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Immune Checkpoint Inhibitor Therapy as a Novel and Effective Therapy for Aggressive Cutaneous Squamous-cell Carcinoma
Research Paper
Immune Checkpoint Inhibitor Therapy as a Novel and Effective Therapy for Aggressive Cutaneous Squamous-cell Carcinoma Georgia M. Beasley,1 James Kurtz,2 Jeff Vandeusen,3 J. Harrison Howard,1 Alicia Terando,1 Doreen Agnese,1 David Liebner,3 Joanne Jeter,3 Thomas Olencki3 Abstract Programmed cell death protein 1 (PD-1) blocking agents were found to have impressive and durable response rates in 18 patients with surgically unresectable or metastatic cutaneous squamous-cell carcinoma. Background: Patients with metastatic or locally aggressive cutaneous squamous-cell carcinoma (cSCC) have historically had limited and noneffective treatment options. The mainstay treatment has been surgery, which can be disfiguring and may not be technically feasible for larger lesions. Patients and Methods: A retrospective review of 18 patients treated with nivolumab (n ¼ 17) or pembrolizumab (n ¼ 1) antieprogrammed cell death protein 1 (PD-1) inhibitors for metastatic or locally advanced cSCC from March 2015 to present was performed. Results: Three patients had metastatic disease, 5 patients had locally aggressive plus regional nodal disease, 8 patients had locally advanced disease, and 2 had multifocal skin disease. Seventeen patients had undergone at least 1 surgery, 12 also had received radiotherapy, 8 had disease that had failed to respond to other systemic treatments, and 2 had chronic lymphocytic leukemia. Of 18 patients treated, 14 had dramatic responses with improvement in clinical symptoms and impressive tumor reduction with equally impressive duration. Objectively, 4 patients had complete response, 10 had partial response, 3 had stable disease, and 1 patient had progression of disease. Three patients died, 1 from an ischemic cerebrovascular incident possibly related to treatment, 1 likely not related to neither treatment nor disease, and 1 due to disease progression. Therapy was otherwise well tolerated, and 10 patients currently continue to receive the therapy. Thirteen patients continue to have stable or no new disease at a median time of 12 months since the start of treatment. Conclusion: PD-1 blocking agents may provide clinically meaningful and palliative therapy for patients with aggressive cSCC who are not surgical candidates. Clinical Skin Cancer , Vol. -, No. -, --- ª 2017 Elsevier Inc. All rights reserved. Keywords: PD-1 therapy, Skin cancer
Introduction Cutaneous squamous-cell carcinoma (cSCC) is the second most common type of skin cancer in the United States.1 More than 1 million cases of cSCC are diagnosed in the United States each year.2 Presented in part at the Society of Surgical Oncology Annual Cancer Symposium, March 8, 2017, Seattle, WA. 1 Division of Surgical Oncology, Ohio State University Wexner Medical Center, Columbus, OH 3 Division of Medical Oncology, Ohio State University Wexner Medical Center, Columbus, OH 2 Department of Surgery, Doctors Hospital, Columbus, OH
Submitted: Apr 5, 2017; Accepted: Apr 17, 2017 Address for correspondence: Georgia M. Beasley, MD, Division of Surgical Oncology, Ohio State University Wexner Medical Center, 410 W 10th Ave, N924 Doan Hall, Columbus, OH 43210 Fax: (614) 293-3654; e-mail contact: [email protected]
2405-8645/$ - see frontmatter ª 2017 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clsc.2017.04.001
Between 40% and 50% of Americans who live to age 65 will have either basal-cell carcinoma or squamous-cell carcinoma (SCC) at least once.2,3 Conventional surgical excision is curative in as many as 95% of cases.4 However, local recurrence can be as high as 12% in high-risk patients, and metastases are reported to be about 2% to 5% overall.5,6 Effective treatment for recurrent disease, metastatic disease, or primary disease not amenable to surgery can be challenging. Radiation can control recurrent cSCC in about 50% of patients.6 However, radiation does not affect overall mortality from recurrent disease, and it certainly would not be advocated in those with metastatic disease.6 The presence of distant metastases is associated with dismal prognosis and median survival less than 2 years.5-10 Systemic chemotherapies such as cisplatin result in a complete response (CR) of only about 20% and have associated toxicities.7,8 Finally, the epidermal growth factor receptor (EGFR) inhibitor cetuximab had a response rate of only 28% when studied
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Immune Checkpoint Inhibitor Therapy in a phase 2 trial of patients with advanced cSCC, with nearly all patients experiencing relapse within 2 months.9 Thus, there persists a need for more effective and durable therapy. One well-known risk factor for the development of cSCC is immunosuppression.10 Specifically, immunosuppression after solid organ transplantation is well known to increase the risk of cSCC.11,12 Recent data also show a higher prevalence of human papillomavirus in cSCC from immunosuppressed patients compared to immunocompetent patients.13 Therapies blocking the immunosuppressive component of cSCC seem logical. Recently, immune checkpoint inhibitors such as ipilimumab, a CTLA-4 inhibitor, and antieprogrammed cell death 1 protein 1 (PD-1) agents including nivolumab and pembrolizumab have revolutionized the treatment of metastatic melanoma by blocking tumor-induced immunosuppression.14 Two trials of antiePD-1 therapy in recurrent head and neck SCC of the oral cavity, pharynx, or larynx that was not amenable to curative treatment have been published with good results.15,16 Treatment of locally recurrent and/or metastatic cSCC with PD-1 inhibitors has been tried in a few cases, but data are still extremely limited.17-19 Here we report our use of PD-1 inhibitory therapy in patients with locally aggressive or metastatic cSCC.
