Treatment After Progression on CDK4/6


Joyce A. O’Shaughnessy, MD: In terms of what we do after progression on CDK4/6, we’ll talk in a moment about the SOLAR-1 data, and maybe mention the BYLieve trial and the early data from that a little bit. One question—because we just recently had alpelisib—is, what about everolimus? We’ll come back to that. You had interesting data here, Aditya, on utilizing a second CDK4/6 inhibitor at some point in the metastatic course. Tell us a little bit about that if you would.

Aditya Bardia, MD, MPH: It essentially came from the clinical scenario question that comes up in the tumor board. If you have a patient who progresses on AI [aromatase inhibitors] plus a CDK4/6 inhibitor in the second-line setting and beyond, can you use abemaciclib as monotherapy? MONARCH 1 led to the approval of abemaciclib as a monotherapy, but that was in the pre-CDK4/6 era. Now, in the post-CDK4/6 era, would you see the same outcomes with abemaciclib? We did a multi-institutional study with different centers, including yours, and pooled the experience of response to abemaciclib in patients who had all received first-line CDK4/6 inhibitors with either ribociclib or palbociclib.

Essentially, what we saw was, overall, the median progression-free survival was 5.6 months, and there was a subset of patients—about one-third—that had early progression, meaning progression within the first 60 days. There was a subset of about one-third of patients that had delayed progression, meaning progression at more than 6 months. It does appear that the post-CDK4/6 setting is a heterogeneous group. There are some patients who will continue to derive benefit with abemaciclib, but there are some patients who will have early progression. Now we’re doing biomarker work to understand if we can identify the ones who would derive benefit versus not.

Joyce A. O’Shaughnessy, MD: Very interesting. I’ll bet others have had that experience, but I generally will not give them right after each other, although I could see that there was a little bit of variation there in terms of practice patterns. A couple of years had gone by in patients that had multiple options and still had a good performance status. I didn’t want to have a toxic therapy. I’ve had some nice clinical benefit in later-line Abema, but what about right after palbo [palbociclib] or ribo [ribociclib] progression, Aditya? There was some data in the poster about that.

Aditya Bardia, MD, MPH: Correct. There were some patients who did derive benefit with Abema right after an AI plus a CDK4/6 inhibitor. In part, it depends on what the mechanism of resistance was. In cell lines, even tumors that lose Rb do derive benefit with abemaciclib, but at higher doses. As you were saying earlier, abemaciclib just appears to be a different drug as compared with ribo [ribociclib] and palbo [palbociclib] because it can affect CDK7 and CDK9, so probably in this setting, it might be a reasonable drug to consider.

Joyce A. O’Shaughnessy, MD: In terms of this theme, again, about what to do after CDK4/6, we have the FDA approval of alpelisib. Would you tell us about that new approval in the SOLAR-1?

Debu Tripathy, MD: The SOLAR-1 trial tested patients who were eligible for fulvestrant therapy, and they were randomized to placebo or alpelisib.

In the SOLAR-1 trial, the median progression-free survival went from 5.7 months to 11 months with the addition of the PI3 kinase inhibitor alpelisib to fulvestrant. This was for patients who were eligible for fulvestrant therapy first or second line. The toxicities were still there, less so than we see with the nonspecific inhibitors, but they included hyperglycemia, GI [gastrointestinal] toxicities, and rash. Much of this can be prevented, and we’re going to have to learn how to proactively manage diarrhea and also the skin rash with antihistamines. I do think this is a step forward and may represent the second-line therapy for patients, or even later lines of therapy.

We don’t have much information as to how this drug will perform in CDK inhibitor-treated patients. Very few patients in that trial had received it, and we need to await other studies. There is early indication from the BYLieve study, which is for a CDK-pretreated population, that there is activity. We will also learn, as that study matures, if there is an ideal partner, because both fulvestrant and aromatase inhibitors can be used. I do think this is going to be a valid option. We are going to need to see how toxicities are going to be managed. I think that’s the biggest issue. The whole field, though, is still evolving. That whole pathway can be targeted. Erika, I think you were going to share with us some information that was presented on AKT inhibition.

Erika P. Hamilton, MD: This was the FAKTION trial. It was a study out of the United Kingdom with a little fewer than 180 patients, but essentially, patients were randomized to receive fulvestrant alone or fulvestrant with AKT inhibitor. What we saw was a 6-month improvement in progression-free survival, from about 4.5 to 10.5 months. What I think was really interesting about this trial, as opposed to the PI3s, is the same percentage had an activation in the pathway—about 40% had a PI3, PTEN, or AKT activation. There was no difference seen between those that had activations in that pathway versus not. And there was also a hint toward overall survival—again, about a 6-month change. P value was not quite statistically significant at 0.07, but it’s very interesting that a predictor of benefit from this pathway doesn’t translate to the AKT inhibitor as we’ve seen with the PI3.

Joyce A. O’Shaughnessy, MD: It’s nice that we see some data with AKT inhibitors.

Erika P. Hamilton, MD: Absolutely.

Joyce A. O’Shaughnessy, MD: Capivasertib was pretty well tolerated. It has some toxicities, although not as much hyperglycemia. Some GI, fatigue, and rash, but still very safe, so we’ll look forward to a phase III trial with capivasertib.

Transcript Edited for Clarity

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