Download Concept to Practice

Concept to Practice:
New Advances in the
Treatment of GI Cancers
2016 Community Oncology Alliance Conference
Orlando, FL
Thomas George, MD, FACP
Director, GI Oncology Program
Director, Experimental Therapeutics Incubator
University of Florida Health
Cancer Center
@TGeorgeMD | [email protected]
Disclosures
Institutional Research Funding:
Bayer
Bristol Myers Squibb
Celgene
NewLink Genetics
Consultant:
Bayer
NewLink Genetics
Educational Objectives
1. Review the past year of research leading to new
treatments for patients with GI cancers
2. Discuss the incorporation of these treatments in
the context of current standards of care
3. Anticipate upcoming trial results which may
further change the treatment landscape
2016 Estimated US Cancer:
New GI Cases
Prostate
21%
Lung & bronchus
14%
Men
Women
29% Breast
13% Lung & bronchus
Colorectal
8%
8%
Colorectal
Urinary bladder
7%
7%
Uterine corpus
Melanoma
6%
6%
Thyroid
NHL
5%
4%
NHL
Kidney
5%
3%
Melanoma
Leukemia
4%
3%
Leukemia
H&N
4%
3%
Pancreas
Liver/Cholangio
3%
3%
Kidney
All Other Sites
23%
21% All Other Sites
ACS – Surveillance Research 2015
2016 Estimated US Cancer:
GI Cancer Deaths
Lung & bronchus
27%
Men
Women
26% Lung & bronchus
Prostate
8%
14% Breast
Colorectal
8%
8%
Colorectal
Pancreas
7%
7%
Pancreas
Liver/Cholangio
6%
5%
Ovary
Leukemia
4%
4%
Uterine corpus
Esophagus
4%
4%
Leukemia
Urinary bladder
4%
3%
Liver/Cholangio
NHL
4%
3%
NHL
Brain/CNS
3%
2%
Brain/CNS
All other sites
25%
24% All other sites
ACS – Surveillance Research 2015
Taken All Together
• Colorectal cancer is 3rd most common cancer and
the 2nd leading cause of cancer deaths
• Slowly declining rates of incidence and deaths
• Pancreatic cancer is the 3rd leading cause of cancer
deaths
• Rising rates  projected as 2nd leading cause of cancer
deaths by 2030
• Liver and cholangio rates are rising worldwide
Rahib L et al. Cancer Res. 2014 Jun 1;74(11):2913-21
Esophagogastric
Adenocarcinoma &
Anti-VEGF therapy
• Bevacizumab FAILED to demonstrate OS advantage in
1st-line therapy (AVAGAST Trial)
• Anti-VEGF therapy demonstrated activity and led to FDAapproval of Ramucirumab alone or in combination with
paclitaxel in previously treated mEGA
• REGARD & RAINBOW trials
• Taxanes are the most widely used 2nd-line tx for mEGA
Ohtsu A, et al. J Clin Oncol. 2011;29:3968-3976
REGARD Trial
BSC ± Ramucirumab
2nd Line Treatment
Pts with metastatic gastric
or GEJ adenocarcinoma
progressing on first-line
platinum- and/or
fluoropyrimidinecontaining combination
therapy, ECOG PS 0-1
(N = 355)
BSC +
Ramucirumab 8 mg/kg IV q2w
(n = 238)
BSC +
Placebo
(n = 117)
Treatment until
PD, unacceptable
toxicity, or death
• Primary objective: OS
• Secondary endpoints: PFS, 12-wk PFS, ORR, DoR, QoL, safety
Fuchs CS, et al. Lancet. 2014;383:31-39
RAINBOW Trial
Paclitaxel ± Ramucirumab
2nd Line Treatment
Pts with metastatic or locally
adv unresectable gastric or GEJ
cancer progressing on first-line
platinum and fluoropyrimidine+/- anthracycline containing
combination therapy,
ECOG PS 0-1
(N = 665)
Paclitaxel 80 mg/m2 Days 1, 8, 15 +
Ramucirumab 8 mg/kg Days 1, 15
(n = 330)
Paclitaxel 80 mg/m2 Days 1, 8, 15 +
Placebo Days 1, 15
(n = 335)
Treat until
PD or
intolerable
toxicity
• Primary endpoint: OS
• Secondary endpoints: PFS, ORR, TTP
Wilke H, et al. Lancet Oncol. 2014;15:1224-1235
BSC +/- Ram
Median OS (mo)
Paclitaxel +/- Ram
BSC
BSC +
Ram
Paclitaxel
Paclitaxel +
Ram
3.8
5.2
7.4
9.6
HR: 0.776 (95% CI: 0.603-0.998;
P=.0473)
Median PFS (mo)
ORR (%)
HR: 0.807 (95% CI: 0.678-0.962;
P = .0169)
1.3
2.1
2.9
4.4
3
3
16
28
Casak SJ, et al. Clin Cancer Res 2015;21:3372-3376
RAINFALL Trial
Capecitabine/5-FU + Cisplatin ±
Ramucirumab
First line mEGA
ClinicalTrials.gov. NCT02314117.
