Immunotherapy for Locally Advanced Cutaneous Squamous Cell Carcinoma (CSCC): Implications for the Mohs Surgeon

Transcription

1 Relevant Financial Relationship Disclosure Statement Immunotherapy for Locally Advanced Cutaneous Squamous Cell Carcinoma (CSCC): Implications for the Mohs Surgeon Michael R. Migden, MD Associate Professor Departments of Dermatology and Head and Neck Surgery University of Texas MD Anderson Cancer Center I will discuss investigational use of the following drug: Cemiplimab The following relevant financial relationship(s) exist related to my role in this session: Honoraria received from Genentech, Lilly, Novartis, Sun Pharmaceuticals, and Regeneron

2 Cutaneous Squamous Cell Carcinoma (CSCC) Second most common skin cancer in the US, 1 rivaled only by BCC 2 Percent of CSCC patients with locally advanced disease not well known Risk factors: UV exposure, fair skin type, advanced age, immunosuppression 3 Median age at time of CSCC diagnosis: 71 years; male predominance 4 US mortality: 3,900 8,800/year 1 BCC, basal cell carcinoma; UV, ultraviolet. 1. Karia PS et al. J Am Acad Dermatol. 2013;68: ; 2. Rodgers HW et al. JAMA Dermatol. 2015;151(10): ; 3. Stratigos A et al. Eur J Cancer. 2015;51: ; 4. Karia PS et al. J Clin Oncol. 2014;32:

3 Why Immunotherapy?

4 Function of PD-1/PD-L1 Axis in Immunosurveillance Activation of PD-1/PD-L1 pathway suppresses T-cell-mediated tumor destruction 1,2 T Cell Receptor Antigen T Cell Receptor Antigen Anti PD-L1 T Cell PD-1 PD-L1 Tumor Cell T Cell PD-1 Anti PD-1 PD-L1 Tumor Cell Binding of PD-L1 to PD-1 suppresses T-cell-mediated tumor destruction 3 Inhibition of PD-1 or PD-L1 restores T-cell function 3 PD-1, programmed cell death protein 1; PD-L1, programmed death-ligand Chen DS, Mellman I. Immunity. 2013;39:1 10; 2. Gong J et al. J Immunother Cancer. 2018;6:8; 3. Caldwell Jr C et al. Sci Rep. 2017;7:13682.

5 Rationale for PD-1 Inhibition in CSCC Higher mutation burden than any tumor type in The Cancer Genome Atlas (TCGA) 1 Mutation burden exceeded by that of BCC 2 Median Somatic Mutation Frequency/Mb HNSCC (n=178) LUSC (n=178) Melanoma (n=121) CSCC (n=39) Immunosuppression is a well-described risk factor for CSCC, especially in solid organ transplant patients 3 PD-L1 expression has been associated with high-risk disease 4 In the phase I dose escalation study of cemiplimab (REGN2810), a durable radiologic complete response to cemiplimab was achieved in a CSCC patient 5,6 BCC, basal cell carcinoma; HNSCC, head and neck squamous cell cancer; LUSC; lung squamous carcinoma. 1. Pickering CR et al. Clin Cancer Res. 2014;15: ; 2. Jayaraman SS et al. J Invest Dermatol. 2014; 134(1): ; 3. Euvrard E et al. New Engl J Med. 2003;348: ; 4. Slater NA, Googe PB. J Cutan Pathol. 2016;43: ; 5. Falchook GS et al. J Immunother Cancer. 2016:4:50; 6. Papadopoulos KP et al. J Clin Oncol. 2016:34 (suppl; abstr 3024).

6 Phase I Open-Label Cemiplimab Study: CSCC Expansion Cohorts (NCT ) Study Design: Phase I Expansion Cohorts Metastatic CSCC Cohort 7 Locally and/or regionally advanced CSCC Cohort 8 Cemiplimab 3 mg/kg Q2W, for up to 48 weeks Response assessments every 8 weeks (RECIST 1.1) Co-primary objectives: To characterize the safety and tolerability of IV cemiplimab, 3 mg/kg Q2W To evaluate the efficacy of cemiplimab by measuring ORR Research tumor biopsies were taken at screening and Day 29±3. IV, intravenous; ORR, overall response rate; Q2W, every 2 weeks; RECIST, Response Evaluation Criteria In Solid Tumors.

