ASCO 2014 update in GI cancer
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Transcript of ASCO 2014 update in GI cancer
ASCO 2014: UPDATES IN GASTROINTESTINAL
ONCOLOGYAnnual Updates on Breakthroughs in Hematology & Oncology (AUBHO) 2014
Kanwal Pratap Singh Raghav, MDThe University of Texas M.D. Anderson Cancer Center, Houston, TX
30th August 2014
ARCHIVES: 1964-65
CALGB/SWOG 80405Alan P. Venook et al.
Abstract: LBA3
CALGB/SWOG 80405Alan P. Venook et al.
✤ In patients with KRAS-WT metastatic CRC where we have option of using two biologics in first line (anti-EGFR and anti-VEGF), does the choice really matter?
Abstract: LBA3
CALGB/SWOG 80405: OVERVIEW
Phase III trial of irinotecan/5-FU/leucovorin (FOLFIRI) or oxaliplatin/5-FU/leucovorin (mFOLFOX6) with bevacizumab (BV) or cetuximab (CET) for patients (pts) with KRAS wild-type (wt) untreated metastatic adenocarcinoma of the colon or rectum (MCRC).
FOLFOX (73%)
✤ Primary Endpoint: OS
✤ Ho = 22 v. 27.5 m
✤ N = 1137
CALGB/SWOG 80405: RESULTS
Similar PFS, Different AE/QoL (Resected disease: Median OS ~ 5.5 yr)
CALGB/SWOG 80405: PAST & PRESENT
NO 16966: FOLFOX/XELOX ± B: Median OS (21.3 v. 19.9m) (P=0.07)
CRYSTAL: FOLFIRI ± Cetux: Median OS (23.5 v. 20m) (P<0.01)
PRIME: FOLFOX ± Pan: Median OS (26 v. 20m) (P=0.04)
FOLFOX
P + FOLFOX
FOLFIRI
C + FOLFIRI
B + FOLFOX/XELOX
FOLFOX/XELOX
Saltz et al. JCO 2008; Tournigard et al. JCO 2004; Van Custem et al. JCO 2011; Douillard et al. NEJM 2013
FOLFIRI
GERCOR: FOLFIRI v. FOLFOX: Median OS (21.5 v. 20.6 m) (P=0.99)
FOLFOX
CALGB/SWOG 80405: PAST & PRESENT
NO 16966: FOLFOX/XELOX ± B: Median OS (21.3 v. 19.9m) (P=0.07)
CRYSTAL: FOLFIRI ± Cetux: Median OS (23.5 v. 20m) (P<0.01)
PRIME: FOLFOX ± Pan: Median OS (26 v. 20m) (P=0.04)
FOLFOX
P + FOLFOX
FOLFIRI
C + FOLFIRI
B + FOLFOX/XELOX
FOLFOX/XELOX
Saltz et al. JCO 2008; Tournigard et al. JCO 2004; Van Custem et al. JCO 2011; Douillard et al. NEJM 2013
FOLFIRI
GERCOR: FOLFIRI v. FOLFOX: Median OS (21.5 v. 20.6 m) (P=0.99)
FOLFOX
CALGB/SWOG 80405: PAST & PRESENT
NO 16966: FOLFOX/XELOX ± B: Median OS (21.3 v. 19.9m) (P=0.07)
CRYSTAL: FOLFIRI ± Cetux: Median OS (23.5 v. 20m) (P<0.01)
PRIME: FOLFOX ± Pan: Median OS (26 v. 20m) (P=0.04)
FOLFOX
P + FOLFOX
FOLFIRI
C + FOLFIRI
B + FOLFOX/XELOX
FOLFOX/XELOX
Saltz et al. JCO 2008; Tournigard et al. JCO 2004; Van Custem et al. JCO 2011; Douillard et al. NEJM 2013
FOLFIRI
GERCOR: FOLFIRI v. FOLFOX: Median OS (21.5 v. 20.6 m) (P=0.99)
FOLFOX
CALGB/SWOG 80405: PAST & PRESENT
NO 16966: FOLFOX/XELOX ± B: Median OS (21.3 v. 19.9m) (P=0.07)
CRYSTAL: FOLFIRI ± Cetux: Median OS (23.5 v. 20m) (P<0.01)
