VIENNA – A wave of new anaplastic lymphoma kinase inhibitors and a second-generation heat shock protein 90 inhibitor are making headway as potential targeted treatments for non-small cell lung cancer.
Early reports on the experimental agents – none has a generic name as yet – suggest at least some may be active in patients not responding to crizotinib (Xalkori), a first-in-class anaplastic lymphoma kinase (ALK) inhibitor that is approved for ALK-driven non-small cell lung cancer (NSCLC) and is under investigation for other ALK-driven malignancies.
Some agents were also active in tumors with epidermal growth factor receptor (EGFR) mutations that were not responding to EGFR inhibitors.
CH5424802
Chugai Pharmaceutical’s selective ALK inhibitor CH5424802 produced an overall response rate of 85%, including 3 complete responses and 36 partial responses among 46 patients with advanced or metastatic ALK-positive NSCLC previously treated with one or more chemotherapies, but not with ALK inhibitors.
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Dr. Makoto Nishio
The oral agent has inhibitory activity against several kinases, including ALK L1196M and ALK C1156Y, two point mutations identified in patients resistant to the reigning ALK inhibitor crizotinib, Dr. Makoto Nishio reported during a developmental therapeutics session at the European Society for Medical Oncology Congress.
Twice-daily treatment at 300 mg exceeded 46 weeks in some patients, with 40 of the 46 patients still on therapy in the second phase of the phase I/II study, said Dr. Nishio, of the Cancer Institute Hospital, Japanese Foundation for Cancer Research in Tokyo.
Session cochair Dr. Sanjay Popat, of Royal Marsden Hospital in London, described the response waterfall plot as "really quite spectacular, with almost every patient having some evidence of benefit from this drug."
In addition, CH5424802 was very well tolerated, with the typical crizotinib-associated vision disturbances rare and gastrointestinal toxicity mild.
AP26113
A first-in-human, dose-finding study in advanced tumors provided preliminary evidence that Ariad Pharmaceuticals’ oral dual ALK-EGFR inhibitor AP26113 is active in ALK-positive as well as EGFR-mutant NSCLC.
Partial responses were achieved at doses of at least 60 mg/day in 6 of 9 evaluable crizotinib-resistant ALK-positive patients and in 2 of 2 crizotinib-naïve patients.
The longest response is 6 months in a crizotinib-resistant patient and 9 months in a crizotinib-naïve patient; both responses are ongoing, said Dr. Scott Gettinger, a thoracic oncologist with the Yale Medical Group in New Haven, Conn.
One ALK-positive crizotinib-resistant patient also showed a response in a preexisting brain metastasis.
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Dr. Scott Gettinger
Among 12 patients with EGFR-mutant lung cancer, one partial response that is ongoing occurred at 120 mg/day in a patient failed by prior erlotinib (Tarceva), bevacizumab (Avastin), and at least one round of chemotherapy.
Four of the 12 patients remain on study. Six have discontinued therapy due to progressive disease, 1 for non–drug-related adverse events and 1 due to sudden death that could be related to AP26113 and is being studied further, Dr. Gettinger said.
The most common adverse events of any grade were nausea (26%), diarrhea (18%), decreased appetite (12%), and vomiting (12%). Noticeably absent were visual disturbances and skin rash.
"What you don’t see on this list is rash, and ... this is very meaningful because this limits us when we treat patients with EGFR-mutant lung cancer with either erlotinib or gefitinib [Iressa]," he said.