Updates in hepatocellular cancer and pancreas cancer

Jordan Berlin, M.D.

Ingram Associate Professor, Medicine

Disclosures

• Advisory Boards here and there

– Genentech

– BMS

– Imclone

– Sanofi-Aventis

– Pfizer

– Abbott

– Astra Zeneca

– Cephalon (not paid)

– Roche

• Spoke for:– Genentech– Nestle

» Not being paid in chocolate

• DSMB– Pfizer

• Presented a lot of data resulting in trips to Europe (ESMO and ECCO)

– Amgen

Hepatocellular Cancer

• What we know about HCC• Known risk factors include hepatitis B and C

–Most common etiology is hep C in the US, but in certain ethnic groups, recent immigrants and in much of the world, hep B is more common

–Other causes: alcohol, Wilson’s, hemochromatosis, idiopathic to name a few

–Previously, SEER data showed a rise in HCC

Hepatocellular Cancer

• SEER Data update–Rising incidence with a tripling form 1975 to

2005» 1.6/100,000 in 1975, 4.9 per 100,000 in 2005

–Steady decrease in mortality » 1 year survival rose from 25% to 47%» 2 year survival rose from 16% to 35%

Altekruse SF< et al JCO 27:1845-51, 2009

Altekruse, S. F. et al. J Clin Oncol; 27:1485-1491 2009

Fig 1. Annual age-adjusted incidence rates per 100,000 and trends, all hepatocellular carcinoma cases and by sex, 1975 to 2005 (Surveillance, Epidemiology, and End Results 9 [SEER9])

Treatments

• Transplantation• Surgery• TACE• PEI• RFA• Chemo (doxorubicin, fluoropyrimidine)• Sorafenib

TACE vs Doxorubicin Beads

• TACE with doxorubicin vs DCE (drug-eluting bead embolization)

• Child’s A or B, PS 0-1• 212 patients in 23 European Centers

–After dropout, 93 in DCE vs 102 in TACE–RR 52% DCE vs 44% in TACE, p = 0.11–Gr 3-4 AE’s, 13% DCE vs 19% TACE–Doxorubicin related AE’s any grade was less

likely with DCE vs TACE p < 0.0001

R Lencioni, et al. GI Symposium 2009 and abstract 4523 at ASCO 2009

Drug-eluting Beads 2009

• 73 patients randomized to drug-eluting –OS 610 vs 284 days (p, 0.03)–Benefit was limited to Child’s A and B

patients

Dhanasekaran, et al

Targeted Therapies

• Sorafenib –Sharp trial:

» 602 Child’s A patients randomized to sorafenib vs placebo

» Median survival 10,7 months vs 7.9 months, HR 0.69, p < 0.001

–Asian Trial» 226 Child’s A patients» Median Survival 6.2 months vs 4.1 months , HR

0.67, p = 0.0155» Median PFS =2.8 vs 1.4 months, p = 0.009

Toh , et al,ASCO 2009, Llovet, et al NEJM 359:378-, 2009

What about other VEGF inhibitors?

• Sunitinib–Phase II study in 34 patients

» PFS 3.9 months» OS 9.8 months» RR 2.9%, SD 50%» Increased levels of inflammatory molecules

predicted poorer outcomes

Zhu, et al. JCO 2008

Other VEGF inhibitors

• Bevacizumab–Phase II study of 46 patients–PFS 6.9 months–OS 12. months–1, 2, and 3 year survivals: 53%, 28%, 23%–RR 13%, 65% progression fre at 6 months

–Gr 3 HTN 15%, Gr 3 bleed

Siegel AB, JCO 26:2992-8, 2008

ASCO 2009

• Brivanib in HCC–Median OS 10 months, TTP 2.8 months, RR

<10% (Raoul, et al)

• Continuous Sunitinib in HCC–Median OS 9.3 months, PFS 2.8 months and

RR <10% (Koeberle, et al)

• ABT 869 in HCC–Median OS 9.9 moths, PFS 3.7 months, RR

<10% (Toh, et al)

