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Phase II study of single-agent panitumumab in patients with incurable cutaneous squamous cell carcinoma
Annals of Oncology Advance Access published August 4, 2014
1 Phase II study of single agent panitumumab in patients with incurable cutaneous squamous cell carcinoma
Key Message: "This is a single institution phase II study of single agent panitumumab in patients with incurable cutaneous squamous cell carcinoma. Results show that panitumumab is safe and effective in this disease, even in a previously extensively pre‐treated cohort."
© The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].
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M. C. Foote1, M. McGrath2, A. Guminski3, B. G. M. Hughes4, J. Meakin5, D. Thomson2, D. Zarate6, F. Simpson7, S. V. Porceddu1 1 Department Radiation Oncology, Princess Alexandra Hospital, Brisbane, Australia 2 Department Medical Oncology, Princess Alexandra Hospital, Brisbane, Australia 3 Department Medical Oncology, Royal North Shore Hospital, Sydney, Australia 4 Department Medical Oncology, Royal Brisbane and Womens Hospital, Brisbane, Australia 5 Research Unit, Cancer Services, Princess Alexandra Hospital, Brisbane, Australia 6 Queensland Cancer Control Analysis Team, Queensland Health, Brisbane, Australia 7 Diamantina Institute, University of Queensland, Brisbane, Australia Corresponding author: Dr. Matthew Foote, Princess Alexandra Hospital, Radiation Oncology, 199 Ipswich Rd, Woolloongabba, Brisbane, Queensland, 4102, Australia, Phone: +61 7 3176 3067, Fax: +61 7 3176 1983, [email protected]
2 Abstract Background Although advanced cutaneous squamous cell carcinoma (CSCC) is quite common there are few prospective trials regarding its optimal management. This study evaluated the efficacy and safety of single agent panitumumab in the treatment of patients with CSCC not suitable for local therapy. Patients and Methods
Results Between May 2010 and May 2012, 16 patients were recruited. Fourteen patients were male and the median age was 68 years. Fifteen patients had locoregionally advanced or recurrent disease with 14 patients receiving previous radiotherapy and 7 patients receiving previous cytotoxic chemotherapy. The best ORR (PR or CR) was 31% (3/16 PR, 2/16 CR) with a further 6 of 16 patients achieving SD. The median PFS and OS were 8 and 11 months respectively. Grade 3 or 4 events were observed in five patients (four being skin toxicity) with one patient ceasing due to skin toxicity. With a median follow up of 24 months, 10 patients died due to progressive disease, 6 are alive, one patient with no evidence of disease at the time of analysis. Conclusions Single agent panitumumab is safe and effective in the management of patients with advanced CSCC even in a previously extensively pre-treated cohort. Key words – cutaneous, squamous cell carcinoma, panitumumab
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Sixteen patients received single agent panitumumab at a dose of 6 mg/kg repeated every two weeks for a minimum of three cycles and continued until progression, a maximum of nine cycles or dose limiting toxicity. The primary endpoint was the best overall response rate (ORR) as assessed by Response Evaluation Criteria in Solid Tumours (RECIST version 1.1) criteria. Secondary endpoints included evaluation of safety, toxicity and progression free survival.
3 Background Non-melanoma skin cancer (NMSC) is the most common malignancy worldwide and a consequence of chronic exposure to the mutagenic solar ultraviolet radiation.[1] The sun-exposed head and neck is the most common site (70% to 80%) for the development of a NMSC, and populations of fair-skin individuals living in countries close to the equator and tropics are more commonly affected. Since the 1960s, the worldwide incidence of NMSC has markedly increased and continues to rise.[2] Australia has the highest incidence of NMSC in the world, with over 300,000 patients diagnosed per year.[3]
Investigation of systemic therapy for this disease has been limited to few prospective trials. Systemic therapies that have been used to treat patients with advanced CSCC include cytotoxic chemotherapy (cisplatin, 5-flurouracil [5-FU], bleomycin and doxorubicin), 13-cis-retinoic acid (13-cRA), and immunotherapy (interferon α-2-a [IFN- α]. [5-10] Although these agents have shown activity in the metastatic setting, the toxic effects of these combinations make their use in this population, which is often elderly, limited. The epidermal growth factor receptor (EGFR) is highly expressed in many epithelial cancers including CSCC.[11, 12] Although tumour EGFR expression correlates inversely with clinical outcome[13], the degree of over expression does not seem to correlate with the effectiveness of EGFR inhibitors and several mechanisms of resistance are under investigation.[14-16] Irrespective, inhibition of this signal transduction pathway in CSCC has been evaluated with the tyrosine kinase inhibitor, gefitinib [17] and humanized monoclonal antibody, cetuximab.[18] These agents appear efficacious and tolerable making them a good therapeutic option particularly in the elderly. Panitumumab is a high affinity human IgG2 monoclonal antibody directed against human EGFR.[19] To date there are no studies evaluating panitumumab in advanced CSCC. We therefore aimed to investigate the efficacy of single agent panitumumab in patients with incurable cutaneous squamous cell carcinoma (CSCC), not suitable for local therapy or chemotherapy.
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Although only 5% will become locally advanced, recur or metastasize this still represents a significant problem. In the United States, at least 2500 people die annually from the consequences of advanced cutaneous squamous cell carcinoma (CSCC), usually as a result of developing metastatic nodal disease.[4] Despite aggressive treatment with surgery and radiotherapy a number of these patients will fail or develop incurable distant metastatic disease.
