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.”


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.”


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.’ ”


Researchers Report Double Dose of Promising Lung Cancer Findings

“Researchers with UCLA’s Jonsson Comprehensive Cancer Centerreport that two new experimental drugs have shown great promise in the treatment of patients with non–small-cell lung cancer, which accounts for about 85 percent of all lung cancers. Lung cancer is the leading cause of cancer death in the United States.

“The drugs—ramucirumab and CO-1868—were shown in separate clinical trials to increase survival times with fewer toxic side effects than standard treatments. The findings were presented this week at the American Society of Clinical Oncology annual meeting in Chicago.”

Editor’s note: For more on the ramucirumab findings, see our previous news post. To learn more about targeted therapies like CO-1686 and ramucirumab, visit our lung cancer Basics.


ASCO: Zykadia Works Before or After Targeted Lung Ca Tx

Ceritinib (Zykadia) produced good response in non-small cell lung cancer (NSCLC) overexpressing ALK, regardless of prior treatment for that target, an early phase trial showed.

Ceritinib was associated with an overall response rate of 55% in patients previously treated with crizotinib (Xalkori) and 66% in those naive to that ALK inhibitor, Dong-Wan Kim, MD, of the Seoul National University Hospital, and colleagues found.

Editor’s note: This article is about a drug called ceritinib (brand name Zykadia), which was recently approved by the U.S. Food and Dug Administration (FDA), allowing doctors in the U.S. to prescribe it to patients who 1) have advanced non-small cell lung cancer (NSCLC), 2) have tumor cells with mutations in the ALK gene, as detected by molecular testing, and 3) have tried treatment with crizotinib (Xalkori) but experienced worsening of their cancer. According to the new research described in this article, ceritinib may actually be beneficial whether or not the patient was previously treated with crizotinib.


ARIAD Presents Updated Phase 1/2 Data on AP26113 in Patients with ALK+ Non-Small Cell Lung Cancer

“ARIAD Pharmaceuticals, Inc. today announced updated clinical results on its investigational tyrosine kinase inhibitor (TKI), AP26113, in patients with advanced non-small cell lung cancer (NSCLC) from an ongoing Phase 1/2 trial. These study results show anti-tumor activity of AP26113 in patients with crizotinib-resistant anaplastic lymphoma kinase (ALK) positive NSCLC, including patients with brain metastases. Crizotinib is approved for ALK-positive NSCLC patients.”

Editor’s note: This story is about a targeted drug called AP26113, which may benefit some patients with advanced non-small cell lung cancer (NSCLC). Specifically, it has shown promise for patients whose tumors have mutations in the ALK gene, as detected by molecular testing, and who have already been treated with the drug crizotinib (Xalkori) but have grown resistant to it.