Locally advanced unresectable disease: treatment options Kalliopi Andrikou Modena Cancer Center Università degli Studi di Modena e Reggio Emilia Policlinico di Modena Italy

Pancreatic cancer deaths in 2030

The “concept” of surgical resectability LAPC

1 cm: 30% of probability of metastases Pancreatic cancer is a systemic disease from the onset Rhim AD et al. Cell 2012 1 cm: 30% of probability of metastases 3 cm: 90% of probability of metastases

Locally advanced pancreatic cancer: aims of treatment To prolong survival by reducing the risk of developing a metastatic disease (PFS) Better patient selection for those who may benefit from consolidative local therapy To achieve secondary resectability

Locally advanced pancreatic cancer: radiotherapy, chemotherapy or chemoradiotherapy

Gemcitabine→ CRT - LAP07 trial Critical issues Gemcitabine as induction therapy Radiotherapy RCT was well controlled in the trial (18% major deviations) 3. Capecitabine as the right choice for RCT??Gemcitabine better??

RCT with Cape less toxic Comparable effectiveness to Gem The SCALOP trial RCT with Cape less toxic Comparable effectiveness to Gem Mukherjee , Lancet Oncol 2013

Induction chemotherapy?

Chemotherapy as first choice: which drug or regimen? Gemcitabine Gem + Cape Gem + Cisplatin Gem + Oxaliplatin Gem + nab Paclitaxel FOLFIRINOX RR % 7-17.3 19.1 12.9 26.8 23 31 mPFS, mo 2.33-3.9 5.3 HR 0.78 3.8 HR 0.97 5.8 HR 1.287 5.5 HR 0.69 6.4 HR 0.47 mOS, mo 5.65-10** 7.1 HR 0.86 7.2 HR 1.10 8.8 HR 1.18 n.s. 8.5 HR 0.72 11.1 HR 0.57

Chemotherapy as first choice: GEMOX? Response and survival Gem (n=156) GEMOX (n=157) p Median OS, months All patients, n=313 7.1 9.0 0.13 LA, n=98 10.3 M, n=215 6.7 8.5 Summary of NCI-CTC Grade 3 to 4 toxicities per patient Toxicity Gem Arm (%) GEMOX Arm (%) p Neutropenia 27.6 20.4 NS Febrile neutropenia 1.3 Thrombocytopenia 3.2 14.0 0.0007 Anemia 10.3 6.4 Nausea 5.8 10.2 Vomiting 8.9 0.03 Diarrhea 5.7 Alopecia, grade 2 Peripheral sensory neuropathy 0.0 19.1 0.0001 Anche la combinazione GEMOX non è compresa tra i trattamenti standard per il IV stadio di malattia a causa dei due studi di fase III negativi. Nello studio europeo erano inclusi 98 pazienti con malattia in stadio III. Le mediane di sopravvivenza per questo sottogruppo di pazienti sono di 10,3 mesi sia per quelli trattati con sola gemcitabina sia per quelli trattati con la combinazione GEMOX. Le differenze in termini di tossicità di grado 3-4 sono invece rilevanti, a vantaggio della monoterapia. Non è pertanto raccomandato l’uso di questa combinazione neppure negli stadi III. Mod. da Louvet C, et al. J Clin Oncol 2005; 23: 3509–3516

Analysis of Pancreatic and Nonpancreatic Target Lesions Effect of nab-P + Gem vs Gem Alone on Pancreatic and Nonpancreatic Lesions in the MPACT Trial Results: Analysis of Pancreatic and Nonpancreatic Target Lesions 13 Variable nab-P + Gem Gem Pancreatic n 334 318 Baseline, median (range), mm 50.75 (10.0 - 157.0) 49.50 (16.0 - 151.0) Percentage change at nadir from baseline, Median (range) Mean (STDEV) −22.15 (−100.0 - 52.2) −24.69 (23.86) −7.02 (−77.0 - 107.1) −10.05 (18.042) P value < 0.001 Nonpancreatic 328 326 85.00 (12.0 - 342.0) 86.25 (10.0 - 364.0) −24.27 (−100.0 - 64.2) −27.34 (32.86) −8.74 (−100.0 - 278.6) −10.40 (34.68) Kunzmann et al. Pancreas 2017

Effect of nab-P + Gem vs Gem Alone on Pancreatic and Nonpancreatic Lesions in the MPACT Trial: Authors’ conclusions 14 In general, the efficacy of nab-P + Gem was similar in pancreatic and nonpancreatic lesions nab-P + Gem was associated with a greater reduction in tumor burden of both pancreatic and nonpancreatic lesions than Gem alone These results suggest that nab-P + Gem may be superior to Gem alone for treating LAPC; however, this will need to be validated in a prospective study Kunzmann et al. Pancreas 2017

