Poster Discussion

Jordan Berlin, M.D.

Ingram Associate Professor, Medicine

Disclosures

• Yes, I have a Consultant or Advisory Role to disclose.

– Amgen – BMS – Genentech – Imclone – Immunogen – Pfizer – Sanofi

• Yes, I have Honoraria to disclose.

– BMS – Genentech – Sanofi-Aventis

• DSMB– Pfizer

• Took a pen– Genentech, but I promise

I’ll give it back

Adjuvant chemotherapy alone vs chemoradiation after curative

resection for pancreatic cancer:Feasibility results of a randomized EORTC/FFCD/GERCOR phase II/III

study (40013/22012/9203)

1JL. Van Laethem, 2E. Van Cutsem, 3P. Hammel, 4F. Mornex, 5D. Azria, 6G. Van Tienhoven, 7M. Peeters, 8M. Praet, 9V.

Budach, 2K. Haustermans

1Hôpital Universitaire Erasme, Brussels (BE) - 2U.Z. Gasthuisberg, Leuven (BE) - 3Hôpital Beaujon, Clichy (FR) - 4CHU Lyon (FR) -

5CRLC Val d’Aurelle, Montpellier (FR) - 6AMC, Amsterdam (NL) - 7Universiteit Gent (BE) - 8EORTC, Brussels (BE) - 9Charite Berlin

(DE)

• Study design

– Multicentre phase II/III study

Within 8 weeks of surgery

R0 Margin status

Arm A (n = 45):

Gemcitabine

x 4 cycles (4 week cycles)

Arm B (n = 45):

Gemcitabine x 2 cycles then

gemcitabine + XRT

R

Results

• Dose delivered was good–Had 20-37% with dose reductions at

some point• Compliance was pretty good with

chemo, but 11/45 did not receive XRT and 4 more are unknown

• Toxicity was manageable• DFS was 10.9 months for the entire

group

Discussion

• 300 mg/m2 gemcitabine with XRT was possible in a multiinstitutional study

• A significant number of patients (>20%) did not receive XRT

• DFS was short (~3 months shorter than CONKO-01 gemcitabine arm)

– Course too short?– XRT arm received even less treatment?– Small study?– Patient selection?

» >70% + for perineural invasion, for example

Adjuvant Therapy of Pancreas Cancer

•42**Answer to the ultimate question according to the 5 books of the Douglas Adams classic Hitchiker’s Guide to the Galaxy trilogy

EORTC set out to answer the ultimate question

Adjuvant Pancreas Cancer Discussion

• After decades with limited studies, we know little more about adjuvant therapy of pancreas cancer than we did before they invented the CT scan machine

• Chemotherapy appears to have benefit (ESPAC-1 and CONKO-01)

The Ultimate Question

• We have no studies that either prove or disprove the use of radiation in adjuvant pancreas cancer–GITSG–EORTC–ESPAC-1–RTOG 9704

Localized Therapy

• Local control is an issue in the adjuvant therapy of pancreas cancer,–But we still have little, if any, systemic

control– In the best studies, ~80% will be dead,

largely due to pancreas cancer, at 5 years

–Should we test a local control issue and how do we best test it in a disease where systemic control is so poor

Adjuvant Pancreas Cancer

• Are there alternatives?–With creative design and endpoints, it

may be possible to test new agents in the adjuvant setting

» After all, resectable pancreas cancer really represents in most patients an earlier stage of metastatic disease

– It is definitely time for a new paradigm and approach to this disease

LV5FU2-cisplatin followed by gemcitabine or the reverse

sequence in metastatic pancreatic cancer: Preliminary results of a randomized phase III trial (FFCD

0301).

