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.”

Genprex Begins Phase II Clinical Trial for Lung Cancer

Genprex, Inc. announced today that it has enrolled the first patient in a clinical trial evaluating its lead product candidate Oncoprex® in combination with erlotinib (Tarceva®) for late-stage lung cancer patients. Oncoprex is a targeted biologic incorporating the pan-kinase inhibitor TUSC2, which inhibits oncogenic kinases via multiple pathways.

“The trial is significant in that it seeks to determine if patients without the EGFR activating mutation as well as patients with the EGFR activating mutation whose cancer has progressed after erlotinib treatment can benefit from the Oncoprex + erlotinib combination therapy. While erlotinib is a blockbuster drug helping many cancer patients worldwide, research shows that the vast majority of patients who have lung cancers without the activating EGFR mutation are unlikely to benefit from erlotinib. Additionally, many patients with the activating EGFR mutation who respond to erlotinib therapy eventually become resistant to the therapy.

Editor’s note: Clinical trials are studies done with volunteer patients to evaluate the safety and effectiveness of new treatments (learn more in our lung cancer KnowledgeBase). This clinical trial is testing a new targeted therapy drug called Oncoprex. When combined with the drug erlotinib (Tarceva), Oncoprex may help treat patients who usually do not benefit from erlotinib or who have grown resistant to it.

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…

Drug Combo May Knock Down Lung Cancer

“Some drug-resistant cancers of the lung, pancreas and breast might be made vulnerable again by treating them with a medication already approved for another type of cancer, according to a new study led by scientists at UC San Diego.

“Researchers at UCSD Moores Cancer Center said they plan to start a clinical trial to test the use of Velcade for lung cancer in about six months. This quick start is possible because the drug is currently on the market, said Dr. Hatim Husain, an author of the study who is designing the clinical trial. For more information about the trial, call (858) 822-5182.”

Editor’s note: Clinical trials can be important treatment options for some patients. This one might be particularly appropriate for people who have taken the drug Tarceva (erlotinib) but became resistant to it. The drug combination being tested in this clinical trial has previously shown disappointing results, but the researchers are hopeful that by using molecular testing to identify patients who are more likely to benefit, they may be able to successfully use the treatment. Learn more about clinical trials here.

Phase II Trial of Efatutazone Shows Challenge of Matching Treatment to Population

“Work at the University of Colorado Cancer Center led to phase II trial of efatutazone with erlotinib in patients with refractory non-small cell lung cancer. Results are reported today at the American Association for Cancer Research (AACR) Annual Meeting 2014. While efatutazone did not improve the efficacy of erlotinib in this trial, researchers hope lessons from the trial will allow them to make better future use of the drug or other drugs in its class.

” ‘In oncology and especially in lung cancer, everything is personalized. We’re exploring different molecular markers that identify which drugs are for the right patient. After this phase II trial, we’re working to find the right biomarker that could help us discover who is most likely to respond to efatutazone. This trial was done in an unselected population. But if we had the right population with the right marker, we hope that we could find a meaningful effect,’ says Ana Oton, MD, investigator at the CU Cancer Center, Associate Professor of Medical Oncology at the University of Colorado School of Medicine, and the study’s first author.”

Editor’s note: This trial tested a treatment without the use of molecular testing to see which patients might have benefited. This is a problem in the design of many clinical trials, as our Chief Scientist explains here. For future testing of the treatment the scientists hope to identify a molecular test that will help them select patients who are more likely to benefit.

Roche Lung Cancer Pill Gets Reprieve in UK Reversal

“Britain’s health cost watchdog NICE on Friday reversed an earlier decision to limit the use of Roche’s Tarceva cancer pill on the state health service in a move the drugmaker said would help around 2,000 patients a year.

“New draft guidance from the National Institute for Health and Clinical Excellence (NICE) now backs use of Tarceva for people with non-small-cell lung cancer that has progressed after chemotherapy in wider circumstances than originally suggested.”