Final analysis of phase II results with cemiplimab in metastatic basal cell carcinoma after hedgehog pathway inhibitors.

BACKGROUND: Metastatic basal cell carcinoma (mBCC) is a rare condition with no effective second-line treatment options. Cemiplimab is an immune checkpoint inhibitor that blocks the binding of programmed cell death-1 (PD-1) to its ligands, programmed death-ligand 1 (PD-L1) and programmed death-ligand 2 (PD-L2). Here, we present the final analysis of cemiplimab in patients with mBCC after first-line hedgehog pathway inhibitor (HHI) treatment (NCT03132636). PATIENTS AND METHODS: In this open-label, single-arm, phase II study, adults with mBCC and Eastern Cooperative Oncology Group performance status ≤1, post-HHI treatment, received cemiplimab 350 mg intravenously every 3 weeks for ≤93 weeks or until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) by independent central review (ICR). Duration of response (DOR) was a key secondary endpoint. Other secondary endpoints were ORR per investigator assessment, progression-free survival (PFS), overall survival (OS), complete response rate, safety, and tolerability. RESULTS: Fifty-four patients were enrolled: 70% were male and the median age of patients was 64 [interquartile range (IQR) 57.0-73.0] years. The median duration of follow-up was 8 months (IQR 4-21 months). The ORR per ICR was 22% [95% confidence interval (CI) 12% to 36%], with 2 complete responses and 10 partial responses. Among responders, the median time to response per ICR was 3 months (IQR 2-7 months). The estimated median DOR per ICR was not reached [95% CI 10 months-not evaluable (NE)]. The disease control rate was 63% (95% CI 49% to 76%) per ICR and 70% (95% CI 56% to 82%) per investigator assessment. The median PFS per ICR was 10 months (95% CI 4-16 months); the median OS was 50 months (95% CI 28 months-NE). The most common treatment-emergent adverse events were fatigue [23 (43%)] and diarrhoea [20 (37%)]. There were no treatment-related deaths. CONCLUSIONS: Cemiplimab demonstrated clinically meaningful antitumour activity, including durable responses, and an acceptable safety profile in patients with mBCC who had disease progression on or intolerance to HHI therapy.

A multicenter real-world analysis of risk factors, therapeutics, and outcomes of patients with metastatic basal cell carcinoma.

BACKGROUND: Metastatic basal cell carcinoma (mBCC) is rare and there are limited data regarding patient and tumor risk factors, optimal treatments, and disease prognosis. OBJECTIVE: To assess patient and tumor characteristics, therapeutics, and outcomes of mBCC stratified by location of metastasis. METHODS: Retrospective cohort study of 53 patients with mBCC treated at 4 large academic centers in Boston, Massachusetts; Philadelphia, Pennsylvania; and Cleveland, Ohio between January 1, 2005 and December 31, 2021. RESULTS: A total of 53 patients with mBCC were identified across 4 centers, 22 (42%) of whom had mBCC with spread limited to lymph nodes and 31 (58%) patients with distant organ spread (with or without lymph node involvement). Overall, half (n = 11) of patients with nodal metastasis achieved complete remission of disease, compared with just 1 (3%) patient with distant metastasis. The 5-year survival for nodal and distant metastatic patients was 89.3% and 61.0%, respectively. LIMITATIONS: Small sample size due to disease rarity. CONCLUSIONS AND RELEVANCE: Patients with nodal disease are more likely to have disease remission whereas patients with distant metastasis are more likely to have persistent disease and die from their disease. However, 5-year survival rates exceed 50%, even for stage IV disease.

Primary Basal Cell Carcinoma Masquerading as Metastatic Basal Cell Carcinoma in the Left Axilla.

Basal cell carcinoma (BCC) is considered the most common malignancy in Caucasians. Despite its high prevalence, BCC has extremely low rates of metastasis. The patient was a 71-year-old male with extensive BCC and squamous cell carcinoma (SCC) skin cancer history who had an extensive, palpable left axillary mass concerning enlarged lymph nodes. No skin lesions were visualized. A lymph node biopsy revealed a sclerosing/infiltrative BCC with perineural invasion extending to the inked margins of the excision and one of four lymph nodes involved by BCC through direct extension. Sectioning revealed a 3.0 x 2.8 x 2.9 cm, ill-defined, fibrotic pink-white mass within the soft tissue. Two tan to pink possible lymph nodes were also identified within the soft tissue, measuring 0.7cm and 0.9cm. There was no definite direct invasion noted, making metastatic BCC suspicious. A left axillary lymph node dissection was performed. In short, he had a nonmobile tumor that showed evidence of invasion of the adjacent pectoralis muscle near the chest wall, abutting the left axillary vein, with extension. In July 2022, approximately one year after diagnosis, the patient received a PET scan and had no remote sites of disease. Every follow-up PET scan since has shown stable disease, most recently in May 2023. The patient continues dermatology follow-ups every three months for clinical surveillance. This case is unique because metastatic disease was never confirmed, though it is still a possibility. The affected lymph nodes were in the regional basin, where the patient had had extensive skin cancers in the past. Their involvement could have been secondary to direct invasion, though this could not be confirmed histologically, making the definitive characterization of this particular tumor difficult. As the PET CT scans have remained stable without evidence of distant disease, we favor that this is a recurrent primary tumor with direct extension to the underlying pectoralis and axillary lymph nodes. As common as BCCs are, this case highlights the importance of diligent treatment and follow-up to avoid the potential for tumor-related morbidity and, rarely, mortality.

