Trial Data: 2L Therapy After ET + CDK4/6i in HR+/HER2- Metastatic Breast Cancer

EP: 1.What to Test for in Patients With Early- or Late-Stage Breast Cancer

EP: 2.Novel Testing Methodologies in Breast Cancer Management

EP: 3.What is the Role of Germline Testing in Patients With Breast Cancer?

EP: 4.Patient Case 1: Mutated ESR1 in HR+/HER2- Metastatic Breast Cancer

EP: 5.Optimal ESR1 Testing Strategies in HR+/HER2- Metastatic Breast Cancer

EP: 6.HR+/HER2- Metastatic Breast Cancer: Impact of ESR1 Mutation on Treatment

Now Viewing

EP: 7.Trial Data: 2L Therapy After ET + CDK4/6i in HR+/HER2- Metastatic Breast Cancer

EP: 8.Considerations for Selecting and Sequencing Therapy in HR+/HER2- mBC

EP: 9.EMERALD: Elacestrant in Relapsed/Refractory HR+/HER2- mBC

EP: 10.Relapsed/Refractory HR+/HER2- mBC: Real-World Applications of the EMERALD Trial

EP: 11.Patient Case 2: Unmutated HR+/HER2- Metastatic Breast Cancer

EP: 12.TROPiCS-02: Sacituzumab Govitecan in Relapsed/Refractory HR+/HER2- mBC

EP: 13.DESTINY-Breast04: T-DXd in HER2-Low Metastatic Breast Cancer

EP: 14.Evolving Role of Antibody Drug Conjugates in Metastatic Breast Cancer

EP: 15.HR+/HER2- Metastatic Breast Cancer: Future Directions in Care

Transcript:

Joyce A. O’Shaughnessy, MD: We have very little sequencing data. Can we use some of the serial evaluation of NGS [next-generation sequencing] ctDNA [circulating tumor DNA] to help us? This is real-world data we’re looking at here, showing across the top in blue. Patients get one of the CDK4/6 inhibitors [in the] first line; what are they getting [in the] second line? And there is a fair amount of use in the real-world setting of CDK, post CDK, [the] so-called recycling of CDK4/6s. And if we look just briefly at some of the data, there’s been randomized phase 2 data. Looking at the case of [the phase 2] MAINTAIN [trial; NCT02632045], for example, patients essentially progressing on palbociclib and an AI [aromatase inhibitor] randomized to switching endocrine therapy [ET]; it was generally to fulvestrant with placebo versus switching both endocrine therapy, going to fulvestrant with switching [the] CDK [inhibitor] from palbociclib to ribociclib. Now here there was an improvement in median PFS [progression-free survival] that met its primary end point. It went from 2.7 months with fulvestrant to 5.29 months. That’s an improvement. It’s not what we call gangbusters, but it is at least a statistically significant improvement.… [Progressing] on palbociclib [and] AI [aromatase inhibitor] and then switching to fulvestrant-palbociclib versus fulvestrant alone, that was negative. That did not help the patient. There was no improvement. It was 4.8 versus 4.6 months median PFS [progression-free survival]. And then we saw at ASCO [American Society of Clinical Oncology annual meeting] the PALMIRA trial [NCT03809988], again, a randomized phase 2 trial…. Essentially…patients [who were] on AI-palbociclib [and] progressing [were] switched to a different endocrine therapy; it was mostly fulvestrant, with or without continuing on palbociclib. And you can see in the black box down on the bottom median PFS a slight numerical improvement, but not statistical. It was negative trial with a hazard [ratio] of 0.84. So a little bit of data that switching to a different CDK might be somewhat beneficial for patients. So that’s one option, but it’s not what we really call level 1 evidence. What else can we do? Well, the PI3 kinase pathway is a very important mechanism of resistance to endocrine therapy in general and to CDK4/6 inhibitors. Now we’re all familiar with the [phase 3] SOLAR-1 [trial] data [NCT02437318], which [included] patients progressing on AI. Only a tiny minority had had a CDK4/6 [inhibitor]. And it was only in the population [with PIK3CA mutations] where if those patients had alpelisib, the inhibitor of PI3 kinase, with fulvestrant versus fulvestrant alone, that they had a substantial improvement in their median progression-free survival. We can see it up at the top there, 5.7 months with fulvestrant versus 11 months with alpelisib and fulvestrant. And I’ll just point out here that when patients haven’t had an antecedent CDK4/6 [inhibitor] and you give them fulvestrant, 5.7 months is not bad, but it’s really a whole different ballgame when patients are progressing on CDK4/6 inhibitors…. The median PFS with single-agent endocrine therapy is nowhere near as good. We can see down at the bottom very, very tiny numbers, for example bottom left, that in a very small percentage of patients who had had a prior CDK4/6 [inhibitor] on SOLAR-1 with fulvestrant alone, the median PFS was 1.8 months. It went up to 5.5 months with alpelisib, but that’s not nearly as good as the 11 months we saw. So the question is, how much more do we know about coming in with alpelisib and fulvestrant upon progression [with] AI plus CDK4/6 inhibitor, and that was the BYLieve [NCT03056755] trial. It’s a prospective trial, was a phase 2 trial. Again, patients mainly progressing on AI plus CDK4/6 single arm, they get fulvestrant plus alpelisib if they [have a] PIK3CA [mutation]. If they were progressing on fulvestrant plus CDK [inhibitor], then they got letrozole plus alpelisib. And we can see in the red box that [the PFS is] 7.3 months, and let’s remember that number because that comes up kind of as a benchmark for patients progressing on CDK4/6 [inhibitors]. [So] 7.3 months with fulvestrant and alpelisib. If they got the AI plus alpelisib because they already had fulvestrant, it was 5.7 months. So, these are not bad, but it’s really a far cry from what we can accomplish in the first-line setting for patients. So now let’s look at the new data. We don’t have availability of capivasertib yet, but we’re hoping by the end of the year that we will have capivasertib. And capivasertib, as Komal had said, is an AKT inhibitor. It inhibits both wild-type and mutant AKT1 and 1, 2, 3, I believe. And this was for patients whose disease was progressing on first-line AI, with or without a CDK4/6 inhibitor—at least 50% of the patients had to have a prior CDK4/6 inhibitor, and the patients were [randomly assigned] to fulvestrant placebo or fulvestrant plus capivasertib. AKT inhibitor, now this is a different schedule. This is 400 mg [twice a day], 4 days on and 3 days off. So we’ve not used that schedule before in the metastatic setting, but that’s what it is to allow for recovery from toxicity, particularly diarrhea. But there are dual primary end points. So, investigator-assessed PFS in the overall population unselected for any mutation in the P13 kinase pathway or an AKT pathway alteration. A PIK3CA mutation, an AKT mutation, or a P10 alteration, loss of function. So primary end point. If we look at the top left in the overall population per PFS, we see a doubling of PFS from 3.6 months to 7.2 months. And we see that in the top right, very similar results in the AKT pathway…about 38 to 40% of patients…had an AKT pathway alteration. And we see the hazard [ratio] there of 0.5, it was quite good. Down [at] the bottom, you see in both the overall population and the AKT pathway–altered population, we see a trend toward improved survival. Not statistically significant yet, but the survival data are trending in the right direction. This was a positive trial, both in the overall population and in the AKT pathway alternate, as Komal said. We await the FDA decision about whether this will be approved just in the AKT pathway–altered [population] or in the overall population. So we don’t know yet at this time.

Transcript is AI-generated and edited for clarity and readability.