Lorlatinib Highly Effective for Relapsed ALK or ROS1 Rearranged NSCLC

Excerpt:

“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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ALK Mutation Variant May Affect Response to Targeted Agents

Excerpt:

“Anaplastic lymphoma kinase (ALK)-targeting agents such as crizotinib may work most effectively in non–small-cell lung cancer (NSCLC) patients with ALK variant 1, according to a recent study published in the Journal of Clinical Oncology.

“Because the magnitude of response as well as durations of response to tyrosine kinase inhibitors (TKIs) that target ALK varies among ALK-positive NSCLC patients, Tatsuya Yoshida, MD, PhD, of the Aichi Cancer Center Hospital in Japan, and colleagues assessed the efficacy of crizotinib among 35 patients whose ALK variant could be determined and who received the treatment as their initial ALK-TKI.

“Ten of the patients received crizotinib as a first-line treatment, while the majority, 18 patients, received the oral drug as a second-line therapy. The median progression-free survival (PFS) among patients in the study was 9.7 months.”

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Pfizer Presents Promising Data from Next Generation ALK/ROS1 Inhibitor in Advanced Non-Small Cell Lung Cancer

Excerpt:

“Pfizer Inc. (NYSE:PFE) today announced encouraging new data from a Phase 1/2 study of lorlatinib, the proposed generic name for PF-06463922, Pfizer’s investigational, next-generation ALK/ROS1 tyrosine kinase inhibitor. The study showed clinical response in patients with ALK-positive or ROS1-positive advanced non-small cell lung cancer (NSCLC), including patients with brain metastases. These data were presented today in an oral presentation at the 52nd Annual Meeting of the American Society of Clinical Oncology (ASCO) in Chicago.

“The results presented are from the dose escalation component of an ongoing Phase 1 study of patients with ALK-positive or ROS1-positive NSCLC, with or without brain metastases, who were treatment-naïve or had disease progression after at least one prior tyrosine kinase inhibitor (TKI). Among patients with ALK-positive metastatic NSCLC, the overall response rate (ORR) with lorlatinib was 46 percent, with three patients achieving complete responses and 16 patients achieving a partial response (95% CI: 31-63). The median progression free survival (PFS) was 11.4 months (95% CI: 3.4 – 16.6). The majority of patients had received two or more prior ALK TKIs. Additionally, lorlatinib showed the ability to decrease the size of brain metastases in patients with ALK-positive or ROS1-positive metastatic NSCLC.”

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Personalizing Cancer Therapies May Combat Resistance to Targeted Therapy Drugs

“The use of drugs that target genetic mutations driving the growth of tumors has revolutionized treatment for several serious forms of cancer, but in almost every case, tumors become resistant to the drugs’ therapeutic effects and resume growth, often through the emergence of new mutations, which has spurred the development of more powerful drugs that can overcome resistance mutations. In the Dec. 24 issue of New England Journal of Medicine, Massachusetts General Hospital (MGH) physicians report their study examining the evolution of drug resistance in a lung cancer patient treated with multiple different targeted therapies. When resistance developed to the third targeted therapy, the new mutation actually restored the cancer’s response to the very first targeted therapy drug used to treat the patient.”


Promising Trial of Brigatinib Shows All Next-Gen ALK Inhibitors May Not Be Created Equal

“Phase I/II clinical trial results reported at the American Society for Clinical Oncology (ASCO) Annual Meeting 2015 show promising results for investigational drug brigatinib against ALK+ non-small cell lung cancer (NSCLC), with 58 of 78 ALK+ patients responding to treatment, including 50 of 70 patients who had progressed after previous treatment with crizotinib, the first licensed ALK inhibitor. Progression-free survival (PFS) in patients previously treated with crizotinib was 13.4 months.

” ‘Although still only in an early phase trial, brigatinib is showing an objective response rate in approximately 70 percent of ALK-positive post-crizotinib and it’s showing about a year of progression-free survival. These results are among the best in the field, offering a lot of hope to people with ALK-positive ,’ says D. Ross Camidge, MD, PhD, director of thoracic oncology at the University of Colorado Cancer Center and the trial’s principal investigator.”


