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The anaplastic lymphoma kinase inhibitor ceritinib showed "substantial and durable" activity against advanced non–small cell lung cancer harboring ALK gene rearrangements in a phase I study designed, analyzed, and sponsored by the manufacturer and reported online March 26 in the New England Journal of Medicine.
The trial involved 122 adults with locally advanced or metastatic NSCLC and 8 with other cancers (breast cancer, alveolar rhabdomyosarcoma, inflammatory myofibroblastic tumor, neoplastic large-cell lymphoma, and rectal adenocarcinoma), all of which harbored genetic alterations in the anaplastic lymphoma kinase (ALK) gene. In preclinical studies, ceritinib was found to be 20 times more potent than crizotinib (also an ALK inhibitor), and it appeared as though it would be effective in patients who had responded to crizotinib but eventually developed resistance to that drug, said Dr. Alice T. Shaw of Massachusetts General Hospital, Boston, and her associates.
In the current trial, the investigators found oral ceritinib to be safe, with a maximum tolerated dose of 750 mg daily in 21-day cycles. The most common adverse events were nausea (82% of patients), diarrhea (75%), vomiting (65%), fatigue (47%), and increased alanine aminotransferase levels (35%). Four cases of interstitial lung disease were thought to be possibly related to the drug, as was one case of asymptomatic grade 3 prolongation of the QT interval; all of these resolved when ceritinib was discontinued. Eight patients (6%) discontinued the drug because of adverse events.
Although this phase I trial (NCT01283516) was designed only to determine the safety and tolerability of ceritinib, the investigators also found that it was effective in NSCLC, both in patients who had never been treated with crizotinib and in those who had. Among the 114 NSCLC patients who received at least 400 mg of ceritinib per day, the overall response rate was 58%, and among the 80 who had previously been treated with crizotinib, the response rate was 56%. Some responses where characterized as "rapid and dramatic," and median progression-free survival was 7 months, the authors reported (New Engl. J. Med. 2014 March 26 [doi: 10.1056/NEJMoa1311107]).
Two of the 8 study participants who had cancers other than NSCLC – one with anaplastic large-cell lymphoma and another with inflammatory myofibroblastic tumor – also showed a treatment response.
"These findings suggest that the large majority of crizotinib-resistant tumors may remain ALK-dependent and that an important factor contributing to crizotinib resistance may be subtherapeutic inhibition of the target, which may be overcome by more potent and structurally distinct ALK inhibitors such as ceritinib. Alternatively, ceritinib may inhibit an unknown kinase that has not yet been found to play a role in the biology of these tumors," Dr. Shaw and her associates said.
This study was funded by Novartis, the National Cancer Institute, the V Foundation, Be a Piece of the Solution, and the Evan Spirito Memorial Foundation. Dr. Shaw reported ties to Novartis, Pfizer, and other companies, and her associates reported ties to numerous industry sources.
The relatively large study population of this phase I clinical trial is "a major advantage," said Dr. Roman K. Thomas.
With 114 patients receiving at least 400 mg of ceritinib and nearly 60% of them achieving remission, "this study is a first proof of concept for the successful targeting of ALK, beyond the establishment of safety and a maximum tolerated dose," he noted.
Even more striking was the finding that treatment response was independent of prior exposure to crizotinib therapy. "Thus, patients appear to have a second chance of response after relapse occurs [with] crizotinib."
Dr. Thomas is in the departments of translational genomics and pathology at the Center of Integrated Oncology Cologne-Bonn, and is on the medical faculty of the University of Cologne, Germany. He reported ties to numerous industry sources. These remarks were taken from his editorial accompanying Dr. Shaw’s report (New Engl. J. Med. 2014 March 26 [doi: 10.1056/NEJMe1316173]).
The relatively large study population of this phase I clinical trial is "a major advantage," said Dr. Roman K. Thomas.
