Harold Burstein, MD, PhD: We’re learning more about mechanisms of resistance. One of the most important is that mutation in the estrogen receptor [ER] itself. We mentioned this a few moments ago, the ESR1 mutation. That happens in about half the cases that recur despite previous aromatase inhibitor therapy. In such cancers, the estrogen receptor usually requires the binding of estrogen to that receptor to be active. If you have an ESR1 mutation, that receptor is active all the time. As I said, it’s as if you have a gas pedal stuck in the down position and the vehicle is accelerating and hurtling forward. That’s an unnatural place for the estrogen receptor to be. In those cases, aromatase inhibitor treatment is substantially less effective, and we usually use a drug like fulvestrant.

It’s also clear that adding CDK4/6 inhibitors clearly helps these patients do better than endocrine therapy alone. That’s not a reason not to use hormonal therapy, and it’s not a reason not to use CDK4/6 inhibitors. But this is a group of patients who are increasingly looking to novel approaches to help them do better because we recognize that they have some resistance to endocrine therapy. Interestingly, about half the cancers don’t have an ESR1 mutation but are still resistant to endocrine treatment, and understanding the mechanisms of that has proven very challenging. It’s not a simple point mutation story, and there’s still more to be learned.

Richard Finn, MD: Even though it’s been about 7 years since the initial approval of palbociclib, which received accelerated approval in 2015 in the frontline setting with letrozole for ER-positive, HER2 [human epidermal growth factor receptor 2]–negative breast cancer, we still haven’t gotten a consistent story as far as what’s driving resistance to these drugs. When I say that, I mean acquired resistance. The clinical benefit rate of these drugs in the frontline setting is in the 80%-plus range. Clearly, most patients get a benefit. It’s been hard to identify patients or biomarkers for de novo resistance. That is, patients who progress right away just because the number of patients isn’t a large population to look at.

There are things we hypothesize as being important, but they haven’t been validated. When I say things that we hypothesize, such as RB loss, 1 is the target of the CDK4/6 pathway. It’s also important to note that the incidence of RB loss in this population is very rare to start with. One of the bigger clinical-management questions is for a patient who’s been on a CDK4/6 inhibitor, and we’re seeing that patients are on these drugs for at least 2 years on average, some even longer, and then progress. If we knew what was driving that progression, then perhaps we could target those alterations specifically.

Harold Burstein, MD, PhD: In terms of resistance to CDK4/6 inhibitors, that’s a very interesting story, and we’re just beginning to sort that out a little more. It doesn’t seem to be that it’s a point mutation resistance story. Many oncologists are familiar with stories like the ones we mentioned—the ESR1 mutation for ER-positive breast cancers or mutations in the EGFR as contributing to resistance to EGFR inhibitors and lung cancer. With CDK4/6 inhibitors, it’s a more complicated story. It seems as if there are physiological changes in the level of CDK4/6 themselves or in some of the coregulatory proteins. That’s interesting because it invites the possibility that reintroduction or extending the use of a CDK4/6 inhibitor after initial use could still be effective.

Additionally, there were data at ASCO [American Society of Clinical Oncology Annual Meeting] from some very nice studies, which look at the use of CDK4/6 inhibitors beyond progression. We’re excited to see those data because if they’re positive, they suggest that there may be ways of persisting in the use of these CDK4/6 inhibitors beyond their first-line indication, because they may continue to suppress the growth of the cancer cells. Especially if there’s been a gap, we know that clinically you can occasionally reintroduce these drugs and see clinical benefit. There’s still much to be learned about resistance in the CDK4/6 inhibitor space, but the takeaway is that it’s not an absolute thing. It probably will be the case that we can eke out more benefit with this class of drugs even beyond progression.

Transcript edited for clarity.