PACE Trial: Palbociclib, Fulvestrant, and Avelumab in Endocrine Pre-treated Metastatic Breast Cancer Erica Mayer MD

PACE Trial: Palbociclib, Fulvestrant, and Avelumab in Endocrine Pre-treated Metastatic Breast Cancer Erica Mayer MD

By Erica Mayer, MD

So a very important standard of care for our patients with metastatic hormone receptor positive HER2-negative breast cancer is using a CDK4/6 inhibitor in combination with endocrine therapy. These are wonderful medicines and they provide great benefit for patients, however, eventually the cancer progresses and a big question has been, when is it time to change therapy? Do you change the, just the endocrine therapy and continue the CDK4/6 inhibitor, or is it time to stop the CDK4/6 inhibitor? So the PACE trial was designed to try to answer that question about continuation of CDK4/6 inhibition beyond progression. Also, there’s been some really interesting preclinical data looking the combination of a CDK4/6 inhibitor and a checkpoint inhibitor, so bringing in immunotherapy. So the PACE trial was also designed to look at a triplet combination.

What is the standard of care in this disease state and why choose to pursue the PACE trial?   

So typically for patients who have progressed on a CDK4/6 inhibitor, an endocrine containing regimen for many years, a standard choice to go to next, assuming the patient had been on aromatase inhibitor would be fulvestrant monotherapy. Fulvestrant is one of our more classic SERDs. However, we do know that increasingly that there, there’s not a lot of activity from going to Fulvestrant, and we want something that’s more active. So the PACE trial was designed to see if we could improve on Fulvestrant monotherapy.

Can you please tell us about the PACE trial design and why it was set up this way?  

So the PACE trial is an investigator initiated trial that has been open at 13 cancer centers in the United States, and we designed the trial to enroll patients with metastatic hormone receptor positive, HER2-negative breast cancer, who had been on their prior endocrine and CDK4/6 inhibitor regimen for at least 6 months. So we wanted people who had some sensitivity to endocrine therapy. Eligible patients were randomized to one of 3 arms. The control arm was fulvestrant alone, fulvestrant monotherapy, which when we started the trial, was the standard of care. The more experimental arm was. Fulvestrant with continuation of CDK4/6 inhibitor using the drug Palbociclib. And the third arm of this study, which is an even more experimental arm, was looking at this triplet and combining Fulvestrant, Palbociclib and a checkpoint inhibitor Avelumab, which is a PD-L1 inhibitor.

Can you give us significant data from the PACE trial?  

So the PACE trial enrolled 220 patients randomized to the 3 arms. We finished enrollment in 2022, and we are presenting data at San Antonio Breast Cancer Symposium (SABCS) with a median follow up of about 24 months for the primary analysis, which is comparing the Fulvestrant alone arm to the Fulvestrant with continuation of CDK4/6 inhibitor using Palbociclib, we found that continuation with Palbociclib did not improve progression-free survival compared to Fulvestrant alone. The combination arm of Fulvestrant and Palbociclib had a median progression-free survival of 4.6 months, and in the Fulvestrant alone arm it was 4.8 months, so no difference there. Now the third arm, which was the triplet of Palbociclib, Fulvestrant and Avelumab interestingly had a progression-free survival that was nearly doubled at 8.1 months, which we found very provocative. That’s a secondary analysis and it’s somewhat hypothesis generating, but it’s something that we want to explore further.

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What were the primary end points of the PACE trial and where they met?  

So the primary endpoint of the PACE trial was to compare the Fulvestrant and palbociclib arm to the Fulvestrant alone arm with an endpoint of progression-free survival. Secondary endpoints included comparing the triplet arm of Fulvestrant, Palbociclib, and Avelumab to Fulvestrant alone. Also looking at response safety, and we looked at predefined molecular endpoints. It’s been an outstanding question for years, when your patient progresses on a CDK4/6 inhibitor, what do you do next? Do you continue it? Do you change to another CDK4/6 inhibitor, or do you do something else? Earlier this year, we saw data from the MAINTAIN study, which is another randomized phase 2 study in which patients who have progressed on CDK4/6 inhibitor. Were randomized to go to Ribociclib. Most of the patients on MAINTAIN and most of the patients on PACE had been on Palbociclib as been, has been the standard of care in this country for several years. So MAINTAIN is a Palbociclib to Ribociclib SWITCH, whereas PACE is a palbociclib to palbociclib continuation. The SWITCH study, the MAINTAIN study did suggest there might be some benefit in switching to a different CDK4/6 inhibitor, but we’re still waiting for data from other studies that are pending, including the PALMIRA study, which is looking at Palbociclib, and there’s the phase 3 post MONARCH study, which is randomizing patients to Abemaciclib or placebo, I hope with more data that’s gonna give us more answers about whether there’s a role to go from one CDK4/6 inhibitor to another. What we learned from the PACE study is that if a patient progresses on a Palbociclib containing regimen, continuing Palbociclib beyond progression, unfortunately is not going to be helpful. But there’s so many new strategies that we have available in the post CDK space, many of which are being discussed right now at San Antonio Breast Cancer Symposium (SABCS). Based on MAINTAIN, we could go to Ribociclib, we also have the option, the PI3 kinase inhibitor Alpelisib the mTOR inhibitor Everolimus, and we saw some exciting data at San Antonio Breast Cancer Symposium (SABCS) about oral SERDs as well as oral AKT inhibitors. We also have PARP inhibitors for patients who have a BRCA 1/2 mutation. So we really do have a wealth of options for patients, and I think the future will be trying to interrogate the cancer for any molecular markers that will help us make the right decision.

7 Key Takeaways from the PACE Clinical Trial in Breast Cancer

1. The PACE trial investigates the use of fulvestrant, palbociclib, and avelumab in patients with ER+/HER2- metastatic breast cancer who have already been treated with CDK4/6 inhibitors and endocrine therapy.

2. The trial enrolled 106 patients across 28 sites in the United States between 2017 and 2019.

3. The primary endpoint of the PACE trial is overall response rate (ORR), which measures the percentage of patients who have a partial or complete response to the treatment.

4. The results of the PACE trial showed that the combination of fulvestrant, palbociclib, and avelumab had an ORR of 45.3%.

5. The median progression-free survival (PFS) was 7.3 months, and the median duration of response (DOR) was 10.7 months.

6. The PACE trial also evaluated the safety of the combination therapy, with the most common adverse events being neutropenia, fatigue, and nausea.

7. A subanalysis of the PACE trial found that patients with lower baseline levels of tumor-infiltrating lymphocytes (TILs) had a higher ORR and longer PFS.

Erica Mayer, MD, MPH – About The Author, Credentials, and Affiliations

Dr. Mayer received her M.D. from Harvard University in the year 2000. She then finished her general medicine residency at Brigham and Women’s Hospital and her medical oncology fellowship at the Dana-Farber Cancer Institute. A graduate of the Harvard School of Public Health, she received her Master of Public Health degree in 2005.

She began working as a medical oncologist and clinical investigator in the Breast Oncology Center at Dana-Farber and Brigham and Women’s Hospital in 2006. Her research is mostly about finding new ways to treat breast cancer at the Dana-Farber Cancer Institute.