Novel EGFR-TKI clears leptomeningeal disease in phase I study

BOSTON – An experimental small-molecule tyrosine kinase inhibitor targeted to the epidermal growth factor receptor showed encouraging clinical activity in patients with heavily pretreated non–small cell lung cancer and leptomeningeal disease, one of the most devastating complications of advanced cancer, investigators report.

Of eight patients evaluable for response in a phase I, open label study of the compound, labeled AZD9291, one had confirmed clearance of malignant cells from cerebrospinal fluid (CSF), and four others had suspected but unconfirmed clearance of cancer from CSF, reported Dr. Dan Ho Lee of the University of Ulsan College of Medicine, Seoul, South Korea.

In addition, six patients had investigator-rated improvements in brain imaging, and three of seven with abnormal neurologic exams at baseline had significant improvement of symptoms, Dr. Lee said at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics.

“Leptomeningeal disease involvement is the nightmare every single clinician taking care of lung cancer patients with EGFR [epidermal growth factor receptor] mutations does not want to face, because that’s a death sentence,” commented Dr. Jean-Charles Soria of the Institut Gustave Roussy, Villejuif, France.

“Having a drug that is delivering in 8 out of 12 patients responding clinically by improvement in their neurological exam, radiologically by MRI, and cytologically by CSF is really transformational for that group of patients,” he said, at a briefing where Dr. Lee presented the data, prior to his presentation in an oral session.

AZD9291 is a tyrosine kinase inhibitor (TKI) selective for EGFR mutations, including T790M resistance mutations, in both preclinical and clinical studies, the compound appeared capable of crossing the blood-brain barrier, making it a candidate for clinical trials in patients with leptomeningeal metastases.

Dr. Lee noted that in patients with EGFR-mutant non–small cell lung cancer (NSCLC), there appears to be an increased risk for CNS involvement, particularly among patients who had received a first-generation EGFR-targeted TKI. Patients with EGFR-mutant NSCLC and leptomeningeal metastases have an expected overall survival of 7-14 months, he said.

As previously reported, in a multicenter clinical trial of AZD9291 (N Engl J Med. 2015 Apr 30. doi: 10.1056/NEJMoa1411817) 123 of 239 patients (51%) who could be evaluated for response had either a partial or complete response. In the subset of patients with known EGFR T790M mutations, the objective response rate was even higher at 61%. In contrast, the objective response rate was 21% in the subset of 61 patients who did not have known EGFR T790M mutations, the investigators said.

Dr. Lee reported here on a cohort of patients with EGFR-mutant NSCLC with leptomeningeal metastases in the BLOOM study. The patients were treated with AZD9291 in a once-daily, 160 mg oral dose.

A total of four men and nine women were enrolled in the cohort. All patients had NSCLC with a sensitizing EGFR mutation, and five were confirmed to have the T790M mutation. The patients had received a median of three prior lines of therapy, including chemotherapy and anti-EGFR TKI. In all, 12 patients were planned for the efficacy analysis, but three withdrew, one at week 6 due to dysphagia, one at week 1 due to aspiration pneumonia, and one at week 3 due to extracranial disease progression.

Of the remaining nine patients, eight had sufficient data to report on all preliminary outcomes, and one had partial data available.

The authors found that, as noted before, three of the eight patients had investigator-rated improvement over baseline in neurologic exams, and of the five patients with normal baseline neurology, four had no change at the most recent follow-up (26 weeks).

Also as noted, one patient had confirmed clearance of cancer from the CSF, and a total of five (including this patient) had negative cytology at their most recent visit. In addition, six of seven patients who had baseline and follow-up brain MRI studies showed improvement at the most recent scan, Dr. Lee said.

The safety profile was similar to that seen with other EGFR-TKIs, with diarrhea and rash, none worse than grade 2, being the most frequent adverse event. There were four grade 3 or greater adverse events, occurring once each in four patients: anemia, hyponatremia, aspiration pneumonia, and neutropenia, the last of which resolved after a 3-day interruption and resumption of the drug at half the original dose (80 mg) daily.

Dr. Soria noted that while the data look very promising, the real test of AZD9291 will come with longer follow-up showing whether the response is durable.

The study was funded by AstraZeneca. Dr. Lee is an advisory board member of Bristol-Myers Squibb, Korea, Boehringer Ingelheim Korea, and Pfizer Korea, and has received lecture fees from AstraZeneca, Ely Lilly, Merck Sharp & Dohme, and Roche. Dr. Soria reported having no disclosures.

