The safety profile of patients treated with the combination of ganetespib (G) and docetaxel (D) was generally similar to that of docetaxel alone, consistent with previously reported results. The most common adverse events (AEs), all grades, were neutropenia (44% vs. 45%), diarrhea (49% vs. 16%) and fatigue (34% vs. 24%), for G+D (N=123) vs. D (N=126), respectively. Diarrhea was effectively managed with supportive care; the incidence of grade 3 or 4 diarrhea was 4% (G+D) vs. 0% (D). Fatigue was predominantly grade 1 and grade 2; grade 3 or 4 fatigue was 6% (G+D) vs. 4% (D). The most common grade 3 or 4 AEs were neutropenia (38% vs. 42%), febrile neutropenia (9% vs. 4%), and anemia (8% vs. 2%). The proportions of patients with AEs leading to death were 15% vs. 12%, and AEs leading to treatment discontinuation were 7% vs. 6% for G+D vs. D, respectively. A high incidence of visual impairment has been reported following treatment with certain other Hsp90 inhibitors. Consistent with prior findings with ganetespib, reports of visual impairment in this study were infrequent: 2 (2%) in the G+D arm and 0 (0%) in the D arm. Both cases of visual impairment were transient and were grade 1 or 2. The safety profile of patients in the chemosensitive population being evaluated in Phase 3 (diagnosis > 6 months) was comparable to the profile in the intent-to-treat population.
Identification of mechanisms of cross-resistance to chemotherapy and to ganetespib
Results from preclinical studies conducted by Synta collaborators at the University of Leicester in the UK showed that intact mitochondrial signaling pathways are required for ganetespib to induce cancer cell death. These studies showed that loss of function of the mitochondrial apoptosis pathway, driven by a mutation in caspase 8, can cause resistance both to ganetespib and to chemotherapy. These results may be supportive of differential activity observed in GALAXY-1, in which patients with refractory disease (diagnosis < 6 months), considered unresponsive to first-line chemotherapy, showed no benefit from ganetespib treatment.