Drugs to Avoid in Patients on Tyrosine Kinase Inhibitors

Editor’s note: More and more people with cancer are being treated with drugs known as tyrosine kinase inhibitors (TKIs). As with any other drug, oncologists who prescribe TKIs must be aware of other drugs a patient is taking to ensure there will not be a dangerous drug-drug interaction. Researchers recently published a report outlining known and potential drug-drug interactions between TKIs and other drugs. Oncologists and patients may wish to take these into account when considering cancer treatment with TKIs.

“With the rapid and widespread uptake of tyrosine kinase inhibitors (TKIs) in oncology over the past several years, serious drug–drug interactions are an “increasing risk,” according a new report.

“To guarantee the safe use of TKIs, ‘a drugs review for each patient is needed,’ write Frank G.A. Jansman, PharmD, PhD, from Deventer Hospital in the Netherlands, and colleagues in a review published in the July issue of the Lancet Oncology.

“The review provides a comprehensive overview of known and suspected interactions between TKIs and conventional prescribed drugs, over-the-counter drugs, and herbal medicines.

“All 15 TKIs approved to date by the US Food and Drug Administration or the European Medicines Agency are evaluated.

“They are axitinib (Inlyta, Pfizer), crizotinib (Xalkori, Pfizer), dasatinib (Sprycel, Bristol-Myers Squibb and Otsuka America), erlotinib (Tarceva, Osi Pharmaceuticals), gefitinib (Iressa, AstraZeneca), imatinib (Gleevec, Novartis), lapatinib (Tykerb, GlaxoSmithKline), nilotinib (Tasigna, Novartis), pazopanib (Votrient, GlaxoSmithKline), regorafenib (Stivarga, Bayer), ruxolitinib (Jakafi, Incyte), sorafenib (Nexavar, Bayer), sunitinib (Sutent, Pfizer), vandetanib (Caprelsa, AstraZeneca), and vemurafenib (Zelboraf, Roche).”


Dasatinib Plus Docetaxel Does Not Improve Overall Survival in Men With Chemotherapy-Naive Metastatic Castration-Resistant Prostate Cancer

“Data suggest that Src kinase-mediated interactions between prostate cancer cells and osteoclasts might promote bone metastasis and that the Src kinase inhibitor dasatinib (Sprycel) might exhibit synergy with docetaxel in prostate cancer. In a phase III trial (READY) reported in The Lancet OncologyJohn. C. Araujo, MD, of The University of Texas MD Anderson Cancer Center, and colleagues investigated the effects of adding dasatinib to docetaxel in chemotherapy-naive men with metastatic castration-resistant prostate cancer. No improvement in overall survival was observed with the combination.”


Treatment-Related Toxicities in a Phase II Trial of Dasatinib in Patients with Squamous Cell Carcinoma of the Lung

Several studies have examined dasatinib in non-small cell lung cancer; these report not only significant toxicities, but also responses in patients found to harbor mutations in discoidin domain receptor tyrosine kinase 2 or BRAF. An open-label phase II trial with dasatinib was carried out to determine the response rates in patients with squamous cell carcinoma who had previously failed standard chemotherapy and to correlate responses with patient genotype.

 

Similar to other studies, this study too found that dasatinib administered at 140 mg/day for the treatment of advanced SqCC of the lung is associated with excess adverse events, so is not recommended in unselected patients. Further work to identify patients likely to benefit from dasatinib and to manage dasatinib-related toxicities is needed.


Two New Targeted Therapies Fail to Improve Survival in Phase III Trials

Two new targeted therapies for castration-resistant prostate cancer (CRPC), aflibercept and dasatinib, did not prove to be effective in phase III clinical trials. Both drugs showed promise in preclinical trials but, when tested in combination with chemotherapy, neither drug improved overall survival. Additionally, patients who took aflibercept had worse side effects than those who took a placebo.


Two Phase III Prostate Cancer Trials Miss Their Mark

Researchers at the 2013 Genitourinary Cancers Symposium presented the results of two negative phase III studies—READY and VENICE—of targeted agents that failed to increase overall survival  when combined with standard first-line chemotherapy docetaxel/prednisone for the treatment of men with metastatic castration-resistant prostate cancer.The two agents are aflibercept and dasatinib. 


Avastin-Containing Chemotherapy May Be Safe in Lung Cancer Patients with Brain Metastases

Bevacizumab (Avastin), which is approved for treatment of a number of advanced-stage cancer types, is commonly avoided in patients with brain metastases (cancer that has spread to the brain) because of fear of brain hemorrhages (bleeding in the brain). A retrospective study of 52 patients with advanced non-small cell lung cancer (NSCLC) who had received chemotherapy containing Avastin found no cases of serious bleeding events and no significant differences in survival or treatment side effects between patients with or without brain metastases. Avastin may therefore be a safe treatment option in NSCLC with brain metastases.

Research paper: https://www.jstage.jst.go.jp/article/acrt/20/2/20_47/_pdf


Overexpression of IGF1R and EGFR Genes May Worsen Lung Cancer Prognosis

The roles of the genes IGF1R and EGFR in lung cancer were examined in patients with non-small cell lung cancer (NSCLC) who had their primary tumor surgically removed. Patients whose tumors had increased expression of both IGFR1R and EGFR were more likely to experience recurrence of the cancer after a shorter amount of time and had shorter survival times after surgery. This finding suggests that concurrent overexpression of IGF1R and EGFR is a negative prognosis factor in NSCLC and may indicate patients who are more likely to benefit from novel treatments with IGF1R inhibitors.

Research paper: http://link.springer.com/article/10.1007/s00280-012-2056-y/fulltext.html


Study Suggests Iressa Effective for Elderly Patients with EGFR-Mutant Lung Cancer

A retrospective study in Japan examined 55 patients aged 75 years or over with inoperable non-small cell lung cancer (NSCLC) who had a mutation in the EGFR gene and received gefitinib (Iressa) as first-line therapy. The treatment was generally well tolerated and patients experienced longer periods without cancer progression (median: 13.8 months) and longer overall survival (median: 29.1 months) than commonly reported for similar patients. While studies using control groups will need to confirm that Iressa is indeed more effective than standard chemotherapy or a placebo, these findings suggest that Iressa may be a preferable first-line treatment in elderly patients with advanced EGFR-mutant NSCLC.

Research paper: http://link.springer.com/article/10.1007/s12032-012-0450-2/fulltext.html


Genetic Variation in P53 May Contribute to Lung Cancer Risk

A study of individuals with and without lung cancer in North India found that those carrying a particular version (or “polymorphism”) of a gene for the protein p53 were more likely to have lung cancer, independent of their age or smoking rate. P53 belongs to a class of proteins called “tumor suppressor proteins,” and is involved in DNA repair, regulating cell growth, and inducing cell death in damaged or abnormal cells. The findings suggest that this version of the p53 gene, called Arg72Pro, may contribute to higher susceptibility for lung cancer, at least in the North Indian population.

Research paper: http://online.liebertpub.com/doi/full/10.1089/dna.2012.1792