Abstract
Novartis's second-generation ALK inhibitor ceritinib has been approved by the FDA for patients with ALK-positive lung cancer who relapse after first-line therapy.
Novartis's second-generation ALK inhibitor ceritinib (Zykadia) has been granted accelerated approval by the FDA, offering a much-needed treatment option for patients with certain lung cancers who relapse after first-line therapy.
Approval was based on a pivotal phase I trial of 163 patients with metastatic ALK-positive non–small cell lung cancer (NSCLC) who progressed on treatment with the ALK inhibitor crizotinib (Xalkori; Pfizer) and were given ceritinib. The overall response rate was 54.6% with a median duration of response of 7.4 months. Side effects included diarrhea, vomiting, dehydration, elevated liver enzymes, and low phosphorous levels.
“We now know that when crizotinib stops working, we have the option of treating those patients with a more potent ALK inhibitor,” says Alice Shaw, MD, PhD, a thoracic oncologist at Massachusetts General Hospital Cancer Center in Boston and the phase I trial's lead investigator. “Ceritinib appears to be effective against many of the known resistance mutations that arise in patients who have been exposed to crizotinib.”
Compelling preliminary results led the FDA to designate ceritinib as a Breakthrough Therapy in March 2013 and grant accelerated approval based solely on phase I data, which is unusual, says Shaw.
“Three years from the beginning of drug development to approval is very fast,” she says. “It signals that the FDA is trying to move these drugs along to give access to patients who may have no other treatment options.”
Investigators noted that tumor regression was seen in patients with and without ALK alterations, suggesting that ceritinib may be effective in patients resistant to crizotinib even in the absence of a secondary ALK resistance mutation.
Many patients with ALK-rearranged tumors, which account for about 5% of all cases of NSCLC, respond well to initial treatment with crizotinib but tend to relapse within the first year of treatment due to acquired resistance. Based on results from this trial, a more potent ALK inhibitor, such as ceritinib, may overcome that resistance, says Shaw.
“Ceritinib is anywhere from five to 20 times more effective against ALK than crizotinib, and it has a chemically distinct structure,” she notes. It also inhibits a different spectrum of targets; for example, unlike crizotinib, ceritinib does not inhibit the kinase activity of MET but does inhibit the IGF-1 receptor.
Investigators have now completed two phase II trials of ceritinib and are awaiting results, says Shaw. One study focused on patients with acquired resistance to crizotinib, while the other targeted crizotinib-naïve tumors. In addition, two phase III randomized studies are under way comparing ceritinib to standard chemotherapy, either combination chemotherapy or single-agent chemotherapy.
“We're looking to see that the efficacy, response rate, and duration of responses hold up in phase II trials,” explains Shaw. “We also need to carefully look at side effects and other potential toxicities in follow-up studies.
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