Mutation Status Guides Advanced NSCLC Therapy

“The presence or absence of mutations in advanced non-small cell lung cancer (NSCLC) should guide selection of first-line systemic therapy, according to an updated clinical guideline from the American Society of Clinical Oncology.

“Patients with squamous-cell tumors that have no gene alterations should begin treatment with combination platinum-based cytotoxic chemotherapy, so long as they have good performance status (0 or 1). Optionally, bevacizumab (Avastin) may be added when the platinum agent is carboplatin. For patients with performance status 2, either chemotherapy or palliative care alone is an acceptable option.

“In the presence of sensitizing EGFR mutations, appropriate first-line therapy is afatinib (Gilotrif), erlotinib (Tarceva), or gefitinib (Iressa). Treatment should begin with crizotinib (Xalkori) when patients have tumors with ALK or ROS1 rearrangements, as published online in the Journal of Clinical Oncology.”


No Benefit of Adding Gefitinib to Platinum-Based Doublet in EGFR-Mutant NSCLC After Progression on First-Line Gefitinib

“In a phase III IMPRESS trial reported in The Lancet Oncology, Soria et al found no progression-free survival benefit of adding gefitinib (Iressa) to platinum-based doublet chemotherapy in patients with advanced EGFR-mutant non–small cell lung cancer (NSCLC) who had acquired resistance to first-line gefitinib.

“In the double-blind trial, 265 chemotherapy-naive patients from 11 countries who had stage IIIB to IV EGFR-mutant disease and disease control with first-line gefitinib and recent disease progression took part. They were randomly assigned between March 2012 and December 2013 to receive cisplatin 75 mg/m2 plus pemetrexed (Alimta) 500 mg/m2 on the first day of a maximum of six chemotherapy cycles plus either daily gefitinib 250 mg (n = 133) or placebo (n = 132) continued until disease progression or discontinuation for other reasons…

“The investigators concluded: ‘Continuation of gefitinib after radiological disease progression on first-line gefitinib did not prolong progression-free survival in patients who received platinum-based doublet chemotherapy as subsequent line of treatment. Platinum-based doublet chemotherapy remains the standard of care in this setting.’ ”


FDA Approves Iressa for EGFR Metastatic Lung Cancer

“Iressa (gefitinib) has been approved by the U.S. Food and Drug Administration to treat patients with metastatic non-small-cell lung cancer (NSCLC) with a specific genetic mutation (epidermal growth factor receptor [EGFR]). A just-approved companion diagnostic test can identify patients who could benefit from this new use.

“Iressa is a kinase inhibitor, a class of drugs designed to block proteins that spur development of cancer cells. The therascreen EGFR RGQ PCR Kit is a newly approved diagnostic that can help doctors detect patients with the genetic mutation who are candidates for treatment with Iressa.

“Iressa was evaluated for this use in clinical trials involving 106 people with previously untreated EGFR mutation-positive metastatic NSCLC. Tumors shrank in about 50 percent of people treated with Iressa 250 mg once daily. This effect lasted an average of six months, the FDA said. Severe side effects of Iressa may include interstitial lung disease, liver damage, gastrointestinal perforation, severe diarrhea, and ocular disorders. More common side effects are diarrhea and skin reactions.”


FDA Accepts AZ' Filing for First-Line Iressa

The gist: A drug called gefitinib (Iressa) may soon be available in the U.S. as an initial treatment choice for people with advanced or metastatic non-small cell lung cancer (NSCLC) that tests positive for an EGFR mutation. The drug is already approved in many other countries. But in the U.S., only people who have already taken it successfully as part of a clinical trial or expanded access program currently have access to it. The company that makes gefitinib has submitted a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA). The FDA will decide whether or not to approve gefitinib as a first-line treatment in late 2015.

“US regulators have accepted AstraZeneca’s New Drug Application for Iressa (gefitinib) as a targeted monotherapy for the first-line treatment of certain lung cancer patients.

