Breast Oncologists Incorporate New Treatments, Grapple With Ongoing Challenges

Hope Rugo, MD

During the 11th International Congress on The Future of Breast Cancer, Hope Rugo, MD, offered a snapshot of the research community’s progress in the study and treatment of the disease.

In two presentations, Rugo, clinical professor and director of the Breast Oncology Trials Program at the Helen Diller Family Comprehensive Cancer Center at the University of California, San Francisco, addressed the elusive promise of angiogenesis inhibitors in metastatic breast cancer, as well as new strategies for treating estrogen-positive metastatic disease.

In addition, Rugo sat down with Oncology & Biotech News to discuss those topics and others, including key developments in the treatment of HER2-positive breast cancer—in particular, the FDA’s recent approval of pertuzumab.

The exchange includes advice on how the newest drugs, techniques for matching patients with treatments, and insights into the cancer genome can be incorporated into community oncology practice.

OBTN: On June 8, the FDA approved pertuzumab, in combination with trastuzumab and docetaxel, for the treatment of metastatic HER2-positive breast cancer. How will this change the treatment paradigm for patients with this disease, and what should oncologists know about using it?

Dr Rugo: Prior to the approval of pertuzumab, our standard was trastuzumab combined with chemotherapy, or in patients who had progressed on a trastuzumab-based regimen in the adjuvant setting within 6 to 12 months, lapatinib and capecitabine.

The approval of pertuzumab has set a new standard of care, which is treating patients in the first-line metastatic setting with trastuzumab, pertuzumab, and a taxane—either docetaxel or paclitaxel.

Thankfully, when we added pertuzumab to trastuzumab, we saw very little additional toxicity—a bit more diarrhea. It’s something to tell your patients so they can take Imodium if they need to. Also, there was no additional cardiac toxicity when we added pertuzumab to trastuzumab, suggesting that the screening we do now is appropriate in patients who have minimal exposure to prior cardiotoxins.

As far as how to apply this in practice, the question is, “Should we use this regimen for everybody in the first-line setting, regardless of how they present?”

And I think that’s hard to answer. There was an early survival benefit in the initial data from the CLEOPATRA trial [N Engl J Med. 2012;366:109-119], so in a patient who has HER2-positive metastatic breast cancer in the first-line setting, I’d go with that. After a good response, I would drop the chemotherapy and continue the two antibodies alone.

Where patients have received adjuvant or neoadjuvant chemotherapy that includes a taxane and then developed metastatic disease, their chances of responding to another taxane or the same taxane is small. But for most patients who relapse after completing their year of trastuzumab, I think that a taxane, trastuzumab, and pertuzumab is still a very reasonable initial regimen to see if we can overcome some degree of resistance.

So what happens to a patient who’s gotten trastuzumab, pertuzumab, and a taxane and then developed progressive disease? I would caution against continuing pertuzumab after progression, because we have no data that it would be beneficial, and it would be very costly. We do know that other HER2-directed therapies may be active in that setting, so when T-DM1 [trastuzumab emtansine] is approved, I would have no hesitancy in giving that agent, and certainly lapatinib and lapatinib combinations, like lapatinib/ trastuzumab, may be active in that setting, as well.

What other investigational agents are in the pipeline for the treatment of HER2-positive disease?

T-DM1 is the next drug that will be approved for the treatment of HER2-positive breast cancer. It’s a novel agent and the first in its class in breast cancer to combine the antibody qualities of trastuzumab and a very potent microtubule toxin derivative of emtansine with a stable linker, so that you can direct the chemotherapy agent directly to the cancer cell.

The EMILIA trial (J Clin Oncol. 2012;30[suppl; abstr LBA1]) demonstrated a marked improvement in progression- free survival [PFS] and response when it compared T-DM1 to lapatinib and capecitabine, and with different, but overall reduced, toxicity. With lapatinib, you see the diarrhea, hand-foot syndrome, and rash, and it involves taking a bunch of pills. With T-DM1, patients just came in every 3 weeks and got an intravenous infusion with a very small amount of GI side effects.

