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CHICAGO -- Upfront CDK4/6 inhibition or second-line use in advanced hormone receptor (HR)-positive/HER2-negative breast cancer led to similar cumulative progression-free survival (PFS) in a large randomized trial.

Patients who received a CDK4/6 inhibitor plus an aromatase inhibitor (AI) as initial therapy and fulvestrant in the second line had a median PFS of 31.0 months at the end of second-line treatment (PFS2). Starting with a nonsteroidal AI and switching to a CDK4/6 inhibitor and fulvestrant after progression led to a median PFS2 of 26.8 months, a difference that failed to achieve statistical significance.

A preliminary analysis of overall survival (OS) showed a trend favoring second-line CDK4/6 inhibition (53.7 vs 45.9 months), reported Gabe Sonke, MD, PhD, of the Netherlands Cancer Institute in Amsterdam, at the American Society of Clinical Oncology (ASCO) annual meeting.

First-line CDK4/6 inhibition did not improve quality of life, but extended the time on CDK4/6 inhibition by 16.5 months, which was associated with more grade 3/4 toxicity and a $200,000 greater cost per patient as compared with the endocrine-first strategy.

The "challenges the need for first-line use of a CDK4/6 inhibitor," said Sonke. "Endocrine monotherapy remains an excellent option, especially in first line. Trials like SONIA can significantly reduce the toxicity of effective drugs and make them accessible to those who would otherwise find them unaffordable."

Sonke noted that the trial was self-funded and the cost was covered by the savings that accrued from use of less expensive drugs.

A presentation that followed Sonke's cast doubt on the value of continuing a CDK4/6 inhibitor beyond progression. The randomized trial showed no significant difference in PFS, response rate, or clinical benefit for patients who received palbociclib (Ibrance) and endocrine therapy or just endocrine therapy after progression on first-line palbociclib and either fulvestrant or an AI, said Antonio Llombart-Cussac, MD, PhD, of University Hospital Arnau de Vilanova in Lleida, Spain.

Questions and More Questions

Before taking the trial results at face value, several issues need to be resolved, according to ASCO-invited discussant Daniel Stover, MD, of Ohio State University's James Comprehensive Cancer Center in Columbus.

• Do CDK4/6 inhibitors differ qualitatively and offer the potential for personalized CDK4/6 inhibitor therapy? Not yet, in the absence of randomized head-to-head trials.
• Should all patients receive a CDK4/6 inhibitor as part of first-line therapy? Endocrine therapy might be sufficient for a subset of patients, but they have yet to be identified.
• Is switching to a different endocrine partner and continuing a CDK4/6 inhibitor after progression a reasonable strategy? Most patients will not benefit, so both the endocrine therapy and CDK4/6 inhibitor partner should be switched or patients should go to a different type of second-line therapy.

"I think one of the things that is perhaps most exciting to think about is who are the very-good-risk patients who can delay a CDK4/6 inhibitor," said Stover. "I think for the majority of patients, endocrine therapy plus a CDK4/6 inhibitor is still the appropriate treatment. But I would argue that we need additional biomarkers."

Sonke reported the primary results of the SONIA trial, conducted entirely at centers in the Netherlands. Investigators enrolled patients with advanced HR-positive/HER2-negative breast cancer and no prior treatment for advanced disease. They received a nonsteroidal AI alone or in combination with a CDK4/6 inhibitor as initial therapy. At disease progression, those on single-agent AI switched to a CDK4/6 inhibitor and fulvestrant, and patients who received a CDK4/6 inhibitor in the first line received single-agent fulvestrant.

The primary endpoint was PFS2. Data analysis included 1,050 patients who had a median age of 63-64. More than 85% of patients were postmenopausal, a majority had visceral metastases, and 91% of the patients received palbociclib.

First-line CDK4/6 inhibition significantly extended PFS versus endocrine therapy (24.7 vs 16.1 months, HR 0.59, 95% CI 0.51-0.69, P<0.0001). However, the advantage dissipated during second-line treatment, resulting in a 4.2-month difference in PFS2 in favor of first-line CDK4/6 inhibition, which represented a 13% reduction in the hazard for progression or death (P=0.10).

A subgroup analysis showed no clear-cut advantages for either strategy. Median OS was 53.7 months with second-line CDK4/6 inhibition versus 45.9 months with a CDK4/6 inhibitor in first line (P=0.83).

A preliminary analysis of quality of life showed no difference in scores between the treatment groups. Sonke said the safety profiles of the regimens were characteristic of CDK4/6 inhibitors, including neutropenia, liver function abnormalities, anemia, and thrombocytopenia. However, patients who started treatment with a CDK4/6 inhibitor had a 42% greater incidence of grade ≥3 adverse events, consistent with the longer duration on treatment with a CDK4/6 inhibitor.

In his summary of the findings, Sonke posed three questions: "If you're a patient, would you consider a treatment that offers improvement in quality of life and does not improve overall survival? As a doctor, would you recommend a treatment that nearly doubles the incidence of side effects? And if you were responsible for covering the cost of this treatment, whether as an individual or as healthcare insurance, would you consider it worth $200,000?"

PALMIRA Results

The European PALMIRA trial added to the questions surrounding the use of CDK4/6 inhibitors to treat advanced HR-positive/HER2-negative breast cancer. Investigators enrolled patients who had disease progression after receiving a CDK4/6 inhibitor as a component of first-line treatment for advanced disease. They randomized 198 patients 2:1 to receive palbociclib plus either fulvestrant or letrozole or to single-agent endocrine therapy with the same two choices.

The primary endpoint was investigator-assessed PFS. The results showed a median PFS of 4.9 months with palbociclib and 3.6 months with single-agent endocrine therapy, representing a 16% reduction in the hazard ratio (95% CI 0.66-1.07, P=0.149). The 6-month PFS favored the palbociclib arm (42.1% vs 29.1%), but 12-month PFS was virtually identical (12.4% vs 12.3%).

A subgroup analysis showed no difference in outcome according to visceral disease status or duration of prior palbociclib treatment. A preliminary analysis of OS yielded median values of 28.3 months with palbociclib and 28.8 months with endocrine therapy.

"A vast biomarker study program is underway to identify which patients are most likely to benefit from CDK4/6 inhibitor maintenance therapy," said Llombart-Cussac.

The SONIA trial raised questions about the appropriateness of CDK4/6 inhibition for all patients, but the findings likely will have a greater impact in Europe, said Maryam Lustberg, MD, MPH, of Yale Cancer Center in New Haven, Connecticut.

"We have overall survival data in other studies using ribociclib [Kisqali] in the first-line setting in metastatic breast cancer, so I'm not ready to change that approach," she told 名媛直播. "If we had certain biomarkers that could pluck out those patients with indolent disease and spare them the additional toxicity and cost of a CDK4/6 inhibitor, and they could just cruise along with single-agent endocrine therapy -- I just don't think we're there yet."

The added cost of prolonged CDK4/6 inhibition is an issue that will continue to evolve.

"Around the world there's more cost consciousness, and I applaud that," Lustberg added. "I think it also speaks to additional countries where we know access to CDK4/6 inhibitors is extremely limited. As we become more resource-sensitive to these global issues, again, I think we need to better understand which patient population would benefit versus not. I think that until then, I just don't think currently in the U.S. that I would feel comfortable restricting it."