Do CDK4/6 Inhibitors Impact Later Therapy in HR+ mBC?

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Andrew D. Seidman, MD: Yes, there’s this whole question of what to do after your CDK4 [cyclin-dependent kinase] 4/6 inhibitor. Does prior CDK4/6 inhibition make you more sensitive to mTOR [mechanistic target of rapamycin] inhibition? What is the impact, if any, on subsequent chemotherapy?

Joyce A. O’Shaughnessy, MD: Yes. We are feeling our way, I would say. I’m feeling my way because we don’t have data to guide us in terms of randomized trials upon progression on CDK4/6. A key question is, who could just get endocrine therapy alone at that point, such as fulvestrant? Who needs an mTOR inhibitor? Who needs chemotherapy? And then, as you said, maybe we’ll get a PI3-kinase inhibitor to put as an option there. I think the randomized trials are ongoing with continuing CDK4/6, or switching to a CDK4/6, or even adding a checkpoint inhibitor to that as well, etc.

And so, Nick Turner brought us a little data from the PALOMA-3 on this fairly recently looking at subsequent therapies on PALOMA-3, which was the fulvestrant plus/minus palbociclib in the second-line setting and looking in patients who received either single-agent endocrine therapy or endocrine therapy plus everolimus or they received chemotherapy. Most common chemotherapy, not surprisingly, was capecitabine. And then it looked at the overall duration of progression, looking at the first-line progression, with the fulvestrant with or without palbociclib plus the progression-free survival [PFS] on the second-line therapy. And you put those altogether and still the use of the palbociclib in the first line was significantly better in terms of PFS than utilizing endocrine therapy followed by something else at progression. So, there was no hint that the progression-free survival on the subsequent therapy after palbociclib was…

Andrew D. Seidman, MD: Wasn’t in any way harmed.

Joyce A. O’Shaughnessy, MD: Wasn’t in any way harmed, exactly.

Andrew D. Seidman, MD: I thought that was important nor did I think there was any priori reason to think that CDK4/6 inhibition would somehow impair or hamper subsequent therapy, so that the hazard ratio through 2 lines of therapy still favored palbociclib and it was very similar through one line in PALOMA-3. It was interesting that in that analysis, the most common chemotherapy, maybe not that surprising to many, that doctors chose after progression on PALOMA-3 for patients who got chemotherapy was capecitabine.

Joyce A. O’Shaughnessy, MD: Yes, continuing with the oral. At least preclinically in some of the preoperative therapy trials, when patients have stopped the CDK4/6 preoperatively, gone to surgery, and then the Ki-67 has been looked at, there is some rebound in proliferation. And so, you wonder, is endocrine therapy going to work by itself there or do you need an mTOR? What do you tend to do in your practice, Andy?

Andrew D. Seidman, MD: For which patient?

Joyce A. O’Shaughnessy, MD: The patient progressing on first-line therapy, who has benefitted from CDK4/6 and now they’re progressing. What do you tend to do?

Andrew D. Seidman, MD: Yes, so typically that benefit is a durable benefit. If the patient has opportunities for other endocrine therapies that they haven’t been exposed to or even if they had been exposed to it many years ago in the adjuvant setting, my default position is to try to exploit endocrine therapy for as long as possible. So, for the woman who has progressed on an AI [aromatase inhibitor] plus CDK4/6 inhibitor, it would either be fulvestrant or it could be exemestane or everolimus. We always forget about tamoxifen. Tamoxifen is still a good drug and we don’t talk about it much. So, the tamoxifen-naïve patients, patients who have more indolent disease, that’s still a possibility.

Joyce A. O’Shaughnessy, MD: What do you see? When you use fulvestrant as a single agent, for example, is there a particular patient population and have you seen prolonged stable disease, some clinical benefit there?

Andrew D. Seidman, MD: Yes. I don’t know that I think there’s a patient population that helps me parse the decision between, let’s say, fulvestrant and exemestane/everolimus. The bigger decision is chemotherapy versus either of those and then it tends to be symptomatic visceral disease that’s the driver. I feel I’ve learned a lot about how to manage everolimus toxicity, and I know some doctors are bashful about using it, primarily because of stomatitis, etc. But I still find it to be very valuable. The hope is that patients will be able to derive some meaningful period of benefit from all of these treatments. So, if it’s not fulvestrant now, it’s fulvestrant later, right?

Joyce A. O’Shaughnessy, MD: Yes. And what I have done, what I’ve kind of come upon, our practice patients are always changing as we get more experience and, of course, even better data in this post-CDK. But what I’ve been doing is if the patient doesn’t have a liver metastasis, I have been going on to an everolimus combination in the second-line setting. But if they’ve got bone disease, lung disease, lymph node disease, chest wall, breast, ER [estrogen receptor]-driven sites of disease, I have found good success with everolimus following CDK with either exemestane or fulvestrant, for example. Now with liver disease, having tried it several times, Andy, I have found a lack of success. And so, for the liver metastasis, just again trial and error, I am now going on to capecitabine for the liver metastasis. And one thing I like to do is if women benefit from everolimus and whatever agent, I tend to use exemestane frequently. If they benefit more than 6 months, I have found that going to tamoxifen next, I can get 8 or 9 months. It really does resensitize to that estrogen receptor. So, that’s kind of one of the reasons I use the everolimus, because I want to try to resensitize.

Andrew D. Seidman, MD: Interesting, interesting.

Joyce A. O’Shaughnessy, MD: To get a longer duration. So, I haven’t done a lot of fulvestrant as a single agent right after CDK. My practice pattern has been to go more to an everolimus.

Andrew D. Seidman, MD: You know, this whole underlying theme sort of speaks to this novel endpoint that I’ve heard a lot of patient advocates talk about, that is time to chemotherapy. How much of my life can I live with metastatic breast cancer before I need to cross that bridge to chemotherapy? You mentioned this earlier. I recently had the privilege of chairing a working group for the NCI [National Cancer Institute] Breast Cancer Steering Committee where we were critically examining meaningful and appropriate endpoints for metastatic breast cancer clinical trials. And several patient advocates were on the panel, which was very valuable. And while we parsed the difference between PFS as a primary endpoint in this setting versus OS [overall survival], there was a lot of discussion about patient-reported outcomes. And patients expressed a value in time without chemotherapy as being important in and of itself. So, these strategies hopefully will allow us to make that many years.

Joyce A. O’Shaughnessy, MD: Yes, absolutely. Look forward to reading your paper on that, Andy. Really lovely effort and contribution.

Transcript Edited for Clarity