New EGFR Inhibitor AZD9291 Shows Promising Activity in Treatment-Resistant Non–Small Cell Lung Cancer

“Findings from a phase I study of a new mutant-selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, AZD9291, point to a promising new treatment option for patients with advanced, EGFR-mutant, non–small cell lung cancer (NSCLC) that is resistant to standard EGFR inhibitors. Roughly 50% of patients experienced tumor shrinkage, and the drug worked particularly well in patients with the T790M mutation (detected in 60% of patients), which causes the most common form of EGFR therapy resistance. The study was presented at a presscast in advance of the 2014 ASCO Annual Meeting (Abstract 8009^).”

Editor’s note: This story is about a new targeted therapy drug called AZD9291 that is designed to attack tumors with a mutation in the EGFR gene, as detected by molecular testing. In particular, it is designed for patients who are resistant to other so-called EGFR inhibitors as a result of developing a particular EGFR mutation known as T790M. In a clinical trial to test the drug in patients, it was found to show promising results for patients with advanced non-small cell lung cancer (NSCLC) with EGFR mutations, and even better results in patients with the T790M mutation.


Combination Therapies for Lung Cancer

“CANCER NETWORK: Dr. Jänne, epidermal growth factor receptor (EGFR) inhibitors are a mainstay of therapy for those advanced-stage lung cancer patients with tumors that harbor specific EGFR mutations. What have we learned in the last few years about which patients respond to which oral agents and antibodies against EGFR? “

Editor’s note: While not strictly “news,” this interview provides a good overview of currently available treatments for lung cancer.


Clovis Oncology’s CO-1686 Demonstrates Compelling Clinical Activity and Progression-free Survival (PFS) in Updated Phase 1 Study Results in Patients with Non-small Cell Lung Cancer (NSCLC)

“Clovis Oncology (NASDAQ:CLVS) announced today updated findings from the Phase 1 portion of its ongoing Phase 1/2 clinical study of CO-1686, the Company’s novel, oral, targeted covalent (irreversible) inhibitor of mutant forms of the epidermal growth factor receptor (EGFR) for the treatment of non-small cell lung cancer in patients with initial activating EGFR mutations as well as the dominant resistance mutation T790M. Interim results from the Phase 1 dose-escalation portion of this Phase 1/2 study are being presented today in an oral presentation by Dr. Heather Wakelee at the 4th European Lung Cancer Conference (ELCC) in Geneva.”

Editor’s note: CO-1686 is a targeted therapy drug that is meant to treat patients whose tumors have mutations in the EGFR gene, as detected by molecular testing. Some tumors with EGFR mutations become resistant to treatment and develop a new mutation called T790M. Researchers are particularly interested in whether patients with T790M can benefit from CO-1686.


Inherited Mutated Gene Raises Lung Cancer Risk for Women, Those Who Never Smoked

“People who have an inherited mutation of a certain gene have a high chance of getting lung cancer—higher, even, than heavy smokers with or without the inherited mutation, according to new findings by cancer researchers at UT Southwestern Medical Center. Although both genders have an equal risk of inheriting the mutation, those who develop lung cancer are mostly women and have never smoked, the researchers found.

“People with the rare inherited T790M mutation of the epidermal growth factor receptor (EGFR) gene who have never smoked have a one-in-three chance of developing lung cancer, researchers found. This risk is considerably greater than that of the average heavy smoker, who has about a one-in-eight chance of developing lung cancer – about 40- fold greater than people who have never smoked and do not have the mutation.”


Early Evidence Supports CO-1686 as a Treatment Option in Drug-Resistant EGFR-Mutant Lung Cancer

Drugs known as EGFR inhibitors—such as erlotinib (Tarceva), gefitinib (Iressa), and afatinib (Gilotrif)—are very effective in treating non-small cell lung cancer (NSCLC) with mutations in the EGFR gene. However, patients eventually develop drug resistance, usually caused by new EGFR mutations. T790M is the most common EGFR drug resistance mutation. CO-1686 is a novel drug that inhibits EGFR with the T790M mutation, as well as other mutant EGFR. A small study showed that eight of nine patients who had the T790M resistance mutation experienced more than 10% tumor shrinkage when treated with CO-1686. And, a new formulation of CO-1686 has been found to produce higher, more consistent, well-tolerated drug concentrations in patients.


New Drug May Offer Option for Lung Cancer Patients Resistant to Tarceva/Iressa

Drugs known as EGFR inhibitors—like erlotinib (Tarceva) and gefitinib (Iressa)—are used to treat non-small cell lung cancer (NSCLC) with so-called ‘activating mutations’ in the EGFR gene. Unfortunately, drug resistance develops relatively quickly in most patients. Resistance is often due to additional EGFR mutations, so-called ‘resistance mutations,’ such as EGFR T790M. Researcher have developed a new EGFR inhibitor, AZD9291, which targets both activating and resistance mutant forms of EGFR. AZD9291 inhibited the growth of EGFR-mutant NSCLC cell cultures and eradicated lung cancer tumors with either activating or resistance mutations in mice. Because AZD9291 is less active against normal, non-mutant EGFR, it may have fewer side effects than other EGFR inhibitors. Initial tests of AZD9291 in patients have been promising.


First T790M Inhibitor Shows Promise in Early Lung Cancer Trial

Researchers may finally have found a treatment for a type of non-small cell lung cancer (NSCLC) that resists currently available therapies, according results presented at the 2013 European Cancer Congress in Amsterdam, Netherlands. These resistant NSCLCs have an EGFR mutation called T790M, which is more common in Asian people; the experimental treatment is a T790M inhibitor called AZD9291. In an ongoing phase I clinical trial that included 12 people with lung cancers that had the T790M mutation, tumors shrank in more than half. This trial is currently enrolling new patients.


Discovery of a Mutant-Selective Covalent Inhibitor of EGFR that Overcomes T790M-Mediated Resistance in NSCLC

CO-1686 is a novel, irreversible and orally delivered kinase inhibitor that specifically targets the mutant forms of EGFR including T790M while exhibiting minimal activity towards the wild-type (WT) receptor. Oral administration of CO-1686 as single agent induces tumor regression in EGFR mutated NSCLC tumor xenograft and transgenic models. In NSCLC cells with acquired resistance to CO-1686 in vitro, there was no evidence of additional mutations or amplification of the EGFR gene, but resistant cells exhibited signs of epithelial-mesenchymal transition (EMT) and demonstrated increased sensitivity to AKT inhibitors.


Patient’s Perspective: The Importance of Clinical Trials


Update:  We are deeply saddened to report that Neil passed away on July 29, 2015. It is a privilege to share his story and keep his memory alive.

Neil Schiffman has lived as healthy a life as one can live. An avid cycler and triathlon participant well into his 60s, Neil was visiting Arizona in April 2011 when he began to cough. The cough mimicked the symptoms of exercise-induced asthma, so at first he thought nothing of it. When the cough failed to disappear, he visited his pulmonologist, who suspected bacterial pneumonia. Meanwhile, Neil’s legs and feet began to swell–he went from wearing a size 10 shoe to a size 14. Alarmed, he had an X-ray and a CT scan, which revealed a mass identified as a neoplasm. He was referred to an oncologist, who delivered the bad news in June: Neil had stage IV non-small cell lung cancer (NSCLC). Continue reading…