Crizotinib Shows Promise against Brain Metastases in Patients with NSCLC

The gist: A drug called crizotinib (Xalkori) has shown promise for some people with non-small cell lung cancer (NSCLC) that has metastasized to the brain. Xalkori is already used to treat NSCLC in patients whose tumors have a genetic abnormality known as “ALK rearrangement.” A recent study focused specifically on people whose NSCLC had spread to the brain. The researchers found that Xalkori may help patients whose brain metastases have not yet caused any symptoms.


Pfizer's Xalkori Shows First-Line Benefit in ALK-Positive NSCLC

The gist: The drug Xalkori (aka crizotinib) has shown promise for treating people with a certain type of non-small cell lung cancer (NSCLC) who have not yet taken any other treatment. A clinical trial tested Xalkori in untreated NSCLC patients whose tumors had mutations of the ALK gene (“ALK-positive”). People who took Xalkori in the trial had almost 4 more months before their cancer worsened than people who took only chemotherapy.

“Pfizer’s targeted cancer therapy Xalkori (crizotinib) significantly extended progression-free survival in previously-untreated patients with a particular form of non-small cell lung cancer taking part in a late-stage trial compared to chemotherapy alone.

“Data from the Phase III PROFILE 1014 study, published in The New England Journal of Medicine, showed that patients with ALK-positive advanced NSCLC given Pfizer’s kinase inhibitor had a median PFS of 10.9 months compared to 7 months for those in the chemotherapy arm. Also, the objective response rate was much higher at 74% versus 45%, the firm noted.

“On the safety side, no unexpected issues arose in the trial, with the most commonly reported adverse events observed in the Xalkori being vision disorder (71%), diarrohea (61%), nausea (56%) and oedema (49%), and with chemotherapy, nausea (59%), fatigue (38%), vomiting (36%) and decreased appetite (34%).

“ALK gene rearrangements are present in about 5% of NSCLC cancers typically occurring in younger patients who don’t smoke. By identifying and enrolling only those patients whose advanced NSCLC tumours are ALK-positive, “this trial was able to demonstrate the superiority of Xalkori over an intravenous platinum-based chemotherapy regimen that has been a standard first-line treatment for more than a decade,” said Mace Rothenberg, chief medical officer for Pfizer Oncology.”


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.’ ”


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…