CDK7 Inhibitor-Based Combo Promising in CDK4/6-Resistant Breast Cancer

SAN ANTONIO — The addition of the CDK7 inhibitor samuraciclib to fulvestrant (Faslodex) demonstrated encouraging antitumor activity among patients with advanced hormone receptor (HR)-positive breast cancer previously treated with a CDK4/6 inhibitor, according to a small, single-arm cohort study.

Among 25 evaluable patients, three had partial responses to therapy (one confirmed and two unconfirmed) and the clinical benefit rate was 36% at 24 weeks, reported Charles Coombes, MD, of Imperial College London.

Of note, the clinical benefit rate was 53% in patients with TP53 wild-type tumors, and 55% in patients with no liver metastases, he added. In total, 72% of patients had some degree of tumor shrinkage.

“It is early days, obviously,” Coombes said during his presentation at the San Antonio Breast Cancer Symposium. “This is only a small study of 31 patients, but the combination appears effective, particularly in patients with wild-type TP53 status, which is measured by cell-free DNA.”

Coombes noted that median progression-free survival (PFS) was 32 weeks in those with TP53 wild-type tumors, while in the TP53-mutant patients it was just 7.9 weeks. In patients without liver metastases, PFS had not been reached compared with 11.9 months in those with liver metastases.

Why is TP53 so important in predicting outcomes with samuraciclib? “We believe it reacts to the stress induced by CDK7 inhibition,” Coombes said. “Essentially, when it is wild-type, it responds to CDK7 inhibition to induce apoptosis and senescence. This is important because at this stage of the disease in ER-positive breast cancer, nearly 70% of patients still have wild-type TP53.”

“I think there is an abundance of these cell cycle control proteins that can be targeted, and this one is fascinating,” Angela DeMichele, MD, of the Perelman School of Medicine at the University of Pennsylvania, told MedPage Today. “That’s because it is upstream of CDK4, and one mechanism of resistance to CDK inhibitors is amplification of CDK4, so if that is what is happening when you give a CDK4/6 inhibitor, and then you bring in a CDK7 inhibitor, you may be overcoming that.”

Samuraciclib is a once-daily, oral, ATP-competitive, selective inhibitor of CDK7, which, according to Coombes, has shown synergy with endocrine therapy in HR-positive breast cancer xenograft models.

The study included 31 women (median age 60 years) with histologically confirmed metastatic or locally advanced HR-positive, HER2-negative breast cancer, who had become resistant to CKD4/6 inhibitors and endocrine therapy.

Of these patients, 23% had received prior chemotherapy in the metastatic setting, 81% had visceral disease, and 45% had liver metastases.

Twenty-five patients received the optimal dose of samuraciclib 360 mg daily plus fulvestrant, while six received a reduced dose of 240 mg daily plus fulvestrant.

The most common adverse events were diarrhea, nausea, and vomiting, which were low-grade and reversible.

“A very important feature is that we didn’t see any neutropenia, or significant myelosuppression,” Coombes said. “And this is completely different from the CDK4/6 inhibitors.”

“I think the side effect profile is pretty similar to what we see with abemaciclib (Verzenio), with all the GI toxicity,” noted DeMichele. “Clearly there is a good response, and a durable response, and the question is whether it adds to what you would see if you simply went to another endocrine therapy or endocrine therapy plus everolimus-exemestane, which some people would say is the next line.”

“Drugs that are as well tolerated as these are, and give people more time, is a win, because the quality of life tends to be so good, and you are forestalling the start of chemo,” she added.