By Anne M Noonan MBBchBAO, MSc Assistant Professor The Ohio State University OSUCCC - James

1. The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
Update on Systemic
Therapy for
Metastatic Pancreas
Adenocarcinoma
Anne M Noonan
MBBChBAO, MSc
Assistant Professor

2. AIMS
 To outline the treatment options for first and second line
therapies for metastatic pancreas cancer
 Review approach to targeted therapies through
molecular profiling

3.  Pancreas adenocarcinoma is an aggressive disease
 85% are adenocarcinomas arising from ductal epithelium
 Surgical resection offers the only chance of cure
 Only 15-20% of patients have resectable disease at
diagnosis
 Median survival:
 locally advanced unresectable disease is 8-12 months
 Metastatic disease – 3 to 6 months
 Chemoresistance is a major problem
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Background

4. First Line
Regimens
4

5.  Single agents – gemcitabine, 5FU, capecitabine and S1
 objective response rates of ≈10%
 median overall survival of 6 to 7 months
 Gemcitabine monotherapy (800mg/m2 IV weekly on
days 1,8 and 15 of 28 day cycle) is generally now only
considered for patients with performance status of ≥2
 Response rate of 11%
 Clinical benefit rate (improvement in pain, PS and weight)
was 27%
 5FU – response rate of 0-9%
 Capecitabine – first line response rate of 7% but CBR of
24%
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In the past….

6.  Multicenter randomized phase 2-3 trial of 342 patients
 FOLFIRINOX (oxaliplatin 85mg/m2, irinotecan 180mg/m2,
leucovorin 400mg and 5FU 400mg/m2 given as a bolus
followed by 2400mg/m2 given as continuous 46hr
intravenous infusion, every 2 weeks)
Versus
 Gemcitabine 1000mg/m2 weekly for 7 of 8 weeks and
then weekly for 3 of 4 weeks
 Objective response rate was 31.6% with FOLFIRINOX
and 9.4% with gemcitabine
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FOLFIRINOX

7. FOLFIRINOX
Median overall survival
was 11.1 months in
FOLFIRINOX group and
6.8 months in
gemcitabine group
Median progression-free
survival was 6.4 months
in FOLFIRINOX group
and 3.3 months in
gemcitabine group

10.  Due to toxicity, FOLFIRINOX is reserved for good
performance status patients aged <76
 Most clinicians would recommend against giving it to
patients >70
 In practice, omitting the bolus of 5FU and the leucovorin
can improve tolerability
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11.  Phase III trial of 861 patients
 Nab-paclitaxel 125mg/m2 followed by gemcitabine
1000mg/m2 on days 1, 8 and 15 every 4 weeks
versus
 Gemcitabine 1000mg/m2 weekly for 7 of 8 weeks then on
days 1,8 and 15 every 4 weeks
 Response rate was 23% in nab-paclitaxel with
gemcitabine group compared to 7% with gemcitabine
alone
 Rate of disease control (confirmed response or stable
disease for ≥16 weeks) was 48% in nab-paclitaxel plus
gemcitabine versus 33% in the gemcitabine alone group
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Gemcitabine and Nab-Paclitaxel

12. • Gemcitabine & Abraxane (nab-
paclitaxel) versus gemcitabine
alone
• Median overall survival of 8.5
months versus 6.7 months
• Median PFS of 5.5months in
gemcitabine plus nab-paclitaxel
versus 3.7 months with
gemcitabine alone

14.  Gemcitabine and nab-paclitaxel is a reasonable first line
treatment option for patients with metastatic pancreas
cancer
 Better tolerated than FOLFIRINOX so gemcitabine and
nab-paclitaxel is preferred for older patients >70 and
patients with ECOG of 2/KPS of 70
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15. Second Line
Regimens
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16.  Global randomized phase III trial of 417 patients
 Previously treated with gemcitabine-based therapy
 Nanoliposomal irinotecan (Onyvide) (80mg/m2 equivalent
to 70mg/m2 of irinotecan base) with 5FU and leucovorin
 Compared to 5FU and LV monotherapy or nanoliposomal
irinotecan (120mg/m2 [100mg/m2 irinotecan base])
monotherapy every 3 weeks
 Primary endpoint was overall survival
 16% of patients assigned nanoliposomal irinotecan with
5FU/LV had an objective response vs 1% in 5FU/LV
group and 6% in the nanoliposomal irinotecan
monotherapy group
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Nanoliposomal irinotecan with fluorouracil and folinic
acid in metastatic pancreatic cancer after previous
gemcitabine-based therapy (NAPOLI-1)

17. Kaplan-Meier survival analysesHR=hazard ratio. (A) Overall survival with nanoliposomal irinotecan plus fluorouracil and folinic acid
versus fluorouracil and folinic acid. (B) Overall survival with nanoliposomal irinotecan monotherapy versus fluorourauracil and folinic
acid. (.
Andrea Wang-Gillam, et al. THE LANCET Volume 387, Issue 10018, 6–12 February 2016, Pages 545–557
Nanoliposomal irinotecan with fluorouracil and folinic acid in metastatic pancreatic cancer after
previous gemcitabine-based therapy (NAPOLI-1): a global, randomised, open-label, phase 3 trial
Median
OS 6.1
months vs
4.2 months
Median
OS 4.9
months vs
4.2 months

