AstraZeneca's first-in-class FDA approval for Truqap marred by surprise restriction
November 18 , 2023
By Angus Liu, Fierce Pharma, Nov 17, 2023

After the landmark success of Enhertu in HER2-low breast cancer, AstraZeneca has blazed another trail in the world’s most common cancer type.

The FDA has approved AstraZeneca’s Truqap, or capivasertib, in combination with the company’s Faslodex to treat certain patients with HR-positive, HER2-negative advanced breast cancer, AZ said Friday.

To be eligible for the therapy, a patient’s cancer must bear at least one of three gene alterations—PIK3CA, AKT1 and PTEN—and have either progressed on at least one endocrine-based regimen in the metastatic setting or recurred within 12 months of completing postsurgical adjuvant therapy.

Truqap is the first AKT inhibitor to cross the FDA finish line. But the biomarker restriction along the PI3K-AKT pathway comes as a disappointment given that the AZ combination showed a significant improvement in delaying tumor progression or death in a broader patient population, regardless of mutation status.

In the CAPItello-291 trial, Truqap and Faslodex reduced the risk of progression or death by 40% against Faslodex alone in patients with previously treated HR+/HER2- breast cancer. The combo’s progression-free survival benefit was more pronounced at 50% in those with AKT-related mutations. But the regimen still improved progression-free survival by 21% in those with AKT pathway-nonaltered tumors, after excluding some patients with unknown gene sequencing results, an exploratory analysis found.

The restriction could indicate that the FDA’s drug reviewers might have seen some additional patient survival data that failed to convince them of Truqap’s utility in the AKT-negative subgroup. Lately, the agency has put a heavy emphasis on overall survival, frequently requiring longer follow-up of studies or balking at the first sight of any potential detriment to patients’ life expectancy.

At an interim analysis of overall survival in CAPItello-291, Truqap and Faslodex slashed the risk of death by 31% in the AKT-altered group and by 26% in the overall trial population. The overall survival result from the AKT-nonaltered group wasn’t publicly available at the time.

As investigators continue to follow patients toward the trial’s final overall survival analysis, “there’s an opportunity for us to revisit whether or not there’s an opportunity to expand the label beyond where we are,” AstraZeneca’s oncology business chief David Fredrickson said in a Friday interview.

The FDA’s limited label “may suggest a change in sentiment that requires the sponsor to have the burden of demonstrating prospectively and conclusively that all patients derive a benefit in order to be granted a broad label,” Leerink Partners analysts said in a Friday note.

AKT alterations account for about half of HR-positive breast cancer cases, Fredrickson noted. About 60% of second-line breast cancer patients are currently being tested with next-generation sequencing, which is necessary to identify patients according to Truqab’s biomarker label, he added.

As a result of the unexpected restriction, the Leerink team lowered its peak sales estimate for Truqap to $1.28 billion, from their previous projection of $2.36 billion.

Nevertheless, Truqap’s arrival is a threat to Novartis’ Piqray, which in 2019 won FDA approval in combination with Faslodex for previously treated HR+/HER2-, PIK3CA-mutated breast cancer.

The FDA evaluated Truqap under priority review and Project Orbis, which facilitates the concurrent submission and review of oncology drugs with regulatory agencies in various parts of the world. Under that initiative, Australia, Brazil, Canada, Israel, Singapore, Switzerland and the U.K. are also reviewing Truqap. AZ has applications underway in China, Europe and Japan, as well. 

Besides HR-positive disease, AZ is also testing Truqap as a treatment for first-line, triple-negative breast cancer in the phase 3 CAPItello-290 trial, with a readout expected in the first half of 2024. Separately, the CAPItello-292 study is adding Pfizer’s CDK4/6 inhibitor Ibrance to Truqap and Faslodex in an earlier HR+/HER2- setting.

AZ acquired rights to Truqap through a licensing deal with the U.K.’s Astex Therapeutics. Back in 2005, AZ paid just 2.75 million pounds upfront and committed up to 150 million pounds in milestone payments to obtain rights to Astex’s AKT candidates.

Truqap adds to AZ’s breast cancer arsenal. The British pharma’s Daiichi Sankyo-partnered Enhertu is allowed in HER2-positive breast cancer. In a first-of-its-kind indication, the antibody-drug conjugate was approved in August 2022 to treat certain breast cancer with low expressions of HER2 that were traditionally considered HER2-negative in a post-chemo setting.

The company is also working on an oral SERD called camizestrant, which returned positive phase 2 data last year and is currently in various phase 3 trials.

Breast cancer is the most common cancer worldwide, with about 2.3 million diagnoses each year.

“The strategy that we’ve had within breast cancer,” Fredrickson said, “is to really think about, how do we put forward a portfolio of medicines that allows oncologists to have an AstraZeneca medicine at different stages of disease and through different types of subtypes that are the drivers of those diseases?”
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