Methods We identified 18 patients with cSCC not amenable to additional surgical resection who were treated with nivolumab (n ¼ 17), or pembrolizumab (n ¼ 1), both PD-1 inhibitors. Data were collected about patients’ demographics, previous treatments, dates of therapy, response to therapy, Foundation One results, and follow-up. The institutional review board approved this study. Foundation One is a validated comprehensive genomic profile that interrogates the entire coding sequence of 315 cancer-related genes plus select introns from 28 genes often rearranged or altered in solid tumor cancers.20 Nivolumab was dosed at 3 mg/kg every 2 weeks, then changed to 3 mg/kg every month if a patient experienced CR or dramatic partial response (PR) with adverse effects such as fatigue. Pembrolizumab was dosed also at 2 mg/kg every 3 weeks. Patients were seen every 4 to 6 weeks to monitor toxicities with thyroidstimulating hormone and complete blood counts checked every 3 to 4 weeks. We utilized immune-related response criteria whereby CR is complete disappearance of all lesions (whether measurable or not, and no new lesions) with confirmation by a repeat, consecutive assessment no less than 4 weeks from the date first documented.21 PR is a decrease in tumor burden 50% relative to baseline confirmed by a consecutive assessment at least 4 weeks after first documentation. Stable disease (SD) does not meeting the criteria for CR or PR in the absence of progressive disease (PD). PD is an increase in tumor burden 25% relative to nadir (minimum recorded tumor burden) confirmation by a repeat, consecutive assessment no less than 4 weeks from the date first documented.21 Common Terminology Criteria for Adverse Events version 4 were used to assess toxicity.22
Results
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At time of treatment initiation, 3 patients (17%) had metastatic disease (lung), 8 (44%) patients had locally advanced disease,
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5 patients had locally advanced plus regional lymph node disease (28%), and 2 patients (11%) had multifocal squamous-cell malignancies (hands, legs, arms, and chest) not amenable to surgical resection. Patients were treated with nivolumab (n ¼ 17) or pembrolizumab (n ¼ 1). Patient characteristics are listed in Table 1. Seventeen patients had at least 2 prior surgeries, which comprised wide local excisions (n ¼ 35), lymph node dissections (n ¼ 6), parotidectomies (n ¼ 3), left eye enucleation (n ¼ 1), and left auriculectomy (n ¼ 1). Twelve patients (67%) had radiotherapy, and 8 (44%) had disease that had failed to respond to other systemic therapies, including 3 whose disease failed to respond to cetuximab. Two patients also had a history of chronic lymphocytic leukemia (CLL). The median time from initial cSCC diagnosis to treatment start was 24 months (range, 2.5 months to 14 years). Foundation One profiling was performed in 6 patients. All 6 patients had a reported TP53 mutation, 4 of 6 had a CDKN2A mutation, and 4 of 6 had reported notch1 or notch3 mutations. The median number of reported mutations per patient was 5 (range, 4-9). In total there were 4 CRs, 10 PR, 3 SD, and 1 PD, as shown in Table 2. There appeared to be no correlation between reported mutations and response in the 6 patients with available data. The median time from treatment initiation to an observed response was 2.7 months. The median duration of response (PR þ CR) was 12 months. Thirteen patients continue to have ongoing response. Overall, 10 of 18 patients continue to receive therapy, and 13 of 18 continue to experience no progression of disease at a median of 12 months since the start of treatment. Four CRs occurred in patients with locally recurrent disease at the following sites: 2 ear, 1 scalp, and 1 temple area. Examples of 2 patients with CR are shown in Figure 1. Patient 1 in Figure 1 also had concurrent CLL. Of patients with CR, 2 patients continue to receive therapy with no disease at 10 months, 1 patient with CLL stopped therapy after 7 months as a result of toxicity occurring in combination with CLL therapy but has no new cSCC disease (patient 1), and 1 patient with a CR chose to stop therapy after 13 months and has had no recurrence.
Table 1 Characteristics of 18 Patients Characteristic
Value
Gender Female
8
Male
10
Age, y, median (range) No. of previous surgeries, median (range) Time from initial diagnosis to treatment start, median (range)
77 (55-91) 3 (0-6) 24 months (2.5 months to 14 years)
Prior skin grafts
10 (59%)
Prior radiotherapy
12 (67%)
Prior systemic therapy
8 (44%)
History of lymph node involvement
6 (33%)
Metastatic disease
3 (17%)
Locally recurrent disease
8 (44%)
Multifocal disease
2 (12%)
Georgia M. Beasley et al Table 2 Response Summary in 18 Patients Response Overall response Complete response Partial response Stable disease Progressive disease Ongoing response Median duration of response
Value 14 (78%) 4 (22%) 10 (56%) 3 (17%) 1 (6%) 13 (72%) 12 months
Ten patients had a PR, including 2 patients with lung metastases, 6 patients with locally advanced disease (shoulder area [n ¼ 3], face [n ¼ 2], skull base [n ¼ 1]), and 2 patients with multifocal disease. Patient 3 had 3 prior surgeries and radiotherapy to the thigh for primary cSCC that was positive for PD-1 and negative for programmed death ligand 1 (PD-L1) by immunohistochemistry (Figure 2). Patient 3 developed multiple lung metastases had a PR, as shown in a sample lesion in Figure 2. While most of the lung lesions in patient 3 dramatically decreased, one lesion grew and was treated with stereotactic body radiotherapy. Two other patients with locally aggressive cSCC of the shoulder area had dramatic
PRs, as shown in Figures 3 and 4. Patient 4 had impressive shrinkage of tumor but developed new jugulodigastric lymphadenopathy and continues to receive nivolumab (Figure 3). Patient 4 also received stereotactic body radiotherapy to the neck for the lymphadenopathy and on recent imaging clinically has no evidence of disease. Patient 5 also had impressive tumor shrinkage of her right shoulder and axilla (Figure 4). After 7 months of therapy, patient 5 underwent radical resection and axillary lymphadenectomy; there was fibrous tissue only (no tumor) in the shoulder mass, and 1 of 9 lymph nodes contained SCC, a 1.8 cm tumor deposit with no extracapsular extension. Two patients who had multiple, primary, and rapidly recurring cSCCs of the hand, temple, face, forearms, and thighs had PR. Specifically, one patient had 21 separate cSCC on her legs, chest, and arms, had mild response to topical Efudex, developed new lesions while receiving Xeloda, and had blistering rashes with no response to cetuximab. After starting nivolumab, this patient has had no new lesions, PR of her existing lesions, and continues to receive nivolumab at 7.5 months. Of all patients with PR (n ¼ 10), 7 continue to receive therapy at a median of 15 months. Three patients had SD, and 2 of 3 patients with SD have died. One patient with locally aggressive lower extremity disease had SD for approximately 12 months, but the disease progressed; the patient
Figure 1 Examples of Complete Response. (A) Patient 1 Was a 60-year-old Man With a History of CLL and 2 Prior Surgeries for cSCC of Posterior Head. (A1) Pretreatment Photo. (A2) After 3 Months of Nivolumab. (B) Patient 2 Was a 92-year-old Man With a History of 3 Surgeries and Radiotherapy for cSCC of Face. (B1) Pretreatment Photo. (B2) After 6 Months of Nivolumab
Abbreviations: CLL ¼ chronic lymphocytic leukemia; cSCC ¼ cutaneous squamous-cell carcinoma.
