Expert perspectives on the mechanisms of resistance to frontline therapy in HR+/HER2- metastatic breast cancer and results from key clinical trials analyzing the safety and efficacy of rechallenging with prior therapy.
Kevin M. Kalinsky, MD, MS: Hi, I’m Kevin Kalinsky. I’m the director of the Glenn Family Breast Center at Winship Cancer Institute [at Emory University] in Atlanta, Georgia. In terms of the question about what we have learned about resistance to endocrine therapy and CDK4/6 inhibition, I think we’ve seen that there can be various mechanisms including the development of ESR1 mutations, particularly if patients received an aromatase inhibitor. We can see numerically a higher rate of PIK3CA mutations. We can see RB mutations; RB loss can be a resistance mechanism. There are also data about various cyclins like cyclin E expression being a resistance mechanism as well.
Kevin M. Kalinsky, MD, MS: So, we can see that about one-third of patients develop ESR1 mutations. That’s been seen across the various studies after a CDK4/6 inhibitor and endocrine therapy. We also see about one-third of patients can have PIK3CA mutations. A good number of those were mutations that were also evident in the primary tumor. Things like RB mutations are much less frequent, around less than 10%. There are multiple mechanisms, but some of these mechanisms are seen with regularity.
Kevin M. Kalinsky, MD, MS: So, there’s been a lot of interest about rechallenge with CDK4/6 inhibitors. Now at this point, we’ve seen 2 randomized trials giving palbociclib after palbociclib. At San Antonio last year, we saw the results of the PACE study [NCT03147287], which demonstrated a negative study in the sense that palbociclib after palbociclib was not efficacious. Even though there was this one arm in there giving avelumab plus, switching the endocrine therapy plus palbociclib after patients had tumors that had progressed on palbociclib where there was some numeric benefit that was seen, though this remains an area of continued research. At ASCO last year, we saw the results of the PALMIRA study [NCT03809988]. In that study, this was, again, a randomized phase 2 trial of less than 200 patients and patients whose tumors have progressed on endocrine therapy plus palbociclib, and they were [randomly assigned] to fulvestrant with or without palbociclib. This, again, did not demonstrate a benefit of giving palbociclib after palbociclib. I think at this point, that question has been answered. At [the] ASCO [Annual Meeting] last year, we saw the results of MAINTAIN [NCT02632045], which have now been published in the Journal of Clinical Oncology, which looked at primarily tumors that have progressed on palbociclib and then switching to fulvestrant with or without ribociclib. That demonstrated an improvement in progression-free survival; again, a randomized, phase 2 study. I think we’re really awaiting the results of phase 3 trials. There are 2 studies that I was going to mention, like postMONARCH [NCT05169567], which is a study of giving fulvestrant with or without abemaciclib after CDK4/6 inhibition. There’s also EMBER [NCT04188548], which is the oral SERD [selective estrogen receptor degrader], and there’s an arm in there giving the new Lilly oral SERD plus abemaciclib. Those are larger studies of greater than 300 patients that will further answer this question about switching CDK4/6 inhibition, but in this case with abemaciclib.
Kevin M. Kalinsky, MD, MS: I’ll say that there are a number of agents that are of interest after CDK4/6 inhibition and a number of potential ways of addressing this. For instance, with PI3K inhibition, whether that’s gedatolisib or also giredestrant in the MORPHEUS study [NCT04802759], giredestrant being the oral SERD. These are smaller studies and are not practice changing. They’re really proof of principle studies. As I mentioned, EMBER is a study that’s looking specifically at patients’ post-CDK4/6 inhibition of giving imlunestrant, the Lilly oral SERD, with or without targeted therapy.
Transcript edited for clarity.