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Continuing CDK4/6 Inhibitor Beyond Progression No Help in Metastatic Breast Cancer

<ѻý class="mpt-content-deck">— Prior therapy, baseline mutations confound results; "intriguing" benefit with PD-L1 inhibitor
MedpageToday

SAN ANTONIO -- Continuing a CDK4/6 inhibitor beyond progression did not improve survival in metastatic breast cancer but adding an immune checkpoint inhibitor to the mix showed promise, a randomized trial showed.

The combination of fulvestrant (Faslodex) and palbociclib (Ibrance) led to a median progression-free survival (PFS) of 4.6 months versus 4.8 months with fulvestrant alone. Single-agent fulvestrant had numerically higher PFS rates at 6 and 12 months. Median overall survival (OS) also did not differ between treatment arms.

A triplet regimen with avelumab (Bavencio), fulvestrant, and palbociclib increased PFS and OS as compared with the other two groups (secondary endpoints), although neither difference achieved statistical significance, reported Erica Mayer, MD, MPH, of Dana-Farber Cancer Institute in Boston, during the San Antonio Breast Cancer Symposium (SABCS).

"The observed longer PFS when a PD-L1 inhibitor was added to fulvestrant-palbociclib is an intriguing signal in this HR [hormone receptor]-positive population and deserves further study," said Mayer. "Baseline ct [circulating tumor] DNA analysis suggests a possible differential impact of targeted agents based on the baseline mutational status."

"Ongoing evaluation of serial ctDNA and CTC [circulating tumor cell] samples from this study will allow exploration of the mutational and resistance landscape, as well as markers of sensitivity to immuno-oncology therapy in HR-positive disease," she added. "Overall, a better understanding of the mechanisms driving progression post-CDK4/6 inhibitor and endocrine therapy will help guide more rational treatment selection for subsequent lines of therapy and improve outcomes for our patients."

The PACE trial reported by Mayer addressed a critical but poorly understood issue about the use of CDK4/6 inhibitors in HR-positive breast cancer, said SABCS discussant Shom Goel, MD, of Peter MacCallum Cancer Centre and the University of Melbourne in Australia.

"When resistance develops, why does that happen?" said Goel. "It reflects a breakdown of the synergy, but we really don't know what has gone wrong. The PACE trial asked whether we can fix that breakdown by simply changing one part of the treatment regimen and keeping the other one going in the background."

Noting that 90% of the patients had already received palbociclib, "it seems pretty clear that we cannot recommend the use of palbociclib beyond progression as a routine strategy for clinical practice, but what does that mean? Does that mean the whole hypothesis about continuing CDK4/6 inhibitors beyond progression is wrong?" he added. "What would happen if we did a study of palbociclib after ribociclib [Kisqali]? We simply don't know."

The best answer for now is to wait for results of ongoing larger randomized trials, Goel suggested, pointing out that data from nonrandomized studies have shown that palbociclib might have activity after progression on other CDK4/6 inhibitors.

As for the avelumab-containing triplet, the improved PFS and OS are "intriguing," but neither difference achieved statistical significance, he said.

"There is strong preclinical rationale for combining CDK4/6 inhibitors with immune checkpoint inhibitors, given that CDK4/6 inhibitors have been shown to promote anti-tumor immunity," Goel noted.

The PACE trial included 220 randomized patients with metastatic HR-positive/HER2-negative breast cancer that had progressed on prior CDK4/6 inhibition plus endocrine therapy after at least 6 months of stable disease. The patients had received as many as two prior endocrine therapies, not including fulvestrant.

Mayer and team randomized patients 1:2:1 to single-agent fulvestrant, fulvestrant plus palbociclib, or the two drugs plus avelumab. The primary objective was the comparison of PFS for fulvestrant alone versus fulvestrant-palbociclib. Secondary endpoints included PFS with the triplet regimen versus single-agent fulvestrant.

The primary analysis yielded a nonsignificant hazard ratio of 1.11 (95% CI 0.74-1.66) for the comparison of the doublet regimen versus single-agent fulvestrant. The 6-month PFS rate (42.9% vs 42.0%) and 12-month PFS rate (17.5% vs 13.1%) favored monotherapy, as did the secondary endpoint of median OS (27.5 vs 24.6 months).

The triplet regimen achieved numerical superiority over both of the other groups, including a median PFS of 8.1 months (HR 0.75 vs fulvestrant, 95% CI 0.47-1.20), a 6-month PFS rate of 50.8%, a 12-month PFS rate of 35.6%, and a median OS of 42.5 months (HR 0.68 vs fulvestrant, 95% CI 0.40-1.15).

No patients had grade 3/4 toxicity with single-agent fulvestrant, as compared with 32.7% of the fulvestrant-palbociclib arm, and 49.1% of the patients treated with avelumab. The most common grade 3/4 toxicity with the doublet was anemia (4.5%), whereas the addition of avelumab led to grade 3/4 fatigue in 5.7% of patients, and anemia, decreased platelet count, and diarrhea in 3.8%.

Mayer and colleagues also performed an exploratory analysis of the relationship between baseline mutation status and treatment outcome, focusing on any ESR1, PIK3CA, or Rb mutations. The results showed non-significant PFS advantages favoring the doublet regimen in patients who had any of the mutations, but particularly ESR1 and PIK3CA mutations. The same was true for the avelumab regimen.

"The presence of the mutations perhaps indicated endocrine resistance," said Mayer.

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

Disclosures

The PACE study was supported by Pfizer.

Mayer disclosed relationships with Novartis, Lilly, Gilead Sciences, and AstraZeneca.

Goel disclosed relationships with Lilly, G1 Therapeutics, Pfizer, and Novartis.

Primary Source

San Antonio Breast Cancer Symposium

Mayer EL, et al "PACE: Palbociclib after CDK and endocrine therapy. A randomized phase II study of fulvestrant +/- palbociclib after progression on CDK4/6 inhibitor for HR+/HER2- metastatic breast cancer" SABCS 2022; Abstract GS3-06.