HER2-Positive Metastatic Breast Cancer

FDA OKs First Targeted Treatment for HER2-Positive Colorectal Cancer

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Second-line tucatinib plus trastuzumab combo gets accelerated approval in metastatic disease

FDA APPROVED tucatinib (TUKYSA) over a computer rendering of colorectal cancer.

The FDA has granted accelerated approval to tucatinib (Tukysa) in combination with trastuzumab (Herceptin) for adult patients with RAS wild-type, HER2-positive unresectable or metastatic colorectal cancer who have progressed following treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, Seagen announcedopens in a new tab or window.

This is the first FDA-approved treatment for HER2-positive metastatic colorectal cancer, the company noted.

Approval was based on results from the phase II MOUNTAINEER trialopens in a new tab or window, showing a 38% overall response rate (95% CI 28-49) with the combination per blinded independent central review. Complete responses were observed in 3.6% of patients and partial responses were seen in 35%. The median duration of response was 12.4 months (95% CI 8.5-20.5).

“Historically, patients with HER2-positive metastatic colorectal cancer who have progressed following frontline therapy have had poor outcomes,” said lead investigator John Strickler, MD, of Duke University Medical Center in Durham, North Carolina, in a press release. “The FDA approval of a chemotherapy-free combination regimen that specifically targets HER2 is great news for these patients.”

The multicenter, open-label, randomized, phase II MOUNTAINEER trial evaluated 84 patients with RAS wild-type, HER2-positive unresectable or metastatic colorectal cancer following previous treatment with standard-of-care therapies. They had not received prior anti-HER2 therapy.

At study entry, 64% and 70% of these patients had liver or lung metastases, respectively.

Patients received tucatinib 300 mg twice daily orally in combination with trastuzumab intravenously (8 mg/kg loading dose, then 6 mg/kg every 3 weeks thereafter) until disease progression or unacceptable toxicity.

The prescribing information for tucatinib includes warnings and precautions for diarrhea, hepatotoxicity, and embryo-fetal toxicity, some of which may be severe or fatal.

The most common adverse reactions (≥20%) in patients treated with the combination were diarrhea, fatigue, rash, nausea, abdominal pain, infusion-related reactions, and pyrexia. Serious adverse reactions occurred in 22% of patients, with intestinal obstruction (7%), urinary tract infection (3.5%), and pneumonia, abdominal pain, and rectal perforation (2.3% each) being the most common.

Adverse reactions leading to permanent discontinuation of tucatinib occurred in 6% of patients.

Cardiac Safety of Paclitaxel Plus Trastuzumab and Pertuzumab in Patients With HER2-Positive Metastatic Breast Cancer

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Abstract

Introduction.

Myocardial strain imaging and blood biomarkers have been proposed as adjuncts to left ventricular ejection fraction (LVEF) monitoring for the early detection of cardiotoxicity during cancer therapy. We report the results of a preplanned cardiac safety analysis of global longitudinal strain (GLS), and troponin-I (TnI) and brain natriuretic peptide (BNP) levels in the phase II study of paclitaxel, trastuzumab, and pertuzumab (THP) for metastatic HER2-positive breast cancer.

Patients and Methods.

Patients with 0–1 lines of prior therapy were treated with weekly paclitaxel (80 mg/m2) plus trastuzumab (8 mg/kg loading dose followed by 6 mg/kg) and pertuzumab (840 mg loading dose followed by 420 mg) every 3 weeks. Exploratory endpoints were GLS measured with speckle-tracking echocardiography every 3 months and TnI and BNP levels measured every 6 weeks (immediately pre- and postchemotherapy infusion) at 6 time points.

Results.

Sixty-seven of 69 enrolled patients were treated with THP: 19 (28%) had hypertension, 8 (12%) had diabetes, 11 (16%) had hyperlipidemia, and 26 (38%) had smoking history. After a median follow-up of 21 months (range: 3–38 months), no patients developed symptomatic heart failure. Two patients (3.0%) experienced asymptomatic LVEF decline (grade 2). The mean GLS (±SD) was 19% ± 2% (baseline), 19% ± 2% (month 6), and 19% ± 3% (month 12). Detectable TnI (>0.06 ng/mL) and elevated BNP (>100 pg/mL) levels were observed in 3 (4.3%) and 2 (3.0%) patients, respectively, but were not associated with LVEF decline.

Conclusion.

The absence of any significant changes in GLS and cardiac biomarkers (TnI and BNP) further support the cardiac safety of THP in patients with metastatic HER2-positive breast cancer.

Implications for Practice:

Dual anti-HER2 therapy with trastuzumab and pertuzumab in combination with taxane-based chemotherapy improves overall survival in patients with metastatic HER2-positive breast cancer. There is a critical need to investigate the potential cardiotoxicity of dual anti-HER2 blockade, given the importance of HER2 signaling in cardiac homeostasis and stress response. Global longitudinal strain and cardiac biomarkers have been proposed as adjuncts to left ventricular ejection fraction for the early detection of cardiotoxicity. In this phase II study of combination trastuzumab and pertuzumab with paclitaxel, no clinically significant change was observed in global longitudinal strain or cardiac biomarkers. These results further support the cardiac safety of dual anti-HER2 blockade previously reported in the CLEOPATRA study. The findings in the current study also call into question the role of intensive cardiac monitoring among patients treated with anti-HER2 therapy in the absence of anthracyclines. Less frequent cardiac assessments could lead to a reduction in unnecessary treatment interruption and is an important consideration given the rise in medical expenditures, but this requires further investigation.