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Expert Point of View: Eric P. Winer, MD, and Jame Abraham, MD


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Eric P. Winer, MD

Eric P. Winer, MD

Jame Abraham, MD

Jame Abraham, MD

Commenting on the findings of the KATHERINE trial were Eric P. Winer, MD, Director of the Breast Oncology Program in the Susan F. Smith Center for Women’s Cancers at Dana-Farber Cancer Institute and the Thompson Senior Investigator in Breast Cancer Research andProfessor of Medicine at Harvard Medical School, Boston; and Jame Abraham, MD, Director of the Breast Oncology Program at Taussig Cancer Institute; Co-Director of the Cleveland Clinic Comprehensive Breast Cancer Program; and Professor of Medicine at the Cleveland Clinic Lerner College of Medicine. 

In his discussion of the study, Dr. Winer noted that ado-trastuzumab emtansine (T-DM1; Kadcyla) is an antibody-drug conjugate linking trastuzumab to emtansine, a microtubule inhibitor that is 400-fold more potent than paclitaxel, providing this high-affinity antibody with a powerful payload. In two metastatic trials, T-DM1 improved progression-free survival and overall survival vs lapatinib (Tykerb)/capecitabine in the EMILIA trial1 and vs physician’s choice of chemotherapy (which largely included trastuzumab [Herceptin] in TH3RESA,2 with limited toxicity. The results were more modest in the MARIANNE trial, where T-DM1 did not outperform a taxane plus trastuzumab and, surprisingly, the addition of pertuzumab (Perjeta) to T-DM1 did not increase the benefit over T-DM1 alone.3

“In truth, MARIANNE took a bit of the wind out of the sails for T-DM1,” Dr. Winer commented. KATHERINE clearly brought a fresh, powerful burst of wind to T-DM1, demonstrating an 11% overall difference vs the standard of care in a group of patients who have the established adverse prognostic factor of residual disease, he said. “This was a big boost for T-DM1, and I think we will use it broadly in this setting [of residual disease]. We will also think about how to use it in other settings in early-stage breast cancer on clinical trials.”

Dr. Winer concluded: “This result was seen despite the fact that more than 70% of patients had estrogen receptor–positive disease, where one might have seen less benefit because of a somewhat lower level of HER2 expression in at least some estrogen receptor–positive cancers. In my view, the standard of care has changed, and T-DM1 should be recommended to the vast majority of patients with residual disease after a taxane-based regimen.”

Exceeded Expectations

Dr. Abraham agreed about the impact of these findings. “The results of KATHERINE will change practice overnight,” he said. “This feels like 2005, when we heard the adjuvant trastuzumab data. It’s that big.”

Dr. Abraham acknowledged that the initial expectation of the investigators was somewhat lower. “We were not expecting this to change practice,” he said. “But all subsets benefited, including patients with any degree of residual disease. In the post-neoadjuvant setting it can be universally used. I am very happy with the results—very happy it will help our patients.”

Although in a literal sense the results cannot be applied “overnight,” since T-DM1 is approved only in the metastatic setting, Dr. Abraham said he “hopes and expects” that the U.S. Food and Drug Administration will move swiftly for an approval in the adjuvant setting. Once he is allowed to do so, he said, he may switch patients currently on another adjuvant schedule to T-DM1 if they are early in their treatment course.

What Happens Now to Other Options?

Dr. Winer and Dr. Abraham said the findings portend much less use of pertuzumab and neratinib (Nerlynx) in the adjuvant setting.

“For pertuzumab, the findings are a bit of a negative because we won’t continue to use pertuzumab in patients who receive it preoperatively and have residual disease. They will get T-DM1 instead,” Dr. Winer said. No direct data currently support adding pertuzumab to adjuvant T-DM1—and he would not do so—though he acknowledged it is possible it might add to the benefit.

The same is true for neratinib. “It’s difficult to be enthusiastic about neratinib in this population, given these data,” he said. “It’s hard to imagine using it in place of T-DM1, and there are no data for using it after T-DM1.”

Dr. Abraham agreed that pertuzumab will continue to be useful only in the neoadjuvant setting, but he said he still sees a use for neratinib in the extended adjuvant therapy setting. As we design new regimens in the future, with another active treatment, it is likely that doxorubicin will be used less and less, Dr. Winer predicted.

Dr. Abraham added that clinicians should remember that while T-DM1 is generally well tolerated, some patients have side effects. “It’s overall safe, but it’s important to make sure we don’t ignore the long-term side effects such as neuropathy, fatigue, and hepatic toxicity,” he said. “Considering the magnitude of benefit, I do think many patients will be willing to pay the price for the benefit they get from it.” 

DISCLOSURE: Dr. Winer has served as an advisor for Roche, Jounce, and GlaxoSmithKline and as a scientific advisor for Leap Therapeutics and Verastem Oncology. Dr. Abraham reported no conflicts of interest.

REFERENCES

1. Verma S, et al: Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med 367:1783-1791, 2012.

2. Krop IE, et al: Trastuzumab emtansine versus treatment of physician’s choice in patients with previously treated HER2-positive metastatic breast cancer (TH3RESA). Lancet Oncol 18:743-754, 2017.

3. Perez EA, et al: Trastuzumab emtansine with or without pertuzumab versus trastuzumab plus taxane for human epidermal growth factor receptor 2-positive, advanced breast cancer. J Clin Oncol 35:141-148, 2017.


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