PACE: A Randomized Phase II Study of Fulvestrant, Palbociclib, and Avelumab After Progression on Cyclin-Dependent Kinase 4/6 Inhibitor and Aromatase Inhibitor for Hormone Receptor–Positive/Human Epidermal Growth Factor Receptor–Negative Metastatic Breast Cancer

Author(s): Erica L. Mayer, MD, MPH^1,2, Yue Ren, MS³, Nikhil Wagle, MD^1,2, Reshma Mahtani, DO⁴, Cynthia Ma, MD, PhD⁵, Angela DeMichele, MD, MSCE⁶, Massimo Cristofanilli, MD⁷, Jane Meisel, MD⁸, Kathy D. Miller, MD⁹, Yara Abdou, MD¹⁰, Elizabeth C. Riley, MD¹¹, Rubina Qamar, MD¹², Priyanka Sharma, MD¹³, Sonya Reid, MD, MPH¹⁴, Natalie Sinclair, MD¹, Meredith Faggen, MD¹, Caroline C. Block, MD^1,2, Naomi Ko, MD¹⁵, Ann H. Partridge, MD, MPH^1,2, Wendy Y. Chen, MD, MPH^1,2, Michelle DeMeo, BS¹, Victoria Attaya, BA¹, Amanda Okpoebo, MS¹, Jillian Alberti, MS¹, Yuan Liu, PhD¹⁶, Eric Gauthier, PhD, PharmD¹⁶, Harold J. Burstein, MD, PhD^1,2, Meredith M. Regan, ScD^2,3, Sara M. Tolaney, MD, MPH^1,2

Source: https://doi.org/10.1200/JCO.23.01940

Dr. Anjan Patel's Thoughts

Findings from the PACE study show that the addition of Palbociclib to Fulvestrant was not better than Fulvestrant alone, and the addition of Avelumab to Fulvestrant improved and nearly doubled the PFS. This is compelling and should be studied further for our patients with HR+ HER2- MBC.

PURPOSE

Cyclin-dependent kinase (CDK) 4/6 inhibitors (CDK4/6is) are an important component of treatment for hormone receptor–positive/human epidermal growth factor receptor 2–negative (HER2–) metastatic breast cancer (MBC), but it is not known if patients might derive benefit from continuation of CDK4/6i with endocrine therapy beyond initial tumor progression or if the addition of checkpoint inhibitor therapy has value in this setting.

METHODS

The randomized multicenter phase II PACE trial enrolled patients with hormone receptor–positive/HER2– MBC whose disease had progressed on previous CDK4/6i and aromatase inhibitor (AI) therapy. Patients were randomly assigned 1:2:1 to receive fulvestrant (F), fulvestrant plus palbociclib (F + P), or fulvestrant plus palbociclib and avelumab (F + P + A). The primary end point was investigator-assessed progression-free survival (PFS) in patients treated with F versus F + P.

RESULTS

Overall, 220 patients were randomly assigned between September 2017 and February 2022. The median age was 57 years (range, 25-83 years). Most patients were postmenopausal (80.9%), and 40% were originally diagnosed with de novo MBC. Palbociclib was the most common previous CDK4/6i (90.9%). The median PFS was 4.8 months on F and 4.6 months on F + P (hazard ratio [HR], 1.11 [90% CI, 0.79 to 1.55]; P = .62). The median PFS on F + P + A was 8.1 months (HR v F, 0.75 [90% CI, 0.50 to 1.12]; P = .23). The difference in PFS with F + P and F + P + A versus F was greater among patients with baseline ESR1 and PIK3CA alterations.

CONCLUSION

The addition of palbociclib to fulvestrant did not improve PFS versus fulvestrant alone among patients with hormone receptor–positive/HER2– MBC whose disease had progressed on a previous CDK4/6i plus AI. The increased PFS seen with the addition of avelumab warrants further investigation in this patient population.

Author Affiliations

¹Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, ²Harvard Medical School, Boston, MA, ³Department of Data Science, Dana-Farber Cancer Institute, Boston, MA, ⁴Department of Medical Oncology, Miami Cancer Institute, Miami, FL, ⁵Division of Oncology, Department of Medicine, Washington University School of Medicine, St Louis, MO, ⁶Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, ⁷Department of Medical Oncology, Weill Cornell Medicine, New York, NY, ⁸Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, ⁹Hematology/Oncology Division, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, ¹⁰Department of Medicine, University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill, NC, ¹¹Department of Medicine, Brown Cancer Center, University of Louisville Health, Louisville, KY, ¹²Aurora Cancer Care, Milwaukee, WI, ¹³Department of Medical Oncology, University of Kansas Medical Center, Westwood, KS, ¹⁴Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, ¹⁵Department of Medical Oncology, Boston Medical Center, Boston, MA, ¹⁶Pfizer, La Jolla, CA

Overall Survival with Inavolisib in PIK3CA-Mutated Advanced Breast Cancer

The INAVO120 trial assessed inavolisib + palbociclib–fulvestrant vs placebo plus palbociclib–fulvestrant in PIK3CA-mutated, HR-positive, HER2-negative advanced breast cancer, showing significant improvements in progression-free survival (PFS) (15.0 vs 7.3 months) and overall survival (OS) (34.0 vs 27.0 months). The triplet regimen achieved a higher overall response rate (ORR) (62.7% vs 28.0%), establishing it as a potential new standard for this endocrine-resistant population. Notably, side effects like hyperglycemia, stomatitis, diarrhea, and ocular effects were more frequent with inavolisib.

Chemotherapy-free neoadjuvant pembrolizumab combined with trastuzumab and pertuzumab in HER2-enriched early breast cancer (WSG-KEYRICHED-1): a single-arm, phase 2 trial

The WSG-KEYRICHED-1 phase II trial evaluated a chemotherapy-free neoadjuvant regimen of pembrolizumab plus trastuzumab and pertuzumab in HER2-enriched early breast cancer, achieving a pathological complete response (pCR) rate of 46.5% (95% CI 31.2–62.6%). No survival data (e.g., EFS or OS) were reported, but the regimen showed an acceptable safety profile with no new cardiac toxicity signals. The chemo-free approach suggests promising potential for de-escalation in this subtype, but we’ll need randomized trials to confirm its efficacy and safety.

Metronomic Capecitabine Plus Aromatase Inhibitor as Initial Therapy in Patients With Hormone Receptor–Positive, Human Epidermal Growth Factor Receptor 2–Negative Metastatic Breast Cancer: The Phase III MECCA Trial

Metronomic dose: low dose cytotoxic therapy at high frequency was studied in combination with an AI (cape at 500mg TID) and showed superiority over AI single agent, this may be an option for patients not tolerating CKD4/6 inhibitors.

Adjuvant Atezolizumab for Early Triple-Negative Breast Cancer

In summary: It did not work in those patients with stages II-III.

Abemaciclib Plus Fulvestrant in Advanced Breast Cancer After Progression on CDK4/6 Inhibition: Results From the Phase III postMONARCH Trial

Yet another combination to consider after CDK4/6i + ET in HR+ MBC!