Managing Trastuzumab-Resistant Breast Cancer: An Expert Interview With Dr. Ian Krop
The demonstration of significant benefit with trastuzumab for the management of HER2-positive breast cancer, in both the metastatic and adjuvant settings,[1,2] ushered in a new era of targeted therapies for breast cancer. However, patients can begin to show signs of disease progression despite treatment in as early as 10 months, requiring physicians to consider how best to initiate the next step in therapy. The recent approval of lapatinib in this setting is only the beginning of exploration in this area, as researchers continue to focus on the development of agents with new mechanisms of action and/or new delivery systems. In an interview with Medscape Oncology, Ian E. Krop, MD, PhD, Assistant Professor of Medicine at Harvard Medical School and the Dana-Farber Cancer Institute in Boston, Massachusetts, discussed the most recent findings that have emerged in this area and reviewed some of the key challenges facing physicians today when managing patients with trastuzumab-resistant breast cancer.
Medscape: Let's start with some background on the issue of trastuzumab-resistant breast cancer. How does one define resistance to treatment? Or, more specifically, at what point should the physician consider alternative treatment options?
Dr. Krop: There are 2 typical scenarios in which trastuzumab resistance could arise. The first is a patient with an HER2-positive breast cancer who received trastuzumab-based treatment in the adjuvant setting but whose tumor has recurred. By definition, because the breast cancer wasn't cured following treatment, this patient's tumor is considered to have some resistance to the drug. The second is a patient with metastatic HER2-positive breast cancer who was on a trastuzumab-containing regimen but whose tumor is starting to progress. In this setting as well, there is, by definition, some form of resistance to trastuzumab.
But what makes things murky is that there is a lot of anecdotal evidence about patients who don't fit neatly into one group or another. There are women whose cancers recur after being given trastuzumab in the adjuvant setting, but when subsequently started on chemotherapy plus trastuzumab in the metastatic setting, they demonstrate a great response. Then there are patients with metastatic disease whose disease progresses despite trastuzumab in the first-line setting and yet demonstrate a good response when trastuzumab is combined with a different chemotherapy in the second-line setting.
The issue of whether a patient's tumor is truly trastuzumab-resistant has not been well defined, but new data are emerging from 2 different corners that might help sort this out.
First, we have positive data on the use of lapatinib plus capecitabine in patients whose tumors had progressed on at least 1 trastuzumab-containing regimen. These data demonstrate that HER2 is still a viable target in these tumors and that HER2-directed therapy can still be beneficial in a tumor that has progressed on trastuzumab.
The second piece of information is from a German study updated at the American Society of Clinical Oncology (ASCO) 2008 meeting. Researchers randomized patients with metastatic disease who had progressed on trastuzumab-containing regimens to receive capecitabine alone or to capecitabine plus trastuzumab. Similar to what we saw with lapatinib, there was significant benefit with the addition of trastuzumab, further validating HER2 as a viable target, even after prior progression on an anti-HER2 therapy.
These data also confirmed the validity of a general clinical practice regarding how best to manage a patient with metastatic HER2-positive disease whose cancer is progressing on an HER2-directed therapy. The general practice has been to switch chemotherapies and to continue HER2-directed therapy at least through the first few lines of therapy. These new data confirm that HER2-directed therapy still works after progression on first-line trastuzumab, so continuing the therapy and changing the chemotherapy is a reasonable option in this setting.
Medscape: At ASCO 2008, study results were presented on 3 new agents being tested in patients with trastuzumab-resistant breast cancer -- pertuzumab, the HSP-90 inhibitor tanespimycin, and trastuzumab-DM1.[8,9] How is research progressing with each of these agents?
Dr. Krop: Pertuzumab blocks the dimerization of HER2 with other HER family members such as HER1 and HER3. There's a good bit of preclinical data showing that this heterodimerization may be a mechanism of resistance to trastuzumab -- and that by blocking this resistance pathway, the cancer cell can't escape from the effects of trastuzumab. Researchers are therefore looking at the additive benefits of pertuzumab and trastuzumab in an attempt to derive the maximal benefit from HER-directed therapy.
The data reported at the recent ASCO meeting on this approach were quite encouraging. The single-arm phase 2 study enrolled 66 patients who had received up to 3 prior trastuzumab-containing regimens. They demonstrated a 24% response rate, with 50% of patients showing at least stable disease. Toxicity was fairly mild compared with a chemotherapy-containing regimen, with some diarrhea but no grade 4 toxicities and no withdrawals due to treatment-related or cardiac adverse events.