18. (C) Progression-free survival with nanoliposomal irinotecan plus fluorouracil and folinic acid versus fluorouracil and folinic acid. (D)
Progression-free survival with nanoliposomal irinotecan monotherapy versus fluorouracil and folinic acid.
Andrea Wang-Gillam, et al. THE LANCET Volume 387, Issue 10018, 6–12 February 2016, Pages 545–557
Nanoliposomal irinotecan with fluorouracil and folinic acid in metastatic pancreatic cancer after
previous gemcitabine-based therapy (NAPOLI-1): a global, randomised, open-label, phase 3 trial
Median
PFS 3.1
months vs
1.5 months
Median
PFS 2.7
months vs
1.6 months

19. 19
Nanoliposomal irinotecan
plus fluorouracil and
folinic acid combination
therapy (n=117)
Nanoliposomal irinotecan
monotherapy (n=147)
Fluorouracil and folinic
acid control (n=134)
Any grade Grades 3–4 Any grade Grades 3–4 Any grade Grades 3–4
Diarrhea 69 (59%) 15 (13%) 103 (70%) 31 (21%) 35 (26%) 6 (4%)
Vomiting 61 (52%) 13 (11%) 80 (54%) 20 (14%) 35 (26%) 4 (3%)
Nausea 60 (51%) 9 (8%) 89 (61%) 8 (5%) 46 (34%) 4 (3%)
Decreased
appetite
52 (44%) 5 (4%) 72 (49%) 13 (19%) 43 (32%) 3 (2%)
Fatigue 47 (40%) 16 (14%) 54 (37%) 9 (6%) 37 (28%) 5 (4%)
Neutropenia* 46 (39%) 32 (27%) 37 (25%) 22 (15%) 7 (5%) 2 (1%)
Anemia 44 (38%) 11 (9%) 48 (33%) 16 (11%) 31 (23%) 9 (7%)
Hypokalemia 14 (12%) 4 (3%) 32 (22%) 17 (12%) 12 (9%) 3 (2%)

20.  5FU and oxaliplatin or capecitabine and oxaliplatin both
demonstrated median overall survival of 4.8 to 5.9
months compared to best supportive care 2.3 to 3.3
months)
 Capecitabine and erlotinib was tested in a phase II trial of
32 patients
 10% response rate
 median overall survival of 6.5 months
 but significant diarrhea
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Other second line regimens after gemcitabine

21.  No randomized data
 Gemcitabine and nab-paclitaxel
 Prospective multicenter cohort study of 57 patients
 Objective response rate of 18%
 Disease control rate of 58%
 Median overall survival of 8.8 months
 Median PFS of 5.1 months
 Gemcitabine alone
 Single agent taxane
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Second-line agents after FOLFIRINOX

22. Molecular
Profiling and
Targeted
Therapies
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23.  Erlotinib is the only targeted agent approved for
metastatic pancreas cancer
 In a phase III trial of gemcitabine and erlotinib versus
gemcitabine alone, overall survival was 6.2 months
versus 5.9 months
 Gain in survival was statistically significant but the two
week improvement in survival is not clinically meaningful
 FDA approved but not used in practice
 Cetuximab and bevacizumab have also been tested in
combination with gemcitabine but no benefit seen
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Targeted Therapies

24.  4 classes identified
 Squamous
 Aberrantly differentiated endocrine
exocrine (ADEX)
 Pancreatic progenitor
 Immunogenic
 ADEX tumors display upregulation of
genes that regulate networks
involved in KRAS activation
 Targeting of KRAS has not been
successful to date
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Molecular classes and transcriptional
networks defining PDAC
P Bailey et al. Nature 1-6 (2016) doi:10.1038/nature16965

25. 25
Immune pathways in PDAC
P Bailey et al. Nature 1-6 (2016) doi:10.1038/nature16965

26. Clinical Trials at
The James
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 OSU-14249 A Phase I/II, Two-Part, Multicenter Study to
Evaluate the Safety and Efficacy of M402 (necuparanib)
in Combination with nab-Paclitaxel and Gemcitabine in
Patients with Metastatic Pancreatic Cancer
 OSU-14146 A Phase Ib Clinical Study of BBI608 in
Combination with Gemcitabine and nab-Paclitaxel in
Adult Patients with Metastatic Pancreatic
Adenocarcinoma
First line metastatic pancreas trials

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 OSU-14250 A Phase 1, Open-label, Multicenter, Safety
Study of Nivolumab (BMS-936558) in Combination with
nab-Paclitaxel Plus or Minus Gemcitabine in Pancreatic
Cancer
 OSU-15169 A Phase 1 Multicenter, Open-label, Dose-
escalation and Dose-expansion Study to Evaluate the
Safety, Tolerability, Pharmacokinetics, Immunogenicity,
and Antitumor Activity of MEDI9447 Alone and in
Combination with MEDI4736 in Adult Subjects with
Select Advanced Solid Tumors
Second line trials

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 Metastatic pancreas cancer is a challenging disease due
to chemoresistance
 FOLFIRINOX as first-line therapy is reserved for good
performance status patients and <70 years of age
 Gemcitabine and nab-paclitaxel is better tolerated and
preferred if ECOG PS is 2
 Nanoliposomal irinotecan with 5FU/LV is an option for
second-line therapy after progression on gemcitabine-
based regimens
 Molecular profiling to define subtypes and immune-based
approaches offer promise for more effective therapies
Conclusions

30. Thank You
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