Safety and efficacy of nivolumab, an anti-PD1 immunotherapy, in patients with advanced basal cell carcinoma, after failure or intolerance to sonic Hedgehog inhibitors: UNICANCER AcSé NIVOLUMAB trial.

BACKGROUND: Basal cell carcinoma (BCC) is the most common human malignancy. In most cases, BCC has slow progression and can be definitively cured by surgery or radiotherapy. However, in rare cases, it can become locally advanced or, even more rarely, metastatic. The alternative recommended treatments are Sonic Hedgehog pathway inhibitors; however, the response is often short-lived. METHODS: This was a phase 2 basket study (NCT03012581) evaluating the efficacy and safety of nivolumab in a cohort of 32 advanced BCC patients, enrolled after failure of Sonic Hedgehog inhibitors, including 29 laBCC (91%) and 3 mBCC (9%). RESULTS: Compared to previously published studies, our population consisted of severe patients with a poor prognosis because they had already received multiple lines of treatment: all patients received previous Sonic Hedgehog inhibitors, 53% of patients already had chemotherapy and 75% radiotherapy. At 12 weeks, we reported 3.1% of complete responses, 18.8% of partial responses, and 43.8% of stable diseases. The best response rate to nivolumab reached 12.5% of complete responses (four patients), 18.8% of partial responses (three patients), and 43.8% of stable diseases (14 patients). Adverse events (AE) were mostly grade 2 or 3, slightly different to the adverse events observed in the treatment of metastatic melanoma (higher rate of diabetes, no thyroid dysfunction). CONCLUSION: Nivolumab is a relevant therapeutic option for patients with advanced relapsing/refractory BCC.

Metastatic basal cell carcinoma to the bone: A case of bone metastasis in uncommon sites.

Basal cell carcinoma (BCC) is the most common malignant tumor of the skin. Despite the indolent nature, metastatic BCC can occur, albeit rarely. Metastasis to the bone is very rare. From its approval, mBCC patients are treated with vismodegib, a selective hedgehog pathway inhibitor. Unfortunately, in recent period, it was demonstrated an emergence of drug resistance, due to Smoothened (SMO) mutation. To date, several groups are studying the effectiveness of immunotherapy in BCC. Clinical trials with Immune Checkpoint Inhibitors are ongoing. We report the rare case of a man with multiple bony metastasis, with a resistance to vismodegib, and we evaluated all manuscripts in literature reporting bone metastasis. Moreover, we review all the manuscripts in literature reporting bone metastasis, and we summarize the main therapeutic strategies, and the further perspectives.

Vismodegib and Sonidegib in Locally Advanced and Metastatic Basal Cell Carcinoma: Update on Hedgehog Pathway Inhibitors. / Vismodegib y sonidegib en el carcinoma de células basales localmente avanzado y metastásico: actualización acerca de los inhibidores de la vía de Hedgehog.

As one of the most common malignancies, basal cell carcinoma (BCC) has evolved as a global burden with incidence annually rising, especially in the older population. Even though the condition is mostly localized, the nature of the disease is destructive and can evolve as either locally advanced BCC (laBCC) or even more rarely as metastatic BCC (mBCC). There are well-established conventional treatment options for these cases, including surgeries and radiotherapy. However, not all cases are eligible for conventional treatments. Recently, biologic treatment has gained a lot of attention and research. This has led to the development of targeted treatment involving the hedgehog pathway inhibitor (HPI), a key pathogenesis in laBCC and mBCC. There are currently two approved HPIs, vismodegib and sonidegib to treat inoperable laBCC and mBCC. This review seeks to explore the pathophysiology of hedgehog pathway behind the development of BCC, and the current update of the efficacy as well as pharmacokinetics properties of HPIs that led to the ideal treatment for laBCC or mBCC, either as monotherapy or in combination with other conventional therapies.

