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.’ “


Alectinib Promising in ALK-Positive Advanced NSCLC

“The ALK and RET inhibitor alectinib yielded good response rates and was very well tolerated in a phase II trial of patients with advanced, ALK-positive non–small-cell lung cancer (NSCLC; abstract 8008). Results were presented at the 2015 American Society of Clinical Oncology (ASCO) Annual Meeting, held May 29 to June 2, in Chicago.

“Crizotinib is currently the standard-of-care for advanced, treatment-naive ALK-positive NSCLC. ‘However, the median progression-free survival (PFS) for these patients on crizotinib is under 12 months,’ said Sai-Hong Ignatius Ou, MD, PhD, of the UC Irvine Medical Center in California. ‘This is in part due to development of ALK mutations that are resistant to crizotinib.’

“Alectinib is a next-generation inhibitor that is highly selective for ALK and RET; as an ALK inhibitor, Ou said, it is approximately five times as potent as crizotinib. It can inhibit the majority of clinically relevant acquired ALK mutations.”


Novartis Presents New Data at ASCO for Zykadia® and Combination of Tafinlar® and Mekinist® in Certain NSCLC Patients with Unmet Needs

“Novartis today announced new data from two Phase II studies of Zykadia® (ceritinib), as well as one Phase II study of Tafinlar® (dabrafenib) in combination with Mekinist® (trametinib) in certain patients with non-small cell lung cancer (NSCLC). Data from these studies were presented at the 51st Annual Meeting of the American Society of Clinical Oncology (ASCO) in Chicago.

“The results of the Zykadia studies – ASCEND-2 and ASCEND-3 – reinforce the efficacy of the medicine in patients with anaplastic lymphoma kinase-positive (ALK+) NSCLC who had received previous treatment with an ALK inhibitor and in those receiving an ALK-targeted therapy for the first time. Overall response rates (ORR) seen in these trials were 38.6% and 63.7%, respectively, based upon investigator assessment. Comparable ORR results were observed in patients with ALK+ NSCLC who entered the studies with brain metastases (33% and 58%, respectively)[1],[2].

“Separately, the study of dabrafenib in combination with trametinib in patients with metastatic BRAF V600E-mutation positive NSCLC who had failed at least one round of chemotherapy demonstrated an ORR of 63% in this population[3].”


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.’ “


Brigatinib Achieves Brain Metastases Control for Over 80% of ALK-Positive NSCLC Patients

“Brigatinib (AP26113), an investigational ALK tyrosine kinase inhibitor, demonstrated significant intracranial antitumor activity in patients with ALK-positive non–small cell lung cancer (NSCLC) and brain metastases, according to findings presented at the European Lung Cancer Conference.1

“A post hoc analysis conducted by Ariad Pharmaceuticals, the company developing brigatinib, looked at 49 NSCLC patients identified as having baseline brain metastasis. The analysis determined that intracranial disease control was achieved with brigatinib in 87% of patients with measurable brain metastases and in 87% of patients with nonmeasurable brain metastases. Intracranial response was reported in 53% of patients with measurable brain metastases and in 30% of patients with nonmeasurable lesions.

“Following treatment, 45 patients achieved median intracranial progression–free survival (PFS) of 22.3 months. The median duration of intracranial response was 18.9 months.

“Adverse events were mild to moderate in severity and included nausea, diarrhea, and fatigue that were reported by 29 (59%), 28 (57%), and 24 (49%) patients, respectively.”


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.”


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.”


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.’ ”