Combined Targeted Agents

• Bevacizumab + erlotinib–Phase II study of 40 patients

» PFS 9 months» OS 15.6 months» RR 25%» PFS at 16 weeks – 62.5%

» Gr 3-4 fatigue, 20%, HTN 15% and diarrhea 10%

Thomas MB, et al JCO 27:843-50, 2009

Bevacizumab + erlotinib in HCC

• ASCO 2009, abstract• Bev 10 mg/kg q 2weeks with erlotinib 150 mg

daily• 58 patients

–14 PR (28%), 32 SD (62%), 4 (10%) PD–Median PFS 7.9 months, OS 12.8 months

(ABSTRACT), but closer to 15 months for patients with no prior therapy

• 2 other trials of similar regimens at ASCO as well

Kaseb, et al

HCC Conclusions

• Drug-eluting beads show promise in comparison to TACE–Larger trials needed

• VEGF inhibition appears effective in this disease, regardless of agent

• Combined VEGF/EGFR inhibition is also showing promise (bevacizumab/erlotinib)–Results of the randomized phase II trial will be

crucial

Pancreas Cancer

CONKO-001: Trial Design

Gem

Obs

Gemcitabine 1000 mg/m²: d1, 8, 15; q 4 weeks

Observation: d1; q 4 weeks

Randomisation

Follow up every 8weeks

Gem

Ultrasoundafter week 8

Ultrasoundafter week 16

CT Scanafter week 32

Obs

Gem

Obs

Gem

Obs

Gem

Obs

Gem

Obs

Gem

Obs

CA 19-9 CA 19-9 CA 19-9 CA 19-9 CA 19-9 CA 19-9

4 weeks 4 weeks 4 weeks 4 weeks 4 weeks 4 weeks

CA 19-9

.Oettle H, et al JAMA 297:267-77, 2007

CONKO-001: Results

Intent-to-Treat

Gem vs obs

Qualified

Gem vs obs

DFS (months) 13.4 vs 6.9

P < 0.001

13.7 vs 6.9

P < 0.001

Median OS (months) 22.1 vs 20.2

P= 0.06

24.2 vs 20.5

P = 0.02

5-year Survival 22.5% vs 11.5% N/A

.Oettle H, et al JAMA 297:267-77, 2007

CONKO-001

• Updated results:–DFS: 13.4 months vs 6.9 months, p < 0.001

» At 3 years: DFS 23.5% vs 8.5%» At 5 years: DFS 16.0% vs 6.5%

–OS: Median 22.8 vs 20.2 months, p = 0.005» At 3 years: 36.5% vs 19.5%» At 5 years: 21% vs 9%

–DFS data, all tested subsets benefitted

Neuhaus, et al asco LBA4504, 2008

ESPAC 3

• Randomized trial of 5FU/LV (Mayo regimen) vs gemcitabine–To be presented this PM

Picozzi Regimen

• Phase II trial– 43 patients– Treated with 54Gy XRT +

» Cisplat 30 mg/m2/week + CI 5-FU 200 mg/m2/d + interferon 3,000,000 units/d

» Followed by 5-FU 200mg/m2/d x 6 weeks repeated x1 (total + 2 cycles)

– Results» 42% hospitalized, no deaths» Median survival not defined» 1,2 and 5-yr actuarial survival: 95%, 64%, and 55%,

respectively– Conclusion: Should be evaluated further

» ACOSOG Trial is repeating this trial with careful monitoring

Picozzi VJ, et al Am J Surg 185:476-80, 2003

Adjuvant pancreas cancer

• ACOSOG Z5031 phase II trial–Cisplat/ifn/5FU + XRT followed by 2 cycles of

infusional 5FU–Planned 93 patients, but stopped early for toxicity

endpoint, although there were no study deaths» 96% had grade ¾ toxicity» 56% initiated all cycles of therapy

–89 patients» Median OS: 27.1 months» Median PFS: 14.1 months» 2 year survival: 58%

Piccozzi, et al ASCO 2008

So, chemo or chemo-XRT?• EORTC/FFCD/GERCOR randomized phase

II trial–90 patients randomized to gem vs gem-XRT

» DFS was 12 vs 11 months» OS was 24 months on both arms» Local recurrence as first site was lower with

chemoradiation (24 vs 11%)» The conclusions by the EORTC were very

appropriate and this was an extremely well done poster:

• Gem-XRT was safe and a larger trial is needed to discern if there is benefit to chemoxrt

