Dataset Information

Phase I/II trial of ruxolitinib in combination with trastuzumab in metastatic HER2 positive breast cancer.

ABSTRACT:

Purpose

Preclinical data demonstrate STAT3 as an important regulator in HER2+ tumors, and disruption of the IL6-JAK2-STAT-S100A8/S100A9 signaling cascade reduces HER2+ cell viability. Ruxolitinib is an FDA approved inhibitor of JAK1 and JAK2. We performed a phase I/II trial investigating the safety and efficacy of the combination of trastuzumab and ruxolitinib in patients with trastuzumab-resistant metastatic HER2+ breast cancer.

Methods

Patients with metastatic HER2+ breast cancer progressing on at least 2 lines of HER2-directed therapy were eligible. The phase I portion determined the tolerable dose of ruxolitinib in combination with trastuzumab. The primary objective of the phase II was to assess the progression free survival (PFS) of the combination of ruxolitinib plus trastuzumab compared to historical control.

Results

Twenty-eight patients were enrolled, with a median number of prior therapies of 4.5. Ruxolitinib 25 mg twice daily was the recommended phase II dose with no dose limiting toxicities (DLTs). Of 26 evaluable patients in phase II, the median PFS was 8.3 weeks (95% CI 7.1, 13.9). Among the 14 patients with measurable disease, 1 patient had a partial response and 4 patients had stable disease. Most of the adverse events were hematologic.

Conclusion

While well tolerated with a strong preclinical rationale, the combination of ruxolitinib and trastuzumab did not lead to an improvement in PFS compared to historical control in patients with trastuzumab-resistant metastatic HER2+ breast cancer.

SUBMITTER: Kearney M

PROVIDER: S-EPMC8487317 | biostudies-literature | 2021 Aug

REPOSITORIES: biostudies-literature

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Publications

Phase I/II trial of ruxolitinib in combination with trastuzumab in metastatic HER2 positive breast cancer.

Kearney Matthew M Franks Lauren L Lee Shing S Tiersten Amy A Makower Della F DF Cigler Tessa T Mundi Prabhjot P Chi Dow-Chung DC Goel Anupama A Klein Pam P Andreopoulou Eleni E Sparano Joseph J Trivedi Meghna M Accordino Melissa M Califano Andrea A Hershman Dawn L DL Silva Jose J Kalinsky Kevin K

Breast cancer research and treatment 20210624 1

<h4>Purpose</h4>Preclinical data demonstrate STAT3 as an important regulator in HER2+ tumors, and disruption of the IL6-JAK2-STAT-S100A8/S100A9 signaling cascade reduces HER2+ cell viability. Ruxolitinib is an FDA approved inhibitor of JAK1 and JAK2. We performed a phase I/II trial investigating the safety and efficacy of the combination of trastuzumab and ruxolitinib in patients with trastuzumab-resistant metastatic HER2+ breast cancer.<h4>Methods</h4>Patients with metastatic HER2+ breast cance ...[more]