4 Patients and Methods Study Design and Objectives The trial was an open label, uncontrolled, single centre prospective phase II study conducted at the Princess Alexandra Hospital, Brisbane, Australia. The primary objective was to investigate the efficacy of panitumumab as a single agent as determined by the best overall response observed, according to Response Evaluation Criteria in Solid Tumours (RECIST version 1.1) criteria, following evaluation of all response assessments per time point.
Patient Eligibility Eligible patients had histopathological or cytopathological confirmation of locally advanced, metastatic or recurrent CSCC not suitable for curative therapy with a life expectancy of greater than three months and adequate haematological, hepatic and renal function. Other eligibility included ≥ 18 years of age, Eastern Collaborative Oncology Group (ECOG) performance status 0-2, and the presence of at least one target lesion measurable by RECIST criteria. Patients could previously have received radiotherapy or cytotoxic chemotherapy. Exclusions included patients receiving concurrent chemotherapy or radiotherapy, known hypersensitivity to EGFR inhibitors, clinically significant cardiovascular disease (including myocardial infarction, unstable angina, symptomatic congestive heart failure and serious uncontrolled cardiac arrhythmia) 1 year before enrolment/randomization and a history of interstitial lung disease, pneumonitis or pulmonary fibrosis or evidence of interstitial lung disease on previous imaging. Study Treatment Eligible patients commenced treatment within two weeks of signing informed consent. No premedication or test dose of panitumumab was required. Panitumumab was administered at a dose of 6 mg/kg, delivered via intravenous infusion over 60 minutes. Panitumumab was delivered on a second weekly basis until documented progressive disease using RECIST criteria, dose-limiting toxicity or a maximum of 9 cycles reached. Panitumumab dose modifications and treatment interruptions were allowed for dermatological toxicity Grade 3 CTCAE V3.0 and higher.
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Secondary endpoints included treatment related acute and late toxicity according to the Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0; safety based on 80% of patients commencing therapy successfully completing treatment with no treatment-related life threatening toxicity or dose limiting toxicity other than skin toxicity; progression free survival (PFS) reported from the time of first study treatment to the date of disease progression of the primary, nodal or primary & nodal disease following the best treatment response, or the development of distant metastases or death.
5 Assessment All patient baseline assessments were undertaken within two weeks of commencing study treatment. Baseline assessment included staging, general physical examination, skin assessment, complete blood count, serum biochemistry and initial tumour biopsy for patients participating in the optional translational study (results to be published separately).
Response assessment (according to RECIST version 1.1) was undertaken after every three cycles of panitumumab by an independent radiologist. An investigator blinded to the clinical outcomes retrospectively reviewed the assessments and if there was discordance the case was adjudicated on by another radiologist blinded to previous assessments. At the time of first documented progression or completion of nine cycles of panitumumab patients had 3 monthly response assessments in the first year followed by four monthly for a minimum of 18 months from commencement of treatment or until progression or death. Statistical Analyses All registered patients were accounted for in the analysis and patients who commenced any therapy were assessed for the main endpoints of efficacy and safety. Target accrual of 16 patients was based on 4 patients (25%) exhibiting either partial or complete response, allowing a response rate confidence interval estimate of 7% to 52% (based on 95% two-tailed binomial limits). Since the response rate for untreated patients is 0% a therapy with 7% response rate was considered potentially clinical valuable. Statistical analyses were performed using Stata (StataCorp, TX). Median follow-up time was calculated using the reverse Kaplan-Meier method. Survival was measured through the Kaplan-Meier estimator calculated from the date of registration to allcause death for overall survival (OS) and earliest progression for progression-free survival (PFS).
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Staging included clinical examination and computer tomography (CT) scans of the head and neck, chest and abdomen. Both Magnetic Resonance Imaging (MRI) scanning and/or Positron Emission Tomography (PET) staging were used at baseline at investigators discretion. On follow-up for response assessment both clinical examination (for dermal disease only) and CT scanning were used but the use of MRI or PET was discretionary.
6 Results A total of 16 patients were accrued between May 2010 and May 2012. All patients were included in the subsequent analyses. Patient Characteristics Of the 16 patients recruited, 14 were male and the median age 68 years. Fifteen (15/16) patients had locoregionally advanced or recurrent disease. Two of these patients also had documented distant metastatic disease. One patient had distant metastatic disease only.
Response Rates The best overall response rate (partial or complete response, PR or CR) was 31% (95% CI 11-59%; 3/16 PR, 2/16 CR) with a further 6 of 16 patients achieving stable disease. The duration of overall response was a median 6 months (range 5-17.5 months). The 6 week disease control rate (DCR) was 69% (11 of 16 patients). Of the patients who achieved a complete response, one was in a site of distant nodal disease and the other was in both recurrent locoregional (in-transit dermal) disease and adjacent nodal disease. This was confirmed by histological examination in the latter patient. One of these patients relapsed with further distant metastatic disease at 16 months since the last dose of panitumumab. The other patient with a complete response, received seven infusions of panitumumab, and had no evidence of disease at 24 months since the last dose. Measures of Survival With a median follow up of 24 months, 10 patients died due to progressive disease, six were alive, one patient with no evidence of disease at the time of analysis. The median OS was 11 months and median PFS was 8 months (Figure 1). For those patients who experienced a grade 3 or 4 panitumumab related skin toxicity there was no relationship between this, duration of response, PFS or OS. Panitumumab Compliance and Toxicity Of the 16 patients who commenced treatment, 9 completed all 9 planned infusions of panitumumab. Six patients ceased due to progression of disease. One patient refused further treatment after seven infusions due to Grade 3 skin toxicity. This patient achieved a complete response and remained disease free at the time of analysis.