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Immune Checkpoint Inhibitor Therapy Figure 2 Example of Partial Response. Patient 3 Was a 77-year-old Woman With a History of 3 Surgeries and Radiotherapy for cSCC of the Right Thigh Who Presented With a Metastatic Lung Lesion (Arrow). Tissue From the Lung Lesion Was Positive by Immunohistochemistry for PD-1 and Negative for PD-L1. (Left) Pretreatment CT Scan. (Right) CT Scan 6 Months After Nivolumab Treatment
Abbreviations: cSCC ¼ cutaneous squamous-cell carcinoma; CT ¼ computed tomography; PD-1 ¼ programmed cell death protein 1; PD-L1 ¼ programmed death ligand 1.
underwent amputation of the affected extremity, and subsequently died from causes related to disease progression. One patient with lung metastases, CLL, and a history of hemolytic anemia received nivolumab for 2 doses, had SD, but redeveloped hemolytic anemia, and nivolumab was withheld. Finally, a patient with a history of extensive head and neck surgeries, radiation, and carboplatin experienced stable recurrent disease of his zygoma 2 months after treatment and continues to receive therapy. Finally, one patient
with a history of SCC in a recurrent sacral decubitus ulcer had PD after 1 month of therapy and discontinued treatment. Treatment was generally well tolerated; toxicities are listed in Table 3. The reasons why drugs were discontinued are listed in Table 3. The most common toxicity was fatigue, which occurred in 4 patients (22%). One 88-year-old patient with a large facial lesion who had impressive tumor shrinkage (PR) had an ischemic cerebrovascular accident and subsequently died. The patient’s tumor had continued
Figure 3 Example of Partial Response. Patient 4 Was a 61-year-old Woman With 2 Prior Surgeries and Radiotherapy for cSCC of the Left Shoulder. (Top Left) Pretreatment CT Scan. (Top Right) CT Scan 2 Months After Nivolumab Treatment. (Bottom Left, A1) Pretreatment Photograph. (A2) Photograph After 3 Months of Receipt of Nivolumab Treatment. (A3) Photograph After 6 Months of Treatment
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Abbreviations: cSCC ¼ cutaneous squamous-cell carcinoma; CT ¼ computed tomography.
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Georgia M. Beasley et al Figure 4 Example of Pathology-confirmed Complete Response. Patient 5 Was a 56-year-old Woman With 2 Prior Surgeries for cSCC Involving the Clavicle and Axillary Lymph Nodes. (Left) Pretreatment CT Scan. Arrow Indicates Clavicular Involvement. (Right) CT Scan 4 Months After Nivolumab Treatment. Arrow Indicates Near Resolution of Tumor Around Clavicle. Patient Underwent Radical Excision of Left Shoulder Mass and Left Axillary Dissection After 7 Months of Nivolumab Therapy. Shoulder Mass Showed Benign Fibrous Tissue; 1 of 9 Lymph Nodes Had Squamous Cells, With a 1.8 cm Tumor Deposit With No Extracapsular Extension
Abbreviations: cSCC ¼ cutaneous squamous-cell carcinoma; CT ¼ computed tomography.
responding to nivolumab before the cerebrovascular accident. Whether or not this was a toxicity from nivolumab is difficult to determine. Another patient with a medical history of CLL and hemolytic anemia was started on nivolumab for metastatic SCC to the lungs; after 2 doses, the patient redeveloped hemolytic anemia. Because of receipt of high doses of prednisone, nivolumab was not restarted. The redevelopment of hemolytic anemia may have been related to nivolumab, although the patient did have a history of hemolytic anemia. This patient subsequently died at 85 years of age 2 months after stopping nivolumab, likely from causes related to CLL and cardiac disease. Finally, one patient who was having excellent tumor response developed grade 3 colitis was hospitalized, but the colitis responded to corticosteroids and she recovered.
Discussion The recurrence and metastases in many cancers including cSCC is mediated in part by immune suppression induced by interaction of the T-cell receptor PD-1 and its corresponding ligand expressed on tumor cells, PD-L1.23,24 Immunosuppression and cell-mediated immunity are important in the progression of cSCC, as demonstrated by the fact that solid organ transplant recipients are at 65- to 250-fold risk and patients with CLL are at 7- to 17-fold increased risk for development of aggressive cSCCs.25,26 The ligand receptor
Table 3 Toxicity Toxicity Fatigue Muscle cramps Poor visual acuity Pneumonitis Dry skin Hemolytic anemia Colitis
Grade 1 or 2 3 1 1 1 1
(17%) (6%) (6%) (6%) (6%) — —
Grade 3 1 (6%) — — — — 1 (6%) 1 (6%)
interaction of PD-1 and PD-L1 negatively regulates T-cell responses, and tumor can thereby elude immune attack.27 Nivolumab and pembrolizumab, fully human IgG4 antiePD-1 monoclonal antibodies, have shown antitumor efficacy by blocking this interaction in multiple tumor types.28-32 In the present study, we observed 78% (14/18) of heavily pretreated patients with recurrent cSCC to have dramatic tumor responses that appear durable with PD-1 antibody therapy. Other case reports that describe in total 7 patients receiving antiePD-1 therapy for cSCC report high rates of CR.18,19 Although the incidence of metastatic or locally aggressive cSCC is predicted to increase because of an aging population, the overall rate of metastatic disease is fairly low, and large trials or large patient experiences will be limited. In fact, there is a paucity of robust data even for historical platinum-based treatment or cetuximab, with some of the largest published series in 28 patients and 36 patients, respectively.9,33 Given the rarity of the disease, our series of 18 patients presented here is important. There is also a planned trial, NCT02964559, a phase 2 trial of pembrolizumab (MK-3475) in metastatic cSCC, that is accruing. Although large cohorts of patients with metastatic or locally aggressive cSCC not amenable to surgery are not common, there are data for recurrent SCC of the head and neck (oral cavity, pharynx, or larynx) and advanced squamous-cell nonesmall-cell lung cancer. A randomized open-label phase 3 trial that explored the use of nivolumab or standard single-agent systemic therapy (methotrexate, docetaxel, or cetuximab) in patients whose disease had progressed within 6 months after platinum-based chemotherapy (CheckMate 141) found the response rate was 13.3% in the nivolumab group versus 5.8% in the standard-therapy group; overall survival was significantly longer in the nivolumab group compared to standard (hazard ratio for death 0.70; 97.73% confidence interval, 0.510.96).15 In the KEYNOTE-012 trial, patients with recurrent or metastatic SCC of the head and neck were treated with pembrolizumab 10 mg/kg every 2 weeks. The proportion of patients with an overall response was 18%.16 Finally, overall survival,
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Immune Checkpoint Inhibitor Therapy response rate, and progression-free survival were significantly better with nivolumab compared to docetaxel in patients with advanced, previously treated squamous-cell lung cancer (CheckMate 017).28 Although squamous-cell cancers originating from different anatomic sites (skin, lung, mucosa) have historically not responded to similar systemic agents, antiePD-1 therapy appears effective for multiple types of SCCs. The lower response rates seen in these studies of SCC from head and neck disease and lung disease compared to our report may reflect more patients with metastatic disease in those studies, more heavily pretreated patients in those trials, or the specific biology of cSCC. The associated immunosuppression coupled with the high mutational burden associated with cSCC lend a rationale for immune checkpoint inhibitor therapy. Specifically, the clinical benefit of immune checkpoint blockade with pembrolizumab seems to be highest in tumors with high mutational loads.34,35 High somatic mutation loads were associated with prolonged progression-free survival in metastatic carcinoma patients treated with pembrolizumab.36-43 Ultraviolet radiationeinduced cSCC, especially in the metastatic setting, has been associated with high mutational burdens, including commonly TP53 mutations, inactivation of notch1 or notch2, and CDKN2A mutations, which were common in our studied population.36-43 The massive mutational burden has likely been part of the challenge in identification of driver genes or mutation-based therapies.37 Mutation-based therapy—namely the EGFR inhibitor cetuximab—had a response rate of only 28% when studied in a phase 2 trial of patients with advanced SCC.9 The mutational burden of cSCC may account for the high response rates seen in our study. Therapy was well tolerated in this study group. In a large melanoma trial (n ¼ 418), the prevalence of grade 3/4 drug-related adverse events was 11.7% in the nivolumab arm.31 Furthermore, most toxicities have been found to be reversible with treatment interruption, or corticosteroids in severe cases.44 The low toxicity profile is especially relevant in cSCC, where the majority of patients with recurrent disease are elderly, such as this study, with a median patient age of 77 years. Given the few adverse effects, there may be a role for neoadjuvant use of nivolumab when initial or repeat surgery would require a more radical approach.
