Reduced Palbociclib Dose Associated With Lower Rate of Neutropenia in HR+ Metastatic Breast Cancer

Hope Rugo, MD

Hope Rugo, MD

A reduced dose of palbociclib (Ibrance) was associated with a lower rate of grade 3 or 4 neutropenia in patients with hormone receptor (HR)-positive metastatic breast cancer who were previously treated with chemotherapy, according to findings from a phase II study, which also investigated retinoblastoma protein phosphorylation (pRB) and Ki67 as biomarkers for response.

Seventy-two patients were randomized 1:1 to receive the CDK4/6 inhibitor in either a 125 mg or 100 mg dose for 3 weeks on and 1 week off in combination with physician’s choice of fulvestrant or tamoxifen.

Grade 3 or 4 neutropenia — the primary endpoint of the study – was found to be more common in the patients who received the 125 mg dose than those who received the reduced dose of 100 mg (56% vs 34%). Progression-free survival (PFS) and clinical benefit were the same in both groups.

“We concluded that you could use 100 mg in patients who are fragile or who have problems with 125 mg in terms of side effects and feel confident that you’re actually hitting the target and that you’re likely to have a similar response and PFS in this pretreated group of patients,” said lead investigatorHope Rugo, MD.

In an interview withTargeted Oncology,Rugo, a professor of medicine at University of California San Francisco Comprehensive Cancer Center, discussed the data from this trial and also shared details from research for a scalp cooling cap to reduce hair loss for patients with breast cancer.

TARGETED ONCOLOGY:Could you share the rationale for the palbociclib trial? How was this study designed?

Rugo:We did a study through our translational breast cancer research consortium called TBCRC035. That study actually started out with the hypothesis that patients who receive prior chemotherapy for metastatic disease and hadn’t yet gotten a CDK4/6 inhibitor — now a vanishingly small group of patients – would have more neutropenia because of bone marrow reserve, and if we gave them 100 mg they might have less toxicity. However, we wanted to have a biomarker to see if we were really hitting the target.

Previous data suggested that you could look at a decrease in pRB, because that is the target for these CDK4/6 inhibitors, to see whether or not you drop the pRB. We thought we would work with our colleagues at Dana-Farber who are working in this area and see whether or not there was any difference in decrease in pRB and skin biopsies from start to day 14 to day 21 of the cycle. Then, we also looked at tumor and cell-free DNA, but we don’t have that data yet.

We randomized 72 patients to receive palbociclib at either 125 mg or 100 mg with 3 weeks on, 1 week off. Physicians could choose the hormone partner with either fulvestrant or tamoxifen because they had already received hormone therapy.

TARGETED ONCOLOGY:What were the findings?

Rugo:What we saw was interesting. If you looked at the number of individual neutropenia events per patient, it was clearly significantly higher in [patients who received] 125 mg than 100 mg. The total incidences of patients who have at least 1 episode of neutropenia was slightly higher but not significantly different. There were more dose delays than dose reductions in the 125 mg arm, but there was no febrile neutropenia in either arm.

We looked at PFS and clinical benefit, and it was identical between the 2 arms. Then we looked at the skin biopsies for RB, pRB and Ki67. RB wasn’t any different, as you would expect. PRB and Ki67 dropped significantly from pretreatment until day 14 to day 21, but there was no difference in the percent decrease, even the start absolute numbers, [on] day 14, day 21, between 100 mg and 125 mg palbociclib.

We concluded that you could use 100 mg in patients who are fragile or who have problems with 125 mg in terms of side effects and feel confident that you’re actually hitting the target and that you’re likely to have a similar response and PFS in this pretreated group of patients. That is encouraging, and we will see what the rest of our data looks like, which we hope to have early next year.

TARGETED ONCOLOGY:You also presented data from a prospective trial evaluating the safety of a scalp cooling cap. Could you discuss these findings?

Rugo:I’ve been working in scalp cooling since we started on it in the United States. It’s now been more than a decade with the idea of getting scalp cooling FDA-cleared eventually. We were successful with that, and in fact, there were 2 FDA devices that were cleared for solid tumors, not even just for breast cancer, based on our original start on this close to 12 years ago.

In our prospective trial, we had a nonrandomized control group with a small number of patients and then patients treated with taxane-based chemotherapy for early-stage breast cancer. We definitely showed that the cold cap using the Dignitana machine resulted in the majority of patients having less than 50% hair loss, which we defined as a success using a specific scale called the Dean scale.

In particular, the weekly paclitaxel success rate was close to 100%. With docetaxel/cyclophosphamide, the success rate is in the mid-sixties, but we didn’t have anthracyclines in ours, so clearly this success is lower. We definitely showed that it worked and is tolerable, so that’s great, but then the question people had was the safety. Looking back 30 to 40 years, if you cool the scalp and reduce blood flow, will you increase the risk of scalp metastasis? Previously unpublished meta-analysis showed that scalp metastases are very uncommon in breast cancer in very tiny percentages, and they weren’t any different in other trials using scalp cooling.

In our trial, we have a prospective database where we can follow these patients, and with about 3.5 years of median follow-up, we have had some patients recur, some people die, unfortunately, of their disease, but no scalp metastases at all, not even in conjunction with other sites of metastatic disease. We are very encouraged by that data, and it was 1 of the goals we had set forth for the FDA clearance.

TARGETED ONCOLOGY:Does the scalp cooling cap have value outside of the early-stage setting?

Rugo:A lot of my patients with metastatic disease use scalp cooling. I have 1 young woman who has gotten many lines of chemotherapy and has never lost her hair. She felt very strongly that that was important to her and she was willing to take the extra time, since scalp cooling takes extra time after the chemotherapy. There is discomfort with your head being cold, but she has figured it all out, and it worked out really well for her, so I’ve had a fair number of women use a cold cap. Some women fatigue and if they are continuing on chemotherapy for a very long time, that makes it really hard, but again, it’s personal choice.