Abstract S3-07: Letrozole plus dasatinib improves progression-free survival (PFS) in hormone receptor-positive, HER2-negative postmenopausal metastatic breast cancer (MBC) patients receiving first-line aromatase inhibitor (AI) therapy

Abstract

Introduction Dasatinib inhibits the protein tyrosine kinase, Src, which can support the development of bone metastases in patients with ER+ breast cancer. The primary objective of this study is to determine if letrozole plus dasatinib increases the clinical benefit rate (CBR) (CR+PR+SD ≥6mo) in first-line MBC patients compared with letrozole alone. Secondary objectives include overall response; progression-free survival; time to treatment failure (TTF); and toxicity. Methods This is a Phase II randomized, noncomparative study of postmenopausal women with locally recurrent or metastatic, measurable or nonmeasurable BC, ER+, HER2-. Patients are allowed to have had prior non-AI endocrine therapy for MBC; prior adjuvant AI therapy if completed at least 1 year prior to study entry; and up to 1 prior chemotherapy regimen for MBC. Patients are stratified by ≤2 yrs vs >2 years disease-free interval (DFI) from initial breast cancer diagnosis (date of definitive surgery) to first locally recurrent or MBC and by prior tamoxifen for MBC. Patients were randomly assigned to Arm 1 (letrozole 2.5mg PO QD + dasatinib 100mg PO QD) or Arm 2 (single-agent letrozole 2.5mg PO QD) on 28-day cycles. Arm 1 patients who experienced intolerable toxicity related to dasatinib discontinued dasatinib and continued single-agent letrozole. Arm 2 patients who developed progressive disease (PD) on letrozole had the option to receive dasatinib plus letrozole. The primary endpoint of CBR was assessed when patients developed progressive disease on their randomly assigned therapies before any crossover therapy. Results Patients with prior adjuvant AI/tamoxifen were 39%/32% Arm 1 and 44%/37% Arm 2; prior metastatic endocrine therapy Arm 1/Arm 2 was 9%/5%; and prior metastatic chemotherapy Arm 1/Arm 2 was 11%/6%. Median DFI Arm 1/Arm 2 was 27.5/21.2 months; patients presenting with de novo MBC Arm 1/Arm 2 was 42%/32%, respectively; measureable disease by RECIST Arm 1/Arm 2 was 58%/75%. The ITT population comprised 120 patients; 57 in Arm 1 and 63 in Arm 2. Clinical benefit rate (CBR) in 116 evaluable patients in Arm 1(55)/Arm 2(61), respectively, was 64% (95% CI, 50-76) and 61% (95% CI, 47-73). Median PFS time was 22 months with letrozole/dasatinib and 11 months with letrozole alone, p = .05. PFS at 6 and 12 months for Arms 1 and 2, respectively, was 78%/66% and 66%/43%. The most common toxicities observed with dasatinib on Arm 1 were fatigue (38%), nausea (38%), anemia (25%), rash (23%), pleural effusion (16%), and edema (13%). 27% of patients required dasatinib dose reduction. Conclusion The addition of dasatinib to letrozole in MBC patients receiving their first AI therapy for metastatic disease did not improve CBR compared with letrozole alone. Median PFS improved from 11 to 22 months (p = .05) with the addition of dasatinib, suggesting dasatinib improved duration of disease control combined with letrozole. Most patients tolerated full dose dasatinib until PD. 25% of patients remain on study therapy; final results will be available at SABCS 2013. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr S3-07.

Clinical Trials Combining Aromatase Inhibitors with Other Targeted Treatments

“…While the PFS difference was not significant in overall study population, a higher CBR in the dasatinib arm and higher PFS in patients with symptomatic bone metastasis (HR = 0.68) suggested that dasatinib may have efficacy in a subset of patients [65]. In contrast, a randomised phase II first-line study (NCT00696072) suggested in an exploratory analysis that the addition of dasatinib to letrozole may improve PFS (median 20.1 vs. 9.9 months, HR 0.69) [66]. It remains to be seen if Src is a viable target to enhance endocrine responsiveness.…”

A new era of improving progression-free survival with dual blockade in postmenopausal HR+, HER2− advanced breast cancer

“…Among the ten phase 2 studies included in this report, the 6 evaluating epidermal growth factor receptor/ERB family inhibitors (gefitinib [47,48], AZD8931 [49], and MM-121 [50]) or various antibodies (ganitumab [51] and AS14012 [52]) demonstrated disappointing efficacy (Table 3) [47][48][49][50][51][52][53][54][55][56][57]. However, four phase 2 randomized studies of endocrine therapy in combination with a targeted agent generated promising clinical data; these studies involved the cyclin-dependent kinase (CDK) 4/6 inhibitor PD0332991 (palbociclib; TRIO-18/PALOMA-1) [54,55], the SRC tyrosine kinase inhibitor dasatinib (NCT00696072) [57], the mTOR inhibitor everolimus (TAMRAD) [53], and the histone deacetylase (HDAC) inhibitor entinostat (ENCORE 301) [56].…”

“…However, four phase 2 randomized studies of endocrine therapy in combination with a targeted agent generated promising clinical data; these studies involved the cyclin-dependent kinase (CDK) 4/6 inhibitor PD0332991 (palbociclib; TRIO-18/PALOMA-1) [54,55], the SRC tyrosine kinase inhibitor dasatinib (NCT00696072) [57], the mTOR inhibitor everolimus (TAMRAD) [53], and the histone deacetylase (HDAC) inhibitor entinostat (ENCORE 301) [56].…”

“…However, a PFS benefit was reported among patients with symptomatic bone metastasis who received dasatinib plus exemestane (HR 0.68; 1-sided p = 0.094) [62]. A recent study compared dasatinib plus letrozole versus letrozole alone as first-or second-line therapy in postmenopausal patients with HR + advanced breast cancer (N = 120; Table 3) [57]. Fifty-five percent of patients had never received any prior endocrine therapy and <10% had received endocrine therapy in the metastatic setting.…”

Bone-Targeted Therapy in Metastatic Breast Cancer - All Well-Established Knowledge?

“…dasatinib, saracatinib, KX2-391, and bosutinib) showed promising preclinical and early-phase clinical data. A recently presented phase II trial of da-satinib in combination with letrozol in metastatic breast cancer not only showed a reduced percentage of patients with a T-score < -1.5 but also a significantly longer progression-free survival (PFS) in the combination arm compared with letrozol alone [60]. A phase II trial investigating bosutinib, which inhibits the Src/Abl tyrosine kinase as well as many other kinases, showed promising antitumor activity as single agent as well; however, no consistent changes in the levels of bone turnover markers were seen [61].…”