Conclusion To our knowledge, this is the largest series examining the use of antiePD-1 therapy for locally aggressive or metastatic cSCC. Dramatic and durable tumor responses were observed with minimal toxicity. AntiePD-1 therapy in patients presenting with locally aggressive or metastatic cSCC should be considered.
Clinical Practice Points Surgical resection remains curative for 95% of cSCCs. PD-1 therapy may be utilized for patients with unresectable
disease or metastatic disease.
Disclosure T.O. has received clinical trial support from Pfizer, Bristol-Myers Squibb, and Tracon, and serves on the advisory board for Genetech. The other authors have stated that they have no conflict of interest.
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Skin cancer in kidney and heart transplant recipients and different long-term immunosuppressive therapy regimens. J Am Acad Dermatol 1999; 40(2 Pt 1):177-86. 12. Chockalingam R, Downing C, Tyring SK. Cutaneous squamous cell carcinomas in organ transplant recipients. J Clin Med 2015; 4:1229-39. 13. Wang J, Aldabagh B, Yu J, Arron ST. Role of human papillomavirus in cutaneous squamous cell carcinoma: a meta-analysis. J Am Acad Dermatol 2014; 70:621-9. 14. Hodi FS, Chesney J, Pavlick AC, et al. Combined nivolumab and ipilimumab versus ipilimumab alone in patients with advanced melanoma: 2-year overall survival outcomes in a multicentre, randomised, controlled, phase 2 trial. Lancet Oncol 2016; 17:1558-68. 15. Ferris RL, Blumenschein G Jr, Fayette J, et al. Nivolumab for recurrent squamouscell carcinoma of the head and neck. N Engl J Med 2016; 375:1856-67. 16. Seiwert TY, Burtness B, Mehra R, et al. Safety and clinical activity of pembrolizumab for treatment of recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-012): an open-label, multicentre, phase 1b trial. Lancet Oncol 2016; 17:956-65. 17. Winkler JK, Schneiderbauer R, Bender C, et al. Anti-PD-1 therapy in nonmelanoma skin cancer. Br J Dermatol 2017; 176:498-502. 18. Borradori L, Sutton B, Shayesteh P, Daniels GA. Rescue therapy with antiprogrammed cell death protein 1 inhibitors of advanced cutaneous squamous cell carcinoma and basosquamous carcinoma: preliminary experience in five cases. Br J Dermatol 2016; 175:1382-6. 19. Assam JH, Powell S, Spanos WC. Unresectable cutaneous squamous cell carcinoma of the forehead with mlh1 mutation showing dramatic response to programmed cell death protein 1 inhibitor therapy. Clin Skin Cancer 2016; 1: 26-9. 20. Frampton GM, Fichtenholtz A, Otto GA, et al. Development and validation of a clinical cancer genomic profiling test based on massively parallel DNA sequencing. Nat Biotechnol 2013; 31:1023-31. 21. Wolchok JD, Hoos A, O’Day S, et al. Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria. Clin Cancer Res 2009; 15:7412-20. 22. National Cancer Institute. Common Terminology Criteria for Adverse Events, version 4.0. May 28, 2009, Available at: https://ctep.cancer.gov/protocold evelopment/electronic_applications/ctc.htm. Accessed: March 6, 2016. 23. Blank C, Mackensen A. Contribution of the PD-L1/PD-1 pathway to T-cell exhaustion: an update on implications for chronic infections and tumor evasion. Cancer Immunol Immunother 2007; 56:739-45. 24. Dong H, Strome SE, Salomao DR, et al. Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med 2002; 8: 793-800. 25. 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; 43:390-4. 26. Hock BD, McIntosh ND, McKenzie JL, et al. Incidence of cutaneous squamous cell carcinoma in a New Zealand population of chronic lymphocytic leukaemia patients. Intern Med J 2016; 46:1414-21. 27. Sfanos KS, Bruno TC, Meeker AK, et al. Human prostate-infiltrating CD8þ T lymphocytes are oligoclonal and PD-1þ. Prostate 2009; 69:1694-703. 28. Brahmer J, Reckamp KL, Baas P, et al. Nivolumab versus docetaxel in advanced squamous-cell nonesmall-cell lung cancer. N Engl J Med 2015; 373:123-35. 29. Borghaei H, Paz-Ares L, Horn L, et al. Nivolumab versus docetaxel in advanced nonsquamous nonesmall-cell lung cancer. N Engl J Med 2015; 373:1627-39.
