Dear Editor,
To date, 2 Hedgehog pathway inhibitors (HHIs) that block the Smoothened protein, sonidegib and vismodegib, are approved for advanced basal cell carcinoma (BCC). 1 As in other targeted cancer therapies, the development of resistance is a hurdle of HHI therapy; therefore, the frequency and mechanisms of resistance are of interest. Resistance to HHI therapy can be classified into 2 types: primary or intrinsic resistance, that is, patients never respond to therapy and progress, and secondary or acquired resistance, that is, patients initially respond to treatment before progressing. 1 , 2 Since resistance develops during HHI treatment, it should not be confused with the progression observed after the discontinuation of the HHI.
The pivotal Basal Cell Carcinoma Outcomes with LDE225 Treatment (BOLT) trial was a randomized, multicenter, double‐blind, Phase II study assessing the efficacy and safety of sonidegib 200 mg or 800 mg in patients with locally advanced BCC (laBCC) and metastatic BCC. 3 The primary endpoint was the objective response rate (ORR) per central review for patients with laBCC. 3 No data on secondary resistance from BOLT are published, and there are limited data from clinical studies on HHI resistance. Here, we report for the first time the rate of secondary resistance in patients with laBCC receiving sonidegib 200 mg in BOLT.
In this post hoc analysis, secondary resistance was defined as progression during treatment after an initial complete response (CR) or partial response (PR; Figure 1).
FIGURE 1.
Resistance to sonidegib in the BOLT trial. *Patients experiencing secondary resistance: 9.1% (6/66) of all patients; 15% (6/40) of patients who responded to treatment with sonidegib 200 mg. BOLT, Basal Cell Carcinoma Outcomes with LDE225 Treatment.
Among the 230 enrolled patients, 66 with laBCC were randomized to sonidegib 200 mg daily. 3 The ORR at 42 months was 60.6% (n = 40) per Response Evaluation Criteria in Solid Tumors (RECIST)‐like criteria by central review. CR was achieved in 14 (21.2%) patients and PR in 26 (39.4%) patients. The clinical benefit (ORR and stable disease) was 90.9% (n = 60), with unknown response status in 7.6% (n = 5) of patients. Of the 40 patients who responded to sonidegib 200 mg, 6 (15%) developed secondary resistance after initially achieving CR (n = 3) and PR (n = 3; Figures 1 and 2a). Event‐free probability estimates of the duration of response in all patients receiving sonidegib 200 mg were 90.8%, 69.2% and 50.4% at 6, 12 and 24 months, respectively (Figure 2b). Consequently, approximately half of the patients who responded to treatment still had a clinical benefit after 2 years.
FIGURE 2.
Type and duration of tumour response in patients with laBCC receiving sonidegib 200 mg daily in the BOLT trial. (a) Tumour response in patients with laBCC receiving sonidegib 200 mg daily is assessed by central review per RECIST‐like criteria. (b) Event‐free probability estimates for patients with laBCC are provided by central review per RECIST‐like criteria. BOLT, Basal Cell Carcinoma Outcomes with LDE225 Treatment; CI, confidence interval; CR, complete response; laBCC, locally advanced basal cell carcinoma; PD, progressive disease; PR, partial response; RECIST, Response Evaluation Criteria in Solid Tumors; SD, stable disease.
In the ERIVANCE trial evaluating vismodegib, 12.7% (8/63) and 40% (12/30) of patients with laBCC developed primary or secondary resistance, respectively. 4 A lower frequency of primary and secondary resistance was observed in the Phase II STEVIE trial in patients with laBCC (6% [9/148] and 9% [14/148], respectively). 5 In BOLT, primary resistance to sonidegib was rare. Of the 66 patients with laBCC receiving the approved 200‐mg daily dose, 1.5% (n = 1) never responded to the therapy (Figure 1). 6 A comparable primary resistance rate was observed in 2 other studies in Italy and Spain. 7 , 8 Importantly, the current lack of clinical trial data directly comparing sonidegib and vismodegib must be considered when examining these results.
In addition to HHIs, patients may benefit from the approved second‐line treatment cemiplimab, a programmed cell death‐1 inhibitor. In a Phase II trial evaluating cemiplimab in patients with laBCC who progressed on or were intolerant to previous HHI therapy, the rates of primary resistance (10.7%) and secondary resistance (14.8%) were comparable to those observed with HHI. 9
This study shows that overall resistance to sonidegib was not an issue in approximately 9 out of 10 patients in BOLT. Moreover, progression due to secondary resistance was not a frequent event in patients receiving sonidegib 200 mg daily. This contrasts with the misconception of high resistance rates arising from a lack of clear distinction between progression during treatment (resistance) and progression after discontinuation.
