Pancreat atic ic C Canc ncer Beyond F FOLF LFIR IRINO INOX: - PowerPoint PPT Presentation

Pancreat atic ic C Canc ncer Beyond F FOLF LFIR IRINO INOX: Novel St Strat ategies f for or Sy Systemic Dis Diseas ase ISGIO 2019 Davendra P. S. Sohal, MD, MPH Associate Professor, Hematology/Oncology Director of Experimental Therapeutics Clinic Medical Director University of Cincinnati

Disclosures Rec ecipi pient: S Sel elf Recipien ent: t: I Insti titu tuti tion Consult lting Resear arch F Funding ng Perthera Agios Ability Pharma Bayer Bristol-Myers Squibb Ho Honorar aria Celgene Foundation Medicine Genentech InCyte Loxo Novartis OncoMed

Audience Question Which of these is NOT a promising novel treatment strategy for metastatic pancreatic cancer? A. CPI-613 (Devimistat) B. Durvalumab/Tremelimumab C. CD40 agonists D. TP53 avoidance

Conroy T. NEJM. 2011.

Sohal D. JCO. 2016. Tempero M. JNCCN . 2019. Ducreux M. Ann Onc . 2015.

mOS 54.4 mths in FFX arm!! Conroy T. NEJM. 2018.

Metastatic Second-Line • After FOLFIRINOX, perhaps Gem/nab-P • After Gem/nab-P, perhaps 5-FU/nal-IRI [mOS 6.1 vs. 4.2 mths] • Test molecular make-up: • MSI-H: Pembrolizumab [RR 53%, DCR 77%] Test by IHC or PCR or NGS o However, only 0.8% of pancreatics are MSI-H o • NTRK fusions: Larotrectinib [RR 75%] Test by targeted platform or NGS o Only 0.5% of pancreatics have NTRK fusions o • Clinical trials Sohal D. JCO. 2018. Wang-Gillam. Lancet . 2016. Le D. Science . 2017. Drilon A. NEJM . 2018.

• PARPi targeting HDR POLO: Double-blind randomized o Ph III trial, worldwide Germline BRCA1 or BRCA2 o mutations (~7.5% of all) Not progressed on first-line o platinum therapy PFS improved vs. placebo o No OS advantage o No activity in non-germline cases o Golan T. NEJM. 2019.

Immunotherapy – No • Gem/nab-P + Nivolumab First-line; Ph I; N = 50 o ORR 18% o mOS 9.9 mths o • Durvalumab +/- Tremelimumab Second-line; Randomized Ph II; N = 65 o ORR 3% (combo); 0% (PD1) o Ott P. JCO . 2018. Wainberg Z. ASCO GI. 2019. O’Reilly E. JAMA Onc . 2019.

Immunotherapy – Maybe… • CD40 Expressed broadly on many cells o Primes antigen presenting cells, esp. dendritic cells and B cells o CD154 (on surface of activated T cells) is natural ligand for CD40 o Not a kinase or phosphatase: acts via adaptor molecules o Vonderheide R. Ann Rev Med . 2019. Public information to FDA by Apexigen.

CD40 Agonism in Pancreatic Cancer • Future Directions: Mild cytokine release syndrome only problem o Encouraging RR, DCR o No Gem/nabP control arm, however o Need to study in randomized trials o O’Hara M. AACR . 2019.

Targeting Metabolism • CPI-613 Blocks tumor-specific mitochondrial enzymes o Toxin accumulation leads to cytotoxicity o Ph I; N=20; with FOLFIRINOX o RR 61%; PFS 11.5 mths, OS NR o Ph III RCT ongoing o Alistar A. Lancet Onc. 2017.

Metastatic – Failures • PEGPH20 – PEGylated recombinant human hyaluronidase enzyme that degrades hyaluronan (HA), allowing better ingress of chemotherapy into tumor SWOG S1313: FOLFIRINOX +/- PEGPH20 with worse o outcomes [mOS 7.7 vs. 14.4 mths] Company sponsored Ph III ongoing… o • MEKi + AKTi for second-line SWOG S1115: Combination vs. FOLFOX, with worse o outcomes [mOS 3.9 vs. 6.1 mths] • PARPi for second-line SWOG S1513: FOLFIRI +/- veliparib, with worse outcomes o

Why Don’t Things Work? • KRAS and TP53, and p16, SMAD4… • AMG 510 – targets KRAS G12C • Enrolling NSCLC, CRC patients • In NSCLC group, of 13 evaluable, 7 had PR, 6 had SD (DCR 100%!) • However, KRAS G12C in only 1% of pancreas cancer cases… Singhi A. Gastroenterology . 2019. Waters A. Cold Spr Har Persp Med . 2018.

TP53 Avoidance • Epigenetic differentiation therapy, avoiding apoptosis pathways Decitabine [DNMT1 inhibitor, leads to epigenetic cell cycle escape] o Tetrahydrouridine [CDA inhibitor, stabilizes decitabine in plasma and avoids o intracellular degradation] • Pilot study of 13 patients in metastatic pancreatic cancer Progressed on prior chemotherapy regimen(s) o ECOG 0-2 o All patients enrolled April – August 2017 o Saunthararajah Y. Semin Oncol . 2012.

TP53 Avoidance – Lessons • Feasible • No responses; only 1 stable disease • Preclinical modeling: Decitabine and 5-Azacitidine are needed in parallel, to overcome enzymatic resistance [DCK, UCK2 act in concert to degrade Dec and 5Aza, respectively]

Summary • FOLFIRINOX for everyone • Test genome: Tumor and patient • Olaparib (gBRCAm), pembrolizumab (MSI-H), larotrectinib (NTRK fusions) • Trials, trials, trials! CD40, CPI-613, KRAS G12C, TP53 avoidance, HDR deficiency targeting, stromal agents…

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