Genetic Profile of Treatment-Resistant Lung Cancer More Variable Than Previously Understood

Excerpt:

“The genetic mutations underlying treatment resistance in non-small cell lung cancer (NSCLC) are more complex and dynamic than previously thought. Analysis of 355 biopsied tumors from patients who acquired resistance to EGFR inhibitors, the most common form of targeted therapy for NSCLC, found that mutations frequently varied between biopsies and that nearly one in five patients harbored more than one type of genetic resistance to treatment. Findings will be presented today at the 2017 Multidisciplinary Thoracic Cancers Symposium.”

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Clovis Oncology's Rociletinib (CO-1686) Phase 2 Study Results Demonstrate Consistent and Promising Clinical Activity and Disease Control in Very Advanced Patients with EGFR-Mutant Non-Small Cell Lung Cancer (NSCLC)

“Clovis Oncology (NASDAQ:CLVS) announced today updated findings from its Phase 2 clinical study of rociletinib (CO-1686), the Company’s novel, oral, targeted covalent (irreversible) mutant-selective inhibitor of the epidermal growth factor receptor (EGFR) for the treatment of non-small cell lung cancer (NSCLC) in patients with initial activating EGFR mutations, as well as the dominant resistance mutation T790M. These data from the TIGER-X trial are being presented today in an oral presentation (Abstract #8001) at the 2015 American Society of Clinical Oncology (ASCO) annual meeting in Chicago.

“ ‘The maturing data for rociletinib confirm in a large patient population what we have seen in our early clinical experience,’ said Jonathan Goldman, MD, TIGER-X investigator and Assistant Professor, UCLA Hematology & Oncology, Associate Director of Drug Development and Director of Clinical Trials in Thoracic Oncology. ‘Rociletinib has shown very encouraging and durable activity in the most advanced mutant EGFR lung cancer patients, including in a large population of patients with CNS metastases. Importantly, the data continue to show activity in both T790M-positive and T790M-negative patients, which gives us a potential treatment option for all patients who have progressed on their initial EGFR targeted therapy.’ “


A Blood-Based Test for EGFR Mutations in NSCLC Is Being Developed

“Clovis Oncology is evaluating a blood-based assay to detect EGFR mutations in circulating tumor DNA in non-small cell lung cancer patients as a way to better identify candidates for treatment with rociletinib (CO-1686), its investigational EGFR inhibitor, a Clovis scientist said this week.

“During a talk at the Cambridge Healthtech Institute Molecular Medicine Tri-Conference held here, Chris Karlovich, principal scientist for molecular diagnostics at Clovis, said that his company is comparing the performance of Sysmex Inostics’ BEAMing assay service to that of Qiagen’s TheraScreen EGFR PCR test in a subset of patients from the company’s “third-generation inhibitor of mutant EGFR lung cancer” (TIGER) clinical trial for rociletinib.

“The goal, Karlovich said, is to overcome some of the limitations of tissue-based PCR testing in identifying EGFR mutations, particularly the T790M resistance mutation, which can be used to identify patients who have become resistant to EGFR-directed therapy and thus are candidates for second- or later-line treatment with rociletinib. In addition, Karlovich said, blood-based assays like BEAMing could potentially be used to more easily monitor response to the drug.

“Rociletinib was designed to selectively target initial activating EGFR mutations and the T790M resistance mutation, while sparing wild-type EGFR at anticipated therapeutic doses, with an improved toxicity profile, according to Clovis’ website.”


Clovis Launches TIGER2 Trial for CO-1686 in Previously Treated T790M-Positive NSCLC Patients

“Clovis Oncology has launched the TIGER2 study for its non-small cell lung cancer drug CO-1686, an agent the company is studying as a treatment for advanced patients with tumors characterized by EGFR mutations and the T790M resistance mutation.

“CO-1686 is an irreversible EGFR inhibitor. Clovis this week said it has dosed the first patient in the TIGER2 Phase I/II trial, which is focused on gauging the efficacy of CO-1686 in NSCLC patients who have progressed on their first and only anti-EGFR treatment.”

Editor’s note: Some people with advanced non-small cell lung cancer (NSCLC) have tumor cells with mutations in the EGFR gene (oncologists often use a tumor biopsy to check for this mutation in a patient). These patients can be treated with targeted drugs known as EGFR inhibitors. EGFR inhibitors can shrink tumors at first, but over time, tumors may become resistant to the drugs and start growing again. Often, this is because of a new, additional mutation that occurs in the EGFR gene called T790M. A new clinical trial is enrolling volunteer patients with the T790M mutation to test a new drug meant to overcome EGFR inhibitor resistance. The drug is called CO1-686.


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.


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.


Researchers Report Double Dose of Promising Lung Cancer Findings

“Researchers with UCLA’s Jonsson Comprehensive Cancer Centerreport that two new experimental drugs have shown great promise in the treatment of patients with non–small-cell lung cancer, which accounts for about 85 percent of all lung cancers. Lung cancer is the leading cause of cancer death in the United States.

“The drugs—ramucirumab and CO-1868—were shown in separate clinical trials to increase survival times with fewer toxic side effects than standard treatments. The findings were presented this week at the American Society of Clinical Oncology annual meeting in Chicago.”

Editor’s note: For more on the ramucirumab findings, see our previous news post. To learn more about targeted therapies like CO-1686 and ramucirumab, visit our lung cancer Basics.