KATHERINE and FeDeriCa Trials Shift Standards in Early-Stage HER2+ Breast Cancer

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Partner | Cancer Centers | <b>University of Chicago Medicine Comprehensive Cancer Center</b>

Olwen Hahn, MD, discusses the clinical significance of the KATHERINE and FeDeriCa trials in the treatment of patients with early-stage HER2-postive breast cancer.

The phase 3 KATHERINE (NCT01772472) and FeDeriCa (NCT03493854) trials represent 2 pivotal advances in the treatment of patients with early-stage HER2-postive breast cancer, according to Olwen Hahn, MD, who added that these trials have led to regulatory approvals that have shifted the standard of care and have provided more convenient options to this population.

In the KATHERINE study, ado-trastuzumab emtansine (T-DM1; Kadcyla) reduced the risk of invasive disease recurrence or death by 50% vs trastuzumab (Herceptin) in patients with HER2-positive early breast cancer (HR, 0.50; 95% CI, 0.39-0.64; P <.0001).1 Additionally, the 3-year invasive disease-free survival (iDFS) rate was 88.3% with T-DM1 versus 77.0% with trastuzumab. These data led to the May 2019 FDA approval of T-DM1 for use as an adjuvant treatment of patients with HER2-positive early breast cancer who have residual invasive disease after neoadjuvant trastuzumab.

“Neoadjuvant chemotherapy plus monoclonal antibodies against HER2 should be considered to be the standard of care for early-stage patients, and based on the presence of residual disease, we can escalate therapy for this high-risk patient population,” Hahn said. “We should be approaching these patients early with systemic therapy prior to surgery, and then learning how to appropriately address their therapy in the adjuvant setting.”

The fixed-dose combination of pertuzumab (Perjeta) and trastuzumab with hyaluronidase-zzxf (Phesgo), administered subcutaneously with intravenous (IV) chemotherapy, was found to showcase noninferiority to IV formulations of the 2 drugs in terms of pharmacokinetics, clinical efficacy, and safety.2 The data resulted in the June 2020 FDA approval of the combination for the treatment of patients with early and metastatic HER2-positive breast cancer.

“We should consider how to best deliver these really important, and disease-changing, monoclonal antibodies, pertuzumab and trastuzumab, in a way that is more patient-centered and convenient,” Hahn added.

In an interview with OncLive® during an Institutional Perspectives in Cancer webinar on Breast Cancer, Hahn, an associate professor of medicine at the University of Chicago Medicine Comprehensive Cancer Center, discussed the clinical significance of the KATHERINE and FeDeriCa trials in the treatment of patients with early-stage HER2-postive breast cancer.

OncLive®: KATHERINE has been referred to as landmark trial. Could you elaborate on what qualifies it for landmark status?

Hahn: I would consider it to be a landmark study because it changed the standard of care. Based on the results of that study, T-DM1, or trastuzumab emtansine, was FDA approved for the residual disease setting after neoadjuvant chemotherapy. The standard of care prior to these results was to give the monoclonal antibody trastuzumab to patients with residual disease. However, we learned that by switching to T-DM1 in this high-risk group, patients had a 50% decreased risk in recurrence and an 11% absolute decrease in recurrence.

Have the results from this study altered thoughts on potential biomarkers for treatment selection?

Yes. We can, as a result of this study, consider the presence of residual disease at the time of surgery as an important biomarker to act on and switch patients in the adjuvant study, as well as to inform the next generation of clinical trials. That is what the phase 3 CompassHER2 RD [NCT04457596] has done; it is [using] the presence of residual disease to further escalate therapy for this high-risk patient population.

Could you elaborate on the trial design for CompassHER2 RD (A011801)?

The National Cancer Institute has sponsored a pair of Compass studies: the phase 2 CompassHER2-pCR trial [NCT04266249] and the CompassHER2 RD trial, which was specifically informed by the KATHERINE results. CompassHER2 RD aims to improve iDFS in patients [who have] residual disease either in the breast or the lymph nodes after receiving neoadjuvant chemotherapy and HER2-directed therapy [and who are at high risk of recurrence]. The trial randomizes them to receive the new standard of care T-DM1, or T-DM1 and tucatinib [Tukysa].

FeDeriCa is another trial that has garnered excitement in this space. What were the clinical and economic implications of this study itself and the subsequent approval?

FeDeriCa led to the approval of the subcutaneous fixed-dose of pertuzumab and trastuzumab in 3 different settings: the neoadjuvant setting, the adjuvant setting, and the first-line metastatic setting. Previously, the patient would receive dual monoclonal antibodies, and the first infusion could be about 150 minutes a time in the IV therapy seat, with subsequent infusions being shorter, probably along the lines of about 60 minutes. Now, instead of our patients having to spend that much time in the IV therapy chair receiving an infusion, they can receive a simple, subcutaneous injection in their thigh, the duration [of which] would take less than 2 minutes.

It definitely is helpful from a patient convenience standpoint in terms of the time that they are spending in the IV infusion seat. It also can be helpful when considering that time and availability of infusion chairs can be a limited resource for a cancer center in the outpatient setting. It also opens up important considerations about the delivery of these drugs in a lower-resource setting.

Do you foresee any competition between this approach and the trastuzumab biosimilars that have become available?

That remains to be seen. With trastuzumab, multiple biosimilars are available. Those biosimilars are given by IV infusion, so it would be akin to the brand of trastuzumab by IV infusion. Pertuzumab is still under patent and will be under patent until 2024, so we will not see a biosimilar until after that patent expires. It is going to be up to individual insurances in terms of pricing and what they are going to accept on insurance plans in our complex insurance system regarding a subcutaneous injection vs an IV injection. Drug pricing is very complex and very individual based on insurance plans, so it will be interesting to see how that plays out in the future.

Would you say that COVID-19 has impacted your treatment recommendations?

With COVID-19, our patients are interested in minimizing the number of trips to the hospital setting, as well as the time that they spend there. In terms of time that they spend here, it has impacted my approach in a big way, and we are now doing home phlebotomy services for our patients to decrease their time in the infusion seat. This has big convenience factors for the patient, which is [especially] important during the pandemic. Also, the increased use of subcutaneous formulations of either trastuzumab or the fixed-dose pertuzumab/trastuzumab is of interest to patients in terms of the amount of time they had to spend there during the pandemic.

Are any emerging approaches under exploration that you are excited about?

An exciting development over the past several years has been the approval of tucatinib in the metastatic setting, especially that we also have seen the activity of tucatinib for patients with central nervous system [CNS] metastases, and potentially the prevention of worsening or new CNS metastases. That drug is being currently studied in the phase 3 HER2CLIMB-02 [NCT03975647] study to look at it in combination with T-DM1 in the second-line metastatic setting, and the CompassHER2 RD study is also investigating this drug as a potential to pair with T-DM1 for patients with residual disease. It will be interesting to see how escalation of therapy in this high-risk patient population looks.


  1. FDA approves Genentech's Kadcyla for adjuvant treatment of people with HER2-positive early breast cancer with residual invasive disease after neoadjuvant treatment. News release. Genentech. April 3, 2019. Accessed April 30, 2021. https://bit.ly/2UYWOVN
  2. FDA approves breast cancer treatment that can be administered at home by health care professional. News release. FDA. June 29, 2020. Accessed June April 30, 2021. https://bit.ly/2ZjoQzI