LAPACT trial: Background Treatment options for LAPC are limited and generally similar to MPC In the phase III MPACT trial of patients with MPC, the reduction in primary pancreatic tumor size was ≈ 3-fold greater with nab-P + Gem vs Gem4 Based on antitumor activity observed against primary pancreatic tumors in the MPACT study, nab-P + Gem is being investigated in this study Includes previously untreated patients with unresectable LAPC only (no borderline resectable disease) Primary objective: evaluate TTF in patients with LAPC treated with nab-P + Gem induction followed by therapeutic options per the investigator’s choice Secondary objectives: evaluation of DCR, ORR, PFS, OS, safety, and QoL assessments The objective of this interim analysis was to assess preliminary safety and efficacy data after at least 45 patients had completed or discontinued the nab-P + Gem induction phase Lacy J, et al. Poster at ASCO GI 2017 [abstract 358].

LAPACT: Interim Phase II Results of nab-Paclitaxel + Gemcitabine for Patients With LAPC Previously untreated, unresectable LAPC Planned N = 110 Induction Phase nab-Paclitaxel 125 mg/m2 qw 3/4 + gemcitabine 1000 mg/m2 qw 3/4 Maximum of 6 cyclesa Investigator’s Choice For patients without disease progression or unacceptable toxicity nab-Paclitaxel + gemcitabine Chemoradiationb Surgical resection Periodic follow-up for PFS and OS Primary endpoint TTF: time from first dose of study therapy to treatment failure (treatment failure defined as discontinuation of study therapy due to disease progression, death by any cause, or the start of a nonprotocol-defined therapy) Secondary endpoints DCRc (after 6 cycles of therapy) ORR PFS OS Safety QoL (EORTC QLQ-C30 and QLQ-PAN26) a Surgical intervention was allowed prior to completing 6 cycles of nab-paclitaxel plus gemcitabine if deemed operable by the treating medical team. b Concurrent capecitabine or gemcitabine plus radiation according to institutional practice. c Combined incidence of CR, PR, and SD measured at the end of the treatment visit. Lacy J, et al. Poster at ASCO GI 2017 [abstract 358].

LAPACT trial: Selected Baseline Characteristics nab-P + Gem Induction Phase (n = 47) Investigator’s Choice Treatment Phasea nab-P + Gem (n = 5) Chemoradiation (n = 10) Surgery Age, median (range), years < 65, n (%) ≥ 65, n (%) 65.0 (43 - 85) 20 (43) 27 (57) 65.0 (56 - 71) 2 (40) 3 (60) 67.0 (58 - 83) 4 (40) 6 (60) 64.5 (55 - 72) 5 (50) Sex, female, n (%) 7 (70) ECOG PS, n (%)a 1 24 (51) 23 (49) 3 (30) Albumin, median (range), g/L 39.2 (28 - 46) 42.0 (37 - 42) 42.1 (37 - 44) 37.0 (28 - 44) CA19-9, median, U/mL 395.0 193.0 1060.8 43.8 Sum of longest diameter of target lesions, median (range), mm 43.0 (17 - 130) 53.2 (38 - 130) 44.5 (34 - 70) 41.0 (24 - 50) NLR, n (%) ≤ 5 > 5 Missing 42 (89) 4 (9) 1 (2) 2 (40) 0 10 (100) 0 0 9 (90) 1 (10) 47 patients received first dose of protocol therapy before February 1, 2016 and completed or discontinued nab-P + Gem induction by August 17, 2016 a Patients selected for investigator’s choice of treatment. Lacy J, et al. Poster at ASCO GI 2017 [abstract 358].

LAPACT: Interim Phase II Results of nab-Paclitaxel + Gemcitabine for Patients With LAPC Lacy J, et al. Poster at ASCO GI 2017 [abstract 358].

LAPACT: Interim Phase II Results of nab-Paclitaxel + Gemcitabine for Patients With LAPC Authors’ conclusions Results from this interim analysis suggest a tolerable safety profile for nab-paclitaxel plus gemcitabine; no new safety signals were identified thus far, and most patients (60%) completed the induction phase The 80% disease control rate for the first 47 patients to complete the nab-paclitaxel plus gemcitabine induction phase is promising and indicative of antitumor activity in patients with locally advanced pancreatic cancer Notably, all patients were identified as unresectable at baseline, yet 13% were resectable after the nab-paclitaxel plus gemcitabine induction phase Most patient-reported symptoms stabilized or improved during the induction phase Lacy J, et al. Poster at ASCO GI 2017 [abstract 358].