7 Patient Characteristics Characteristics Locally Advanced CSCC (n=16) Median age, years (min max) 73 (56 88) Males, n (%) 13 (81.3) ECOG PS, n (%) 0 6 (37.5) 1 10 (62.5) Primary CSCC site, n (%) Head/neck 13 (81.3) Extremity 2 (12.5) Trunk 1 (6.3) Genital 0 Any prior systemic therapy, n (%) 6 (37.5) Any prior radiation therapy, n (%) 14 (87.5) Data cut-off date: April 27, 2017 ECOG, Eastern Cooperative Oncology Group; PS, performance status. Papadopoulos KP. REGN2810, A Human Anti-PD-1 Monoclonal Antibody, for Patients with Unresectable Locally Advanced or Metastatic Cutaneous Squamous Cell Carcinoma (CSCC): Initial Safety and Efficacy. Presented at the 2017 Annual Meeting of the American Society of Clinical Oncology; 2017 Jun 2-6; Chicago, IL.

8 Treatment-Related TEAEs in Patients with Locally Advanced CSCC (N=16) Treatment-related TEAEs of any grade occurring in 2 patients, or Grade 3 in any patient Number of Patients (%) Any Grade Grade 3 Fatigue 4 (25.0) 0 Nausea 2 (12.5) 0 Arthralgia 1 (6.3) 1 (6.3) Hypothyroidism 2 (12.5) 0 AST elevation 1 (6.3) 1 (6.3) ALT elevation 1 (6.3) 1 (6.3) Data cut-off date: April 27, 2017 ALT, alanine transaminase; AST, aspartate aminotransferase; TEAE, treatment-emergent adverse event.

9 Investigator Assessed Preliminary Response Rate by RECIST 1.1 is 37.5% (ITT Population) Investigator Assessment Locally Advanced CSCC (n=16) n (%) Complete response 2 (12.5) Partial response 4 (25.0) Stable disease 5 (31.3) Progressive disease 4 (25.0) Not evaluated 1 (6.3) ORR (CR + PR) = 37.5% (6/16 patients; 95% CI: 15.2% 64.6%) DCR (ORR + SD) = 68.8% (11/16 patients; 95% CI: 41.3% 89.0%) Data cut-off date: April 27, 2017 CI, confidence interval; CR, complete response; DCR, disease control rate; ITT, intention-to-treat; ORR, objective response rate; PD, progressive disease; PR, partial response; SD, stable disease. Papadopoulos KP. REGN2810, A Human Anti-PD-1 Monoclonal Antibody, for Patients with Unresectable Locally Advanced or Metastatic Cutaneous Squamous Cell Carcinoma (CSCC): Initial Safety and Efficacy. Presented at the 2017 Annual Meeting of the American Society of Clinical Oncology; 2017 Jun 2-6; Chicago, IL.

10 Clinical Activity in All Patients with At Least One Response Evaluation of Target Lesions Progressive disease Stable disease Confirmed response Number of patients with confirmed responses = 6 Data cut-off date: April 27, 2017 Data shown for 13 patients with at least one response assessment (RECIST 1.1) on study

11 Cemiplimab Produced Rapid, Deep and Durable Tumor Reductions in Target Lesions (N=16) Percent change in target lesions from baseline Locally Advanced (RECIST responses) Locally Advanced (SD, PD) First CR/PR First PD Months Data cut-off date: April 27, 2017 Data shown for 13 patients with at least one response assessment (RECIST 1.1) on study Papadopoulos KP. REGN2810, A Human Anti-PD-1 Monoclonal Antibody, for Patients with Unresectable Locally Advanced or Metastatic Cutaneous Squamous Cell Carcinoma (CSCC): Initial Safety and Efficacy. Presented at the 2017 Annual Meeting of the American Society of Clinical Oncology; 2017 Jun 2-6; Chicago, IL.

12 Cemiplimab is Active Across All PD-L1 Strata in CSCC (Tumor PD-L1 Expression by Immunohistochemistry; Dako 22C3 Clone) 91% (10/11) of evaluated tumors were positive ( 1%) for tumor expression of PD-L1 by IHC Tumor PD-L1 Total CR PR SD PD NE ORR Number of Patients 50% % (1/5) 1 49% % (3/5) <1% No apparent association between PD-L1 IHC results and objective responses 5 patients not evaluated by IHC: 1 CR, 1 PR, 2 SD, 1 PD. IHC, immunohistochemistry; NE, not evaluable.