Vismodegib y sonidegib en el carcinoma de células basales localmente avanzado y metastásico: actualización acerca de los inhibidores de la vía de Hedgehog / Vismodegib and Sonidegib in Locally Advanced and Metastatic Basal Cell Carcinoma: Update on Hedgehog Pathway Inhibitors

El carcinoma de células basales (CBC) es una de las neoplasias malignas más frecuentes, por lo que se ha convertido en una importante carga asistencial. Su incidencia se incrementa anualmente, especialmente en la población con mayor edad. A pesar de que generalmente está bien localizado, el CBC tiene la capacidad de destruir tejidos y evolucionar a un CBC localmente avanzado (CBCla) o incluso, aunque de forma más rara, a un CBC metastásico (CBCm). Las opciones terapéuticas convencionales en estos casos están bien establecidas, entre las cuales se incluyen la cirugía y la radioterapia. Sin embargo, no todos los casos son elegibles para realizar un tratamiento de tipo convencional. Recientemente, los tratamientos biológicos vienen ganando una mayor atención y son objeto de diversos estudios de investigación. De este modo se ha desarrollado una terapia dirigida utilizando los inhibidores de la vía de Hedgehog (IVH), teniendo en cuenta que se trata de una vía patogénica clave tanto en el CBCla como en el CBCm. En la actualidad, para poder tratar el CBCla y el CBCm no operables existen dos IVH aprobados: el vismodegib y el sonidegib. Esta revisión busca explorar la fisiopatología de la vía del Hedgehog responsable del desarrollo del CBC y hacer una actualización en cuanto a la eficacia, así como de las propiedades farmacocinéticas de los IVH, características que los convirtieron en la opción terapéutica ideal en el CBCla o en el CBCm, ya sea en forma de monoterapia o en combinación con alguno de los tratamientos convencionales (AU)

As one of the most common malignancies, basal cell carcinoma (BCC) has evolved as a global burden with incidence annually rising, especially in the older population. Even though the condition is mostly localized, the nature of the disease is destructive and can evolve as either locally advanced BCC (laBCC) or even more rarely as metastatic BCC (mBCC). There are well-established conventional treatment options for these cases, including surgeries and radiotherapy. However, not all cases are eligible for conventional treatments. Recently, biologic treatment has gained a lot of attention and research. This has led to the development of targeted treatment involving the hedgehog pathway inhibitor (HPI), a key pathogenesis in laBCC and mBCC. There are currently two approved HPIs, vismodegib and sonidegib to treat inoperable laBCC and mBCC. This review seeks to explore the pathophysiology of hedgehog pathway behind the development of BCC, and the current update of the efficacy as well as pharmacokinetics properties of HPIs that led to the ideal treatment for laBCC or mBCC, either as monotherapy or in combination with other conventional therapies (AU)

[Translated article] Vismodegib and Sonidegib in Locally Advanced and Metastatic Basal Cell Carcinoma: Update on Hedgehog Pathway Inhibitors / Vismodegib y sonidegib en el carcinoma de células basales localmente avanzado y metastásico: actualización acerca de los inhibidores de la vía de Hedgehog

As one of the most common malignancies, basal cell carcinoma (BCC) has evolved as a global burden with incidence annually rising, especially in the older population. Even though the condition is mostly localized, the nature of the disease is destructive and can evolve as either locally advanced BCC (laBCC) or even more rarely as metastatic BCC (mBCC). There are well-established conventional treatment options for these cases, including surgeries and radiotherapy. However, not all cases are eligible for conventional treatments. Recently, biologic treatment has gained a lot of attention and research. This has led to the development of targeted treatment involving the hedgehog pathway inhibitor (HPI), a key pathogenesis in laBCC and mBCC. There are currently two approved HPIs, vismodegib and sonidegib to treat inoperable laBCC and mBCC. This review seeks to explore the pathophysiology of hedgehog pathway behind the development of BCC, and the current update of the efficacy as well as pharmacokinetics properties of HPIs that led to the ideal treatment for laBCC or mBCC, either as monotherapy or in combination with other conventional therapies (AU)

