucatinib) in combination with trastuzumab for people with previously treated RAS wild-type, HER2-positive unresectable or metastatic colorectal cancer that has progressed following treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy.
In the US, colorectal cancer is the third leading cause of cancer-related deaths. Approximately 153,000 people will be diagnosed with colorectal cancer in the US this year alone, with an anticipated 52,550 deaths by the close of 2023. The rate of the disease is also increasing in younger adults. Around 22% of cases in the US are diagnosed at the advanced stage.
In what is the first FDA-approved treatment for HER2-positive metastatic colorectal cancer, Seagen’s combination regimen is approved for use in the second-line treatment setting and beyond. Accelerated Approval was given based on tumour response rate and durability of response from the phase 2 MOUNTAINEER clinical trial. Previously, the FDA granted TUKYSA Breakthrough Therapy Designation and Priority Review in the same setting.
Results from the MOUNTAINEER trial showed a 38% overall response rate (ORR) per blinded independent central review (BICR) in patients of a median age of 55 (from a range between 24 and 77 years old) who received TUKYSA in combination with trastuzumab. Complete responses were observed in 3.6% of patients and partial responses observed in 35% of patients. The median duration of response (DOR) per BICR was 12.4 months.
Serious side effects recorded in the MOUNTAINEER trial occurred in 22% of patients. The most common 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 of which was increased alanine aminotransferase (ALT), in 2.3%.
Continued approval could be contingent upon verification and description of clinical benefit in confirmatory trials: the FDA’s Accelerated Approval Program allows for approval of a medicine based on a surrogate endpoint that is reasonably likely to predict clinical benefit if the medicine fills an unmet medical need for a serious condition.
Dr John Strickler, associate professor of medicine at Duke University Medical Center and lead investigator for the MOUNTAINEER trial, said: “Historically, patients with HER2-positive metastatic colorectal cancer, who have progressed following frontline therapy, have had poor outcomes. The FDA approval of a chemotherapy-free combination regimen that specifically targets HER2 is great news for these patients.”
Michal Sapienza, CEO of the Colorectal Cancer Alliance, commented: “Biomarker testing is bringing new hope to people living with some types of colorectal cancer by opening the door to targeted treatments like TUKYSA […]”
He continued: “It is critical that physicians and patients understand the importance of comprehensive biomarker testing at diagnosis because it can inform treatment decisions and help improve outcomes.”
The Accelerated Approval expands TUKYSA-based therapy to patients across two types of cancer now, and Dr Marjorie Green, senior vice president and head of late-stage development at Seagen, stated that the company “[believes] the efficacy and safety profile of the TUKYSA and trastuzumab-based regimen further establishes its role as an important backbone of dual HER2 inhibition in the treatment of adult patients with certain HER2-expressing breast and colorectal cancers.”
Side effect warnings for TUKYSA prescribing include diarrhoea, hepatotoxicity, and embryo-foetal toxicity, some of which can be severe or fatal.
A global, randomised phase 3 clinical trial (MOUNTAINEER-03) is ongoing and will compare TUKYSA in combination with trastuzumab and mFOLFOX6 with standard of care – intended to serve as a confirmatory trial and potentially support future global regulatory submissions.
Rumours that Merck was interested in a bid for Seagen emerged in June 2022, but had stalled by August, the big pharma originally reportedly considering a $200-plus per share offer for the antibody-drug conjugate (ADC) specialist that would value the company at around $40 billion. According to Bloomberg, the two sides could not agree on a price.
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