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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.

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