ASCO Poster Review PANCREATIC CANCER

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1 ASCO Poster Review PANCREATIC CANCER Dr.ssa Michela Squadroni U.O. Oncologia Humanitas Gavazzeni Bergamo

2 TOPICAL ISSUES Gemcitabine/Nab-paclitaxel and FOLFIRINOX comparison Neoadjuvant and perioperative treatment New drugs, immunotherapy Genomics and molecular biology

3 Gemcitabine-Nabpaclitaxel and FOLFIRINOX comparison (first line) AIOM post ASCO Potential first line treatment: FOLFIRINOX or Gemcitabine and Nab-paclitaxel Which one should we use? No comparative prospective trial 861 patients with metastatic pancreatic cancer Median OS 8.5 vs 6.7 months (Gem/Nab-paclitaxel vs Gem) 342 patients with metastatic/locally advanced pancreatic cancer Median OS 11.1 vs 6.8 months (FOLFIRINOX vs Gem)

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5 Kim S. et al Retrospective cohort study from US oncologist record PATIENTS selection: Metastatic pancreatic cancer Treated from april to december 2015 with Gem/Nab-paclitaxel or FOLFIRINOX Not enrolled in clinical trial COMPARISON First line therapy: Gem/Nab-paclitaxel vs FOLFIRINOX Second line therapy: Gem/Nab-paclitaxel vs FOLFIRINOX treated with second line 654 patients analyzed, median follow-up 10.7 months Gem/Nab-paclitaxel: 337 (51.5%) vs FOLFIRINOX: 317 (48.5%)

6 RESULTS Patients treated with gem-abraxane were Older (median age 64 vs 59) Worst clinical condition(ecog % vs 9.2%; more comorbidities) than patients treated with FOLFIRINOX Similar percentage of second line chemotherapy (36.1 vs 41% gem abraxane vs FOLFIRINOX) Toxicity: incidence of any grade 3-4 toxicity were similar in Gem-Abraxane and FOLFIRINOX (35% vs 33.6%, p 0.57). Nausea/vomiting, diarrhea, stomatitis and fatigue more frequent in FOLFIRINOX Non statistically significant difference in term of OS by first and second line between Gem-Abraxane and FOLFIRINOX

7 Gemcitabine-Nabpaclitaxel and FOLFIRINOX comparison (second line) AIOM post ASCO 30-40% of patients do not receive second line chemotherapy Many phase II trials and retrospective analysis Nanoliposomal irinotecan is the only validated drug for second line chemotherapy (NAPOLI-1 Wang-Gillam et al; Lancet 2016) 417 patients randomized, 117 5FU+NALIRI, 151 NALIRI, 151 5FU Median OS 6.1 vs 4.2 months (5FU/NALIRI vs 5FU) No difference between monotherapy (NALIRI and 5FU)

8 FOLFIRINOX or Nab-Paclitaxel based second line? Phase II and retrospectitve data supporting potential role of both FOLFIRINOX and Nab-paclitaxel based chemotherapy in second line setting

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10 AIM of the study Comparison of second line mfolfirinox after Gem/Abraxane and Gem/Nab-paclitaxel after mfolfirinox Similar patients characteristics (age, ECOG performance Status, metastatic sites, primary tumor site and biliary stent presence) GnP N=25

11 RESULTS No statistically significant difference in term of OS and PFS and DCR

12 Neoadjuvant and perioperative therapy Phase II trials, retrospective analysis and meta analysis support neoadjuvant treatment (chemotherapy and chemoradiotherapy) Phase III trials are ongoing Adjuvant chemotherapy improves survival in pts treated with preoperative treatment (Roland et al; Ann Surg Oncol 2015) Why neoadjuvant? Patients selection Tumor shrinkage to improve R0 resection rate Better delivery of chemotherapy and radiotherapy

13 Neoadjuvant therapy Neoadjuvant therapy is not a standard yet, but it should be considered in locally advanced and border line resectable pancreatic cancer (3rd St. Gallen Gastrointestinal Cancer Conference; 2017)

14 Neoadjuvant therapy UNSOLVED QUESTIONS Which chemotherapy Chemotherapy alone or chemoradiotherapy Treatment duration Postoperative treatment

