New agents for the treatment of advanced HER2-positive breast cancer are coming soon to your clinic, according to , of the University of Texas MD Anderson Cancer Center.
Speaking to 鶹ý at the recent San Antonio Breast Cancer Symposium, Tripathy discusses why we are making such rapid advances, and what he sees for the future of these treatments.
Following is a transcript of his remarks:
The landscape of HER2-positive breast cancer has changed a lot as of today. The general treatment for advanced HER2-positive breast cancer has typically consisted of induction therapy with chemotherapy and also with trastuzumab and pertuzumab. But as most clinicians know, patients ultimately do become refractory to these therapies. Some patients are having very, very long remissions, but it's very common now to move on to standard second-line therapy, which is now the amino conjugate T-DM1. After that, really, there is no standard of care. We have typically used combinations of trastuzumab with other chemotherapies. The kinase inhibitor, lapatinib, is used either in combination with capecitabine or with trastuzumab.
But this is a niche where many new drugs are being tested now, so it's a very busy landscape. Kinase inhibitors, new immunoconjugates, and innovative bispecific antibodies represent the primary classes of drugs that are being tested. The data from today showing the first randomized trial with the HER2-specific kinase inhibitor tucatinib, which is different from other kinase inhibitors in that it is specifically targeted to HER2. It has very little activity on eGFR, and so the toxicity profile is different. There isn't as much in the way of GI and skin toxicities, but importantly, it's active in refractory disease.
Most of the original work with this drug was done in combination with trastuzumab and capecitabine. That did show activity not only systemically, but with CNS lesions that hadn't been treated. The randomized trial, HER2CLIMB, really tested the addition of tucatinib to what would be standard trastuzumab and capecitabine and showed dramatic activity, response rates, and importantly improvements in survival. Roughly a one-third fewer death rate lowered by one-third and progression events lowered by over a half. The toxicity profile, very good, only 6% of patients had to discontinue. What this means now is that this triplet is going to really be our third-line therapy and the future path for this drug is bringing it into earlier lines of therapy, either first or second line or even in the adjuvant setting, and these types of trial designs are ongoing.
But the broader issue here, though, is how does the HER2 pathway escape its different therapies? One way we know that is a problem is that HER2 expression can be heterogenous in many cases. Some cells express more HER2 than others, and so the HER2-targeted drugs will work only against the HER2-positive ones. The HER2-negative ones may survive and many times patients' progression samples lack HER2. Here's where other therapies come in, the other drug that reported results from a phase II trial is trastuzumab deruxtecan. This is an antibody-drug conjugate that uses essentially the trastuzumab antibody linked to a topotecan derivative, a topoisomerase-1 inhibitor. This showed remarkable efficacy, 61% of patients responded who had been treated with a median of six prior HER2-targeted therapies. This one, the toxicity profile is a little bit different. There is more GI toxicity and there's a rare or infrequent, I should say, interstitial lung disease. In fact, the mortality rate was around 2%, so this is going to really require further exploration.
Part of the reason we're making more rapid advances not only because we have more drugs in play at the current time, but we're understanding more about the biology because of the emphasis on tissue-based research that is now built into these studies. What I see for the future is two general areas. One is learning more about detecting these pathways and getting more specific targeted agents, and the other is learning the immunology connection because both trastuzumab and pertuzumab not only work by inhibiting HER2, but they also activate the immune system. There are trials now adding checkpoint inhibitors to these antibodies and that's going to be another area of armamentarium that will improve things. What this means for practical purposes is that we will have new drugs at our disposal as clinicians, and that it is important to biopsy the tumor and get genomic characteristics not only to confirm the HER2 status, but to look for opportunities for clinical trials.