Click Here to
Subscribe
Breaking
News, Updates,
& More
Stay Up
to Date

Concise Reviews of Studies Relevant to Hematology Oncology Pharmacy

JHOP - April 2020 Vol 10, No 2 - From the Literature
Download pdf
Robert J. Ignoffo, PharmD, FASHP, FCSHP

Professor of Pharmacy
College of Pharmacy
Touro University–California, Mare Island
Vallejo, CA
Clinical Professor Emeritus
University of California
San Francisco, CA

Professor Emeritus, Professor
Professor

In This Article


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.

Commentary by Robert J. Ignoffo

This phase 3 clinical trial of tucatinib showed improved PFS and overall survival in all subgroups of patients with heavily pretreated, HER2-positive breast cancer, including those with untreated and previously treated brain metastases, which is a population typically excluded from clinical trials. Patients with and without brain metastases showed benefit. Almost 50% of the more than 600 patients in this study had brain metastases; at 2 years, these patients had 4.5-month longer survival than those who received placebo. At 12 months, the proportion of disease-free patients was more than 2.5 times that in the placebo group (33.1% vs 12%, respectively), and the overall survival rate was 34% better in the tucatinib group than in the placebo group.

In a review of real-world data (nonrandomized from 5 institutions in China), trastuzumab plus lapatinib and capecitabine, given as second-line therapy, resulted in a PFS of 11.4 months.1 These results were comparable with the current study showing improvement of 7.8 months in all patients and 7.6 months improvement for those with brain metastases. In the real-world study, the PFS for those with brain metastases was 10.6 months.1

The results from both studies suggest that triple therapy (with a tyrosine kinase inhibitor plus trastuzumab and capecitabine) is effective in patients with heavily treated, metastatic HER2 positive breast cancer. The National Comprehensive Cancer Network (NCCN) has not evaluated the use of tucatinib therapy in its latest treatment recommendation update, but based on the current phase 3 clinical trial, the use of tucatinib as part of a triple therapy for this patient population should be classified as an “other recommended regimen” in the NCCN guidelines.

1. Li Y, Gong C, Lu Q, et al. Real-world data of triplet combination of trastuzumab, lapatinib, and chemotherapy in HER2-positive metastatic breast cancer: a multicenter retrospective study. Front Oncol. 2020;10:271.

Return to Top


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.

Commentary by Robert J. Ignoffo

This phase 2 clinical trial showed a remarkable response rate with trastuzumab deruxtecan treatment in heavily pretreated patients with HER2-positive metastatic breast cancer. A 60% response rate after an average of 6 treatments indicates that this antibody–drug conjugate is a truly effective agent. Trastuzumab deruxtecan is designed to have a higher drug-to-antibody ratio (8:4 vs 3:4) than trastuzumab emtansine. In addition, the released cytotoxic payload with trastuzumab deruxtecan crosses cell membranes more easily than with trastuzumab emtansine. Because trastuzumab emtansine is very effective in the second-line setting, it would be of interest to compare this drug in a clinical trial with trastuzumab deruxtecan.

The National Comprehensive Cancer Network (NCCN) has included trastuzumab deruxtecan as an option in its guidelines for patients with HER2-positive metastatic breast cancer who have received ≥2 lines of HER2-targeted therapy. However, the NCCN cautions that trastuzumab deruxtecan is contraindicated in patients with interstitial lung disease.

Return to Top


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.

Commentary by Robert J. Ignoffo

In a previous analysis of the FLAURA study, the hazard ratio for disease progression or death was 0.46), regardless of T790M mutation status.1 The new phase 3 clinical trial has shown that osimertinib is one of the most effective treatments to date for advanced NSCLC with sensitizing EGFR-positive status. In its guidelines for the treatment of NSCLC (version 3.2020), the NCCN designated osimertinib as the preferred first-line drug in this setting. This study showed a long period of follow-up of 39 months in both groups, and, in the osimertinib group, a 6.8-month longer median survival, a 20% lower mortality risk, and 3 times as many patients who continued receiving osimertinib compared with the comparator group. Of note, osimertinib treatment is effective in patients with CNS metastases. Regarding the safety of osimertinib, most adverse events in the study were grade 1, and serious adverse events occurred in 27% of the patients in both groups.

In another study of subsequent therapy, patients who had disease progression with another EGFR inhibitor (ie, erlotinib, gefitinib, or afatinib) had increased PFS for much longer than patients who received chemotherapy.2

Osimertinib is a very effective treatment for EGFR mutation–positive advanced NSCLC and deserves its first-line treatment status.

  1. Soria J-C, Ohe Y, Vansteenkiste J, et al; for the FLAURA Investigators. Osimertinib in untreated EGFR-mutated advanced non–small-cell lung cancer. N Engl J Med. 2018;378:113-125.
  2. Mok TS, Wu Y-L, Ahn M-J, et al; for the AURA3 Investigators. Osimertinib or platinum–pemetrexed in EGFR T790M–positive lung cancer. N Engl J Med. 2017;376:629-640.

Return to Top

Related Items
Concise Reviews of Studies Relevant to Hematology Oncology Pharmacy
JHOP - March 2019 Vol 9, No 1 published on March 13, 2019 in From the Literature
Concise Reviews of Studies Relevant to Hematology Oncology Pharmacy
JHOP - June 2018 Vol 8, No 2 published on May 31, 2018 in From the Literature, Prostate Cancer
Concise Reviews of Studies Relevant to Hematology Oncology Pharmacy
JHOP - December 2017 Vol 7, No 4 published on December 8, 2017 in From the Literature
Novel Systemic Therapies for Advanced Non–Small-Cell Lung Cancer
Robert J. Ignoffo, PharmD, FASHP, FCSHP, Tristan Lindfelt, PharmD, BCPS, BCACP, BCOP, Eric Lozano
JHOP - March 2017 Vol 7, No 1 published on March 13, 2017 in Review Article
Concise Reviews of Studies Relevant to Hematology Oncology Pharmacy
JHOP - March 2017 Vol 7, No 1 published on March 13, 2017 in From the Literature
Concise Reviews of Studies Relevant to Hematology Oncology Pharmacy
JHOP - December 2016 Vol 6, No 4 published on December 2, 2016 in From the Literature
Concise Reviews of Studies Relevant to Hematology Oncology Pharmacy
JHOP - Sept 2016 Vol 6, No 3 published on August 22, 2016 in From the Literature
Concise Reviews of Studies Relevant to Hematology Oncology Pharmacy
JHOP - June 2016 Vol 6, No 2 published on June 13, 2016 in From the Literature
Concise Reviews of Studies Relevant to Hematology Oncology Pharmacy
Online First published on June 3, 2016 in From the Literature, Online First
Concise Reviews of Studies Relevant to Hematology Oncology Pharmacy
JHOP - March 2016 Vol 6, No 1 published on March 4, 2016 in From the Literature
Last modified: April 27, 2020