Tucatinib combined with trastuzumab and capecitabine improved overall survival and progression-free survival compared with trastuzumab/capecitabine alone in heavily pretreated patients with locally advanced unresectable or metastatic HER2-positive breast cancer.
Roger Dansey, MD
Tucatinib combined with trastuzumab (Herceptin) and capecitabine (Xeloda) improved overall survival (OS) and progression-free survival (PFS) compared with trastuzumab/capecitabine alone in heavily pretreated patients with locally advanced unresectable or metastatic HER2-positive breast cancer, according to topline findings from the phase II HER2CLIMB trial (NCT02614794).1
Results showed that that the addition of the small molecule TKI to trastuzumab and capecitabine led to a 34% reduction in the risk of death over trastuzumab/capecitabine alone (HR, 0.66; 95% CI, 0.50-0.88; P = .0048).
Additionally, the tucatinib triplet improved PFS over trastuzumab/capecitabine alone, demonstrating a 46% reduction in the risk of disease progression or death (HR, 0.54; 95% CI, 0.42-0.71; P <.00001). The tucatinib arm was also associated with a 52% reduction in the risk of disease progression or death in patients who had brain metastases at baseline (HR, 0.48; 95% CI, 0.34-0.69; P <.00001).
“There is significant unmet medical need following treatment with trastuzumab, pertuzumab, and T-DM1 in patients with metastatic HER2-positive breast cancer,” Roger Dansey, MD, chief medical officer at Seattle Genetics, the developer of tucatinib, stated in a press release. “The addition of tucatinib to the commonly used doublet of trastuzumab and capecitabine represents a potential significant clinical advance for patients with metastatic HER2-positive breast cancer, importantly, including those with brain metastases.
“Based on these findings, we plan to unblind the trial and offer tucatinib to patients on the control arm. We also plan to submit a New Drug Application to the FDA in the first quarter of 2020, with the goal of bringing a much-needed new medicine to patients.”
Regarding safety, tucatinib plus trastuzumab/capecitabin was found to be well tolerated with a manageable safety profile. The most frequent adverse events (AEs) with the 3-drug regimen was diarrhea, palmar-plantar erythrodysesthesia syndrome, nausea, fatigue, and vomiting. Grade ≥3 AEs with the tucatinib regimen versus trastuzumab/capecitabine alone included diarrhea (12.9% vs 8.6%, respectively), increased aspartate aminotransferase (4.5% vs 0.5%), increased alanine aminotransferase (5.4% vs 0.5%). and increased bilirubin (0.7% vs 2.5%).
Additionally, there was no requirement for prophylactic antidiarrheals. AEs that led to discontinuations were infrequent in both arms (5.7% and 3.0%).
In the international, double-blind, placebo-controlled, active comparator, pivotal HER2CLIMB trial, patients with locally advanced or metastatic HER2-positive breast cancer who were previously treated with trastuzumab, pertuzumab (Perjeta), and ado-trastuzumab emtansine (T-DM1; Kadcyla) were randomized 2:1 to receive tucatinib in combination with trastuzumab and capecitabine or trastuzumab and capecitabine alone. Forty-seven percent of patients had brain metastases at time of enrollment. No crossover was permitted.
Tucatinib was administered orally at 300 mg twice daily, capecitabine at 1000 mg/m2 orally twice daily on days 1 to 14 of each 21-day cycle, and trastuzumab is given at 8 mg/kg intravenously on day 1 of cycle 1 and followed by 6 mg/kg on day 1 of each 21-day cycle. Where indicated, trastuzumab can be given at 600 mg subcutaneously once every 3 weeks at either study initiation or crossing over from prior IV trastuzumab.
To be eligible for enrollment, patients had to have histologically confirmed HER2-positive breast carcinoma; received prior treatment with trastuzumab, pertuzumab, and T-DM1; had progression of unresectable locally advanced or metastatic breast cancer after last systemic therapy or be intolerant of last systemic therapy; have measurable or nonmeasurable disease assessable by RECIST v1.1 criteria; have an ECOG performance status of 0 or 1; have adequate hepatic and renal function and hematologic parameters; and a left ventricular ejection fraction ≥50%.
Patients who were treated with lapatinib (Tykerb) within 12 months of starting study treatment, neratinib (Nerlynx), afatinib (Gilotrif), another investigational HER2/EGFR or HER2 TKI, or capecitabine were excluded from enrollment. Additionally, those with clinically significant cardiopulmonary disease; hepatitis B, C, or another chronic liver disease; were HIV positive; were unable to undergo brain MRIs; received strong CYP3A4 or CYP2C8 inhibitors within a specific time frame; and have known dihydropyridine dehydrogenase deficiency also could not enroll on the trial.
Stratification factors included the presence or history of treated or untreated brain metastases or brain lesions of equivocal significance, ECOG performance status of 0 or 1, and region of world.
The primary endpoint is PFS per RECIST v1.1 criteria as determined by blinded independent central review in the first 480 patients enrolled on the study; secondary endpoints include PFS in patients with brain metastases at baseline, OS, investigator-assessed PFS via RECIST v1.1 criteria, objective response rate (ORR), duration of response (DOR), clinical benefit rate, incidence of AEs, incidence of health resources utilization, quality of life as measured by EQ-5D-5L questionnaire, and pharmacokinetic measure for Ctrough.
The trial enrolled 612 patients total to support the analyses of key secondary endpoints, including OS as well as PFS in patients with brain metastases at baseline. The safety data were evaluated throughout the study.
Further HER2CLIMB data are expected to be presented at the 2019 San Antonio Breast Cancer Symposium.
Previously, phase Ib results of a nonrandomized, open-label study showed that tucatinib used in combination with capecitabine, trastuzumab, or both agents showed promising antitumor activity in heavily pretreated women with HER2-positive breast cancer with or without brain metastases.2 Results showed that 83% of patients with measurable disease treated with tucatinib/capecitabine had an objective response, as did 40% of patients receiving tucatinib/trastuzumab. A total 61% of patients treated with all 3 drugs had an objective response.
Moreover, the median DOR was 8.9 months (range, 1.4-8.9) in the tucatinib/trastuzumab arm, 5.2 months (range, 2.1-7.6) in the tucatinib/capecitabine arm, and 11.0 months (range, 2.9-18.6) with the triplet regimen.
Tucatinib is also being evaluated in a randomized, double-blind, placebo-controlled, multi-center phase III trial (NCT03975647) in combination with T-DM1 compared with T-DM1 alone in patients with unresectable, locally advanced or metastatic HER2-positive breast cancer, including those with brain metastases, who have had prior treatment with a taxane and trastuzumab. The primary endpoint is PFS per RECIST criteria; secondary endpoints include OS, ORR, and DOR. The trial is being conducted in North America, Europe and Asia and is expected to enroll approximately 460 patients.