What about
Immunotherapy?
KEYNOTE-012: Gastric Cancer Cohort
Yung-Jue Bang et al. J Clin Oncol 33, 2015 (suppl; abstr 4001)
Maximum Percentage Change From Baseline in Tumor Sizea (RECIST v1.1, Central Review)
Yung-Jue Bang et al. J Clin Oncol 33, 2015 (suppl; abstr 4001)
Not Quite Ready for Prime Time
• Pembrolizumab - pIb (restricted to PD-L1 overexpressing)
•
•
•
•
Toxicity – Nothing new
22% ORR
Median duration of response = 10mo
Median OS = 11mo
• Avelumab - unselected 2nd line mEGA
• 15% ORR; 50% disease control rate; mPFS = ~4mo
• Ongoing studies (phase I, II and III) w/ single and double
checkpoint inhibitors in EGA
Yung-Jue Bang et al. J Clin Oncol 33, 2015 (suppl; abstr 4001)
Chung HC et al. J Clin Oncol 34, 2016 (suppl 4S; abstr 167)
Gastroesophageal Update
Summary
• New approval for Ramucirumab alone or in
combination with paclitaxel in second-line mEGA
• Immunomodulators look promising, but not home run
• More studies are ongoing
• Don’t forget to confirm HER2 status of patient’s tumor
• Trastuzumab in combination with chemotherapy
Systemic Therapy Options (PDAC)
Study
Treatment
Control
Patients Median OS
(n=total) (mo)
1-year OS p-value
(%)
(median
OS)
Burris III HA
Gem
Gem+erlotinib
Gem+
nab-paclitaxel
5FU
Gem
Gem
126
569
861
5.6 vs 4.4
6.2 vs 5.9
8.5 vs 6.7
18 vs 2 0.0025
23 vs 17 0.038
35 vs 22 <0.001
FOLFIRINOX
Gem
342
11.1 vs 6.8 48 vs 20 <0.001
NCI Canada
Von Hoff DD
PRODIGE
Intergroup
20 years of “Progress”
Burris HA, et al. J Clin Oncol. 1997;15:2403-2413
Moore MJ, et al. J Clin Oncol. 2007;25:1960-1966
Von Hoff DD, et al. N Engl J Med. 2013;369:1691-1703
Conroy T, et al. N Engl J Med. 2011;364:1817-1825
Systemic Therapy Options (PDAC)
Study
Treatment
Control
Patients Median OS
(n=total) (mo)
1-year OS p-value
(%)
(median
OS)
Burris III HA
Gem
Gem+erlotinib
Gem+
nab-paclitaxel
5FU
Gem
Gem
126
569
861
5.6 vs 4.4
6.2 vs 5.9
8.5 vs 6.7
18 vs 2 0.0025
23 vs 17 0.038
35 vs 22 <0.001
FOLFIRINOX
Gem
342
11.1 vs 6.8 48 vs 20 <0.001
NCI Canada
Von Hoff DD
PRODIGE
Intergroup
20 years of “Progress”
Burris HA, et al. J Clin Oncol. 1997;15:2403-2413
Moore MJ, et al. J Clin Oncol. 2007;25:1960-1966
Von Hoff DD, et al. N Engl J Med. 2013;369:1691-1703
Conroy T, et al. N Engl J Med. 2011;364:1817-1825
My Summary of Metastatic PCa
Gemcitabine
Gem + nab Pac
FOLFIRINOX
My Summary of Metastatic PCa
Gemcitabine
Gem + nab Pac
FOLFIRINOX
6mo
9mo
12mo
My Summary of Metastatic PCa
Gemcitabine
Gem + nab Pac
FOLFIRINOX
6mo
9mo
12mo
PS <2
PS <1
PS 0
My Summary of Metastatic PCa
Gemcitabine + Erlotinib
6mo (unless rash ~9)
PS <2
Gemcitabine
Gem + nab Pac
FOLFIRINOX
6mo
9mo
12mo
PS <2
PS <1
PS 0
Then What….
