Anti‐programmed cell death‐1 therapy in nonmelanoma skin cancer

Dear Editor, Nonmelanoma skin cancer (NMSC) is the most common type of cancer in the white population. Approximately 75% of NMSCs are basal cell carcinomas (BCC) and 20% are squamous cell carcinomas (SCC).1 Besides environmental, phenotypic and genetic factors, immunosuppression plays a major role in the pathogenesis of NMSCs.1 After organ transplantation the incidence of SCC is increased 65‐ to 250‐fold and that of BCC 10‐fold.2 While there are various treatment options for localized NMSCs, for example surgery, radiotherapy and topical treatment, management of advanced or metastatic NMSCs remains difficult. Single‐agent or combination chemotherapy regimens, as well as antibodies targeting epidermal growth factor receptor, may be used in the treatment of advanced or metastatic SCC.3 However, the duration of response to the often toxic treatment regimens is limited in most patients. For the treatment of locally advanced or metastatic BCC, the oral hedgehog signalling pathway inhibitor vismodegib has been approved.4 Yet, resistance to vismodegib may occur, for example through Smoothened receptor mutations.5 NMSCs show ideal preconditions for immunotherapy such as tumour‐specific immune response and the presence of tumour‐associated antigens.6 Tumour nests of BCC and SCC are frequently surrounded by mononuclear cells, indicating that an immune response has been initiated to control tumour growth.6 Furthermore, the mutation load in skin cancers is high compared with other tumours.7 Various immunotherapeutic approaches have been evaluated in NMSCs.8 The first experiments were done in the 1970s with topical application of dinitrochlorobenzene and microbial antigens in combination with cytokines.8 Meanwhile, imiquimod, a local immune‐response modifier, is approved for the topical treatment of biopsy‐confirmed superficial BCC with a maximum tumour diameter of 2·0 cm on the trunk, neck or extremities, and for clinically typical, nonhyperkeratotic, nonhypertrophic actinic keratosis on the face and scalp in immunocompetent adults. Recently, immune checkpoint blockade with antibodies targeting programmed cell death (PD)‐1 and its ligand, PD‐L1, has demonstrated promising results in various tumour entities, including melanoma.9 The PD‐1/PD‐L1 pathway plays a major role in cancer immunology and immune evasion of tumour cells.10 As little is known about PD‐1 blockade in NMSCs, we present two patients with NMSCs undergoing treatment with an anti‐PD‐1 antibody. A 74‐year‐old woman presented with cutaneous SCC on the left ear in February 2014. Excision of the 9‐mm‐thick tumour was performed in April 2014. Four months later, partial resection of the left helix followed because of local tumour recurrence. Owing to another disease relapse, partial ablation of the left ear, lateral parotidectomy and selective neck dissection were performed in January 2015. With lymph node metastases confirmed in three out of 38 excised lymph nodes, tumour relapse was classified as rpT3 rpN2 (3/38) L1 R0. From February to March 2015, adjuvant radiation of the left helix and lymph nodes was conducted. However, in April 2015, the patient presented with rapidly growing nodules in the left auricular region, on the left cheek and distributed over the scalp (Fig. 1a), and histology confirmed metastatic spread. Molecular diagnostics revealed no Ras mutation but mutant tumour protein p53. As the patient declined systemic chemotherapy, treatment with cetuximab and the cyclooxygenase‐2 antagonist celecoxib was initiated in May 2015.11 Initially, it appeared as if the cutaneous metastases partially responded (Fig. 1b), but imaging in July 2015 revealed a progression of the cutaneous tumour manifestations and a tumour infiltration into the left pterygopalatine fossa (Fig. 1c). After detailed discussion, the patient consented to treatment with pembrolizumab in July 2015. Histological assessment revealed substantial immune infiltration and a significant expression of PD‐L1 on tumour and infiltrating immune cells, even before the initiation of pembrolizumab (Fig. 2a–c). Within a few weeks of treatment, a significant reduction of the extent of cutaneous tumour spread became evident (Fig. 1d). Restaging after four cycles of pembrolizumab in September 2015 confirmed a regression of the cutaneous tumour manifestations. Some remaining plaques were biopsied and a massive infiltration with immune cells was found in lymphatic vessels around some persisting tumour nodules (Fig. 2d–f). After imaging, therapy with pembrolizumab was continued until November 2015, when rapid disease progression occurred. Extent of tumour of the left temple, cheek and auricular region. (a) Before initiation of systemic treatment (recurrence after several operations and radiotherapy; May 2015); (b) after 1 month of combination therapy with cetuximab and celecoxib (initial response; June 2015); (c) after 2 months of combination therapy with cetuximab and celecoxib (progressive disease; July 2015); and (d) after four cycles of pembrolizumab (September 2015). (a, d) Haematoxylin and eosin staining and (b, e) immunohistochemical analysis of programmed cell death ligand 1 expression, and (c, f) T‐cell infiltration (CD3+) of cutaneous tissue before (July 2015; a–c) and during (September 2015; d–f) treatment with pembrolizumab. Asterisks mark tumour. Original magnification × 100 (all panels). A 62‐year‐old woman was diagnosed with a BCC measuring 8 × 8 cm on the right flank in August 2012. Postnatally, radiation of a