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ONCAlert | Upfront Therapy for mRCC

Novel Therapies On The Horizon For Breast Cancer

Greg Kennelty
Published Online: 2:16 AM, Fri June 17, 2016

Maura Dickler, MD

Single-agent abemaciclib as well as taselisib in combination with fulvestrant (Faslodex) could both play a substantial role in breast cancer in the near future, says Maura Dickler, MD.
 
In an interview with Targeted Oncology, Dickler, medical oncologist, Memorial Sloan Kettering Cancer Center, discusses the treatments and their recent phase II studies. Single-agent abemaciclib was recently tested in the phase II MONARCH1 study, while the combination of taselisib and fulvestrant were examined in a phase II study.
 
TARGETED ONCOLOGY:  Can you tell us about the MONARCH1 trial?

Dickler:  The MONARCH1 was a straight phase II study of single-agent abemaciclib, a CDK4 and CDK6 inhibitor, in previously-treated women with hormone-receptor(HR) positive metastatic breast cancer. It was a multi-center trial. The study enrolled 132 women who had previously received endocrine therapy and also at least one, but not more than two, chemotherapies for metastatic disease. It was a group of women where we typically wouldn't offer additional endocrine therapy, and that their typical next treatment would be chemotherapy. We know in that setting, response rates for chemotherapy are in the order of 10% to 20% with progression-free survival (PFS) of about 3 to 4 months.
 
This trial was specifically testing single-agent abemaciclib in a more heavily-pretreated patient population, and I mention that because it's different from the other abemaciclib studies that are ongoing, which are actually earlier in metastatic disease, either in first-line endocrine therapy with the aromatase inhibitors, or in combination with second-line endocrine therapy like fulvestrant.
 
What they found was that women treated with abemaciclib in this setting had a response rate of 19.7% and a clinical benefit rate of about 42%, which was impressive because it was not only a heavily-pretreated population, but about 90% of the patient had visceral metastases, 70% had liver metastases, more than half had 3 sites of metastatic disease, and then in terms of prior therapy, all patients had received taxanes, with about 70% receiving taxanes in the metastatic setting.
 
TARGETED ONCOLOGY:  What do you think the next steps after this study are?
 
Dickler: Abemaciclib is presently in phase III studies in combination with endocrine therapy. There's the MONARCH2 study which is a fulvestrant backbone with and without abemaciclib, and MONARCH3 is an aromatase-based study, looking at either letrozole or anastrozole, plus or minus abemaciclib. They're really looking at abemaciclib in combination with endocrine therapy because there's a rationale for dual ER and cell-cycle inhibition. I suspect those trials will probably provide the best insight as to where this drug might be used in the future.
 
TARGETED ONCOLOGY:  Can you tell us about the mechanism of action for abemaciclib?
 
Dickler: Abemaciclib inhibits both CDK4 and CDK6. It inhibits CDK4 more potently than CDK6, and therefor it's thought to impact potentially its toxicities, in that there appears to be less myelosuppression with abemaciclib. So continuous dosing is feasible. With some of the other cell-cycle inhibitors, the dose-limiting toxicity is neutropenia and continuous dosing is not possible.
 
With palbociclib, the present dosage is 125 mg for 21 out of 28 days, and that 7-day break is needed for recovery of the white blood cell count. With abemaciclib, neutropenia is less of a problem. However, with abemaciclib, diarrhea is more of a problem. This diarrhea is typically seen early. The average onset was 7 days, but the diarrhea was responsive to supportive measures, to anti-diarrheal agents, and then dose reduction.
 
TARGETED ONCOLOGY:  Is this already being investigated in HER2-positive patients?
 
Dickler: Actually, the biomarker to best select patients that might be responsive to abemaciclib, and cell-cycle inhibitors in general, is ER-positivity. In the phase I study of abemaciclib, there was activity in ER-positive/HER2-negitive and ER-positive/HER2-positive, and a study looking at abemaciclib in the HER2-positive population is recently open and now accruing. It's called the MONARCH HERS trial.
 
TARGETED ONCOLOGY:  What should community oncologists take away from this study?
 
Dickler: The MONARCH1 study was really a proof-of-concept trial, so it's a relatively small phase II study looking at a cell-cycle inhibitor as a single-agent. At least to date, this is the first cell-cycle inhibitor that has single-agent activity. So that was really the intent of the trial, to confirm the activity that was seen in the phase I trial. I think doctors in the community should look for the results of MONARCH2 and MONARCH3, which should be coming soon.
 
TARGETED ONCOLOGY:  Can you also tell us about the phase II study looking at taselisib combined with fulvestrant that you were involved in?
 
Dickler: This was a phase II study of fulvestrant in combination with taselisib in women with hormone-receptor positive/HER2-negative breast cancer. This was really a phase II study that was embedded in a phase I/II trial, and this study enrolled 60 women with HR-positive/HER2-negative breast cancer. Of them, 30 of the patients were required to have a PIC3CA mutation, and the other half were required to be wild type. This study was performed to get a signal of activity in women with HR-positive disease. Patients who were enrolled were allowed to have only up to one line of prior chemotherapy, and they were not allowed to have had prior fulvestrant. They were required to have prior therapy with an aromatase inhibitor.
 
TARGETED ONCOLOGY:  What do you think are some of the big takeaways from this study?
 
Dickler: This was a small phase II study and definitely showed some activity of this agent in combination with fulvestrant. It really wasn't powered to look at activity in the PIC3CA wild type versus mutant population, but numerically there was a higher clinical benefit rate and response rate in the patients who were ER-positive and PIC3CA mutant compared to the patients who were ER-positive and PIC3CA wild type.
 
A randomized trial is now ongoing called the SANDPIPER trial, which is fulvestrant with or without taselisib in a similar patient population. HR-positive, HER2-positive, prior treatment with endocrine therapy with a limitation on prior chemotherapy. The SANDPIPER trial will enroll patients with wild type and mutant PIC3CA and the trial will be adequately powered to answer the question as to whether there's activity in the wild type population.

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