The FDA Gives an Ariad Drug Candidate ‘Breakthrough Therapy Designation’

The gist: A new lung cancer treatment called AP26113 has shown promise for certain people with metastatic non-small cell lung cancer (NSCLC). Specifically, it is meant to treat people whose tumors have mutations in the ALK gene and who are resistant to the standard drug crizotinib. It has been tested in volunteer patients in clinical trials. The U.S. Food and Drug Administration (FDA) has now granted breakthrough therapy designation for AP26113, meaning that review and approval will be accelerated so that the drug can more quickly reach patients in the U.S., outside of clinical trials.

“Ariad Pharmaceuticals Inc. of Cambridge said Thursday that federal regulators have granted “breakthrough therapy designation” to a drug candidate for a form of lung cancer.

“According to the Food and Drug Administration’s website, a breakthrough therapy designation means that the FDA will expedite the development and review of such drug. The designation is given to drug candidates designed to treat a serious or life threatening disease that have shown great promise based on preliminary clinical evidence.

“Ariad’s drug candidate, currently dubbed AP26113, is for the treatment of patients with anaplastic lymphoma kinase positive metastatic non-small cell lung cancer who are resistant to crizotinib, an existing treatment on the market.

“Ariad’s press release cited data from the American Cancer Society. According to the society, non-small cell lung cancer is the most common form of lung cancer, accounting for about 85 percent of the estimated 228,190 new cases of lung cancer diagnosed each year in the United States.”


Data Confirm Anti-ALK Activity in Rare NSCLC

The gist: This article discusses the results of a clinical trial—a research study with volunteer patients. The goal of the trial was to test whether the drug crizotinib (Xalkori) works for certain people with advanced non-small cell lung cancer (NSCLC). All of the patients who participated in the trial had a tumor mutation known as a ROS1 rearrangement, which can be detected using molecular testing. When treated with Xalkori, these patients experienced promising results. The researchers say the results highlight the importance of molecular testing for ROS1 rearrangement in people with advanced NSCLC.

“Objective responses occurred in 72% of patients with mutation-specific non-small cell lung cancer (NSCLC) treated with crizotinib (Xalkori), final results from a small clinical trial showed.

“Median response duration approached 1½ years, and median progression-free survival (PFS) had reached 19.2 months with follow-up ongoing.

“All 50 patients enrolled in the study had chromosomal rearrangements in ROS1, which several lines of evidence suggested would be susceptible to ALK inhibitors such as crizotinib, Alice T. Shaw, MD, PhD, of Massachusetts General Hospital in Boston, reported here at the European Society of Medical Oncology.

” ‘ROS1 rearrangement defines a second molecular subgroup of NSCLC for which crizotinib is highly active,’ Shaw and colleagues concluded in an article published simultaneously in the New England Journal of Medicine. ‘In the majority of patients, crizotinib induced durable clinical responses and was associated with grade 2 or lower toxic effects.

” ‘These results highlight the importance of screening for this genetic alteration in patients with advanced NSCLC.’ “


New ALK Inhibitor Alectinib Shows Activity vs Crizotinib-Resistant NSCLC

The gist: This article describes the results of a clinical trial—a research study with volunteer patients. The goal of the trial was to test a new lung cancer treatment called alectinib. Specifically, the researchers wanted to find out if alectinib could be used to treat people with non-small cell lung cancer (NSCLC) who are resistant to treatment with the drug crizotinib (Xalkori). All patients who participated in the trial had tumor mutations in the ALK gene, as detected by molecular testing. (Both alectinib and crizotinib work by targeting tumor cells with mutated ALK genes.) The trial had promising results, and researchers will continue to study the drug to see how well it works.

“In the phase I portion of a phase I/II study reported in The Lancet Oncology, Gadgeel et al found that the novel ALK inhibitor alectinib showed activity against systemic disease and brain metastases in patients with non–small cell lung cancer (NSCLC) resistant to the ALK inhibitor crizotinib (Xalkori). Alectinib exhibits in vitro activity against both wild-type and mutated ALK, including mutations that confer resistance to crizotinib. An alectinib dose of 600 mg twice daily has been moved forward to phase II testing…

“In the study, 47 patients with ALK-mutant NSCLC who progressed on (n = 46) or were intolerant of (n = 1) crizotinib received oral alectinib 300 mg to 900 mg twice daily during the dose-escalation phase. Central nervous system (CNS) metastases were present at baseline in 21 patients. Seventy percent of all patients and 72% of those with CNS metastases had received at least two prior lines of chemotherapy…

“The investigators concluded: ‘Alectinib was well tolerated, with promising antitumour activity in patients with ALK-rearranged NSCLC resistant to crizotinib, including those with CNS metastases. On the basis of activity, tolerability, and pharmacokinetic data, we chose alectinib 600 mg twice a day as the recommended dose for phase 2.’ ”


Lung Cancer Study Reveals New Drug Combination Targets

Editor’s note: Oncologists often prescribe lung cancer treatments based on specific proteins found in patients’ tumors. These treatments are known as targeted therapies. This article describes how a patient with an unexpected response to treatment contributed to new research into targeted therapies. This patient responded exceptionally well to a drug that targets a protein called IGF-1R. She was found to have a mutation in the ALK protein, and was then successfully treated with the ALK-targeted drug crizotinib. Based on her success, researchers hope that combining an IGF-1R-targeted drug with crizotinib could help treat other patients with ALK mutations.

