Based on preclinical data, higher doses are expected for future EGFR cohorts in the ongoing study. The maximum tolerated dose (MTD) has not been identified.
LDK378
Dr. Alice Shaw provided the latest crizotinib news at the meeting, as well as further data from the first-in-human trial of Novartis’ selective oral ALK inhibitor LDK378 in advanced tumors, including crizotinib-refractory patients.
At doses of at least 400 mg/day, complete plus partial responses were reported in 41% of 59 NSCLC patients and in 47% of the 45 crizotinib-refractory NSCLC patients. When partial responses documented on only one occasion were also included, response rates rose to 71% and 80%, respectively.
More information is needed on the biology of these patients, particularly the crizotinib-refractory patients who failed to benefit from LDK378, to determine whether they might be better off being treated with a heat shock protein 90 (HSP90) inhibitor, Dr. Popat said.
Responses were only seen in NSCLC, said Dr. Shaw, a thoracic oncologist at Massachusetts General Hospital Cancer Center in Boston.
Since initial data were reported on 31 patients at this year’s American Society of Clinical Oncology meeting, the MTD has been identified as 750 mg/day.
LDK378 was well tolerated, with grade 3/4 reversible increased transaminases in 3% and diarrhea in 5% of patients. Grade 3/4 hyperglycemia in 10% merits further attention and likely reflects an off-target effect of LDK378, Dr. Popat said.
AUY922
Finally, a phase II study of Novartis/Vernalis’ second-generation HSP90 inhibitor AUY922 in previously treated stage IIIb or IV NSCLC showed responses in 50% of crizotinib-naïve and 32% of previously treated ALK-positive patients, Dr. Enriqueta Felip reported.
Patrice Wendling/IMNG Medical Media
Dr. Enriqueta Felip
There was also a 26% response rate in patients with EGFR mutations who progressed following treatment with EGFR tyrosine kinase inhibitors.
"This compares relatively favorably with the second-generation EGFR inhibitors, specifically afatinib, which in the LUX-[Lung]1 study reported a radiologically confirmed 7% response rate," Dr. Popat observed.
As previously observed with HSP90 inhibitors, ocular toxicity was common, occurring in 74% across all grades and 7% at grade 3/4 among the 121 patients.
No new safety signals were observed at the previously identified dose of 70 mg/m2 IV once weekly, said Dr. Felip, of Vall d’Hebron University Hospital in Barcelona.
Expansion of the EGFR mutation group is ongoing, and further studies are planned to confirm these efficacy signals, she said. AUY922 is in broad development, with phase I/II trials ongoing in breast cancer, gastric cancer, and multiple myeloma.
Dr. Nishio and his coauthors reported research funding from the study sponsor, Chugai Pharmaceutical, as well as Pfizer. Dr. Gettinger reported no conflicts; several coauthors reported financial ties including employment with the study sponsor Ariad Pharmaceuticals. Dr. Shaw reported an advisory role with Pfizer, Novartis, Chugai, Ariad, and Daiichi, and her coauthors reported ties including employment and stock ownership with study sponsor Novartis. Dr. Felip reported no conflicts; several coauthors reported financial ties including employment with the study sponsor Novartis. Dr. Popat reported no conflicts of interest.