Clinical Challenges: HR+/HER2- Advanced Breast Cancer and CDK4/6 Inhibitors

In Clinical Studies News by Barbara Jacoby

By: Mike Bassett

From: medpagetoday.com

The agents have significantly extended progression-free survival, but what are the options post-progression?

The development and approval of cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors have been called game-changers in the treatment of patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer.

Treatment with these drugs — palbociclib, ribociclib, and abemaciclib — has significantly extended progression-free survival. But the disease does eventually progress, and the question then becomes, what next?

“These drugs have all been approved in the last 5 years, so the pace of progress has been very rapid,” Debu Tripathy, MD, of the University of Texas MD Anderson Cancer Center in Houston, told MedPage Today. “We haven’t had the chance to do large-scale randomized trials on patients who progress on CKD4/6 inhibitors. Currently, we don’t have a dedicated drug that we know is more effective in that group of patients.”

“A good proportion of these patients, if they progress on an aromatase inhibitor plus CDK4/6 inhibitors, will get fulvestrant alone,” he said. “Some are getting fulvestrant in combination with everolimus because that’s an approved drug in this setting, and then some are moving on to chemotherapy, the most common one being capecitabine.”

As for whether patients should continue with CDK4/6 inhibitors after progression, Aditya Bardia, MBBS, MPH, of Massachusetts General Hospital in Boston, pointed out that while there are no clinical data at this point supporting it, there are several ongoing trials examining the question, and “it is an appealing potential option.”

The ongoing PACE (Palbociclib After CDK and Endocrine Therapy) trial is comparing progression-free survival in patients receiving fulvestrant alone with fulvestrant plus palbociclib, and fulvestrant plus palbociclib and avelumab in the setting of acquired resistance to previous CDK4/6 inhibition for advanced HR+/HER2− breast cancer. The MAINTAIN trial is examining the efficacy of ribociclib after progression on CDK4/6 inhibition in patients with HR+/HER2- advanced breast cancer.

At the 2019 American Society of Clinical Oncology annual meeting, Bardia presented findings from the TRINITI-1 trial showing that a combination of ribociclib, everolimus, and exemestane was effective and appeared tolerable among patients with endocrine therapy-refractory, HR+/HER2- advanced breast cancer that progressed on a CDK4/6 inhibitor.

“At our institution we looked at our experience with CDK4/6 inhibitors after progression, and the question involved looking at abemaciclib — which has slightly different properties compared to ribociclib and palbociclib in the sense that it is given continuously, as opposed to 3 weeks on and 1 week off,” Bardia told MedPage Today. “Its most common side effect is diarrhea, as opposed to neutropenia. Also, it affects CDK4/6, but also has some activity on other CDKs, like CDK2.”

“We looked at the experience of patients who received abemaciclib after palbociclib and ribociclib, and found there is a subset of patients who derive benefit from abemaciclib despite progression on prior palbociclib or ribociclib,” he continued. “So moving forward we are interested in doing a prospective study on these patients.”

Another potential option is the PI3K inhibitor alpelisib, which in combination with fulvestrant was shown in the SOLAR-1 trial to extend progression-free survival compared with endocrine therapy alone in patients with HR+/HER2− advanced breast cancer characterized by a PIK3CA mutation.

That led to approval by the FDA — “but, that drug was so early on that it was only about 20% of the patients in the study who had a CDK4/6 inhibitor,” said Tripathy. “There weren’t enough patients who had gotten a prior CDK4/6 inhibitor for it to be statistically significant, but if you look at the few patients who did, the benefits of alpelisib seemed to be seen in that patient group as well.”

Building upon the results of that study, researchers led by Hope Rugo, MD, of the University of California San Francisco Helen Diller Family Comprehensive Cancer Center, presented a study at the recent ASCO virtual meeting in which they evaluated alpelisib with endocrine therapy (fulvestrant or letrozole) in patients with HR+/HER2– PIK3CA-mutated advanced breast cancer who progressed on/after prior therapy, including CDK4/6 inhibitors.

The results of the phase II BYLieve trial showed that among 121 patients, the primary endpoint of progression-free survival at 6 months was reached by half (50.4%), while the median progression-free survival was 7.3 months (95% CI 5.6-8.3). Over a median follow-up of 11.7 months, the overall response rate was 17.4% for the total cohort and 21.0% for the 100 patients with measurable disease at baseline.

“Considering SOLAR-1 and a real-world evidence analysis, BYLieve supports the use of alpelisib and fulvestrant hormone receptor for HR-positive advanced breast cancer in the post-CDK4/6 inhibitor setting, confirming findings that were observed in SOLAR-1,” Rugo said during her presentation.

Said Tripathy: “We have a lot of patients who have been on these [CDK4/6 inhibitor] trials who are starting to progress and I think within the next year or so we will begin to see larger trials with a variety of different drugs — like oral SERDs [selective estrogen receptor degraders], PI3 kinase inhibitors, and everolimus.”