13 Ongoing Pivotal Phase 2 CSCC Study (NCT ) Enrollment Group 1 (N=59 patients) Metastatic (nodal and distant) CSCC Group 2 (N=78 patients) Unresectable locally advanced CSCC Regimen: 3 mg/kg cemiplimab every 14 days Tumor assessment at the end of each 8 week cycle Group 3 (N = 56 patients) Metastatic (nodal and distant) CSCC Regimen: 350 mg cemiplimab every 21 days (PK-equivalent exposure for all ongoing cemiplimab studies) All Groups are Fully enrolled. PK, pharmacokinetic. Primary Endpoint: Objective response rate by Central Review in each group Study Site Locations: US, Australia, Germany

14 My Clinical Trial Experience with Cemiplimab The images on the following slides are used with patient permission and may not be fully representative of observations from the ongoing Phase 2 trial

15 Response to Cemiplimab in Patients with Locally Advanced CSCC: Exophytic Type Screening Response after 11 mo. of cemiplimab Resolution of exophytic tumor Biopsies negative Nearly complete resolution of perineural tumor on MRI Hx: Multiple extensive surgeries Poor diff CSCC I d rather die than have another big surgery Hx: Chemoradiation Extensive perineural tumor on MRI

16 Response to Cemiplimab in Patients with Locally Advanced CSCC: Endophytic Type (Deep Recurrence) Screening Bx negative after 6 mo. Treatment MRI: IMPRESSION: 1. Resolution of parotid mass 2. No evidence of perineural spread 3. No adenopathy Response after 12 mo. of cemiplimab Hx of CSCC removed with WLE margins reported neg, 1 LN neg 4 mo. later tender subcutaneous nodule developed, grew rapidly Mass effect obstruction of EAC MRI Bulky intraparotid tumor Retrograde PNI through foramen ovale and to stylomastoid foramen Anterograde PNI through mandibular foramen along inferior alveolar nerve

17 Response to Cemiplimab in Patients with Locally Advanced CSCC: Deeply Eroded with Functional Morbidity Screening Response after 3 mo. of cemiplimab Improvement at 3 months Substantially less pain Closure of orocutaneous fistula! Massive premaxillary tumor Boney invasion into maxillary sinus Destruction of anterior zygoma PNI infraorbital to pterygopalatine fossa Invasion of masseter muscle Orocutaneous fistula Difficulty eating: pain + saliva leak Surgery functionally debilitating

18 Response to Cemiplimab in Patients with Locally Advanced CSCC: Disfigurement Potential Screening Rapid improvement After 4 months treatment, biopsies negative for CSCC Full thickness defect granulated closed Response after 12 mo. of cemiplimab Full thickness mod diff CSCC, invasive intranasally Hx: years of topical therapy, cryotherapy, herbal/holistic tx Sent from Head and Neck Surgery, planned rhinectomy

19 Response to Cemiplimab in Patients with Locally Advanced CSCC: In-transit Field, No Clear Surgical Target Screening Biopsies of sites in-transit tumor negative at 7 months Lesions resolved Response after 8 mo. of cemiplimab Mohs tumor in periosteum, diffuse small nests, doublets and single cells Sent to head and neck surgery for bone burring, additional resection and latissimus flap performed Recurrences noted months later at multiple margins of free flap

20 Pseudoprogression with Immunotherapy Inflammatory changes that can be interpreted as an increase in tumor size may precede tumor shrinkage 1-3 Pseudoprogression results from treatment rather than true disease progression 3 Mechanism is likely due to infiltration of tumor by activated T-cells 1,2 Uncommon and may indicate a high likelihood of >1 year survival 3 Misclassification as disease progression may lead to premature treatment discontinuation Immune-related RECIST (irrecist) developed to avoid misclassification 4 If standard RECIST used to assess these cases, may understate ORR 1. Wolchok JD et al. Clin Cancer Res. 2009;15: ; 2. Ribas A et al. Clin Cancer Res. 2009; 15: ; 3. Vikram K et al. J Clin Oncol. 2016;34(15 suppl): ; 4. Carter BW et al. Cancer April 19 [epub ahead of print].

21 Immune-Related Adverse Events 1-3 PD-1 checkpoint inhibition can cause immune-related adverse events (iraes), including but not limited to: endocrinopathies (mostly hypothyroidism), hepatitis, pneumonitis, and rash The clinician must have a high index of suspicion for iraes, and a low threshold to consult with other colleagues (e.g., pulmonary, endocrine, medical oncology) for evaluation and management of possible iraes The majority of iraes are mild-to-moderate Most serious iraes can be successfully managed by pausing or discontinuing anti- PD-1 treatment and prompt intervention with immunosuppressive treatment 1. Puzanov I et al. J ImmunoTher Cancer. 2017;5:95; 2. Haanen JB et al. Ann Onc. 2017; 28 (suppl 4): iv ; 3. Weber JS et al. Oncologist. 2016;21:

