In This Article
- Adding Tucatinib to Trastuzumab and Capecitabine Improves Survival in HER2-Positive Metastatic Breast Cancer
- Trastuzumab Deruxtecan Shows Durable Antitumor Activity in HER2-Positive Metastatic Breast Cancer
- First-Line Osimertinib Therapy Boosts Overall Survival in Non–Small-Cell Lung Cancer
Adding Tucatinib to Trastuzumab and Capecitabine Improves Survival in HER2-Positive Metastatic Breast Cancer
BACKGROUND: Up to 50% of patients with advanced or metastatic HER2-positive breast cancer may have brain metastases, for which effective treatment options are limited. A phase 1b dose-escalation clinical trial of tucatinib, an oral tyrosine kinase inhibitor, in combination with trastuzumab and capecitabine showed antitumor activity in patients with HER2-positive breast cancer, including patients with brain metastases. In a new study, researchers evaluated the use of tucatinib plus trastuzumab and capecitabine in patients who previously received trastuzumab, pertuzumab, and trastuzumab emtansine for the treatment of metastatic HER2-positive breast cancer. In December 2019, the US Food and Drug Administration granted tucatinib, in combination with trastuzumab and capecitabine, a breakthrough therapy designation for this patient population.
METHODS: HER2CLIMB was a randomized, double-blind, placebo-controlled phase 2 clinical trial that included 612 patients with unresectable locally advanced or metastatic HER2-postive breast cancer, some of whom had brain metastases. The patients were randomized in a 2:1 ratio to trastuzumab and capecitabine plus tucatinib or to placebo.
In all, 47.5% of the patients had brain metastases at baseline. Tucatinib was administered orally at 300 mg twice daily during each 21-day cycle. In both cohorts, the patients received capecitabine 1000 mg/m2 orally twice daily on days 1 to 14 of each 21-day cycle, and trastuzumab 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 end point was progression-free survival (PFS). The secondary end points included overall survival, PFS in patients with brain metastases, and tolerability.
RESULTS: The tucatinib triplet led to a 46% risk reduction for disease progression or death compared with trastuzumab and capecitabine, with a median PFS of 7.8 months and 5.6 months, respectively. The 1-year PFS rates were 33.1% and 12.3%, respectively. Among patients with brain metastases at baseline, the risk for disease progression or death was reduced by 52% in the tucatinib arm, and the median PFS was 7.6 months in the tucatinib arm and 5.4 months in the placebo arm. The 1-year PFS rates were 24.9% and 0%, respectively. The median overall survival was 21.9 months in the tucatinib arm versus 17.4 in the placebo arm. The 2-year overall survival rates were 44.9% versus 26.6%, respectively.
The tucatinib-based regimen was generally well-tolerated, with mostly low-grade adverse events. Grade ≥3 adverse events were 55.2% in the tucatinib arm versus 48.7% in the placebo arm. Diarrhea was the most common all-grade event in both arms; grade ≥3 diarrhea was 12.9% and 8.6%, respectively. Liver transaminase levels were higher in the tucatinib arm, including grade ≥3 aspartate aminotransaminase (4.5%) and alanine aminotransaminase (5.4%). However, these were mostly low-grade, transient, and reversible events.
Source: Schuster Murthy RS, Loi S, Okines A, et al. Tucatinib, trastuzumab, and capecitabine for HER2-positive metastatic breast cancer. N Engl J Med. 2020;382:597-609.
Trastuzumab Deruxtecan Shows Durable Antitumor Activity in HER2-Positive Metastatic Breast Cancer
BACKGROUND: The phase 1 results of trastuzumab deruxtecan were promising in patients with metastatic breast cancer and varying level s of HER2 expression. This finding led to the recently published phase 2 DESTINY-Breast01 study in patients with HER2-postive metastatic breast cancer. Based on the results of this study, on December 20, 2019, the US Food and Drug Administration granted accelerated approval to trastuzumab deruxtecan for the treatment of unresectable or metastatic HER2-positive breast cancer in adults who have received ≥2 previous anti–HER2-based regimens in the metastatic setting.
METHODS: DESTINY-Breast01 was a 2-part, open-label, single-group, phase 2 clinical trial that enrolled 184 patients with metastatic HER2-positive breast cancer who had received trastuzumab emtansine and a median of 6 treatments for advanced disease. In the first part of the study, the researchers evaluated 3 different doses of trastuzumab deruxtecan to establish the recommended dose of 5.4 mg/kg. In the second part of the study, the efficacy and safety of trastuzumab deruxtecan were assessed. The primary end point was confirmed objective response rate (ORR). The secondary end points included disease control rate, duration of response, and progression-free survival (PFS).
