Patients & Disease Areas Focus

Nodular Basal Cell Carcinoma in High-Risk Anatomical Sites

Background and rationale for SP-002

High-risk sites: the H and M zones

NCCN classifies BCCs on the head, neck, hands, feet, pretibial skin, and anogenital area as high risk regardless of size. These include the facial H zone—central face, eyelids, nose, lips, chin, temples, and ears—and M-zone sites such as the cheeks, forehead, scalp, neck, jawline, and pretibial skin. Nodular histology does not alter this location-based high-risk designation.1

The challenge extends beyond recurrence: complete tumor removal must be balanced against tissue loss and lasting functional or cosmetic harm. Limited tissue mobility and proximity to critical structures can complicate reconstruction even after removal of a small tumor.2,3

Reconstruction, complications, and lasting consequences

Surgery, including Mohs micrographic surgery, remains the standard of care. Although Mohs preserves uninvolved tissue, defects may still require local flaps, skin grafts, or staged reconstruction. Nasal repairs may also require cartilage grafts to restore structural support.1–3

Flap and graft reconstruction can be technically demanding and time-consuming, involving donor-site wounds, multiple procedures, prolonged wound care, and repeated follow-up visits. Complications include bleeding, infection, wound separation, delayed healing, and partial flap or graft loss. Larger defects and certain complex staged repairs carry greater complication or revision risk; pretibial graft repairs present additional healing challenges.2–5

Even successful tumor removal can leave permanent scarring, altered contour, or functional impairment. Site-dependent distortion or contraction may affect eyelid closure, nasal airflow, or lip function. Grafts may differ from surrounding skin in color or texture, while flaps may require contour refinement. Corrective surgery may therefore be needed despite complete tumor clearance.2,3

Current unmet need

No FDA-approved drug is currently indicated specifically as a nonsurgical alternative for localized, operable nodular BCC in these H- and M-zone sites. Imiquimod is approved for selected superficial BCCs, not nodular BCC; approved systemic therapies address defined advanced-BCC settings.6–8 There remains an unmet need for a minimally invasive, nonsurgical treatment with curative potential that could spare the majority of treated patients surgical tissue loss, flap or graft reconstruction, postoperative morbidity, and the associated recovery burden.

References

  1. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Basal Cell Skin Cancer. Version 1.2027. August 21, 2026. Risk stratification, BCC-2. oregon.gov. Accessed October 29, 2026.
  2. Factors Associated With Outcomes of Facial Reconstruction After Mohs Micrographic Surgery. Craniomaxillofac Trauma Reconstr. 2024;17(4):NP131–NP137. doi:10.1177/19433875241257981
  3. Avoidance and Management of Complications in Soft Tissue Facial Reconstruction. PubMed Central. PMC3743917. Accessed October 29, 2026.
  4. Association of Smoking and Other Factors With the Outcome of Mohs Reconstruction Using Flaps or Grafts. PubMed Central. PMC6567844. Accessed October 29, 2026.
  5. Evaluating complications in below-knee skin cancer surgery after introduction of preoperative appointments: A 2-year retrospective cohort study. Int Wound J. 2020;17(2):363–369. doi:10.1111/iwj.13280
  6. Imiquimod cream. US prescribing information. DailyMed. Sections 1.2 and 1.3. DailyMed PDF. Accessed October 29, 2026.
  7. ODOMZO (sonidegib). US prescribing information. US Food and Drug Administration; 2023. Section 1. FDA Prescribing Information. Accessed October 29, 2026.
  8. US Food and Drug Administration. FDA approves cemiplimab-rwlc for locally advanced and metastatic basal cell carcinoma. February 9, 2021. Oncology approval notifications. fda.gov. Accessed October 29, 2026.

Cutaneous Squamous Cell Carcinoma

Natural history

Cutaneous squamous cell carcinoma (cSCC) arises from keratinocytes, usually in sun-damaged skin and often from a preexisting actinic keratosis.2 Most tumors are cured by surgery or ablation, but a subset recur, metastasize, and cause death.1 In a cohort of 985 patients with 1,832 tumors, 4.6% of patients developed a local recurrence, 3.7% developed nodal metastasis, and 2.1% died of cSCC. Distant organ metastasis was uncommon (0.4% of patients), and 17 of 21 disease-specific deaths resulted from uncontrolled locoregional disease.1

Tumor diameter of 2 cm or more, poor differentiation, invasion beyond subcutaneous fat, perineural invasion, and ear, temple, or anogenital location were independent predictors of nodal metastasis and death from disease.1 Immunosuppression adds to the risk. Solid organ transplant recipients develop cSCC 65 to 250 times more often than the general population, and their tumors tend to be multiple and more aggressive.2,6

