Treatment Following Relapse on CDK4/6 Inhibitors

Joyce O’Shaughnessy, MD:We are still at the early stages of learning about resistance mechanisms in the clinic to the CDK4/6 [cyclin-dependent kinases 4 and 6] inhibitors, and we don’t have any clinical data yet that give us clear guidance about which therapeutic options have efficacy after progression on CDK4/6 inhibitors. There was an interesting paper by Nick Turner [MD] and colleagues from the PALOMA-3 trial of fulvestrant and palbociclib in the second-line metastatic setting looking at ctDNA [circulating tumor DNA] before and after treatment with palbociclib. And about 5% of patients had new mutations inRb, and that was probably a mechanism of resistance to the palbociclib. Interestingly, there was a bit of an increase in estrogen receptor [ER]ESR1mutations. Again, maybe that was a bit more of a resistance mechanism to the fulvestrant, potentially. There was a little bit of an increase as well inPIK3CAmutations, PI3-kinase mutations, also some HER2 [human epidermal growth factor receptor 2] mutations, so it looks like a variety of mechanisms.

Carlos Arteaga [MD] and colleagues have shown thatFGFR1amplification can be a resistance mechanism to CDK4/6 inhibitors. So it’s actually going to be a variety of mechanisms. Preclinically, the PI3-kinase pathway appears to be quite important, so that if you then block the estrogen receptor CDK4/6 and the PI3-kinase pathway, you can get some very good antitumor synergy against the cancer. So I think the PI3-kinase pathway will be a very important one resistance wise. We await the FDA approval of the first oral PI3-kinase inhibitor for breast cancer patients, alpelisib, based on the SOLAR-1 clinical trial result. That was with fulvestrant plus alpelisib showing substantial improvement in progression-free survival for patients with PIK3CA mutations. About 40% of patients with ER-positive metastatic breast cancer have a PIK3CA mutation.

What I think is going to happen once that agent is available to us is when our patients are receiving first-line CDK4/6 inhibitor therapy, we will probably send off their tissue for the analysis of the PI3-kinase. Most of these mutations are present in the primary breast cancer, so that you can utilize a primary breast cancer to do the next-generation sequencing and see the PI3-kinase mutations. Interestingly though, it also looks like ctDNA in the metastatic setting will also be useful to find PI3-kinase mutations. I think that upon progression on CDK4/6, utilizing ctDNA over time will end up being useful to us. So we wait. We don’t have that agent available now, but over time, I think we will have alpelisib and will be able to utilize it upon progression on CDK4/6 inhibitors for those patients with aPIK3CAmutation.

Assuming that this patient does well with the abemaciclib and the letrozole, upon progression with multiple liver metastasis, probably my next recommendation would be single-agent capecitabine, outside of a clinical trial. There are clinical trials that I would immediately want to put her on. But outside of a clinical trial, probably capecitabine. I do utilize everolimus and exemestane for some patients, so that’s a possibility for the patient as well. But in my experience with diffuse liver metastasis, generally I would go on to capecitabine next for the patient. Although the everolimus would be something I would consider potentially after the capecitabine. Then hopefully if her cancer has aPIK3CAmutation, I would consider alpelisib down the line for her as well, but if she were not mutant onPIK3CA, probably capecitabine and then consideration of the everolimus, exemestane.

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