GAP trial: Study Design Phase II, randomized, open-label, multicenter study ARM A nab-paclitaxel + gemcitabine 3 cycles ALL Capecitabine + RT 5 weeks Locally advanced pancreatic cancer R ARM B gemcitabine 3 cycles If PD Second Line Chemotherapy Arm A: nab-paclitaxel 125 mg/mq + gemcitabine 1000 mg/mq days 1-8-15 q28 Arm B: gemcitabine 1000 mg/mq

LAPC: resectability after induction treatment

NCCN but not ESMO guidelines for LAPC Evolved to Mirror MPC Consider Surgical Resection Significant response to therapy Preferred: Clinical trial Category 2A: FOLFIRINOX (ECOG 0-1) Gem + ABX (KPS>70) Gem Mono Gem-based therapy Category 2B: Capecitabine, 5-FU +/- oxaliplatin ChemoRT in select patients following an adequate course of chemo no clear survival benefit * Gem Mono (cat. 1) Palliative and BSC Good PS Recommendation for AG and FFX based on extrapolation from RCTs in MPC Poor Good PS = ECOG 0-1 with good pain management, biliary stent, and adequate nutritional intake *Based on LAP-07 preliminary data, there’s no clear survival benefit to chemoRT after Gem therapy NCCN categories Category 1: based upon high-level evidence, there is uniform NCCN consensus that intervention is appropriate Category 2A: based upon lower-level evidence, there is uniform consensus that intervention is appropriate Category 2B: based upon lower-level evidence, there is NCCN consensus that intervention is appropriate Updates to NCCN guidelines in v1.2016 from v2.2015 (same changes made to MPC at this time) 2nd line therapy separated into recommendations dependent on gem based vs 5FU based therapy” Footnote added: “FFX should be limited to those with ECOG 0-1, AG is reasonable for pts KPS >70” “Small retrospective and prospective studies suggest FFX may have rendered some patients with LAPC resectable. However, it is too early to recommend FFX” (2015) Standard of Care: Gem Mono (6 months) Other options: Chemoradiation (Cape / RT recommended)

mOS: 24·2 months mPFS: 15 months R0 resection: 78.4%

A population-based study. Outcomes of FOLFIRINOX (and gemcitabine+nab-paclitaxel in initially unresectable locally advanced pancreatic cancer: A population-based study.   All pts in Ontario who started first-line FFX, GnP or gemcitabine (G) for uLAPC between April 2015 and March 2016 were identified in Cancer Care Ontario’s New Drug Funding Program database. Surgical resection after initial chemotherapy was not associated with better OS in multivariable analysis (HR 0.26, 95%CI 0.03-1.98, p= 0.19). Regimen N° patients 6-months OS Resection FOLFIRINOX 90 87.8 12 Nab-Paclitaxel 40 75.1 10 GEM 17 76.4 2 Chan et al. Journal of Clinical Oncology 35, no. 4_suppl (February 2017) 394-394.

RFA (Radiofrequency Ablation) IRE (Irreversible Electroporation) HIFU (High Intensity Focused Ultrasound) Photodynamic therapy Cryoablation Microwave Ablation

The treatment of locally advanced unresectable disease: conclusions Applicability of results from trials on stage IV to stage III may be tricky (different disease) Stage-specific trials are mandatory and patients should be offered Optimal chemo for stage III disease remains undefined. Actually, gemcitabine alone should be(?) considered as a standard of care Define the role of novel ablative therapies I risultati degli studi condotti in popolazioni di pazienti con stadio IV di malattia non sono necessariamente applicabili anche allo stadio III. Questa generalizzazione può essere insidiosa, è metodologicamente scorretta e non consente un’adeguata valutazione del rapporto rischio-beneficio. È perciò necessario implementare gli studi stadio-specifici per poter dare una risposta basata sull’evidenza ai tanti quesiti irrisolti, primo tra i quali quello della scelta dello schema chemioterapico ottimale. Inoltre, studi che permettano di identificare biomarcatori predittivi di progressione locale o sistemica sono assolutamente necessari.

I risultati degli studi condotti in popolazioni di pazienti con stadio IV di malattia non sono necessariamente applicabili anche allo stadio III. Questa generalizzazione può essere insidiosa, è metodologicamente scorretta e non consente un’adeguata valutazione del rapporto rischio-beneficio. È perciò necessario implementare gli studi stadio-specifici per poter dare una risposta basata sull’evidenza ai tanti quesiti irrisolti, primo tra i quali quello della scelta dello schema chemioterapico ottimale. Inoltre, studi che permettano di identificare biomarcatori predittivi di progressione locale o sistemica sono assolutamente necessari.