Debu Tripathy, MD:For many years, the standard treatment for patients with hormone-receptor positive cancers has been the use of endocrine therapy. Now, in the last few decades, we’ve witnessed a shift from starting with chemotherapy for metastatic cases to starting with endocrine therapy, which, of course, has fewer toxicities. In fact, recent studies have shown that starting with chemotherapy or hormonal therapy gives you equivalent outcomesmaybe even slightly better outcomes with hormonal therapy—and certainly better quality of life.
When aromatase inhibitors first came into clinical use in the 1990s, they were compared with tamoxifen and found to be roughly equivalent or slightly better in some studies, but they had fewer side effects. For example, the clotting risk with tamoxifen wasn’t seen, nor was the risk of endometrial hyperplasia. This became the standard for most patients, certainly for postmenopausal patients. For premenopausal patients, blockade of ovarian function was also important. That was actually described nearly 20 years ago, and that has become a standard: ovarian blockade with tamoxifen, and since the emergence of aromatase inhibitors, of course, using aromatase inhibitors.
In the last 4 years or so, we have now had the development of biological agentsin fact, everolimus was the first approved 6 years ago, in 2012, as second-line therapy—as we’ve started to understand mechanisms of resistance, particularly the activation of growth factor pathways, which are blocked by mTOR inhibitors. More recently, the cyclin-dependent kinase inhibitors came into the forefront, with the first approval now 3 years ago. The integration of these new therapies clearly has represented a benefit but has left a lot of questions about…the role of endocrine therapy alone and what is the best sequence of therapies to use.
Initially, the development of cyclin-dependent kinase inhibitors was greatly improved when more selective inhibitors were brought into the clinic that had fewer toxicities, particularly the CDK4/6 inhibitors. The first of these to be tested was palbociclib, and the preclinical data suggested that activity was seen more in hormone receptor­positive cells, that these cells were more sensitive to these drugs, and that they did require endocrine therapy to be partnered with them.
The first of these trials, the PALOMA-1 study, was a randomized phase II study that also attempted to look at which biomarkers might be important. It was known that there are some aberrations in hormone receptorpositive cancer cells in the cell cycle machineryfor example, amplification of cyclin D1 or loss of the retinoblastoma protein. It turns out that in these early studies, there didn’t seem to be an impact of these biomarkers. The larger phase III study, PALOMA-2, was then activated comparing letrozole alone with letrozole plus palbociclib. This was the first of many studies that have shown very similar results, and that is a doubling of progression-free survival from approximately 10 to 20 months—20 to 24 months, in that range—with pretty good toxicities; mostly neutropenia that is subclinical and some degree of fatigue.
And then, of course, the following CDK4/6 inhibitors that were also in preclinical development ultimately generated results from their pivotal studies: ribociclib being the next one, with a very similar design of letrozole plus or minus ribociclib showing equivalent results; and then abemaciclib, initially in second line with fulvestrant and ultimately as first-line therapy. Now we really have a large, robust body of data with all of these inhibitors.
Transcript edited for clarity.