El carcinoma de células basales (CBC) es una de las neoplasias malignas más frecuentes, por lo que se ha convertido en una importante carga asistencial. Su incidencia se incrementa anualmente, especialmente en la población con mayor edad. A pesar de que generalmente está bien localizado, el CBC tiene la capacidad de destruir tejidos y evolucionar a un CBC localmente avanzado (CBCla) o incluso, aunque de forma más rara, a un CBC metastásico (CBCm). Las opciones terapéuticas convencionales en estos casos están bien establecidas, entre las cuales se incluyen la cirugía y la radioterapia. Sin embargo, no todos los casos son elegibles para realizar un tratamiento de tipo convencional. Recientemente, los tratamientos biológicos vienen ganando una mayor atención y son objeto de diversos estudios de investigación. De este modo se ha desarrollado una terapia dirigida utilizando los inhibidores de la vía de Hedgehog (IVH), teniendo en cuenta que se trata de una vía patogénica clave tanto en el CBCla como en el CBCm. En la actualidad, para poder tratar el CBCla y el CBCm no operables existen dos IVH aprobados: el vismodegib y el sonidegib. Esta revisión busca explorar la fisiopatología de la vía del Hedgehog responsable del desarrollo del CBC y hacer una actualización en cuanto a la eficacia, así como de las propiedades farmacocinéticas de los IVH, características que los convirtieron en la opción terapéutica ideal en el CBCla o en el CBCm, ya sea en forma de monoterapia o en combinación con alguno de los tratamientos convencionales (AU)

Cemiplimab for locally advanced and metastatic basal cell carcinoma.

INTRODUCTION: Locally advanced basal cell carcinoma (laBCC) represents approximatively 1% of all BCCs. Metastatic BCC (mBCC) is even more rare. Most cases are observed in immunocompromised patients, particularly solid organ transplant recipients (OTRs). When surgery and/or radiation therapy for laBCC or mBCC is not reasonable, oral hedgehog inhibitor (HHI) therapy may be initiated. LaBCC or mBCC patients with primary or secondary resistance, progression or intolerance to HHIs could benefit from programmed cell death protein-1 (PD-1) inhibitors as this has recently been published for cemiplimab, a recombinant IgG4 human monoclonal antibody anti-PD-1 for the intravenous treatment of laBCC and mBCC. AREAS COVERED: Principal studies evaluating the efficacy and safety of cemiplimab for laBCC and mBCC are presented and discussed. EXPERT OPINION: Cemiplimab is the first FDA (2021) approved anti-PD-1 antagonist for the systemic treatment of laBCC and mBCC which had previously shown disease progression on or intolerance to HHIs. Experts currently recommend cemiplimab as a first-line systemic alternative. As cemiplimab therapy is associated with a risk of organ graft rejection, advantages and disadvantages should be evaluated for every individual OTR patient with laBCC or mBCC, eligible for cemiplimab therapy.

Metastatic head and neck cutaneous basal cell carcinomas: a retrospective observational study.

Cutaneous basal cell carcinoma is usually an indolent and slow-growing tumor with potential for local invasion and recurrence; however, metastatic events are exceedingly rare. The annual incidence of metastasis is estimated to range between 0.00281 and 0.05%. A retrospective search in the pathology database of a single tertiary institution was performed in the period between 1999 to 2019. Primary cutaneous metastatic basal cell carcinomas had paraffin blocks and glass slides retrieved. A total of 8673 cases was identified. The overall prevalence of metastatic tumors was 0.05% (4/8673). The median patient's age at diagnosis was 61 years old (range 52-79). The most common primary site of tumor was nose (2/4) and the most common histological subtype was infiltrative. The sampled lymph nodes were identified during primary tumor resection, except for 1 patient who had a sentinel lymph node biopsy performed as a surgeon individual decision. One patient had hematogenous spread to the pleura, diagnosed 5 years after diagnosis. In summary, this study adds new data to the current literature in metastatic primary cutaneous basal cell carcinomas and highlights the importance of early diagnosis and appropriate surgical excision in an effort to prevent local advanced disease, recurrence and lymphovascular dissemination.

Metastatic basal cell carcinoma with atypical pattern of spread.

Basal cell carcinoma is the most common malignancy in the United States. However, metastasis of basal cell carcinoma is exceedingly rare, with incidence estimates of 0.0028-0.055%. When it does metastasize, basal cell carcinoma most commonly spreads to regional lymph nodes and lungs, although other sites of disease can occur. This case report presents multi-modality imaging of a 54-year-old male who developed multifocal metastatic basal cell carcinoma approximately three years after initial presentation with an ulcerated groin lesion. Ultimately, metastases included many common and uncommon sites, including lymph nodes, lung, duodenum, spleen, and adrenal glands. This case provides an interesting example of an uncommon pattern of spread and associated symptoms of treatment-resistant metastatic basal cell carcinoma.

Sonic Hedgehog Pathway Inhibition in the Treatment of Advanced Basal Cell Carcinoma.