Current treatment

Surgical excision is the standard of care for localized disease, with Mohs micrographic surgery preferred for tumors with high-risk features. Five-year recurrence is about 3.1% after Mohs surgery and 8.1% after standard excision, and for previously treated lesions the figures are about 10% and 23.3%, respectively.2 Radiation is used after surgery for perineural invasion, positive margins, or extracapsular nodal extension, and as primary treatment when surgery is not feasible. Topical agents, cryotherapy, photodynamic therapy, and ablative laser are options for patients who cannot have surgery, but recurrence is higher and clearance cannot be confirmed histologically.2

For locally advanced unresectable or metastatic disease, the anti-PD-1 antibodies cemiplimab and pembrolizumab are FDA-approved, and cemiplimab is the preferred systemic option in NCCN guidelines.2 In EMPOWER-CSCC-1, cemiplimab produced an objective response rate of 47.2% in 193 patients, with a median progression-free survival of 26.0 months.3 In KEYNOTE-629, pembrolizumab produced objective response rates of 35% in recurrent or metastatic disease and 52% in locally advanced disease.5 An anti-PD-L1 antibody has also recently been approved for advanced cSCC.4

Limitations and unmet need

Even with anti-PD-1 therapy, most patients with advanced cSCC do not achieve a complete response, and a substantial group has no benefit at all. In a series of 72 patients whose disease progressed on anti-PD-1 treatment, 62.5% had primary resistance. Progression was locoregional in 37% and distant in 42%. Subsequent therapy, mainly cetuximab-based regimens or local treatment, produced a complete or partial response in 30% of patients, median event-free survival after that treatment was 7.1 months, and cSCC-specific mortality reached 50% at five years.4 No approved option has an established role once checkpoint blockade fails.

Patients who are immunosuppressed are poorly served. Registration trials excluded patients who required immunosuppression,5 and checkpoint inhibitors can precipitate graft rejection in transplant recipients; in a pooled analysis of 90 recipients with advanced skin cancers, 37.8% had acute rejection.7 Surgery for tumors of the head and neck also carries a functional and cosmetic cost, and grade 3 or higher serious adverse events occurred in 31.1% of patients on cemiplimab in EMPOWER-CSCC-1.2,3 There remains a need for treatments that deepen and prolong responses in patients who are eligible for checkpoint blockade, and for safe options in patients who are not.

References

  1. Schmults CD, Karia PS, Carter JB, Han J, Qureshi AA. Factors predictive of recurrence and death from cutaneous squamous cell carcinoma: a 10-year, single-institution cohort study. JAMA Dermatol. 2013;149(5):541-547. doi:10.1001/jamadermatol.2013.2139
  2. Hadian Y, Howell JY, Ramsey ML, Buckley C. Cutaneous squamous cell carcinoma. In: StatPearls. Treasure Island, FL: StatPearls Publishing; 2024. Updated July 2, 2024. Bookshelf ID: NBK441939
  3. Hughes BGM, Guminski A, Bowyer S, et al. A phase 2 open-label study of cemiplimab in patients with advanced cutaneous squamous cell carcinoma (EMPOWER-CSCC-1): final long-term analysis of groups 1, 2, and 3, and primary analysis of fixed-dose treatment group 6. J Am Acad Dermatol. 2025;92(1):68-77. doi:10.1016/j.jaad.2024.06.108. PMID: 39245360
  4. Khaddour K, Kote P, Liu M, et al. Progression patterns and clinical outcomes in patients with cutaneous squamous-cell carcinoma following anti-PD-1 therapy failure. ESMO Open. 2026;11(3):106081. doi:10.1016/j.esmoop.2026.106081. PMID: 41819748
  5. Merck Sharp & Dohme LLC. KEYTRUDA (pembrolizumab): KEYNOTE-629 clinical trial results in advanced cutaneous squamous cell carcinoma. Accessed October 20, 2026. keytrudahcp.com
  6. Kim C, Cheng J, Colegio OR. Cutaneous squamous cell carcinomas in solid organ transplant recipients: emerging strategies for surveillance, staging, and treatment. Semin Oncol. 2016;43(3):390-394. doi:10.1053/j.seminoncol.2016.02.019. PMID: 27178693
  7. Ji S, Liu H, Pachella L, Stephenson RD, Groisberg R, Weiss SA. Use of immune checkpoint inhibitors in solid organ transplant recipients with advanced cutaneous malignancies. Front Transplant. 2023;2:1284740. doi:10.3389/frtra.2023.1284740