So, we’re excited about T-DM1. It clearly has singleagent activity that can be quite durable. I have a couple of patients who have been on it for over 3 years who were previously treated with trastuzumab, lapatinib, and many chemotherapy agents. So it is an effective agent in late-line, as well as in the earlier-line, post-trastuzumab setting.

There are other agents being tested. Everolimus, recently approved in estrogen receptor [ER]-positive metastatic breast cancer, is being tested in combination with trastuzumab in HER2-positive disease in the first-line and later-line settings. However, the toxicity profile of everolimus is likely to be not quite as cheery as that of pertuzumab, because you’ll see some stomatitis and other side effects.

Now being tested in a phase I trial is an ant hracycline— doxorubicin inside a liposome—that has a non-trastuzumab HER2-targeting antibody, and then there are a number of tyr osine kinase inhibitors, including afatinib. And there’s interest in trying to block angiogenesis with bevacizumab and other agents.

Although bevacizumab’s approval for the treatment of HER2-negative breast cancer was revoked in 2011 by the FDA, you mentioned that it is being investigated in HER2-positive breast cancer. Ultimately, what kind of role do you anticipate for this drug in the treatment of breast cancer?

It’s been a sad story, the use of antiangiogenic agents in the treatment of breast cancer in the advanced setting. Every single study, outside of the first trial we did in patients who had very chemotherapy-resistant disease, met its endpoint of improved PFS in the firstor second-line setting.

Unfortunately, the trials all differed substantially in design and took all comers who had HER2- normal disease. Some of t he data were hard to analyze because patients in t he control arms were allowed to cross over to bevacizumab and/or a menu of chemotherapy agents. Most importantly, we didn’t stratify based on different tumor subtypes because we didn’t even really understand what they were when we started these trials. So, there’s clearly a subset of patients who respond, but we weren’t clever enough to find out who those patients were beforehand.

It appears that we really have to go back to the drawing board to reevaluate where the drug is most effective. One biomarker—plasma levels of VEGF, the vascular endothelial growth factor—has shown promise in data from the AVEREL trial. In trial participants who had low levels of plasma VEGF, bevacizumab didn’t change PFS. But in those with high levels of VEGF, who had a much worse expected outcome overall, bevacizumab was able to reverse that outcome so the patients did just as well as those with low VEGF levels. That’s now being tested in the MERIDIAN trial.

There were two adjuvant trials published earlier this year that looked at bevacizumab and pathologic complete response, demonstrating some efficacy there as well, but it was very hard to tell who benefited the most. Data from RIBBON-1 and RIBBON-2 suggest that maybe patients with triple-negative disease benefit more.

At the moment, we’re waiting for the adjuvant trial, ECOG 5103, which I’m hoping will have the power to look at subsets. MERIDIAN, too, will be very important in looking at the VEGF biomarker as a way to get bevacizumab back into our treatment paradigm for patients with advanced breast cancer.

Meanwhile, other antiangiogenic therapies are being studied. Sorafenib and ramucirumab, an antibody to the VEGF receptor, are in phase III trials, and other agents that block angiogenesis, including angiopoietins, are in earlier-stage trials.

What is the status of work toward understanding and treating hormone-positive metastatic breast cancer?

Treatment of ER-positive disease in the metastatic setting has recently benefited from a number of positive studies and a drug approval—all quite encouraging.

On July 20, the FDA approved the mTOR inhibitor everolimus, in combination with exemestane, in patients with hormone receptor [HR]-positive metastatic breast cancer that had previously progressed on a nonsteroidal aromatase inhibitor. The approval was based on the results of the BOLERO-2 trial [N Engl J Med. 2012;366:520-529] and 12-month follow-up data demonstrating an improvement in PFS, as well as in response rate, in those patients.

We’re really looking at a new treatment paradigm for advanced HR-positive metastatic breast cancer. I think we’re all going to try adding everolimus to exemestane when patients show early evidence of progression, even though we have no data to support that. But that would be a way of trying to add in the drug a little bit later in patients who are already on exemestane and responding. I also think it’s reasonable to start with a combination and then drop the everolimus if you have unacceptable toxicity. Everolimus has been associated with an 8% rate of grade 3 stomatitis, but we can treat that by first holding the dose and then either starting at the same dose or at a reduced dose; a steroid mouthwash can also help.