22 Summary and Conclusions Locally advanced CSCC is a nuanced, multifaceted concept encompassing a subset of the disease spectrum seen by Mohs surgeons Locally advanced CSCC is highly responsive to cemiplimab ORR of 37.5% in Phase 1 locally advanced CSCC trial, 44% if locally advanced definition from phase 2 trial is used (4 responses among 9 patients) Topline results from ongoing Phase 2 CSCC study demonstrate an ORR of 46.3% as determined by independent review, 1 consistent with Phase 1 trial Generally well tolerated; safety profile is consistent with approved anti-pd-1 agents Granted a breakthrough therapy designation by the FDA Currently under review by the FDA and EMA as a potential treatment for advanced CSCC Immunotherapy for NMSC is becoming increasingly relevant to MSDO practice/fellowship training Care for larger advanced CSCC falls within our scope of practice; we should play an essential role, inclusive of appropriate multidisciplinary care, in the management and follow-up of these patients EMA, European Medicines Agency; FDA, US Food and Drug Administration; NMSC, non-melanoma skin cancer; ORR, overall response rate. 1. Regeneron Pharmaceuticals Press Release (December 17, 2017). Regeneron and Sanofi announce positive topline pivotal results for the PD-1 antibody cemiplimab in advanced cutaneous squamous cell carcinoma. Retrieved from (Accessed April 20, 2018.)

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24 Which of the following is definitely a locally advanced CSCC? A) 2.2 cm moderately differentiated SCC at nasal tip B) 4 cm poorly differentiated SCC at left cheek C) 3.5 moderately differentiated SCC with perineural invasion right forehead D) 3.5 cm moderately differentiated SCC at left tragus, MRI shows PNI auriculotemporal to mandibular nerve and through foramen ovale E) 2.2 cm poorly differentiated SCC invading cartilage right helix

25 Which of the following is definitely a locally advanced CSCC? A) 2.2 cm moderately differentiated SCC at nasal tip B) 4 cm poorly differentiated SCC at left cheek C) 3.5 moderately differentiated SCC with perineural invasion right forehead D) 3.5 cm moderately differentiated SCC at left tragus, MRI shows PNI auriculotemporal to mandibular nerve and through foramen ovale E) 2.2 cm poorly differentiated SCC invading cartilage right helix

26 Back Up

27 No Widely Accepted Standard of Care Systemic Therapy for Locally Advanced or Metastatic CSCC 1 Study Treatment(s) N Locoregional (%) Age (years)* Response Rate (%) PFS (months)* Duration of Response (months)* Maubec et al. J Clin Oncol Cetuximab Foote et al. Ann Oncol Panitumumab Jarkowski et al. Am J Clin Oncol Systemic therapy (platinum-based, capecitabine, taxane, cetuximab) NR William et al. J Am Acad Dermatol Getfitinib Bossi et al. ASCO Dacomitinib Conventional cytotoxic chemotherapy may induce tumor responses, but is often poorly tolerated by elderly or immunosuppressed patients 7 *Median value, mean value. NR, not reported; PFS, progression-free survival; RR, response rate. 1. Cranmer LD et al. Oncologist. 2010;15: ; 2. Maubec E et al. J Clin Oncol. 2011;29: ; 3. Foote MC et al. Ann Oncol. 2014;25: ; 4. Jarkowksi A et al. Am J Clin Oncol. 2016;39: ; 5. Wiliam WN et al. J Am Acad Dermatol. 2017;77: ; 6. Bossi P et al. J Clin Oncol. 2017;35(15 suppl): ; 7. Samstein RM et al. J Skin Cancer. 2014; 2014:

28 Select Inclusion and Exclusion Criteria for Phase I Trial Inclusion criteria: ECOG Performance Status of 0 or 1 Measureable disease by RECIST 1.1 Adequate organ function (bone marrow, kidney, liver) Metastatic CSCC (M1): Expansion Cohort 7 Unresectable locally and/or regionally advanced CSCC (M0): Expansion Cohort 8: Acceptable reasons for surgery to be deemed inappropriate: Recurrence of CSCC after 2 or more surgical procedures and an expectation that curative resection would be unlikely, and/or Substantial morbidity or deformity anticipated from surgery Exclusion criteria: Autoimmune disease within 5 years Active brain metastases Other invasive malignancy within 5 years (no exclusion for tumors considered cured by localized treatment) Immunosuppressive doses of steroids (>10mg prednisone daily or equivalent) Systemic antitumor treatment within 4 weeks of initial dose of cemiplimab History of solid organ transplant Tumors of lip or eyelid not eligible for CSCC cohorts

29 Potentially Dangerous Systemic Agents in Dermatology Rituximab Cyclophosphamide Methotrexate Cyclosporine Azathioprine CellCept Anti-Il-17 antibodies IVIG Embrel Humira Stelara