Co Contempo porary Treatment Appr pproache ches s for r - - PowerPoint PPT Presentation

Co Contempo porary Treatment Appr pproache ches s for r Patients s with h Pancr ncreatic c Ca Cance ncer r

Philip A Philip, MD, PhD, FRCP Kathryn Cramer Endowed Chair in Cancer Research Professor of Oncology and Pharmacology Leader, GI and Neuroendocrine Oncology Karmanos Cancer Institute Wayne State University Detroit, Michigan

Sequencing therapy in metastatic disease First-line treatment

• “Younger older” patients
• Patients who have received prior neoadjuvant

therapy

Later-line treatment (Nal-IRI)

Sequencing therapy in metastatic disease First-line treatment

• “Younger older” patients
• Patients who have received prior neoadjuvant

therapy

Later-line treatment (Nal-IRI)

Co Contempo porary Treatment Appr pproache ches s for r Patients s with h Pancr ncreatic c Ca Cance ncer r

Philip A Philip, MD, PhD, FRCP Kathryn Cramer Endowed Chair in Cancer Research Professor of Oncology and Pharmacology Leader, GI and Neuroendocrine Oncology Karmanos Cancer Institute Wayne State University Detroit, Michigan

Disclosures

Advisory Committee ASLAN Pharmaceuticals, BioLineRx, Caris Life Sciences, Celgene Corporation, Eisai Inc, Erytech Pharma, Halozyme Inc, Ipsen Biopharmaceuticals Inc, Merck, TriSalus Life Sciences Consulting Agreements AbbVie Inc, Merck, Rafael Pharmaceuticals Inc, TriSalus Life Sciences Contracted Research Astellas, AstraZeneca Pharmaceuticals LP, Bayer HealthCare Pharmaceuticals, BeiGene, BioLineRx, Boston Biomedical Inc, Bristol-Myers Squibb Company, Caris Life Sciences, Celgene Corporation, Halozyme Inc, Incyte Corporation, Lilly, Novartis, Novocure, QED Therapeutics, Rafael Pharmaceuticals Inc, Roche Laboratories Inc, Taiho Oncology Inc Data and Safety Monitoring Board/Committee ASLAN Pharmaceuticals, Blueprint Medicines, Erytech Pharma, Lexicon Pharmaceuticals Inc Speakers Bureau Bayer HealthCare Pharmaceuticals, Bristol-Myers Squibb Company, Celgene Corporation, Ipsen Biopharmaceuticals Inc, Merck

In Incr cremen emental imp mprovemen ement in systemi emic c ther erapies es that are e largel ely y based sed on cy cytotoxic c drugs gs

1 year 6 mon

Gemcitabine1 Gemcitabine Erlotinib2 Gemcitabine nab-Paclitaxel3 FOLFIRINOX4 POLO5

• 1. Burris HA 3rd, et al. J Clin Oncol. 1997;15(6):2403-2413.1 2. Moore MJ, et al. J Clin Oncol. 2007;25(15):1960-1966. 3. Von

Hoff DD, et al. N Engl J Med. 2013;369(18):1691-1703. 4. Conroy T, et al. N Engl J Med. 2011;364(19):1817-1825; 5. Golan et al, NEJM, 2019.

Me Metastatic Pancrea eatic Cancer: er: AS ASCO Cl Clinical P Practice G e Guidel eline Up e Update In Initial As Asses essmen ent

• The goals of care
• Include discussion of an advance directive
• Patient preferences
• Support systems should be discussed with every patient with

metastatic pancreatic cancer and his or her caregivers

Sohal D et al. J Clin Oncology, 2018, 36(24):2545-2556

Me Metastatic Pancrea eatic Cancer: er: AS ASCO Cl Clinical P Practice G e Guidel eline Up e Update Tr Treatment recommendations