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17 RESULTS Interim analysis About 70% in both arms had borderline resectable disease After induction chemotherapy 22.6 % of patients discontinued therapy (mainly progressive disease, and adverse events) 68% of patients completed treatment after randomization No survival data available Preliminary results of randomized patients Arm A nabpac/gem (N=42) DCR (%) PD(%) 7 11 Exploratory laparotomy (%) R0/R1 resection (%) RO/R1 resection (of surgically explored pts) 11/23 13/21 CONCLUSIONS ARMB FOLFIRINOX (N=44) Both FOLFIRINOX and nabpac/gem are effective and feasible High disease control rate (90%) Promising surgical conversion rates

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19 AIM of the study: evaluate the impact of neoadjuvant chemoradiotherapy (NACRT) on perioperative and long term clinical outcome Retrospective analysis 290 pts from 2006 to 2016: 160 treated with neoadjuvant CRT and 130 with upfront surgery) Of 160 NACRT pts 153 completed treatment (96%) 139 underwent surgery (87%)

20 RESULTS CONCLUSIONS High rate of treatment completion (96%) Long term better survival in NACRT (with the exception of arterial invasive tumor) Favourable pathological effect (lower N+ rate and higher R0 resection rate)

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22 Potential novel therapy AIOM post ASCO New chemotherapy combinations Biological agents Moleculer/genomics driven treatment Immunotherapy

23 Novel Chemotherapy Combination AIOM post ASCO

24 Multicentric phase I/II trial investigating the substituion of CPT11 or Oxaliplatin with Nab-paclitaxel in FOLFIRINOX Primary Endpoint: To assess the activity of NabFOLFIRI and NabFOLFOX in first line in term of ORR Secondary Endpoint: Clinical Benefit, PFS, OS, Safety profile Inclusion Criteria: Age >18 and < 75 years Metastatic disease Non prior chemotherapy o radiotherapy for advanced cancer Performance Status ECOG 0-1

25 RESULTS Best Overall Response TUMOR ASSESSMENT Arm A (Nab-FOLFIRI) %(N) CR 0 0 PR 31%(13) 31%(13) SD 38%(16) 49%(17) ArmB (Nab-FOLFOX) No significant difference in term of CBR and ORR Grade 3 toxicity was 24% and 50% for NabFOLFIRI and nabfolfox respectively Grade 4 toxicity was 17% and 5% for NabFOLFIRI and nabfolfox respectively PD 26%(11) 12%(5) Not assessed 5%(2) 12%(5%) CBR (CR+PR+SD) 69%(29) 71%(30%) Nab-FOLFIRI PFS 6 month, OS 13.6 months Nab-FOLFOX PFS 5.6 months, OS 10.5 months CONCLUSION NabFOLFIRI and NabFOLFOX could represent a potential alternative firts line CT (achieving similar OS and PFS rate of FOLFIRINOX; with lower toxicity rate) Need for further investigation and validation (phase III trial)

26 Immunotherapy?

27 Analyzing the efficacy and safety of immunotherapy in pancreatic ductal adenocarcinoma (PDA): a systematic review and meta-analysis Babiker HM, et al. Meta-analysis and review of published and presented data of immunotherapy in pancreatic cancer Many data derive from ongoing trials (16%) or abstract (44%) Fifty four trials met criteria for further analysis (39 metastic, 12 adjuvant and 3 neoadjuvant) Modest activity and inconclusive data Need for further investigation!

28 Pancreatic cancer microenvironment Pancreatic stellate cells and fibroblasts: produce ECM (collagen,laminin, fibronectin). Reduce therapeutic sensitivity Inflammatory fibroblasts (CAF: cancer asociated fibroblasts): CAFs promote tumor growth and favour immunosuppression Myeloid cells: induce dense stromal cell reaction, and immunosoppressive microenvoronment. Immune infiltrate is mainly constituted by myeloid suppressor cells. Possible correlation with fibrosis T cells: not clear correlation and presence in pancreatic cancer. About a quarter present CD4 and CD8, but functional cells are rare No benefit from T cell regulatory immunotherapy Possibility to enhance immunotherapy acitivy in pancreatic cancer Use of chemotherapy to enhance antigen expression Repletion of myeloid cells (in order to reduce fibrosis and imunosuppression) Recruitment and augmentation of T cells expressione

29 Immunotherapy?

30 Phase II randomized trial of double immunotherapy (Durvalumab and Tremelimumab) + Chemotherapy (gemcitabine/nab-paclitaxel) vs Gemcitabine /Nab-paclitaxel PRIMARY ENDPOINT: Overall Survival SECONDARY ENDPOINT: PFS, ORR, safety and toxicity Rational for immunotherapy and chemotherapy in pancreatic cancer Durvalumab: specific binding PD L-1 Tremelimumab: anti CTLA-4 antibody Cancer associated fibroblast (CAF)reduce immunotherapy activity and nab paclitaxel induce CAF depletion Chemotherapy may induce antigens expression Double immunotherapy (anti PDL1 and CTLA-4) has sinergistic activity in mouse models

