Sprycel Shows Promising Efficacy Data in First-Line Metastatic ER+/HER2- Disease

Endocrine therapy is a mainstay of therapy for breast cancer patients with estrogen receptor (ER) and/or progesterone receptor (PR) positive disease, with use in the adjuvant setting for early stage disease as well as in the metastatic setting.  In the first-line metastatic setting, aromatase inhibitors (AI) can offer clinical benefit in post-menopausal ER+/PR+ patients, with progression-free survival (PFS) in clinical trials ranging from eight to 10 months.1 However, patients will eventually become resistant to endocrine therapy such as AIs, and that point, treatment often needs to shift to use of the more toxic chemotherapy options.

In recent years, as researchers have started to better understand the ER’s interaction with other cellular signaling pathways and the role that cross-talk between these pathways and the ER may play in the development of resistance to endocrine therapy, there has been increasing interest in and investigation of the ability of targeted therapies in combination with endocrine therapy to improve outcomes in ER+ patients, potentially through postponing the development of resistance or “re-sensitizing” patients with acquired resistance.

Sprycel® (dasatinib, Bristol-Myers Squibb) is a multi-targeted tyrosine kinase inhibitor that is currently approved for use in chronic myeloid leukemia (CML) and Ph+ acute lymphoblastic leukemia. Sprycel inhibits the Bcr-Abl fusion protein that is present in CML patients. However, it is also known to inhibit c-KIT, PDGFR, Ephrin, and Src kinases.  Because there is evidence that Src interacts with the ER and may potentially play a role in the development of hormonal resistance,2 Sprycel was investigated in ER+ breast cancer patients.

A Phase II trial evaluated the efficacy and safety of first-line Sprycel in combination with the AI letrozole and results were presented at the 2013 San Antonio Breast Cancer Symposium (SABCS) meeting on the morning of Thursday, December 12.3 In this trial, post-menopausal, ER+, HER2- patients with metastatic breast cancer (mBC) who were AI-naïve were randomized to receive either letrozole alone (n=63) or letrozole plus Sprycel (n=57).  Of patients who had received prior therapy in the adjuvant setting, 39% and 48% of patients in the Sprycel plus letrozole and letrozole alone arms, respectively, had received adjuvant chemotherapy; 32% and 37% of patients, respectively, had received adjuvant tamoxifen. A very small minority of patients (2% in Sprycel plus letrozole and 10% in letrozole alone arms) received an AI in the adjuvant setting, but these patients were required to have stopped adjuvant AI therapy at least a year before entry into the study.

The combination of Sprycel plus letrozole showed very promising clinical activity. The median PFS in patients who received Sprycel plus letrozole was 20.1 months, more than double the median PFS of 9.9 months seen in patients who received letrozole alone (see Table 1). This was a non-comparative trial that was not designed for a comparison between treatment arms; however, there was an exploratory PFS hazard ratio of 0.69. In contrast, the Sprycel plus letrozole combination did not appear to offer any major improvement in clinical benefit rate (CBR; objective responses plus stable disease) over letrozole alone (71% vs. 66%). There appeared to be more limited benefit in patients who had received prior letrozole, as patients who crossed over from the letrozole arm to the Sprycel plus letrozole arm upon progression had a clinical benefit rate of 23%.

As would be expected, the addition of Sprycel to letrozole treatment did add some toxicity, and 26% of patients in the Sprycel plus letrozole arm required a Sprycel dose reduction. However, Sprycel was generally well-tolerated and there were no new safety signals compared to the general safety profile that has been observed in CML patients. The most commonly observed adverse events (AEs) were fatigue, rash, nausea, edema, and neutropenia.