FUNDING INFORMATION
The BOLT study was sponsored and funded by Novartis; this analysis was funded by Sun Pharma. Medical writing and editorial support were funded by Sun Pharma Europe B.V.
CONFLICT OF INTEREST STATEMENT
EMC has received honoraria from Bristol Myers Squibb, Merck Sharp and Dohme, Novartis, Pierre Fabre, Roche and Sanofi; consulting fees or advisory roles from Bristol Myers Squibb/Celgene, Merck Sharp and Dohme, Novartis, Pierre Fabre, Roche, Sanofi and MSD; and speaker fees from Bristol Myers Squibb/Celgene, Novartis, Pierre Fabre, Sanofi and MSD. CB has received honoraria for presentations or consulting from Almirall Hermal, Bristol Myers Squibb, Delcath, Immunocore, InflaRx, LEO Pharma, Merck Sharp and Dohme, Novartis, Pierre Fabre, Regeneron Pharmaceuticals and Sanofi‐Aventis. JFB reports that his institution has received fees for advisory boards from Amgen, Bristol Myers Squibb, Merck Serono, Merck Sharp & Dohme, Novartis, Pierre Fabre, Sun Pharma and Sanofi‐Regeneron. SM and RA are employees of Sun Pharmaceutical Industries, B.V. PS has no conflicts of interest to declare.
ETHICS STATEMENT
The patients in this manuscript have given written informed consent for the publication of their case details.
ETHICS APPROVAL
The study adhered to the ethical principles of the Declaration of Helsinki. At all investigational sites, the study protocols and all amendments were approved by the relevant independent ethics committees or institutional review boards.
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.
REFERENCES
- 1. Danhof R, Lewis K, Brown M. Small molecule inhibitors of the hedgehog pathway in the treatment of basal cell carcinoma of the skin. Am J Clin Dermatol. 2018;19(2):195–207. [DOI] [PubMed] [Google Scholar]
- 2. Nguyen NM, Cho J. Hedgehog pathway inhibitors as targeted cancer therapy and strategies to overcome drug resistance. Int J Mol Sci. 2022;23(3):1733. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3. Dummer R, Guminksi A, Gutzmer R, Lear JT, Lewis KD, Chang ALS, et al. Long‐term efficacy 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] [PMC free article] [PubMed] [Google Scholar]
- 4. Sekulic A, Migden MR, Lewis K, Hainsworth JD, Solomon JA, Yoo S, et al. Pivotal ERIVANCE basal cell carcinoma (BCC) study: 12‐month update of efficacy and safety of vismodegib in advanced BCC. J Am Acad Dermatol. 2015;72(6):1021–10266. [DOI] [PubMed] [Google Scholar]
- 5. Yurchenko AA, Pop OT, Ighilahriz M, Padioleau I, Rajabi F, Sharpe HJ, et al. Frequency and genomic aspects of intrinsic resistance to vismodegib in locally advanced basal cell carcinoma. Clin Cancer Res. 2022;28(7):1422–1432. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6. Lear JT, Migden MR, Lewis KD, Chang ALS, Guminski A, Gutzmer R, et al. Long‐term efficacy and safety of sonidegib in patients with locally advanced and metastatic basal cell carcinoma: 30‐month analysis of the randomized phase 2 BOLT study. J Eur Acad Dermatol Venereol. 2018;32(3):372–381. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7. Mannino M, Piccerillo A, Fabbrocini G, Quaglino P, Argenziano G, Dika E, et al. Clinical characteristics of an Italian patient population with advanced BCC and real‐life evaluation of HHI safety and effectiveness. Dermatology. 2023;239(6):868–876. [DOI] [PubMed] [Google Scholar]
- 8. Moreno‐Arrones OM, Bea‐Ardebol S, Mayo‐Martinez F, Perez‐Pastor G, Torres‐Navarro I, Bonfill‐Orti M, et al. Sonidegib as a locally advanced basal cell carcinoma therapy in real‐life clinical setting: a national multicentre study. Actas Dermosifiliogr. 2023;114(7):565–571. [DOI] [PubMed] [Google Scholar]
- 9. Stratigos AJ, Sekulic A, Peris K, Bechter O, Prey S, Lewis KD, et al. Phase 2 open‐label, multicenter, single‐arm study of cemiplimab in patients with locally advanced basal cell carcinoma after hedgehog inhibitor therapy: extended follow‐up. J Am Acad Dermatol. 2023;90(2):414–418. [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.