31 RESULTS Preliminary data from safety run in (11 patients enrolled) Median follow-up of 8.3 months Toxicity: 1 patient had grade 3 colitis Most common grade 2 toxicity:fatigue, anemia, abnormal WBC and lipase, hyponatremia Efficacy: 8/11 (73%) had partial response, median duration of 7.4 months Median PFS 7.9 months Median OS not reached, 6 Months survival rate 80% CONCLUSION Data of safety run in showed interesting acivity and acceptable toxicity profile Phase II trial is ongoing (planned enrollment of 130 patients)

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33 Genetic profile of pancreatic cancer Most common genetic mutation: KRAS, TP53, CDKN2A, SMAD4, RNF43, ARID1A, TGFbR2, GNAS, RREB1, and PBRM1 KRAS mutation in > 90% pancreatic cancer 10% harbor mutation in BRCA1/2, PALB 2 and ATM MMR gene mutation could be observed BRAF mutation and mtor pathway activation are frequent in KRAS WT

34 Therapeutical and clinical implication Potential therapeutic target -BRCA, PALB2 (platinum sensitivity, potential PARP inhibitor sensitivity) -BRAF -Currently no other potential target Pihlak R. et al. Cancers 2018 PROPOSED GENOMIC CLASSIFICATION On the basis of mutational status and clinical characteristics BAYLEY (Nature 2016): - Squamous and adenosquamous - Pancreatic progenitor - Immunogenic - ADEX (aberrantly differentiated endocrine exocrine) WADDEL (Nature 2015) - Stable - Scaterred - Locall rearranged - Unstable. MOFFITT - Basal like - Classical

35 Genomic and molecular biology

36 BACKGROUND AND AIM OFTHE STUDY Pancreatic cancer can have BRCA 1/2 mutation and other homologous recombinant paththway genes. AIM of the study is to investigate the therapeuthic prognostic significance of these mutations 3030 patients analyzed comparing carriers and non carrieris of BRCA 1/2, PALB2 and ATM deletereous mutations (4.6% of patients had germline mutation) Comparison of clinical outcome with chemotherapy according to mutational status

37 RESULTS Relative distribution of BRAC1/2, PALB and ATM mutations in 139 (4.6%) patients with deletereous mutations Survival benefit slightly better in patients with mutation (14.3 vs 11.3 months, p=0.07) When analyzed post-folfirinox era, 40 patients with these mutation had better outcome than 668 non carriers (adjusted HR 0.62, p=0.0062) CONCLUSIONS BRCA1/2, PALB2 and ATM mutation is present in about 5% of patients, In post-folfirinox era pts with mutation had longer survival Development of trial incorporating this information could have potential value for PDAC (olaparib? Other treatment)

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39 MultiOmic: gemonic,proteomic and phspoproteomic analysis AIM of the study: to define frequency of genetic and proteomic mutation in primary tumor and metastatic site and identify potential differences between them To explore potential moleculal target for treatment Methods 505 patients, tumor sample analyzed according to Perthera reports 182 primary sites and 323 metastatic site

40 RESULTS The 4 most common mutations seen in pancreatic cancer (SMAD4, CDKN2Am p53 and KRS ) were similar between primary and metastatic site Proportion of actionable mutations was similar between groups Within metastatic site specific tissue pattern expression was observed (liver vs lung higher TUBB3 and lower PTEN mutation) CONCLUSION No statistically significant difference in specific gene mutation observed between primary tumor and metastatic site Confirm the reason of early metastatization Potential molecular target even in early disease Non need for rebiopsy

41 CONCLUSION Gemcitabine-Nabpaclitaxel and FOLFIRINOX comparison o Comparison in real life shows similar activity both in first and second line o NB different patients characteristics and toxicity profile Neoadjuvant and perioperative treatment o FOLFIRINOX and Gem-Nabpaclitaxel potentially active in LAPC o Long term benefit confirmed with preoperative CT-RT o New treatment/schedules under investigation (Gem/Nabp+RT) and Phase III clinicl trial New drugs, immunotherapy o Nab FOLFOx/Nab FOLFIRI o Excaping immunotherapy resistance (immunotherapy and chemotherapy combination) o Other moleculer treatment under evaluation (immunotherapy, olaparib) Genomics and molecular biology o Prognostic and predictive role o Potential molecular target identification