Other ways of trying to reverse hormone resistance are being tested, and there’s some exciting early data. A Cancer and Leukemia Group B study has looked at first-line hormone therapy for metastatic, ERpositive disease with bevacizumab or not. There are studies looking at histone deacetylase inhibitors in reversing hormone resistance. And then there’s interest in using novel inhibitors of the HER pathway to reverse hormone resistance. There’s some data with EGFR inhibition, so t here’s been interest in using pan-HER inhibitors.

We’re just now opening a randomized phase II trial looking at ridaforolimus and exemestane versus ridaforolimus/exemestane with the addition of the IGFR inhibitor dalotuzumab, to see whether or not it improves response, and who it’s necessary in. Finally, the Eastern Cooperative Oncology Group is starting an adjuvant trial looking at the addition of everolimus to adjuvant hormone therapy in patients with higherrisk, early-stage disease.

There are some gene-analysis tools available—Oncotype DX Breast Cancer Assay and MammaPrint—to help oncologists determine how to treat hormone receptor—positive patients. Can you please discuss how they fit into practice?

Both the Oncotype recurrence score and the MammaPrint 70-gene assay are being widely used in community practices and in academic settings in the United States. They’ve given us more confidence about when to give or forego chemotherapy in patients with HR-positive disease. The outcome is often that we omit chemotherapy when previously we would have given it.

Typically, we use MammaPrint as a screening tool to decide which patients are eligible for our large, multicenter, neoadjuvant I-SPY 2 trial, which includes a menu of novel agents. Their eligibility depends on their likelihood to have a good pathologic response rate.

In the adjuvant setting, I would use one of these tests in patients who have node-negative, ER-positive disease where I’m unsure about the benefit of chemotherapy. I order it rarely in a patient with HER2- positive disease who has lower-grade histology, where I’m thinking this is not phenotypic HER2-positive disease. In addition, I use these tests in some patients who have one to three positive lymph nodes in strongly ER-positive disease, and I’m questioning the value of chemotherapy.

I think we just have to keep in mind that not every patient needs every test, and that we want to use these in patients where we have a question.

Are there other ways for oncologists to take advantage of the growing understanding of the cancer genome in order to best match treatments to patients?

There are a lot of fancy genomic tests, some reasonably expensive. We’ve seen some really impressive and interesting data, but, right now, we don’t know how to use them in the clinical setting.

On the other hand, clinical trials may really help patients. MD Anderson has published interesting data showing that patients triaged to specific therapies based on their genomic testing did better than non-triaged patients. It suggests that, by enrolling patients in clinical trials, particularly where it’s marker-driven, you might be able to help patients stay on treatment for longer or live longer with their disease.

Right now, we don’t know that that’s the case. So, for a patient who does not live near a clinical trial center, I’m loathe to suggest that they travel far away from their family and spend the rest of their life living in a foreign city on a phase I trial.

It’s something that we, as researchers, are committed to continuing to study, and it’s of critical importance.

You presented phase III results at ASCO 2012 demonstrating that the newer and more expensive breast cancer treatments nab-paclitaxel and ixabepilone did not have superior efficacy versus weekly paclitaxel. Will you comment on the steep costs of targeted therapies and what your study might show about their value?

The study, CALGB 40502 (J Clin Oncol. 2012;30[suppl; abstr CRA1002]) looked at patients in the first-line setting with locally recurrent or metastatic breast cancer who were randomized to receive paclitaxel, nabpaclitaxel, or ixabepilone in combination with bevacizumab; it showed that the paclitaxel and bevacizumab arm was the best tolerated and most effective. So that gave us important information: We don’t know that the new agents are always better.

What implications that has for targeted biologic therapy is a huge question. When we give targeted biologic agents appropriately— for example, HER2-directed therapies to patients with HER2-positive disease—our long-term goal is to move the effective agents to the early-stage setting, so that we have fewer and fewer patients with metastatic disease. That means that, overall, you’re going to save a lot of money because patients aren’t recurring.

I think that’s why it’s so important for us to find biomarkers for the patients whose tumors are most likely to benefit from bevacizumab, from mTOR inhibition, from inhibition of PI3 kinase, and from combination targeted therapy.