The combination of a CDK4/6 inhibitor and endocrine therapy is a standard of care for our patients with metastatic hormone receptor positive HER2 negative breast cancer. And these medicines have been very effective. Unfortunately, eventually, disease progresses. And a big question has been, when the cancer worsens, is it appropriate to change the endocrine backbone? The CDK4/6 inhibitor? Or both? And what are the mechanisms of resistance to all of these different agents? So the PACE trial was designed to determine whether there is benefit in continuation of a CDK4/6 inhibitor beyond progression on a prior CDK4/6 inhibitor containing regimen. The PACE trial has three arms. The first arm is a control arm, where patients are randomized to fulvestrant alone. The second arm is the experimental arm, where patients receive fulvestrant and palbociclib. PACE also has a third arm, which looks at a triplet combination of fulvestrant, palbociclib, and the PD-L1 inhibitor avelumab.
The rationale from this arm comes from preclinical data from my colleague, Schome Goel, suggesting that this is a synergistic combination. Now, combinations using CDK4/6 inhibitors and checkpoint inhibitors have been explored before, including combinations of palbociclib and nivolumab or abemaciclib and pembrolizumab. Unfortunately, these combinations have had difficulty with side effects, particularly immune related toxicities, such as elevated liver function tests or pulmonary inflammation. What we found in the PACE trial was that the toxicity profile of that triplet arm was actually better than what had been seen before, without substantial liver toxicity, lung toxicity, or other immune related toxicities. Why we see this difference is hard to know. It could reflect that avelumab is a PD-L1 inhibitor, whereas the other agents used were PD-1 inhibitors, and that might have an influence on the side effect profile. So in the PACE trial, the control arm of fulvestrant alone was given at standard fulvestrant dosing, which is once a month intramuscular injections.
In the second arm, in the third arm where palbociclib was offered, most patients were offered the standard dose of 125 milligrams daily, three weeks on, one week off. However, many of the patients were coming to the PACE trial from previously receiving a palbociclib based regimen, and sometimes, when someone's been on that for several months or years, there can be a need to dose reduce. And so, we allowed patients to enter PACE at the dose they were receiving on their previous regimen, which may have been 100 milligrams daily or even 75 milligrams daily. The avelumab is an intravenous infusion every two weeks, and so, it matches well with the fulvestrant administration. The PACE trial enrolled patients who had previously received a CDK4/6 inhibitor and endocrine containing regimen for at least six months before progression. Patients had metastatic hormone receptor positive HER2 negative breast cancer and were randomized into one of the three arms. Fulvestrant alone, fulvestrant with palbociclib, and the fulvestrant palbociclib avelumab triplet.
A total of 220 patients were randomized from 13 US cancer centers. What we found for the primary endpoint of progression-free survival was that continuation of a CDK4/6 inhibitor, using palbociclib, with a change to fulvestrant, did not prolong progression-free survival, compared to making a change to fulvestrant alone. The progression-free survival with fulvestrant and palbociclib was 4.6 months, and with fulvestrant alone, it was 4.8 months. Interestingly, the triplet of fulvestrant, palbociclib, and nivolumab almost doubled progression-free survival with a median PFS of 8.1 months, which we thought was a really intriguing signal. What we learned from the PACE trial is that, for our patients who are progressing on a CDK4/6 inhibitor, continuing with palbociclib is not something that we would recommend, based on the data in PACE. However, there are many exciting new agents that are available or emerging in the post-CDK space. And so, we hope to have some very interesting and important options available for patients at that moment in their treatment.