Van Laethem ASCO 2009

RTOG 0848

RANDOMIZE

GEM X 5 CYCLESRANDOMIZEGEM + ERLOTINIB

X 5 CYCLES

GEM X 1 CYCLE THEN STOP

GEM X 1 CYCLE THEN CHEMOXRT

GEM + ERLOTINIB X 1 CYCLE THEN STOP

GEM + ERLOTINIB X 1 CYCLE THEN CHEMOXRT

Metastatic Pancreas Cancer

• Over the last decade or so, numerous trials of gemcitabine alone vs gemcitabine + any drug was negative, except with the addition of erlotinib

• CALGB 80303, gem vs gem + beva–590 patients randomized–Phase II trial had median survival > 8.5 months

(> 12 months initially but as tie went on, this went down)

–Phase III trial was negative

AVITA

• Gem-erlotinib vs gem-erlotinib-bevacizumab–607 patients randomized phase III trial

» Median OS: 6.0 vs 7.1 months, HR 0.89, P, 0.21» Median PFS: 3.6 vs 4.6 months, HR 0.73, P, 0.0002» RR 8.6 vs 13.5%» Time to KPS deterioration 10.1 vs 7.9 months, p 0.08» SAE’s similar

Vervenne W, et al ASCO 2008 abst 4507

Rationale for new VEGF targeted Phase III trials?

• Gem vs gem-axitinib randomized phase II–Endpoints: OS 10 vs 6 months or alternative, HR

of 0.6–Results:

» OS 6.9 vs 5.6 months (p, NS)» HR 0.76 uncorrected (p, NS)» HR 0.71, corrected (p, NS)» Toxicity greater in gem-axitinib» Looked better in PS 0-1 patients than in PS =2» My favorite: QOL favored gemcitabine alone

Gem vs gem-enzastaurin

• Randomized phase II, 130 patients (2:1 randomization)–Median Survival: 5.4 vs 5.1 months–1-year survival: 20% vs 16%

–No further study warranted. Thank you Dr. Richards and Lilly for reading and interpreting your own study correctly

Richards DA, et al GI Symposium 2009

Old ideas in new ways

• 2 trials with novel delivery of taxanes–Nab-paclitaxel + gemcitabine

» All patients (n = 67) PFS 6.9 months, OS 10.3 months» Patients at phase II dose (n =44) 40% RR by CT, PFS

7.9 months, OS >15 months so far

–Cationic liposomal paclitaxel» Randomized phase II of gem vs gem + one of 3 dose

levels of cationic liposomal paclitaxel» RR 13-16%» PFS: 2.5, 4.6, 5.0 and 4.5 months» OS: 7.2, 8.4, 8.7 and 9.4 months

Von Hoff, et al and Loehr, et al

2nd Line?

• 5FU is de facto “standard”• CONKO-003

–Randomization (168 patients) to Folinic acid/5FU vs oxali/Folinic acid/5FU

» 160 patients eligible» Median PFS 13 weeks vs 9 weeks, p 0.012» Median OS 26 weeks vs 13 weeks, p 0.014

Pelzer U, et al ASCO 2009, abst 4508

Pancreas Cancer

• Adjuvant therapy–Chemo definitely benefits patients (only gemcitabine

data shown)–Chemo-XRT regimens may also help, but full role of

XRT not elucidated» Local control may matter a lot more once we have better

systemic therapy

• Metastatic Disease–Angiogenesis inhibition—didn’t work, doesn’t work,

unlikely to work—STOP IT–Nab-paclitaxel has promising data worthy of phase III

trial, not standard care

Can we stop this pattern?

RANDOMIZE

Gemcitabine Alone

Gemcitabine + Your Drug HereYour Drug = Tecans

platinums

fluoropyrimidines

EGFR inhibitors

VEGF inhibitors and lots of them

Many have a hard time considering treatment without gem first

Javle

• Polymorphisms and gemcitabine effect–120 patients in 2 neoadjuvant trials, 1 of

chemo before chemoxrt and the other just chemoxrt

–2 alleles, one of cytidine deaminase and one of deoxycytidine kinase predicted for poorer survival and less neutropenia

–Looking at 7 deleterious alleles, number of alleles, 0 vs 1-2 vs 3 that were present predicted survival

Javle, ASCO 2008

Overall

• Data like Javle’s needs further development–Not proven at this time, but encouraging

that we may some day be able to determine who will benefit from which treatment

• We need to figure out which patients benefit from gemcitabine and which don’t