The addition of Tukysa (tucatinib) to Kadcyla (ado-trastuzumab emtansine) improved progression-free survival compared with placebo plus Kadcyla.
In patients with previously treated HER2-positive metastatic breast cancer, including those with brain metastases, the addition of Tukysa (tucatinib) to Kadcyla (ado-trastuzumab emtansine) enhanced progression-free survival (PFS; the time a patient lives without their disease spreading or worsening) compared with placebo plus Kadcyla, according to findings from the primary analysis of a phase 3 trial.
Data presented at the 2023 San Antonio Breast Cancer Symposium showed that Tukysa plus Kadcyla generated 151 PFS events and a median PFS of 9.5 months versus 182 PFS events and a median PFS of 7.4 months in patients who received Kadcyla plus placebo.
The 99 patients with brain metastases who received Tukysa in combination with Kadcyla experienced 70 PFS events and achieved a median PFS of 7.8 months. Conversely, those with brain metastases in the placebo arm (105 patients) experienced 85 PFS events and achieved a median PFS of 5.7 months.
The selective, HER2-directed tyrosine kinase inhibitor Tukysa was previously approved by the Food and Drug Administration in 2020 for patients with previously treated, HER2-positive, unresectable locally advanced or metastatic breast cancer, including those with brain metastases, who had received at least one prior HER2-directed therapy in the metastatic setting.
This regulatory decision was supported by findings from the phase 2 HER2CLIMB trial, in which the addition of Tukysa to Herceptin (trastuzumab) and capecitabine led to a one-year PFS rate of 24.9% in patients with brain metastases. Among patients with brain metastases enrolled in the placebo arm, the one-year PFS rate was 0%.
“Both preclinical and phase 1 and 2 clinical data have indicated that the combination of (Kadcyla) with (Tukysa) has promising clinical activity and antitumor responses, as well as a manageable safety profile (in HER2-positive disease),” lead study author, Dr. Sara A. Hurvitz of Fred Hutchinson Cancer Center in Seattle, Washington, stated during a presentation of the data.
The phase 3 HER2CLIMB-02 trial enrolled patients with HER2-positive locally advanced or metastatic breast cancer whose disease had progressed following treatment with Herceptin and a taxane in any setting.
Patients were required to have an ECOG performance status (PS) of 1 or 0, meaning they can perform daily tasks with little or no help, and have previously treated stable, progressing or untreated brain metastases that did not require immediate local therapy.
Patients were not eligible for enrollment if they had previously received Tukysa, Gilotrif (afatinib), Enhertu (fam-trastuzumab deruxtecan-nxki) or any investigational EGFR inhibitors, HER2 inhibitors or HER2-directed TKIs.
Patients who had received prior Tykerb (lapatinib) and Nerlynx (neratinib) were not eligible for enrollment if they received these agents within 12 months of initiating the HER2CLIMB-02 regimen.
Patients with prior Tykerb and Nerlynx exposure were permitted to enroll in the study provided they received the agents for no more than 21 days and discontinued the drugs for reasons other than disease progression or severe toxicity. Patients who had received prior pyrotinib for metastatic or recurrent breast cancer were ineligible.
Patients were stratified by line of treatment for metastatic disease (first line versus other), hormone receptor (HR) status (positive versus negative), presence or history of brain metastases (yes versus no), and ECOG PS (0 versus 1).
The primary endpoint of this trial was investigator-assessed PFS. Key hierarchical secondary endpoints included overall survival (OS; how long patients lived regardless of disease status), PFS in patients with brain metastases, confirmed overall response rate (patients whose disease responded partially or completely to treatment) criteria and OS in patients with brain metastases.
The 228 patients in the Tukysa arm had a median age of 55, and 99.1% of patients were female. In total, 46.1%, 23.2% and 30.7% of patients were from North America, Europe/Israel and Asia-Pacific regions, respectively.
Most patients had HR-positive disease (60.1%) and an ECOG PS of 0 (60.1%). Overall, 43.4% of patients had a presence or history of brain metastases, 21.9% of patients had active metastases and 21.5% of patients had treated stable metastases. Most patients had stage 0 to 3 disease at diagnosis (52.6%) and patients had a median of one prior line of therapy in the metastatic setting.
The 235 patients in the placebo arm had a median age of 53 and all patients were female. In total, 39.6%, 32.8% and 27.7% of patients were from North America, Europe/Israel and Asia-Pacific regions, respectively. Most patients had HR-positive disease (59.6%) and an ECOG PS of 0 (60%).