• Most patients will only see one line of treatment
• For those that are fit, there are several options:
• Clinical trial
• Use what you didn’t use in first line
• OR…..
Nanoliposomal irinotecan (MM-398)
w/ 5-FU/LV
NCCN guidelines. v1.2016
Wang-Gillam A, el al. Lancet 2016;387(10018):545-57
NAPOLI-1: Phase III Second-line mPCa
Nanoliposomal formulation increases half-life/AUC
preferentially increases tumor exposure to irinotecan (SN-38)
Pts with
metastatic
pancreatic cancer
who progressed
on gemcitabinebased therapy,
KPS ≥ 70
(N = 417)
Nal-IRI 120 mg/m2 q3w
(n = 151)
Nal-IRI 80 mg/m2 +
5-FU/LV* 2400/400 mg/m2 q2w
(n = 117)
5-FU/LV
2000/200 mg/m2/wk x 4 q6w
(n = 119)
Wang-Gillam A, el al. Lancet 2016;387(10018):545-57
Median OS 6.1 vs. 4.2mo
Median PFS 3.1 vs. 1.5mo
Wang-Gillam A, el al. Lancet 2016;387(10018):545-57
Wang-Gillam A, el al. Lancet 2016;387(10018):545-57
Adjuvant Trials On Horizon
With appreciation to M. Tempero
Pancreatic Update Summary
• Still continue to struggle with development of REALLY
effective systemic therapies
• Immunotherapies? – combinations will be required
• 1st AND 2nd line systemic treatment options are now
supported by data
• Will have data soon on the value of moving multiagent
treatments to earlier stages of disease
Colorectal Cancer
• Prevention is the best treatment
• 80% by 2018 screening national initiative
• FIT testing now recommended over FOBT
• Don’t do the following….
Bouvard V, et al. Lancet Oncol. 2015 Dec;16(16):1599-600
Colorectal Cancer
An interesting potential Do…
4 cups/day was associated with reduced recurrence and mortality
(HR 0.48; 95% CI, 0.25 to 0.91; P=0.002)
Guercio B, et al. J Clin Oncol. 2015 Nov 1;33(31):3598-607
Colorectal Cancer
Another interesting potential Do…
Clinical trial in mCRC measuring and treating w/ VitD
as adjunct to chemo is ongoing
Ng K, et al. J Clin Oncol 33, 2015 (suppl; abstr 3503)
Colorectal Cancer
• Another interesting potential Do…
A definite DO…
Clinical trial in mCRC measuring and treating w/ VitD
as adjunct to chemo is ongoing
Cao Y, et al., JAMA Oncol. 2016 Mar 3. doi: 10.1001/jamaoncol.2015.6396
Rectal Cancer in 2015
• TCGA data confirm rectal and colon are same disease –
just differ geographically
• Trimodality therapy is SOC for stage II and III disease
• Pre-op chemoRT (CIVI 5FU or Capecitabine)
• Lap-assisted is non-inferior to open resection
• Systemic therapy is recommended regardless of pathology after CRT
• THE FOCUS of active NCI clinical trials is now modality
“relevancy” in the context of Total Neoadjuvant Therapy
NCCN guidelines 1.2016
Allegra CJ, et al. J Natl Cancer Inst. 2015 Sep 14;107(11)
Stevenson AR, et al., JAMA. 2015 Oct 6;314(13):1356-63
Rectal Cancer
in 2016 & onward
Using neoadjuvant chemotherapy to test ….
