Shared insight on the potential role of CDK4/6 inhibitors in the second-line setting of relapsed/refractory HR+/HER2- breast cancer.
Hope S. Rugo, MD, FASCO: Anne, there’s been a lot of really interesting data we are trying to understand: we’ve been talking about everolimus and alpelisib, but CDK4/6 inhibitors are our best tolerated agents. There’s been a lot of interest about this topic. We have given trastuzumab forever in the United States; should we continue to use CDK4/6 inhibitors? It is not the same idea as an antibody, but still quite intriguing. I was really impressed by Kevin Kalinsky [MD, MS,]’s presentation of the MAINTAIN trial. I am interested in what you think about that, and what next trials are going to inform us about this area?
Anne O'Dea, MD: Kevin presented a very thoughtfully designed IIT [investigator-initiated trial]. It was a randomized phase 2 trial looking at that question: should we continuing CDK4/6 inhibitors post progression on a CDK4/6 inhibitor? In MAINTAIN, essentially, we took patients who had endocrine therapy in the first line with either fulvestrant or exemestane, and upon progression all of the patients received ribociclib and a switch endocrine therapy. Those patients who had received fulvestrant in the first line would receive exemestane, and those patients who had received exemestane would receive fulvestrant. For those who had received neither, it was the physician’s discretion, although fulvestrant was encouraged. In practice it ended up being about 83% of the patients got fulvestrant. This was largely a trial of fulvestrant plus ribociclib post progression.
They saw a 57% risk reduction of progression or death with ribociclib in the intent-to-treat population. One of the things that I found interesting about this, because we think, “well is this a group of patients with indolent luminal disease,” but there were about 30% of patients who had a less than 12-month response to their initial CDK4/6. This is not just the people who sat on CDK4/6 for 5 years, and then we put them on another CDK4/6 for example. About one-third of the patients had what appeared to be a bit of resistance to the initial CDK4/6 inhibitor. About 84% of the patient had received palbociclib in the first line. Despite the author’s diligent efforts to enrich for ribociclib and abemaciclib, effectively it was almost always palbociclib. Kevin showed the subgroup analysis for those who received prior palbociclib and switched to ribociclib, and those who were on ribociclib and continued on ribociclib, and effectively there were such small numbers in the ribociclib group that it was hard to draw any conclusion from that. But it appeared that all the groups benefited from the continuation of the CDK4/6, which I think is very encouraging.
It absolutely makes sense that you have a cell cycle regulatory drug and just keep that going, changing the endocrine therapy partner; I think it absolutely makes sense. What we’ll be looking for is postMONARCH, which is a phase 3 study. This is a trial that not only will include first-line patients on fulvestrant plus abemaciclib, but will also include patients who are receiving adjuvant abemaciclib, a more contemporary patient population, and what we’ll begin to see in our clinics. I’m excited to see those results. This is a trial that opened just in January. It’s in 18 countries and has 350 patients, so we’ll be excited to see those results.
Hope S. Rugo, MD, FASCO: This [MAINTAIN trial] is a phase 2, a nonregistration-based trial. Kevin also presented some really fascinating data on mutations and whether people had the same benefit… numbers are very tiny. Aditya what was your take on that? Maybe you could describe it a bit.
Aditya Bardia, MD, MPH: Kevin in the MAINTAIN trial looked at biomarkers as well, looking at ESR1 mutation, as well as Rb and other alterations. Interestingly in the ESR1 mutation group, you didn’t see much benefit between fulvestrant plus ribociclib vs fulvestrant alone. But in the ESR1 nondetected group, you could clearly see a signal. Now these are exploratory analysis. The numbers are very small, so we need to interpret this with caution, and we need more data before these can change clinical practice. The other thing that was interesting is patients who had FGFR alterations. That’s another group where the benefit was not seen, which makes sense because FGFR alterations can confer resistance to CDK4/6 inhibitors. The ESR1 piece, I'm still not sure in terms of how that fits in. Maybe it’s a fulvestrant issue, and if you do the same trial with better ER [estrogen receptor] degraders like oral SERD [selective estrogen receptor degrader] in that setting, we’ll be able to see a signal.
