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