PRIME: FOLFOX ± Pan: Median OS (26 v. 20m) (P=0.04)
FOLFOX
P + FOLFOX
FOLFIRI
C + FOLFIRI
B + FOLFOX/XELOX
FOLFOX/XELOX
Saltz et al. JCO 2008; Tournigard et al. JCO 2004; Van Custem et al. JCO 2011; Douillard et al. NEJM 2013
FOLFIRI
GERCOR: FOLFIRI v. FOLFOX: Median OS (21.5 v. 20.6 m) (P=0.99)
FOLFOX
CALGB/SWOG 80405: PAST & PRESENT
NO 16966: FOLFOX/XELOX ± B: Median OS (21.3 v. 19.9m) (P=0.07)
CRYSTAL: FOLFIRI ± Cetux: Median OS (23.5 v. 20m) (P<0.01)
PRIME: FOLFOX ± Pan: Median OS (26 v. 20m) (P=0.04)
FOLFOX
P + FOLFOX
FOLFIRI
C + FOLFIRI
B + FOLFOX/XELOX
FOLFOX/XELOX
Saltz et al. JCO 2008; Tournigard et al. JCO 2004; Van Custem et al. JCO 2011; Douillard et al. NEJM 2013
FOLFIRI
GERCOR: FOLFIRI v. FOLFOX: Median OS (21.5 v. 20.6 m) (P=0.99)
FOLFOX
CALGB/SWOG 80405: PAST & PRESENT
NO 16966: FOLFOX/XELOX ± B: Median OS (21.3 v. 19.9m) (P=0.07)
CRYSTAL: FOLFIRI ± Cetux: Median OS (23.5 v. 20m) (P<0.01)
PRIME: FOLFOX ± Pan: Median OS (26 v. 20m) (P=0.04)
FOLFOX
P + FOLFOX
FOLFIRI
C + FOLFIRI
B + FOLFOX/XELOX
FOLFOX/XELOX
Saltz et al. JCO 2008; Tournigard et al. JCO 2004; Van Custem et al. JCO 2011; Douillard et al. NEJM 2013
FOLFIRI
GERCOR: FOLFIRI v. FOLFOX: Median OS (21.5 v. 20.6 m) (P=0.99)
FOLFOX
CALGB/SWOG 80405: PAST & PRESENT
NO 16966: FOLFOX/XELOX ± B: Median OS (21.3 v. 19.9m) (P=0.07)
CRYSTAL: FOLFIRI ± Cetux: Median OS (23.5 v. 20m) (P<0.01)
PRIME: FOLFOX ± Pan: Median OS (26 v. 20m) (P=0.04)
FOLFOX
P + FOLFOX
FOLFIRI
C + FOLFIRI
B + FOLFOX/XELOX
FOLFOX/XELOX
Saltz et al. JCO 2008; Tournigard et al. JCO 2004; Van Custem et al. JCO 2011; Douillard et al. NEJM 2013
FOLFIRI
GERCOR: FOLFIRI v. FOLFOX: Median OS (21.5 v. 20.6 m) (P=0.99)
FOLFOX
CALGB/SWOG 80405: PAST & PRESENT
NO 16966: FOLFOX/XELOX ± B: Median OS (21.3 v. 19.9m) (P=0.07)
CRYSTAL: FOLFIRI ± Cetux: Median OS (23.5 v. 20m) (P<0.01)
PRIME: FOLFOX ± Pan: Median OS (26 v. 20m) (P=0.04)
FOLFOX
P + FOLFOX
FOLFIRI
C + FOLFIRI
B + FOLFOX/XELOX
FOLFOX/XELOX
Saltz et al. JCO 2008; Tournigard et al. JCO 2004; Van Custem et al. JCO 2011; Douillard et al. NEJM 2013
FOLFIRI
GERCOR: FOLFIRI v. FOLFOX: Median OS (21.5 v. 20.6 m) (P=0.99)
FOLFOX
CALGB/SWOG 80405: PAST & PRESENT
NO 16966: FOLFOX/XELOX ± B: Median OS (21.3 v. 19.9m) (P=0.07)
CRYSTAL: FOLFIRI ± Cetux: Median OS (23.5 v. 20m) (P<0.01)
PRIME: FOLFOX ± Pan: Median OS (26 v. 20m) (P=0.04)
FOLFOX
P + FOLFOX
FOLFIRI
C + FOLFIRI
B + FOLFOX/XELOX
FOLFOX/XELOX
Saltz et al. JCO 2008; Tournigard et al. JCO 2004; Van Custem et al. JCO 2011; Douillard et al. NEJM 2013
FOLFIRI
GERCOR: FOLFIRI v. FOLFOX: Median OS (21.5 v. 20.6 m) (P=0.99)
FOLFOX
SWOG 80405: LESSONS LEARNED!
