Two investigational drugs, AstraZeneca's AZD9291 and Clovis Oncology's CO-1686, both showed encouraging results in early trials of patients with EGFR-mutated non–small cell lung cancer (NSCLC) who have developed resistance to targeted therapies. Pfizer's investigational agent PF-06463922, developed for patients with ALK-mutated NSCLC who have developed resistance to crizotinib, demonstrated strong activity and selectivity in preclinical research and will be studied in a phase I clinical trial launching by year-end.
Agents show promise for patients with either EGFR- or ALK-mutated tumors.
For patients with either EGFR- or ALK-mutated non–small cell lung cancer (NSCLC), targeted therapies often deliver partial responses, but those responses generally don't last. Three agents under development that show promise in extending survival for such patients were presented at conferences in October.
About 15% of NSCLC tumors in Western populations—and about twice that percentage in Asian populations—are driven by EGFR mutations, said Susan Galbraith, MD, PhD, head of Oncology Innovative Medicines at AstraZeneca, speaking at the International Conference on Molecular Targets and Cancer Therapeutics. Held in Boston, MA, the conference was sponsored by the American Association for Cancer Research, the National Cancer Institute, and the European Organisation for Research and Treatment of Cancer.
Most patients treated with the tyrosine kinase inhibitors gefitinib (Iressa; AstraZeneca) and erlotinib (Tarceva; Genentech and Astellas Oncology) develop resistance in less than a year. More than half of these resistant tumors are positive for the EGFR T790M mutation, for which there are no approved treatments, Galbraith noted.
In July, the U.S. Food and Drug Administration approved the second-generation irreversible inhibitor afatinib (Gilotrif; Boehringer Ingelheim Pharmaceuticals) for use in metastatic NSCLC, and that drug has shown some response in clinical trials of NSCLC patients who show T790M mutations. Galbraith remarked, however, that problems with side effects have limited its use.
AstraZeneca's AZD9291 small-molecule drug was designed to irreversibly inhibit both the activating and resistance EGFR mutations in NSCLC patients but not inhibit wild-type EGFR that is present in normal skin and gut cells, she said. The tyrosine kinase inhibitor, whose structure was disclosed at the conference, showed high activity in preclinical studies and was well tolerated in animal models. Xenograft studies identified a breakdown metabolite of AZD9291 called AZ5104 that was about five times as potent as AZD9291 itself.
A phase I clinical trial for AZD9291 in patients with advanced NSCLC who have progressed following EGFR inhibitor treatment launched in March. “We continue to enroll very rapidly in this study, which is going well,” Galbraith said. “We're excited by the response data.”
Preliminary data on the trial presented the following week at the International Association for the Study of Lung Cancer's World Conference on Lung Cancer in Sydney, Australia, showed that the drug has produced RECIST partial responses with good tolerability, no events of EGFR rash, and only grade 1 diarrhea, AstraZeneca said.
Also at the World Conference on Lung Cancer, Clovis Oncology of Boulder, CO, released an update on a phase I/II trial of its CO-1686 drug. Like AZD9291, the small-molecule drug was developed as an irreversible inhibitor of EGFR and T790M mutations in heavily pretreated NSCLC patients who have developed resistance to EGFR inhibitors. To date, six of nine evaluable patients with the T790M mutation have shown RECIST partial responses. With 56 patients treated at various dosage levels, neither dose-limiting toxicities nor rash or diarrhea of any grade have been observed, Clovis said.
The results “confirm and extend the initial data reported at ASCO 2013 for this new agent,” said Jean-Charles Soria, MD, PhD, professor of medicine and medical oncology at Paris University XI in France, in a statement at the conference. “CO-1686 appears to be meaningfully benefiting these patients, without triggering the skin and gastrointestinal toxicities typically seen with older EGFR inhibitors that are not mutant-selective.”
Among four patients in a previous cohort who showed partial response to an earlier formulation of the drug, median progression-free survival has not yet been reached but is longer than 181 days, according to Clovis.
Addressing crizotinib resistance
ALK mutations are implicated in about 4% of NSCLC cases. The standard of care for these patients is treatment with crizotinib (Xalkori; Pfizer), but they typically develop resistance to the drug. Developed for this population, Pfizer's investigational tyrosine kinase inhibitor PF-06463922 “at least in preclinical models, appears much more potent and selective than other ALK inhibitors across ALK and crizotinib-resistant mutations,” said Tod Smeal, PhD, associate research fellow in the company's Oncology Research Unit in San Diego, CA, at the Molecular Targets conference.
“Brain metastasis is an issue for this population of patients,” said Smeal, who noted estimates that lung cancer accounts for about half of the 200,000 brain metastases diagnosed annually in the United States. Importantly, research in mice indicated that PF-06463922 can cross the blood-brain barrier, achieving levels in the brain that were 20% to 30% of levels found in plasma.
Additionally, the agent shows preclinical activity against mutations of ROS1 (a close relative of ALK) that also have been found in lung, brain, and many other cancers, he said. While crizotinib has shown promising clinical response in ROS1-fusion–positive NSCLC, patients with that condition are also likely to develop resistance, and ROS1 mutations have been found in such patients.
Pfizer plans to launch a phase I trial for PF-06463922 in patients with crizotinib-resistant NSCLC by year-end. –Eric Bender