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

• r 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 Consult lting Perthera Ability Pharma Ho Honorar aria Foundation Medicine Recipien ent: t: I Insti titu tuti tion Resear arch F Funding ng Agios Bayer Bristol-Myers Squibb Celgene 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
• However, only 0.8% of pancreatics are MSI-H
• NTRK fusions: Larotrectinib [RR 75%]
• Test by targeted platform or NGS
• 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 HDR
• POLO: Double-blind randomized

Ph III trial, worldwide

• Germline BRCA1 or BRCA2

mutations (~7.5% of all)

• Not progressed on first-line

platinum therapy

• PFS improved vs. placebo
• No OS advantage
• No activity in non-germline cases

Golan T. NEJM. 2019.

Immunotherapy – No

• Gem/nab-P + Nivolumab
• First-line; Ph I; N = 50
• ORR 18%
• mOS 9.9 mths
• Durvalumab +/- Tremelimumab
• Second-line; Randomized Ph II; N = 65
• ORR 3% (combo); 0% (PD1)

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

Immunotherapy – Maybe…

• CD40
• Expressed broadly on many cells
• Primes antigen presenting cells, esp. dendritic cells and B cells
• CD154 (on surface of activated T cells) is natural ligand for CD40
• 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:
• Mild cytokine release syndrome only problem
• Encouraging RR, DCR
• No Gem/nabP control arm, however
• Need to study in randomized trials

Targeting Metabolism

• CPI-613
• Blocks tumor-specific mitochondrial enzymes
• Toxin accumulation leads to cytotoxicity
• Ph I; N=20; with FOLFIRINOX
• RR 61%; PFS 11.5 mths, OS NR
• Ph III RCT ongoing

Alistar A. Lancet Onc. 2017.

Metastatic – Failures

• PEGPH20 – PEGylated recombinant human hyaluronidase

enzyme that degrades hyaluronan (HA), allowing better ingress

• f chemotherapy into tumor
• SWOG S1313: FOLFIRINOX +/- PEGPH20 with worse
• utcomes [mOS 7.7 vs. 14.4 mths]
• Company sponsored Ph III ongoing…
• MEKi + AKTi for second-line
• SWOG S1115: Combination vs. FOLFOX, with worse
• utcomes [mOS 3.9 vs. 6.1 mths]
• PARPi for second-line
• 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 pathways
• Decitabine [DNMT1 inhibitor, leads to epigenetic cell cycle escape]
• Tetrahydrouridine [CDA inhibitor, stabilizes decitabine in plasma and avoids

intracellular degradation]

• Pilot study of 13 patients in metastatic pancreatic cancer
• Progressed on prior chemotherapy regimen(s)
• ECOG 0-2
• 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?