Overall, 44.7% of patients had a presence or history of brain metastases, 24.3% of patients had active metastases and 20.4% of patients had treated stable metastases. Most patients had stage 0 to 3 disease at diagnosis (55.3%), and patients had a median of one prior line of therapy in the metastatic setting.
At a median follow-up of 24.4 months, 53% of the prespecified OS events had been observed. There were 71 and 63 OS events that occurred in the Tukysa and placebo arms, respectively.
The median OS was not reached (meaning more than half of those patients were still alive) in the Tukysa arm versus 38 months in the placebo arm. Patients in both arms received comparable subsequent systemic therapies. Approximately 50% and 30% of patients received subsequent Enhertu or Tukysa, respectively.
Of the 231 patients evaluable for safety in the Tukysa arm, any-grade treatment-emergent side effects occurred in 99.6% of patients, with those of grade 3 or higher observed in 68.8% and serious side effects occurred in 30.3%.
Treatment discontinuation due to treatment-emergent side effects occurred in 17.3% and 20.3% of patients on Tukysa or Kadcyla, respectively. Treatment-emergent side effects led to death in 1.3% of patients.
The median duration of treatment was 7.4 months with Tukysa and 7.5 months with Kadcyla. Increased alanine aminotransferase (ALT; potentially indicating liver damage) led to Tukysa discontinuation in 2.6% of patients in this arm.
All 233 patients evaluable for safety in the placebo arm experienced any grade side effects. Treatment-emergent side effects of grade 3 or higher were observed in 41.2% of patients and serious treatment-emergent side effects occurred in 22.3%.
Furthermore, 6.9% and 11.2% of patients discontinued placebo and Kadcyla, respectively, because of treatment-emergent side effects. Treatment-emergent side effects led to death in two patients. The median duration of treatment was 6.2 months for both placebo and Kadcyla. No patients in this arm experienced discontinuation of placebo because of increased ALT.
The most common treatment-emergent side effects leading to Kadcyla discontinuation were increased ALT (Tukysa arm, 2.2%; placebo arm, 0%), thrombocytopenia (low platelet count in the blood; 2.2% versus 0%) and interstitial lung disease (0% versus 2.1%).
Overall, the most common treatment-emergent side effects in the Tukysa arm were nausea (grade 1/2, 61.9%; grade 3 or higher, 3.5%), diarrhea (51.9%; 4.8%), fatigue (42.8%; 6.1%), vomiting (35.1%; 1.7%), increased aspartate aminotransferase (AST, a potential indicator of liver disease; 19.4%; 16.5%), increased ALT (18.1%; 16.5%), headache (34.6%; 1.3%), epistaxis (nosebleeds; 33.8%; 0.4%), decreased appetite (32.9%; 0.9%), constipation (25.9%; 0.9%), pyrexia (fever; 22.9%; 0.9%) and arthralgia (joint pain; 23.0%; 0.4%).
The most common treatment-emergent side effects in the placebo arm were nausea (grade 1/2, 47.3%; grade 3 or higher, 2.1%), diarrhea (25.7%; 0.9%), fatigue (34.3%; 3.0%), vomiting (15.1%; 2.1%), increased AST (16.7%; 2.6%), increased ALT (14.6%; 2.6%), headache (38.2%; 0.9%), epistaxis (19.3%; 0.4%), decreased appetite (21.8%; 0.9%), constipation (32.6%; 0.4%), pyrexia (14.6%; 0.0%) and arthralgia 24.9%; 2.1%).
The most common treatment-emergent side effects of grade 3 or higher in the Tukysa and placebo arms, respectively, were increased ALT (16.5% versus 2.6%), increased AST (16.5% versus 2.6%), anemia (8.2% versus 4.7%), thrombocytopenia (7.4% versus 2.1%) and fatigue (6.1% versus 3.0%).
“Looking closer at the hepatic (treatment-emergent side effects) … increases in grade 3 or higher observed events in the (Tukysa) arm were driven by transaminase elevations,” Hurvitz noted. “The majority of these hepatic (events) resolved or returned to grade 1, with a median of 22 days to resolution.”
“The types of (side effects) were consistent with previous reporting, and this is the second randomized study that included patients with brain metastases to demonstrate that a (Tukysa)-based regimen delays disease progression in this disease setting,” Hurvitz concluded.
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