Debu Tripathy, MD, discusses the subgroup analysis from the MONALEESA-7 trial, as well as data from a pooled analysis looking at ribociclib in several clinical trials.
Debu Tripathy, MD
In the phase III MONALEESA-7 trial,treatment with ribociclib (Kisqali) led to a progression-free survival (PFS) benefitfor pre- and perimenopausal patients with hormone receptor-positive, HER2-negative breast cancer.
Patients received either the CDK4/6 inhibitor ribociclib in combination with tamoxifen or a nonsteroidal aromatase inhibitor (NSAI; letrozole or anastrozole) plus goserelin (n = 335), or endocrine treatment plus goserelin (n = 337). The median PFS across the study population was 23.8 months for the ribociclib arm compared with 13.0 months for the control arm (HR, 0.553; 95% CI, 0.441-0.694;P<.0001).
“Of course, breast cancer is a heterogenous disease, and there are several different subgroups that are of interest,” explained lead study author Debu Tripathy, MD.
In a subset analysis, investigators found that patients with visceral disease had a shorter PFS. However, the relative benefit of ribociclib was slightly higher in this group. The analysis additionally showed that patients with de novo disease had better outcomes than those with recurrent disease. The PFS was about doubled in this patient population.
In an interview withTargeted Oncology,Tripathy, professor and chair, Department of Breast Medical Oncology at The University of Texas MD Anderson Cancer Center, discussed the subgroup analysis from the MONALEESA-7 trial, as well as data from a pooled analysis looking at ribociclib in several clinical trials.
TARGETED ONCOLOGY:Can you start by discussing the findings from the MONALEESA-7 trial?
Tripathy:The MONALEESA-7 trial, which was for premenopausal patients, compared goserelin ovarian suppression for all patients along with either the aromatase inhibitor tamoxifen with placebo compared to ribociclib. [It] showed a benefit of ribociclib that was comparable to what we have seen with other CDK4/6 inhibitors, about a doubling in the PFS. Of course, breast cancer is a heterogenous disease, and there are several different subgroups that are of interest. In patients who are being treated with endocrine therapy or biotherapy, probably 1 of the biggest ones is whether or not the patient has visceral disease. We know that, historically, patients with visceral disease have shorter times to progression.
The subset analysis of this group of patients does indeed show that they do have a shorter PFS. However, the relative benefit of a treatment with ribociclib was actually a little bit higher in the visceral group, though not statistically different, but the important message here is that these patients do respond. In fact, if you look at the response rates of these patients, they are in the 50% range for those who had visceral disease. This is an important message for patients who, for example, are symptomatic, where our reflex might be to treat them with chemotherapy first. These are patients that could be expected to respond and that the relative benefit they are getting from the addition of ribociclib is equivalent.
The other group of patients are the de novo patients compared to the recurrent patients. Patients who present with metastatic disease, known as de novo, tend to have better outcomes, probably because they have not been pretreated before. In the sub analysis, these patients again did have a better outcome than patients with recurrent disease. Again, the benefit of ribociclib is similar with about a doubling of PFS.
TARGETED ONCOLOGY:Do you see these findings swaying physicians to consider using CDK4/6 inhibitors now?
Tripathy:I think [physicians] are more likely to use CDK4/6 inhibitors, especially in patients with visceral disease who may be symptomatic. The concern has always been that endocrine may not be enough, and they may need to be treated with chemotherapy. Now that we are seeing higher response rates, I think that it is an important consideration. There’s still a lot of debate as to which patients should get chemotherapy anyway, but what I think this does is it allows us to set the threshold a bit differently and save more patients from getting chemotherapy.
TARGETED ONCOLOGY:Can you also discuss the pooled analysis of first-line ribociclib and endocrine therapy in patients with HR+, HER2-negative breast cancer?
Tripathy:This was a study that combined all of the first- and second-line ribociclib studies looking at both first-line with aromatase inhibitor therapy for postmenopausal patients in MONALEESA-2, the pre- and peri-menopausal first-line in MONALEESA-7, and the MONALEESA-3 which looked at fulvestrant with either placebo or ribociclib in either first- or second-line therapy. Looking at all these studies together, we see that they are roughly similar. The largest benefit was seen in the MONALEESA-3 study, probably because of the inclusion of fulvestrant, but the hazard ratios were all in the 0.55 range, suggesting a similar benefit across all of these.
We didn’t really find a clear identifying factor that might have suggested a difference in the benefit. Some subtle differences, for example, in MONALEESA-7, the median PFS times in both the control and treatment groups were a little shorter, consistent with the fact that younger patients may have slightly more aggressive disease. It really wasn’t that notably different.
TARGETED ONCOLOGY:What kind of implications did this study bring up?
Tripathy:It provides us a greater degree of confidence in terms of what we might expect. To be honest with you, each of the trials was adequately powered to answer that question within its own group. The power of pooled studies probably comes more when one is trying to identify subgroups that are not that common that may be different. We were not able to really do that, although we haven’t delved deeply into the data to pick out, for example, significantly older patients, patients who had to discontinue due to toxicities. These analyses will be coming, so it will be very valuable to tap in to the pooled data set.
The other area that wasn’t really included in this poster is the safety implications, rare events such as elevation of liver function tests, elongation of QT intervals. These are things best looked at in larger data sets.
TARGETED ONCOLOGY:What are some challenges we still need to overcome in this space?
Tripathy:We desperately need to understand why patients become resistant to the first-line therapies that we use, particularly with CDK4/6 inhibitors. There are other abstracts that have highlighted some of the markers over time that may predict who becomes resistant. There were some interesting findings presented at AACR and again at SABCS, looking at cyclin E as perhaps a baseline predictor of who might be resistant. That is an area we need to understand better.
We also need to understand if there are particular subgroups that we might be able to spare CDK4/6 inhibitor therapy in. Patients that have very long disease-free intervals are potentially patients that might be able to be spared that, but we don’t have enough data yet. When we look at the aggregate data, clearly the PFS has been improved and again, the quality of life is improved too.