COMMENTARY

Beyond APHINITY: What Now After the Pivotal Early Breast Cancer Trial?

Gunter von Minckwitz, MD, PhD; Kathy D. Miller, MD

Disclosures

February 15, 2018

Kathy D. Miller, MD: Hi. I'm Dr Kathy Miller, professor of medicine at the Indiana University School of Medicine in Indianapolis. Welcome to Medscape Oncology Insights. We're here in Chicago at the 2017 Annual Meeting of the American Society of Clinical Oncology (ASCO).

For those of us interested in breast cancer, we have been waiting and waiting for the APHINITY trial data.[1] We don't have to wait anymore. This study should tell us whether the addition of pertuzumab to adjuvant therapy improves survival in patients with HER2-positive early breast cancer.

Here to talk about the findings of the APHINITY study is the lead author, Dr Gunter von Minckwitz, associate professor at the University of Frankfurt and managing director of the German Breast Group Research Institute in Neu-Isenburg, Germany. Welcome back, Gunter.

Gunter von Minckwitz, MD, PhD: Hello, Kathy.

The Rationale for APHINITY

Dr Miller: This is such exciting news. Before we get to the results, can you give us a little reminder of how we got to the APHINITY trial in the first place?

Dr Minckwitz: The biologic concept behind it is that we know that trastuzumab and pertuzumab are [complementary, but do] not work identically. Whereas trastuzumab binds to the transmembrane region and inhibits shedding of the HER2, pertuzumab inhibits the interaction between various subtypes of the HER2 receptor, inhibiting the whole conversation of the HER2 and HER3 receptors.

We have quite a large number of trials showing that the simultaneous application of the two antibodies seems to be very efficient at prolonging overall survival in the setting of metastatic breast cancer.[2,3]

When it comes to early breast cancer, results from the NeoSphere study, for example, show that adding pertuzumab to trastuzumab improved the pathologic complete response rates in patients with HER2-positive breast cancer.[4] [NeoSphere] was operating concurrently with the APHINITY study, but of course all of the metastatic data indicated that there was a clear need to have a conventional adjuvant study.

Dr Miller: APHINITY really is a very traditional adjuvant study. Patients had had primary surgery and radiation, if needed. Was radiation administered before or after the systemic therapy?

Dr Minckwitz: It came after. It was given [during] the period where only the antibodies were still in [use].

An International Collaboration

Dr Miller: This was a worldwide study. How many patients did you enroll? And as adjuvant chemotherapy regimens differ a bit from region to region, how did you make this work as a large, international study?

Dr Minckwitz: We randomized 4805 patients. As you said, it was a global effort, and especially one between academia and pharma. Although Roche was the sponsor of the study, it was conducted mainly by the Breast International Group as an academic group, which was the linkage for many different national groups participating from the United States, Asia, and Eastern Europe. It was a really global effort.

It wasn't so difficult. We allowed one of the following basic regimens: three or four cycles of 5-fluorouracil plus either epirubicin or doxorubicin plus cyclophosphamide, followed by three or four cycles of docetaxel plus 12 weekly cycles of paclitaxel; four cycles of cyclophosphamide plus doxorubicin or epirubicin, followed by four docetaxel cycles or 12 weekly paclitaxel cycles; or six cycles of docetaxel plus carboplatin. These were the main groups of chemotherapies.

Three quarters of the patients were treated with the anthracycline-containing regimens, whereas only one quarter received docetaxel/carboplatin/trastuzumab (TCH).

Dr Miller: Tell us about the results. Did pertuzumab add to the standard chemotherapy and trastuzumab?

Dr Minckwitz: Yes; the trial met its primary objective. The 3-year rate of invasive-disease–free survival was 94.1% [in the pertuzumab group] and 93.2% [in the placebo group]. We were lucky, as it was quite close, with a P value [in favor of pertuzumab] of .045. But we could demonstrate this already at a very early point of time, with a median follow-up of only 45 months—very early-out read, but it met statistical significance.

It was even a little bit more challenging, given that the control arm, as in many former trials, did much better than expected. We expected 3-year disease-free survival of 89%, and it came out to be 93%. Therefore, demonstrating superiority for pertuzumab was even more difficult. But in the end, we got it and it's a positive study.

Toxicity Findings

Dr Miller: Toxicity is always an issue for our patients. Particularly when we're talking about fairly small differences at this point, this has to be a bigger part of the discussion. What toxicities did you see by this change in therapy?

Dr Minckwitz: First, there was no new toxicity signal. Of course, when we're talking about anti-HER2 agents, cardiac toxicity is the most important, so we included specific primary safety endpoints regarding this.

There was no difference between the treatment arms. There was a numerical difference—primary cardiac events occurred in 17 patients receiving pertuzumab and in eight patients receiving placebo—but that did not reach statistical significance. Secondary cardiac events, mildly symptomatic or asymptomatic decreases of the left ventricular ejection fraction, were actually completely similar between the two arms.

To me, the most important clinical safety difference between the two treatment arms is diarrhea. We observed almost 10% grade ≥3 diarrhea with pertuzumab, compared with <4% in the control arm.

Going into a little more detail here, we've found that this was mainly a problem with the TCH regimen, as we know that docetaxel is not so easy and has a more diarrheic capacity than paclitaxel. Here, the grade 3 diarrhea rate with pertuzumab went up to 18%, and that was where most of the signal derived from.

Also, as we expected, we observed that the diarrhea was a problem only during the period when the antibodies were given together with the chemotherapy, but after that point it just disappeared.

Dr Miller: It's a lot of therapy, with the chemotherapy and both antibodies for a total of a year. How many patients were able to complete the whole planned therapy?

Dr Minckwitz: The compliance was very good and not really different between the two arms. It was around 90% of the patients.

Room for Improvement?

Dr Miller: Where do we go from here? We're at 93% disease-free survival. It's hard to think about how we make that better.

Dr Minckwitz: First, I believe that we have to be careful, because this is only the 3-year snapshot. There will be more relapses coming in these patients in the next years, as the trial is designed to have a full 10-year observation period. The overall risk in these patients will, of course, be larger than what we can currently see.

Nevertheless, this study clearly shows how good prognosis is nowadays for HER2-positive breast cancer, especially if we look at the -negative patients. It's very hard to become better here, or to at least demonstrate further superiority in the conventional randomized fashion.

I believe that in these low-risk patients, we have to move more into the direction of reducing treatment intensity. Putting to the side financial considerations, the question is, can we, for example, avoid chemotherapy and just give a dual blockade in very low-risk patients? Or can we just give the well-tolerated weekly paclitaxel with trastuzumab and pertuzumab, maybe in a group of patients that is a little bit of a higher risk compared with the data that we have for very small tumors? Here, I believe that we are at the end of where we can go in the approach of treating everybody.

The other strategy will be to identify resistant patients, those who will have a relapse despite this intense treatment. APHINITY will probably give us a lot of answers to that. We have collected a tremendous amount of biomaterials and have already started trying to characterize the tumors. We are collecting even residual disease tissue to find out [more about] the patients in whom such a treatment is not successful.

Dr Miller: Thank you, Gunter, for coming in and sharing these results with us, and to our audience for joining us today. This is Dr Kathy Miller, reporting from ASCO 2017.

Comments

3090D553-9492-4563-8681-AD288FA52ACE
Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.
Post as:

processing....