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Fourteen patients had received previous radiotherapy and six patients previous cytotoxic chemotherapy. Three patients received cisplatin concurrently with radiotherapy in the adjuvant setting after resection of high risk locoregional disease. Two patients received carboplatin/5-flurouracil for relapsed locoregional and distant disease. One patient received topical mitomycin C adjuvantly for presumed superficial disease. Patient baseline characteristics are outlined in table 1.
7 Grade 3 or 4 events were observed in 5 patients. Four of these were treatment related skin toxicity which resulted in delayed infusions or dose reductions for these patients. Treatment related toxicities are outlined in table 2. Safety and Tolerability
Discussion Although advanced CSCC is quite common there are few prospective trials regarding its optimal management. This study demonstrates the efficacy, safety and tolerability of panitumumab in patients with incurable cutaneous squamous cell carcinoma (CSCC), not suitable for local therapy or chemotherapy. In the phase II study reported by Maubec et al.[18] the primary endpoint reported was a disease control rate at 6 weeks. For these patients with unresectable CSCC cetuximab was given as first-line treatment and the DCR at 6 weeks was 69%. The response rate was 11% at 6 weeks with a best overall response rate in the intention to treat population of 28%. The median duration of control was 5 months. This study reports that some patients were slow to respond to therapy. Given that some patients have an indolent course with advanced CSCC this is not unexpected and brings into question the value of a 6 week DCR. In the phase II study by Lewis et al. [17] gefitinib was given neoadjuvantly prior to surgery and/or radiotherapy with a complete response in 18.2% of patients and partial response in 27.3%. In our study of panitumumab most of the patients had been pre-treated; 12 patients had previous surgery, 14 of 16 patients receiving previous radiotherapy and seven of 16 patients having prior chemotherapy. The best ORR was 31%, with a DCR at 6 weeks of 69% and duration of response being 6 months. These figures compare favourably with the published literature using cetuximab [18] and gefitinib.[17]. In this series there also were several sustained complete responses, with one patient still disease free over 2 years since registration. The use of cisplatin, 5-flurouracil and bleomycin [5] and cisplatin and doxorubicin [6] have been evaluated in up front inoperable setting. The overall response rates were 84% and 68% respectively. Responses in advanced CSCC have also been observed with a combination of IFNα, 13cRA and cisplatin biochemotherapy regimen.[8] In this setting the overall and complete response rates were reported to be 34% and 17% respectively which is comparable to the current study. Despite these good responses these regimens are rarely used in clinical practice due to relatively high rates of significant toxicity which often prohibits their use in the elderly population. The safety of single agent panitumumab in this cohort of patients was confirmed with a 31 % rate of grade 3 or 4 toxicity which was largely due to the expected skin toxicity associated with EGFR inhibitors. Although the rate of grade 3 and 4 skin toxicity is higher than the study performed by Maubec et al. [18] it is not uncommon
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Adverse Events (AEs) were reported for all 16 patients. Significant AEs are listed in table 2. The study was completed meeting the predetermined safety criteria of 80% of patients who commence therapy successfully completing treatment with no treatmentrelated life threatening toxicity or dose limiting toxicity other than skin toxicity. There were no panitumumab related hypersensitivity reactions to the first infusion. Grade 3 or 4 AEs occurred in 31 % of patients (5 of 16 patients); four being skin toxicity and one treatment related fatigue.
8 in elderly patients in Australia where chronic sun exposed skin may be a contributor. [20] We were unable to establish a relationship between panitumumab skin toxicity and duration of response, OS or PFS, however, this may reflect the small number of patients in the study. In this study patients were not screened prior to entry for over expression of EGFR. In a translational sub study total EGFR expression levels were not associated with treatment efficacy. EGFR plasma membrane expression versus internalised EGFR was measured in the development of a novel assay and data will be analysed for possible correlation with treatment efficacy as a method for prediction would be clinically useful.
Conclusions In conclusion, this is the first prospective trial evaluating single agent panitumumab in the treatment of patients with incurable CSCC not suitable for local therapy. It highlights the clinical usefulness of EGFR inhibition in CSCC but also the need for molecular markers to select treatment for those most likely to respond. Funding This work was support by Amgen. No grant numbers apply.
Disclosures The authors have declared no conflicts of interest.
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Finally, it must be emphasised that the efficacy of panitumumab in this study is for incurable CSCC. In mucosal squamous cell carcinoma the combination of EGFR inhibition with chemotherapy [21] and radiotherapy [22] is well established and caution should be used in extrapolating these studies to the cutaneous setting.
9 References 1. 2. 3.
5. 6.
7. 8. 9. 10. 11. 12. 13. 14. 15.
16.
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4.
