Sonidegib Plus Calcium Supplementation for Improved Management of BCC and HHI-Related Muscle Spasms

Nodular basal cell carcinoma | Image credit: © DermNet

A recent retrospective review published in PLOS ONE evaluated patients treated for locally advanced or metastatic basal cell carcinoma (BCC) with hedgehog inhibitors (HHI) for progression-free survival, as well as the addition of coenzyme Q10 (CoQ10) and calcium supplementation for HHI-related muscle spasms. Although BCCs can be treated with surgical resection or ablation, some BCC cases require systemic therapies. According to Patel et al, first-line BCC treatment includes the HHIs vismodegib and sonidegib and second-line treatment is usually cemiplimab, a monoclonal antibody PD-1 inhibitor.

With HHIs comes muscle spasms, the most common adverse event in nearly half of patients. During BCC oncogenesis, when the G protein-coupled receptor Smoothened (SMO) triggers second messengers such as CA²⁺, and Sonic hedgehog (SHH) increases Ca²⁺ spike activity through activation of the SHH coreceptor SMO, there is both intracellular Ca²⁺ stores and Ca²⁺ influx. “Therefore, inhibition of SHH depletes the muscle cells of Ca²⁺, inducing muscle spasms,” wrote Patel et al.

The study authors hypothesized that CoQ10 and calcium replacements could support muscle health and prevent muscle spasms in patients taking HHI.

Patel et al’s single-center retrospective review evaluated the safety and efficacy of vismodegib and sonidegib for the treatment of locally advanced and metastatic BCC in patients who were treated from December 2021 to August 2022. The primary end point of the study was to assess progression-free survival (PFS). PFS was measured from the start of HHI treatment to evidence of targeted BCC recurrence, the start of a different class of BCC therapy, death, or lost to follow-up. Secondary end points included the assessment of overall survival (OS), the safety and tolerability of HHIs, including reported adverse events and their grade, and the use of concomitant CoQ10, calcium supplements, and/or other medications to prevent the musculoskeletal toxicity related to HHIs. OS was measured from the start of treatment to the date of death or last date known to be alive per medical records review. Both BCC-specific and other causes of mortality were recorded.

Eligible patients had a locally advanced or metastatic BCC diagnosis confirmed through a pathology report, were aged 18 years and older, and received an HHI for BCC prescribed by an Ohio State University Comprehensive Cancer Center (OSUCCC) medical oncologist with a documented start of treatment in the electronic medical record.

Results

Overall, 60 patients met the inclusion criteria. In all 60 cases, HHIs were started for a specific lesion due to being inoperable or not suitable for radiation; the patient refused surgery or radiation; or multiple BCCs were present with excessive frequency, making excision or Mohs surgery too frequent for tumor control. The majority of patients were white men with an age range of 29 to 88 years.

Thirty-seven patients (62%) received vismodegib and 23 (38%) received sonidegib. For vismodegib dosing, 70% of patients were initiated on the standard once-daily dosing, but 18% started vismodegib on a 5-times-per-week frequency. For sonidegib dosing, 83% of patients started the standard once-daily dosing, but 9% were prescribed a 5-times-per-week frequency. Dose reduction occurred in 85% of patients. Only 9 patients were able to maintain daily dosing. Overall, 19 patients continued on HHIs for >6 months and entered the maintenance phase. Seven patients crossed over to the alternate HHI due to various toxicities: 1 from sonidegib to vismodegib and 6 from vismodegib to sonidegib. Of these 7 patients, 3 remained on the crossover HHI for >6 months.

“Five patients were not assessable for the primary outcome for the following reasons: 2 patients did not take 1 month of therapy and stopped for subjective adverse events, 2 patients had a mixed BCC with squamous cell carcinoma (SCC) and died of SCC progression, and 1 patient was given HHI as secondary prevention in the setting of Gorlin syndrome. Of these 5 patients, 4 died as of the cutoff date and 1 remains alive (the patient with Gorlin syndrome),” wrote Patel et al.

The median PFS was not reached in the whole cohort (95% CI, 34.7 months not reached for sonidegib and 34.4 months not reached for vismodegib).

Overall, there were 25 (45.4%) complete responders and 9 (16.3%) partial responders, for an overall response rate (ORR) of 61.8%. Fourteen patients had stable disease (25.4%) and 7 (12.7%) had progression. Of the 25 complete responders, 19 (79%) remain in remission, 4 (17%) had new primary BCC leading to HHI discontinuation, 1 developed urothelial cancer (leading to death), and 1 developed metastatic disease treated further with cemiplimab with a complete response (CR). Of the 9 partial responders, 2 patients (22.2%) progressed on HHI therapy and 5 patients received additional therapies (XRT and/or surgery) making them free of disease.

