Questions and Controversies in Treating Breast Cancer - Episode 10
Transcript:Hope S. Rugo, MD: The APHINITY trial is an incredibly practice important study. What this trial did was capitalize on the results seen in the CLEOPATRA study, which tested an alternate HER2 antibody, pertuzumab, in combination with trastuzumab and chemotherapy, specifically a taxane docetaxel, and compared that to docetaxel and trastuzumab in a patient population, who are largely naïve to prior trastuzumab. Only 10% had seen prior adjuvant trastuzumab. The progression-free survival was significantly longer with pertuzumab, and overall survival was dramatically longer, more than 2-fold greater than the difference in progression-free survival. These really striking results, combined with a modest and really well-managed increase in toxicity, led to wide-spread approval of pertuzumab in combination with trastuzumab and taxane chemotherapy, as first-line treatment for metastatic HER2-positive breast cancer.
Of course, the next step after that is to go to the adjuvant setting. But first, we had data in the neoadjuvant setting from a trial called NeoSphere, that showed if you just gave a taxane, docetaxel, and trastuzumab before surgery for HER2-positive breast cancer, you could improve the pathologic complete response rate, by adding pertuzumab to the trastuzumab and docetaxel. Those data actually combined with another study called TRYPHAENA, that looked at a non-anthracycline-based chemotherapy regimen, which led to accelerated approval of pertuzumab in the United States, as a companion with trastuzumab and chemotherapy as neoadjuvant treatment for HER2-positive breast cancer.
The reason we could get an accelerated approval was because accrual to the adjuvant trial, which of course had already started, had completed. In fact, it was a rapidly accruing trial. People are very excited about adding pertuzumab, based on the CLEOPATRA results. In context, we understand that patients with HER2-positive breast cancer do very well in general, with very good disease-free and overall survival, with a combination of standard chemotherapy and trastuzumab. The chemotherapy regimens that are used include either an anthracycline/taxane-based regimen, or an all-taxane combined with carboplatin regimen.
In the APHINITY trial, patients received the chemotherapy of choice of the treating physician, with trastuzumab and either a placebo infusion or pertuzumab. And like we’ve done with trastuzumab, the pertuzumab was continued for an entire year.
Part way through the trial, people got a little bit nervous about the fact that a lot of patients with node-negative disease were being enrolled. Those patients do very well. The outcome is great. We’ve made huge strides in the treatment of this subset of breast cancer. So, actually, they capped the number of patients with node-negative disease, to try and amplify the number of patients with node-positive disease, who might have a worse outcome with trastuzumab and chemotherapy alone, to better see the benefit of pertuzumab. So, the number of patients enrolled in the trial went up to its final number, which was about 4800 patients.
At this time, we have almost 4 years of median follow-up of patients on the trial, where the primary endpoint was disease-free survival. What we saw was an improvement in disease-free survival with the addition of pertuzumab, but that improvement was very small. It was under 2% and showed an absolute difference of 1.7%. That difference was much smaller than we all expected we would see with the addition of pertuzumab. So, as we all do, the trial was then divided into its prespecified differential groups by differential risk of recurrence and death from cancer. If you looked at patients who had node-negative disease, there was no benefit from the addition of pertuzumab. In patients with node-positive disease, there was a modest benefit of just over 2% of absolute difference.
If you looked at patients with hormone receptor-positive disease, the difference was very small—if there was any—and the difference in patients with hormone receptor-negative disease and HER2-positive disease was a little bigger, over 2%. But, again, still quite modest.
When you look at these data, you think that we already made such a big impact with trastuzumab, and that pertuzumab’s additional impact is quite small—a tiny increment. Pertuzumab increased toxicity, particularly in patients who were receiving the taxane/carboplatin regiment, where grade 3 diarrhea was seen in 18% of patients. Now, of course, that’s less than we’ve seen in some other treatments that we find perfectly acceptable. But you only want to get toxicity that you can control with antidiarrheal therapy and education, if you also have a bigger bang for the buck—in other words, a greater difference in disease-free survival.
They also looked at endpoints, of course—invasive disease-free survival—and one of the things that’s very interesting to us as oncologists is, what is the difference in the rate of distant disease-free survival? They usually look at that at time to recurrence. That difference was only 0.6%, so it was quite modest.
Now, we expect that over time, we’ll potentially see a difference in those endpoints—invasive disease-free survival, for example. But there’s no difference in overall survival as of yet, and as many recall, by 3 years we already saw a difference in overall survival with the addition of trastuzumab. That difference has been maintained for up to 10 years of follow-up, with the initial trials that looked at trastuzumab versus not in HER2-positive breast cancer.
So, that takes us to a trial with a large number of patients, well-powered to look at differences, where the benefit of pertuzumab was modest, and only seen in patients with the highest-risk disease. Indeed, in this particular trial, two-thirds of the patients had ER-positive disease, which is quite different from what we saw in the past and in other trials. It’s likely that the patients with ER-negative disease got neoadjuvant therapy, so they weren’t randomized on the APHINITY trial.
In addition, we saw that about two-thirds, a little less, had node-positive disease. That group of patients was quite reasonably sized. So, I think that pertuzumab won’t be a mainstay of our treatment in the adjuvant setting. We’ll probably still use it for patients with high-risk disease in the neoadjuvant setting, but not so much in the lower risk node-negative or ER-positive patients in the adjuvant setting. We don’t really know how long we should be treating patients. All the patients in APHINITY got a year of pertuzumab, but in the neoadjuvant setting we already saw an impact in just giving it with chemotherapy—so for a few months. So, maybe in the patients who have a pathologic complete response, we could stop the pertuzumab, as we have been doing, and continue with trastuzumab alone. We don’t really know the answer to that.
Transcript Edited for Clarity