Sequencing and Role of Everolimus in HR-Positive Breast Cancer
Panelists: Joyce A. O
Joyce A. O’Shaughnessy, MD: Sara, you have been quite involved with abemaciclib in the preoperative setting. But in the MONARCH 1 study, there were very nice late-line data for monotherapy at a higher dose. Would you ever use that in practice, or should everybody basically be getting a CDK inhibitor up front with endocrine therapy?
Sara A. Hurvitz, MD: Well, women live for so long, fortunately, with this disease. I do have a number of patients who are eligible for this monotherapy; namely, patients who’ve been treated with a line or 2 of chemotherapy, which was the design of MONARCH 1, and patients who’ve exhausted all other endocrine options—aromatase inhibitors or fulvestrant, for example. I think it’s a good option to try. I don’t use it in patients who have been pretreated with another CDK4/6 inhibitor and have progressed. I’ve seen that happen in other practices, but I don’t condone that.
That’s not how the study was done, and I think those patients really should be going on clinical trials. We need to address how we treat patients who have been exposed to and are resistant to CDK4/6 inhibitors. I think the tolerability is pretty good. You are able to use this higher-dose option—the 200-mg bid dose. You still have to watch for diarrhea and cytopenias in about a quarter of patients. But at the median follow-up of about 18 months, the median overall survival was almost 2 years 22 months in a pretty heavily pretreated patient population. So, I do think they’re impressive data—albeit, this was phase II data, but it was impressive data supporting its use in heavily pretreated patients.
Joyce A. O’Shaughnessy, MD: And compared with our other options, it looks very good. Compared with chemotherapy, it has a shorter median progression-free survival and shorter overall survival. But yes, the data look good for those who haven’t had a CDK4/6 inhibitor.
Hope S. Rugo, MD: It just seems so unlikely that we’re going to find a group of patients who received multiple lines of endocrine therapy and chemotherapy and haven’t had a CDK4/6 inhibitor.
Joyce A. O’Shaughnessy, MD: It’s going to be our long-livers—our 5-plus-year patients who are way out there, etc. So, it’s a small subset. There is a lot going on in the CDK4/6 world. Then we come to everolimus. Komal, do you still use everolimus in your practice? Where do you think there is a role for it?
Komal Jhaveri, MD, FACP: I do. I know we all, as a community, are very disturbed about the mucositis rates and the side effects that we see from everolimus, but I do still end up using a lot of everolimus in my practice. And with the data now emerging with fulvestrant as a partner with everolimus, I think it has been more compelling, in some ways, to think about everolimus yet again, just outside of exemestane/everolimus from the BOLERO-2 data that we’ve been utilizing thus far. I also use everolimus with tamoxifen based on the TAMRAD trial, and I do think that there are data that suggest that even in the ESR1-mutant patients, tamoxifen could have some role. I feel like I kind of use that as an excuse to use tamoxifen with everolimus in certain patients.
And now, the PrECOG study that has published in the Journal of Clinical Oncology looked at the combination of fulvestrant with everolimus and showed a doubling of progression-free survival—5 to 10 months. I thought that was very impressive. The MANTA trial that Peter Schmid presented last year also caught my attention. The MANTA trial looked adding vistusertib, an mTORC1/2 inhibitor. While they couldn’t show any benefit for that compound, the control arm, where they looked at fulvestrant/everolimus, had a progression-free survival of 12.4 months, compared with fulvestrant—a little over 5 months. What we don’t have, like we don’t have with everything else, is post-CDK4/6 data. Does this hold true? Having said that, I think it’s certainly something that we use in practice even now, until we get this data of what happens post-CDK4/6.
Joyce A. O’Shaughnessy, MD: Yes.
Hope S. Rugo, MD: In the PrECOG study, which I think really does support the use of fulvestrant in combination with everolimus, because they started the trial before we had the data on dexamethasone mouthwash, from what was called the SWISH study, which is now on the everolimus label—they didn’t use the mouthwash. They saw the expected stomatitis rate, which is quite high—up to 8%, 9% grade 3. And with the mouthwash, we have eliminated grade 3 stomatitis.