Ramirez CC, Federman DG, Kirsner RS. Skin cancer as an occupational disease: the effect of ultraviolet and other forms of radiation. Int J Dermatol 2005; 44: 95-100. de Vries E, van de Poll-Franse LV, Louwman WJ et al. Predictions of skin cancer incidence in the Netherlands up to 2015. Br J Dermatol 2005; 152: 481-8. Staples MP, Elwood M, Burton RC et al. Non-melanoma skin cancer in Australia: the 2002 national survey and trends since 1985. Med J Aust 2006; 184: 6-10. Silverberg E, Boring CC, Squires TS. Cancer statistics, 1990. CA Cancer J Clin 1990; 40: 9-26. Sadek H, Azli N, Wendling JL et al. Treatment of advanced squamous cell carcinoma of the skin with cisplatin, 5-fluorouracil, and bleomycin. Cancer 1990; 66: 1692-6. Guthrie TH, Jr., Porubsky ES, Luxenberg MN et al. Cisplatin-based chemotherapy in advanced basal and squamous cell carcinomas of the skin: results in 28 patients including 13 patients receiving multimodality therapy. J Clin Oncol 1990; 8: 342-6. Cartei G, Cartei F, Interlandi G et al. Oral 5-fluorouracil in squamous cell carcinoma of the skin in the aged. Am J Clin Oncol 2000; 23: 181-4. Shin DM, Glisson BS, Khuri FR et al. Phase II and biologic study of interferon alfa, retinoic acid, and cisplatin in advanced squamous skin cancer. J Clin Oncol 2002; 20: 364-70. Lippman SM, Kavanagh JJ, Paredes-Espinoza M et al. 13-cis-retinoic acid plus interferon alpha-2a: highly active systemic therapy for squamous cell carcinoma of the cervix. J Natl Cancer Inst 1992; 84: 241-5. Brewster AM, Lee JJ, Clayman GL et al. Randomized trial of adjuvant 13-cisretinoic acid and interferon alfa for patients with aggressive skin squamous cell carcinoma. J Clin Oncol 2007; 25: 1974-8. Salomon DS, Brandt R, Ciardiello F, Normanno N. Epidermal growth factorrelated peptides and their receptors in human malignancies. Crit Rev Oncol Hematol 1995; 19: 183-232. Maubec E, Duvillard P, Velasco V et al. Immunohistochemical analysis of EGFR and HER-2 in patients with metastatic squamous cell carcinoma of the skin. Anticancer Res 2005; 25: 1205-10. Grandis JR, Zeng Q, Drenning SD, Tweardy DJ. Normalization of EGFR mRNA levels following restoration of wild-type p53 in a head and neck squamous cell carcinoma cell line. Int J Oncol 1998; 13: 375-8. Camp ER, Summy J, Bauer TW et al. Molecular mechanisms of resistance to therapies targeting the epidermal growth factor receptor. Clin Cancer Res 2005; 11: 397-405. Burtness B, Goldwasser MA, Flood W et al. Phase III randomized trial of cisplatin plus placebo compared with cisplatin plus cetuximab in metastatic/recurrent head and neck cancer: an Eastern Cooperative Oncology Group study. J Clin Oncol 2005; 23: 8646-54. Hecht JR, Mitchell E, Neubauer MA et al. Lack of correlation between epidermal growth factor receptor status and response to Panitumumab monotherapy in metastatic colorectal cancer. Clin Cancer Res 2010; 16: 220513.
10 17. 18. 19. 20.
22.
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21.
Lewis CM, Glisson BS, Feng L et al. A phase II study of gefitinib for aggressive cutaneous squamous cell carcinoma of the head and neck. Clin Cancer Res 2012; 18: 1435-46. Maubec E, Petrow P, Scheer-Senyarich I et al. Phase II study of cetuximab as first-line single-drug therapy in patients with unresectable squamous cell carcinoma of the skin. J Clin Oncol 2011; 29: 3419-26. Yang XD, Jia XC, Corvalan JR et al. Eradication of established tumors by a fully human monoclonal antibody to the epidermal growth factor receptor without concomitant chemotherapy. Cancer Res 1999; 59: 1236-43. Pryor DI, Porceddu SV, Burmeister BH et al. Enhanced toxicity with concurrent cetuximab and radiotherapy in head and neck cancer. Radiother Oncol 2009; 90: 172-6. Vermorken JB, Mesia R, Rivera F et al. Platinum-based chemotherapy plus cetuximab in head and neck cancer. N Engl J Med 2008; 359: 1116-27. Bonner JA, Harari PM, Giralt J et al. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med 2006; 354: 56778.
11
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12
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13
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Table 1 – Patient baseline characteristics Table 1 Baseline characteristics
No. of patients Total patients
16
(%) (100)
68 47 - 86
Sex Male Female
14 2
ECOG PS 0 1 2
2 12 2
Disease stage Locoregional, no distant metastases Locoregional, with distant metastases Distant metastases only
13 2 1
(81) (13) (6)
1 1 1 1 7 5
(6) (6) (6) (6) (44) (31)
Previous therapy None RT alone CT alone RT and CT only Surgery and RT only Surgery, RT, and CT
(88) (13)
(13) (75) (13)
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Age, years Median Range
Table 2 – Panitumumab related adverse events Table 2 Toxicities ` Toxicity
All Grades No. of Patients
Any toxicity
No. of Patients
(%)
16
(100)
5
(31)
0 16 16 13 11 11 6 6 4 4 3 2 2 1
(100) (100) (81) (69) (69) (38) (38) (25) (25) (19) (13) (13) (6)
0 1 4 0 0 0 0 0 0 0 0 0 0 0
(6) (25) (0) (0) (0) (0) (0) (0) (0) (0) (0) (0) (0)
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Transfusion reaction Fatigue Rash Nausea Dermatology Mucositis Nail changes Pruritus Constipation Ocular Vomiting Abdominal Pain Cough Diarrhoea
(%)
Grade 3 to 4
1 Phase II study of single agent panitumumab in patients with incurable cutaneous squamous cell carcinoma
Key Message: "This is a single institution phase II study of single agent panitumumab in patients with incurable cutaneous squamous cell carcinoma. Results show that panitumumab is safe and effective in this disease, even in a previously extensively pre‐treated cohort."
