Hope S. Rugo, MD: So, the indications for palbociclib with endocrine therapy for metastatic breast cancer are in the first-line setting in combination with an aromatase inhibitor, if we have patients who relapse while taking an aromatase inhibitor and then go on to receive subsequent-line hormone therapy. Palbociclib is also approved in combination with fulvestrant for the treatment of metastatic hormone receptor-positive breast cancer that has previously been treated with an aromatase inhibitor. And, in fact, those patients could have received 1 line of chemotherapy for the treatment of metastatic disease, so it’s a fairly broad indication.

In terms of dosing, the dose that’s approved is 125 mg as a flat dose, and it’s given 3 weeks in a row daily with a week off in order to allow bone marrow recovery. Then you check the blood counts and patients start again. The approval includes a blood count check on day 14 of the first 2 cycles and then continuing, but many of us don’t actually check the blood counts routinely in patients who have a normal blood count in the first-line setting because we don’t adjust the dose unless they have a serious toxicity, which is extraordinarily rare.

Sara Hurvitz, MD: The PALOMA-1 study is a phase II, randomized, open-label clinical trial evaluating palbociclib/letrozole compared to letrozole alone in hormone receptor—positive postmenopausal women with previously untreated metastatic breast cancer. The study enrolled about 165 patients and it was conducted in 2 different parts.

The progression-free survival associated with palbociclib/letrozole was roughly double compared to letrozole alone. This was not a blinded study. It was a phase II study, and so these data obviously needed to be confirmed in a larger phase III study. In addition, the overall survival, while it trended toward being improved with palbociclib, it did not meet statistical significance. That said, the therapeutic index of this drug was so good that the FDA granted accelerated approval of the drug in February of 2015 for patients with postmenopausal metastatic breast cancer that was hormone receptor—positive. The main side effects seen in this clinical trial were grade 3/4 neutropenia just seen in roughly 60% of patients. The fact that patients were having grade 3/4 neutropenia sounds a bit alarming. However, it should be noted that the rates of infection and febrile neutropenia were very low and most patients were unaware that they were experiencing a low white blood cell count. Because of neutropenia, patients were dosed with palbociclib 21 days on, followed by 7 days off, and have a blood count checked before going on to their next cycle of palbociclib. Other than that, patients were very well. Other than that, most patients tolerated the therapy very well.

Hope S. Rugo, MD: So, PALOMA-3 actually was the second randomized phase III trial to start looking at palbociclib in the treatment of metastatic hormone receptor—positive breast cancer, but it reported earlier because the time to progression is shorter in subsequent line therapy than it is in the first-line setting. So, of course, the number of events were achieved faster in that setting. PALOMA-3 was a randomized trial where there are patients still on therapy, where patients who had metastatic hormone receptor-positive breast cancer and were postmenopausal—either naturally postmenopausal or postmenopausal on medications like a GNRH agonist—and whose cancer had progressed on an aromatase inhibitor at some point were randomized to receive fulvestrant and a placebo or fulvestrant and palbociclib. The randomization favored the palbociclib arm, so more patients were randomized to palbociclib and fulvestrant than the placebo and fulvestrant, which is the way the PALOMA-2 was designed as well.

And patients received the drug until they stopped either due to progressive disease or due to toxicity. Very few patients discontinued due to toxicity. The patients were followed very closely in terms of their response to therapy and for progression with regular scans, of course, and visits in the clinic. And their blood counts were checked every month with dose reductions as needed. The tolerance of the drug was very, very good. There were no additional toxicities seen with PALOMA-3 that had not already been described in PALOMA-1 and then were described in PALOMA-2. And even with long-term administration, so patients who stayed on over time, there were no new toxicities that were described.

And then the primary endpoint of that trial, which was progression-free survival, was markedly longer with more than a doubling of progression-free survival in patients who received palbociclib versus those who received the placebo. And in fact, those results were updated at San Antonio Breast Cancer Symposium 2016 with even a longer progression-free survival in the patients receiving the palbociclib versus what had been originally published in the first pivotal publication with palbociclib in a phase III trial. And, of course, as we talked about earlier, that data led to FDA approval of palbociclib in combination with fulvestrant as subsequent line therapy in patients with hormone receptor-positive breast cancer. You could have received chemotherapy in that trial, so about one-third of the patients had received 1 line of chemotherapy for metastatic disease, and in that group of patients, toxicity was not increased, which is important.

In addition, patients were allowed, as I mentioned earlier, who were premenopausal but who were on chemical ovarian suppression. This is an area we feel very passionately about as breast cancer oncologists, that patients should be allowed to enter on these clinical trials even if they have their ovaries and are on chemical ovarian suppression. However, they have, in large part, been excluded, for example, from the first-line trials mainly because of concern that suppression might not be adequate and that would interfere with response. But you can measure estrogen levels, and you know whether the suppression is going to be adequate or not.

True to form and true to what we all feel so passionately about, the premenopausal women who were postmenopausal with chemical suppression had the same degree of benefit in terms of progression-free survival as did the women who were truly postmenopausal. So, the results really held up in a variety of different areas. There has been a number of substudies that have shown that across the board, the benefit is fairly uniform with the addition of palbociclib in these patients who have already had progressive disease on aromatase inhibitor therapy.

Sara Hurvitz, MD: Ribociclib was FDA approved in spring of 2017 based on the results of MONALEESA-2, which showed that ribociclib in combination with an aromatase inhibitor significantly improved progression-free survival for patients with metastatic hormone receptor-positive breast cancer. Ribociclib is approved as a 21-day on, 7-day off formulation, which is similar to palbociclib. The packaging of ribociclib is interesting in that the company has made a packaging that includes the letrozole tablets as well, which in some ways is easier for patients because it’s all included together. So, the scheduling of the ribociclib being 21 days on, 7 days off and yet having the whole 28 days of letrozole there makes it easier for the patient to understand what they should be taking on which day. Ribociclib is given as a dose of 600 mg and each tablet is a 200-mg tablet. The main side effects associated with ribociclib are neutropenia, and although it is a rare side effect, patients need to be monitored by an ACG at baseline, at 2 weeks, and intermittently for the first few cycles because of a rare complication of QTc prolongation.

The MONALEESA-2 study also had over 650 patients enrolled. Patients were postmenopausal, hormone receptor-positive metastatic breast cancer patients who had not previously been treated for metastatic breast cancer, so it was the frontline setting. Patients were randomly assigned 1:1 to receive ribociclib plus an AI versus the AI alone. So, it’s a similar design to that seen in the PALOMA-2 study. The outcomes showed that the patients who received ribociclib had roughly a 10-month improvement in their progression-free survival with a hazard ratio on the order.

Transcript Edited for Clarity