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Study Suggests Infinity's NSCLC Hsp90 Chaperone Inhibitor May Be Effective in Genetic Subpopulation


Infinity Pharmaceuticals last week announced results from a Phase II study of an investigational non-small cell lung cancer drug that suggest the IV-administered Hsp90 chaperone inhibitor may be efficacious in patients with oncogenic anaplastic lymphoma kinase gene rearrangements.

The study, led by Lecia Sequist of Harvard Medical School, was published online last week in the Journal of Clinical Oncology and enrolled 76 advanced NSCLC patients between December 2007 and May 2009 from 10 US cancer centers. Out of three patients with ALK gene rearrangements, two responded partially to Infinity's investigational drug IPI-504, and one experienced prolonged stable disease for 7.2 months and had a 24 percent reduction in tumor size.

"These results support molecular analysis as a key tool in clinical trials to determine the signature of the best responding patients, and suggest that patients with NSCLC and ALK rearrangements may preferentially respond to Hsp90 chaperone inhibition," said Sequist in a statement. "We hope the ongoing study of IPI-504 in NSCLC patients with ALK rearrangements will validate these initial findings."

According to Julian Adams, president of R&D at Infinity, the company will craft a development pathway for IPI-504 based on results from an ongoing Phase Ib study involving IPI-504 in combination with Sanofi-Aventis' Taxotere, as well as based on the results from Sequist et al.

The JCO study aimed to evaluate the safety and tolerability of IPI-504-enrolled patients with stage IIIb/IV NSCLC whose tumors had progressed after treatment with an EGFR tyrosine kinase inhibitor. Researchers stratified the 76 patients by their EGFR mutation status. Of these patients, 25 underwent EGFR genotyping, while 30 patients were genotyped for KRAS mutations, and 5 patients were genotyped for BRAF mutations.

Analysis by a fluorescent in situ hybridization detected ALK gene rearrangements in three study participants. The primary endpoint was objective response rate, and secondary endpoints were safety, progression-free survival, and analysis of activity by molecular subtypes.

"Although both EGFR groups were below the target ORR of 20 percent, among the three patients with an ALK gene rearrangement, two had partial responses and the third had prolonged stable disease (7.2 months, 24 percent reduction in tumor size)," the study authors reported in the abstract.

According to Infinity, all three patients with ALK rearrangements received IPI-504 for at least six months.

In the study, the most common adverse events included grades 1 and 2 fatigue, nausea, and diarrhea. Grade 3 or higher liver function abnormalities were observed in nine patients. Based on the toxicities seen in this study, Infinity believes that "IPI-504 was generally well-tolerated" by these study participants.

Hsp90, a protein chaperone, is involved in regulating proteins involved in oncogenesis, proliferation and survival, and research shows that blocking Hsp90 leads to cancer cell death and keeps tumors from growing. Oncogenic forms of ALK, BCR-ABL, EGFR, FLT3, HER2, JAK2 and KRAS are known to be "chaperoned" by Hsp90.

Infinity has two Hsp90 chaperone inhibitors in its pipeline, the IV formulation IPI-504 and the oral drug IPI-493. Both drugs are being developed for multiple indications. IPI-493 is currently being investigated in two Phase I trials in advanced solid tumor patients and in patients with hematological malignancies.

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