FOLFIRINOX

• ECOG PS 0-1
• Favorable comorbidity profile
• Patient preference
• Support system for aggressive medical

therapy

Gem Nab- paclitaxel

• ECOG PS 0-1
• Favorable comorbidity profile
• Patient preference
• Support system for a relatively

aggressive medical therapy

Gem

• ECOG PS of 2,
• r
• A comorbidity profile that precludes more

aggressive regimens and who wish to pursue cancer-directed therapy. Supportive care

• ECOG PS >3
• r
• with poorly controlled comorbid

conditions despite ongoing active medical care Sohal D et al. J Clin Oncology, 2018, 36(24):2545-2556

Se Second-Line Line Oxalipla aliplatin tin-Ba Based R Regi gimens: Con Confl flicting R g Results F From

• m P

Phase I III T Trials

CONKO-003 PANCREOX Patients (N = 268) PD on Gem Therapy (n = 160) Previous Gem Therapy (n = 108) Treatment OFF (n = 76) 5-FU/LV (n = 84) mFOLFOX6 (n = 54) 5-FU/LV (n = 54) OS, median 5.9 months 3.3 months 6.1 months 9.9 months HR 0.66 (95% CI, 0.48–0.91) P = .01 HR 1.78 (95% CI, 1.08–2.93) P = .02 PFS, median 2.9 months 2.0 months 3.1 months 2.9 months HR 0.68 (95% CI, 0.50–0.94) P = .02 HR 1.00 (95% CI, 0.66–1.53) P = .99

Oettle H, et al. J Clin Oncol. 2014;32(23):2423-2429. Gill S, et al. J Clin Oncol. 2016;34(32):3914-3920.

Phase 3 trial of Nano-liposomal irinotecan + 5-FU/LV as 2nd-line therapy for metastatic pancreatic cancer (NAPOLI-1)

Nal-IRI

(120 mg/m2 Q3W) n=151

Nal-IRI + 5-FU/LV

(80 mg/m2 + 2400 mg/m2 over 46 h / 400 mg/m2 Q2W) n=117

5-FU/LV

(2000 mg/m2 over 24 h / 200 mg/m2 weekly Q6W) n=149

• Metastatic

pancreatic cancer

• Received prior

gemcitabine-based therapy

• N=417

Primary endpoint: OS Secondary endpoints: PFS, ORR, CA19-9 response, safety Stratification: Albumin, KPS, ethnicity

Wang-Gillam et al. Lancet 2016;387:536

R

NAP NAPOLI LI-1: 1: Stu tudy y outcome me

Grade 3 or 4 Toxicity Nano-liri-5FU/LCV 5FU/LCV Diarrhea 13 % 4% Vomiting 11% 3% Appetite 4% 2% Fatigue 14% 4% Neutropenia 27% 1%

Wang-Gillam A, et al. Lancet 2016; Update Wang-Gillam, et al, JCO, 2016, 34:abstract 417

Cohort A

70/2400/400/60

Cohort C

50/2400/400/85

Cohort B 50/2400/400/60

Dose exploration & expansion

Cohort D

55/2400/400/70

Nal-Iri/5FU/LV/Oxaliplatin

NA NAPOX: X: mo movin ing Na Nal-Ir Iri to to the front nt line

Wainberg et al, ESMO GI, 2019

Nal-Iri 50 mg/m2 5FU 2,400 mg/m2 Oxaliplatin 60 mg/m2 Q 2 weeks Gemcitabine/ Nab-paclitaxel standard

R

N = 750, Overall Survival NCT04083235 Phase III No grade 3 or higher fatigue or neuropathy

PR PRODIGE 24/CC CCTG PA.6: Ph Phas ase III ad adjuvan ant trial al in res resec ected ed pa pancr ncreatic c c cance ncer

Stratification, by

• Center
• CA 19-9
• pN status
• Resection margin

R A N D O M I Z E

Modified FOLFIRINOX Oxaliplatin 85 mg/m2 Irinotecan 180 (150) mg/m2 5FU 2,400 mg/m2 X 12 cycles Gemcitabine Standard dose X 6 cycles

