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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

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Page 1: What is new in anal cancer in the last 12 months · • ~ 70% of squamous histology • HPV infection detected in 80%-90% of cases • Only a few standard options especially when

What is new in anal cancer in the last 12 months

Michel Ducreux, MD, PhDChef du Service d’Oncologie Digestive

Département de Médecine Oncologique

Page 2: What is new in anal cancer in the last 12 months · • ~ 70% of squamous histology • HPV infection detected in 80%-90% of cases • Only a few standard options especially when

Anal cancer: Epidemiology and treatment

• Relatively rare cancer – incidence : ~1-2 cases/100 000 worldwide1

• Increasing incidence by 1%-3% per year in developpedcountries

• ~ 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;9:504-82NCCN Guidelines for the treatment of Anal Canal Carcinoma

Page 3: What is new in anal cancer in the last 12 months · • ~ 70% of squamous histology • HPV infection detected in 80%-90% of cases • Only a few standard options especially when

Active drugs in advanced anal canal cancer: an unmet need!

Page 4: What is new in anal cancer in the last 12 months · • ~ 70% of squamous histology • HPV infection detected in 80%-90% of cases • Only a few standard options especially when

Active drugs in advanced anal canal cancer: an unmet need!

Page 5: What is new in anal cancer in the last 12 months · • ~ 70% of squamous histology • HPV infection detected in 80%-90% of cases • Only a few standard options especially when

CHEMOTHERAPY

Page 6: What is new in anal cancer in the last 12 months · • ~ 70% of squamous histology • HPV infection detected in 80%-90% of cases • Only a few standard options especially when

A recent review:

Morris VK and Eng C: Surg Oncol Clin N Am 2017;26:133 - 42

Page 7: What is new in anal cancer in the last 12 months · • ~ 70% of squamous histology • HPV infection detected in 80%-90% of cases • Only a few standard options especially when

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

Page 8: What is new in anal cancer in the last 12 months · • ~ 70% of squamous histology • HPV infection detected in 80%-90% of cases • Only a few standard options especially when

IRCI anal cancer metastatic trial

Page 9: What is new in anal cancer in the last 12 months · • ~ 70% of squamous histology • HPV infection detected in 80%-90% of cases • Only a few standard options especially when

TARGETED THERAPIES

Page 10: What is new in anal cancer in the last 12 months · • ~ 70% of squamous histology • HPV infection detected in 80%-90% of cases • Only a few standard options especially when

Cetuximab + CT-RT in immunocompetent patients

Garg MK et al. J Clin Oncol 2017;35:718-26

Page 11: What is new in anal cancer in the last 12 months · • ~ 70% of squamous histology • HPV infection detected in 80%-90% of cases • Only a few standard options especially when

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

Page 12: What is new in anal cancer in the last 12 months · • ~ 70% of squamous histology • HPV infection detected in 80%-90% of cases • Only a few standard options especially when

Cetuximab + RT-CT inHIV-associated anal carcinoma

Sparano JA et al. J Clin Oncol 2017;35:727-33

Page 13: What is new in anal cancer in the last 12 months · • ~ 70% of squamous histology • HPV infection detected in 80%-90% of cases • Only a few standard options especially when

Cetuximab + RT-CT inHIV-associated anal carcinoma

• 20% LRF only but

Sparano JA et al. J Clin Oncol 2017;35:727-33

Page 14: What is new in anal cancer in the last 12 months · • ~ 70% of squamous histology • HPV infection detected in 80%-90% of cases • Only a few standard options especially when

Cetuximab in metastatic disease: only a few series

• MD Anderson1

– 17 patients, progression after one line of treatment for metastaticdisease, cetuximab or panitumumab with different CT

– 6 / 17 radiological response (ORR = 35%)

• Manheim2

– 5 patients with Ras wild tye cancer: cetuximab with or withoutirinotecan: 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;77:293-93Malka D et al. 2017. JFHOD 2017 abstracts

Page 15: What is new in anal cancer in the last 12 months · • ~ 70% of squamous histology • HPV infection detected in 80%-90% of cases • Only a few standard options especially when

An example of response

Patient #9

Patient #1

Patient #10

Malka D et al. 2017 JFHOD abstracts

Page 16: What is new in anal cancer in the last 12 months · • ~ 70% of squamous histology • HPV infection detected in 80%-90% of cases • Only a few standard options especially when