© The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].
Downloaded from http://annonc.oxfordjournals.org/ at RMIT University Library on September 3, 2014
M. C. Foote1, M. McGrath2, A. Guminski3, B. G. M. Hughes4, J. Meakin5, D. Thomson2, D. Zarate6, F. Simpson7, S. V. Porceddu1 1 Department Radiation Oncology, Princess Alexandra Hospital, Brisbane, Australia 2 Department Medical Oncology, Princess Alexandra Hospital, Brisbane, Australia 3 Department Medical Oncology, Royal North Shore Hospital, Sydney, Australia 4 Department Medical Oncology, Royal Brisbane and Womens Hospital, Brisbane, Australia 5 Research Unit, Cancer Services, Princess Alexandra Hospital, Brisbane, Australia 6 Queensland Cancer Control Analysis Team, Queensland Health, Brisbane, Australia 7 Diamantina Institute, University of Queensland, Brisbane, Australia Corresponding author: Dr. Matthew Foote, Princess Alexandra Hospital, Radiation Oncology, 199 Ipswich Rd, Woolloongabba, Brisbane, Queensland, 4102, Australia, Phone: +61 7 3176 3067, Fax: +61 7 3176 1983, [email protected]
2 Abstract Background Although advanced cutaneous squamous cell carcinoma (CSCC) is quite common there are few prospective trials regarding its optimal management. This study evaluated the efficacy and safety of single agent panitumumab in the treatment of patients with CSCC not suitable for local therapy. Patients and Methods
Results Between May 2010 and May 2012, 16 patients were recruited. Fourteen patients were male and the median age was 68 years. Fifteen patients had locoregionally advanced or recurrent disease with 14 patients receiving previous radiotherapy and 7 patients receiving previous cytotoxic chemotherapy. The best ORR (PR or CR) was 31% (3/16 PR, 2/16 CR) with a further 6 of 16 patients achieving SD. The median PFS and OS were 8 and 11 months respectively. Grade 3 or 4 events were observed in five patients (four being skin toxicity) with one patient ceasing due to skin toxicity. With a median follow up of 24 months, 10 patients died due to progressive disease, 6 are alive, one patient with no evidence of disease at the time of analysis. Conclusions Single agent panitumumab is safe and effective in the management of patients with advanced CSCC even in a previously extensively pre-treated cohort. Key words – cutaneous, squamous cell carcinoma, panitumumab
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Sixteen patients received single agent panitumumab at a dose of 6 mg/kg repeated every two weeks for a minimum of three cycles and continued until progression, a maximum of nine cycles or dose limiting toxicity. The primary endpoint was the best overall response rate (ORR) as assessed by Response Evaluation Criteria in Solid Tumours (RECIST version 1.1) criteria. Secondary endpoints included evaluation of safety, toxicity and progression free survival.
3 Background Non-melanoma skin cancer (NMSC) is the most common malignancy worldwide and a consequence of chronic exposure to the mutagenic solar ultraviolet radiation.[1] The sun-exposed head and neck is the most common site (70% to 80%) for the development of a NMSC, and populations of fair-skin individuals living in countries close to the equator and tropics are more commonly affected. Since the 1960s, the worldwide incidence of NMSC has markedly increased and continues to rise.[2] Australia has the highest incidence of NMSC in the world, with over 300,000 patients diagnosed per year.[3]
Investigation of systemic therapy for this disease has been limited to few prospective trials. Systemic therapies that have been used to treat patients with advanced CSCC include cytotoxic chemotherapy (cisplatin, 5-flurouracil [5-FU], bleomycin and doxorubicin), 13-cis-retinoic acid (13-cRA), and immunotherapy (interferon α-2-a [IFN- α]. [5-10] Although these agents have shown activity in the metastatic setting, the toxic effects of these combinations make their use in this population, which is often elderly, limited. The epidermal growth factor receptor (EGFR) is highly expressed in many epithelial cancers including CSCC.[11, 12] Although tumour EGFR expression correlates inversely with clinical outcome[13], the degree of over expression does not seem to correlate with the effectiveness of EGFR inhibitors and several mechanisms of resistance are under investigation.[14-16] Irrespective, inhibition of this signal transduction pathway in CSCC has been evaluated with the tyrosine kinase inhibitor, gefitinib [17] and humanized monoclonal antibody, cetuximab.[18] These agents appear efficacious and tolerable making them a good therapeutic option particularly in the elderly. Panitumumab is a high affinity human IgG2 monoclonal antibody directed against human EGFR.[19] To date there are no studies evaluating panitumumab in advanced CSCC. We therefore aimed to investigate the efficacy of single agent panitumumab in patients with incurable cutaneous squamous cell carcinoma (CSCC), not suitable for local therapy or chemotherapy.
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Although only 5% will become locally advanced, recur or metastasize this still represents a significant problem. In the United States, at least 2500 people die annually from the consequences of advanced cutaneous squamous cell carcinoma (CSCC), usually as a result of developing metastatic nodal disease.[4] Despite aggressive treatment with surgery and radiotherapy a number of these patients will fail or develop incurable distant metastatic disease.
