New agent targets EGFR resistance in NSCLC

A new agent targeting tumors that develop resistance to EGFR tyrosine kinase inhibitors proved to be “highly active” in a phase I clinical trial involving 253 patients with advanced, resistant NSCLC, according to a report published online April 30 in the New England Journal of Medicine.

Most patients who initially respond to EGFR tyrosine kinase inhibitors such as gefitinib, erlotinib, and afatinib develop resistance and show disease progression within 2 years, because the tumors develop additional EGFR mutations, particularly T790M resistance mutations. Preliminary studies suggested that a new oral agent, AZD9291, would target T790M-mediated resistance. In a phase I trial to assess its safety and efficacy, 127 study participants had known EGFR T790M mutations, and the remainder had other or unknown mutations, said Dr. Pasi A. Janne of the Lowe Center for Thoracic Oncology and the Belfer Institute for Applied Cancer Science, Dana-Farber Institute, Boston, and his associates.

The study – designed and funded by AstraZeneca, which also collected and analyzed the data in conjunction with the scientific authors – was conducted at 33 sites in Japan, South Korea, Taiwan, France, Spain, Germany, Australia, the United Kingdom, and the United States. Of the 239 patients who could be evaluated for a response, 123 (51%) showed 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 (N. Engl. J. Med. 2015 April 30 [doi:10.1056/NEJMoa1411817]). Median progression-free survival was estimated to be 9.6 months in patients with EGFR T790M-positive tumors, although many are still alive and the final survival data have yet to be calculated. In contrast, progression-free survival was 2.8 months in patients with EGFR T790M-negative tumors.

No dose-limiting toxic effects occurred and therefore the maximal efficacy dose with an acceptable level of adverse events cannot be established yet. The most common adverse events were diarrhea (47% of patients), rash (40%), nausea (22%), and decreased appetite (21%). Serious events that were considered to be possibly treatment-related occurred in 6% of patients, and included one fatal case of pneumonia and six cases of pneumonitis-like events that resolved when the drug was discontinued.

These findings demonstrate that “a structurally distinct EGFR inhibitor, one that is selective for the mutated form of EGFR, can be clinically effective and has a side-effect profile that is not dose limiting in the majority of patients in whom T790M-mediated drug resistance has developed,” Dr. Janne and his associates said.

Astra Zeneca is the maker of AZD9291. Dr. Janne reported ties to AstraZeneca, Boehringer Ingelheim, Chugai, Pfizer, Merrimack, Clovis Oncology, Roche, and Gatekeeper, as well as several patents related to genetically targeted cancer treatments; his associates reported ties to numerous industry sources.

A new agent targeting tumors that develop resistance to EGFR tyrosine kinase inhibitors proved to be “highly active” in a phase I clinical trial involving 253 patients with advanced, resistant NSCLC, according to a report published online April 30 in the New England Journal of Medicine.

Most patients who initially respond to EGFR tyrosine kinase inhibitors such as gefitinib, erlotinib, and afatinib develop resistance and show disease progression within 2 years, because the tumors develop additional EGFR mutations, particularly T790M resistance mutations. Preliminary studies suggested that a new oral agent, AZD9291, would target T790M-mediated resistance. In a phase I trial to assess its safety and efficacy, 127 study participants had known EGFR T790M mutations, and the remainder had other or unknown mutations, said Dr. Pasi A. Janne of the Lowe Center for Thoracic Oncology and the Belfer Institute for Applied Cancer Science, Dana-Farber Institute, Boston, and his associates.

The study – designed and funded by AstraZeneca, which also collected and analyzed the data in conjunction with the scientific authors – was conducted at 33 sites in Japan, South Korea, Taiwan, France, Spain, Germany, Australia, the United Kingdom, and the United States. Of the 239 patients who could be evaluated for a response, 123 (51%) showed 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 (N. Engl. J. Med. 2015 April 30 [doi:10.1056/NEJMoa1411817]). Median progression-free survival was estimated to be 9.6 months in patients with EGFR T790M-positive tumors, although many are still alive and the final survival data have yet to be calculated. In contrast, progression-free survival was 2.8 months in patients with EGFR T790M-negative tumors.

No dose-limiting toxic effects occurred and therefore the maximal efficacy dose with an acceptable level of adverse events cannot be established yet. The most common adverse events were diarrhea (47% of patients), rash (40%), nausea (22%), and decreased appetite (21%). Serious events that were considered to be possibly treatment-related occurred in 6% of patients, and included one fatal case of pneumonia and six cases of pneumonitis-like events that resolved when the drug was discontinued.

These findings demonstrate that “a structurally distinct EGFR inhibitor, one that is selective for the mutated form of EGFR, can be clinically effective and has a side-effect profile that is not dose limiting in the majority of patients in whom T790M-mediated drug resistance has developed,” Dr. Janne and his associates said.

Astra Zeneca is the maker of AZD9291. Dr. Janne reported ties to AstraZeneca, Boehringer Ingelheim, Chugai, Pfizer, Merrimack, Clovis Oncology, Roche, and Gatekeeper, as well as several patents related to genetically targeted cancer treatments; his associates reported ties to numerous industry sources.

A new agent targeting tumors that develop resistance to EGFR tyrosine kinase inhibitors proved to be “highly active” in a phase I clinical trial involving 253 patients with advanced, resistant NSCLC, according to a report published online April 30 in the New England Journal of Medicine.

Most patients who initially respond to EGFR tyrosine kinase inhibitors such as gefitinib, erlotinib, and afatinib develop resistance and show disease progression within 2 years, because the tumors develop additional EGFR mutations, particularly T790M resistance mutations. Preliminary studies suggested that a new oral agent, AZD9291, would target T790M-mediated resistance. In a phase I trial to assess its safety and efficacy, 127 study participants had known EGFR T790M mutations, and the remainder had other or unknown mutations, said Dr. Pasi A. Janne of the Lowe Center for Thoracic Oncology and the Belfer Institute for Applied Cancer Science, Dana-Farber Institute, Boston, and his associates.

The study – designed and funded by AstraZeneca, which also collected and analyzed the data in conjunction with the scientific authors – was conducted at 33 sites in Japan, South Korea, Taiwan, France, Spain, Germany, Australia, the United Kingdom, and the United States. Of the 239 patients who could be evaluated for a response, 123 (51%) showed 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 (N. Engl. J. Med. 2015 April 30 [doi:10.1056/NEJMoa1411817]). Median progression-free survival was estimated to be 9.6 months in patients with EGFR T790M-positive tumors, although many are still alive and the final survival data have yet to be calculated. In contrast, progression-free survival was 2.8 months in patients with EGFR T790M-negative tumors.

No dose-limiting toxic effects occurred and therefore the maximal efficacy dose with an acceptable level of adverse events cannot be established yet. The most common adverse events were diarrhea (47% of patients), rash (40%), nausea (22%), and decreased appetite (21%). Serious events that were considered to be possibly treatment-related occurred in 6% of patients, and included one fatal case of pneumonia and six cases of pneumonitis-like events that resolved when the drug was discontinued.

These findings demonstrate that “a structurally distinct EGFR inhibitor, one that is selective for the mutated form of EGFR, can be clinically effective and has a side-effect profile that is not dose limiting in the majority of patients in whom T790M-mediated drug resistance has developed,” Dr. Janne and his associates said.

Astra Zeneca is the maker of AZD9291. Dr. Janne reported ties to AstraZeneca, Boehringer Ingelheim, Chugai, Pfizer, Merrimack, Clovis Oncology, Roche, and Gatekeeper, as well as several patents related to genetically targeted cancer treatments; his associates reported ties to numerous industry sources.