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).”

Disturbing Discovery: New Generation of Targeted Cancer Drugs Cause Tumors To Become Drug Resistant and More Aggressive


“In a modest-sized lab at the Moores Cancer Center at the University of California, San Diego, scientists investigating how cancer cells develop resistance to drug treatments recently discovered something that surprised even the most seasoned members of the research team: A new generation of drugs that are currently among the most popular treatments for lung, breast and pancreatic cancers actually induce drug resistance and spur tumor growth.

“These popular cancer drugs, known as receptor tyrosine kinase inhibitors (RTKs), are actually making cancers stronger. That’s the bad news. The good news is that researchers believe they have found a way to eliminate that threat.

“Researchers found that two of the drugs — Erlotinib for lung cancer and Lapatinib for breast cancer — are effective for a while, but eventually stop killing cancer cells and begin prompting them to resist the drug and become more aggressive.

“ ‘We knew that cancer typically builds up a resistance to these and other drugs. But we did not know that these drugs actually induce tumor progression,’ said David Cheresh, Moores’ vice chair of pathology and the lead researcher on this study.”

Image: A breast cancer cell. London Research Institute EM Unit/Cancer Research UK

General Oncology – Survival Differences After Docetaxel, Erlotinib are EGFR Dependent

“Results from the DELTA trial indicate no significant differences in progression-free (PF) or overall survival (OS) after treatment with docetaxel versus erlotinib in non-small-cell lung cancer (NSCLC) patients unselected for their epidermal growth factor receptor (EGFR) mutation status.

“By contrast, in the subgroup of patients whose tumours were positive for EGFR mutations, PFS and OS were nonsignificantly longer in the erlotinib than the docetaxel group, whereas in those with wild-type tumours, docetaxel was significantly superior to erlotinib in terms of PFS, observe the researchers in the Journal of Clinical Oncology.”

Editor’s note: This story discusses the results of a clinical trial comparing the targeted drug erlotinib (aka Tarceva) with the chemotherapy drug docetaxel in volunteer patients with non-small cell lung cancer (NSCLC). In the trial, patients whose tumors had mutations in the EGFR gene benefitted more from erlotinib than docetaxel, while patients without EGFR mutations (as detected by molecular testing) had better results from docetaxel.

At ASCO, Next-Gen EGFR Inhibitors Show Early Promise in Lung Cancer Patients with T790M Mutations

“Next-generation EGFR inhibitors for treating metastatic non-small cell lung cancer patients who have acquired resistance to first-generation drugs in this class accurately hit mutant EGFR tumor cells and caused fewer serious side effects, early data presented at a major cancer conference showed.

“Researchers at the American Society of Clinical Oncology’s annual meeting here this week, presented preliminary data from human studies on three next-generation EGFR inhibitors: AstraZeneca’s AZD9291, Clovis Oncology’s CO-1686, and Hanmi Pharmaceutical’s HM61713. All three agents showed promising activity against patients who had EGFR mutations, had received prior treatment with a first-generation tyrosine kinase inhibitor – such as Roche’s Tarceva (erlotinib) and AstraZeneca’s Iressa (gefinitib) – and had T790M mutations.”

Editor’s note: For a more reader-friendly explanation of these new drugs, check out the “Drug resistance” section of our Chief Scientist’s latest blog post.

ASCO 2014 Lung Cancer Roundup

Every year, thousands of people gather in Chicago, Illinois, for the American Society of Clinical Oncology (ASCO) Annual Meeting. The largest meeting of its kind, ASCO brings together doctors, researchers, nurses, patient advocates, pharmaceutical company representatives, and more to discuss the latest in cancer research. Here are some of the most exciting new developments in lung cancer research presented last week at ASCO 2014: Continue reading…

Resistance to Lung Cancer Targeted Therapy Can be Reversed, Study Suggests

“Up to 40 percent of lung cancer patients do not respond to a targeted therapy designed to block tumor growth—a puzzling clinical setback that researchers have long tried to solve. Now, scientists at Georgetown Lombardi Comprehensive Cancer Center and the National Cancer Institute have discovered why that intrinsic resistance occurs—and they pinpoint a drug they say could potentially reverse it.”