4 Patients and Methods Study Design and Objectives The trial was an open label, uncontrolled, single centre prospective phase II study conducted at the Princess Alexandra Hospital, Brisbane, Australia. The primary objective was to investigate the efficacy of panitumumab as a single agent as determined by the best overall response observed, according to Response Evaluation Criteria in Solid Tumours (RECIST version 1.1) criteria, following evaluation of all response assessments per time point.
Patient Eligibility Eligible patients had histopathological or cytopathological confirmation of locally advanced, metastatic or recurrent CSCC not suitable for curative therapy with a life expectancy of greater than three months and adequate haematological, hepatic and renal function. Other eligibility included ≥ 18 years of age, Eastern Collaborative Oncology Group (ECOG) performance status 0-2, and the presence of at least one target lesion measurable by RECIST criteria. Patients could previously have received radiotherapy or cytotoxic chemotherapy. Exclusions included patients receiving concurrent chemotherapy or radiotherapy, known hypersensitivity to EGFR inhibitors, clinically significant cardiovascular disease (including myocardial infarction, unstable angina, symptomatic congestive heart failure and serious uncontrolled cardiac arrhythmia) 1 year before enrolment/randomization and a history of interstitial lung disease, pneumonitis or pulmonary fibrosis or evidence of interstitial lung disease on previous imaging. Study Treatment Eligible patients commenced treatment within two weeks of signing informed consent. No premedication or test dose of panitumumab was required. Panitumumab was administered at a dose of 6 mg/kg, delivered via intravenous infusion over 60 minutes. Panitumumab was delivered on a second weekly basis until documented progressive disease using RECIST criteria, dose-limiting toxicity or a maximum of 9 cycles reached. Panitumumab dose modifications and treatment interruptions were allowed for dermatological toxicity Grade 3 CTCAE V3.0 and higher.
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Secondary endpoints included treatment related acute and late toxicity according to the Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0; safety based on 80% of patients commencing therapy successfully completing treatment with no treatment-related life threatening toxicity or dose limiting toxicity other than skin toxicity; progression free survival (PFS) reported from the time of first study treatment to the date of disease progression of the primary, nodal or primary & nodal disease following the best treatment response, or the development of distant metastases or death.
5 Assessment All patient baseline assessments were undertaken within two weeks of commencing study treatment. Baseline assessment included staging, general physical examination, skin assessment, complete blood count, serum biochemistry and initial tumour biopsy for patients participating in the optional translational study (results to be published separately).
Response assessment (according to RECIST version 1.1) was undertaken after every three cycles of panitumumab by an independent radiologist. An investigator blinded to the clinical outcomes retrospectively reviewed the assessments and if there was discordance the case was adjudicated on by another radiologist blinded to previous assessments. At the time of first documented progression or completion of nine cycles of panitumumab patients had 3 monthly response assessments in the first year followed by four monthly for a minimum of 18 months from commencement of treatment or until progression or death. Statistical Analyses All registered patients were accounted for in the analysis and patients who commenced any therapy were assessed for the main endpoints of efficacy and safety. Target accrual of 16 patients was based on 4 patients (25%) exhibiting either partial or complete response, allowing a response rate confidence interval estimate of 7% to 52% (based on 95% two-tailed binomial limits). Since the response rate for untreated patients is 0% a therapy with 7% response rate was considered potentially clinical valuable. Statistical analyses were performed using Stata (StataCorp, TX). Median follow-up time was calculated using the reverse Kaplan-Meier method. Survival was measured through the Kaplan-Meier estimator calculated from the date of registration to allcause death for overall survival (OS) and earliest progression for progression-free survival (PFS).
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Staging included clinical examination and computer tomography (CT) scans of the head and neck, chest and abdomen. Both Magnetic Resonance Imaging (MRI) scanning and/or Positron Emission Tomography (PET) staging were used at baseline at investigators discretion. On follow-up for response assessment both clinical examination (for dermal disease only) and CT scanning were used but the use of MRI or PET was discretionary.
6 Results A total of 16 patients were accrued between May 2010 and May 2012. All patients were included in the subsequent analyses. Patient Characteristics Of the 16 patients recruited, 14 were male and the median age 68 years. Fifteen (15/16) patients had locoregionally advanced or recurrent disease. Two of these patients also had documented distant metastatic disease. One patient had distant metastatic disease only.
Response Rates The best overall response rate (partial or complete response, PR or CR) was 31% (95% CI 11-59%; 3/16 PR, 2/16 CR) with a further 6 of 16 patients achieving stable disease. The duration of overall response was a median 6 months (range 5-17.5 months). The 6 week disease control rate (DCR) was 69% (11 of 16 patients). Of the patients who achieved a complete response, one was in a site of distant nodal disease and the other was in both recurrent locoregional (in-transit dermal) disease and adjacent nodal disease. This was confirmed by histological examination in the latter patient. One of these patients relapsed with further distant metastatic disease at 16 months since the last dose of panitumumab. The other patient with a complete response, received seven infusions of panitumumab, and had no evidence of disease at 24 months since the last dose. Measures of Survival With a median follow up of 24 months, 10 patients died due to progressive disease, six were alive, one patient with no evidence of disease at the time of analysis. The median OS was 11 months and median PFS was 8 months (Figure 1). For those patients who experienced a grade 3 or 4 panitumumab related skin toxicity there was no relationship between this, duration of response, PFS or OS. Panitumumab Compliance and Toxicity Of the 16 patients who commenced treatment, 9 completed all 9 planned infusions of panitumumab. Six patients ceased due to progression of disease. One patient refused further treatment after seven infusions due to Grade 3 skin toxicity. This patient achieved a complete response and remained disease free at the time of analysis.
