Dataset Information

Safety and Efficacy of Tucatinib, Letrozole, and Palbociclib in Patients with Previously Treated HR+/HER2+ Breast Cancer.

ABSTRACT:

Purpose

To overcome resistance to antihormonal and HER2-targeted agents mediated by cyclin D1-CDK4/6 complex, we proposed an oral combination of the HER2 inhibitor tucatinib, aromatase inhibitor letrozole, and CDK4/6 inhibitor palbociclib (TLP combination) for treatment of HR+/HER2+ metastatic breast cancer (MBC).

Patients and methods

Phase Ib/II TLP trial (NCT03054363) enrolled patients with HR+/HER2+ MBC treated with ≥2 HER2-targeted agents. The phase Ib primary endpoint was safety of the regimen evaluated by NCI CTCAE version 4.3. The phase II primary endpoint was efficacy by median progression-free survival (mPFS).

Results

Forty-two women ages 22 to 81 years were enrolled. Patients received a median of two lines of therapy in the metastatic setting, 71.4% had visceral disease, 35.7% had CNS disease. The most common treatment-emergent adverse events (AE) of grade ≥3 were neutropenia (64.3%), leukopenia (23.8%), diarrhea (19.0%), and fatigue (14.3%). Tucatinib increased AUC10-19 hours of palbociclib 1.7-fold, requiring palbociclib dose reduction from 125 to 75 mg daily. In 40 response-evaluable patients, mPFS was 8.4 months, with similar mPFS in non-CNS and CNS cohorts (10.0 months vs. 8.2 months; P = 0.9). Overall response rate was 44.5%, median duration of response was 13.9 months, and clinical benefit rate was 70.4%; 60% of patients were on treatment for ≥6 months, 25% for ≥1 year, and 10% for ≥2 years. In the CNS cohort, 26.6% of patients remained on study for ≥1 year.

Conclusions

TLP combination was safe and tolerable. AEs were expected and manageable with supportive therapy and dose reductions. TLP showed excellent efficacy for an all-oral chemotherapy-free regimen warranting further testing. See related commentary by Huppert and Rugo, p. 4993.

SUBMITTER: Shagisultanova E

PROVIDER: S-EPMC10722138 | biostudies-literature | 2023 Dec

REPOSITORIES: biostudies-literature

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Publications

Safety and Efficacy of Tucatinib, Letrozole, and Palbociclib in Patients with Previously Treated HR+/HER2+ Breast Cancer.

Shagisultanova Elena E Gradishar William W Brown-Glaberman Ursa U Chalasani Pavani P Brenner Andrew J AJ Stopeck Alison A Parris Hannah H Gao Dexiang D McSpadden Tessa T Mayordomo Jose J Diamond Jennifer R JR Kabos Peter P Borges Virginia F VF

Clinical cancer research : an official journal of the American Association for Cancer Research 20231201 24

<h4>Purpose</h4>To overcome resistance to antihormonal and HER2-targeted agents mediated by cyclin D1-CDK4/6 complex, we proposed an oral combination of the HER2 inhibitor tucatinib, aromatase inhibitor letrozole, and CDK4/6 inhibitor palbociclib (TLP combination) for treatment of HR+/HER2+ metastatic breast cancer (MBC).<h4>Patients and methods</h4>Phase Ib/II TLP trial (NCT03054363) enrolled patients with HR+/HER2+ MBC treated with ≥2 HER2-targeted agents. The phase Ib primary endpoint was saf ...[more]