E. Mitry, L. Dahan, M. Ychou, J. Arthaud, M. Gasmi, J. Raoul, C. Mariette, J. M.

Phelip, L. Bedenne, J.F. Seitz, Fédération Francophone de Cancérologie Digestive

• Study design

– Multicentre phase III study

– To compare the best sequence of chemotherapy

Gemcitabine: 1000 mg/m² on D1 as a 30 mn infusion or with an infusion rate of 10 mg/m2/min* , weekly 7 weeks /8, then 3 weeks / 4LV5FU2-P: 2-hour infusion of LV 200 mg/m2 followed by a FU bolus 400 mg/m2 and 46-hour infusion 2,400 mg/m2 every 2 weeks, with cisplatin 50 mg/m2 as a 2-hour infusion on D1 or D2(* Each participating centre had to always use the same administration method)

Stratification:

- Centre- WHO PS (0,1 vs 2)

- Location (head vs other)

- GEM infusion rate

Arm A:

LV5FU2-P followed by Gemcitabine

at progression or toxicity

Arm B:

Gemcitabine followed by LV5FU2-P

at progression or toxicity

R(Minimization)

Results

• Response rates similar –18.6% (LVU2-P 1st) vs 22% (gem 1st)

• PFS similar–3.83 mos (LVU2-P 1st) vs 4.73 mos (gem

1st), p = 0.9

• OS similar–6.63 mos (LVU2-P 1st) vs 8.03 mos (gem

1st), p = 0.77

What does this study tell us?

• Too small to be a true equivalency trial

• LVFU2-P is not a replacement for gemcitabine 1st line

• It is okay to use something without gemcitabine 1st line on clinical trial

2nd line pancreas cancerA PHASE 2 STUDY OF BEVACIZUMAB PLUS

ERLOTINIB IN PATIENTS WITH GEMCITABINE-REFRACTORY METASTATIC PANCREATIC CANCER

AH Ko, E Dito, B Schillinger, AP Venook, EK Bergsland, WM Korn, MA Tempero

A Phase II Trial of Sunitinib (S) in Previously-Treated Pancreas Adenocarcinoma (PAC),

CALGB 80603E.M. O’Reilly, D. Niedzwiecki, D. Hollis, T. Bekaii-

Saab, T. Pluard, A. Duffy, F. Overcash, P. Ivy, R.M. Goldberg

Results

• Ko, et al: erlotinib + bevacizumab (n = 32)–1 PR (3.6%), 7 SD (25%)–TTP 40 days (1.33 months)–OS 104 days (3.5 months)

• O’Reilly, et al: sunitinib (n = 77)–1 CR (1%), 14 SD (20%)–PFS 1.35 months–OS 3.2 months

Ko and O’Reilly Papers

• Both regimens had limited antitumor effect– But both had some effect

• Why were they ineffective?– Were these the right agents to hit the targets?

– Should these have been tested in first-line?

– Is VEGF and/or angiogenesis a relevant target in pancreas cancer?

– Is targeting EGFR smart in a disease where 90% of patients have activating mutations?

VEGF/Angiogenesis as Target

• Pancreas cancers frequently overexpress VEGF, PDGF, and PDGFR

• In tumor samples from patients with pancreatic cancer, in some studies, ↑ VEGF expression correlated with

– Increased microvascular density

– Increased incidence of liver metastasis

– Decreased survival

• Inhibition of VEGF or its receptors prevents growth of pancreatic tumor xenografts in animal models

• In other studies, microvessel density did not correlate with prognosis (Ellis, et al Eur J Cancer 34:337-40, 1998)

2nd line pancreas cancer Commentary

• While the drugs may not have worked because the target was wrong–Maybe the drugs did not hit enough

targets–Maybe the drugs did not hit the right

combination of targets–Maybe it is time to go back to the basics

Pancreas Cancer Overall

• In each setting, one theme emerges– We need to rethink our study designs and

paradigms

• We have spent a decade looking for incremental differences

– We achieved this goal with erlotinib and many are displeased with that

– Let’s look for real change again

• Trials should be designed with intelligence– Let science guide the trial-don’t just use it to

rationalize a foregone conclusion

Pancreas Cancer overall

• Like most disease sites we do our trials empirically–The science is used as a rationalization

• The flaws here are many–Science should guide our choices rather

than be used to support what we already decided to do

–Published lab data is highly biased towards positive trials

» We need get the negative data as well.• Editors, authors and reviewers take note

