Hydroxychloroquine Enhances the Efficacy of Palbociclib, Letrozole Therapy in Patients With HR+, HER2– Metastatic Breast Cancer

Hydroxychloroquine (HCQ, Plaquenil; Sanofi) enhances the clinical benefits of low-dose palbociclib (Ibrance; Pfizer) and standard letrozole (Femara; Novartis Pharmaceuticals Corporation) therapy in patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2−) metastatic breast cancer (MBC), according to study results published in npj Breast Cancer.¹

Pharmacist holding prescription bottle of hydroxychloroquine | Image Credit: © Sherry Young - stock.adobe.com

HR+, HER2– MBC accounts for 75% of all breast cancer diagnoses and deaths every year in the United States. Although survival outcomes improved with increased screening and prevention, the 5-year survival rate for patients with HR+, HER2– is only 34%. Endocrine therapy (ET) in combination with CDK4/6 inhibitors has become increasingly common for patients with HR+, HER2– MBC. However, despite advancements, early progression within 8 weeks occurs in approximately 20% of patients. Most patients will not respond to therapy, and almost all develop resistances.^1,2

In a single-center, open-label, non-randomized, standard 3 plus 3 dose-escalation design phase 1 trial (NCT03774472), HCQ enhanced the efficacy of low dose palbociclib, a CDK4/6 inhibitor, and letrozole, as well as demonstrating favorable safety and tolerability in patients with HR+, HER2– MBC. The study included 14 evaluable patients over the age of 18 with confirmed diagnosis of HR+, HER2– MBC and were eligible for treatment with a CDK4/6 inhibitor plus ET with an aromatase inhibitor as standard of care.^1,3

Patients were assigned to receive either 400 (n=4), 600 (n=4), or 800 (n=6) mg per day of HCQ with palbociclib (75 mg per day continuous) and letrozole (2.5 mg per day). The primary end points of the study were safety and tolerability, as well as determining the recommended dose of HCQ for a phase 2 trial. Additional secondary end points included tumor response and biomarker analysis.¹

The safety analysis reported no treatment-related mortalities, and 79% of patients treated with any of the 3 HCQ doses experienced only grade 1 or 2 adverse events (AEs). The most common grade 3 AEs in the 400, 600, and 800 mg daily HCQ doses were anorexia, skin rash, and hematological, respectively. The researchers reported no grade 4 AEs at any dose level in all patients. The treatment was also tolerable, yielding partial (n=2) and stable (n=11) responses. One patient experienced progression. The tumor response was favorable, with reductions ranging from 11% to 30%, with 1 55% increase.¹

The biomarker analysis results suggested a correlation between biomarkers and treatment response. The HCQ combination therapy demonstrated significant decreases in in Ki67, Rb, and nuclear cyclin E levels, as well as increases in autophagy markers p62 and LAMP1.¹

The findings suggest that the addition of HCQ may enhance the efficacy and safety of ET, CDK4/6 inhibitor therapy, potentially improving patient response and mitigating treatment resistance. The study had some limitations; namely, the small sample size. Continued studies are needed, but the initial data support verification of this treatment in larger, randomized studies.

REFERENCES

1. Raghavendra A.S., Kettner N.M., Kwiatkowski D, et al. Phase I trial of hydroxychloroquine to enhance palbociclib and letrozole efficacy in ER+/HER2− breast cancer. npj Breast Cancer. January 26, 2025. doi: 10.1038/s41523-025-00722-1

2. Gerlach A. Study shows real-world outcomes of first-line palbociclib plus fulvestrant in HR+, HER2– metastatic breast cancer. Pharmacy Times. January 18, 2025. Accessed January 27, 2025. https://www.pharmacytimes.com/view/study-shows-real-world-outcomes-of-first-line-palbociclib-plus-fulvestrant-in-hr-her2-metastatic-breast-cancer

3. Hydroxychloroquine, palbociclib, and letrozole before surgery in treating patients with estrogen receptor positive, HER2 negative breast cancer. Updated April 19, 2024. Accessed January 27, 2025. https://clinicaltrials.gov/study/NCT03774472