“Their findings, published in the Journal of Clinical Investigation, found that over-expression of the growth protein Cripto-1 makes lung cancer cells resistant to the drug erlotinib (Tarceva®). Experiments in cell lines and in animals demonstrated that blocking Cripto-1 signaling transduction restored sensitivity to the drug, one of a number of EGFR inhibitors used in non-small cell lung carcinoma and other cancers.”

Editor’s note: Lung cancer patients who try the targeted therapy drug erlotinib (brand name Tarceva) may be intrinsically resistant to it; it has no effect on their tumor growth. Researchers have now found that abnormalities involving a gene called Cripto-1 can make a tumor resistant to Tarceva, and that drugs that block Cripto-1’s role in tumor cells can restore sensitivity to Tarceva. These studies were done on human cancer cells in the lab and in animals, but a new clinical trial with volunteer patients will test whether a drug called AZD0424 might undo Tarceva resistance in patients with non-small cell lung cancer (NSCLC), allowing them to benefit from Tarceva treatment.

ASCO: Targeted Tx Combo Stalls NSCLC

“Adding bevacizumab (Avastin) to first-line targeted therapy delayed progression in a subgroup of non-small cell lung cancer (NSCLC), an open-label trial showed.

“Progression-free survival was 46% better with bevacizumab plus erlotinib (Tarceva), at 16.0 months compared with 9.7 on erlotinib alone in an EGFR mutation-positive population (P=0.0015), Terufumi Kato, MD, of Kanagawa Cardiovascular and Respiratory Center in Yokohama, Japan, and colleagues found.”

Editor’s note: A combination of two targeted therapy drugs has shown promise for treating some patients with non-small cell lung cancer (NSCLC). The two drugs are called bevacizumab (brand name Avastin) and erlotinib (brand name Tarceva). The research described in this story found that the combination works better for patients whose tumors have mutations in the EGFR gene (as detected by molecular testing) than erlotinib alone.

No Progression-Free or Overall Survival Benefit With Second- or Third-Line Erlotinib vs Docetaxel in EGFR-Unselected Japanese NSCLC Patients

“In a Japanese phase III trial (DELTA) reported in the Journal of Clinical Oncology, Kawaguchi et al found that erlotinib (Tarceva) was associated with no progression-free survival or overall survival advantage as second- or third-line therapy in EGFR-unselected patients with non–small cell lung cancer.

“In this open-label trial, 301 patients with stage IIIB or IV NSCLC, previous treatment with one or two chemotherapy regimens, evaluable or measurable disease, and Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 were randomly assigned between August 2009 and July 2012 to erlotinib at 150 mg daily (n = 150) or docetaxel at 60 mg/m2every 3 weeks (n = 151). The primary endpoint was progression-free survival. In total, 109 patients (73%) in the erlotinib group and 90 (60%) in the docetaxel group had EGFR wild-type disease. Study treatment was third line in 19% and 14%, respectively.”

Editor’s note: This clinical trial tested a drug called erlotinib (brand name Tarceva), which is already known to be an effective treatment for lung cancer patients whose tumors have mutations in the EGFR gene. However, in this trial, the scientists were interested in whether erlotinib might help all patients, regardless of whether EGFR is mutated. The results show that erlotinib is no more effective than chemo for patients without EGFR mutations. But we recently posted another story about a protein test that may predict whether a patient without EGFR mutations might benefit from erlotinib treatment.

Proteomic Signature for EGFR Inhibitor Therapy Predicts Survival Benefit of Second-Line Chemotherapy vs Erlotinib in NSCLC

“There are conflicting data on whether epidermal growth factor receptor (EGFR) inhibitor therapy is beneficial in second-line treatment of lung cancer patients with unknown or wild-type EGFR status. In a phase III trial (PROSE) reported in The Lancet Oncology, Gregorc et al assessed the predictive value of a proteomic signature serum protein test for likely outcome of EGFR inhibitor therapy in non–small cell lung cancer (NSCLC) patients receiving second-line therapy with the EGFR inhibitor erlotinib (Tarceva) vs chemotherapy. They found that the test was predictive of differential survival benefit for erlotinib vs chemotherapy, with patients classified by the test as likely to have poor outcome on EGFR inhibitor therapy having better outcome on chemotherapy.”

Overall survival was significantly better with chemotherapy among patients with a proteomic classification of poor, whereas there was no difference between chemotherapy and erlotinib in patients with a classification of good.”