IMMUNOTHERAPY

Page 17: What is new in anal cancer in the last 12 months · • ~ 70% of squamous histology • HPV infection detected in 80%-90% of cases • Only a few standard options especially when

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

Page 18: What is new in anal cancer in the last 12 months · • ~ 70% of squamous histology • HPV infection detected in 80%-90% of cases • Only a few standard options especially when

Phase II nivolumab: Patients characteristics

Page 19: What is new in anal cancer in the last 12 months · • ~ 70% of squamous histology • HPV infection detected in 80%-90% of cases • Only a few standard options especially when

Efficacy results

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

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

Page 20: What is new in anal cancer in the last 12 months · • ~ 70% of squamous histology • HPV infection detected in 80%-90% of cases • Only a few standard options especially when

Efficacy results

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

Page 21: What is new in anal cancer in the last 12 months · • ~ 70% of squamous histology • HPV infection detected in 80%-90% of cases • Only a few standard options especially when

Survival

Progression-free survivalMedian = 4.1 months

Overall survivalMedian = 11.5 months

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

Page 22: What is new in anal cancer in the last 12 months · • ~ 70% of squamous histology • HPV infection detected in 80%-90% of cases • Only a few standard options especially when

KEYNOTE-028: Phase 1b multicohortstudy 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

Page 23: What is new in anal cancer in the last 12 months · • ~ 70% of squamous histology • HPV infection detected in 80%-90% of cases • Only a few standard options especially when

Analysis of PD-L1 expression

• Tumor samples: archival or newly obtained core or excisionalbiopsy 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

Page 24: What is new in anal cancer in the last 12 months · • ~ 70% of squamous histology • HPV infection detected in 80%-90% of cases • Only a few standard options especially when

PD-L1 screening Keynote 28

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

Page 25: What is new in anal cancer in the last 12 months · • ~ 70% of squamous histology • HPV infection detected in 80%-90% of cases • Only a few standard options especially when

Baseline characteristicsCharacteristics N=25

Median age, years (range) 63 (46 – 82)

Female 23 (92)

RaceWhiteBlack or AfricanAmericanNot specified

19 (76)1 (4)

5 (20)

ECOG performance status01

5 (20)20 (80)

Histology at baseline, n (%)Squamous cell carcinomaPerineal epidermoidcarcinoma

24 (96)

1 (4)

Characteristics N=25

Adjuvant or neoadjuvant systemic therapy, n (%)

6 (24)

Prior lines of therapy for advanced disease

012>3Unknown

3 (12)7 (28)6 (24)7 (28)2 (8)

Prior therapies for advanceddisease5FU + mitomycin5FU + platinum + otherGemcitabine + platinum + otherChk-1 inhibitorEtirinotecan pegolOther

15 (60)12 (48)4 (16)2 (8)2 (8)

10 (40)

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

Page 26: What is new in anal cancer in the last 12 months · • ~ 70% of squamous histology • HPV infection detected in 80%-90% of cases • Only a few standard options especially when

Toxicity

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

Page 27: What is new in anal cancer in the last 12 months · • ~ 70% of squamous histology • HPV infection detected in 80%-90% of cases • Only a few standard options especially when

Efficacy data

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

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

Page 28: What is new in anal cancer in the last 12 months · • ~ 70% of squamous histology • HPV infection detected in 80%-90% of cases • Only a few standard options especially when

Longitudinal change from Baseline in Tumor Size

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

Page 29: What is new in anal cancer in the last 12 months · • ~ 70% of squamous histology • HPV infection detected in 80%-90% of cases • Only a few standard options especially when

Longitudinal change from Baseline in Tumor Size

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

Page 30: What is new in anal cancer in the last 12 months · • ~ 70% of squamous histology • HPV infection detected in 80%-90% of cases • Only a few standard options especially when

BIOLOGY…

Page 31: What is new in anal cancer in the last 12 months · • ~ 70% of squamous histology • HPV infection detected in 80%-90% of cases • Only a few standard options especially when

Comprehensive genomic profiling of metastatic squamous cell carcinoma of

the anal canal

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

Page 32: What is new in anal cancer in the last 12 months · • ~ 70% of squamous histology • HPV infection detected in 80%-90% of cases • Only a few standard options especially when

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?