• Selective incorporation of novel chemo or radiotherapy
sensitizers to drive up pCR (NRG “TNT Trial”; NCT#Pending)
• Selective elimination of radiotherapy (ALLIANCE PROSPECT;
NCT01515787)
• Selective elimination of surgery (“Watch and Wait” trials;
NCT02008656)
NCCN guidelines 1.2016
mCRC Treatment Sequencing
Still awaiting updates to CALGB 80405
Venook AP, et al. J Clin Oncol 32:5s, 2014 (suppl; abstr LBA3)
mCRC First line therapy:
Dealer’s Choice
Venook AP, et al. J Clin Oncol 32:5s, 2014 (suppl; abstr LBA3)
Definition of RAS Mutation
ASCO Provisional Clinical Opinion Update 2015
Allegra CJ, et al. J Clin Oncol 2009;27:2091-2096
Allegra CJ, et al. J Clin Oncol. 2016 Jan 10;34(2):179-85
Then What….
• Most patients will see multiple lines of palliative
treatments
• For those that are fit, there are several options:
• Clinical trial
• Use what you didn’t use in first line
• Regorafenib or alternative anti-VEGF therapies
• OR…..
TAS-102
NCCN guidelines. v2.2016
Mayer RJ, el al. N Engl J Med. 2015 May 14;372(20):1909-19
Oral combination of trifluridine and tipiracil
• Trifluridine is a fluoropyrimidine which inhibits TS
• Tipiracil interferes with the deactivation of trifluridine
• 35mg/m2 PO BID D1-5, D8-12 q28 days
• TAS-102 vs. Placebo in 800 patients
• Had to have previously been treated w/ FP, oxali, iri, bev +/anti-EGFR
• Well balanced arms
• Primary endpoint = OS
Mayer RJ, el al. N Engl J Med. 2015 May 14;372(20):1909-19
Mayer RJ, el al. N Engl J Med. 2015 May 14;372(20):1909-19
Mayer RJ, el al. N Engl J Med. 2015 May 14;372(20):1909-19
Median OS 7.1 vs 5.3mo
HR 0.68; P<0.001
Median PFS 2 vs 1.7 mo
HR for progression at 6mo
0.48; P<0.001
Mayer RJ, el al. N Engl J Med. 2015 May 14;372(20):1909-19
Not
Capecitabine
Mayer RJ, el al. N Engl J Med. 2015 May 14;372(20):1909-19
Mayer RJ, el al. N Engl J Med. 2015 May 14;372(20):1909-19
How to incorporate?
• No head to head comparisons w/ Regorafenib
• Activity: Equitable
• Tolerability: TAS-102 > Regorafenib
• Two options:
•
•
•
•
Use Rego first – since you know benefit is tied to tolerance
Use TAS-102 first – since you may not get another shot
Extended survival is related to seeing all active agents
Sequencing studies are coming….
What about
Immunotherapy?
MMR-Deficient CRC
Baseline Characteristics
(n = 13)
MMR-Proficient
CRC
(n = 25)
MMR-Deficient
Other Tumors
(n = 10)
Median age, yrs
46
62
59
Diagnosis, %
 CRC
 Ampullary/biliary
 Endometrial
 Small bowel
 Prostate
 Gastric
100
0
0
0
0
0
100
0
0
0
0
0
0
40
20
20
10
10
≥ 2 prior therapies, %
100
100
90
Lynch syndrome, %
ORR
85
62
0
0
40
60
Disease control rate
92
16
70
Le DT, el al. N Engl J Med. 2015 May 14;372(20):2509-20
Le DT, el al. N Engl J Med. 2015 May 14;372(20):2509-20
• Ongoing studies to confirm benefit including 1st line Pembro
vs. chemo (KEYNOTE-177; NCT02563002)
in MSI-H or MMR-D mCRC
• Additional combinations with diff agents/chemo ongoing
• MSI testing should be performed on ALL patients w/ mCRC
• Identification of family syndrome in absence of + FH
• Biomarker for immunotherapy consideration
NCCN guidelines. v2.2016
Summary
• New agents in refractory EGA, pancreatic and CRC have
come into clinical practice
• Moving them earlier in treatment is high priority
• Upcoming results of perioperative trials in pancreatic and
rectal cancers could be clinical practice game changers
• Immunotherapy is gaining relevancy in GI cancers
• Personalized treatment decisions continue to be refined by
patient selection
• Extended RAS testing (negative predictive biomarker)
• MSI-H/MMR-D testing (positive predictive biomarker)
• HER2 testing (positive predictive biomarker)
Thank you
@TGeorgeMD | [email protected]