Chemo-Bev equivalent to Chemo-Cetux in 1st-line mCRC Rx of KRAS-WT (12/13) tumors.
Median OS in patient with resected mCRC ~ 5.5 yrs.
✤ ? Clinical applicability to extended RAS Mutants.
✤ ? FIRE-3: Better OS with FOLFIRI + C as 1st-line.
✤ ? PEAK: Better OS with FOLFOX + P as 1st-line.
✤ ? Sequential question unanswered (PDT rates ?).
✤ ? EPOC: Inferior PFS in resectable group.
✤ Future: Think ahead and homogenize population using molecular profiles.
✤ FOLFOX is preferred first line chemotherapy in the US.
In patients with rectal cancer who have received standard of care pre-operative chemoradiotherapy followed by surgery, is post-operative chemotherapy with FOLFOX better than 5FU alone in pathologic stage II/III disease in delaying recurrence?
Primary Endpoint: 3-yr. DFS.
ADORE TRIALTAE WON KIM ET AL. (ABSTRACT 3502)
✤ Subgroup effect: Stage III & poor neoadjuvant therapy response, LVI -ve
✤ FOLFOX: BMD, Neuropathy, Fatigue
CAIRO-3 TRIALMIRIAM KOOPMAN ET AL. (ABSTRACT 3504)
In patients with metastatic CRC, after 6 cycles of CAPOX-B does maintenance therapy with Cape + Bev improve PFS?
Primary Endpoint: PFS2 [Re-intro: 60% (o) v. 47% (m)]
ARCHIVES: 1964-65
STORM TRIALJordi Bruix et al.Abstract: 4006
STORM TRIALJordi Bruix et al.
✤ In patients hepatocellular cancer who have undergone resection or local ablation and are without residual disease, does adjuvant sorafenib decrease recurrence?
Abstract: 4006
STORM TRIAL: OVERVIEW
A phase III randomized, double-blind, placebo-controlled trial of adjuvant sorafenib after resection or ablation to prevent recurrence of hepatocellular carcinoma (HCC).
Child-Pugh A/B7 (2-3% only) & ECOG PS 0
Background: 5-yr OS 50-80% (Patient selection) & Sorafenib active in metastatic setting
HCC (N = 1114)
No Residual Disease
Sorafenib 4 years
Placebo4 years
Surgeryor
Ablation
Primary Endpoint: RFS
* Sorafenib 400mg BID
STORM TRIAL: RESULTS
No subgroup effectSimilar OS (HR=0.99)TEAE significant (DC 25%) (Dose Δ 80%)Rx duration ~12.5 (v. 22 m)
STORM: PAST & PRESENT
Meta-analysis (2001)
N = 180 (3 PTs)
Radical resection and
IA Epi + PO Tegafur
IA Epi + IV Epi
IV Epi
Similar OS/DFS (All Patients); Poorer OS/DFS (Cirrhosis)
Surgery
Adjuvant Rx
Ono et al. Cancer 2001
STORM: PAST & PRESENT
Meta-analysis (2001)
N = 180 (3 PTs)
Radical resection and
IA Epi + PO Tegafur
IA Epi + IV Epi
IV Epi
Similar OS/DFS (All Patients); Poorer OS/DFS (Cirrhosis)
Surgery
Adjuvant Rx
Ono et al. Cancer 2001
STORM: PAST & PRESENT
Meta-analysis (2001)
N = 180 (3 PTs)
Radical resection and
IA Epi + PO Tegafur
IA Epi + IV Epi
IV Epi
Similar OS/DFS (All Patients); Poorer OS/DFS (Cirrhosis)
Surgery
Adjuvant Rx
Ono et al. Cancer 2001
STORM: LESSONS LEARNED!
Adjuvant Sorafenib does not improve RFS in locally resected or ablated HCC.