With 114 patients receiving at least 400 mg of ceritinib and nearly 60% of them achieving remission, "this study is a first proof of concept for the successful targeting of ALK, beyond the establishment of safety and a maximum tolerated dose," he noted.
Even more striking was the finding that treatment response was independent of prior exposure to crizotinib therapy. "Thus, patients appear to have a second chance of response after relapse occurs [with] crizotinib."
Dr. Thomas is in the departments of translational genomics and pathology at the Center of Integrated Oncology Cologne-Bonn, and is on the medical faculty of the University of Cologne, Germany. He reported ties to numerous industry sources. These remarks were taken from his editorial accompanying Dr. Shaw’s report (New Engl. J. Med. 2014 March 26 [doi: 10.1056/NEJMe1316173]).
The relatively large study population of this phase I clinical trial is "a major advantage," said Dr. Roman K. Thomas.
With 114 patients receiving at least 400 mg of ceritinib and nearly 60% of them achieving remission, "this study is a first proof of concept for the successful targeting of ALK, beyond the establishment of safety and a maximum tolerated dose," he noted.
Even more striking was the finding that treatment response was independent of prior exposure to crizotinib therapy. "Thus, patients appear to have a second chance of response after relapse occurs [with] crizotinib."
Dr. Thomas is in the departments of translational genomics and pathology at the Center of Integrated Oncology Cologne-Bonn, and is on the medical faculty of the University of Cologne, Germany. He reported ties to numerous industry sources. These remarks were taken from his editorial accompanying Dr. Shaw’s report (New Engl. J. Med. 2014 March 26 [doi: 10.1056/NEJMe1316173]).
The anaplastic lymphoma kinase inhibitor ceritinib showed "substantial and durable" activity against advanced non–small cell lung cancer harboring ALK gene rearrangements in a phase I study designed, analyzed, and sponsored by the manufacturer and reported online March 26 in the New England Journal of Medicine.
The trial involved 122 adults with locally advanced or metastatic NSCLC and 8 with other cancers (breast cancer, alveolar rhabdomyosarcoma, inflammatory myofibroblastic tumor, neoplastic large-cell lymphoma, and rectal adenocarcinoma), all of which harbored genetic alterations in the anaplastic lymphoma kinase (ALK) gene. In preclinical studies, ceritinib was found to be 20 times more potent than crizotinib (also an ALK inhibitor), and it appeared as though it would be effective in patients who had responded to crizotinib but eventually developed resistance to that drug, said Dr. Alice T. Shaw of Massachusetts General Hospital, Boston, and her associates.
In the current trial, the investigators found oral ceritinib to be safe, with a maximum tolerated dose of 750 mg daily in 21-day cycles. The most common adverse events were nausea (82% of patients), diarrhea (75%), vomiting (65%), fatigue (47%), and increased alanine aminotransferase levels (35%). Four cases of interstitial lung disease were thought to be possibly related to the drug, as was one case of asymptomatic grade 3 prolongation of the QT interval; all of these resolved when ceritinib was discontinued. Eight patients (6%) discontinued the drug because of adverse events.
Although this phase I trial (NCT01283516) was designed only to determine the safety and tolerability of ceritinib, the investigators also found that it was effective in NSCLC, both in patients who had never been treated with crizotinib and in those who had. Among the 114 NSCLC patients who received at least 400 mg of ceritinib per day, the overall response rate was 58%, and among the 80 who had previously been treated with crizotinib, the response rate was 56%. Some responses where characterized as "rapid and dramatic," and median progression-free survival was 7 months, the authors reported (New Engl. J. Med. 2014 March 26 [doi: 10.1056/NEJMoa1311107]).
Two of the 8 study participants who had cancers other than NSCLC – one with anaplastic large-cell lymphoma and another with inflammatory myofibroblastic tumor – also showed a treatment response.
"These findings suggest that the large majority of crizotinib-resistant tumors may remain ALK-dependent and that an important factor contributing to crizotinib resistance may be subtherapeutic inhibition of the target, which may be overcome by more potent and structurally distinct ALK inhibitors such as ceritinib. Alternatively, ceritinib may inhibit an unknown kinase that has not yet been found to play a role in the biology of these tumors," Dr. Shaw and her associates said.
