VIDEO: Targeted therapies in breast cancer

Editor’s note: This is a previously posted video, and the below is an automatically generated transcript to be used for informational purposes. Please notify editor@healio.com if there are concerns regarding accuracy of the transcription.

Targeted therapies are being increasingly used for all of the subsets of breast cancers based on our understanding of the biology and, of course, clinical trials to prove these. One of the first targeted therapies was for hormone receptor positive breast cancer using drugs that block the effects of estrogen and, of course, since that time now we've uncovered some of the mechanisms of resistance to endocrine therapy that involve growth factor receptor pathways. The first of these to be approved was the MTOR inhibitor Everolimus and so that one is still used in combination with either aromatase inhibitor or a fulvestrant endocrine therapy even with Moxifen and more recently has been the approval of the cyclin dependent kinase inhibitors. This is an important class of drugs that has now been available to us for about six years. And the cell cycle is tightly controlled by many factors including signals that come from growth factors, from the activated estrogen receptor and from other areas and the hormone receptor positive cancers tend to have the architecture of the cell cycle that is amenable to targeting with the cyclin dependent or sixth selective kinase inhibitors and these now have become the standard of care on the basis of trials that have shown that doubling of progression pre-survival and some of the drugs now even showing an improvement in survival, ribociclib and abemaciclib, so they all have a utility both in first line therapy with aromatase inhibitors or with fulvestrant and then in second line therapy with fulvestrant. In the case of abemaciclib as a single agent in patients that are multiply refractory. So this now has become a standard of care. These drugs are generally well tolerated although they do have important side effects that are less frequent that need to be monitored. And then the most recent edition to our targeted therapies for hormone receptor positive breast cancers is pi3 kinase inhibitors, specifically in patients whose tumors harbor a mutation in a PIK3CA which is the catalytic domain of the alpha pi3 kinase of isoform.

So this now is approved in second line therapy in combination with fulvestrant and there is more recent data now that these can be combined with aromatase inhibitor therapy as well. Now in HER2+ breast cancer this is another area where now, for 25 years, it was 25 years ago that the first Phase 2 trial was published with trastuzumab, the HER2 antibody, and since that time targeting HER2 has been a critical component of HER2+ breast cancers and in the advanced setting we actually continue to block HER2 even after resistance to initial therapy with trastuzumab and some of the newer drugs as well because we feel this is a situation where HER2 continues to be a driver and so there's been a lot of innovation in this field, both antibodies, trastuzumab and pertuzumab are now used together as first line therapy for metastatic disease in combination with taxanes. The immunoconjugates or antibody drug conjugate TDM1 is typically used in second line. And then we've had three new approvals just in the last year or two with the advent of tucatinib which is a more HER2 specific kinase inhibitor, doesn't inhibit the EGFR as much, also known as HER1, and this drug showed remarkable effectiveness when added to trastuzumab and capecitabine in their HER2 clime study, improving both disease free and overall survival, in patients who'd had two or more prior lines of therapy in a metastatic setting. And it was a trial that also enrolled patients with brain metastases and those patients also had an improved outcome, survival and disease free survival, and patients who were actually untreated for brain metastases that had it either minimal or no symptoms, were also allowed in that trial and they actually had responses in the cns so some of our HER2 targeted therapies do also work in cns disease and this has been important given the frequency of that type of metastasis in this subset of breast cancers. The antibody drug conjugate trastuzumab deruxtecan also received accelerated approval on the basis of very dramatic Phase 2 activity and is now being tested in a definitive Phase 3 trial.

The drug neratnib, a kinase inhibitor that had already been approved in the early stage setting also was approved in combination with capecitabine and may also have some impact on the cns. And then, finally, an engineered antibody named margetuximab was approved as well just recently and this is an interesting antibody that engages the immune system to a greater degree. We think that trastuzumab and pertuzumab also engage the immune system. These are IGG1s that are able to activate both the B cell and T cell arm of immunity in a HER2 specific fashion so the margetuximab is actually engineered so that the FC portion of the antibody will bind the FC3 gamma receptor with higher affinity and exert a greater immunologic response at least is the theory behind it. And it was a little bit better in comparison to trastuzumab and chemotherapy in the pivotal SOPHIA trial which lead to its approval. So there's really a wealth of new drugs and it's a very active field. Many new antibody drug conjugates, kinase inhibitors, and even other forms of immunotherapy in combination are in testing now. And then, finally, we come to triple-negative breast cancer. It's always been a hard cancer to treat with chemotherapy really being the primary effective drug that will be really used in the recent past. However, it is one of the more immunogenic breast cancers and breast cancer is not generally that responsive to immunotherapy except for triple-negative breast cancers, especially with the ones that express PDL1 and that is now what we have found in several of the pivotal trials that have lead to, initially, the approval of atezolizumab with nab-paclitaxel on the basis of the IMpassion130 trial showing an improvement in progression-free survival and overall survival in patients receiving first line therapy although the approval is broader. It's really with atezolizumab in patients who have greater than one percent of immune cells that are infiltrating the tumor staining positive for PDL1. And then, more recently, pembrolizumab has been approved with either paclitaxel or nab-paclitaxel or with gemcitabine and carboplatin. Again, in patients with PDL1+ tumors. This one is using a different antibody and using what's called a CPS score of ten or more which is PDL1 staining in both the tumor and the immune cells. So that is really a key direction that's new in triple-negative breast cancer although, again, targeted therapies are being looked at as more.

And so, just to close, I'll say that the field is evolving rapidly. A lot of this is because we are now coupling bio-marker studies to our randomized trials and learning from these trials in terms of what are the predictive bio-markers, what works and what doesn't. But more importantly we're learning about the overall genomic landscape of these tumors and how they signal and how they signal when there's sensitivity and resistance and which one of these targets are credible that we can develop some sort of treatment whether it's a small molecule kinase inhibitor or an antibody or other agents. So we expect that the pace of trials is gonna pick up. Certainly the conclusions that are coming from the trials and the completion rates of the trials are coming at a more accelerated pace which is what's driving these rapid approvals. In some cases, they cause confusion, however, because the trials are done with drugs that were the standard of care at the time of the trials and those standards are continually shifting so that's a good challenge to have but, nevertheless, it makes for a little bit of a complicated situation. But clearly things are moving ahead and we expect more approvals across all the spectrum of agent types in all of the sub-types of breast cancer in the coming years.