Regarding overall survival, of the 25 patients who obtained an initial CR, 3 patients died of non-BCC-related causes: 1 of COVID and 2 of other types of cancer. Of the 9 patients who obtained a partial remission, 6 are living and 3 died, 2 of different conditions, and 1 of BCC progression after refusing further treatments. Of the 14 patients with SD, 6 have died: 3 of BCC and 3 of other conditions. Of the 7 patients who progressed on HHI, 5 have died, 4 of BCC and 1 of an unrelated condition.

For recurrence, out of the 25 patients obtaining an initial CR, 7 had recurrences or new BCC later (28%). Of these 7 patients, 4 had a new primary BCC while on treatment, 1 had a new metastatic progression while still on HHI, and 2 recurred 1 year after stopping vismodegib because of adverse effects.

Of the 9 partial responders, 2 died of other causes and 1 of BCC. Of the remaining 6 patients, 2 were lost to follow-up and are not known to have had a recurrence, including a patient with Gorlin syndrome; 1 remains on treatment after more than 3 years; and 1 was treated with XRT and 1 with surgery, without recurrences. Only 1 patient who had metastatic disease when starting on HHI recurred after 12 months, and was then later treated with cemiplimab and achieved a CR.

After progression, 14 patients received immunotherapy, 6 had salvage surgery, 3 underwent radiotherapy, and 2 received cetuximab with chemotherapy. Of the patients who received immunotherapy when they progressed, 9 patients (64%) received cemiplimab with a 56% CR and 36% received alternative immune checkpoint inhibitors; only 1 patient had a CR on the combination of ipilimumab and nivolumab. Overall, 3 of 6 patients (50%) who had salvage surgeries did not experience recurrence.

Muscle Spasms and Supplementation

The most common adverse events related to HHI treatment were myalgia/muscle spasm (46%), dysgeusia (37%), fatigue (30%), gastrointestinal effects (28%), weight loss (15%), and alopecia (15%). In the crossover group, the adverse event rates were similar with myalgia/muscle spasm (43%), fatigue (29%), and weight loss (28%) being the most common.

Of the 24 patients who had treatment resumption upon toxicity resolution, 58% required dose reduction. More patients in the vismodegib group (59%) needed changes in the regimen versus those in the sonidegib group (24%). The rate of treatment discontinuation was higher in the vismodegib group (30%) compared to the sonidegib group (9%).

For the HHI-induced muscle spasms, 19 patients received calcium supplementation for either prevention (63%) or treatment (37%) of muscle spasms. Of the 19, 8 patients received CoQ10 plus calcium supplementation. Patients who received prophylactic calcium and/or CoQ10 supplementation required fewer dose reductions (17%) than patients who did not receive prophylaxis (42%). However, the incidences of myalgia/muscle spasms did not differ between the prophylaxis and non-prophylaxis groups (42% and 46%, respectively).

Conclusion

“Our real-world data has similar outcomes, combining all stages of disease, with a 62% response rate and a progression-free survival that has not yet been reached with a 95% CI of about 34.5 months to not reached for both drugs.... However, our safety analysis showed significant differences in adverse events, with fewer dosing changes needed for sonidegib than for vismodegib (24% vs. 59%), and a rate of treatment discontinuation that was higher for vismodegib compared to sonidegib (30% vs. 9%). Our data strongly suggest that sonidegib is better tolerated than vismodegib and is equally efficacious,” wrote Patel et al.

The study authors concluded that sonidegib may be a better treatment option compared to vismodegib due to better tolerability and that a less frequent dosing may enhance tolerability. Calcium and CoQ10 supplementation also have the ability to decrease HHI-associated muscle spasms.

Patel et al noted that the limitations of their study included a small sample size and inconsistent documentation in electronic medical records. The study authors wrote that a larger prospective trial should be conducted in the future to better assess the differences in efficacy and tolerability between HHIs.

Reference

1. Patel S, Armbruster H, Pardo G, et al. Hedgehog pathway inhibitors for locally advanced and metastatic basal cell carcinoma: a real-world single-center retrospective review. PLoS One. 2024;19(4):e0297531. Published 2024 Apr 30. doi:10.1371/journal.pone.0297531