NIH Announces the Launch of 3 Integrated Precision Medicine Trials; ALCHEMIST is for Patients with Certain Types of Early-Stage Lung Cancer

Editor’s note: Oncologists sometimes treat late-stage lung cancer patients based on the results of molecular tumor tests, which can reveal genetic mutations that cause tumor growth. This story is about a new study launched to find early stage lung cancer patients whose tumors have mutations in the EGFR or ALK genes. The study will explore whether drugs targeted against those genes will improve survival for the patients.

“The Adjuvant Lung Cancer Enrichment Marker Identification and Sequencing Trials, or ALCHEMIST, was launched today to identify early-stage lung cancer patients with tumors that harbor certain uncommon genetic changes and evaluate whether drug treatments targeted against those changes can lead to improved survival.

“ ‘We believe that the findings from ALCHEMIST will not only help answer an important question about the addition of targeted therapies in earlier stage disease but will also help us in understanding the prevalence and natural history of these genomic changes in earlier stage lung cancer. We also hope to gain a better understanding as well regarding the genetic changes in the tumor at the time of recurrence,’ said Shakun Malik, M.D., head of Thoracic Cancer Therapeutics in the Clinical Investigations Branch of the National Cancer Institute (NCI). ‘The findings will help to define clinical, biologic and molecular behaviors of this type of lung cancer.’ “


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).”


Increased Overall Survival for Advanced Stage NSCLC Patients Associated with Availability of Less Toxic Chemotherapy

The gist: A long-term study investigated the effects of new lung cancer treatments over time. They found that survival has improved for people with advanced non-small cell lung cancer (NSCLC) as new, better chemotherapy and targeted therapy treatments have been developed. The researchers also noted that survival has improved for patients who receive chemotherapy and specifically additional (“second-line”) treatment after their initial treatment.

“A 10-year population-based study shows that increased availability of better systemic chemo- and targeted-therapies for patients with advanced non-small cell lung cancer (NSCLC) coincides with increased usage of these therapies. This in turn leads to a significant increase in overall survival.

“Researchers from the British Columbia Cancer Agency, Vancouver, Canada, performed a retrospective chart review of all patients referred to the agency with advanced stage (IIIB or IV) lung cancer and grouped the patients into 4 one-year time frame cohorts; one termed ‘baseline’ and three other groups that each started 6-months after a new second-line agent (docetaxel, erlotinib and pemetrexed) was made commercially available and put into practice. In British Columbia, Canada, the implementation of the second-line agents docetaxel, erlotinib and pemetrexed occurred in December 2000, October 2005 and June 2007, respectively. Cohort 1 (January to December 1998) with 555 patients was the baseline and cohort 2 (May 2001-April 2002) had 613 patients, cohort 3 (March 2006-February 2007) had 688 patients and Cohort 4 (November 2007-Ocotober 2008) had 750 patients.

“The results published in the August Issue of the Journal of Thoracic Oncology, the official journal of the International Association for the Study of Lung Cancer, show that the usage of second-line therapy increased significantly over time. At baseline only 21% of the patients received second-line therapy but in Cohorts 2 and 3 this increased to 27% and 37% respectively, and by Cohort 4 more than half, 55%, received second-line therapy. The most common agent in Cohort 1 was docetaxel (48%) but by Cohort 4 erlotinib (EGFR TKIs) and pemetrexed were used 50% and 26% of the time. The research also found that the proportion of patients who received at least first-line systemic chemotherapy also increased over the four time points from 16% in Cohort 1 to 23%, 34% and 33% for Cohorts 2-4, respectively.”


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

Breast-cancer-cell

“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 – Six-Gene Signature Predicts Survival After Targeted Therapy for NSCLC

“The presence of a six-gene profile in the microRNA of patients with advanced non-squamous non-small-cell lung cancer (NSCLC) predicts reduced survival likelihood after first-line treatment with targeted therapy followed by chemotherapy for disease progression, indicate research results.

“While the findings ‘should be further validated’, the researchers believe their analysis ‘supports the hypothesis that circulating [microRNA’s] may further be developed as predictive markers for EGFR-targeted treatment’ in an NSCLC population whose response to epidermal growth-factor receptor (EGFR) tyrosine kinase inhibitors is unknown.”

Editor’s note: This story describes a new, blood test-based method by which oncologists may be able to predict the effects of targeted therapy treatment on the survival of patients with non-squamous non-small cell lung cancer (NSCLC). Specifically, it may be able to predict the effects of first-line treatment with drugs known as EGFR inhibitors, which are prescribed to people whose tumors have mutations in the EGFR gene, as detected by molecular testing. In a study with volunteer patients, scientists took blood samples just before and just after the patients began taking the drugs bevacizumab or erlotinib. The scientists identified six different kinds of a molecule called microRNA that, if present, were associated with a lower chance of survival (29 months versus more than 45 months). More testing will be needed to determine if this six-gene signature can be used widely; it would be a non-invasive alternative to making predictions and monitoring treatment effectiveness using repeat tumor biopsies.


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.