Rob Glynne-Jones Mount Vernon Cancer Centre

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1 ESMO Preceptorship Programme Anal Cancer Valencia May 2018 Standard of care for anal squamous cancer Rob Glynne-Jones Mount Vernon Cancer Centre

2 My Disclosures: last 5 years Speaker: Roche, Merck Serono, Sanofi Aventis, Pfizer, AIS Advisory Boards: Roche, Merck Serono, Sanofi Aventis, Astra Zeneca Funding to attend meetings: Roche, Merck Serono, Sanofi Aventis, Research funding: Roche, Merck Serono, Sanofi Aventis

3 Squamous cell carcinoma of the Anus SCCA usually a localized disease with a low risk of metastatic disease at presentation. The majority 60-80% respond to CRT (depending on stage) But the results for treatment of recurrent or disseminated disease remain poor So investigation of better treatment options in the firstline CRT setting are needed.

4 Site of relapse after CRT from ACT II (940 patients) Primary Inguinal/pelvic nodes Metastases/oligometastases Number % total relapses Pelvic - no metastases % Pelvic - with metastases 30 14% Distant metastases only 46 22% Total crude pelvic failure (with or without metastases) Total relapses 209/ % Data from ACT II Sebag-Montefiore D et al ASCO 2012

5 Prognostic factors ACT I validated against ACT II Prognostic for LRF and OS Clinically palpable nodes Male sex Prognostic for ACD and OS Haemoglobin Glynne-Jones R et al., Cancer 2013 Feb 15;119(4):

6 Determine Clinical Stage (DRE/MRI/CT)

7 Staging with PET/CT A systematic review and meta-analysis showed that PET/CT led to a change in nodal staging in 28% of patients following conventional imaging with CT and MRI Jones M, Hruby G, Solomon M et al The role of FDG-PET in the initial staging and response assessment of anal cancer: a systematic review and meta-analysis. Ann Surg Oncol 2015; 2:

8 Determine Clinical Stage (DRE/MRI/CT) P16+/HPV

9 Prognostic Relevance of HPV and p16 Author Patients (n) Results Körber 105 increased local control, PFS, OS Mai 106 increased 5 years local control and trend to increased OS Rödel 95 improved local control, CSS and OS Serup-Hansen 143 improved DSS and OS Baricevic 110 improved relapse-free survival and OS HPV and p16 positivity associated with a favourable clinical response and increased survival Körber S, Radiother Oncol 2014; Mai S, Int J Radiat Oncol Biol Phys 2015; Rödel F, Int J Cancer 2015; Baricevic I, Eur J Cancer 2015; Serup-Hansen E, J Clin Oncol 2014.

10 Meta-analysis HPV/p16 HPV+/p16+ cancers were significantly associated with improved OS (HR = 0.30, 95% CI: ) DFS/DSS/RFS/PFS (HR = 0.23, 95% CI: ). However, patients with HPV-/p16+ or HPV+/p16- do not compared with HPV+/p16+ patients. Sun G et al Oncotarget 2018 Jan 30; 9(8):

11 Determine Clinical Stage (DRE/MRI/CT) P16/HPV TILS

12 Immune Markers: CD8(+) TILs and checkpoints Balermpas et al, Oncoimmunology 2017

13 Prognostic relevance of TILs Author Patients (n) Results Grabenbauer 38 CD3/CD4: decreased 3 years NED Rubio 277 CD3/CD8: increased 15 years survival Hu 40 intratumoral CD8: increased DFS peritumoral CD8: increased OS Gilbert 153 increased relapse-free survival High levels of TILs, especially CD8(+) cells, are associated with a favourable clinical response and survival Grabenbauer G, Clin Cancer Res 2006; Rubio C, Int J Clin Exp Pathol 2008; Hu W, J Surg Oncol. 2015; Gilbert DC, Br J Cancer 2016

14 SCCA low tumor mutational burden (TMB), mean number of 2.5 to 3.5 somatic mutations/mb Morris V,, et al. Comprehensive Genomic Profiling of Metastatic Squamous Cell Carcinoma of the Anal Canal. Mol Cancer Res. 2017;15(11):

15 SCC of Anus Nigro et al 1983 Preop chemoradiation to primary tumour, pelvic and inguinal nodes Radiotherapy 2 fields 30 Gy /15/21 days Chemotherapy 5FU 1000mg/m2 Days 1-4, Mitomycin C 15mg/m2 Day 1

16 ACT I Trial N = 585 patients R A N D O M I Z A T I O N 45Gy in # 45Gy in # CRT+ 5FU /MMC Reassess and? boost after 6 weeks 15Gy Boost 15Gy Boost