Georgia M. Beasley et al 30. González-Cao M, Arance A, Piulats JM, et al, Spanish Melanoma Group. Pembrolizumab for advanced melanoma: experience from the Spanish Expanded Access Program. Clin Transl Oncol 2017. http://dx.doi.org/10.1007/s12094-0161602-1 [Epub ahead of print]. 31. Robert C, Long GV, Brady B, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med 2015; 372:320-30. 32. Brahmer JR, Tykodi SS, Chow LQM, et al. Safety and activity of anti-PDL1 antibody in patients with advanced cancer. N Engl J Med 2012; 366: 2455-65. 33. Jarowski A, Hare R, Loud P, et al. Systemic therapy in advanced cutaneous squamous cell carcinoma (CSCC): the Roswell Park experience and a review of the literature. Am J Clin Oncol 2016; 39:545-8. 34. Le DT, Uram JN, Wang H, et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med 2015; 372:2509-20. 35. Meucci S, Keilholz U, Tinhofer I, et al. Mutational load and mutational patterns in relation to age in head and neck cancer. Oncotarget 2016; 7: 69188-99. 36. South AP, Purdie KJ, Watt SA, et al. NOTCH1 mutations occur early during cutaneous squamous cell carcinogenesis. J Invest Dermatol 2014; 134: 2630-8.
37. Harwood CA, Proby CM, Inman GJ, Leigh IM. The promise of genomics and the development of targeted therapies for cutaneous squamous cell carcinoma. Acta Derm Venereol 2016; 96:3-16. 38. Al-Rohil RN, Tarasen AJ, Carlson JA, et al. Evaluation of 122 advanced-stage cutaneous squamous cell carcinomas by comprehensive genomic profiling opens the door for new routes to targeted therapies. Cancer 2016; 122:249-57. 39. Li YY, Hanna GJ, Laga AC, et al. Genomic analysis of metastatic cutaneous squamous cell carcinoma. Clin Cancer Res 2015; 21:1447-56. 40. Kress S, Sutter C, Strickland PT, et al. Carcinogen-specific mutational pattern in the p53 gene in ultraviolet B radiationeinduced squamous cell carcinomas of mouse skin. Cancer Res 1992; 52:6400-3. 41. Okuyama R, Tagami H, Aiba S. Notch signaling: its role in epidermal homeostasis and in the pathogenesis of skin diseases. J Dermatol Sci 2008; 49:187-94. 42. Eshkoor SA, Ismail P, Rahman SA, et al. Increased protein expression of p16 and cyclin D1 in squamous cell carcinoma tissues. Biosci Trends 2009; 3:105-9. 43. Falchook GS, Leidner R, Stankevich EJ, et al. Responses of metastatic basal cell and cutaneous squamous cell carcinomas to anti-PD1 monoclonal antibody REGN2810. J Immunother Cancer 2016; 4:70. 44. Topalian SL, Hodi FS, Brahmer JL, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 2012; 366:2443-54.
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Immune Checkpoint Inhibitor Therapy as a Novel and Effective Therapy for Aggressive Cutaneous Squamous-cell Carcinoma Georgia M. Beasley,1 James Kurtz,2 Jeff Vandeusen,3 J. Harrison Howard,1 Alicia Terando,1 Doreen Agnese,1 David Liebner,3 Joanne Jeter,3 Thomas Olencki3 Abstract Programmed cell death protein 1 (PD-1) blocking agents were found to have impressive and durable response rates in 18 patients with surgically unresectable or metastatic cutaneous squamous-cell carcinoma. Background: Patients with metastatic or locally aggressive cutaneous squamous-cell carcinoma (cSCC) have historically had limited and noneffective treatment options. The mainstay treatment has been surgery, which can be disfiguring and may not be technically feasible for larger lesions. Patients and Methods: A retrospective review of 18 patients treated with nivolumab (n ¼ 17) or pembrolizumab (n ¼ 1) antieprogrammed cell death protein 1 (PD-1) inhibitors for metastatic or locally advanced cSCC from March 2015 to present was performed. Results: Three patients had metastatic disease, 5 patients had locally aggressive plus regional nodal disease, 8 patients had locally advanced disease, and 2 had multifocal skin disease. Seventeen patients had undergone at least 1 surgery, 12 also had received radiotherapy, 8 had disease that had failed to respond to other systemic treatments, and 2 had chronic lymphocytic leukemia. Of 18 patients treated, 14 had dramatic responses with improvement in clinical symptoms and impressive tumor reduction with equally impressive duration. Objectively, 4 patients had complete response, 10 had partial response, 3 had stable disease, and 1 patient had progression of disease. Three patients died, 1 from an ischemic cerebrovascular incident possibly related to treatment, 1 likely not related to neither treatment nor disease, and 1 due to disease progression. Therapy was otherwise well tolerated, and 10 patients currently continue to receive the therapy. Thirteen patients continue to have stable or no new disease at a median time of 12 months since the start of treatment. Conclusion: PD-1 blocking agents may provide clinically meaningful and palliative therapy for patients with aggressive cSCC who are not surgical candidates. Clinical Skin Cancer , Vol. -, No. -, --- ª 2017 Elsevier Inc. All rights reserved. Keywords: PD-1 therapy, Skin cancer
Introduction Cutaneous squamous-cell carcinoma (cSCC) is the second most common type of skin cancer in the United States.1 More than 1 million cases of cSCC are diagnosed in the United States each year.2 Presented in part at the Society of Surgical Oncology Annual Cancer Symposium, March 8, 2017, Seattle, WA. 1 Division of Surgical Oncology, Ohio State University Wexner Medical Center, Columbus, OH 3 Division of Medical Oncology, Ohio State University Wexner Medical Center, Columbus, OH 2 Department of Surgery, Doctors Hospital, Columbus, OH
Submitted: Apr 5, 2017; Accepted: Apr 17, 2017 Address for correspondence: Georgia M. Beasley, MD, Division of Surgical Oncology, Ohio State University Wexner Medical Center, 410 W 10th Ave, N924 Doan Hall, Columbus, OH 43210 Fax: (614) 293-3654; e-mail contact: [email protected]
2405-8645/$ - see frontmatter ª 2017 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clsc.2017.04.001
Between 40% and 50% of Americans who live to age 65 will have either basal-cell carcinoma or squamous-cell carcinoma (SCC) at least once.2,3 Conventional surgical excision is curative in as many as 95% of cases.4 However, local recurrence can be as high as 12% in high-risk patients, and metastases are reported to be about 2% to 5% overall.5,6 Effective treatment for recurrent disease, metastatic disease, or primary disease not amenable to surgery can be challenging. Radiation can control recurrent cSCC in about 50% of patients.6 However, radiation does not affect overall mortality from recurrent disease, and it certainly would not be advocated in those with metastatic disease.6 The presence of distant metastases is associated with dismal prognosis and median survival less than 2 years.5-10 Systemic chemotherapies such as cisplatin result in a complete response (CR) of only about 20% and have associated toxicities.7,8 Finally, the epidermal growth factor receptor (EGFR) inhibitor cetuximab had a response rate of only 28% when studied
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Immune Checkpoint Inhibitor Therapy in a phase 2 trial of patients with advanced cSCC, with nearly all patients experiencing relapse within 2 months.9 Thus, there persists a need for more effective and durable therapy. One well-known risk factor for the development of cSCC is immunosuppression.10 Specifically, immunosuppression after solid organ transplantation is well known to increase the risk of cSCC.11,12 Recent data also show a higher prevalence of human papillomavirus in cSCC from immunosuppressed patients compared to immunocompetent patients.13 Therapies blocking the immunosuppressive component of cSCC seem logical. Recently, immune checkpoint inhibitors such as ipilimumab, a CTLA-4 inhibitor, and antieprogrammed cell death 1 protein 1 (PD-1) agents including nivolumab and pembrolizumab have revolutionized the treatment of metastatic melanoma by blocking tumor-induced immunosuppression.14 Two trials of antiePD-1 therapy in recurrent head and neck SCC of the oral cavity, pharynx, or larynx that was not amenable to curative treatment have been published with good results.15,16 Treatment of locally recurrent and/or metastatic cSCC with PD-1 inhibitors has been tried in a few cases, but data are still extremely limited.17-19 Here we report our use of PD-1 inhibitory therapy in patients with locally aggressive or metastatic cSCC.