✤ Another lesson in distinctive adjuvant & metastatic setting:
✤ ? Micro v. Macro metastatic disease & distinct biology
✤ ? Angiogenesis (Adjuvant)
✤ ? Cytostatic v. Cytocidal drug
✤ Future: Molecular characterization and biology oriented therapy and risk stratification !
✤ 5-yr. OS in patient with resected or ablated HCC ~ 70%.
✤ Drug toxicity profile very important in adjuvant settings.
Ono et al. Cancer 2001
LAP 07 STUDYFlorence Huguet et al.
Abstract: 4001
LAP 07 STUDYFlorence Huguet et al.
✤ In patients with locally advanced pancreatic adenocarcinoma, can use of chemoradiotherapy impact local control and time without systemic therapy?
Abstract: 4001
LAP-07: OVERVIEWImpact of chemoradiotherapy (CRT) on local control and time without treatment in patients with locally advanced pancreatic cancer (LAPC) included in international phase III LAP 07 study.
Primary Endpoint: OS
LAPC (N = 128) R1
Gemcitabine 4 months
Gemcitabine + Erlotinib
No Progression R2
Cape XRT(N = 136)
Same ChemoRx2 months (N = 133)
Retrospective analysis: GERCOR study: 128 patients treated with XRT or chemotherapy after induction chemotherapy (3 months). Median PFS 10.8 v. 7.4 m (P .005) and Median OS 15.0 v. 11.7 m (P .0009).
Huguet et al. JCO 2007
LAP-07 TRIAL: RESULTS
Toxicity profile similar (except nausea more in CRT arm)Progression site: All v. R2 (32 v. 39% local, 54 v. 52% distant)
Median time to CTx reintroduction: 5.2 v. 3.2 m
LAP-07: PAST & PRESENTFFCD/SFRO study: Induction CRT v. Gem followed by Gem maintenance showed poorer OS (8.6 v. 13 m, P=0.03).
ECOG 4201: Gem RT better OS v. Gem alone (11.1 v. 9.2 m) but higher G4/5 toxicity (41 v. 9%).
Chauffert et al. Annals of Oncology 2008; Loehrer et al. JCO 2011; Huguet et al. JCO 2007
CRT Arm FFCD Study
CTx Arm FFCD Study
CTx Arm ECOG Study
CRT Arm ECOG Study
Continued CTx Arm
CRT Arm GERCOR
Retrospective series (N = 181): Gem-based therapy X 3 m followed by continuation or CRT (concurrent inf. FU) at investigator discretion. CRT improved median PFS (10.8 v. 7.4 m) & OS (15 v. 11.7 m).
LAP-07: PAST & PRESENTFFCD/SFRO study: Induction CRT v. Gem followed by Gem maintenance showed poorer OS (8.6 v. 13 m, P=0.03).
ECOG 4201: Gem RT better OS v. Gem alone (11.1 v. 9.2 m) but higher G4/5 toxicity (41 v. 9%).
Chauffert et al. Annals of Oncology 2008; Loehrer et al. JCO 2011; Huguet et al. JCO 2007
CRT Arm FFCD Study
CTx Arm FFCD Study
CTx Arm ECOG Study
CRT Arm ECOG Study
Continued CTx Arm
CRT Arm GERCOR
Retrospective series (N = 181): Gem-based therapy X 3 m followed by continuation or CRT (concurrent inf. FU) at investigator discretion. CRT improved median PFS (10.8 v. 7.4 m) & OS (15 v. 11.7 m).
LAP-07: PAST & PRESENTFFCD/SFRO study: Induction CRT v. Gem followed by Gem maintenance showed poorer OS (8.6 v. 13 m, P=0.03).
ECOG 4201: Gem RT better OS v. Gem alone (11.1 v. 9.2 m) but higher G4/5 toxicity (41 v. 9%).
Chauffert et al. Annals of Oncology 2008; Loehrer et al. JCO 2011; Huguet et al. JCO 2007
CRT Arm FFCD Study
CTx Arm FFCD Study
CTx Arm ECOG Study
CRT Arm ECOG Study
Continued CTx Arm
CRT Arm GERCOR
Retrospective series (N = 181): Gem-based therapy X 3 m followed by continuation or CRT (concurrent inf. FU) at investigator discretion. CRT improved median PFS (10.8 v. 7.4 m) & OS (15 v. 11.7 m).
