The hedgehog signalling pathway plays an important role in the normal development and maintenance of many tissues and organs. However, if it goes awry, it can play a role in tumorigenesis, by promoting the proliferation, survival and differentiation of cancer cells.
Numerous potential cancer therapies that target the pathway are being developed. One of these, in the pipeline at Novartis, is sonidegib, also referred to as erismodegib.1 The smoothened antagonist is being investigated in multiple different cancer types.
In a Phase I open label, dose escalation, first in human trial, 103 patients with advanced solid tumours, including basal cell carcinoma and medulloblastoma, were given doses in the 100 to 3,000mg daily and 250 to 750mg twice daily range, on a continuous basis, after a single dose run in the period to assess pharmacokinetics.2 The maximum tolerated doses were established at 800mg in a once daily dosing schedule, and 250mg when given twice daily. The main dose limiting toxicity was a reversible grade 3.4 elevated serum creatine kinase, which was seen in 18% of patients at doses above the maximum tolerated level, in an exposure dependent manner. Other common side-effects included myalgia, muscle spasm, fatigue, gastrointestinal problems, dysgeusia and hair loss. Those tumour responses that were seen in medulloblastoma and basal cell carcinoma were shown to be associated with hedgehog pathway activation.
Another randomised, double blind, Phase II study was carried out in patients with basal cell carcinoma, of whom the disease was locally advanced in 194, and metastatic in another 36.3 Subjects were given 200mg or 800mg of sonidegib every day. In locally advanced disease, the overall response rate was 47% at the lower dose and 35% at the higher; the figures for metastatic disease were 15% and 17% respectively. Two patients with locally advanced disease achieved a complete response at the lower dose. Adverse events were less common at the lower dose, and side-effects that led to discontinuation in small numbers of patients included muscle spasms, dysgeusia, nausea and weight loss.
It has also been studied in combination with etoposide and cisplatin in a Phase I trial in 14 patients with extensive stage small cell lung cancer.4 Subjects were given four to six 21 day cycles of etoposide and cisplatin, plus daily doses of 200, 400 or 800mg of sonidegib. One patient discontinued as a result of toxicity causing colitis and acute kidney injury. Other toxicities observed included fatigue, fever, anaemia, thrombocytopenia and CPK elevation, and more serious levels of neutropenia. Partial responses were confirmed in half of the patients, and Phase II expansion of the trial is underway, with the recommended starting dose of sonidegib set at 800mg.
Many other trials are in progress, both as a single agent and in combination with other anticancer drugs, in a range of solid tumours and blood cancers, including leukaemias, breast and pancreatic cancers and myelofibrosis.
References
1. S. Pan et al. ACS Med. Chem. Lett. 2010, 1, 130
2. J. Rodon et al. Clin. Cancer Res. 2014, 20, 1900
3. M.R. Migden et al. J. Clin. Oncol. 2014, 32 (suppl.), Abst. 9009a^
4. M.C. Pietanza et al. J. Clin. Oncol. 32 (suppl.) Abst. 7602