PracticeUpdate: Haematology & Oncology

CONFERENCE COVERAGE 28

New data onmanaging HER2+ disease fromSABCS 2016

Hope Rugo, MD, is Clinical Professor in the Department of Medicine (Hematology/Oncology), and Director of the Breast Oncology Clinical Trials Program at the University of California, San Francisco. She talks with Dr Farzanna Haffizulla about managing HER2-positive breast cancer from data presented at SABCS 2016.

DrHaffizulla: Can you talk about thePERTAIN trial on pertuzumab and trastuzumab along with an aromatase inhibitor, to highlight the key findings of this particular trial? Dr Rugo: It’s an interesting trial …because it tells us something that they didn’t really intend to tell us. The trial (randomised) about 250 patients with HER2-positive metastatic breast cancer, who also was oestrogen receptor-positive, to receive trastuzumab and an aromatase inhibitor or trastuzumab, pertuzumab, and an aromatase inhibitor. Their question was, does pertuzumab add to that combination of trastuzumab and an aromatase inhibitor? The problem is that they did show an improvement of about 3 months in progression-free survival and the usual reasonably easily managed side effects from pertuzumab. But the thing is that we’ve seen a survival advantage of 15 months with adding pertuzumab to trastuzumab and a taxane as first-line therapy for metastatic HER2- positive breast cancer. So it doesn’t make a lot of sense to start with hormone therapy unless you’re too old, and then you’re still getting diarrhoea from pertuzumab, for some very compelling reason, and it would be an unusual patient. But what it did tell us was that you can safely combine hormone therapy with the two antibodies. It just didn’t tell us the question we really wanted to know, which is that if you get chemo herceptin trastuzumab and a pertuzumab, and then you stop the chemo and continue the double antibody maintenance, which is what we do, should you add back in hormone therapy because it asked about adding pertuzumab, but not the hormone therapy. So that’s what we do. And the CLEOPATRA trial that showed the survival advantage, they didn’t give hormone therapy as maintenance, but we do, and this

trial I think definitely told us it’s an effective approach. Dr Haffizulla: The SUMMIT trial looked at neratinib alone and neratinib with fulvestrant in Erb-B2 mutant disease. Was that studied in patients with HER2-positive disease? Dr Rugo: It actually didn’t test neratinib in HER2-positive disease, and that’s a finesse point and a really good one to bring up. It’s a randomised phase 2 trial, and this was just an initial look at the data. It’s an international collaboration looking at patients who have what has been tested as HER2-normal disease. HER2 is a gene which is amplified, so you get many copies of it, and then it translates into an increased protein expression on the cell surface. We found that there’s a small percentage of tumours that have what are called somatic mutations in HER2. So they were looking for patients who had what’s now referred to as Erb-B2 mutations. It turns out that it’s maybe 2–2.5% of the population of patients with breast cancer who are HER2-negative, and they don’t test positive by FISH or ImmunoHistoChemistry because they actually have mutations in the DNA. There’s some preclinical data that shows that these cancers would respond better to a potent oral tyrosine-kinase inhibitor like neratinib. Cynthia Ma has been working for a long time, and with Matt Ellis initially before he left Washington University in St. Louis, on studying this in patients who have mutations, and this is a sort of extension of that study. Their trial did show that neratinib had activity in patients who have these HER2 or Erb-B2 somatic mutations. It’s just uncommon. So what we’ve discovered actually in the last year, and some of this was known before, but it’s just important to define it clinically, is that you see these mutations much more frequently in patients who have a lobular histology in their cancer. Fascinating, right?

Dr Haffizulla : Yes, very much. Dr Rugo: And in that patient population, it’s less than 10%, but it’s more common; that’s an important thing to keep in mind if you have a patient who has a lobular cancer that’s acting very hormone resistant, this could be a treatment that would be important. What they did in their trial, a little bit different fromCynthia Ma’s trial, is that they said, okay, you can either be randomised to neratinib as monotherapy or neratinib and fulvestrant, because these patients mostly have ER- positive lobular cancer. And they actually have a small number of patients, 25 patients in the neratinib arm, 17 in the combination arm with fulvestrant, but they showed responses in both groups. It’s so early that they showed the responses as waterfall plots, and they don’t have a durability, the duration of response, they just don’t have enough information. So it’s a very early look at this data, small numbers, but in a rare subtype of breast cancer it shows that the oral tyrosine-kinase inhibitor is effective and the fulvestrant and neratinib was effective. It’s hard to tell any difference actually in this small number of patients right now. It will be interesting to see what the ongoing data shows.

Go to practiceupdate.com to watch the full video

interview with Dr Hope Rugo.

PRACTICEUPDATE HAEMATOLOGY & ONCOLOGY