Expert Expects T-DM1 to Transform Treatment in HER2+ Breast Cancer

Charles E. Geyer, Jr, MD

Ado-trastuzumab emtansine (T-DM1; Kadcyla) has the potential to transform the way that HER2-positive breast cancer is treated, said Charles E. Geyer, Jr, MD, following the data from the phase III KATHERINE trial.

Results from KATHERINE, which were presented at the 2018 San Antonio Breast Cancer Symposium, showed that T-DM1 reduced the risk of invasive disease recurrence or death by 50% versus trastuzumab (Herceptin) in patients with early HER2-positive breast cancer who did not achieve a pathologic complete response (pCR) after neoadjuvant therapy.

In the study, 1486 patients were randomized to receive adjuvant treatment with either T-DM1 at 3.6 mg/kg intravenously (IV; n = 743) or trastuzumab at 6 mg/kg IV (n = 743). Both agents were administered every 3 weeks for 14 cycles.

Furthermore, the 3-year invasive disease survival (iDFS) rate was 88.3% with T-DM1 compared with 77.0% with standard trastuzumab. Notably, this benefit was observed across all subgroups in the study, said Geyer, professor of medicine at Virginia Commonwealth University and associate director for clinical research and Harrigan, Haw, Luck Families Chair in Cancer Research at Massey Cancer Center.

OncLive: Please provide some background on the KATHERINE study.

What was the rationale for using T-DM1?

What was the design of the trial?

What were the findings?

In an interview with OncLive, Geyer, who is lead study author of the KATHERINE trial, discussed the clinical implications of the KATHERINE trial and the outlook for T-DM1 in patients with HER2-positive breast cancer.Geyer: KATHERINE was a global phase III trial conducted by investigators committed to [exploring the use of] neoadjuvant therapy in HER2-positive breast cancer as the optimal way to treat their patients, but also as a way to identify high-risk patients. This was a trial to determine if T-DM1 might help the subset of patients who do not achieve pCR who are at a higher risk of recurrence rather than continuing their HER2-targeted therapy for 1 year.T-DM1 seemed to be the obvious choice, because we know that the drug was approved by the FDA and is active for patients with metastatic disease who had prior exposure to taxanes and HER2-targeted therapy. We wanted to find a drug that would probably work in patients with early breast cancer who had less than an optimal response to these prior therapies.The design was straightforward; we did not enter patients at the point where they started their neoadjuvant therapy. With it being a global study, we knew that there would be several different regimens. The study was designed to accrue patients who received neoadjuvant therapy and achieved other standards. They had to have 6 cycles total of chemotherapy and at least 9 weeks each of trastuzumab and a taxane; they also had to have residual invasive breast cancer. We felt like that covered the “waterfront” of standard regimens. They also had to have residual invasive breast cancer. It was a pretty broad net of patients and we put some heterogeneity into the study, which is a strength of it.Our primary endpoint was iDFS. We saw a hazard ratio (HR) of 0.5 for patients who had been receiving T-DM1; that is a full 50% in iDFS events for these patients. With that information, they then suggested we publish the results, but more importantly, conduct a full analysis so we can better understand these data sets.

What are the biggest implications of these data?

How has the implementation of pertuzumab (Perjeta) impacted the care of these patients?

The other thing you will see in these data sets are the subgroup analyses. You'll see the breakout of iDFS events across subgroups. The striking findings were twofold; there was striking heterogeneity across the subgroups. Patients with estrogen receptor (ER)—negative disease experienced the 50% reductions just like the ER-positive patients. We also allowed for use of a second HER2-targeted therapy. When we broke out the iDFS events, the major one was distant recurrence; the HR for reducing those was 0.6.In terms of this specific patient population, we now have effective therapy for women who have to hear the disappointing news that they did not have a pCR [to neoadjuvant therapy]. Even beyond that, the availability will now transform the way HER2-positive breast cancer is treated. Previously, neoadjuvant therapy was considered optional; not everyone embraced it. However, these data will change the treatment paradigm to the majority of patients receiving neoadjuvant therapy, so we can also identify the subset that will benefit from T-DM1. The very small tumors that have to be mammographically detected—T1a, T1bs, which we excluded from our study—clearly would not be candidates. The area where will there will be a lot of discussion are the T1c patients—those with 1 cm to 2 cm tumors. This will be an area of clinical judgement.Personally, I view pertuzumab as a very important drug in HER2-positive early breast cancer; a lot of that is based on the CLEOPATRA results in metastatic disease. These antibodies were developed with an intent to engage the immune system, but we haven't seen it clearly until CLEOPATRA. You see that remarkable improvement in overall survival [in this study] that reflected something going on when these patients received pertuzumab. I feel like if it is having that impact in the frontline setting of metastatic disease, it should have a major impact in early breast cancer. I have been eager to incorporate it. Of course, it results in higher pCR rates; I don't think anyone disputes that.

How has the prognosis of HER2-positive breast cancer changed?

I know people look at the APHINITY results and thought, "Well, these are not as impressive as we thought." People do very well with trastuzumab, but when you look at the APHINITY subsets, there is some benefit to pertuzumab.It has been transformed. I was around for the period when we identified HER2 as an adverse prognostic factor. We were essentially delivering patients bad news. It went from being, "Oh no, this patient has HER2-positive breast cancer," to now, [we] are almost happy to see it. We know what is driving their cancer and we have effective therapies. We have a high probability of curing patients. It is a completely different disease. Biologically, it is obviously the same, and if we don't use our therapies effectively, it is still an aggressive cancer. However, in my career, HER2-positive breast cancer has been the transformative disease.

Geyer Jr CE, Huang C-S, Mano MS, et al. Phase III study of trastuzumab emtansine (T-DM1) vs trastuzumab as adjuvant therapy in patients with HER2-positive early breast cancer with residual invasive disease after neoadjuvant chemotherapy and HER2-targeted therapy including trastuzumab: primary results from KATHERINE (NSABP B-50-I, GBG 77 and Roche BO27938). In: Proceedings from the 2018 San Antonio Breast Cancer Symposium; December 4-8, 2018; San Antonio, TX. Abstract GS1-10.