Skip to main content
Premium Trial:

Request an Annual Quote

FDA Acts Quickly on Personalized NSCLC Drugs; Reviewing Xalkori in ROS1-Positive Cases


NEW YORK (GenomeWeb) – Quick action from the US Food and Drug Administration in recent weeks has expanded the number of personalized treatment options available to non-small cell lung cancer patients.

The FDA last week granted accelerated approval to Genentech's Alecensa (alectinib) for metastatic NSCLC patients with ALK-positive tumors who no longer respond to Pfizer's Xalkori (crizotinib). "Different ALK inhibitors interact with the ALK protein in slightly different ways, and there is evidence that specific mutations conferring resistance to one ALK inhibitor do not necessarily confer resistance to other ALK inhibitors," Josina Reddy, Genentech's senior group medical director of product development, told GenomeWeb. "Alecensa is designed to work by selectively binding to ALK, preventing it from sending signals that promote cell growth."

Last year, the FDA approved Novartis' Zykadia (ceritinib) also for advanced NSCLC patients who don't respond to Xalkori. Neither Alecensa nor Zykadia were approved with a companion diagnostic since patients receiving them will have already been tested for ALK rearrangements when considering treatment with Xalkori.

Pfizer's ALK inhibitor was approved in 2011 alongside Abbott Molecular's Vysis ALK Break Apart Fluorescence In Situ Hybridization Probe Kit. However, for several years, Pfizer has been studying Xalkori's efficacy and safety in other molecularly defined NSCLC subsets, and the fruit of that work has finally resulted in a new regulatory filing with the FDA. Pfizer announced last week that the agency had granted priority review for its supplemental new drug application for Xalkori as an option for metastatic NSCLC patients whose tumors have ROS1 rearrangements.

Meanwhile, Genentech is also hoping to expand the indication for Alecensa into the first-line, ALK-positive, advanced NSCLC setting by comparing it against Xalkori in the Phase III ALEX trial. In that study, patients' tumors will be characterized for ALK fusions using the Ventana ALK (D5F3) CDx immunohistochemistry assay.

Of the approximately 1.5 million new cases of NSCLC each year globally, between 3 percent and 7 percent have tumors with ALK fusions, while 1 percent have ROS1 fusions. EGFR mutations are also important predictive markers in NSCLC, occurring in 10 percent of cases, and there are now multiple precision treatment options for this subset of patients.

The latest accelerated approval from the FDA was for AstraZeneca's Tegrisso (osimertinib) for advanced NSCLC patients who have the EGFR resistance mutation T790M and who have progressed despite receiving other EGFR inhibitors. The agency approved the drug based on data from two studies involving 411 patients with T790M mutation-positive disease, where more than half the participants experienced partial or complete tumor shrinkage.

Simultaneously, the agency also approved Roche's supplemental premarket application for an updated version of its qPCR-based Cobas EGFR Mutation Test, which now can be used to gauge T790M EGFR mutations for patients considering Tegrisso, in addition to Exon 19 deletions and the Exon 21 substitution the first version of the test could gauge for identifying best responders to Genentech's Tarceva (erlotinib).

Genentech launched Alecensa at a list price of $12,500 per month. Comparatively, the list price for one month of Zykadia is $13,500 and $11,500 for Xalkori. The monthly list price of Tegrisso is $12,750. Most drug sponsors have programs to help qualifying patients with the cost of these drugs.


FDA's accelerated approval of Alecensa took only three months after the agency granted it priority review in September. The agency approved the drug based on data from two single-arm studies, in which the objective response rates were 38 percent and 44 percent, and the median duration of responses were 7.5 months and 11.2 months.

Moreover, in 51 patients in these studies whose disease had spread to the brain or other parts of the central nervous system, the objective response rate was 61 percent and the median duration of response was around nine months. "More than half of the people with ALK-positive lung cancer will have their cancer spread to the brain during or after prior treatment so there is a need for new options for people with this type of lung cancer," Reddy said.

Some patients in these studies had serious adverse events affecting the liver and lungs, as well as slow heartbeat after treatment with Alecensa. Common drug side effects seen in the trials were tiredness, constipation, and swelling of the hands, feet, ankles, and eyelids.

A condition of getting accelerated approval is that sponsors must submit more definitive evidence on their treatments. For Alecensa, Genentech is hoping to submit data from the Phase III ALEX study.

Expanding indication

Meanwhile, having priority review for the sNDA for Xalkori means that the FDA will also review the data submitted by Pfizer in a expedited timeline, with the decision expected around April 2016. If approved, Xalkori will be the first treatment option for ROS1-positive NSCLC patients.

Pfizer submitted to the agency data from the Phase I Study 1001, which involved 53 metastatic NSCLC patients with ROS1-positive tumors. Researchers published data on 50 of these patients in the New England Journal of Medicine last November, showing there was a 72 percent objective response rate. Median duration of response was nearly 18 months and median progression-free survival was 19 months.

While Pfizer has been conducting Study 1001 to formally expand the label for Xalkori in ROS1-positive NSCLC, medical practice has marched ahead. Three years ago, when researchers first presented data from Study 1001 on 15 evaluable ROS1-positive patients treated with Xalkori, some academic oncologists said they were already testing lung cancer patients for this marker.

Treatment guidelines now recommend ROS1 assessment in advanced lung cancer patients, and suggest Xalkori as a first-line option for Stage IV NSCLC. However, because there is no FDA-approved diagnostic for this purpose, patients' ROS1 status is assessed with lab-developed tests.

In Study 1001, for example, researchers employed break-apart FISH testing at local labs to identify ROS1 rearrangements in 49 patients and an RT-PCR test to analyze the marker in one patient. "Pfizer is currently discussing options for diagnostic testing with the FDA, but cannot comment on any specific plans or recommendations from the FDA," a Pfizer spokesperson told GenomeWeb.

Although ALK and ROS1 fusions don't co-occur in a patients' tumor, patients in these molecular subgroups tend to be younger, never smokers, and have adenocarcinoma histology. However, Study 1001 suggested that the ROS1 subgroup might do even better than the ALK subset, with median progression free survival of 19 months and around 10 months, respectively.