Margaret Tempero, M.D.Director, UCSF Pancreas Center

San Francisco, CA

The Case for Post Operative

Adjuvant Therapy

DISCLOSURE INFORMATIONMargaret Tempero, M.D.

AstraZeneca: Advisory Board Advance Medical: ConsultantBioPharm: Consultant Bristol-Myers Squibb: Advisory Board CPRIT: Advisory Board EcoR1 Capital, LLC: Consultant Eisai: Consultant FibroGen: Advisory Board Ignyta: Consultant Immunovia: Advisory Board

Karyopharm Therapeutics: Consultant Mayo Clinic: Consultant Merck & Co.: Advisory Board Pharmacyclics: Consultant Pharmcyte Biotech: ConsultantTocagen: Consultant

Pancreatic Cancer Moved From 4th Place to 3rd Place as Leading Cause of Cancer Death

• Pancreatic cancer is the only one of the top 5 cancer killers for which deaths are projected to increase

• In 2016, pancreatic cancer moved from 4th to 3rd leading cause of cancer death in the US, surpassing breast cancer2

Pancreatic Cancer Action Network, website. “The alarming rise of pancreatic cancer deaths in the United states: Why we need to stem the tide today”, accessed at: https://www.pancan.org/wpcontent/uploads/2013/01/incidence_report_2012_executive_summary.pdf and “Pancreatic Cancer Facts”, accessed at: https://www.pancan.org/wp-content/uploads/2016/02/2016-GAA-PC-Facts.pdf. Accessed 18 August 2017.

Projected Cancer Deaths

Proj

ecte

d C

ance

r Dea

ths,

Th

ousa

nds

Age at Diagnosis

All Races

Both Sexes Males

20-24 0.1 -

25-29 0.2 0.2

30-34 0.5 0.4

35-39 1.0 1.1

40-44 2.7 3.0

45-49 5.6 6.3

50-54 10.7 13.1

55-59 18.9 22.8

60-64 30.1 36.4

65-69 44.4 52.4

70-74 60.5 68.2

75-79 78.3 85.8

80-84 92.9 102.8

85+ 101.2 109.5

Age-Specific SEER Incidence Rates, 2007-2011

SEER 18 areas. Rates are per 100,000 and are age-adjusted to the 2000 US Std Population (19 age groups)http://seer.cancer.gov/csr/1975_2011/browse_csr.php?sectionSEL=22&pageSEL=sect_22_table.07.html

Life Cycle of Cancer Therapy

Metastatic disease

Locally advanced disease

Resectable disease

Longer survivalMore Cures

New agents

a Superior arm of treatment.

Study Intervention Best Median OS, mo

GITSG (1985)1 Observation vs RT + 5-FUa 21.0

EORTC Trial 40891 (1999, 2007)2,3 Observation vs chemo RT 17.1

ESPAC-1 (2004)4 Observation vs 5-FU/LVa vs chemo RT vs chemo RT + 5-FU/LV 20.1

RTOG 97-04 (2008)5

Gemcitabine + chemo RT vs c.i. 5-FU + chemo RT 20.5

CONKO-001 (2013)6 Observation vs gemcitabinea 22.8

ESPAC-3 (2010)7 Gemcitabine vs 5-FU/LV 23.6

ESPAC-4 (2017)8 Gemcitabine vs gemcitabine/capecitabinea 28.0

Let’s Review 30 Years of Adjuvant Therapy

c.i.: continuous infusion; OS: overall survival.1. Kalser MH, Ellenberg SS. Arch Surg. 1985;120:899-903. 2. Klinkenbijl JH et al. Ann Surg. 1999;230:776-782. 3. Smeenk HG et al. Ann Surg. 2007;246:734-740. 4. Neoptolemos JP et al. N Engl J Med. 2004;350:1200-1210. 5. Regine WF et al. JAMA. 2008;299:1019-1026. 6. Oettle H et al. JAMA. 2013;310:1473-1481. 7. Neoptolemos J et al. JAMA. 2010;304:1073-1081. 8. Neoptolemos J et al. Lancet. 2017;389:1011-1024.

CONKO-001 OS2

ObservationMedian: 20.2 mo (95% CI, 17.7-22.8)Log rank P = .01

GemcitabineMedian: 22.8 mo (95% CI, 18.5-27.2)

1. Regine WF et al. JAMA 2008;299:1019-1026. 2. Oettle H et al. JAMA. 2013;310:1473-1481. 3. Neoptolemos J et al. JAMA.2010;304:1073-1081. 4. Neoptolemos JP et al. Lancet. 2017;389:1011-1024.

Adjuvant Trials: Snapshot of Overall SurvivalRTOG-9704 OS: All Patients1

ESPAC-4 OS4Time, y

OS,

%

Time, mo

Cum

ulat

ive

Surv

ival

Time, mo

OS,

%

HR: 0.82 (95% CI, 068-0.98);P = .032

OS,

%

Time From Resection, mo

ESPAC-3 OS3

Gem vs ci 5FUboth with chemo RT

Lessons• Adjuvant therapy works

• 25-30% of patients die in the first year

• gemcitabine and optimal administration of 5FU perform similarly

• gemcitabine plus capecitabine has a better outcome over gemcitabine monotherapy

Progress in Pancreatic Ductal AdenocarcinomaHas Been Very Slow

S1b

Slide courtesy of Philip Philip

1994 1998 2002 2006 2010 2014 2015

1. Herrmann R et al. J Clin Oncol. 2007;25:2212-2217. 2. Cunningham D et al. J Clin Oncol. 2009;27:5513-5518.

a Subsequently, gemcitabine-based combinations (eg, gemcitabine/capecitabine) also validated as treatment options in metastatic disease.1,2 b Approved only in Japan. c Liposomal irinotecan is not approved in adjuvant/neoadjuvant setting.

Gemcitabinea FOLFIRINOX

Nab-paclitaxel with

gemcitabineErlotinibLiposomalIrinotecan (Nal-Iri)c

Into the next era–adjuvant therapy with more

active regimens!

NCCN Category 1 Recommendation for Metastatic Disease

• FOLFIRINOX

• gemcitabine and nab-paclitaxel

New Age of Adjuvant Therapy

Study Intervention Best Median OS

PRODIGE 24 (2018) FOLRIRINOX vs gemcitabine

54.4 mos

APACT (2019) gemcitabine and nab-paclitaxel vs gemcitabine

40.6 mos

Better Pictures!PRODIGE 24 APACT

Differences:• APACT with more restrictive CA19-9• PRODIGE 24 with stratification within CA19-9 and node count

New Lessons• Median survival with gemcitabine monotherapy

is improving—better patient selection, better treatment upon recurrence

• FOLFIRINOX is the gold standard

• Gem/cape or Gem/nab-paclitaxel are options for less fit patients

• 20% of patients are still dying in the first year

Arguments for Immediate Surgery • No delay- if disease is refractory to treatment,

progression could preclude successful resection

• No need to expose patient to biliary stent placement or subsequent complications

• Avoids preemptive therapy in 10-15% of patients explored and found to be unresectable

• Chemotherapy after surgery could be more effective—growth factors that stimulate wound healing, also stimulate metastatic growth

Thank you!