Pertuzumab is now being evaluated in a phase 3 study of first-line chemotherapy plus trastuzumab with or without pertuzumab, which will more specifically address the question of whether pertuzumab provides an additive benefit.
The HSP90 inhibitor tanespimycin is actually a new formulation of a drug that had been tested previously. The earlier version was a Cremophor-based drug, which added some level of toxicity. With the new suspension formulation that does not use Cremophor, the data are promising and the toxicities were mild. HSP90 inhibitors lead to degradation of HER2 and other proteins that require HSP90 for proper folding.
The phase 2 trial of tanespimycin enrolled 31 patients with metastatic disease who had progressed on 1 prior regimen of trastuzumab. The researchers reported a response rate of about 26% and an impressive overall benefit rate of 63%.
From a research perspective, these findings are particularly encouraging because the drug has a completely different mechanism of action. There is a greater potential to provide benefit in tumors that are fully resistant to trastuzumab therapy.
The third study reported in this setting was a phase 1 trial evaluating the use of trastuzumab as a vector to specifically deliver a chemotherapy known as DM1 to the HER2-positive breast cancer cell.[8,9] This idea of chemically linking a chemotherapeutic or a toxin to an antibody that delivers it to a target has been around for a while, but it hasn't been too successful in practice. This agent has 2 advantages that could account for the early positive results reported. First, the chemistry that links the DM1 to the antibody is much stronger than was used in previous attempts, so the amount of leakage of the chemotherapy into the circulation is very low, allowing for the maximal benefit to be realized at the tumor site and for the side effect profile to be more manageable.
Second, and perhaps more important, is that HER2 may be the perfect target for this type of therapy. On a normal cell, there might be a few thousand copies of HER2. But with an HER2-positive breast cancer, there can be millions of copies of HER2 protein on the cells' surfaces. So there is a potential to deliver large amounts of chemotherapy into those cells without the side effects typically seen with conventional chemotherapy.
The data presented at ASCO 2008 were from a pair of phase 1 studies looking at an every-3-weeks schedule and a weekly schedule of trastuzumab-DM1 in heavily pretreated patients. In both studies, the toxicity was minimal, with some transient thrombocytopenia, transient elevations of liver function tests, and some mild fatigue. These data validate the basic idea of a drug conjugate because the low toxicity indicates that the chemotherapy didn't get into the normal tissues, which was confirmed by the pharmacokinetic data demonstrating that the amount of circulating DM1 was negligible.
In terms of efficacy, the data were also very encouraging. The response rate for patients who received the every-3-weeks schedule and who had measurable disease was 44%, and additional patients had stable disease. For those who received the weekly schedule, the response rate was 53% -- an extraordinarily high rate in a population with a median of 5 prior therapies.
Several phase 2 studies are either already underway or will soon be launched testing the every-3-weeks schedule in a larger number of patients. It is hoped that data will be available by the end of the year.
Medscape: So where are we going from here? What are the next research steps in determining how best to manage patients with trastuzumab-resistant breast cancer?
Dr. Krop: It's incredibly encouraging to consider how rapidly new therapies are being brought into clinical trials. We are optimistic that this new crop of drugs will provide a number of new therapeutic options for patients whose tumors have become refractory to HER2-directed therapy.
Ideally, we need to move these agents as quickly as possible into the adjuvant setting since that presents the only opportunity to cure patients. Given the number of patients and the amount of time required to determine outcomes in adjuvant studies, this will always remain a challenge. Nevertheless, working hard to identify new targets and therapies against those targets that can be used in the early stages of breast cancer remain critical goals.
Identification of patients best suited for and most likely to respond to each drug is also a continual struggle. Especially as the number of new therapies increases, we need to have a better way of prioritizing who should be getting which agent. Even today, with data showing that both trastuzumab and lapatinib work in patients who have progressed on trastuzumab, we're unsure of which agent to use. As additional agents start coming to market, we might have 5 or 6 approved therapies. Presumably some will work better in one type of cancer than in another, so the need for correlative studies to identify predictive markers is going to become more and more important in the years to come.
This activity is supported by an independent educational grant from Genentech.
Disclosure: Ian E. Krop, MD, PhD, has disclosed that he has served as an advisor or consultant for Novartis. Dr. Krop has also disclosed that he has received clinical trial support from Genentech, Novartis, and Lilly.
Disclosure: Shira Berman has disclosed no relevant financial relationships