“The drug giant is seeking approval to market Iressa for the treatment of patients with advanced or metastatic non-small cell lung cancer (NSCLC) who test positive for an epidermal growth factor receptor mutation (EGFRm).

“AZ is working with Qiagen in the US to develop a companion diagnostic test to guide the use of Iressa in this setting; In Europe, their collaboration resulted in the drug becoming the first EGFR tyrosine kinase inhibitor to have a European label allowing the use of circulating tumour DNA (ctDNA) obtained from a blood sample, to be used for the assessment of EGFR mutation status in those patients where a tumour sample is not an option.”


Therapy Found Effective in Older, African-American Lung Cancer Patients

“University of Cincinnati researchers have found in a phase-2 clinical trial that a Food and Drug Administration-approved therapy could be effective in treating both older and African American patients with advanced lung cancer who may not be candidates for chemotherapy.

“These findings are published Nov. 25, 2014, in the online journal Clinical Medicine Insights: Oncology (Libertas Academica).

“Nagla Karim, MD, PhD, associate professor in the division of hematology oncology at the UC College of Medicine and member of the Cincinnati Cancer Center and the UC Cancer Institute, says gefitinib, a drug that targets and interrupts signaling through the epidermal growth factor receptor and is used to control the progression of cancer, could help patients with non-small cell lung cancer, which has few treatment options.

“Non-small-cell lung cancer is any type of lung cancer other than small-cell lung cancer—the most common type of lung cancer.”


Results of New Drug, ASP8273, Show Response in Patients with Treatment-Resistant NSCLC

The gist: People with non-small cell lung cancer (NSCLC) that has both the EGFR and T790M mutations might benefit from a new drug. The drug is called ASP8273. A clinical trial tested ASP8273 in volunteer patients in Japan. In the trial, it shrank people’s tumors. More research is needed, but it is hoped that the drug might be a good alternative for people whose tumors are resistant to drugs like erlotinib, gefitinib and afatinib.

“In a second presentation looking at new ways of treating non-small cell lung cancer (NSCLC) that has both the EGFR and T790M mutations, researchers will tell the 26th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics in Barcelona, Spain, that an oral drug called ASP8273 has caused tumour shrinkage in patients in a phase I clinical trial in Japan.

“Mutations of the epidermal growth factor (EGFR) occur in about 30-35% of Asian patients with NSCLC (and in 10-15% of Caucasian patients). EGFR inhibitors called tyrosine kinase inhibitors (TKI), such as erlotinib, gefitinib and afatinib, can be used to treat EGFR-mutated NSCLC. However, these patients will eventually develop resistance to EGFR TKI therapy, rendering their disease resistant to current treatments. A further mutation called T790M accounts for 60% of this acquired resistance.

“ASP8273 is a new drug that inhibits the EGFR mutation and the T790M resistance mutation. Earlier research in mice had shown that it caused NSCLC to disappear completely, and so a I clinical trial was started in January 2014 to assess the drug’s safety and efficacy in humans.

“Twenty-four Japanese patients have enrolled so far to receive one of six levels of doses (25, 50, 100, 200, 400 and 600mg) once a day. A further seven patients have been enrolled into a second group to evaluate doses of 100mg, 200mg and 400mg a day (a dose escalation study), and the researchers are planning to enrol a total of 124 patients. Cancer had progressed in all the patients after prior treatment with EGFR TKI therapy, and most of them had the T790M mutation.”


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).”


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.


Thwarting Drug Resistance in Lung Cancer


If you’ve read up on lung cancer research in the last few years, you probably know that large strides have been made in targeted therapies for non-small cell lung cancer (NSCLC). Targeted therapies are drugs that identify and attack specific mutated proteins that are detected in tumors. Because noncancerous cells do not have these specific mutations, targeted therapies can make a beeline for cancer, while leaving healthy tissue unharmed. Continue reading…