haemangioma on the right back had been performed. According to the patient, the ulcerated tumour had been growing for about 20 years. A computed tomography (CT) scan revealed multiple suspicious intrapulmonary nodules. A lung biopsy was taken and histology confirmed basaloid tissue differentiation with an immunohistochemical profile comparable with the one found in the cutaneous lesion. Later on, molecular diagnostics on both skin and lung tissue revealed a deletion (c.2395_2401del, p.799_801del) in PTCH1 exon 15. In October 2012, therapy with vismodegib was initiated in a clinical trial. After the occurrence of new BCC lesions on the right flank, treatment within the trial was stopped. Owing to stable pulmonary disease, therapy was resumed outside the trial 2 months later. During therapy, hair loss, taste disorders and muscle cramps were reported. Vismodegib was continued until August 2014 when the performed CT scan showed a significant increase of the lung metastases over the past year. The patient was referred to the thoracic surgery department in an attempt to excise the growing metastases by performing left thoracotomy, but a resection with negative margins was estimated not to be feasible. Therefore, individualized therapy with the anti‐PD‐1 antibody pembrolizumab was initiated in November 2014 (Fig. 3a). A CT scan performed in February 2015 after four cycles revealed new and increased lung lesions (Fig. 3b); subsequently, new suspicious mediastinal and hilar lymph nodes and a progressive disease were suspected. However, a transbronchial needle aspiration of a mediastinal lymph node was without any evidence of malignancy. As the level of serum angiotensin‐converting enzyme was elevated, a sarcoid‐like lymph node reaction was assumed. Another biopsy from the lung lesions was not taken. Therapy with pembrolizumab was stopped after the fourth cycle. In April 2015, imaging revealed stable lung lesions (Fig. 3c). Decreased size of the mediastinal and hilar lymph nodes was found 3 months later (Fig. 3d). In March, May and November 2015, new cutaneous BCC lesions on the right flank were surgically excised. Lung lesions stabilized without any further therapy, showing only a discrete increase in size in the CT scans performed in July and October 2015. Histological assessment from pulmonary tumour tissue resected in September 2014 was conducted retrospectively for scientific reasons and revealed a rather low expression of PD‐L1 and only some infiltrating immune cells (Fig. 4). Computed tomography scans of the thorax, lung window. (a) Before initiation of treatment with pembrolizumab (November 2014); (b) suspicion of progressive disease with new and increased lung lesions and sarcoid‐like reaction of the mediastinal lymph nodes after four cycles of pembrolizumab (February 2015); (c) stable size of the lung lesions (April 2015); and (d) lung lesions showing discretely enhanced density and slightly increased size, as well as decreasing size of the mediastinal and hilar lymph nodes (July 2015). (a) Haematoxylin and eosin staining and (b) immunohistochemical analysis of programmed cell death ligand 1 expression, and (c) T‐cell infiltration (CD3+) of lung tissue resected in September 2014 and assessed retrospectively. Asterisks mark tumour. Original magnification × 100 (all panels). Antibodies targeting immune checkpoints have revolutionized treatment for patients with melanoma.9 A high mutation load and a pre‐existing immune response to the tumour, most likely as a result of the number of neoantigens available, seem to favour immunotherapeutic approaches.7,12 However, little is known about these highly promising treatment approaches in NMSCs. Our cases provide the first evidence for the efficacy of an anti‐PD‐1 antibody in advanced NMSC. We report a patient with advanced SCC responsive to therapy with pembrolizumab. Very recently, another case report on a male patient with unresectable cutaneous SCC treated with pembrolizumab was published.13 Significantly decreased size of the tumour tissue mass located next to the Meckel cave was reported after three cycles of pembrolizumab.13 Moreover, immune checkpoint inhibitors have been evaluated in other tumour entities with squamous differentiation. Initial studies have shown the efficacy of anti‐PD‐1/anti‐PD‐L1 antibodies in SCC of the head and neck, and anti‐PD‐1 antibodies have recently been approved for the treatment of squamous cell lung cancer.14 Furthermore, preclinical models have shown that PD‐1 blockade may delay development of murine SCC.15 In the murine model, lymphocyte infiltration within the tumour sites was enhanced after blockade of PD‐1.15 To our knowledge, this is the first case report on pembrolizumab in metastatic BCC. After an initial increase in size, lung lesions stabilized during subsequent months without continuing therapy with pembrolizumab. Concerning enlargement of the mediastinal lymph nodes, a sarcoid‐like lymph node reaction under therapy was assumed. Sarcoid‐like reactions have previously been reported during immunotherapy with the cytotoxic T lymphocyte‐associated protein 4 antibody ipilimumab.16 Altogether, owing to the still limited evidence, further reports and studies are necessary to determine the efficacy of immune checkpoint inhibition in advanced cutaneous SCC and metastatic BCC. Funding sources: none declared. Conflicts of interest: The authors have no conflicts of interests directly linked to the present work. However, most of the authors receive honoraria for talks and travel costs to congresses from different companies.