Methods We identified 18 patients with cSCC not amenable to additional surgical resection who were treated with nivolumab (n ¼ 17), or pembrolizumab (n ¼ 1), both PD-1 inhibitors. Data were collected about patients’ demographics, previous treatments, dates of therapy, response to therapy, Foundation One results, and follow-up. The institutional review board approved this study. Foundation One is a validated comprehensive genomic profile that interrogates the entire coding sequence of 315 cancer-related genes plus select introns from 28 genes often rearranged or altered in solid tumor cancers.20 Nivolumab was dosed at 3 mg/kg every 2 weeks, then changed to 3 mg/kg every month if a patient experienced CR or dramatic partial response (PR) with adverse effects such as fatigue. Pembrolizumab was dosed also at 2 mg/kg every 3 weeks. Patients were seen every 4 to 6 weeks to monitor toxicities with thyroidstimulating hormone and complete blood counts checked every 3 to 4 weeks. We utilized immune-related response criteria whereby CR is complete disappearance of all lesions (whether measurable or not, and no new lesions) with confirmation by a repeat, consecutive assessment no less than 4 weeks from the date first documented.21 PR is a decrease in tumor burden 50% relative to baseline confirmed by a consecutive assessment at least 4 weeks after first documentation. Stable disease (SD) does not meeting the criteria for CR or PR in the absence of progressive disease (PD). PD is an increase in tumor burden 25% relative to nadir (minimum recorded tumor burden) confirmation by a repeat, consecutive assessment no less than 4 weeks from the date first documented.21 Common Terminology Criteria for Adverse Events version 4 were used to assess toxicity.22
Results
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At time of treatment initiation, 3 patients (17%) had metastatic disease (lung), 8 (44%) patients had locally advanced disease,
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5 patients had locally advanced plus regional lymph node disease (28%), and 2 patients (11%) had multifocal squamous-cell malignancies (hands, legs, arms, and chest) not amenable to surgical resection. Patients were treated with nivolumab (n ¼ 17) or pembrolizumab (n ¼ 1). Patient characteristics are listed in Table 1. Seventeen patients had at least 2 prior surgeries, which comprised wide local excisions (n ¼ 35), lymph node dissections (n ¼ 6), parotidectomies (n ¼ 3), left eye enucleation (n ¼ 1), and left auriculectomy (n ¼ 1). Twelve patients (67%) had radiotherapy, and 8 (44%) had disease that had failed to respond to other systemic therapies, including 3 whose disease failed to respond to cetuximab. Two patients also had a history of chronic lymphocytic leukemia (CLL). The median time from initial cSCC diagnosis to treatment start was 24 months (range, 2.5 months to 14 years). Foundation One profiling was performed in 6 patients. All 6 patients had a reported TP53 mutation, 4 of 6 had a CDKN2A mutation, and 4 of 6 had reported notch1 or notch3 mutations. The median number of reported mutations per patient was 5 (range, 4-9). In total there were 4 CRs, 10 PR, 3 SD, and 1 PD, as shown in Table 2. There appeared to be no correlation between reported mutations and response in the 6 patients with available data. The median time from treatment initiation to an observed response was 2.7 months. The median duration of response (PR þ CR) was 12 months. Thirteen patients continue to have ongoing response. Overall, 10 of 18 patients continue to receive therapy, and 13 of 18 continue to experience no progression of disease at a median of 12 months since the start of treatment. Four CRs occurred in patients with locally recurrent disease at the following sites: 2 ear, 1 scalp, and 1 temple area. Examples of 2 patients with CR are shown in Figure 1. Patient 1 in Figure 1 also had concurrent CLL. Of patients with CR, 2 patients continue to receive therapy with no disease at 10 months, 1 patient with CLL stopped therapy after 7 months as a result of toxicity occurring in combination with CLL therapy but has no new cSCC disease (patient 1), and 1 patient with a CR chose to stop therapy after 13 months and has had no recurrence.
