Crizotinib Highly Active in ROS1-Rearranged NSCLC

The gist: The drug Xalkori (aka crizotinib) could help treat people with advanced non-small cell lung cancer (NSCLC) whose tumors have mutations known as ROS1-rearrangement. (Tumor mutations can be detected by molecular testing.) Xalkori is already known to help some people with tumor mutations in the ALK gene.

“In a study reported in The New England Journal of Medicine, Shaw et al found that crizotinib (Xalkori) produced a high response rate in patients with ROS1-rearranged non–small cell lung cancer (NSCLC).

“Chromosomal rearrangements in ROS1, which encodes the proto-oncogene receptor tyrosine kinase ROS1, define a distinct molecular subgroup in NSCLC. In addition to inhibiting ALK, crizotinib inhibits ROS1 and MET. As noted by the investigators, oncogenic ROS1 fusions may account for approximately 15,000 of the worldwide 1.5 million new cases of NSCLC each year. ALK and ROS1 rearrangements are infrequently found within the same tumor. Both are more common in patients with a history of never or light smoking and in adenocarcinoma.

“The investigators concluded: ‘In this study, crizotinib showed marked antitumor activity in patients with advanced ROS1-rearranged NSCLC. ROS1 rearrangement defines a second molecular subgroup of NSCLC for which crizotinib is highly active.’ ”


Two Novel Mutations Linked to ALK Inhibitor Resistance in NSCLC

The gist: Genetic mutations in a patient’s tumor can help determine which drugs are more likely to work. But a tumor can sometimes develop a new genetic mutation that makes it stop responding to a particular drug. When a person becomes resistant to his or her treatment, knowing about any new tumor mutations can help determine which treatment to try next. A recent study looked at mutations in non-small cell lung cancer (NSCLC). Different kinds of mutations in a gene called ALK can make NSCLC tumors treatable with different drugs. Certain ALK mutations make NSCLC tumors resistant to certain drugs. The scientists identified two new mutations that are associated with resistance to the drugs crizotinib and alectinib. Based on the findings, they suggest that a patient should get tested for new tumor mutations each time he or she becomes resistant to a particular drug. This will allow the doctor to select the best-fitting treatment to try next.

“Two novel ALK mutations, V1180L and I1171T, were associated with resistance to crizotinib and alectinib but were sensitive to other next-generation ALK tyrosine kinase inhibitors for non–small-cell lung cancer, according to study results.

“Although crizotinib (Xalkori, Pfizer) is the standard therapy for ALK-rearranged non–small cell lung cancer (NSCLC), patients often develop resistance to this agent and the next-generation ALK tyrosine kinase inhibitor (TKI) alectinib (CH5424802/RO5424802; Chugai Pharmaceuticals, Roche), according to study background information…

“ ‘These data highlight the need for repeat tumor biopsies at the time of resistance to each individual agent to determine if ALK mutations are present in the tumor, and if so, which ones,’ Politi and Gettinger wrote. ‘This practice will allow subsequent treatment to be tailored to the most current mutational state of the tumor.’ ”


Immune System-Boosting Drugs, New and Old, Are Explored in Combination Treatments for Lung Cancer


Readers of this blog will already know a thing or two about immunotherapy (immune system-activating drugs) and targeted therapy in lung cancer. Both approaches have benefited many patients in recent years. Now, research is being done to combine immunotherapies with other types of drugs. Of particular interest are immunotherapies that target PD-1, PD-L1, and CTLA4. These drugs, also known as immune checkpoint antibodies, are being tested in combination with other drugs in patients participating in the clinical trials below. Continue reading…


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.’ ”


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).”