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Fourteen patients had received previous radiotherapy and six patients previous cytotoxic chemotherapy. Three patients received cisplatin concurrently with radiotherapy in the adjuvant setting after resection of high risk locoregional disease. Two patients received carboplatin/5-flurouracil for relapsed locoregional and distant disease. One patient received topical mitomycin C adjuvantly for presumed superficial disease. Patient baseline characteristics are outlined in table 1.
7 Grade 3 or 4 events were observed in 5 patients. Four of these were treatment related skin toxicity which resulted in delayed infusions or dose reductions for these patients. Treatment related toxicities are outlined in table 2. Safety and Tolerability
Discussion Although advanced CSCC is quite common there are few prospective trials regarding its optimal management. This study demonstrates the efficacy, safety and tolerability of panitumumab in patients with incurable cutaneous squamous cell carcinoma (CSCC), not suitable for local therapy or chemotherapy. In the phase II study reported by Maubec et al.[18] the primary endpoint reported was a disease control rate at 6 weeks. For these patients with unresectable CSCC cetuximab was given as first-line treatment and the DCR at 6 weeks was 69%. The response rate was 11% at 6 weeks with a best overall response rate in the intention to treat population of 28%. The median duration of control was 5 months. This study reports that some patients were slow to respond to therapy. Given that some patients have an indolent course with advanced CSCC this is not unexpected and brings into question the value of a 6 week DCR. In the phase II study by Lewis et al. [17] gefitinib was given neoadjuvantly prior to surgery and/or radiotherapy with a complete response in 18.2% of patients and partial response in 27.3%. In our study of panitumumab most of the patients had been pre-treated; 12 patients had previous surgery, 14 of 16 patients receiving previous radiotherapy and seven of 16 patients having prior chemotherapy. The best ORR was 31%, with a DCR at 6 weeks of 69% and duration of response being 6 months. These figures compare favourably with the published literature using cetuximab [18] and gefitinib.[17]. In this series there also were several sustained complete responses, with one patient still disease free over 2 years since registration. The use of cisplatin, 5-flurouracil and bleomycin [5] and cisplatin and doxorubicin [6] have been evaluated in up front inoperable setting. The overall response rates were 84% and 68% respectively. Responses in advanced CSCC have also been observed with a combination of IFNα, 13cRA and cisplatin biochemotherapy regimen.[8] In this setting the overall and complete response rates were reported to be 34% and 17% respectively which is comparable to the current study. Despite these good responses these regimens are rarely used in clinical practice due to relatively high rates of significant toxicity which often prohibits their use in the elderly population. The safety of single agent panitumumab in this cohort of patients was confirmed with a 31 % rate of grade 3 or 4 toxicity which was largely due to the expected skin toxicity associated with EGFR inhibitors. Although the rate of grade 3 and 4 skin toxicity is higher than the study performed by Maubec et al. [18] it is not uncommon
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Adverse Events (AEs) were reported for all 16 patients. Significant AEs are listed in table 2. The study was completed meeting the predetermined safety criteria of 80% of patients who commence therapy successfully completing treatment with no treatmentrelated life threatening toxicity or dose limiting toxicity other than skin toxicity. There were no panitumumab related hypersensitivity reactions to the first infusion. Grade 3 or 4 AEs occurred in 31 % of patients (5 of 16 patients); four being skin toxicity and one treatment related fatigue.
8 in elderly patients in Australia where chronic sun exposed skin may be a contributor. [20] We were unable to establish a relationship between panitumumab skin toxicity and duration of response, OS or PFS, however, this may reflect the small number of patients in the study. In this study patients were not screened prior to entry for over expression of EGFR. In a translational sub study total EGFR expression levels were not associated with treatment efficacy. EGFR plasma membrane expression versus internalised EGFR was measured in the development of a novel assay and data will be analysed for possible correlation with treatment efficacy as a method for prediction would be clinically useful.
Conclusions In conclusion, this is the first prospective trial evaluating single agent panitumumab in the treatment of patients with incurable CSCC not suitable for local therapy. It highlights the clinical usefulness of EGFR inhibition in CSCC but also the need for molecular markers to select treatment for those most likely to respond. Funding This work was support by Amgen. No grant numbers apply.
Disclosures The authors have declared no conflicts of interest.
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Finally, it must be emphasised that the efficacy of panitumumab in this study is for incurable CSCC. In mucosal squamous cell carcinoma the combination of EGFR inhibition with chemotherapy [21] and radiotherapy [22] is well established and caution should be used in extrapolating these studies to the cutaneous setting.
9 References 1. 2. 3.
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7. 8. 9. 10. 11. 12. 13. 14. 15.