Table 1 Characteristics of 18 Patients Characteristic
Value
Gender Female
8
Male
10
Age, y, median (range) No. of previous surgeries, median (range) Time from initial diagnosis to treatment start, median (range)
77 (55-91) 3 (0-6) 24 months (2.5 months to 14 years)
Prior skin grafts
10 (59%)
Prior radiotherapy
12 (67%)
Prior systemic therapy
8 (44%)
History of lymph node involvement
6 (33%)
Metastatic disease
3 (17%)
Locally recurrent disease
8 (44%)
Multifocal disease
2 (12%)
Georgia M. Beasley et al Table 2 Response Summary in 18 Patients Response Overall response Complete response Partial response Stable disease Progressive disease Ongoing response Median duration of response
Value 14 (78%) 4 (22%) 10 (56%) 3 (17%) 1 (6%) 13 (72%) 12 months
Ten patients had a PR, including 2 patients with lung metastases, 6 patients with locally advanced disease (shoulder area [n ¼ 3], face [n ¼ 2], skull base [n ¼ 1]), and 2 patients with multifocal disease. Patient 3 had 3 prior surgeries and radiotherapy to the thigh for primary cSCC that was positive for PD-1 and negative for programmed death ligand 1 (PD-L1) by immunohistochemistry (Figure 2). Patient 3 developed multiple lung metastases had a PR, as shown in a sample lesion in Figure 2. While most of the lung lesions in patient 3 dramatically decreased, one lesion grew and was treated with stereotactic body radiotherapy. Two other patients with locally aggressive cSCC of the shoulder area had dramatic
PRs, as shown in Figures 3 and 4. Patient 4 had impressive shrinkage of tumor but developed new jugulodigastric lymphadenopathy and continues to receive nivolumab (Figure 3). Patient 4 also received stereotactic body radiotherapy to the neck for the lymphadenopathy and on recent imaging clinically has no evidence of disease. Patient 5 also had impressive tumor shrinkage of her right shoulder and axilla (Figure 4). After 7 months of therapy, patient 5 underwent radical resection and axillary lymphadenectomy; there was fibrous tissue only (no tumor) in the shoulder mass, and 1 of 9 lymph nodes contained SCC, a 1.8 cm tumor deposit with no extracapsular extension. Two patients who had multiple, primary, and rapidly recurring cSCCs of the hand, temple, face, forearms, and thighs had PR. Specifically, one patient had 21 separate cSCC on her legs, chest, and arms, had mild response to topical Efudex, developed new lesions while receiving Xeloda, and had blistering rashes with no response to cetuximab. After starting nivolumab, this patient has had no new lesions, PR of her existing lesions, and continues to receive nivolumab at 7.5 months. Of all patients with PR (n ¼ 10), 7 continue to receive therapy at a median of 15 months. Three patients had SD, and 2 of 3 patients with SD have died. One patient with locally aggressive lower extremity disease had SD for approximately 12 months, but the disease progressed; the patient
Figure 1 Examples of Complete Response. (A) Patient 1 Was a 60-year-old Man With a History of CLL and 2 Prior Surgeries for cSCC of Posterior Head. (A1) Pretreatment Photo. (A2) After 3 Months of Nivolumab. (B) Patient 2 Was a 92-year-old Man With a History of 3 Surgeries and Radiotherapy for cSCC of Face. (B1) Pretreatment Photo. (B2) After 6 Months of Nivolumab
Abbreviations: CLL ¼ chronic lymphocytic leukemia; cSCC ¼ cutaneous squamous-cell carcinoma.
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Immune Checkpoint Inhibitor Therapy Figure 2 Example of Partial Response. Patient 3 Was a 77-year-old Woman With a History of 3 Surgeries and Radiotherapy for cSCC of the Right Thigh Who Presented With a Metastatic Lung Lesion (Arrow). Tissue From the Lung Lesion Was Positive by Immunohistochemistry for PD-1 and Negative for PD-L1. (Left) Pretreatment CT Scan. (Right) CT Scan 6 Months After Nivolumab Treatment
Abbreviations: cSCC ¼ cutaneous squamous-cell carcinoma; CT ¼ computed tomography; PD-1 ¼ programmed cell death protein 1; PD-L1 ¼ programmed death ligand 1.
underwent amputation of the affected extremity, and subsequently died from causes related to disease progression. One patient with lung metastases, CLL, and a history of hemolytic anemia received nivolumab for 2 doses, had SD, but redeveloped hemolytic anemia, and nivolumab was withheld. Finally, a patient with a history of extensive head and neck surgeries, radiation, and carboplatin experienced stable recurrent disease of his zygoma 2 months after treatment and continues to receive therapy. Finally, one patient
with a history of SCC in a recurrent sacral decubitus ulcer had PD after 1 month of therapy and discontinued treatment. Treatment was generally well tolerated; toxicities are listed in Table 3. The reasons why drugs were discontinued are listed in Table 3. The most common toxicity was fatigue, which occurred in 4 patients (22%). One 88-year-old patient with a large facial lesion who had impressive tumor shrinkage (PR) had an ischemic cerebrovascular accident and subsequently died. The patient’s tumor had continued
Figure 3 Example of Partial Response. Patient 4 Was a 61-year-old Woman With 2 Prior Surgeries and Radiotherapy for cSCC of the Left Shoulder. (Top Left) Pretreatment CT Scan. (Top Right) CT Scan 2 Months After Nivolumab Treatment. (Bottom Left, A1) Pretreatment Photograph. (A2) Photograph After 3 Months of Receipt of Nivolumab Treatment. (A3) Photograph After 6 Months of Treatment
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Abbreviations: cSCC ¼ cutaneous squamous-cell carcinoma; CT ¼ computed tomography.
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Georgia M. Beasley et al Figure 4 Example of Pathology-confirmed Complete Response. Patient 5 Was a 56-year-old Woman With 2 Prior Surgeries for cSCC Involving the Clavicle and Axillary Lymph Nodes. (Left) Pretreatment CT Scan. Arrow Indicates Clavicular Involvement. (Right) CT Scan 4 Months After Nivolumab Treatment. Arrow Indicates Near Resolution of Tumor Around Clavicle. Patient Underwent Radical Excision of Left Shoulder Mass and Left Axillary Dissection After 7 Months of Nivolumab Therapy. Shoulder Mass Showed Benign Fibrous Tissue; 1 of 9 Lymph Nodes Had Squamous Cells, With a 1.8 cm Tumor Deposit With No Extracapsular Extension
Abbreviations: cSCC ¼ cutaneous squamous-cell carcinoma; CT ¼ computed tomography.
responding to nivolumab before the cerebrovascular accident. Whether or not this was a toxicity from nivolumab is difficult to determine. Another patient with a medical history of CLL and hemolytic anemia was started on nivolumab for metastatic SCC to the lungs; after 2 doses, the patient redeveloped hemolytic anemia. Because of receipt of high doses of prednisone, nivolumab was not restarted. The redevelopment of hemolytic anemia may have been related to nivolumab, although the patient did have a history of hemolytic anemia. This patient subsequently died at 85 years of age 2 months after stopping nivolumab, likely from causes related to CLL and cardiac disease. Finally, one patient who was having excellent tumor response developed grade 3 colitis was hospitalized, but the colitis responded to corticosteroids and she recovered.
