HR+/HER2- MBC: CDK4/6 Inhibitors + ET as Frontline Therapy

Joyce O’Shaughnessy, MD: Sarah, there are other CDK4/6 inhibitors: palbociclib and abemaciclib. Where are we in the first-line data of those? Any new data coming out about them on first or second line?

Sarah Sammons, MD: We’ve been through most of the ribociclib trials. Moving on to abemaciclib, the phase 3 randomized trial in the first line for abemaciclib is MONARCH 3. In that clinical trial, 493 postmenopausal women were randomized to nonsteroidal aromatase inhibitor plus abemaciclib or nonsteroidal aromatase inhibitor plus placebo. We know from that clinical trial that the addition of abemaciclib led to a progression-free survival advantage of 28 vs 14 months in that population. The populations in all the first-line trials are fairly similar. Nobody in MONARCH 3 could have prior therapy in the metastatic setting, but about half had had prior endocrine therapy in the adjuvant setting more than 12 months prior to relapse.

We don’t have overall survival data from the first-line abemaciclib trial. We’re still waiting for that. This year at ESMO [European Society for Medical Oncology Congress], they did report a pooled analysis from MONARCH 2, which is the fulvestrant-abemaciclib trial. What I didn’t realize about that trial was that they did treat about 110 patients who were endocrine therapy-naïve, but they were not included in the intent-to-treat population. What they showed in this ESMO abstract was that patients who got abemaciclib and fulvestrant in MONARCH 2 who were endocrine therapy–naïve had very good outcomes. They had a similar overall response rate as the rest of the population. For me, that’s not practice changing. Going back to what we just talked about, my choice of endocrine therapy backbone in the first line has to do with what endocrine therapy they’ve had before. If they’re endocrine therapy-naïve or if they’ve relapsed greater than 12 months and they don’t have an ESR1 mutation, then I’ll still choose an aromatase inhibitor backbone. That’s where we are with the abemaciclib first-line trials. We’re still waiting for overall survival data.

For palbociclib, our other CDK4/6 inhibitor—the first CDK4/6 inhibitor to result—PALOMA-2 is the first-line clinical trial. In that clinical trial, patients who’ve had no prior therapy in the metastatic setting were randomized 2:1 to either palbociclib and a nonsteroidal aromatase inhibitor or placebo with a aromatase inhibitor. We still see a progression-free survival benefit similar to the other trials, 24 vs 14 months. We also still await overall survival for that trial. One data point that came out at ESMO this year was the pooled time to chemotherapy from PALOMA-2 and PALOMA-3. That’s an extremely important end point that ties along with quality of life, which we first talked about. We’ve established that the CDK4/6 inhibitors are controlling disease. We’ve now established that they’re improving survival. They’re also improving quality of life. Now we’re showing in this pooled analysis of PALOMA-2 and PALOMA-3 that we’re prolonging the time to chemotherapy, which of course is going to improve quality of life.

Transcript edited for clarity.