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Ramirez CC, Federman DG, Kirsner RS. Skin cancer as an occupational disease: the effect of ultraviolet and other forms of radiation. Int J Dermatol 2005; 44: 95-100. de Vries E, van de Poll-Franse LV, Louwman WJ et al. Predictions of skin cancer incidence in the Netherlands up to 2015. Br J Dermatol 2005; 152: 481-8. Staples MP, Elwood M, Burton RC et al. Non-melanoma skin cancer in Australia: the 2002 national survey and trends since 1985. Med J Aust 2006; 184: 6-10. Silverberg E, Boring CC, Squires TS. Cancer statistics, 1990. CA Cancer J Clin 1990; 40: 9-26. Sadek H, Azli N, Wendling JL et al. Treatment of advanced squamous cell carcinoma of the skin with cisplatin, 5-fluorouracil, and bleomycin. Cancer 1990; 66: 1692-6. Guthrie TH, Jr., Porubsky ES, Luxenberg MN et al. Cisplatin-based chemotherapy in advanced basal and squamous cell carcinomas of the skin: results in 28 patients including 13 patients receiving multimodality therapy. J Clin Oncol 1990; 8: 342-6. Cartei G, Cartei F, Interlandi G et al. Oral 5-fluorouracil in squamous cell carcinoma of the skin in the aged. Am J Clin Oncol 2000; 23: 181-4. Shin DM, Glisson BS, Khuri FR et al. Phase II and biologic study of interferon alfa, retinoic acid, and cisplatin in advanced squamous skin cancer. J Clin Oncol 2002; 20: 364-70. Lippman SM, Kavanagh JJ, Paredes-Espinoza M et al. 13-cis-retinoic acid plus interferon alpha-2a: highly active systemic therapy for squamous cell carcinoma of the cervix. J Natl Cancer Inst 1992; 84: 241-5. Brewster AM, Lee JJ, Clayman GL et al. Randomized trial of adjuvant 13-cisretinoic acid and interferon alfa for patients with aggressive skin squamous cell carcinoma. J Clin Oncol 2007; 25: 1974-8. Salomon DS, Brandt R, Ciardiello F, Normanno N. Epidermal growth factorrelated peptides and their receptors in human malignancies. Crit Rev Oncol Hematol 1995; 19: 183-232. Maubec E, Duvillard P, Velasco V et al. Immunohistochemical analysis of EGFR and HER-2 in patients with metastatic squamous cell carcinoma of the skin. Anticancer Res 2005; 25: 1205-10. Grandis JR, Zeng Q, Drenning SD, Tweardy DJ. Normalization of EGFR mRNA levels following restoration of wild-type p53 in a head and neck squamous cell carcinoma cell line. Int J Oncol 1998; 13: 375-8. Camp ER, Summy J, Bauer TW et al. Molecular mechanisms of resistance to therapies targeting the epidermal growth factor receptor. Clin Cancer Res 2005; 11: 397-405. Burtness B, Goldwasser MA, Flood W et al. Phase III randomized trial of cisplatin plus placebo compared with cisplatin plus cetuximab in metastatic/recurrent head and neck cancer: an Eastern Cooperative Oncology Group study. J Clin Oncol 2005; 23: 8646-54. Hecht JR, Mitchell E, Neubauer MA et al. Lack of correlation between epidermal growth factor receptor status and response to Panitumumab monotherapy in metastatic colorectal cancer. Clin Cancer Res 2010; 16: 220513.
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Lewis CM, Glisson BS, Feng L et al. A phase II study of gefitinib for aggressive cutaneous squamous cell carcinoma of the head and neck. Clin Cancer Res 2012; 18: 1435-46. Maubec E, Petrow P, Scheer-Senyarich I et al. Phase II study of cetuximab as first-line single-drug therapy in patients with unresectable squamous cell carcinoma of the skin. J Clin Oncol 2011; 29: 3419-26. Yang XD, Jia XC, Corvalan JR et al. Eradication of established tumors by a fully human monoclonal antibody to the epidermal growth factor receptor without concomitant chemotherapy. Cancer Res 1999; 59: 1236-43. Pryor DI, Porceddu SV, Burmeister BH et al. Enhanced toxicity with concurrent cetuximab and radiotherapy in head and neck cancer. Radiother Oncol 2009; 90: 172-6. Vermorken JB, Mesia R, Rivera F et al. Platinum-based chemotherapy plus cetuximab in head and neck cancer. N Engl J Med 2008; 359: 1116-27. Bonner JA, Harari PM, Giralt J et al. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med 2006; 354: 56778.
11
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Table 1 – Patient baseline characteristics Table 1 Baseline characteristics
No. of patients Total patients
16
(%) (100)
68 47 - 86
Sex Male Female
14 2
ECOG PS 0 1 2
2 12 2
Disease stage Locoregional, no distant metastases Locoregional, with distant metastases Distant metastases only
13 2 1
(81) (13) (6)
1 1 1 1 7 5
(6) (6) (6) (6) (44) (31)
Previous therapy None RT alone CT alone RT and CT only Surgery and RT only Surgery, RT, and CT
(88) (13)
(13) (75) (13)
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Age, years Median Range
Table 2 – Panitumumab related adverse events Table 2 Toxicities ` Toxicity
All Grades No. of Patients
Any toxicity
No. of Patients
(%)
16
(100)
5
(31)
0 16 16 13 11 11 6 6 4 4 3 2 2 1
(100) (100) (81) (69) (69) (38) (38) (25) (25) (19) (13) (13) (6)
0 1 4 0 0 0 0 0 0 0 0 0 0 0
(6) (25) (0) (0) (0) (0) (0) (0) (0) (0) (0) (0) (0)
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Transfusion reaction Fatigue Rash Nausea Dermatology Mucositis Nail changes Pruritus Constipation Ocular Vomiting Abdominal Pain Cough Diarrhoea
(%)
Grade 3 to 4