“A Vanderbilt lung cancer patient’s exceptional response to different types of therapies spurred research that suggests lung cancer patients with specific gene alterations may benefit from combination therapy that targets two different cancer pathways.

The study, led by Christine Lovly, M.D., Ph.D., assistant professor of Medicine and Cancer Biology, was published online in Nature Medicine.

The work was based on an intriguing clinical observation of a female patient with advanced lung cancer who had an unexpected response to a monoclonal antibody that targets the insulin-like growth factor receptor (IGF-1R). IGF-1R helps cancer cells survive and evade anti-cancer therapies.

Remarkably, the patient remained on the IGF-1R therapy for 17 months – far longer than any other patient on the clinical trial. The Vanderbilt researchers, led by Lovly, became interested in why this particular patient’stumor responded to the experimental therapy so dramatically. Investigators decided to test for gene mutations and found an unexpected result – the patient’s tumor was positive for an ALK gene fusion. Only about 5 percent of lung cancer patients have this gene fusion in their tumor.


ALCHEMIST Aims to Curtail Return of Early-Stage Lung Cancer


A series of three new clinical trials (research studies with volunteer patients) is big news for some people affected by early-stage lung cancer. The trials focus on two drugs typically used to treat late-stage adenocarcinoma. These two drugs, Tarceva and Xalkori, may also help stage I, II, and IIIA patients prevent relapse (return of cancer) after their tumors have been surgically removed. The new clinical trials will put the treatments to the test. Continue reading…


Pfizer to Test Xalkori Lung Cancer Drug with Merck Immunotherapy

Editor’s note: This article is about two big drug companies that are teaming up to see if their non-small cell lung cancer drugs work even better when combined. The two drugs are called pembrolizumab and crizotinib (aka Xalkori). Pembrolizumab is an immunotherapy, meaning that it boosts a patient’s own immune system to fight cancer. Crizotinib is a targeted therapy that is meant to treat people whose tumors have mutations in the ALK gene. To test the combo, the companies are organizing a clinical trial—a research study with volunteer patients. The clinical trial will not begin until 2015.

“Pfizer Inc said Tuesday it will test its Xalkori lung cancer drug with Merck & Co’s experimental immunotherapy pembrolizumab, in hopes the combination will improve the outcomes for patients taking the approved Pfizer therapy.

“The largest U.S. drugmakers said the combination study will begin in 2015 and be conducted by Pfizer. Financial terms of the deal were not disclosed.

“Xalkori, which has annual sales of $400 million and is also known by its chemical name, crizotinib, was approved in 2011 for lung cancer patients who have a specific mutation in the so-called ALK gene, as determined by an approved diagnostic test.

“The mutation occurs in a small percentage of patients with non small cell lung cancer, the most common form of lung cancer. It makes them good candidates for treatment with Xalkori, a targeted drug that can help shrink or slow tumor growth for these patients.

“Pembrolizumab works by removing the brakes from the immune system, allowing it to detect and destroy cancer cells.”

 


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).”


Ros1 Gene Fusions Found in 2.4% of Asian Patients with Lung Adenocarcinoma, Associated with Young Age at Diagnosis

The gist: Oncologists can sometimes look for certain genetic mutations in a patient’s tumor to help determine the best treatment options for that patient. Researchers have recently found that a particular mutation called ROS1 fusion is present in a subgroup of patients consisting of young East Asian patients with lung adenocarcinoma. People with ROS1 mutations in their lung tumors might benefit from treatment with a drug called crizotinib. The drug has not yet been approved for widespread use by the U.S. Food and Drug Administration (FDA), but patients can enroll in clinical trials to gain access to it.

“ROS1 fusion genes were successfully detected independent of gender or smoking history in young East Asian patients with lung adenocarcinoma, a histological subgroup in non-small cell lung cancer (NSCLC), using multiplex reverse transcriptase-polymerase chain reaction (RT-PCR) and immunohistochemistry (IHC) diagnostic tests.

“In NSCLC treatment algorithms, a personalized therapy approach is now being taken based on the genetic characteristics of the cancer. Patients with specific oncogenic molecular aberrations, for example EGFR mutations and ALK gene fusions, respond well to drugs that target these molecular abnormalities. ROS1 is another potential oncogenic molecular driver and this target is sensitive to crizotinib, a drug approved for the treatment of ALK gene fusion NSCLC .

“Researchers from the National Taiwan University Hospital examined 160 surgical specimens from early-stage and 332 specimens of fluid around the lungs (malignant pleural effusions) from late-stage lung adenocarcinoma patients. They initially examined these specimens for EGFR and KRAS mutations as well as ALK gene. Specimens that were negative for these three oncogenic drivers were then examined for ROS1 fusions using RT-PCR and IHC. Fluorescence in situ hybridization (FISH) was used if there was a discrepancy between RT-PCR and IHC.”