Hope S. Rugo, MD, FASCO: That is being studied, as Komal mentioned earlier. Many of these multiarm nonrandomized trials are adding the oral SERDs with all different CDK4/6 inhibitors to look at, of course, safety. I think then that will provide some additional reasons for trials. Although, depending on results, it may be hard to randomize to single-agent endocrine therapy alone. I was intrigued by the fact that if you had an ESR1 mutation, you were much more likely to have another mutation. The rate of comutations was higher, but it wasn’t just higher. There were no comutations in the ESR wild type that were significant for resistance pathways. I think that’s something worthwhile to continue to look at. As you were talking about, the more complex mutational landscape is seen in these tumors that are more endocrine resistant and have shorter responses. Maybe that’s what the ESR1 mutation is a marker of. Are those data going to change your practice at all? What is your take on that, and would you then only do that in people who don’t have mutations?
Komal Jhaveri, MD, FACP: No, I see them as providing a proof of concept and a proof of principle in a first randomized setting. We had some data from retrospective studies and single institutional studies where we had seen that potentially doing abemaciclib after patients had already progressed on a prior CDK4/6 inhibitor might be active; so we had some sense of it. In the community we were seeing that happening a little already for a given patient. MAINTAIN is the first randomized study that is showing that. Having said that, I think it’s a small, randomized phase 2 study, and the biomarker groups are even smaller. I don't think I’m going to make a blanket change in my practice based on these data. But studies like postMONARCH and other trials are ongoing, which are larger phase 3 trials, might be able to address this question more definitively. We still have to understand, should we just change the endocrine partner? Should we keep the same CDK4/6 or change it? Should we change both endocrine and CDK4/6, and if at all, which CDK4/6? We are now confused about what we use in the first line, palbociclib or ribociclib. What happens in the second line? I think there’s a lot of good dynamic evolution in this space, but we need to get a little more to make a definitive statement about “this is what I would do for all my patients in the clinic.”
Hope S. Rugo, MD, FASCO: Could you think of a patient for whom you might give a CDK4/6 inhibitor in the second-line setting?
Mark Pegram, MD: What surprises me, going around the country, is the fraction of doctors who are already doing this even before the presentation of the MAINTAIN trial. It’s actually quite high. I was very surprised to see that, absent data, this concept of a CDK on multiple lines, analogous to trastuzumab in multiple lines. People are just doing it. They’re swapping out the endocrine agent, and there were no data to support that whatsoever until now. I think it probably will become somewhat more popular. But I agree with the discussion in this case, and I agree with your point, they are smaller phase 2 data. We need to await the pivotal phase 3 trials before anybody would consider it practice-changing. But could there be a selected patient where I might be compelled to make a switch, and they’re otherwise doing OK, maybe subtle progression and asymptomatic, 1 or 2 areas of bone activity on imaging? Sure, you could always see….
Hope S. Rugo, MD, FASCO: Change the endocrine agent plus the CDK4/6 inhibitor because they do have a bit of difference in their targets.
Anne O'Dea, MD: Clinically, I have a small number of patients in my practice who for whatever reason had a toxicity that required discontinuation of the frontline CDK4/6. To say that patient isn’t able to benefit from ongoing CDK4/6 at the time of progression; this opens up the idea that you could try a different CDK4/6 that perhaps has a different toxicity profile. You mentioned the diarrhea with abemaciclib. If that was why the patient had to discontinue perhaps, or if it was a neutropenia issue, you could switch those. I think this allows us to be a bit more of a chef and not as much of a cook. We don't have to be quite as algorithmically driven, and I like that this opens that possibility up for patients.
Transcript edited for clarity.