Hormone Receptor Positive Breast Cancer: CDK4/6 inhibitors
BCRF previously reported on updates of a new class of drugs called CDK4/6 inhibitors in clinical trials for hormone receptor positive (HR+), metastatic breast cancers. There are currently two FDA-approved anti- CDK4/6 drugs available, palbociclib (Ibrance®) which was approved in 2016 and ribociclib (Kisqali®) which was approved this year. A third CDK4/6 inhibitor, abemaciclib is currently in late phase clinical trials. The MONARCH-2 trial (NCT02107703) is a Phase III trial comparing the combination of abemaciclib plus fulvestrant, versus fulvestrant alone.
At ASCO’s annual meeting this week, BCRF Investigator, Dr. George Sledge presented new data from Monarch 2 that showed the addition of abemaciclib improved progression free survival from 9.3 months to 16.4 months, further demonstrating a clinical benefit of CDK4/6 inhibitors for this group of patients. In addition, early results from another trial suggest that abemaciclib may have some antitumor activity in brain metastases as well. These positive results suggest that abemaciclib will be approved later this year or in 2018.
Discussing the promising results seen with CDK 4/6 inhibitors, Dr. Ingrid Mayer of Vanderbilt University Medical Center summarized the current status of CDK4/6 in the treatment of HR+ metastatic breast cancer:
1) CDK4/6 inhibitors are likely to be most effective in combination with other treatments, as has been shown with endocrine (anti-estrogen) therapies.
2) CDK4/6 inhibitor are good options as second line therapies.
3) CDK4/6 should definitely be considered for treatment of HR+ metastatic breast cancer.
HER2+ Breast Cancer
As more HER2-targeted treatments become available, there is a growing interest in combining these targeted therapies and reducing exposure to chemotherapies. T-DM1 (Kadcyla®) was originally approved as second line treatment based on results from the EMELIA trial. Those results led researchers to ask if T-DM1 could be a better first line treatment than current treatments.
The MARIANNE trial was a Phase III study comparing dual HER2- targeting (adding pertuzumab to T-DM1) to standard of care (trastuzumab plus chemotherapy. New data from the MARIANNE trial were presented this week that showed that addition of T-DM1 was as good as, but not better than the standard of care. There were fewer adverse effects however, which suggests T-DM1 may be an option for first line HER2+ metastatic breast cancer patients. Results from other trials, like ALTERNATIVE, suggest that in patients with HER2+/ HR+ metastatic breast cancer, combining dual HER2-targeted therapies with hormone therapy may be as effective as regimens that include chemotherapy.
Triple Negative Breast Cancer
Triple negative breast cancer is notoriously difficult to treat with targeted therapies. Since it doesn’t express hormone receptors or the HER2 receptor, there are fewer biological molecules to target. Data presented at ASCO does suggest there may be ways to determine which patients will respond best to different treatments.
Jelmar Quist from King’s College, London, presented data on a 4-gene signature of TNBC. Depending on if each of these 4 genes has high expression or low expression, 6 different subtypes can be determined. From these subtypes, it can be determined which patients would be most responsive platinum-based chemotherapy. Further study may reveal other subtypes susceptible to other interventions, such as immunotherapy. In fact, results from KEYNOTE-012 showed that the immunotherapy drug, pembrolizumab (Keytruda®) had few side effects and may be effective. New kinds of drugs are also being evaluated in TNBC patients, such as PARP inhibitors. Results from the ABRAZO study suggest the PARP inhibitor, talazoparib, was well tolerated and may have antitumor activity in patients with TNBC and BRCA1 or BRCA2 mutations.
Overall for TNBC treatments, as BCRF Investigator, Dr. Leisha Emens, stated in her discussion of these trials, integrating the biology of TNBC tumors will be key to improving therapy selection for patients.
In a late breaking abstract presentation, Dr. Mark Robson, presented new data on OlympiAD study, a Phase III clinical trial comparing the single agent PARP inhibitor olaparib (Lynparza) to standard-of-care chemotherapy in patients harboring inherited mutations in BRCA1 or BRCA2 with HER2-negative metastatic breast cancer. Earlier this year, the study met its primary endpoint in showing an improvement in progression free survival of 7 months versus 4.2 months in patients receiving standard of care. At this week’s ASCO meeting, Dr. Robson presented additional analysis from the study. Sixty percent of patients in the olaparib group experienced tumor shrinkage compared to 29 percent in the chemotherapy group and subgroup analysis suggests that olaparib may be more effective in triple negative breast cancer, the most common BRCA- associated breast cancer subtype. You can read more about the study here.
Emerging targeted therapies bring new hope for metastatic breast cancer. Specifically, for HER2+ breast cancers, there seems to be a drive to use more targeted treatments and decrease the use of chemotherapy. For TNBC, there are more studies that attempt to better categorize or define subtypes to better select patients for specific treatments.
Several studies are still early, but we look forward to additional results being presented at the San Antonio Breast Cancer Symposium in December, where BCRF will be blogging and reporting live.