PMID: 37363965

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Project description:PurposeThis research designeded to: 1. Analyze the efficacy and safety of Palbociclib treatment in HR-positive and HER2-negative (HR + /HER2-) metastatic breast cancer(MBC) patients. 2. Establish and validate a nomogram model for predicting the progression-free survival (PFS) rates of 6 months, 12 months, and 18 months in HR + /HER2- MBC patients after receiving Palbociclib plus endocrine therapy (ET).Patients and methods1. This research retrospectively analyzed the efficacy and safety of Palbociclib combined with ET in 214 patients with HR + /HER2- MBC. 2. A nomogram was designed and constructed with the retrospective clinical data of 214 patients with HR + /HER2- MBC who received Palbociclib plus ET at Zhejiang Cancer Hospital in China from August 2018 to August 2022. Among these patients, 161 were randomly assigned to the training cohort, while 53 to the validation cohort. The predictive accuracy of the nomogram was assessed through the analysis the area under the receiver operating characteristic(ROC) curve, calibration curve, and decision curve analysis(DCA).Results1. Median PFS was 7.17 months (95% CI: 7.61-10.05 months), with an objective response rate (ORR) of 2.80% and a disease control rate (DCR) of 34.58%. The most prevalent grade 3-4 adverse event was neutropenia (38.79%). 2. Multiple variable analysis of the training set revealed that age < 60 years old, PR < 20%, Ki-67 ≥ 20%, luminal B molecular subtype, primary resistance to ET, receipt of late-stage chemotherapy, and presence of liver metastasis or ≥ 2 visceral metastases were independent prognostic factors associated with poor PFS (P < 0.05). Then, the predictive model underwent development and validation utilizing the aforementioned parameters. On the one hand, the area under the ROC curve (AUC) values of the training set at 6 months, 12 months, and 18 months were 0.771, 0.783, and 0.790, respectively, indicating a strong predictive ability of the developed model. On the other hand, the AUC of the validation set at 6 months, 12 months, and 18 months were 0.720, 0.766, and 0.754, respectively, suggesting the favorable discriminatory ability of the model. The calibration curves also exhibited a good fit with the ideal curves, and the DCA demonstrated the clinical applicability of the model. The nomogram's different scores could distinguish PFS.ConclusionThis retrospective study demonstrates the efficacy of Palbociclib in Chinese breast cancer patients. Moreover, the clinical parameters showed a significant association with the prognosis of HR + /HER2- MBC, and the prognostic models constructed based on these variables also displayed robust predictive power, which could offer more intuitive and convenient references for clinical doctors to formulate follow-up treatment plans.

Project description:Endocrine therapy with CDK4/6 inhibitors is standard for estrogen receptor-positive, HER2-negative metastatic breast cancer (ER+/HER2- MBC), yet clinical resistance develops. Previously, we demonstrated that low doses of palbociclib activate autophagy, reversing initial G1 cell cycle arrest, while high concentrations induce off-target senescence. The autophagy inhibitor hydroxychloroquine (HCQ) induced on-target senescence at lower palbociclib doses. We conducted a phase I trial (NCT03774472 registered in ClinicalTrials.gov on 8/20/2018) of HCQ (400, 600, 800 mg/day) with palbociclib (75 mg/day continuous) and letrozole, using a 3 + 3 design. Primary objectives included safety, tolerability, and determining the recommended phase 2 dose (RP2D) of HCQ. Secondary objectives included tumor response and biomarker analysis. Fourteen ER+/HER2- MBC patients were evaluable [400 mg (n = 4), 600 mg (n = 4), 800 mg (n = 6)]. Grade 3 adverse events (AEs) included hematological (3 at 800 mg), skin rash (2 at 600 mg), and anorexia (1 at 400 mg), with no serious AEs. The best responses were partial (2), stable (11), and progression (1). Tumor reductions ranged from 11% to 30%, with one 55% increase. The two partial responders sustained tumor size reductions of 30% to 55% over an extended treatment period, lasting nearly 300 days. Biomarker analysis in responders demonstrated significant decreases in Ki67, Rb, and nuclear cyclin E levels and increases in autophagy markers p62 and LAMP1, suggesting a correlation between these biomarkers and treatment response. This phase I study demonstrated that HCQ is safe and well-tolerated and the RP2D was established at 800 mg/day with continuous low-dose palbociclib (75 mg/day) and letrozole (2.5 mg/day). These findings suggest that adding HCQ could potentially enhance the efficacy of low-dose palbociclib and standard letrozole therapy, pending verification in larger randomized studies.

Dataset Information

Safety and Efficacy of Tucatinib, Letrozole, and Palbociclib in Patients with Previously Treated HR+/HER2+ Breast Cancer.

Purpose

Patients and methods

Results

Conclusions

Publications

Safety and Efficacy of Tucatinib, Letrozole, and Palbociclib in Patients with Previously Treated HR+/HER2+ Breast Cancer.

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