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Pancreatic CancerBeyond FOLFIRINOX:

Novel Strategies for Systemic Disease

ISGIO 2019

Davendra P. S. Sohal, MD, MPHAssociate Professor, Hematology/Oncology

Director of Experimental TherapeuticsClinic Medical DirectorUniversity of Cincinnati

Disclosures

Recipient: Self

ConsultingPertheraAbility Pharma

HonorariaFoundation Medicine

Recipient: Institution

Research FundingAgiosBayerBristol-Myers SquibbCelgeneGenentechInCyteLoxoNovartisOncoMed

Audience Question

Which of these is NOT a promising novel treatment strategy for metastatic pancreatic cancer?

A. CPI-613 (Devimistat)B. Durvalumab/TremelimumabC. CD40 agonistsD. 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%]

o Test by IHC or PCR or NGSo However, only 0.8% of pancreatics are MSI-H

• NTRK fusions: Larotrectinib [RR 75%]o Test by targeted platform or NGSo Only 0.5% of pancreatics have NTRK fusions

• Clinical trials

Sohal D. JCO. 2018. Wang-Gillam. Lancet. 2016. Le D. Science. 2017. Drilon A. NEJM. 2018.

• PARPi targeting HDRo POLO: Double-blind randomized

Ph III trial, worldwideo Germline BRCA1 or BRCA2

mutations (~7.5% of all)o Not progressed on first-line

platinum therapyo PFS improved vs. placebo o No OS advantageo No activity in non-germline cases

Golan T. NEJM. 2019.

Immunotherapy – No

• Gem/nab-P + Nivolumabo First-line; Ph I; N = 50o ORR 18%o mOS 9.9 mths

• Durvalumab +/- Tremelimumabo Second-line; Randomized Ph II; N = 65o ORR 3% (combo); 0% (PD1)

Ott P. JCO. 2018. Wainberg Z. ASCO GI. 2019. O’Reilly E. JAMA Onc. 2019.

Immunotherapy – Maybe… • CD40

o Expressed broadly on many cellso Primes antigen presenting cells, esp. dendritic cells and B cellso CD154 (on surface of activated T cells) is natural ligand for CD40o Not a kinase or phosphatase: acts via adaptor molecules

Vonderheide R. Ann Rev Med. 2019. Public information to FDA by Apexigen.

CD40 Agonism in Pancreatic Cancer

O’Hara M. AACR. 2019.

• Future Directions:o Mild cytokine release syndrome only problemo Encouraging RR, DCRo No Gem/nabP control arm, howevero Need to study in randomized trials

Targeting Metabolism • CPI-613

o Blocks tumor-specific mitochondrial enzymeso Toxin accumulation leads to cytotoxicityo Ph I; N=20; with FOLFIRINOXo RR 61%; PFS 11.5 mths, OS NRo Ph III RCT ongoing

Alistar A. Lancet Onc. 2017.

Metastatic – Failures • PEGPH20 – PEGylated recombinant human hyaluronidase

enzyme that degrades hyaluronan (HA), allowing better ingress of chemotherapy into tumoro SWOG S1313: FOLFIRINOX +/- PEGPH20 with worse

outcomes [mOS 7.7 vs. 14.4 mths]o Company sponsored Ph III ongoing…

• MEKi + AKTi for second-lineo SWOG S1115: Combination vs. FOLFOX, with worse

outcomes [mOS 3.9 vs. 6.1 mths]

• PARPi for second-lineo SWOG S1513: FOLFIRI +/- veliparib, with worse outcomes

Why Don’t Things Work?

• KRAS and TP53, and p16, SMAD4…

Singhi A. Gastroenterology. 2019. Waters A. Cold Spr Har Persp Med. 2018.

• 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…

TP53 Avoidance

• Epigenetic differentiation therapy, avoiding apoptosis pathwayso Decitabine [DNMT1 inhibitor, leads to epigenetic cell cycle escape]o Tetrahydrouridine [CDA inhibitor, stabilizes decitabine in plasma and avoids

intracellular degradation]

• Pilot study of 13 patients in metastatic pancreatic cancero Progressed on prior chemotherapy regimen(s)o ECOG 0-2o All patients enrolled April – August 2017

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…

Thank You!

Questions/Comments?