Anal Cancer in the Last 12 Months

What is new in anal cancer in the last 12 months

Michel Ducreux, MD, PhD Chef du Service d’Oncologie Digestive Département de Médecine Oncologique  Anal cancer: Epidemiology and treatment

• Relatively rare cancer – incidence : ~1-2 cases/100 000 worldwide1 • Increasing incidence by 1%-3% per year in developped countries • ~ 70% of squamous histology • HPV infection detected in 80%-90% of cases • Only a few standard options especially when : – The disease recurs after radio-chemotherapy – In metastatic setting

1Grulich AE et al. Sex Health 2012;9:504-8 2NCCN Guidelines for the treatment of Anal Canal Carcinoma  Active drugs in advanced anal canal cancer: an unmet need!  Active drugs in advanced anal canal cancer: an unmet need! CHEMOTHERAPY  A recent review:

Morris VK and Eng C: Surg Oncol Clin N Am 2017;26:133 - 42  ASCO 2018: FOLFCIS • FOLFCIS, which is essentially FOLFOX with cisplatin substituted for oxaliplatin, • 53 AC patients (48 metastatic; 5 unresectable, locally advanced) Median age: 59 years, 32% had metastatic disease at diagnosis • 41 AC patients underwent targeted NGS • PFS: 7.1 months (95% CI, 4.4 - 8.6) OS: 22.1 months (95% CI, 16.9 - 28.1) • Most frequent genomic alterations consisted of chromosome 3q amplification (17%) and mutations in PIK3CA (24%) and KMT2D (24%). • Genomic alterations of the phosphatidylinositol 3-kinase pathway in PIK3CA, PTEN, or AKT2 54% of cases Mondaca S et al J Clin Oncol 2018;36:suppl, 3567  IRCI anal cancer metastatic trial TARGETED THERAPIES  Cetuximab + CT-RT in immunocompetent patients

Garg MK et al. J Clin Oncol 2017;35:718-26  Cetuximab + CT-RT in immunocompetent patients

• 61 patients • Approximately 20% of local regional failure versus 35%(historical control)… but

Garg MK et al. J Clin Oncol 2017;35:718-26  Cetuximab + RT-CT inHIV- associated anal carcinoma

Sparano JA et al. J Clin Oncol 2017;35:727-33  Cetuximab + RT-CT inHIV- associated anal carcinoma

• 20% LRF only but

Sparano JA et al. J Clin Oncol 2017;35:727-33  Cetuximab in metastatic disease: only a few series • MD Anderson1 – 17 patients, progression after one line of treatment for metastatic disease, cetuximab or panitumumab with different CT – 6 / 17 radiological response (ORR = 35%) • Manheim2 – 5 patients with Ras wild tye cancer: cetuximab with or without irinotecan: 3 / 5 PR • Gustave Roussy3 – 10 patients,75% HPV+ – Folfiri cetuximab in all, median previous lines: 2 [1 – 3] – Median number of cycles: 8 [1 – 23] – 9 evaluable for response : 1 CR, 4 PR (55% ORR) – Median SSP: 5.1 months, median OS: 10.8 months 1Rogers JE et al. Anticancer Drug 2016;27:804-8; 2Lukan N et al. Oncology 2009;77:293-9 3Malka D et al. 2017. JFHOD 2017 abstracts  An example of response

Patient #9

Patient #1

Patient #10

Malka D et al. 2017 JFHOD abstracts IMMUNOTHERAPY  Nivolumab: only one phase II study

• Nivolumab: 3 mg/kg/15 jours • Population : – 37 patients, – 12 men, 25 women, – 1 to 8 lines of previous treatment, – HPV and/or HIV positivity allowed

Morris VK et al Lancet Oncol 2017;18:446-53  Phase II nivolumab: Patients characteristics  Efficacy results

RESPONSE RATE: • 9 / 37; 24% • 95%CI: [15 – 33]

Morris VK et al Lancet Oncol 2017;18:446-53  Efficacy results

Morris VK et al Lancet Oncol 2017;18:446-53  Survival

Progression-free survival Overall survival Median = 4.1 months Median = 11.5 months

Morris VK et al Lancet Oncol 2017;18:446-53  KEYNOTE-028: Phase 1b multicohort study of pembrolizumab for PDL1+ advanced solid tumors

• Response assessment: every 8 weeks for the first 6 months; every 12 weeks thereafter • Primary endpoint: ORR per RECIST v1.1 • Secondary endpoints: PFS, OS, duration of response, and safety

Ott P et al. Ann Oncol 2017;28:1036-41  Analysis of PD-L1 expression

• Tumor samples: archival or newly obtained core or excisional biopsy of non irradiated lesion • Immunohistochemistry: assessed at a central laboratory • Positivity: membranous PD-L1 expression in >1% of cells in tumor and stroma

Ott P et al. Ann Oncol 2017;28:1036-41  PD-L1 screening Keynote 28

Ott P et al. Ann Oncol 2017;28:1036-41  Baseline characteristics

Characteristics N=25 Characteristics N=25 Median age, years (range) 63 (46 – 82) Adjuvant or neoadjuvant 6 (24) Female 23 (92) systemic therapy, n (%) Race Prior lines of therapy for White 19 (76) advanced disease Black or African 1 (4) 0 3 (12) American 5 (20) 1 7 (28) Not specified 2 6 (24) >3 7 (28) ECOG performance status Unknown 2 (8) 0 5 (20) 1 20 (80) Prior therapies for advanced disease Histology at baseline, n (%) 5FU + mitomycin 15 (60) Squamous cell carcinoma 24 (96) 5FU + platinum + other 12 (48) Perineal epidermoid Gemcitabine + platinum + other 4 (16) carcinoma 1 (4) Chk-1 inhibitor 2 (8) Etirinotecan pegol 2 (8) Other 10 (40)

Ott P et al. Ann Oncol 2017;28:1036-41  Toxicity

Ott P et al. Ann Oncol 2017;28:1036-41  Efficacy data

• 4 partial response, ORR = 17% • 10 stable disease (42%) • 1 not assessed

Ott P et al. Ann Oncol 2017;28:1036-41  Longitudinal change from Baseline in Tumor Size

Ott P et al. Ann Oncol 2017;28:1036-41  Longitudinal change from Baseline in Tumor Size

Ott P et al. Ann Oncol 2017;28:1036-41 BIOLOGY…  Comprehensive genomic profiling of metastatic squamous cell carcinoma of the anal canal

Morris V et al. Mol Cancer Res 2017;15:1542-50  Conclusion

• Nothing has recently changed in the treatment of metastatic anal canal cancer • But changes are coming… – New backbone of chemotherapy?? – A role to define for targeted therapies • Anti-EGFR: small series, promising results in metastatic disease – Role of immunotherapy++++ • 25 to 30% of refractory patients benefit from anti PD1 • Selection of these patients?