Insights From: Hope S. Rugo, MD, UCSF Helen Diller Family Comprehensive Cancer Center; Sara Hurvitz, MD, UCLA Jonsson Comprehensive Cancer Center
Hope S. Rugo, MD: We saw in the preclinical studies that there was benefit in cell lines that were HER2-positive from CDK4/6 inhibition with palbociclib. So, there has been a lot of interest in trying to study now that we’ve got approval of these agents in HER2-positive disease. We’ve seen low level responses in disease that’s HER2-positive that has become refractory to HER2-targeted therapies, and there are ongoing trials combining CDK4/6 inhibitors with HER2-targeted therapy in the refractory setting to better understand that response. I don’t know that CDK4/6 inhibitors are going to have a huge play in that very refractory setting, but there has been a lot more interesting earlier settings with ER-positive, HER2-positive disease.
Now, we’ve just seen the approval of neratinib in the extended adjuvant setting where we saw, in subset analysis, significantly bigger effects in ER-positive, HER2-positive disease than in ER-negative, HER2-positive disease. And then we saw the results of the APHINITY trial with pertuzumab, and we’ve seen results with neoadjuvant data with pertuzumab, where we saw a bigger impact in ER-negative, HER2-positive breast cancer. So, there are clearly differences in these groups. And when people have looked at genomic studies, they found that the HER2-enriched population by intrinsic subtyping is much more common in ER-negative, HER2-positive disease and you see better responses in that group that are HER2-enriched.
So, it makes us believe that ER-positive, HER2-positive disease is actually a different kettle of fish. Some of the cancer is driven more by HER2, but some is driven more by ER. And HER2 can cause resistance to endocrine therapy as we’ve seen in randomized trials that have added HER2-targeted therapy to ER-targeted therapy in the metastatic setting and led to approval of those combinations with both trastuzumab and lapatinib.
So, where could we go with CDK4/6 inhibitors? I think the nicest design, and quite intriguing, is called the PATINA study. What that trial is doing, which is run by Otto Metzger from Dana-Farber Cancer Institute, is actually looking at patients who’ve gotten a CLEOPATRA-like regimen with a taxane—trastuzumab and pertuzumab—had a nice response, and you drop the taxane. In CLEOPATRA, you just continued the double antibodies until progression, but in clinical practice and supported by a number of different trials which have recently been presented, we actually add in a hormone agent for hormone receptor-positive disease. We know that those cancers had traditionally not stayed controlled on antibody therapy alone for as long a period of time as ER-negative disease. So, in the PATINA trial, patients who are on the triplet of antibody plus hormone agent after chemotherapy response will be randomized to receive the CDK4/6 inhibitor, palbociclib, or a placebo. And I think that’s going to be a fascinating trial, really looking at whether or not you can control the disease for longer. We know it’s a safe combination. Transcript Edited for Clarity