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.’ “


Pfizer Drug Shows Early Promise in Xalkori-Resistant Lung Cancer-Study

“An experimental Pfizer Inc drug that aims to help lung cancer patients with specific genetic mutations who have stopped responding to the company’s Xalkori was showing promise in a small, early stage study, according to preliminary data revealed on Wednesday.

“The ongoing Phase I trial of the drug, PF-3922, was designed to determine if there is a maximum tolerable dose and which dose or doses to test in future larger trials.

“But researchers found some early evidence of efficacy, according to a brief summary of the study that will be presented at the upcoming American Society of Clinical Oncology (ASCO)meeting in Chicago later this month.

“Of 15 patients evaluated for efficacy, six, or 40 percent, had partial responses, meaning tumor shrinkage of at least 30 percent. Intracranial responses were observed in five patients, indicating that the drug had successfully crossed the blood/brain barrier to attack tumors in the brain, which are common in advanced, or metastatic, lung cancer.

” ‘There’s encouraging clinical activity despite that it’s an early study,’ said Ronit Simantov, head of medical affairs for Pfizer oncology.”


Xalkori Granted a Breakthrough Designation for ROS Positive NSCLC

“Pfizer Inc. announced today that XALKORI® (crizotinib) received Breakthrough Therapy designation by the U.S. Food and Drug Administration (FDA) for the potential treatment of patients with ROS1-positive non-small cell lung cancer (NSCLC). Occurring in approximately one percent of NSCLC cases1, ROS1-positive NSCLC represents a particular molecular subgroup of NSCLC.2 XALKORI currently is approved in the U.S. for the treatment of patients with metastatic NSCLC whose tumors are anaplastic lymphoma kinase (ALK)-positive as detected by an FDA-approved test.

“Enacted as part of the 2012 FDA Safety and Innovation Act (FDASIA), Breakthrough Therapy designation is intended to expedite the development and review of a potential new medicine if it is “intended to treat a serious or life-threatening disease and preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over existing therapies.”3The Breakthrough Therapy designation is distinct from the FDA’s other mechanisms to expedite drug development and review.4

“ ‘We are excited that the FDA has granted Breakthrough Therapy designation for XALKORI as a potential treatment for patients with ROS1-positive NSCLC,’ said Dr. Mace Rothenberg, senior vice president of Clinical Development and Medical Affairs and chief medical officer for Pfizer Oncology. ‘XALKORI pioneered precision medicine for ALK-positive metastatic NSCLC, and ROS1 represents a second molecular subgroup of NSCLC in which XALKORI has demonstrated a level of anti-tumor activity that can potentially make a real difference for patients.’ ”


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.’ ”


Novartis Lung Cancer Drug Zykadia® Recommended for EU Approval in Patients with ALK+ NSCLC Previously Treated with Crizotinib

“Novartis announced today that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency adopted a positive opinion for Zykadia® (ceritinib) to treat adult patients with anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer (NSCLC) previously treated with crizotinib[2]. If approved in the European Union (EU), Zykadia will be the first treatment option to address an unmet medical need for patients with ALK+ NSCLC previously treated with crizotinib.

” ‘Patients with advanced ALK+ NSCLC have few options when their cancer does not respond to currently approved therapy,’ said Alessandro Riva, MD, Global Head, Novartis Oncology Development and Medical Affairs. ‘As a leader in the development of precision oncology medicines, Novartis is committed to developing and bringing to market new treatments for patients with ALK+ NSCLC. This positive CHMP opinion for Zykadia brings us one step closer to providing the lung cancer community with new hope in the fight against this terrible disease.’

“Each year, there are 1.6 million people diagnosed with lung cancer, the leading cause of cancer death worldwide[3]. The most common type of lung cancer is NSCLC, accounting for 85-90% of all cases[4]. Of those, 2-7% are driven by a rearrangement of the ALK gene, which increases the growth of cancer cells and can be identified by a molecular test of the cancer tumor[1]. Despite significant treatment advances for patients with ALK+ NSCLC, disease progression is often inevitable and more treatment options are needed[5].”


Crizotinib Shows Promise against Brain Metastases in Patients with NSCLC

The gist: A drug called crizotinib (Xalkori) has shown promise for some people with non-small cell lung cancer (NSCLC) that has metastasized to the brain. Xalkori is already used to treat NSCLC in patients whose tumors have a genetic abnormality known as “ALK rearrangement.” A recent study focused specifically on people whose NSCLC had spread to the brain. The researchers found that Xalkori may help patients whose brain metastases have not yet caused any symptoms.


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.”


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.’ ”


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.’ ”