Roche: "Investigational Medicine Alectinib Shrank Tumours in Nearly Half of People with Specific Type of Lung Cancer"

“Roche (SIX: RO, ROG; OTCQX: RHHBY) today announced positive results from two pivotal studies (NP28673 and NP28761) that showed alectinib, its oral investigational anaplastic lymphoma kinase inhibitor (ALKi), shrank tumours (overall response rate; ORR: 50% and 47.8%, respectively) in people with advanced ALK-positive (ALK+) non-small cell lung cancer (NSCLC) whose disease had progressed following treatment with crizotinib. In addition, alectinib was shown to shrink tumours in people whose cancer had spread to the central nervous system (CNS) (CNS ORR: 57.1% and 68.8%, respectively). Additionally, people whose tumours shrank in response to alectinib continued to respond for a median of 11.2 and 7.5 months, respectively (duration of response; DOR). Alectinib demonstrated a safety profile consistent with that observed in previous studies. The most common adverse events (Grade 3 or higher occurring in at least 2% of people) were an increase in muscle enzymes (increased blood levels of creatine phosphokinase), increased liver enzymes and shortness of breath (dyspnea).1,2

“ ‘Cancer spreads to the brain in about half of people with ALK-positive lung cancer, and these studies suggest that alectinib can shrink tumours in people with this difficult-to-treat disease,’ said Sandra Horning, MD, Chief Medical Officer and Head of Global Product Development. ‘We plan to submit these data to the FDA this year to support alectinib as a potential new option for people whose advanced ALK-positive lung cancer progressed on crizotinib.’ “


New Guideline Will Expand List of Lung Cancer Molecular Tests Doctors Can Use to Help Make Treatment Decisions

The gist: A new guideline will expand the list of tumor abnormalities that doctors can test for to help their lung cancer patients make treatment decisions. Different drugs have been developed to treat patients with different tumor abnormalities, such as mutations in the ALK and EGFR genes. Molecular testing lets doctors see which abnormalities a patient might have, and suggest the best-fitting treatments. The new guidelines will include recommendations for molecular testing of abnormalities in the  ROS1, MET, ERBB2, RET, NTRK1, ALK, and EGFR genes.

“The College of American Pathologists (CAP), the International Association for the Study of Lung Cancer (IASLC), and the Association for Molecular Pathology (AMP) are teaming to revise the evidence-based guideline, “Molecular Testing Guideline for Selection of Lung Cancer Patients for EGFR and ALK Tyrosine Kinase Inhibitors.”

“The updated guideline will include new recommendations for ALK testing by IHC, ALK-EGFR resistance, and a number of emerging target molecular targets which will include, but is not limited to, ROS1, MET, ERBB2, RET, NTRK1. Multiplexed “Next Generation Sequencing” multigene panels and the reassessment of immunohistochemistry will be reviewed. The role of rebiopsy and repeat analysis in the setting of post-treatment relapse, along with testing of blood samples for mutations in circulating tumor cells, cell free tumor DNA, or exosomes will be considered.

“The revision of the guideline will again be based on evidence from unbiased review of published experimental literature. The revisions will be recommended by an expert panel made up of renowned worldwide leaders in the field. The revision will start in early 2015, taking around 18 months to complete.

” ‘Although only one year has passed since the molecular testing guideline was published, rapid accumulation of scientific knowledge and new evidence in this field indicate that the guidelines should be updated. Thus, an update has begun that includes an expanded list of genes and new methods that are clinically relevant,’ said Yasushi Yatabe, MD, PhD, chief, Department of Pathology and Molecular Diagnostics, Aichi Cancer Center, Nagoya, Japan and IASLC member.”


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.’ “


Xcovery Presents Interim Phase 1 Results of X-396 in ALK positive NSCLC at the American Society for Clinical Oncology Annual Meeting

“Xcovery , a developer of next-generation targeted therapeutics for cancer, today presented preliminary results at the annual meeting of the American Society for Clinical Oncology (ASCO) from a phase 1 study of X-396, a potent small molecule anaplastic lymphoma kinase (ALK) inhibitor, that showed X-396 is well tolerated and has antitumor activity in patients with ALK positive non-small cell lung cancer (NSCLC).”

Editor’s note: Scientists have developed a new targeted drug called X-396. The drug is meant to treat patients with non-small cell lung cancer (NSCLC) whose tumors have mutations in the ALK gene, as detected by molecular testing. A clinical trial to test the drug in volunteer patients found promising results for X-396. It appeared to benefit patients whether or not they had previously taken and grown resistant to crizotinib, another ALK-targeted drug.