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Beyond CDK4/6 Inhibitors for HR-Positive Breast Cancer

— Switching drugs, taking aim at different targets under investigation

MedpageToday

MIAMI BEACH -- As clinical investigation pushes the envelope with CDK4/6 inhibitors, multiple lines of research examine "what's next" when hormone receptor-positive breast cancer progresses or develops resistance.

The search for optimal therapy at progression on a CDK4/6 inhibitor has given rise to multiple strategies. Three possibilities are to continue the CDK4/6 inhibitor and switch the endocrine agent; keep the endocrine agent and switch to a different CDK4/6 inhibitor; and continue both the endocrine agent and the CDK4/6 inhibitor and target a collateral pathway with another agent.

"This is just three of the many that are available out there," said Adam Brufsky, MD, PhD, of the University of Pittsburgh, during a presentation here at the .

Several phase I and II trials evaluating the three strategies are ongoing, he added. In the meantime, analyses of "real-world" experience with progression beyond CDK4/6 inhibitors have provided some insights.

Switching CDK4/6 Inhibitors

Switching CDK4/6 inhibitors has already been evaluated in a of 58 patients who received abemaciclib (Verzenio) after progression on palbociclib (Ibrance). Some patients received the drugs sequentially; others received abemaciclib after one or more intervening treatments. Some received abemaciclib alone and others received it in combination with endocrine therapy.

About a third of the patients remained on abemaciclib for more than 6 months, suggesting continued benefit, but a similar number also had early disease progression, suggesting cross-resistance between CDK4/6 inhibitors, said Brufsky.

Another evaluated switching to a different type of agent after progression on a CDK4/6 inhibitor. The analysis involved 33 patients, with HR-positive metastatic breast cancer treated with the mTOR inhibitor everolimus (Afinitor) plus exemestane. The cohort included 17 patients with prior exposure to a CDK4/6 inhibitor.

Patients with and without prior anti-CDK4/6 therapy had similar progression-free survival (PFS, 5.7 vs 4.7 months, respectively) and overall survival (OS, 17.8 vs 11.4 months), although investigators noted a trend toward improved OS in patients with prior anti-CDK4/6 treatment.

A from the Mayo Clinic in Rochester, Minnesota, included 81 patients with advanced HR-positive breast cancer treated in first line with a CDK4/6 inhibitor and 55 who received a drug from the class in second line. Patients received a variety of single-agent and combination therapies, but the combination of everolimus and exemestane stood out from the others with a median time to treatment failure of 13.2 months.

Targeting mTOR, PI3k

Investigators in a phase II trial evaluated in 309 patients with advanced HR-positive/HER2-negative breast cancer: everolimus as a single agent or in combination with exemestane or single-agent capecitabine. Median PFS ranged from 6.8 months with single-agent everolimus to 9.6 months with capecitabine but did not differ significantly among the groups.

A evaluated fulvestrant alone or in combination with everolimus in 131 patients with HR-positive/HER2-negative metastatic breast cancer and aromatase inhibitor resistance. Adding everolimus to fulvestrant doubled median PFS compared with single-agent fulvestrant (10.3 vs 5.1 months, P=0.02).

"In my practice, this is something I tend to use in patients who have progressed through a CDK4/6 inhibitor and an aromatase inhibitor," said Brufsky. "It is one of my go-to regimens, or at least it was, until [PI3K inhibitors became available]."

The PI3K pathway is a key route for transmission of cell signals from the surface to the nucleus, making it the target for development of PIK3 inhibitors, particularly those targeting the PI3K-α isoform, which is associated with less toxicity. The validated the targeting of PIK3 and the PIK3CA mutation in advanced HR-positive breast cancer, evaluating fulvestrant with or without the PI3K-α inhibitor alpelisib (Piqray).

Patients randomized to the combination had almost twice the PFS duration (11.0 vs 5.7 months, P<0.001). The finding was supported by a blinded independent review committee. The combination also led to 13 percentage points' absolute improvement in 12-month PFS (46.3% vs 32.9%).

In the subgroup of patients with PIK3CA mutations, alpelisib plus fulvestrant resulted in an objective response rate (ORR) of 35.7% versus 16.2% with fulvestrant alone (P=0.0002). In the entire study population, the ORR was 26.6% with the combination and 12.8% with single-agent fulvestrant (P=0.0006).

Hyperglycemia is a recognized on-target adverse effect of PI3K inhibition, and the drug is contraindicated for patients with uncontrolled hyperglycemia, said Brufsky. In SOLAR-1, hyperglycemia occurred in 64% of patients treated with alpelisib, including grade 3 in 32.7% and grade 4 in 3.9%.

More recently, alpelisib was paired with fulvestrant or letrozole in an involving 160 patients with PIK3CA-mutant HR-positive advanced breast cancer that exhibited resistance to a CDK4/6 inhibitor. Preliminary results from the study showed a higher response rate with letrozole (27% vs 14-15% with fulvestrant), but more patients had stable disease with fulvestrant (55-59% vs 32-35%).

"Alpelisib is a new standard of care for PIK3CA-mutant HR-positive metastatic breast cancer post-CDK4/6 inhibitor therapy," said Brufsky.

Another evaluated the AKT inhibitor capivasertib plus fulvestrant versus fulvestrant and placebo in 140 patients with HR-positive metastatic breast cancer resistant to an aromatase inhibitor. Median PFS doubled in patients who received the combination (10.3 vs 4.8 months, P=0.0035). Median OS favored the capivasertib arm but the difference did not achieve statistical significance (26.0 vs 20.0 months, P=0.071).

Trials evaluating other agents are underway or planned, including different AKT inhibitors, antibody-drug conjugates, other novel strategies, and an oral formulation of paclitaxel, Brufsky said in conclusion.

  • author['full_name']

    Charles Bankhead is senior editor for oncology and also covers urology, dermatology, and ophthalmology. He joined 鶹ý in 2007.

Disclosures

Brufsky disclosed relationships with Bioarray, Novartis, Roche, Eisai, Celgene, Eli Lilly, Pfizer, Agendia, Genomic Health, NanoString Technologies, and Biotheranostics.

Primary Source

Miami Breast Cancer Conference

Brufsky AM "Beyond CDK inhibitors: Targeting PI3KCA" MBCC 2020; Medical Oncology Breakout Session.