PMID: 34169393

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Project description:BACKGROUND:Immune checkpoint inhibitors are active in a broad range of cancers, including programmed death ligand 1 (PD-L1)-positive, triple-negative, metastatic breast cancer (MBC). Antibody-dependent cell-mediated cytotoxicity is a mechanism of action of trastuzumab. We performed a phase Ib trial of durvalumab and trastuzumab in HER2-positive MBC previously treated with chemotherapy and anti-HER2 antibodies to assess safety, efficacy, and correlative endpoints. PATIENTS AND METHODS:Patients with HER2-positive MBC were enrolled on a standard 3 + 3 design. Dose level 1 was durvalumab (1,125 mg intravenously day 1) and trastuzumab (8 mg/kg intravenously loading, then 6 mg/kg day 1) on a q3 weekly cycle. An expansion cohort at the recommended phase II dose (RP2D) performed tumor biopsies at baseline and after cycle 1. The primary endpoint was to establish the RP2D. RESULTS:Fifteen patients were accrued from April to December 2016, of which 14 were evaluable for response. Median age was 54 years (range 40-86); the majority had visceral disease (87%) and at least three prior (adjuvant and/or metastatic) lines of chemotherapy (73%), including trastuzumab (93%), pertuzumab (60%), and trastuzumab-emtansine (93%) for MBC. No dose-limiting toxicities were observed at dose level 1 (n = 6) or dose expansion (n = 9) during cycle 1. One patient developed a grade ?3 immune-related adverse event (grade 4 diabetes mellitus). No responses by RECIST were seen, with 4 of 14 patients (29%) demonstrating stable disease as best response at week 6 (median duration, 2.7 months). All patients had <1% PD-L1 expression on either archival tissue (7/15) or prestudy biopsy (8/15). In the dose expansion cohort, evaluable pretreatment and on-treatment tumor biopsies (n = 5) showed minimal CD8 cell infiltration. CONCLUSION:The RP2D of durvalumab and trastuzumab is standard full doses of both agents. No significant clinical activity was observed in patients with heavily pretreated HER2-positive PD-L1-negative MBC. IMPLICATIONS FOR PRACTICE:This phase Ib trial with associated correlative endpoints provides insights into the lack of activity of the combination of durvalumab and trastuzumab in heavily pretreated HER2-positive metastatic breast cancer (MBC). No significant clinical activity was observed in patients with heavily pretreated HER2-positive programmed death ligand 1 (PD-L1)-negative MBC with evidence of cytotoxic T-cell exhaustion. Furthermore, all patients had no expression of PD-L1 in the tumor cells. These data support the importance of PD-L1 as an important selection biomarker and the need to assess the tumor microenvironment for immune regulatory cells. Further work is needed to understand how to activate the "cold" tumors to be able to combine current immune-oncology agents.

Project description:BackgroundPreclinical and clinical data support potential synergy between anti-HER2 therapy plus immune checkpoint blockade. The safety and tolerability of trastuzumab emtansine (T-DM1) combined with pembrolizumab is unknown.MethodsThis was a single-arm phase Ib trial (registration date January 26, 2017) of T-DM1 plus pembrolizumab in metastatic, human epidermal growth factor receptor 2 (HER2)-positive breast cancer. Eligible patients had HER2-positive, metastatic breast cancer previously treated with taxane, trastuzumab, and pertuzumab, and were T-DM1-naïve. A dose de-escalation design was used, with a dose-finding cohort followed by an expansion cohort at the recommended phase 2 dose (RP2D), with mandatory baseline biopsies. The primary endpoint was safety and tolerability. Secondary endpoints included objective response rate (ORR) and progression-free survival (PFS). Immune biomarkers were assessed using histology, protein/RNA expression, and whole exome sequencing. Associations between immune biomarkers and treatment response, and biomarker changes before and during treatment, were explored.Results20 patients received protocol therapy. There were no dose-limiting toxicities. The RP2D was 3.6 mg/kg T-DM1 every 21 days plus 200 mg pembrolizumab every 21 days. 85% of patients experienced treatment-related adverse events (AEs) ≥grade 2, 20% of patients experienced grade 3 AEs, and no patients experienced grade >4 AEs. Four patients (20%) experienced pneumonitis (three grade 2 events; one grade 3 event). ORR was 20% (95% CI 5.7% to 43.7%), and median PFS was 9.6 months (95% CI 2.8 to 16.0 months). Programmed cell death ligand-1 and tumor infiltrating lymphocytes did not correlate with response in this small cohort.ConclusionsT-DM1 plus pembrolizumab was a safe and tolerable regimen. Ongoing trials will define if there is a role for checkpoint inhibition in the management of HER2-positive metastatic breast cancer.Trial registration numberNCT03032107.

