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http://www.nature.com/nrd/journal/v11/n6/full/nrd3753.html

News and Analysis

Nature Reviews Drug Discovery 11, 437-438 (June 2012) | doi:10.1038/nrd3753

PIPELINE PIONEERS:
Vismodegib
Andrzej Dlugosz1, Sid Agrawal2 & Peter Kirkpatrick3

In January 2012, vismodegib (Erivedge; Curis/Genentech), a small-molecule inhibitor of the Hedgehog signalling pathway, was approved by the US Food and Drug Administration (FDA) for the treatment of basal cell carcinoma (BCC).

BCC is a common form of skin cancer, largely caused by exposure to ultraviolet radiation1. Although most cases are curable by surgery, if the disease progresses to unresectable locally advanced or metastatic forms it can be life-threatening1.

BCC is associated with inappropriate activation of the Hedgehog signalling pathway (Fig. 1a), which has a key role in cell growth and differentiation during embryogenesis and early development but appears to be inactive in most adult tissues2. Most patients with BCC tumours (such as those with Gorlin syndrome) have loss-of-function mutations affecting the protein Patched homologue 1 (PTCH1), which normally inhibits signalling by the protein Smoothened homologue (SMO)1, 2. Activating mutations in SMO are present in ~10% of BCCs2. Hedgehog pathway activation caused by overexpression of Hedgehog ligands has also been observed in several other tumour types including pancreas, colon, prostate and ovarian carcinomas2.

Basis of discovery

Evidence that the Hedgehog signalling pathway could be a tractable pharmacological target came from the characterization of the teratogenic natural product cyclopamine as an antagonist of SMO3. Vismodegib (Fig. 1b), a selective SMO antagonist with greater potency and more favourable pharmaceutical properties than cyclopamine, was identified through high-throughput screening and subsequent medicinal chemistry optimization3.

Drug properties

Vismodegib inhibits Hedgehog pathway signalling by binding to and inhibiting SMO3, 4. It showed promising antitumour activity in preclinical studies3 (for example, producing tumour regression in a medulloblastoma allograft mouse model that is dependent on the Hedgehog pathway for growth) as well as in its first Phase I trial in patients with advanced BCC5.

Clinical data

The efficacy and safety of vismodegib (150 mg per day orally) was investigated in a single-arm, open-label, two-cohort trial involving 104 patients with either metastatic BCC (n = 33) or locally advanced BCC (n = 71)4. Patients with locally advanced BCC were required to have lesions that were considered to be inoperable and that had recurred after radiotherapy, unless radiotherapy was contraindicated or inappropriate (for example, in patients with Gorlin syndrome, which was diagnosed in 21% of the trial population)4. In the metastatic BCC cohort 97% of patients had received prior therapy, and in the locally advanced BCC cohort 94% of patients had received prior therapy4.

The main efficacy outcome measure of the trial was objective response rate (ORR) as assessed by an independent review facility4. In the metastatic BCC cohort, tumour response was assessed according to the RECIST (Response Evaluation Criteria in Solid Tumors) criteria, whereas in the locally advanced BCC cohort the tumour response evaluation included measurement of the externally assessable tumour, photographic assessment of ulceration, radiographic assessment of target lesions (if appropriate) and tumour biopsy4. An objective response for patients in the locally advanced BCC cohort required at least one of the following criteria and the absence of any criterion for disease progression: =30% reduction in lesion size (sum of the longest diameter (SLD)) from the baseline in target lesions by radiographic assessment; =30% reduction in SLD from the baseline in the externally visible dimension of target lesions; and complete resolution of ulceration in all target lesions4. Complete response was defined as an objective response with no residual BCC on sampling tumour biopsy4.

Of the 104 patients enrolled, 96 patients were evaluable for ORR4. In the efficacy-evaluable metastatic BCC cohort (33 patients) the ORR was 30.3% with no complete responses, and in the efficacy-evaluable locally advanced BCC cohort (63 patients) the ORR was 42.9%, which included 13 patients (20.6%) with a complete response4. The median response duration was 7.6 months in both the metastatic BCC cohort and the locally advanced BCC cohort4.

Indications

Vismodegib is approved by the FDA for the treatment of adults with metastatic BCC, or with locally advanced BCC that has recurred following surgery or who are not candidates for surgery, and who are not candidates for radiation4.

Analysis | basal cell carcinoma

Analysing issues in the treatment of BCC is Andrzej Dlugosz, M.D., Poth Professor of Cutaneous Oncology, Department of Dermatology and the University of Michigan Comprehensive Cancer Center, Michigan, USA.

Although the fraction of BCC patients with either metastatic or advanced disease is far less than 1%, the lack of effective treatments makes vismodegib (and other Hedgehog pathway antagonists in development) an important therapeutic advancement.

Side effects associated with the use of vismodegib are generally considered to be minor to moderate, and include muscle spasms, altered taste perception, weight loss, fatigue, nausea and hair loss. The development of hair loss is not surprising given the important role of Hedgehog signalling in hair growth, and additional class-specific side effects may help to uncover previously unappreciated roles for Hedgehog signalling in other adult organs or tissues. It will be important to see whether modified dosing regimens, combination therapies or other approaches can maintain efficacy while minimizing side effects.

The relatively benign side-effect profile of vismodegib could help in expanding its use as a systemic therapy for additional groups of patients with BCC. For example, given the ability of vismodegib to cause impressive tumour shrinkage, it may be highly useful in a neoadjuvant setting for 'medical debulking' prior to surgery: a smaller tumour would mean a smaller surgical scar. This would be applicable to BCCs arising sporadically or in patients with Gorlin syndrome. Prior to adopting this approach, however, it will be important to rigorously assess whether any potential tumour cells remain in clinically regressed regions, as there could be an increased risk of recurrence if surgical excision leaves some of these cells behind.

As with other drugs targeting key oncogenic drivers, resistance to vismodegib has been reported in patients with advanced or metastatic BCC and medulloblastoma, including mutations leading to a drug-resistant form of SMO or amplification of the Hedgehog pathway transcriptional effector GLI2. However, in these patients, previous treatments with DNA-damaging agents may have contributed to the development of resistance, and a recently completed prevention trial in patients with Gorlin syndrome (ClinicalTrials.gov identifier: NCT00957229) could clarify whether resistance develops in patients with treatment-naive BCC. Given the initial report of a >90% reduction in new BCC development in these patients with Gorlin syndrome (Tang , J. Y.et al. J. Invest. Dermatol. 131, S92; 2011), studies are also needed to investigate whether systemic Hedgehog pathway blockade could prevent sporadic BCC development in other high-risk patients.

Another area in which future study seems to be warranted is the use of topical formulations of SMO antagonists in patients with BCC, for which discordant results have been reported in clinical trials so far. One agent, CUR61414, had no clinical activity despite showing encouraging preclinical data, whereas another agent, LDE225, produced complete or partial responses in 12 out of 13 treated BCCs6, although residual nests of apparent tumour cells were detected at the end of the 4-week treatment interval.

Overall, the promising efficacy of vismodegib as a single agent in BCC underscores the pivotal role of mutation-driven Hedgehog pathway activation in the development and maintenance of these cancers. It is not yet clear whether vismodegib or related drugs in development will be efficacious in Hedgehog-activated internal cancers with other driver mutations. However, based on the data currently available and emerging, it seems likely that these agents will be useful for preventing and treating at least some BCCs.