Dalle et al13 reported 25 SPMs in 120 vemurafenib-treated patients. Median delay in SPM development was 14 weeks (range, 4–42 weeks). All tumors were thin, ranging from in situ to 0.45-mm thick. Wild-type BRAF was detected in the 21 melanomas sampled; 1 lesion showed mutated NRAS.13
The exact incidence of SPM in the setting of BRAF inhibition is thought to be at least 10-fold less than SCC and KA.2 Patients on BRAF inhibitor therapy should have routine full-body skin examinations, given the increased risk for SPM and SCC.
Another drug belonging to the tyrosine kinase inhibitor family, sorafenib, is used in the treatment of solid tumors, particularly hepatocellular and renal cell carcinomas, and also has been associated with development of cutaneous SCC and KAs.14 Sorafenib is a multiple tyrosine kinase inhibitor that also inhibits the RAF serine/threonine kinases. Similar to vemurafenib and dabrafenib, SCCs and KAs associated with sorafenib tend to arise in patients with chronic actinic damage during the first 2 months of treatment. It has been hypothesized that inhibition of RAF kinases is pathogenic in inducing SCCs because these lesions have not been reported with sunitinib, another multiple tyrosine kinase inhibitor that lacks the ability to inhibit serine/threonine kinases.15,16 Although SCCs and KAs associated with sorafenib tend to be low grade, it is reasonable to consider sunitinib or an alternative tyrosine kinase inhibitor in patients who develop multiple SCCs while taking sorafenib.16
Sonic Hedgehog–Inhibiting Agents
Vismodegib, the first small molecule inhibitor of the signaling protein smoothened, gained FDA approval for the treatment of metastatic or locally advanced basal cell carcinoma (BCC) in 2012. A second agent with an identical mechanism of action, sonidegib, was approved by the FDA for locally advanced BCC in 2015. Approximately 90% of BCCs contain mutations in the sonic hedgehog pathway, which lead to constitutive smoothened activation and uncontrolled cell proliferation.17 The development of smoothened inhibitors introduced a much-needed treatment for inoperable or metastatic BCC,17,18 though long-term utility is limited by drug resistance with extended use in this patient population.19,20 Several case reports have documented the emergence of KA21 and cutaneous SCC following vismodegib treatment of advanced or metastatic BCC.22-24 A larger case-control study by Mohan et al25 showed that patients with BCC treated with vismodegib had an increased risk for non-BCC malignancy (hazard ratio [HR]=6.37), most of which were cutaneous SCC (HR=8.12).
The mechanism by which selective inhibition of smoothened leads to cutaneous SCC is unclear. A study found that patients on vismodegib who developed SCC within the original BCC site had elevated ERK levels within tumor tissue, suggesting that the RAS/RAF/MAPK pathway can become upregulated during hedgehog inhibition.26 Other studies looking at hedgehog inhibition in medulloblastoma models also have shown activated RAS/RAF/MAPK pathways.25 These findings suggest that tumors under smoothened inhibition might be able to bypass the sonic hedgehog pathway and continue to grow by upregulating alternative growth pathways, such as RAS/RAF/MAPK.25,26
The incidence of cutaneous SCC following vismodegib treatment is unknown. Chang and Oro27 examined BCC tumor regrowth from secondary (acquired) resistance to vismodegib and noted that lesions recurred within 1 cm of the original tumor 21% of the time. Although none of the 12 patients whose tumors regrew during treatment were reported to have developed SCC, several demonstrated different BCC subtypes than the pretreatment specimen. The authors proposed that regrowth of BCC was due to upregulated alternative pathways allowing tumors to bypass smoothened inhibition, which is similar to the proposed mechanism for SCC development in vismodegib patients.27
Prospective studies are needed to confirm the link between vismodegib and cutaneous SCC; establish the incidence of SCC development; and identify any pretreatment factors, tumor characteristics, or treatment details (eg, dosage, duration) that might contribute to SCC development. Furthermore, because Mohan et al25 observed that vismodegib-treated patients were less likely to develop SCC in situ than controls, it is unknown if these tumors are more aggressive than traditional SCC. At this point, careful surveillance and regular full-body skin examinations are advised for patients on vismodegib for treatment of advanced BCC.