NEW YORK – For patients whose HER2-negative and hormone receptor-positive metastatic breast cancers progress after treatment with combination CDK4/6 inhibitors and hormone therapy, there is no additional benefit to continuing treatment with Pfizer Ibrance’s CDK4/6 inhibitor (palbociclib) plus another hormone therapy as the next line of treatment, suggest phase II study results presented at the San Antonio breast cancer symposium.
In a presentation Thursday, Erica Mayer, director of clinical breast cancer research at the Dana-Farber Cancer Institute in Boston, shared results from the randomized phase II of palbociclib after CDK and endocrine therapy, or PACE, clinical test, in which 220 patients were randomized to receive either the endocrine therapy fulvestrant, fulvestrant plus Ibrance, or a triple combination of fulvestrant, Ibrance and Pfizer and the EMD PD-1 inhibitor Serono Bavencio (avelumab).
“Whether a CDK4/6 inhibitor should be continued at the time of disease progression is an open question,” Mayer said.
The primary objective of the study was to compare progression-free survival in the fulvestrant monotherapy and doublet arms; studying the relative results with the Bavencio tritherapy was a secondary objective. Mayer said the third arm was included in the study based on preclinical data suggesting that CDK4/6 inhibitors and checkpoint inhibition may have synergistic efficacy after patients have progressed on treatment. prior.
All patients included in the trial had to have HR-positive, HER2-negative metastatic breast cancer and had to have previously received treatment with a combination of hormone therapy – with the exception of fulvestrant – and any CDK4 inhibitor /6, including Ibrance, Eli Lilly’s Verzenio (abemaciclib) or Novartis’ Kisqali (ribociclib). For more than 90% of patients, Mayer noted, that prior CDK4/6 inhibitor received was Ibrance.
After a median follow-up of 23.6 months, Mayer reported, it was clear that combining Ibrance with fulvestrant had no advantage over fulvestrant alone. Indeed, the median progression-free survival time in patients receiving fulvestrant monotherapy was 4.8 months versus 4.6 months for those receiving Ibrance and fulvestrant.
“It seems fairly clear that we cannot recommend continued use of palbociclib beyond progression of palbociclib [plus endocrine therapy] as a routine strategy for clinical practice,” said Shom Goel, clinician-scientist at the Peter MacCallum Cancer Center in Melbourne, Australia, during a discussion of the PACE results after Mayer’s presentation.
Interestingly, progression-free survival times were nearly double in the triplet arm; patients receiving Ibrance, fulvestrant and Bavencio lived an average of 8.1 months without their cancer progressing. The one-year progression-free survival rates were 17.5% for fulvestrant alone and 13.5% and 35.6% for the doublet and triplet arms, respectively.
“The longer progression-free survival observed when a PD-L1 inhibitor was added to fulvestrant and palbociclib is an intriguing signal in this hormone receptor positive population and warrants further study,” Mayer said.
In his discussion, Goel also called the improved results with the triplet an “intriguing trend” and said the effect may be due to the ability of CDK4/6 inhibitors to promote anti-tumor immunity and suppress tumors. otherwise immunosuppressive regulatory T cells and, in turn, stimulate differentiation of CD8-positive T cells in the direction of a more memory-like or stem-like state. “It’s the kind of phenomenon that gives the immune system the stamina to last,” Goel said.
Overall, 10.8%, 13.7% and 17.9% of patients in the respective monotherapy, doublet and triplet arms of the PACE study responded to the treatment regimens. And although the trial was not designed with overall survival as one of its endpoints, Mayer reported that data as well; the median overall survival times in the three arms were 27.5 months, 24.6 months and 42.5 months for monotherapy, doublet and triplet, respectively. The safety profile of the treatments was manageable in all arms, with no unexpected immunotherapy-related toxicity, she said.
Biomarker analyzes
Prior to randomization into the PACE trial, researchers collected baseline archival tissue samples from patients and circulating tumor DNA samples. Using Guardant Health’s Guardant360 next-generation blood sequencing panel, they sequenced these samples, which were available for 200 of the 220 patients in the trial.
Here, Mayer and his colleagues were particularly interested in mutations of three pre-specified genes: ESR1, PIK3CA and all Rb mutations. At baseline, 54% of patients had ESR1 mutations, 35% PIK3CA mutations, and 11.5% Rb mutations. Through an exploratory analysis considering these basic genomic characteristics with results, the researchers found that patients who had a basic mutation in one of these three pre-specified genes tended to derive more benefit from the continuation of Ibrance.
“The presence of the mutations may indicate endocrine resistance,” Mayer suggested.
For example, in patients with ESR1 mutations present in their core cDNA, the combination of fulvestrant and Ibrance improved progression-free survival compared to fulvestrant alone, which contrasts with the overall trial conclusions regarding the lack of additional benefit. Patients with ESR1 mutations at baseline lived for an average of 3.3 months without their cancer progressing when they received fulvestrant alone, but 5.2 months when they received fulvestrant plus Ibrance. The same was not true, however, for patients with wild-type ESR1 who, like the overall trial population, had better outcomes with fulvestrant alone than with the combination. For patients with wild-type PIK3CA tumors versus PIK3CA-mutated tumors, Mayer and colleagues found a similar trend in ESR1 analysis; patients carrying the mutations actually benefited from the addition of Ibrance.
Given these exciting exploratory findings, Mayer said she and her colleagues continue to evaluate serial ctDNA and CTC samples from the study to explore the mutational and resistance landscape as well as potential markers of susceptibility. to immunotherapy in this patient population.
Continuing uncertainties on CDK4/6 resistance
In his discussion, Goel pointed out that the key question behind the PACE trial — which he called a “really misunderstood problem” in the field right now — is: why, exactly, do patients relapse after their treatment? initial with CDK4/6 inhibitors and endocrine therapy?
“It reflects a break in synergy, but we don’t really know what went wrong,” Goel said. “The question the PACE trial asks is, ‘Can we solve this problem by just changing one part of the treatment regimen and leaving the other in the background?'”
Given the PACE results, the answer seemed to be a clear no, but Goel pointed out that the results appeared to disagree with those from Phase II. HOLD try, which was designed to evaluate another CDK4/6 inhibitor, Kisqali, after patients progressed on a prior CDK4/6 inhibitor plus an aromatase inhibitor or tamoxifen or fulvestrant. In this trialthe combination of hormone therapy and Kisqali improved progression-free survival.
Goel was careful to point out the important differences between the trials, namely that one was essentially Ibrance after Ibrance and the other was Kisqali after Ibrance. “We can only speculate if this has anything to do with the differences we see here. … Could there be something beneficial in switching CDK4/6 inhibitors?” he asked hypothetically. “What would happen if we did the reverse [with] palbociclib after ribociclib? We just don’t know.”
Ultimately, Goel cautioned against interpreting PACE or MAINTAIN trials as the be-all and end-all of clinical practice, not least because of their small size and other limitations. “There are imbalances in patient characteristics between trials, within arms of each trial, and in the performance of control groups in each study,” he noted.
Looking ahead, Goel suggested that more valuable information may come from the results of several larger ongoing clinical trials, including phase III. EMBER-3 trial evaluating hormone therapy versus Eli Lilly’s investigational imlunestrant versus imlunestrant and Verzenio after prior treatment with a CDK4/6 inhibitor, and Phase III PostMONARCH study evaluating fulvestrant plus or minus Verzenio after any CDK4/6 inhibitor.
“Even if a day comes when we decide that continuing these drugs beyond progression is a reasonable strategy, we will have to choose when to deploy this strategy while simultaneously considering all of the other drugs that appear in this therapeutic landscape,” he said. added.
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