Alectinib: ALEX and ALUR trials show CNS benefit in NSCLC

Excerpt:

“Data from two separate phase 3 studies to be presented at the ESMO 2017 Congress in Madrid, show alectinib’s particular central nervous system (CNS) activity in patients with advanced non-small cell lung cancer involving a mutation of the anaplastic lymphoma kinase gene (ALK-positive NSCLC).

Findings from the ALUR trial (1), as well as a secondary analysis of the ALEX trial (2) show alectinib can significantly decrease CNS progression of NSCLC, both in the first-line as well as the second-line treatment setting.

” ‘Patients with NSCLC have a high risk of CNS and brain metastases,’ commented Prof. Fiona Blackhall, from the University of Manchester and The Christie Hospital, UK.”

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Expert Discusses Abemaciclib Potential in HR+/HER2- Breast Cancer Patients With Brain Mets

Excerpt:

“Abemaciclib penetrated brain metastases and had antitumor activity in patients with hormone receptor (HR)-positive, HER2-negative metastatic breast cancer, preliminary evidence suggests.

“Results were presented in a poster at the 2017 ASCO Annual Meeting for 23 patients from a stage 1 efficacy analysis from a phase II study.

” ‘What we found were 2 patients who experienced partial responses within the CNS, suggesting there is activity of the agent in the brain and in patients who have HR-positive disease,’ explained lead author Sara M. Tolaney, MD, MPH.”

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ARIAD Presents Updated Phase 1/2 Clinical Data on Brigatinib in Patients with ALK+ Non-Small Cell Lung Cancer

Excerpt:

ARIAD Pharmaceuticals, Inc. (NASDAQ: ARIA) today announced updated clinical data on its investigational tyrosine kinase inhibitor, brigatinib, in patients with advanced malignancies, including anaplastic lymphoma kinase positive (ALK+) non-small cell lung cancer (NSCLC), from an ongoing Phase 1/2 trial. This report includes updated data on the brigatinib safety profile and pharmacokinetics (PK) from all patients treated in the trial, with a focus on brigatinib clinical activity in patients with ALK+ NSCLC, including those with intracranial CNS metastases at study entry. The report also details overall survival outcomes of patients in the study.”

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Alectinib Shows Response in Crizotinib-Refractory NSCLC

“The ALK inhibitor alectinib was highly active and well-tolerated in patients with ALK-rearranged, crizotinib-refractory, advanced non–small-cell lung cancer (NSCLC), according to results of a phase II trial.

“In this trial, 138 patients with crizotinib-refractory ALK-positive NSCLC were treated with alectinib; 122 of these patients were evaluable for response, and 61% had central nervous system (CNS) metastases at baseline. The results were published in the Journal of Clinical Oncology.

“ ‘Almost all patients invariably experience progression on crizotinib, and approximately 40% of the patients with ALK-rearranged NSCLC develop CNS metastases as an initial site of progression,’ wrote study authors led by Sai-Hong Ignatius Ou, MD, PhD, of the Chao Family Comprehensive Cancer Center, University of California Irvine School of Medicine in Orange, California. Alectinib is approximately five times as potent an ALK inhibitor as crizotinib, and can inhibit most of the acquired ALK resistance mutations to crizotinib.”


AZD9291 Shows Clinical Activity in Non-Small Cell Lung Cancer Patients with Leptomeningeal Disease

“The epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) AZD9291 crossed the blood-brain barrier and showed clinical activity in heavily pretreated non-small cell lung cancer (NSCLC) patients with leptomeningeal disease, a disease in which lung cancer cells spread to the membranes surrounding the brain and spinal cord, according to data from a phase I BLOOM clinical trial presented at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics, held Nov. 5–9.

” ‘Leptomeningeal disease at initial diagnosis of NSCLC is rare; however, as their lung cancer progresses, up to 15 percent of patients will develop this devastating complication. Additionally, an increased risk of central nervous system [CNS] involvement has been reported among patients with EGFR-mutant NSCLC, in particular those treated with a first-generation EGFR-TKI,’ said Dae Ho Lee, MD, PhD, associate professor in the Department of Oncology in the University of Ulsan College of Medicine and Asan Medical Center, Seoul, Korea.”


FDA Grants Alectinib Priority Review in NSCLC

“Alectinib has received an FDA priority review designation for patients with ALK-positive, locally advanced or metastatic non–small cell lung cancer (NSCLC) who have progressed or are intolerant to crizotinib (Xalkori), according to Genentech, the manufacturer of the oral second-generation ALK inhibitor. The FDA’s action date for an approval decision is March 4, 2016.

“The priority review is based on two phase II trials (NP286731and NP287612) which demonstrated that alectinib had robust activity in patients with ALK-positive NSCLC following progression on crizotinib (Xalkori), including individuals with CNS metastases.

“ ‘Alectinib was granted priority review by the FDA based on results from two studies showing the medicine shrank tumors in people with ALK-positive NSCLC that progressed on crizotinib,’ Sandra Horning, MD, chief medical officer and head of Global Product Development at Genentech, said in a statement. ‘There is a need for new treatment options in this patient population, especially because the disease often spreads to the brain at progression.’ “


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.’ “


Kadcyla May Be Better than Lapatinib for Advanced, HER2-Positive Breast Cancer That Has Spread to the Central Nervous System

The gist: People whose HER2-positive breast cancer has spread to their central nervous system (CNS) might survive longer if they are treated with the drug Kadcyla than if they take capecitabine plus lapatinib. That was the conclusion of a recent clinical trial with volunteer patients. Our Chief  Scientist speculates that the mild side effects of Kadcyla compared to those of the capecitabine/lapatinib combo might also make it a better choice.

“Patients with HER-2–positive advanced breast cancer treated with ado-trastuzumab emtansine experienced similar rates of central nervous system progression as those treated with capecitabine plus lapatinib, according to study results.

“However, among patients with treated, asymptomatic central nervous system (CNS) metastases at baseline, those assigned the antibody–drug conjugate ado-trastuzumab emtansine (Kadcyla, Genentech) experienced significantly longer OS than those assigned capecitabine plus lapatinib (Tykerb, GlaxoSmithKline).

“Ian E. Krop, MD, of the department of medical oncology at Dana-Farber Cancer Institute and Harvard University School of Medicine, and colleagues conducted a retrospective, exploratory analysis of data from the phase 3 EMILIA study.

“The EMILIA study included 991 patients with HER-2–positive advanced breast cancer who underwent previous treatment with trastuzumab (Herceptin, Genentech) and a taxane. Researchers randomly assigned 495 patients to ado-trastuzumab emtansine, and the other 496 received capecitabine plus lapatinib. Treatment continued until disease progression.”


Primary Melanoma of the CNS in Children Is Driven by Congenital Expression of Oncogenic NRAS in Melanocytes

“NRAS mutations are common in human melanoma. To produce a mouse model of NRAS-driven melanoma, we expressed oncogenic NRAS (NRASG12D) in mouse melanocytes. When NRASG12D was expressed in the melanocytes of developing embryos, it induced melanocyte proliferation and congenital melanocytic lesions reminiscent of human blue nevi but did not induce cutaneous melanoma…”