OPINION STATEMENT: Advanced basal cell carcinoma (BCC) represents a small proportion of BCCs that are not amenable to standard therapies due to lack of efficacy, high recurrence risk, and excessive morbidity. Implication of the Sonic hedgehog (Shh) pathway in the development of BCC has led to the development of systemic Shh pathway inhibitors, providing patients with advanced BCCs new treatment options and improved survival. There are currently two Food and Drug Administration (FDA)-approved Shh inhibitors, vismodegib and sonidegib, for advanced basal cell carcinomas. Vismodegib has approval for locally advanced BCCs (laBCC) and metastatic BCC (mBCC), while sonidegib has approval for laBCC. These agents have also been used for prevention in nevoid basal cell carcinoma syndrome and as neoadjuvant therapy before surgery, and we feel that there is a growing role of Shh inhibitors in these settings. Head-to-head randomized controlled trials comparing vismodegib to sonidegib are lacking. Adverse events can limit the utility of these medications by leading to treatment discontinuation in a large proportion of patients, and it is thus essential that prescribers be able to anticipate and manage the most frequent side effects of muscle spasms, alopecia, dysgeusia, nausea, and weight loss. Other Shh inhibitors, including the antifungal itraconazole, have been investigated in small trials, but further research is needed before recommending their routine clinical use. Additionally, there are several new agents under investigation that may have improved efficacy for resistant tumors by utilizing different mechanisms of action than the two currently approved medications.

A Rare Report of Lung Metastasis of the Common Non-Melanotic Skin Cancer.

Basal cell carcinoma is a common non-melanotic skin cancer with a prevalence of 74.5%-82.6% in the Iranian population. BCC rarely metastasizes. However, metastasis can cause significant morbidity. The prevalence of metastatic basal cell carcinoma varies between 0.0028% and 0.55% of all cases. We describe a case of lung metastasis of basal cell carcinoma of the scalp.

Anti-PD-1 Therapy Leads to Near-Complete Remission in a Patient with Metastatic Basal Cell Carcinoma.

BACKGROUND: Metastatic basal cell carcinoma is rare and the prognosis is poor, with a lack of established treatment options for patients progressing on or after treatment with inhibitors of the hedgehog signaling pathway. CASE REPORT: A man with pulmonary metastases of a basal cell carcinoma progressing after treatment with sonidegib and vismodegib was started on treatment with the anti-PD-1 antibody pembrolizumab. Upon treatment, rapid clinical improvement occurred, and after 5 cycles, the computed tomography scan showed near-complete remission of all tumor lesions. The tumor cells showed the absence of PD-L1 expression. DISCUSSION: We report the first case of a patient with metastatic basal cell carcinoma experiencing an exceptional response to treatment with pembrolizumab in the absence of PD-L1 expression on the tumor cells. Immune checkpoint inhibition seems a promising treatment strategy for metastatic basal cell carcinoma. Our case suggests that the lack of PD-L1 expression does not rule out potential benefit from checkpoint inhibitor treatment.

Characterization and survival of patients with metastatic basal cell carcinoma in the Department of Veterans Affairs: a retrospective electronic health record review.

Available descriptive statistics for patients with metastatic basal cell carcinoma (mBCC) are limited. To describe disease characteristics, treatment patterns, survival outcomes, and prognostic factors of patients with mBCC, we conducted a retrospective review of electronic health records in the Department of Veterans Affairs (VA). The primary outcome was survival. Data were also collected on demographics, comorbidities, medications, and procedures. Median (IQR) age of patients with mBCC (n = 475) was 72.0 (17.0) years; 97.9% of patients were male. Almost two-thirds of patients received no initial therapy for mBCC. Median overall survival was 40.5 months [95% CI (confidence interval) 4.8-140.0], and was shorter in patients with distant metastases (17.1 months; 95% CI 2.8-58.0) than in those with regional metastases (59.4 months; 95% CI 17.6-140.0). Because the VA mBCC population is largely male and elderly, the generalizability of these results in other populations is limited and must be interpreted cautiously. Data from this large cohort add valuable information on a rare and poorly researched disease and refine previously wide estimates of overall survival for mBCC.

Treatment of advanced basal cell carcinoma with sonidegib: perspective from the 30-month update of the BOLT trial.

Sonidegib, a hedgehog pathway inhibitor, was approved by the US FDA for the treatment of locally advanced basal cell carcinoma which cannot be readily treated with surgery or radiotherapy. The pharmacology and pharmacokinetics of sonidegib will be discussed in this review. Additionally, an in-depth analysis of the BOLT trial and data from the 30-month update will be included. This will serve as an update to a previously published article which reported the 12-month update of the BOLT trial.