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Targeting autophagy plus high-dose CDK4/6 inhibitors in advanced HR+HER2- breast cancer: A phase 1b/2 trial
Chang Gong1, Qun Lin1, Tao Qin1
1Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China; Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China.
Background:
The unmet needs of managing patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) breast cancer who progress after cyclin-dependent kinase (CDK)4/6 inhibitor (CDK4/6i) treatment remain unclarified.
Methods:
This was a phase 1b/2, single-arm, open-label study that enrolled 29 patients with HR+/HER2- breast cancer who experienced first-line palbociclib treatment failure. The primary endpoint was the incidence of dose-limiting toxicity (DLT). The secondary endpoints were the objective response rate (ORR) and progression-free survival (PFS). The clinical trial registration number is ClinicalTrials.gov: NCT05953350.
Findings:
The phase 1b study demonstrated no DLT in patients treated with hydroxychloroquine (HCQ; 600 mg, bis in die [bid]) plus increasing doses of palbociclib (100, 150, or 200 mg, quaque die [qd]). The plasma pharmacokinetics of palbociclib were not significantly affected by HCQ. The recommended phase 2 dose (RP2D) was HCQ (600 mg, bid) plus palbociclib (200 mg, qd). The dose-expansion cohort demonstrated that HCQ plus palbociclib (200 mg, qd) treatment was tolerable. Grade 3 treatment-emergent adverse events (TEAEs) with an incidence higher than 15.0% included neutropenia (25.0%), leukopenia (25.0%), fatigue (20.0%), and back pain (15.0%). The ORR of all enrolled patients in our present trial was 41.4% (12/29). In the dose-expansion cohort, with the last enrolled patient having a follow-up duration of 32.3 weeks, the median PFS was not reached. The clinical benefit rate (CBR) at 6 months was 90.0% (95% confidence interval [CI]: 68.3%-98.8%). These findings were supported by preclinical data.
Conclusions:
Combined HCQ with high-dose CDK4/6i palbociclib (200 mg, qd) showed tolerable toxicity and promising efficacy for patients with advanced HR+/HER2- breast cancer after CDK4/6i failure.
Funding:
This work was funded by the National Natural Science Foundation of China.
Insights
Hydroxychloroquine combined with high-dose palbociclib is safe and effective for advanced hormone receptor-positive breast cancer patients who have progressed on CDK4/6 inhibitors. This combination shows promising efficacy and tolerable toxicity in managing this patient population.
Area of Science:
- Oncology
- Pharmacology
- Clinical Trials
Background:
- Unmet needs exist for managing hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) breast cancer progressing after cyclin-dependent kinase (CDK)4/6 inhibitor (CDK4/6i) treatment.
- This study addresses the lack of clarity in treatment strategies for this patient subgroup.
Purpose of the Study:
- To evaluate the safety and efficacy of combining hydroxychloroquine (HCQ) with high-dose palbociclib in patients with advanced HR+/HER2- breast cancer who have previously failed CDK4/6 inhibitor therapy.
- To determine the recommended phase 2 dose (RP2D) for this combination therapy.
Main Methods:
- A phase 1b/2, single-arm, open-label study enrolled 29 patients with HR+/HER2- breast cancer post-first-line palbociclib failure.
- Primary endpoint was dose-limiting toxicity (DLT); secondary endpoints included objective response rate (ORR) and progression-free survival (PFS).
- Patients received hydroxychloroquine (HCQ; 600 mg, bis in die [bid]) plus escalating doses of palbociclib (100, 150, or 200 mg, quaque die [qd]).
Main Results:
- No dose-limiting toxicities (DLTs) were observed in phase 1b. The recommended phase 2 dose (RP2D) was established as HCQ (600 mg, bid) plus palbociclib (200 mg, qd).
- The combination was tolerable, with Grade 3 treatment-emergent adverse events (TEAEs) including neutropenia (25.0%) and leukopenia (25.0%).
- The objective response rate (ORR) was 41.4% (12/29), and the 6-month clinical benefit rate (CBR) was 90.0% (95% CI: 68.3%-98.8%). Median PFS was not reached.
Conclusions:
- Combined hydroxychloroquine with high-dose palbociclib demonstrates tolerable toxicity and promising efficacy in advanced HR+/HER2- breast cancer patients post-CDK4/6 inhibitor failure.
- This combination represents a potential therapeutic option for patients with advanced HR+/HER2- breast cancer who have progressed on prior CDK4/6 inhibitor treatment.
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