The strong efficacy results from this trial could support a move into Phase III development, but BMS’ development plans for Sprycel in this setting are not currently known. If Sprycel does move into Phase III development, it will enter an increasingly competitive corner of the market. Based on the results of the Phase III BOLERO-2 trial,4 the mTOR inhibitor Afinitor® (everolimus, Novartis) was approved in July 2012 in the United States and the European Union for use in post-menopausal ER+/PR+ and HER2- patients who have received prior treatment with an AI (i.e., second-line treatment or later).  The pan-PI3K inhibitor buparlisib (BKM120, Novartis) is also being investigated in two Phase III trials in the second- and third-line settings. The BELLE-2 trial is evaluating Faslodex with or without buparlisib in post-menopausal ER+/HER2- patients who have received prior treatment with an AI, and the BELLE-3 trial is evaluating Faslodex with or without buparlisib in post-menopausal ER+/HER2- patients who have received prior treatment with an AI as well as an mTOR inhibitor (most likely Afinitor).

Both Afinitor and buparlisib are currently positioned for relapsed/refractory metastatic ER+/HER2- patients, and if Sprycel were to enter Phase III development in the first-line metastatic ER+/HER2- setting, it wouldn’t be competing in the same line of therapy as these agents. However, it would be competing directly with palbociclib, the CDK 4/6 inhibitor that has received Breakthrough Therapy status from the U.S. Food and Drug Administration (FDA). Palbociclib is currently being evaluated in combination with letrozole in a Phase III trial in first-line ER+/HER2- metastatic patients.

How does the efficacy data for Sprycel stack up against that for palbociclib? As would be expected considering its Breakthrough Therapy designation, the Phase II data for palbociclib set an extremely high bar for efficacy in this setting, and the initial Phase II results for palbociclib was one of the most-discussed presentation of the 2012 SABCS annual meeting. In this Phase II trial, the addition of palbociclib to letrozole as first-line therapy for post-menopausal ER+/HER2- metastatic patients significantly improved PFS from 7.5 months to 26.1 months, with an impressive hazard ratio of 0.37 (p<0.001).5 In addition, the clinical benefit rate was increased from 44% in the letrozole alone arm to 70% in the palbociclib plus letrozole arm. While the Phase II data presented for Sprycel plus letrozole do not match this high benchmark, the median PFS of 20.1 comes quite close to the remarkable 26.1 month median PFS for palbociclib. While Sprycel would not be likely to outcompete palbociclib on efficacy based on these results alone, it is always possible that the situation could change with results from a Phase III trial, and the promising PFS result for Sprycel certainly provides hope that this strategy for combining hormone therapy with targeted therapies will prove to have a major impact on outcomes for ER+/HER2- patients with metastatic disease.

As hormone therapy generally has a relatively benign safety profile, safety will also be another major factor when physicians are considering whether to add a targeted therapy to hormone therapy in metastatic ER+/HER2- patients.  While Sprycel is clearly well-tolerated enough to be administered to CML patients for relatively long durations, palbociclib was also generally well-tolerated. However, in the Phase II trial, the addition of palbociclib did markedly increase the incidence of Grade 3/4 neutropenia compared to letrozole alone (51% vs. 1%). Therefore, Sprycel could potentially end up with a slight advantage over palbociclib in terms of safety. In this patient population, where physicians attempt to prolong the time on hormone therapy in order to avoid the poor safety profiles of the more toxic chemotherapy regimens, safety will likely play a major role in physicians’ decisions among available agents.

Although the landscape for the treatment of post-menopausal, metastatic ER+/HER2- breast cancer patients is clearly on track to become a crowded market in the future, the increasing number of agents in development offer the hope of significant advances in outcomes for these patients in upcoming years.

By: Stephanie Hawthorne, PhD, Director, Clinical and Scientific Assessment, Kantar Health and Cory Blaiss, PhD, Analyst, Clinical and Scientific Assessment, Kantar Health


  1. Bonneterre, JCO, 2001; Nabholtz, JCO, 2003; Mouridsen, JCO, 2003
  2. Vallabhaneni et al., Breast Cancer Res, 2011; Renoir et al., Biochem Pharmacol, 2013
  3. Paul et al., SABCS 2013, Abstract S3-07
  4. Baselga et al., NEJM, 2012
  5. Finn et al., SABCS 2012, Abstract S1-06
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