Komal Jhaveri, MD, FACP: Absolutely.
Hope S. Rugo, MD: We see that in practice. It wasn’t just the phase II study. Joyce, you’ve done a study that showed very similar data. I think that we can think about the toxicity in a slightly different way. Of course, we still see some of the other toxicities from everolimus, but much less than we did before.
Joyce A. O’Shaughnessy, MD: I’m not seeing that much pneumonitis with the everolimus. It’s reported. It’s a very small number. It’s low single digits for people who are on it for quite a long time. But I think we’re all much more aware of it. We’re aware of that cough and shortness of breath, and know to get that CT scan. So, we can manage that. A lot of people will use the CDK4/6 inhibitor and then go on to capecitabine. Should we think about everolimus instead of capecitabine?
Komal Jhaveri, MD, FACP: That’s a very important question that was actually set out by the BOLERO-6 study. We have many BOLERO studies now, and the sixth BOLERO study looked at a 3-arm comparison. Patients were randomized to get either the combination from BOLERO-2, which is exemestane with everolimus, versus everolimus alone. I think this is the only study that has some data with everolimus alone versus capecitabine. The primary endpoint for this BOLERO-6 trial was to look at the hazard ratio of progression-free survival comparing exemestane/everolimus with everolimus. That was 0.7. We know from PI3K inhibitors that endocrine therapy in combination with PI3K inhibitors is better than PI3K alone. We saw that with this primary endpoint.
The secondary endpoint was to look at the hazard ratio of progression-free survival for the BOLERO regimen, the exemestane/everolimus with capecitabine regimen—a very important question that we want to look at in clinic. The hazard ratio there is 1.26, but the capecitabine arm might have been favored because of the imbalances in the baseline characteristics of that patient population. Fewer patients in the capecitabine arm had more than 3 metastatic sites. More patients had chemotherapy in the exemestane/everolimus arm compared with the capecitabine arm. More visceral metastatic sites were seen in the everolimus group compared with the capecitabine group—more bone metastases in the capecitabine group. Perhaps that could have been a reason why the hazard ratios were the way they were. In clinic, I think we end up using Xeloda (capecitabine) after the endocrine therapy manipulations as the first treatment option for most patients, unless we’re thinking about a taxane.
Debu Tripathy, MD: But it’s interesting. I do think that if you just compare them side by side, PALOMA-3 was one of the few studies that reported how patients did after treatment. And when they looked at the different options—of course, this was up to physician and patient choice, but the longest progression-free survival was actually with capecitabine, and the shorter progression-free survivals were with endocrine therapy. One general statement that I think is important in practice for all of these combinations, and Hope alluded to this earlier, is that you have to have some degree of intrinsic hormonal sensitivity. So, if you enroll patients with very low ER content, those patients aren’t going to do as well. If you enroll patients who actually are not luminal A or B, they won’t do well. That has been shown as well. So, that’s a very important point to make.
And secondly, if the patient still is hormonally responsive, you need to block both of the pathways—the escape pathway and the endocrine pathway. For example, with HER2 mutations, most of them are ER-positive. When you use neratinib, for example, the results are going to be better if you also use fulvestrant or some hormonal blockade. And so, this is a general principle that we need to follow in this strategy.
Hope S. Rugo, MD: Which is really quite intriguing.
Joyce A. O’Shaughnessy, MD: It’s very interesting. Capecitabine or everolimus/exemestane—we’re going to probably use them both. Do you know what I mean? It is intriguing that capecitabine, which is an S phase agent after a G1 S phase agent CDK4/6…it works like a champ. But everolimus/exemestane also had some benefit in patients after CDK4/6 inhibition in the PALOMA-3 trial. Certainly, we need more data, but it’s kind of an individual patient choice. We’re going to use them all eventually, I think.