17 0 Percentage of patients having a local relapse (%) ACT I :Time to first local relapse HR 0.46, p<0.001 RT alone CMT Time since randomisation (years)

18 Squamous cell carcinoma of the Anus Randomized phase III trials have established 1. The standard of care is chemoradiation with 5FU/capecitabine and MMC 2. Reasonable agreement on fluoropyrimidine but not MMC dose (1 or 2?) 3. No standard of care for RT (hence PLATO)

19 Options for chemotherapy Induction chemotherapy prior to CRT Different concurrent chemotherapy in CRT Consolidation chemotherapy after CRT

20 Intergroup RTOG N = 644 patients T2-4 N0 N+ R A N D O M I Z A T I O N NACT 5FU/cisplat 45 to 59 Gy + 5FU /MMC 45 to 59 Gy RT + 5-FU/CDDP

21 RTOG 9811 Gunderson et al 2012 Long-term analysis 03/01/13

22 RTOG 9811 Gunderson et al 2012

23 RTOG 9811 Protocol

24 ACCORD- 03 Therapeutic intensification Induction chemotherapy (CRT cisplatin) High dose radiotherapy (CRT cisplatin) Primary endpoint: colostomy-free-survival(cfs).

25 ACCORD 03 Titre du diagramme 307 patients R CT CDDP 5FU 2 cycles CT CDDP 5FU 2 cycles No CT No CT 45 Gy CDDP 5 FU 2 cycles 45 Gy CDDP 5 FU 2 cycles 45 Gy CDDP 5 FU 2 cycles 45 Gy CDDP 5 FU 2 cycles low boost 15 Gy high boost Gy low boost 15 Gy high boost Gy 5 years CFS Standard arm 70% 82% 77% 73%

26 ACCORD CFS : induction versus no induction

27 ACCORD CFS : boost versus no boost

28 2 Trials No advantage to induction chemotherapy prior to CRT (actually worse in RTOG 9811)

29 ACT II 2 x 2 Factorial Design Concurrent and Maintenance Comparison R 50.4Gy in 28 fractions over 38 days NO GAP MMC 5FU CRT CisP 5FU CRT MMC 5FU CRT Maintenance MMC 5FU CRT No maintenance CisP 5FU CRT Maintenance RESPONSE CR primary 90% 90% CR N0 83% (358) 84% (362) CisP 5FU CRT No maintenance

30 Best time to assess complete clinical response (ccr) after CRT in Anal-Cancer: ACT II data n=691 attended all three assessments ccr: 64%, 80% and 85% at assessments 1, 2 and 3, respectively 72%: no ccr at assessment 1; ccr by assessment 3 5-year OS (at assessment 3): ccr=87%; non-ccr=48% Glynne-Jones et al, Lancet Oncolology 2017

31 The 5 R's Of Radiobiology/ Fractionation Repair Redistribution Reoxygenation Repopulation Radiosensitivity

32 Repair The 5 R's Of Radiobiology/ Redistribution Reoxygenation Repopulation Radiosensitivity? Add Fractionation Reinvigoration of immune defences

33 ACT II Progression free survival Comparison group 3-year rate, % (95%CI) 5-year rate, % (95% CI) MMC 73 (69 to 77) 69 (65 to 73) HR (95% CI), p value CisP 74 (69 to 77) 69 (64 to 73) 0.95 (0.75 to 1.19), p= 0.63 No-maint 73 (68 to 77) 69 (64 to 73) Maint 74 (69 to 77) 70 (65 to 74) 0.95 (0.75 to 1.21), p=0.70

34 Progression-free (%) No benefit for maintenance chemotherapy ACT 2 2x 100 Cis 5FU vs No maintenence HR: 0.95 (95% CI: 0.75 to 1.21, p=0.70) Age<65 > Number at risk No-maint Maint No-maint Maint Time since randomisation (years) Female Male T1/T2 T3/4 N0 N+ Squamous Non-squamous Canal Margin Well Mod Poor GFR<60 GFR>60 Overall

35 Colostomy free survival in ACT II Comparison group 3-year rate, % (95%CI) 5-year rate, % (95% CI) MMC 74 (69 to 78) 67 (63 to 72) HR (95% CI), p value CisP 73 (69 to 78) 67 (63 to 72) 1.01 (0.80 to 1.27), p=0.94 No-maint 67 (62 to 71) 65 (61 to 70) Maint 74 (69 to 78) 68 (63 to 73) 0.88 (0.69 to 1.11), p=0.28

36 Overall survival ACT II Comparison group 3-year rate, % (95%CI) 5-year rate, % (95% CI) MMC 84 (80 to 87) 79 (74 to 82) HR (95% CI), p value CisP 84 (80 to 87) 77 (73 to 81) 1.05 (0.80to 1.38), p=0.70 No-maint 85 (81 to 88) 79 (75 to 83) Maint 83 (79 to 86) 76 (72 to 80) 1.07 (0.81 to 1.41). p=0.65

