Agulnik Assesses Treatments for Basal Cell Carcinoma

Mark Agulnik, MD

Mark Agulnik, MD, professor of medicine, Hematology and Oncology, Northwestern Medicine, Feinberg School of Medicine, Chicago, IL, discussed the guidelines and data supporting possible treatment decisions for an 88-year-old male patients with basal cell carcinoma, during a virtual Case Based Peer Perspectives event.

Targeted Oncology™: What do the National Comprehensive Cancer Network (NCCN) guidelines suggest for this patient?

AGULNIK: Using the NCCN guidelines helps us by giving risk factors for basal cell carcinoma for patients at high risk compared with low risk.1 Immunosuppression, site of prior radiation, and aggressive growth pattern [leading to] neural invasion are all high-risk features. Looking at the affected area with respect to whether it’s on the trunk and extremities, area H [mask areas of the face], genitalia, hands, or feet—[all] are going to be higher risk. Looking at different areas with respect to size is going to be a little bit different.

How do the Hedgehog pathway inhibitors that are available in this setting compare?

Essentially there are 2: vismodegib and sonidegib (Odomzo). Both are approved for patients with locally advanced disease, but vismodegib also is indicated for patients with metastatic disease.²

Dosing is daily for both; they’re both capsules. Vismodegib can be taken with or without food; sonidegib is taken 1 hour before or 2 hours after a meal. From that point of view, vismodegib is easier. You’re going to need to look at drug-drug interactions to see whether you could safely use [either agent].

The adverse effects are similar. There are muscle spasms, arthralgias, alopecia, anorexia, weight loss, nausea, vomiting, fatigue, and increased creatine kinase levels.

The response rates were similar. In the locally advanced setting, response rates were similar for both agents at around 43% to 44% of patients; in the metastatic setting, the response rate for vismodegib was 30%.³

Which clinical trials have looked at vismodegib in this patient population?

The phase 2 ERIVANCE trial [NCT00833417] of vismodegib for advanced BCC had 104 patients, and it was a multicenter trial.⁴ It’s for patients with RECIST-measurable metastatic disease or locally advanced BCC that was inoperable [or] surgically inappropriate. They all received vismodegib 150 mg daily until progression, toxicity, or withdrawal.

The primary end point was the overall response rate [ORR] determined by independent review. Secondary end points were ORR determined by investigator, progression-free survival, duration of response, overall survival, and absence of residual BCC in patients with locally advanced disease. These data are from 2012.

From an independent assessment, the ORRs were 30% in the metastatic setting and 43% in the locally advanced setting. Looking at the maximum decrease in tumor size, however, more patients exhibited what I would call a response, but it is not a RECIST-appropriate response.

What are some other important data in this setting?

The phase 2 BOLT study [NCT01327053] of sonidegib evaluated patients with locally advanced disease or metastatic disease, and they were stratified to 2 different dosing schedules: 200 mg versus 800 mg daily in a 1:2 stratification.⁵

In the 200-mg and 800-mg groups, 8% and 3% remained on treatment for 42 months, respectively.⁶ The primary end point was centrally reviewed and confirmed ORR. The ORR at 200 mg [for patients with locally advanced disease] was 56% compared with 46% at 800 mg; it was 7.7% versus 17.4% for the metastatic setting, respectively. There were no safety concerns that emerged from this trial. The update was presented in 2019.

How do you manage toxicities with these regimens?

My go-to when I’m using drugs—and it seems of late we are using some of the newer drugs that have come to market in the sarcoma world or using drugs for NTRK [neurotrophic TRK] fusions—is the pathway inhibitor. I go to the website of the companies, pick up the pathway inhibitor, and for me that becomes the gold standard on how to follow the patients: what [I am] looking for, what intervals [am I using], and checking off all the boxes with respect to [whether patients] need to get electrocardiograms. [Some questions that I consider:] How often do I need to order electrocardiograms? Do I need to be checking their thyroid-stimulating hormone? What should I be looking at from a toxicity standpoint? What do I want them to call me for or not call me for? What do I do for managing toxicities for drugs that I don’t use very often?

What adverse events are associated with Hedgehog pathway inhibitors?

Patients aren’t always inclined to continue to take these long term. The benefit of having a response rate and possibly the complete response is that you could take the patients off these drugs, but we do have to think about the alopecia. There are musculoskeletal issues with respect to spasms, whether there’s a change in taste buds and their ability to be responsive to bitter and sweet. There is also a weight loss issue associated with these drugs.⁷

_References:

_{1. NCCN. Clinical Practice Guidelines in Oncology. Basal cell skin cancer. V1.2020. Accessed July 9, 2020. https://bit.ly/38HAZT4}

_{2. Harris L. Basal cell carcinoma: a pharmacist’s guide. US Pharm. 2019;44(8):29-35. https://bit.ly/3euIbDi}

_{3. Sekulic A. Management of rare melanomas and non-melanoma skin cancers. American Society of Clinical Oncology Annual Meeting 2019. Education Session. https://bit.ly/3h0hWGC}

_{4. Sekulic A, Migden MR, Oro AE, et al. Effi cacy and safety of vismodegib in advanced basal-cell carcinoma. N Engl J Med. 2012;366(23):2171-2179. doi:10.1056/NEJMoa1113713}

_{5. Migden MR, Guminski A, Gutzmer R, et al. Treatment with two diff erent doses of sonidegib in patients with locally advanced or metastatic basal cell carcinoma (BOLT): a multicentre, randomised, double-blind phase 2 trial. Lancet Oncol. 2015;16(6):716-728. doi:10.1016/S1470-2045(15)70100-2}

_{6. Dummer R, Guminksi A, Gutzmer R, et al. Long-term effi cacy and safety of sonidegib in patients with advanced basal cell carcinoma: 42-month analysis of the phase II randomized, double-blind BOLT study. Br J Dermatol. 2020;182(6):1369-1378. doi:10.1111/bjd.18552}

_{7. Lacouture ME, Dr.no B, Ascierto PA, et al. Characterization and management of Hedgehog pathway inhibitor-related adverse events in patients with advanced basal cell carcinoma. Oncologist. 2016;21(10):1218-1229. doi:10.1634/theoncologist.2016-0186}