Project description:Importance:Treatment options for patients with disease progression after treatment with trastuzumab, pertuzumab, and ado-trastuzumab emtansine (T-DM1) are limited. Tucatinib is an oral, potent, human epidermal growth factor receptor 2 (HER2)-specific tyrosine kinase inhibitor (TKI) being developed as a novel treatment for ERBB2/HER2-positive breast cancer. Objective:To determine the maximum tolerated dosage of tucatinib in combination with T-DM1 in the treatment of patients with ERBB2/HER2-positive metastatic breast cancer with and without brain metastases. Design, Setting, and Participants:In this phase 1b open-label, multicenter, clinical trial, 57 participants enrolled between January 22, 2014, and June 22, 2015, were 18 years of age or older with ERBB2/HER2-positive metastatic breast cancer previously treated with trastuzumab and a taxane. Data were analyzed between January and March 2018. Interventions:Tucatinib 300 mg or 350 mg administered orally twice per day for 21 days and T-DM1 3.6 mg/kg administered intravenously once every 21 days. Main Outcomes and Measures:Safety assessments, pharmacokinetics, and response were assessed using RECIST 1.1 every 2 cycles for 6 cycles, followed by every 3 cycles. Results:Fifty-seven T-DM1-naive patients (median [IQR] 51 [44.0-63.0] years of age) who had undergone a median of 2 earlier HER2 therapies (range, 1-3) were treated. The tucatinib maximum tolerated dosage was determined to be 300 mg administered twice per day with dose-limiting toxic reactions seen at 350 mg twice per day. Pharmacokinetic analysis showed that there was no drug-drug interaction with T-DM1. Adverse events seen among the 50 patients treated at the maximum tolerated dosage regardless of causality included nausea (36 patients; 72%), diarrhea (30 patients; 60%), fatigue (28 patients; 56%), epistaxis (22 patients; 44%), headache (22 patients; 44%), vomiting (21 patients; 42%), constipation (21 patients; 42%), and decreased appetite (20 patients; 40%); the majority of adverse events were grade 1 or 2. Tucatinib-related toxic reactions that were grade 3 and above included thrombocytopenia (7 patients; 14%) and hepatic transaminitis (6 patients; 12%). Conclusions and Relevance:In this study, tucatinib in combination with T-DM1 appeared to have acceptable toxicity and to show preliminary antitumor activity among heavily pretreated patients with ERBB2/HER2-positive metastatic breast cancer with and without brain metastases. Trial Registration:ClinicalTrials.gov Identifier: NCT01983501.

Project description:BackgroundIn patients with metastatic breast cancer that is positive for human epidermal growth factor receptor 2 (HER2), progression-free survival was significantly improved after first-line therapy with pertuzumab, trastuzumab, and docetaxel, as compared with placebo, trastuzumab, and docetaxel. Overall survival was significantly improved with pertuzumab in an interim analysis without the median being reached. We report final prespecified overall survival results with a median follow-up of 50 months.MethodsWe randomly assigned patients with metastatic breast cancer who had not received previous chemotherapy or anti-HER2 therapy for their metastatic disease to receive the pertuzumab combination or the placebo combination. The secondary end points of overall survival, investigator-assessed progression-free survival, independently assessed duration of response, and safety are reported. Sensitivity analyses were adjusted for patients who crossed over from placebo to pertuzumab after the interim analysis.ResultsThe median overall survival was 56.5 months (95% confidence interval [CI], 49.3 to not reached) in the group receiving the pertuzumab combination, as compared with 40.8 months (95% CI, 35.8 to 48.3) in the group receiving the placebo combination (hazard ratio favoring the pertuzumab group, 0.68; 95% CI, 0.56 to 0.84; P<0.001), a difference of 15.7 months. This analysis was not adjusted for crossover to the pertuzumab group and is therefore conservative. Results of sensitivity analyses after adjustment for crossover were consistent. Median progression-free survival as assessed by investigators improved by 6.3 months in the pertuzumab group (hazard ratio, 0.68; 95% CI, 0.58 to 0.80). Pertuzumab extended the median duration of response by 7.7 months, as independently assessed. Most adverse events occurred during the administration of docetaxel in the two groups, with long-term cardiac safety maintained.ConclusionsIn patients with HER2-positive metastatic breast cancer, the addition of pertuzumab to trastuzumab and docetaxel, as compared with the addition of placebo, significantly improved the median overall survival to 56.5 months and extended the results of previous analyses showing the efficacy of this drug combination. (Funded by F. Hoffmann-La Roche and Genentech; CLEOPATRA ClinicalTrials.gov number, NCT00567190.).

Dataset Information

Phase I/II trial of ruxolitinib in combination with trastuzumab in metastatic HER2 positive breast cancer.

Purpose

Methods

Results

Conclusion

Publications

Phase I/II trial of ruxolitinib in combination with trastuzumab in metastatic HER2 positive breast cancer.

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