Lorlatinib Highly Effective for Relapsed ALK or ROS1 Rearranged NSCLC


“While several targeted therapies have emerged in recent years for treatment of non-small cell lung cancer (NSCLC) carrying the anaplastic lymphoma kinase (ALK) gene fusion, development of resistance to ALK inhibitors is an increasing problem. Furthermore, only one tyrosine kinase inhibitor (TKI), crizotinib, is currently approved for patients with ROS proto-oncogene 1 (ROS1) rearrangements. Lorlatinib, a novel, highly selective ALK and ROS1 targeting third-generation TKI has shown preclinical activity against known ALK resistance mutations and can penetrate the central nervous system (CNS), a common site of metastasis in ALK-positive or ROS1-positive NSCLC.”

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Ceritinib Demonstrates Activity in ROS1–Positive Non–Small Cell Lung Cancer


“Ceritinib appeared safe and effective in patients with ROS1–rearranged non–small cell lung cancer, according to a multicenter, open-label phase 2 study.

“ALK inhibitors — especially crizotinib (Xalkori, Pfizer) — effectively treat ROS1–positive cell lines and tumors. However, patients eventually develop resistance and experience a high incidence of brain recurrence.

” ‘Treatment options beyond crizotinib are needed, and clinical development of other ROS1 inhibitors should be accelerated to improve treatment outcome of patients with ROS1–positive NSCLC,’ Byoung Chul Cho, MD, PhD, assistant professor at Yonsei Cancer Center of Yonsei University College of Medicine, and colleagues wrote.”

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Crizotinib Is Highly Active in Lung Cancer with ROS1 Abnormality

“In a retrospective study in the European EUROS1 cohort reported in the Journal of Clinical Oncology, Mazières found that crizotinib (Xalkori) treatment was associated with an 80% response rate in patients with stage IV lung adenocarcinoma with ROS1 rearrangement.

“The study involved 31 patients who received crizotinib therapy through individual off-label use. Patients had a median age of 50.5 years, 64.5% were women, and 67.7% were never-smokers. Patients had received zero (n = 1), one (n = 9), two (n = 5), three (n = 3), or more than three (n = 13) lines of chemotherapy before crizotinib.

“Among 30 patients evaluated for response, 24 (80.0%) had objective response, including complete response in 5; 2 had stable disease (disease control rate of 86.7%); and 4 had disease progression. Median progression-free survival was 9.1 months, and 12-month progression-free survival was 44%. No unexpected adverse effects were observed…

“The investigators concluded: ‘Crizotinib was highly active at treating lung cancer in patients with a ROS1 rearrangement, suggesting that patients with lung adenocarcinomas should be tested for ROS1. Prospective clinical trials with crizotinib and other ROS1 inhibitors are ongoing or planned.’ ”

New Blood Test for ROS1 Could Help People with Non-Small Cell Lung Cancer Make Personalized Treatment Decisions

The gist: A new blood test might help people with non-small cell lung cancer (NSCLC) make decisions about their treatment. Doctors often use molecular testing to look for tumor mutations that might affect which treatments they suggest to a patient. Molecular testing requires tumor cells, which are usually taken directly from the tumor in a biopsy. A new, less invasive molecular test for NSCLC just requires a blood sample. The test uses circulating tumor DNA, pieces of DNA released by tumor cells into the bloodstream. It looks for a mutation known as ROS1 gene rearrangement. Patients with this mutation might be able to take specific drugs that target the mutation to treat cancer.

“Biocept, Inc. (Nasdaq:BIOC), a molecular oncology diagnostics company specializing in biomarker analysis of circulating tumor DNA (ctDNA) and Circulating Tumor Cells (CTCs), today announced the launch of ROS1 testing on CTCs, which will help physicians identify which of their patients may be receptive to certain drugs for the treatment of non-small cell lung cancer.

“Biocept’s new blood test identifies chromosomal rearrangements of the gene encoding ROS1 proto-oncogene receptor tyrosine kinase (ROS1), thereby defining a distinct molecular subgroup of NSCLCs. Patients with ROS1-positive tumors may be receptive to a number of therapeutic options that inhibit this target.

“It can be difficult to obtain enough tissue material for molecular testing of biomarkers like ROS1 from lung cancer patients due to the small size of tissue biopsies. Occasionally, tissue biopsies are altogether impossible because of risks associated with a surgical procedure for these patients. Biocept’s ‘liquid biopsy’ offers a method of determining the crucial genomic status of a tumor using a simple blood test.”

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.’ ”

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.’ “