Dieter Hörsch, Vikas Prasad, Richard P. BaumDepartment of Internal Medicine and Nuclear Medicine /

Center for PET/CT Zentralklinik Bad Berka

Long Term Outcome of Peptide Receptor Radionuclide Therapy in Long Term Outcome of Peptide Receptor Radionuclide Therapy in

441 Patients with Progressive Neuroendocrine Tumors Using 441 Patients with Progressive Neuroendocrine Tumors Using

Yttrium-90 and Lutetium-177 labelled Somatostatin Receptor Yttrium-90 and Lutetium-177 labelled Somatostatin Receptor

Targeting PeptidesTargeting Peptides

Long Term Outcome of Peptide Receptor Radionuclide Therapy in Long Term Outcome of Peptide Receptor Radionuclide Therapy in

441 Patients with Progressive Neuroendocrine Tumors Using 441 Patients with Progressive Neuroendocrine Tumors Using

Yttrium-90 and Lutetium-177 labelled Somatostatin Receptor Yttrium-90 and Lutetium-177 labelled Somatostatin Receptor

Targeting PeptidesTargeting Peptides

Is this the future of radiation for NE tumors?

Studies before therapy

Renal scintigraphy [99mTc- MAG3]

GFR measurement [99Tc- DTPA]

Receptor PET/CT*[68Ga-DOTA-NOC]

Infusion (15 min.) of90Y / 177Lu- DOTA-TATE

Infusion of aminoacid solution (- 0.5 til 4 hrs)

Urine sampling

Blood sampling

177Lu- DOTA-TATE WB scan[planar scans for dosimetry]

177Lu- DOTA-TATE- SPECT of the tumor region

90Y / 177Lu-DOTA-TATE Peptide Receptor Radiotherapy

- 2 days3 days

01 2

Studies under therapy

* Since July 2004. Previously, Tc-99m EDDA Hynic TOC (planar & SPECT) was performed.In selected patients, also F-18 FDG and / or F-18 fluoride PET/CT is performed as well as MRI of the liver / bones

BAD BERKA PROCEDURE FOR PRRT

61

31

8

35

65

37

54

9

CR/PR/MR SD PD

Per

cent

age

of P

atie

nts Y-

90

Y-90

Y-90

Lu-Lu-177177

Y-90Y-90Lu-Lu-177177

Lu-Lu-177177

Y-90Y-90Lu-Lu-177177

Y-90Y-90Lu-Lu-177177

RESPONSE TO PRRT – DIFFERENT TREATMENT REGIMENSHighest response rate was observed with Y-90 followed by

Lu-177 + Y-90 and Lu-177 DOTA-TATE alone

Horsch, et al Commentary

• This study was conducted with:– Highly selected patients with high

somatostatin receptor density of primary tumor / metastases by 68Ga-DOTA-NOC receptor PET/CT

– All were “progressive”– Not all patients treated were presented

» “Only progressive GEP NET patients treated with at least 3 cycles of PRRT were included in this analysis”

Horsch, et al Commentary

• Methods–3 different strategies employed

» PRRT using Y-90, » PRRT using Lu-177 » Combined use of Y-90 & Lu-177 labeled

DOTA-TATE

– It appears that they have been modifying methods to reduce toxicity all along

» And frequency of re-treatments

So, where is PRRT?

• There remain more questions than answers (3 slides on the poster)–Despite large numbers of patients

treated on these studies» We don’t know best way to give» Can we prevent nephrotoxicity?

• How bad is it?

» How bad is the heme toxicity?• 7/454 (1.5%) developed MDS or AML, and not everybody may have

been followed long enough

» What about the other patients?» What is the denominator (number of

patients rejected for this treatment)?

Should PRRT be moved forward?

• Certainly, it appears effective– It also appears toxic

• What role this therapy will play needs to be seen

– It needs multiinstitutional assessment before it can even be considered for use off clinical trials

» Who can give this?» Who can do the studies needed for eligibility?

– Targeted (misnomer) therapies are showing efficacy

» Will they make PRRT irrelevant?