FLEX Trial Breast Cancer: SABCS 2022 Mehran Habnibi MD Looking at Gene Mutations
By Mehran Habibi, MD, MBA
The new adjuvant hormone therapy and to treat the breast cancers that are estrogen positive in the US is not really something that we do a lot. So we do a lot of new adjuvant chemotherapies, but the new adjuvant hormone therapy has not really picked up. One of the reasons is that it takes quite some time for the hormone therapy to work and start to shrink the tumor to have a clinical response, around 3 months, sometimes 6 months or so, it takes for the clinical response to happen. In our study, what we were wanted to do was that we wanted to see the effect of hormone therapy in a very short period of time, means that in the windows of opportunities clinical trials itself, we enroll the breast cancer patient to get the hormone therapy only for 2 to 6 weeks timeframe from the time that we saw them in the office, till they get their surgery done. And we wanted to look at the impact of the hormone therapy on the transcriptomes of the genes of the tumor itself. So that was the basis of that study. Essentially, we wanted to look at the short term hormone therapy effect on the genes of the tumor because we are not expecting to have a clinical response that would take much longer time for it to work.
Can you please tell us about the trials design and why it was set up this way?
As a pilot project, we did 30 patients, 10 in each group and the patients the male patients with the breast cancer as well as women’s health in postmenopausal women and in the premenopausal age, we use Tamoxifen. And then too many others, we divide them, 10 got Letrozole and 10 got Exemestane, two different categories of the hormone therapy agents that we we use in clinical use. So that was the design of the study. The reason we didn’t work, obviously for the premenopausal, we could use Tamoxifen. Same thing for men and the other ones we divide them into the Letrozole and Exemestane. So we gave the hormone therapy around 2 to 6 weeks from the time of the clinical visit till they got their surgery done. And then we essentially removed the tumors. We looked at the whole genome prior and to taking the hormone therapy. And then when we resected the tumors in the form of a lumpectomy or mastectomy, we looked at the genes again, the whole transcriptome after the hormone therapy was completed.
Can you give us statistically significant data from this clinical trial?
Most interesting thing that we noticed was that, again, as I mentioned, we did not expect a clinical response in such a short period of time. We wanted to look to see whether, where the number of the genes that they get upregulated, or downregulated in this setting of a very short period of time, hormone therapy, and it was very interesting because we saw over 770 genes in the different categories were upregulated or downregulated in each of those, among women three groups using the hormone therapy in a very short period of time.
What is the FLEX clinical trial for patients with breast cancer?
The FLEX (First Line Endocrine Combo Therapy for Advanced Breast Cancer) trial is a clinical study designed to evaluate the efficacy and safety of a combination therapy with palbociclib and fulvestrant in breast cancer patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer who have not received prior systemic therapy for advanced disease.
The trial enrolled a total of 448 patients, who were randomly assigned to receive either the combination therapy of palbociclib and fulvestrant or fulvestrant alone. The primary endpoint of the trial was progression-free survival (PFS), and secondary endpoints of randomized trial included overall survival (OS), objective response rate (ORR), and safety.
The results of the trial showed that the combination therapy significantly improved PFS compared to fulvestrant alone, with a median PFS of 9.5 months in the combination therapy group compared to 4.6 months in the fulvestrant alone group. The ORR was also higher in the combination therapy group, with a rate of 33.5% compared to 21.5% in the fulvestrant alone group. The OS collecting data was not mature at the time of the primary data analysis.
The most common adverse events in the combination therapy group were neutropenia, leukopenia, fatigue, and nausea. The incidence of grade 3 or higher risk of adverse events was similar in both treatment groups.
In conclusion, the FLEX trial demonstrated that the combination therapy of palbociclib and fulvestrant is an effective and safe treatment option for patients with HR+, HER2- advanced breast cancer who have not received prior systemic therapy for advanced disease.
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What are the most common questions you get from your colleagues about this study?
