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PD1 blockade: The next step for aggressive basal cell carcinomas?

DII small banner By Warren R. Heymann, MD
April 19, 2017

I was about to start the weekend, relishing that delightful TGIF feeling, with one final task — go through lab reports in my bin. My mood became morose when I read the follow-up letter about Sue (not her real name). She is a lovely woman in her 40s who did not pay attention to a non-healing scalp lesion when she was in her 20s. Years went by, until it started growing rapidly. It proved to be a basal cell carcinoma (BCC) that eroded her parietal calvarium, extending into her brain parenchyma. She had done reasonably well with extensive surgery and radiation. Her latest MRI suggested a brain recurrence, which was subsequently confirmed by biopsy.

Sue’s surgery preceded the release of Hedgehog signaling pathway inhibitors (vismodegib and sonidegib) by a couple of years. Now, of course, all options need to be explored. These medications have been a major breakthrough for advanced or metastatic BCCs; unfortunately adverse reactions severely limit tolerability. The most frequent side effects are alopecia, muscle spasms, dysgeusia, and weight loss. This has been countered by altering the dosing regimens. Becker at al, in a retrospective study of seven patients, including one with the nevoid basal cell carcinoma syndrome, were treated with intermittent doses of vismodegib. They determined that prescribing vismodegib for only one week, followed by three weeks off the drug, and then repeating this cycle, allowed for far greater tolerability. No patients discontinued their regimen because of adverse reactions. As the authors correctly note, however, “pharmacokinetic and prospective randomized clinical trials are needed to determine the ideal intermittent regimen without causing resistance.” (1)

Response to programmed death 1 (PD-1) inhibitors has been associated with programmed death ligand 1 (PD-L1) expression levels in several cancers, Chang et al assessed PD-L1 expression in treatment-naive and treated BCCs by performing a cross-sectional study utilizing immunohistochemical stains on BCCs. Treated BCCs (including those recurrent after surgery, radiotherapy, systemic chemotherapy, or topical chemotherapy) versus treatment-naive BCCs were examined, noting the percentage of tumor cells and tumor-infiltrating lymphocytes (TILs) with PD-L1 expression, intensities of expression, and association with treatment modalities. They found that among 138 BCCs from 62 patients (43 males and 19 females) 89.9% (124 of 138) were positive for PD-L1 expression in tumor cells, and 94.9% (131 of 138) were positive for PD-L1 expression in TILs. The PD-L1 immunohistochemical staining intensity of 78 treated BCCs compared with 60 treatment-naive BCCs was significantly different in tumor cells (32% versus 7%, P = .003) and TILs (47% versus 18%, P = .008) after adjusting for the age at diagnosis. In a multivariable model adjusting for age, sex, and BCC location, PD-L1 staining intensity in tumor cells increased with the number of distinct prior treatment modalities. The authors suggested that PD-1 immunotherapy may have activity against BCCs, including in those that have been previously treated, and recommended that this hypothesis be tested in future clinical trials (2).

Lipson et al investigated the expression of PD-L1 and its association with PD-1 expression in the basal cell carcinoma tumor microenvironment. Among 40 basal cell carcinoma specimens, 9/40 (22%) demonstrated PD-L1 expression on tumor cells, and 33/40 (82%) demonstrated PD-L1 expression on tumor-infiltrating lymphocytes and associated macrophages. PD-L1 was observed in close geographic association to PD-1+ tumor infiltrating lymphocytes. Additionally, they presented the first report of an objective anti-tumor response to pembrolizumab (anti-PD-1) in a 67 year-old woman with pulmonary metastases from PD-L1 (+) basal cell carcinoma. Her disease had previously progressed through hedgehog pathway-directed therapy (including a trial of saridegib), an experimental MEK inhibitor, and a monoclonal antibody directed against insulin-like growth factor receptor-1. The patient remains in a partial response 14 months after initiation of therapy, with a clear diminution of her pulmonary metastases. The authors concluded that there is a rationale for testing anti-PD-1 therapy in patients with advanced basal cell carcinoma, either as initial treatment or after acquired resistance to hedgehog pathway inhibition (3). Ikeda at al described the molecular genetics and response of a 58 year-old man with Hedgehog inhibitor-resistant metastatic basal cell carcinoma who achieved rapid tumor regression (ongoing near complete remission at 4 months) with nivolumab (anti-PD1 antibody) (4).

Overall, PD-1/PD-L1 inhibitors are better tolerated than chemotherapy. In a systematic review, PD1/PD-L1 inhibitors demonstrated a lower risk of treatment-related symptoms (fatigue, anorexia, nausea, diarrhea, constipation, and sensory neuropathy) but have a higher risk of immune-related adverse events (5). Dermatologically, pruritus, morbilliform eruptions, vitiligo, exacerbated psoriasis, a lichenoid reactions, bullous pemphigoid, and xerostomia may be observed, as we have discussed in prior entries of DI&I (May 21, 2016 and August 25, 2016).

While this will not be the final step on the road to curing aggressive or metastatic BCCs, it is encouraging nevertheless. I just called Sue to inform her of these findings. She will discuss this with her medical and radiation oncologists. I could hear in her voice that her Easter holiday just got a little happier.

1. Becker L, et al. A novel alternate dosing of vismodegib for treatment of patients with advanced basal cell carcinomas. JAMA Dermatol 2017; 153: 321-2.
2. Chang J, et al. Association between programmed death ligand 1 expression in patients with basal cell carcinomas and the number of treatment modalities. JAMA Dermatol 2017; 153: 285-90.
3. Lipson EJ, et al. Basal cell carcinoma: PD-L1/PD-1 checkpoint expression and tumor regression after PD-1 blockade. J Immunother Cancer 2017 Mar 21; 5:23.
4. Ikeda S, et al. Metastatic basal cell carcinoma with amplification of PD-L1: exceptional response to anti-PD1 therapy. NPJ Genom Med 2016; Epub Oct 19 online.
5. Nishijima TF, et al. Safety and tolerability of PD-1/PD-L1 inhibitors compared with chemotherapy in patients with advanced cancer: A meta-analysis. Oncologist 2017; 22: 470-9.

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