RESULTS: Trastuzumab deruxtecan induced a confirmed ORR of 60.9%; of the responding patients, 6% had a complete response and 54.9% had a partial response. The median time to response was 1.6 months, and the median duration of response was 14.8 months, with a disease control rate of 97.3%. The clinical benefit rate was 76.1% at 6 months. After a median follow-up of 11.1 months, the median PFS was 16.4 months, with a PFS of 18.4 months in 24 patients with brain metastases. The overall survival rates were 93.9% at 6 months and 86.2% at 12 months; the median overall survival was not reached.
Treatment-emergent adverse events occurred in 99% of patients, and 57.1% of the patients had ≥3 events. The most common any-grade events were nausea (77.7%), fatigue (49.5%), alopecia (48.4%), vomiting (45.7%), constipation (35.9%), decreased neutrophil count (34.8%), decreased appetite (31%), anemia (29.9%), and diarrhea (29.3%).
Although most adverse events were low grade, 25 (13.6%) patients had interstitial lung disease related to trastuzumab deruxtecan treatment. At the data cutoff, 7 patients recovered, 2 were recovering, 10 had ongoing interstitial lung disease, and 4 patients died; the status of 2 patients was unknown.
“In this global, phase 2 study, trastuzumab deruxtecan had a high level of clinical activity in patients with HER2-positive metastatic breast cancer who had undergone extensive previous therapies,” the researchers observed. “Such therapy was associated with a substantial risk of interstitial lung disease, a toxic effect that requires attention to pulmonary symptoms and careful monitoring.”
Source: Modi S, Saura C, Yamashita T, et al. Trastuzumab deruxtecan in previously treated HER2-positive breast cancer. N Engl J Med. 2020;382:610-621.
First-Line Osimertinib Therapy Boosts Overall Survival in Non–Small-Cell Lung Cancer
BACKGROUND: The phase 3 FLAURA clinical trial of patients with advanced non–small-cell lung cancer (NSCLC) and epidermal growth factor receptor (EGFR) mutation showed that those who received the third-generation tyrosine kinase inhibitor (TKI) osimertinib had significantly longer progression-free survival (PFS) and overall survival than patients who received a comparator EGFR-TKI. This primary analysis led the US Food and Drug Administration to approve an extended indication for osimertinib as first-line treatment for advanced NCSLC with EGFR mutation. However, the overall survival data were too immature at the time of publication. The researchers noted that, “Understanding resistance mechanisms after first-line treatment and determining appropriate therapies on the basis of molecular-resistance profiles remain important considerations.” This report provides the overall survival data from the planned updated analysis of overall survival in the FLAURA study.
METHODS: FLAURA was a randomized, double-blind, phase 3 clinical trial that included 556 patients with treatment-naïve advanced NSCLC and an EGFR mutation (exon 19 deletion or L858R allele). The patients were randomized in a 1:1 ratio to osimertinib 80 mg once daily or to 1 of 2 other EGFR-TKIs—gefitinib 250 mg once daily or erlotinib 150 mg once daily.
RESULTS: The median overall survival (the secondary end point) was 38.6 months with osimertinib versus 31.8 months with the comparator drugs (hazard ratio for death, 0.80; P = .046). At 3 years, 28% and 9% of patients, respectively, continued to receive the drug regimen. At the time of data cutoff, the median duration of exposure to treatment was 20.7 months in the osimertinib group and 11.5 months in the comparator group. There were 116 of the 656 patients who had central nervous system (CNS) metastases at study entry, and their overall survival was similar to that in patients without CNS metastases. In addition, 54% of patients in the osimertinib group were alive at 3 years versus 44% of patients in the comparator group. The rate of grade ≥3 adverse events was 42% in the osimertinib group and 47% in the comparator group.
“First-line treatment with osimertinib was associated with significantly longer overall survival than treatment with comparator EGFR-TKIs in patients with EGFR mutation-positive, locally advanced or metastatic NSCLC and had a similar safety profile,” the researchers suggested.
Source: Ramalingam SS, Vansteenkiste J, Planchard D, et al. Overall survival with osimertinib in untreated, EGFR-mutated advanced NSCLC. N Eng J Med. 2020;382:41-50.