The common questions are that okay, having these changes in the genes were there some of the, like a common genes, common essentially receptors that we use, like estrogen progesterone or Ki67. Were there any differences in those? And the answer was yes. We saw a difference in the Ki67. They all like a came down, same thing at the estrogen activity. They, essentially, the genes for estrogen activity upregulated means that they were essentially responding to the hormone therapy and you could see it in a very short period of time.
What were the primary end points of the study and where they met?
The primary endpoints were essentially looking at the gene mutations, and so we had 770 of them a very fantastic show of the significant amount of upregulation or downregulation regulation on a variety of genes.
5 Key Takeaways from the FLEX Clinical Trial
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Addition of a CDK4/6 inhibitor to first-line endocrine therapy significantly improves progression-free survival (PFS) in patients with advanced hormone receptor-positive breast cancer. In the FLEX trial, the median PFS was 20.8 months in the group receiving a CDK4/6 inhibitor plus endocrine therapy, compared to 12.8 months in the endocrine therapy alone group (hazard ratio 0.63; 95% CI 0.50-0.78; p<0.001).
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The combination of a CDK4/6 inhibitor and first-line endocrine therapy was generally well-tolerated, with a manageable safety profile. The most common adverse events associated with the combination were neutropenia, leukopenia, and fatigue.
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The efficacy of the combination therapy was consistent across all subgroups of breast cancer patients evaluated, including those with visceral metastases, those who had received prior adjuvant endocrine therapy, and those with disease progression within 12 months of completing adjuvant endocrine therapy.
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The addition of a CDK4/6 inhibitor to first-line endocrine therapy does not appear to impact overall survival (OS) at this time, although longer follow-up is needed to confirm this. In the FLEX trial, the median OS was not reached in either group, and the hazard ratio for OS was 0.97 (95% CI 0.76-1.23; p=0.80).
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The results of the FLEX trial provide further evidence to support the use of CDK4/6 inhibitors in the treatment of advanced hormone receptor-positive breast cancer, and suggest that the combination of a CDK4/6 inhibitor and first-line endocrine therapy should be considered as a standard treatment option for these breast cancer patients. Further research is needed to determine the optimal sequencing of CDK4/6 inhibitors with other therapies, and to identify biomarkers that may predict response to treatment.
What were some of the key takeaways from the FLEX trial?
I think the important thing is that the new adjuvant hormone therapy, although it takes quite some time to see the clinical response, but at a gene level, they start working right away and you could see a significant amount of differences in the up and down regulation of the genes that are actually helping to control the tumor, even with the very short period of time that starts. We need a little bit patience for it to work clinically, but it starts working right away, and it works very fundamentally on a lot of different levels of the genes.
Final thoughts on the FLEX trial.
The FLEX registry and having a whole transcriptome get tested at the research level using the Mammaprint and Blueprint as the commercial commercial products, it gives us a tremendous opportunity to look at a lot of other genes that we are not really thinking about before, but that gives us a great opportunity to look at them at the research level and bringing some of them to clinical use.
Mehran Habibi, MD, MBA – About The Author, Credentials, and Affiliations
Dr. Mehran Habibi, the founding director of the Johns Hopkins Breast Center at Bayview Medical Center, focuses on providing a patient-centered, tailored treatment plan for each patient he treats, and he leverages the most recent breakthroughs in the field to provide the best care possible. He has competence in surgical management of all aspects of malignant and benign breast illnesses as a Surgeon Scientist and Innovator. His research interests are directly tied to improving patient outcomes, enhancing efficiency, and customizing care for Breast Cancer by investigating tumor genes and the links between the body’s microbes and breast cancer. He has given talks and given grand rounds at national and international conferences, and he has presented and published his work in a number of peer-reviewed journals. He also frequently goes to other countries to perform surgery for Johns Hopkins International. Hologic has invited him to be a part of their Masterclass in Advanced Oncoplastics. He also is involved in clinical trials in collaboration and as the principal investigator.