Tucatinib Takes Step Toward EU Approval in HER2+ Breast Cancer

January 31, 2020

The European Medicines Agency has validated a Marketing Authorization Application for tucatinib in combination with trastuzumab and capecitabine for the treatment of adult patients with unresectable locally advanced or metastatic HER2-positive breast cancer, including those with brain metastases, who have received ≥2 prior anti-HER2 treatment regimens.

Roger Dansey, MD

The European Medicines Agency (EMA) has validated a Marketing Authorization Application (MAA) for tucatinib in combination with trastuzumab (Herceptin) and capecitabine (Xeloda) for the treatment of adult patients with unresectable locally advanced or metastatic HER2-positive breast cancer, including those with brain metastases, who have received ≥2 prior anti-HER2 treatment regimens.¹

The application is based on findings from the pivotal, phase II HER2CLIMB trial, in which tucatinib combined with trastuzumab/capecitabine led to a 34% reduction in the risk of death compared with trastuzumab and capecitabine alone in this patient population (HR, 0.66; 95% CI, 0.50-0.88; P = .0048).^2,3

The validation of the MAA confirms that the submission is sufficiently complete to begin the formal review process, Seattle Genetics, the manufacturer of the highly selective small molecule TKI, stated in a press release.

“Today, we achieved a significant milestone towards our goal of making tucatinib available to patients with locally advanced unresectable or metastatic HER2-positive breast cancer, including those with brain metastases, around the world,” Roger Dansey, MD, chief medical officer, Seattle Genetics, stated in the press release. “We look forward to working with the EMA throughout the review process. If approved, tucatinib has the potential to be a clinically meaningful advance for patients in this disease setting.”

In the international, double-blind, placebo-controlled, HER2CLIMB trial (NCT02614794), 612 patients with unresectable locally advanced or metastatic HER2-positive breast cancer who previously received trastuzumab, pertuzumab (Perjeta), and ado-trastuzumab emtansine (T-DM1; Kadcyla) were randomized 2:1 to receive trastuzumab and capecitabine combined with either tucatinib (n = 410) or placebo (n = 202).  

Tucatinib was administered orally at 300 mg twice daily during each 21-day cycle. In both arms, patients received capecitabine at 1000 mg/m² orally twice daily on days 1 to 14 of each 21-day cycle, and trastuzumab at 8 mg/kg intravenously on day 1 of cycle 1, followed by 6 mg/kg thereafter on day 1 of each 21-day cycle.

  The primary endpoint was progression-free survival (PFS); secondary endpoints included OS, PFS in patients with brain metastases, and confirmed objective response rate (ORR). The primary PFS endpoint was measured in the first 480 patients enrolled. Through an early amendment to the study protocol, the target population was increased from 480 to 600 patients to provide adequate power to the secondary endpoint of PFS in patients with brain metastases.  

The key baseline characteristics were well balanced between the 2 arms. The median age was approximately 55 years old, and 99% of patients were female. Approximately half of the patients in each arm had an ECOG performance status of 0 or 1, and about two-thirds of patients in each arm were estrogen receptor— and/or progesterone receptor–positive. Patients in both arms had received a median of 4 prior therapies overall and a median of 3 prior therapies in the metastatic setting.

  In the tucatinib arm, 48% (n = 198) of patients had brain metastases at baseline compared with 46% (n = 93) of patients in the control arm.

 The data cutoff date was September 4, 2019, and the median follow-up was 14 months. Results showed that the confirmed ORR was 41% in the tucatinib arm compared with 23% in the control arm (P = .00008). The ORR in the tucatinib group comprised a 1% complete response (CR) rate and 40% partial response (PR) rate; the stable disease (SD) rate 46% and the progressive disease (PD) rate was 8%. In the control group, the CR rate was 1%, the PR rate was 22%, the SD rate was 59%, and the PD rate was 14%.

Additionally, the median OS was 21.9 months (95% CI, 18.3-31.0) with the tucatinib triplet compared with 17.4 months (95% CI, 13.6-19.9) with trastuzumab and capecitabine alone. The 1- and 2-year OS rates were 76% versus 62% and 45% versus 27% in the tucatinib and control arms, respectively. The OS benefit was upheld across all prespecified subgroups.  

The addition of tucatinib also led to a median PFS of 7.8 months (95% CI, 7.5-9.6) versus 5.6 months with trastuzumab/capecitabine alone (95% CI, 4.2-7.1), leading to a 46% reduction in the risk of disease progression or death (HR, 0.54; 95% CI, 0.42-0.71; P <.00001). The 6-month and 1-year PFS rates were 63% versus 46% and 33% versus 12%, respectively. The PFS benefit was upheld across all clinically significant prespecified subgroups.  

Notably, the tucatinib triplet reduced the risk of disease progression or death by 52% (HR, 0.48; 95% CI, 0.34-0.69; P <.00001) in patients with brain metastases at baseline. The median PFS in this subpopulation with high unmet medical need was 7.6 months with tucatinib versus 5.4 months in the control arm. The 1-year PFS rates were 25% versus 0%, respectively. A subgroup analysis also indicated an OS benefit with tucatinib in this subgroup (HR, 0.58, 95% CI, 0.40-0.85).  

The safety population included patients who received ≥1 dose of study treatment (n = 601). The median duration of treatment exposure was 5.8 months in the tucatinib arm and 4.4 months in the placebo arm. At the data cutoff, 29% of patients remained on treatment in the tucatinib group versus 14% in the placebo group. In both arms, disease progression was the main reason for treatment discontinuation at 49% versus 66%, respectively.  

Moreover, grade ≥3 adverse events (AEs) occurred in 55% of patients on the tucatinib arm compared with 49% of those on the control arm. There were 6 and 5 AE-related deaths in the tucatinib and control groups, respectively.   The most frequently occurring all-grade AE in both arms was diarrhea at 81% (13% grade ≥3) versus 53% (9% grade ≥3) in the tucatinib versus control arms, respectively; however, antidiarrheal prophylaxis was not required.

  All-grade palmar-plantar erythrodysesthesia syndrome was also common in both groups at 63% (13% grade ≥3) versus 53% (9% grade ≥3) with the triplet versus trastuzumab/capecitabine alone, respectively.

In December 2019, Seattle Genetics submitted a new drug application to the FDA for tucatinib for use in combination with trastuzumab and capecitabine for the treatment of patients with unresectable locally advanced or metastatic HER2-positive breast cancer, including patients with brain metastases, following ≥3 prior HER2-directed agents separately or in combination, in the neoadjuvant, adjuvant, or metastatic setting. The submission was also based on the HER2CLIMB findings.

References

EMA Validates Seattle Genetics’ Marketing Authorization Application for Tucatinib for Patients with Locally Advanced or Metastatic HER2-Positive Breast Cancer [news release]: Bothell, WA. Seattle Genetics, Inc. Published January 31, 2020. https://bwnews.pr/31eti3d. Accessed January 31, 2020.
Murthy R, Loi S, Okines A, et al. Tucatinib vs placebo, both combined with capecitabine and trastuzumab, for patients with pretreated HER2-positive metastatic breast cancer with and without brain metastases (HER2CLIMB). Presented at: 2019 San Antonio Breast Cancer Symposium; December 10-14; San Antonio, TX. Abstract GS1-01.
Murthy RK, Loi S, Okines A, et al. Tucatinib, trastuzumab, and capecitabine for HER2-positive metastatic breast cancer [published online December 11, 2019]. N Engl J Med. doi: 10.1056/NEJMoa1914609.