37 Impact of day 29 Chemo Compliance on PFS (n=862) HR 1.63 (95% CI: 1.23 to 2.17 ) p=0.001

38 Capecitabine integrated into CRT in anal cancer Study RT MMC Capecitabine Glynne-Jones Gy in 28 fractions in 2 phases Single dose of MMC 12mg/m2 max 20mg 825 mg/m 2 b.i.d on radiation days Deenen 2013 Goodman 2014 Retrospective 59.4 Gy in 33 fractions with SIB- IMRT Single dose of MMC 10mg/m2 max 15mg Gy Mitomycin 10 mg/m2 day 1, mg/m 2 b.i.d on radiation days 825 mg/m 2 b.i.d on radiation days Oliveira 2016 phase II 54-59Gy mitomycin 15 mg/m2 IV day 1 Peixoto Gy Mitomycin 10 mg/m2 day 1, mg/m 2 b.i.d on radiation days 825 mg/m 2 b.i.d on radiation days Goodman 2017 *IMRT Gy Mitomycin 10 mg/m2 day 1, mg/m 2 b.i.d on radiation days

39 Goodman KA et al IJROBP 2017;5

40 Conclusions 1. MMC/capecitabine probably now a standard (cisplatin not better) 2. Maintenance chemotherapy no benefit 3. Induction chemotherapy no benefit in other studies 4. Compliance is important 5. Need a 6 th R (reinvigoration of immune system)

41 Centrum Onkologii-Instytut im. Marii Skłodowskiej-Curie, Warsaw Pilot of carbo/taxol (Cross regimen) in patients with cardiac problems? Study through IRCI in elderly frail/cardiac morbidity

42 PLATO PERSONALISING RADIOTHERAPY DOSE FOR ANAL CANCER T1 N0 Anal margin T1,T2<4cm N0 T3/4 NO T2N2, T3/4 N1-3 Local excision ACT3 Standard ACT4 Obs Adverse 41.4Gy 23F 50.4Gy 28F 41.4Gy 23F Pilot Ph II 53.2Gy 28F 58.8Gy 28F 61.6Gy 28F Courtesy of David Sebag-Montefiore Phase II trial Stratify for Cape vs. 5-FU Ph III Phase II/III trial

43 Plato design 5 Different doses ( but within a range) 41.4Gy/ 50.4Gy/ 53.2Gy/ 58.8Gy / 61.6Gy Allows current prognostic groups (p16+etc..) To be validated as predictive

44 ESMO guidelines for follow-up evaluate every 3 6 months for a period of 2 years, and 6 12 monthly until 5 years, with clinical examination including DRE and palpation of the inguinal lymph nodes. Anoscopy or proctoscopy is an additional option, but is sometimes poorly tolerated and too painful following CRT. Some recommend MRI on a 6 monthly basis for 3 years. Suspicious progressing lesions should be biopsied.

45 ESMO guidelines Regular CT scans for metastatic surveillance outside trials remains controversial, as the evidence for benefit of resection of metastases as performed in colorectal cancer is lacking Data from ACT II suggest very few (<1%) relapses occur after 3 years, so extended imaging surveillance after this time is not recommended

46 SCCA and metastatic disease Patients with small volume and/or few metastases (OLIGOMETASTASES) should be discussed in appropriate MDT In case 1. Surgical 2. CRT 3. SBRT options

47 InterAACT: IRCI anal cancer metastatic trial Trial design With Thanks to Sheela Rao chief investigator Arm A Cisplatin 60 mg/mq d1 q21 5FU 1000 mg/mq d1-4 q21 R 24 weeks of treatment (continue until PD or unacceptable toxicity upon investigators discretion) Arm B Carboplatin AUC5 d1 q28 Paclitaxel 80 mg/mq d1,8,15 q28 Stratification factors: Region (Europe vs. North America vs. Australia) ECOG PS (0-1 vs. 2) HIV +ve (yes vs. no) Inoperable locally recurrent vs. metastatic Phase II (selection trial design) Primary endpoint: ORR Sample Size: 80 patients 36 patients to be recruited to each arm in order to detect 10% difference in response rates between the experimental arms with 80% power (20% withdrawal rate taken into account) assuming 40% ORR in the Cisplatin/5FU arm

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49 Results: interim analysis: 65 patients The objective response rate is 87.7%, 36.9% complete responses. Among the first 32 patients with 12 months of follow-up, 15 (46.9%) patients were progressionfree at 12 months ESMO Kim S et al., Annals of Oncology 2017 ;28 (suppl_5): v158-v208.

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51 Thank you