When to Choose Chemotherapy vs CDK4/6 Inhibitors

Joyce O’Shaughnessy, MD:This woman who’s presenting with de novo metastatic breast cancer, age 62, with multiple liver metastasis, pretty good liver function, however, the transaminases are a little bit elevated, asymptomatic from that perspective, but a large breast mass and adenopathy, she’s a woman that heretofore, I would have recommended chemotherapy for initially, up until pretty recently.

Historically, my standard of care would have probably been a combination of a taxane and capecitabine for 6 to 8 cycles, get maximal cytoreduction, and then proceed to capecitabine alone as a maintenance therapy for the patient, and then considering what to do with the locoregional disease, depending on whether it was likely to become a local control issue for her down the road. If it had a very nice response, I would have probably not recommended lumpectomy, radiation, or mastectomy because of her liver metastasis. But on the other hand, if it had been more of an inflammatory breast cancer, something that could create a bad local control problem down the road, I would have also been considering surgery and potentially radiation therapy for her.

So, up until recently, I would have recommended chemotherapy for the patient because of the tempo of the disease and the multiple liver metastasis. However, over the last couple of years, I have switched my practice pattern, and I would give serious consideration to utilizing a CDK4/6 [cyclin-dependent kinases 4 and 6] inhibitor for this postmenopausal woman with letrozole because of the extremely good results with regard to progression-free survival with the CDK4/6 inhibitors. The median progression-free survival in the first-line setting is a bit over 2 years. And even with combination chemotherapy in the first-line setting, median progression-free survival is in the range of about 9, maybe 10 months or so. So it’s a vast difference in terms of progression-free survival.

The other thing we think about is we need a response pretty quickly for this patient. She’s not in extremis, but with the diffuse liver metastasis, you really do want to get control of the disease pretty quickly. The response rate with combination chemotherapy is in the order of 50%, maybe 60%. And, interestingly, that’s about the same response rate that you’ll get with the CDK4/6 inhibitors in the first-line setting. The clinical benefit rate in the first-line setting is about 80%. So about 80% of patients will have either a response or prolonged stable disease for 6 months or longer. So it’s comparable in terms of the chances of getting substantial cytoreduction.

The other issue we think about in chemotherapy versus CDK4/6 inhibitors is what’s the tempo of response because we want a more rapid response. Endocrine therapies, the response tempo tends to be slower. But with the CDK4/6 inhibitors, if you look from cycle to cycle at the degree of tumor reduction in terms of the volume of the disease or the measurements of the disease, they fall very quickly from cycle to cycle. We don’t have head-to-head comparison data yet, although studies are planned to look at patients such as this in the first-line setting with chemotherapy versus CDK4/6 inhibitor. It looks similar to me in terms of the tempo of response. So I’ve switched my practice patterns and would really give some serious consideration to a CDK4/6 inhibitor for this patient.

Really the only patients I’m still utilizing chemotherapy for first-line are patients with truly visceral crisis, immediately life-threatening disease such as lymphangitic spread in the lungs with substantial dyspnea or liver function tests that are more markedly elevated where you may only have 1 therapeutic opportunity for the patients and you really have to get a response. This patient, I would definitely not put her in the category. So I think the definition of visceral crisis needing chemotherapy has become more narrow. We’re not utilizing the chemotherapy so much in the first-line setting.

All of the CDK4/6 inhibitors have been studied with both the aromatase inhibitors, mainly letrozole but others as well, in addition to fulvestrant. And I think the hazard ratios are pretty uniformly the same across all of the studies, whether it’s with aromatase inhibitors, whether it’s with fulvestrant. It’s all around 0.55 or so. So it does not appear to me that it makes a difference what the endocrine therapy partner is. Of course, the vast majority of our data are with the aromatase inhibitors and fulvestrant. There are some safety data and a little bit of efficacy data with tamoxifen. And again, it looks good. It’s a much smaller data set. Tamoxifen/ribociclib, we want to avoid that because there could be some QTc prolongation with each of the agents. Very small percent chance, but there could be some QTc prolongation that could be overlapping, so we don’t want to use that with ribociclib. But that is also a possibility that’s been studied with palbociclib and abemaciclib. But I think either, usually we’re going to use the aromatase inhibitors or fulvestrant. I don’t think it makes any difference.

Transcript edited for clarity.

Case: A 62-Year-Old Woman WithDe NovoInvasive Ductal Carcinoma

• A 62-year-old woman presented to her gynecologist with a large mass in her right breast
• Breast MRI confirmed the presence of a 6-cm mass and axillary adenopathy
• Labs: ALT 95, AST 70 (elevated)
• Core needle biopsy confirmed ER+ PR (-) HER2(-) carcinoma, grade 3
• CT chest, abdomen, and pelvis showed widely scattered liver metastases