Discussion The recurrence and metastases in many cancers including cSCC is mediated in part by immune suppression induced by interaction of the T-cell receptor PD-1 and its corresponding ligand expressed on tumor cells, PD-L1.23,24 Immunosuppression and cell-mediated immunity are important in the progression of cSCC, as demonstrated by the fact that solid organ transplant recipients are at 65- to 250-fold risk and patients with CLL are at 7- to 17-fold increased risk for development of aggressive cSCCs.25,26 The ligand receptor
Table 3 Toxicity Toxicity Fatigue Muscle cramps Poor visual acuity Pneumonitis Dry skin Hemolytic anemia Colitis
Grade 1 or 2 3 1 1 1 1
(17%) (6%) (6%) (6%) (6%) — —
Grade 3 1 (6%) — — — — 1 (6%) 1 (6%)
interaction of PD-1 and PD-L1 negatively regulates T-cell responses, and tumor can thereby elude immune attack.27 Nivolumab and pembrolizumab, fully human IgG4 antiePD-1 monoclonal antibodies, have shown antitumor efficacy by blocking this interaction in multiple tumor types.28-32 In the present study, we observed 78% (14/18) of heavily pretreated patients with recurrent cSCC to have dramatic tumor responses that appear durable with PD-1 antibody therapy. Other case reports that describe in total 7 patients receiving antiePD-1 therapy for cSCC report high rates of CR.18,19 Although the incidence of metastatic or locally aggressive cSCC is predicted to increase because of an aging population, the overall rate of metastatic disease is fairly low, and large trials or large patient experiences will be limited. In fact, there is a paucity of robust data even for historical platinum-based treatment or cetuximab, with some of the largest published series in 28 patients and 36 patients, respectively.9,33 Given the rarity of the disease, our series of 18 patients presented here is important. There is also a planned trial, NCT02964559, a phase 2 trial of pembrolizumab (MK-3475) in metastatic cSCC, that is accruing. Although large cohorts of patients with metastatic or locally aggressive cSCC not amenable to surgery are not common, there are data for recurrent SCC of the head and neck (oral cavity, pharynx, or larynx) and advanced squamous-cell nonesmall-cell lung cancer. A randomized open-label phase 3 trial that explored the use of nivolumab or standard single-agent systemic therapy (methotrexate, docetaxel, or cetuximab) in patients whose disease had progressed within 6 months after platinum-based chemotherapy (CheckMate 141) found the response rate was 13.3% in the nivolumab group versus 5.8% in the standard-therapy group; overall survival was significantly longer in the nivolumab group compared to standard (hazard ratio for death 0.70; 97.73% confidence interval, 0.510.96).15 In the KEYNOTE-012 trial, patients with recurrent or metastatic SCC of the head and neck were treated with pembrolizumab 10 mg/kg every 2 weeks. The proportion of patients with an overall response was 18%.16 Finally, overall survival,
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Immune Checkpoint Inhibitor Therapy response rate, and progression-free survival were significantly better with nivolumab compared to docetaxel in patients with advanced, previously treated squamous-cell lung cancer (CheckMate 017).28 Although squamous-cell cancers originating from different anatomic sites (skin, lung, mucosa) have historically not responded to similar systemic agents, antiePD-1 therapy appears effective for multiple types of SCCs. The lower response rates seen in these studies of SCC from head and neck disease and lung disease compared to our report may reflect more patients with metastatic disease in those studies, more heavily pretreated patients in those trials, or the specific biology of cSCC. The associated immunosuppression coupled with the high mutational burden associated with cSCC lend a rationale for immune checkpoint inhibitor therapy. Specifically, the clinical benefit of immune checkpoint blockade with pembrolizumab seems to be highest in tumors with high mutational loads.34,35 High somatic mutation loads were associated with prolonged progression-free survival in metastatic carcinoma patients treated with pembrolizumab.36-43 Ultraviolet radiationeinduced cSCC, especially in the metastatic setting, has been associated with high mutational burdens, including commonly TP53 mutations, inactivation of notch1 or notch2, and CDKN2A mutations, which were common in our studied population.36-43 The massive mutational burden has likely been part of the challenge in identification of driver genes or mutation-based therapies.37 Mutation-based therapy—namely the EGFR inhibitor cetuximab—had a response rate of only 28% when studied in a phase 2 trial of patients with advanced SCC.9 The mutational burden of cSCC may account for the high response rates seen in our study. Therapy was well tolerated in this study group. In a large melanoma trial (n ¼ 418), the prevalence of grade 3/4 drug-related adverse events was 11.7% in the nivolumab arm.31 Furthermore, most toxicities have been found to be reversible with treatment interruption, or corticosteroids in severe cases.44 The low toxicity profile is especially relevant in cSCC, where the majority of patients with recurrent disease are elderly, such as this study, with a median patient age of 77 years. Given the few adverse effects, there may be a role for neoadjuvant use of nivolumab when initial or repeat surgery would require a more radical approach.
Conclusion To our knowledge, this is the largest series examining the use of antiePD-1 therapy for locally aggressive or metastatic cSCC. Dramatic and durable tumor responses were observed with minimal toxicity. AntiePD-1 therapy in patients presenting with locally aggressive or metastatic cSCC should be considered.
Clinical Practice Points Surgical resection remains curative for 95% of cSCCs. PD-1 therapy may be utilized for patients with unresectable
disease or metastatic disease.
Disclosure T.O. has received clinical trial support from Pfizer, Bristol-Myers Squibb, and Tracon, and serves on the advisory board for Genetech. The other authors have stated that they have no conflict of interest.
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37. Harwood CA, Proby CM, Inman GJ, Leigh IM. The promise of genomics and the development of targeted therapies for cutaneous squamous cell carcinoma. Acta Derm Venereol 2016; 96:3-16. 38. Al-Rohil RN, Tarasen AJ, Carlson JA, et al. Evaluation of 122 advanced-stage cutaneous squamous cell carcinomas by comprehensive genomic profiling opens the door for new routes to targeted therapies. Cancer 2016; 122:249-57. 39. Li YY, Hanna GJ, Laga AC, et al. Genomic analysis of metastatic cutaneous squamous cell carcinoma. Clin Cancer Res 2015; 21:1447-56. 40. Kress S, Sutter C, Strickland PT, et al. Carcinogen-specific mutational pattern in the p53 gene in ultraviolet B radiationeinduced squamous cell carcinomas of mouse skin. Cancer Res 1992; 52:6400-3. 41. Okuyama R, Tagami H, Aiba S. Notch signaling: its role in epidermal homeostasis and in the pathogenesis of skin diseases. J Dermatol Sci 2008; 49:187-94. 42. Eshkoor SA, Ismail P, Rahman SA, et al. Increased protein expression of p16 and cyclin D1 in squamous cell carcinoma tissues. Biosci Trends 2009; 3:105-9. 43. Falchook GS, Leidner R, Stankevich EJ, et al. Responses of metastatic basal cell and cutaneous squamous cell carcinomas to anti-PD1 monoclonal antibody REGN2810. J Immunother Cancer 2016; 4:70. 44. Topalian SL, Hodi FS, Brahmer JL, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 2012; 366:2443-54.
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