what is new in anal cancer in the last is new in a… · anal cancer: epidemiology and treatment...

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

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. Anicancer Drug 2016;27:804-8; 2Lukan N et al. Oncology 2009;77:293-93Malka D et al. 2017. JFHOD 2017 abstracts

An example of response

Paient #9

Paient #1

Paient #10

Malka D et al. 2017 JFHOD abstracts

IMMUNOTHERAPY

Nivolumab: only one phase II study

• Nivolumab: 3 mg/kg/15 jours

• Populaion :

– 37 paients,

– 12 men, 25 women,

– 1 to 8 lines of previous treatment,

– HPV and/or HIV posiivity allowed

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

Phase II nivolumab: Patients

characteristics

Efficacy results

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

RESPONSE RATE:

• 9 / 37; 24%• 95%CI: [15 – 33]

Efficacy results

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

Survival

Progression-free survival

Median = 4.1 months

Overall survival

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 irst 6 months; every 12

weeks thereater

• Primary endpoint: ORR per RECIST v1.1

• Secondary endpoints: PFS, OS, duraion of response, and safety

Ot 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

• Posiivity: membranous PD-L1 expression in >1% of cells in

tumor and stroma

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

PD-L1 screening Keynote 28

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

Baseline characteristics

Characterisics N=25

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

Female 23 (92)

RaceWhiteBlack or African AmericanNot speciied

19 (76)1 (4)

5 (20)

ECOG performance status01

5 (20)20 (80)

Histology at baseline, n (%)Squamous cell carcinomaPerineal epidermoid carcinoma

24 (96)

1 (4)

Characterisics 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 advanced disease5FU + mitomycin5FU + plainum + otherGemcitabine + plainum + otherChk-1 inhibitorEirinotecan pegolOther

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

10 (40)

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

Toxicity

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

Efficacy data

• 4 parial response, ORR = 17%

• 10 stable disease (42%)

• 1 not assessed

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

Longitudinal change from Baseline

in Tumor Size

Ot 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?