BOSTON – An experimental small-molecule tyrosine kinase inhibitor targeted to the epidermal growth factor receptor showed encouraging clinical activity in patients with heavily pretreated non–small cell lung cancer and leptomeningeal disease, one of the most devastating complications of advanced cancer, investigators report.

Of eight patients evaluable for response in a phase I, open label study of the compound, labeled AZD9291, one had confirmed clearance of malignant cells from cerebrospinal fluid (CSF), and four others had suspected but unconfirmed clearance of cancer from CSF, reported Dr. Dan Ho Lee of the University of Ulsan College of Medicine, Seoul, South Korea.

In addition, six patients had investigator-rated improvements in brain imaging, and three of seven with abnormal neurologic exams at baseline had significant improvement of symptoms, Dr. Lee said at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics.

“Leptomeningeal disease involvement is the nightmare every single clinician taking care of lung cancer patients with EGFR [epidermal growth factor receptor] mutations does not want to face, because that’s a death sentence,” commented Dr. Jean-Charles Soria of the Institut Gustave Roussy, Villejuif, France.

“Having a drug that is delivering in 8 out of 12 patients responding clinically by improvement in their neurological exam, radiologically by MRI, and cytologically by CSF is really transformational for that group of patients,” he said, at a briefing where Dr. Lee presented the data, prior to his presentation in an oral session.

AZD9291 is a tyrosine kinase inhibitor (TKI) selective for EGFR mutations, including T790M resistance mutations, in both preclinical and clinical studies, the compound appeared capable of crossing the blood-brain barrier, making it a candidate for clinical trials in patients with leptomeningeal metastases.

Dr. Lee noted that in patients with EGFR-mutant non–small cell lung cancer (NSCLC), there appears to be an increased risk for CNS involvement, particularly among patients who had received a first-generation EGFR-targeted TKI. Patients with EGFR-mutant NSCLC and leptomeningeal metastases have an expected overall survival of 7-14 months, he said.

As previously reported, in a multicenter clinical trial of AZD9291 (N Engl J Med. 2015 Apr 30. doi: 10.1056/NEJMoa1411817) 123 of 239 patients (51%) who could be evaluated for response had either a partial or complete response. In the subset of patients with known EGFR T790M mutations, the objective response rate was even higher at 61%. In contrast, the objective response rate was 21% in the subset of 61 patients who did not have known EGFR T790M mutations, the investigators said.

Dr. Lee reported here on a cohort of patients with EGFR-mutant NSCLC with leptomeningeal metastases in the BLOOM study. The patients were treated with AZD9291 in a once-daily, 160 mg oral dose.

A total of four men and nine women were enrolled in the cohort. All patients had NSCLC with a sensitizing EGFR mutation, and five were confirmed to have the T790M mutation. The patients had received a median of three prior lines of therapy, including chemotherapy and anti-EGFR TKI. In all, 12 patients were planned for the efficacy analysis, but three withdrew, one at week 6 due to dysphagia, one at week 1 due to aspiration pneumonia, and one at week 3 due to extracranial disease progression.

Of the remaining nine patients, eight had sufficient data to report on all preliminary outcomes, and one had partial data available.

The authors found that, as noted before, three of the eight patients had investigator-rated improvement over baseline in neurologic exams, and of the five patients with normal baseline neurology, four had no change at the most recent follow-up (26 weeks).

Also as noted, one patient had confirmed clearance of cancer from the CSF, and a total of five (including this patient) had negative cytology at their most recent visit. In addition, six of seven patients who had baseline and follow-up brain MRI studies showed improvement at the most recent scan, Dr. Lee said.

The safety profile was similar to that seen with other EGFR-TKIs, with diarrhea and rash, none worse than grade 2, being the most frequent adverse event. There were four grade 3 or greater adverse events, occurring once each in four patients: anemia, hyponatremia, aspiration pneumonia, and neutropenia, the last of which resolved after a 3-day interruption and resumption of the drug at half the original dose (80 mg) daily.

Dr. Soria noted that while the data look very promising, the real test of AZD9291 will come with longer follow-up showing whether the response is durable.

The study was funded by AstraZeneca. Dr. Lee is an advisory board member of Bristol-Myers Squibb, Korea, Boehringer Ingelheim Korea, and Pfizer Korea, and has received lecture fees from AstraZeneca, Ely Lilly, Merck Sharp & Dohme, and Roche. Dr. Soria reported having no disclosures.