Primary endpoint = DFS CT scans Q 3 months

Conroy T, et al. N Engl J Med 2018; 379:2395-2406

Di Disease-fr free ee surviv vival al an and over erall all surviv vival al wer ere e sig ignific ifican antly ly im improved ed wit ith modified ified FOLFIR IRIN INOX

Conroy T, et al. N Engl J Med 2018; 379:2395-2406

Disease-free Survival Overall Survival

AP APACT: Pha Phase se III, Ope pen-La Label, Ra Randomized Tri rial of Adjuvant t nab nab-Pa Paclitaxel plus Gemcitabine vs Gemcitabine fo for Resected Pa Pancreatic Adenocarcinoma

Resected PDAC R0/R1; ECOG PS 0

• r 1; CA19-9 < 100

Arm A nab-Paclitaxel 125 mg/m2 qw 3/4 + Gemcitabine 1000 mg/m2 qw 3/4 × 6 cycles Arm B Gemcitabine 1000 mg/m2 qw 3/4 × 6 cycles

Randomized 1:1

• Patients were randomized no later than 12 weeks post surgery
• Stratification factors: R0 vs R1; LN+ vs LN−; North America, Europe and Australia vs Asia Pacific

Tempero et al, Abstract #4000, ASCO, 2019 866 patients; 179 sites; 21 countries

APACT did not meet the primary endpoint but demonstrated significant improvement in OS

Tempero et al, Abstract #4000, ASCO, 2019

19 20.5 21.6 22.8 23.6 24.5 28.0 30.4 28.0 46.5

Observe RTOG ESPAC1 CONKO1 ESPAC3 EORTC ESPAC4 IMPRESS CONKO5 JASPAC1

54.4

PRODIGE

FOLFIRINOX

Ev Evolution of adjuvant therapies in pancreatic cancer: me median overall survival time mes in mon months

S1

40.5

APACT

Nab-pacli/gem

PRODIGE[a] ESPAC-4[b] FOLFIRINOX Gemcitabine Gemcitabine/ Capecitabine Gemcitabine Completed all cycles 66.4 79.0 54 65 Relative dose intensity of > 0.70 48.7% 91.4%

• It Is a Challenge to Give Enough Combination

Chemo After Surgery!

• a. Conroy T, et al. N Engl J Med. 2018;379:2395-2406; b. Neoptolemos JP, et al. Lancet. 2017:389:1011-1024

More Patients Will Receive Effective Systemic Therapy With the Neoadjuvant Approach

100 Newly diagnosed resectable Surgery 80 R0/R1 R2+ 50 Adjuvant chemo 35 Complete adjuvant 15 Relapsed

NeoAdj Chemo 85 Surgery

15 Progression 50 Adjuvant chemo

≤ 50% receive chemo. 100% receive chemo. > 15% futile surgery 15% spared futile surgery

S-1505: picking a winner neoadjuvant regimen for resectable disease

mFOLFIRINOX 12 weeks Gemcitabine Nab-paclitaxel 12 weeks R E S E C T A B L E R R E S T A G I N G S U R G E R Y mFOLFIRINOX 12 weeks Gemcitabine Nab-paclitaxel 12 weeks Off study if, Toxicity Unresectability Primary endpoint is survival at 20 months N = 150

Role of Multimodality Therapy: The Literature Helps, But Also Confusing!

• FOLFIRINOX and gemcitabine/nab-paclitaxel are appropriate regimens

for first line therapy with comparable efficacy

• Careful patient assessment and discussion is very important
• Nal-Iri/5FU/LCV improves survival in patients after gemcitabine based

therapy

• Current development of Nal-Iri in frontline therapy
• mFOLFIRINOX is preferred adjuvant treatment, other options include

gemcitabine/capecitabine, gemcitabine/nab-paclitaxel, or gemcitabine

• Neoadjuvant therapy is preferred in patients with potentially

resectable pancreatic cancer

Conclusions