This study was funded by Novartis, the National Cancer Institute, the V Foundation, Be a Piece of the Solution, and the Evan Spirito Memorial Foundation. Dr. Shaw reported ties to Novartis, Pfizer, and other companies, and her associates reported ties to numerous industry sources.
The anaplastic lymphoma kinase inhibitor ceritinib showed "substantial and durable" activity against advanced non–small cell lung cancer harboring ALK gene rearrangements in a phase I study designed, analyzed, and sponsored by the manufacturer and reported online March 26 in the New England Journal of Medicine.
The trial involved 122 adults with locally advanced or metastatic NSCLC and 8 with other cancers (breast cancer, alveolar rhabdomyosarcoma, inflammatory myofibroblastic tumor, neoplastic large-cell lymphoma, and rectal adenocarcinoma), all of which harbored genetic alterations in the anaplastic lymphoma kinase (ALK) gene. In preclinical studies, ceritinib was found to be 20 times more potent than crizotinib (also an ALK inhibitor), and it appeared as though it would be effective in patients who had responded to crizotinib but eventually developed resistance to that drug, said Dr. Alice T. Shaw of Massachusetts General Hospital, Boston, and her associates.
In the current trial, the investigators found oral ceritinib to be safe, with a maximum tolerated dose of 750 mg daily in 21-day cycles. The most common adverse events were nausea (82% of patients), diarrhea (75%), vomiting (65%), fatigue (47%), and increased alanine aminotransferase levels (35%). Four cases of interstitial lung disease were thought to be possibly related to the drug, as was one case of asymptomatic grade 3 prolongation of the QT interval; all of these resolved when ceritinib was discontinued. Eight patients (6%) discontinued the drug because of adverse events.
Although this phase I trial (NCT01283516) was designed only to determine the safety and tolerability of ceritinib, the investigators also found that it was effective in NSCLC, both in patients who had never been treated with crizotinib and in those who had. Among the 114 NSCLC patients who received at least 400 mg of ceritinib per day, the overall response rate was 58%, and among the 80 who had previously been treated with crizotinib, the response rate was 56%. Some responses where characterized as "rapid and dramatic," and median progression-free survival was 7 months, the authors reported (New Engl. J. Med. 2014 March 26 [doi: 10.1056/NEJMoa1311107]).
Two of the 8 study participants who had cancers other than NSCLC – one with anaplastic large-cell lymphoma and another with inflammatory myofibroblastic tumor – also showed a treatment response.
"These findings suggest that the large majority of crizotinib-resistant tumors may remain ALK-dependent and that an important factor contributing to crizotinib resistance may be subtherapeutic inhibition of the target, which may be overcome by more potent and structurally distinct ALK inhibitors such as ceritinib. Alternatively, ceritinib may inhibit an unknown kinase that has not yet been found to play a role in the biology of these tumors," Dr. Shaw and her associates said.
This study was funded by Novartis, the National Cancer Institute, the V Foundation, Be a Piece of the Solution, and the Evan Spirito Memorial Foundation. Dr. Shaw reported ties to Novartis, Pfizer, and other companies, and her associates reported ties to numerous industry sources.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Major finding: Oral ceritinib was found to be safe, with a maximum tolerated dose of 750 mg daily, and it elicited an overall tumor response rate of 58% in patients who received at least 400 mg daily.
Data source: A phase I clinical trial involving 130 adults with NSCLC or other cancers harboring ALK gene rearrangements who were treated with 50-750 mg of oral ceritinib daily.
Disclosures: This study was funded by Novartis, the National Cancer Institute, the V Foundation, Be a Piece of the Solution, and the Evan Spirito Memorial Foundation. Dr. Shaw reported ties to Novartis, Pfizer, and other companies, and her associates reported ties to numerous industry sources.