BOSTON – An experimental small-molecule tyrosine kinase inhibitor targeted to the epidermal growth factor receptor showed encouraging clinical activity in patients with heavily pretreated non–small cell lung cancer and leptomeningeal disease, one of the most devastating complications of advanced cancer, investigators report.

Of eight patients evaluable for response in a phase I, open label study of the compound, labeled AZD9291, one had confirmed clearance of malignant cells from cerebrospinal fluid (CSF), and four others had suspected but unconfirmed clearance of cancer from CSF, reported Dr. Dan Ho Lee of the University of Ulsan College of Medicine, Seoul, South Korea.

In addition, six patients had investigator-rated improvements in brain imaging, and three of seven with abnormal neurologic exams at baseline had significant improvement of symptoms, Dr. Lee said at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics.

“Leptomeningeal disease involvement is the nightmare every single clinician taking care of lung cancer patients with EGFR [epidermal growth factor receptor] mutations does not want to face, because that’s a death sentence,” commented Dr. Jean-Charles Soria of the Institut Gustave Roussy, Villejuif, France.

“Having a drug that is delivering in 8 out of 12 patients responding clinically by improvement in their neurological exam, radiologically by MRI, and cytologically by CSF is really transformational for that group of patients,” he said, at a briefing where Dr. Lee presented the data, prior to his presentation in an oral session.

AZD9291 is a tyrosine kinase inhibitor (TKI) selective for EGFR mutations, including T790M resistance mutations, in both preclinical and clinical studies, the compound appeared capable of crossing the blood-brain barrier, making it a candidate for clinical trials in patients with leptomeningeal metastases.

Dr. Lee noted that in patients with EGFR-mutant non–small cell lung cancer (NSCLC), there appears to be an increased risk for CNS involvement, particularly among patients who had received a first-generation EGFR-targeted TKI. Patients with EGFR-mutant NSCLC and leptomeningeal metastases have an expected overall survival of 7-14 months, he said.

As previously reported, in a multicenter clinical trial of AZD9291 (N Engl J Med. 2015 Apr 30. doi: 10.1056/NEJMoa1411817) 123 of 239 patients (51%) who could be evaluated for response had either a partial or complete response. In the subset of patients with known EGFR T790M mutations, the objective response rate was even higher at 61%. In contrast, the objective response rate was 21% in the subset of 61 patients who did not have known EGFR T790M mutations, the investigators said.

Dr. Lee reported here on a cohort of patients with EGFR-mutant NSCLC with leptomeningeal metastases in the BLOOM study. The patients were treated with AZD9291 in a once-daily, 160 mg oral dose.

A total of four men and nine women were enrolled in the cohort. All patients had NSCLC with a sensitizing EGFR mutation, and five were confirmed to have the T790M mutation. The patients had received a median of three prior lines of therapy, including chemotherapy and anti-EGFR TKI. In all, 12 patients were planned for the efficacy analysis, but three withdrew, one at week 6 due to dysphagia, one at week 1 due to aspiration pneumonia, and one at week 3 due to extracranial disease progression.

Of the remaining nine patients, eight had sufficient data to report on all preliminary outcomes, and one had partial data available.

The authors found that, as noted before, three of the eight patients had investigator-rated improvement over baseline in neurologic exams, and of the five patients with normal baseline neurology, four had no change at the most recent follow-up (26 weeks).

Also as noted, one patient had confirmed clearance of cancer from the CSF, and a total of five (including this patient) had negative cytology at their most recent visit. In addition, six of seven patients who had baseline and follow-up brain MRI studies showed improvement at the most recent scan, Dr. Lee said.

The safety profile was similar to that seen with other EGFR-TKIs, with diarrhea and rash, none worse than grade 2, being the most frequent adverse event. There were four grade 3 or greater adverse events, occurring once each in four patients: anemia, hyponatremia, aspiration pneumonia, and neutropenia, the last of which resolved after a 3-day interruption and resumption of the drug at half the original dose (80 mg) daily.

Dr. Soria noted that while the data look very promising, the real test of AZD9291 will come with longer follow-up showing whether the response is durable.

The study was funded by AstraZeneca. Dr. Lee is an advisory board member of Bristol-Myers Squibb, Korea, Boehringer Ingelheim Korea, and Pfizer Korea, and has received lecture fees from AstraZeneca, Ely Lilly, Merck Sharp & Dohme, and Roche. Dr. Soria reported having no disclosures.