LAP-07: PAST & PRESENTFFCD/SFRO study: Induction CRT v. Gem followed by Gem maintenance showed poorer OS (8.6 v. 13 m, P=0.03).
ECOG 4201: Gem RT better OS v. Gem alone (11.1 v. 9.2 m) but higher G4/5 toxicity (41 v. 9%).
Chauffert et al. Annals of Oncology 2008; Loehrer et al. JCO 2011; Huguet et al. JCO 2007
CRT Arm FFCD Study
CTx Arm FFCD Study
CTx Arm ECOG Study
CRT Arm ECOG Study
Continued CTx Arm
CRT Arm GERCOR
Retrospective series (N = 181): Gem-based therapy X 3 m followed by continuation or CRT (concurrent inf. FU) at investigator discretion. CRT improved median PFS (10.8 v. 7.4 m) & OS (15 v. 11.7 m).
LAP-07: PAST & PRESENTFFCD/SFRO study: Induction CRT v. Gem followed by Gem maintenance showed poorer OS (8.6 v. 13 m, P=0.03).
ECOG 4201: Gem RT better OS v. Gem alone (11.1 v. 9.2 m) but higher G4/5 toxicity (41 v. 9%).
Chauffert et al. Annals of Oncology 2008; Loehrer et al. JCO 2011; Huguet et al. JCO 2007
CRT Arm FFCD Study
CTx Arm FFCD Study
CTx Arm ECOG Study
CRT Arm ECOG Study
Continued CTx Arm
CRT Arm GERCOR
Retrospective series (N = 181): Gem-based therapy X 3 m followed by continuation or CRT (concurrent inf. FU) at investigator discretion. CRT improved median PFS (10.8 v. 7.4 m) & OS (15 v. 11.7 m).
LAP-07: PAST & PRESENTFFCD/SFRO study: Induction CRT v. Gem followed by Gem maintenance showed poorer OS (8.6 v. 13 m, P=0.03).
ECOG 4201: Gem RT better OS v. Gem alone (11.1 v. 9.2 m) but higher G4/5 toxicity (41 v. 9%).
Chauffert et al. Annals of Oncology 2008; Loehrer et al. JCO 2011; Huguet et al. JCO 2007
CRT Arm FFCD Study
CTx Arm FFCD Study
CTx Arm ECOG Study
CRT Arm ECOG Study
Continued CTx Arm
CRT Arm GERCOR
Retrospective series (N = 181): Gem-based therapy X 3 m followed by continuation or CRT (concurrent inf. FU) at investigator discretion. CRT improved median PFS (10.8 v. 7.4 m) & OS (15 v. 11.7 m).
LAP-07: PAST & PRESENTFFCD/SFRO study: Induction CRT v. Gem followed by Gem maintenance showed poorer OS (8.6 v. 13 m, P=0.03).
ECOG 4201: Gem RT better OS v. Gem alone (11.1 v. 9.2 m) but higher G4/5 toxicity (41 v. 9%).
Chauffert et al. Annals of Oncology 2008; Loehrer et al. JCO 2011; Huguet et al. JCO 2007
CRT Arm FFCD Study
CTx Arm FFCD Study
CTx Arm ECOG Study
CRT Arm ECOG Study
Continued CTx Arm
CRT Arm GERCOR
Retrospective series (N = 181): Gem-based therapy X 3 m followed by continuation or CRT (concurrent inf. FU) at investigator discretion. CRT improved median PFS (10.8 v. 7.4 m) & OS (15 v. 11.7 m).
LAP-07: LESSONS LEARNED!
Consolidation CRT after induction CTx in LAPC increases treatment free interval without improvement in overall survival.
May play a role in select subset of patients with biology favoring local growth over distant metastases.
✤ ? Is LAPC truly different from metastatic disease.
✤ ? FOLFIRINOX or Gem + Abraxane alter the role of radiation.
✤ Is the duration of induction chemotherapy important to tease out biology
✤ Future: Need for effective systemic therapies and predictive biomarkers of response to both chemotherapy & radiation!
RAINBOW TRIALShuichi Hironaka et al.
Abstract: 4005
RAINBOW TRIALShuichi Hironaka et al.
✤ In patients with advanced gastric or gastroesophageal cancer refractory/intolerant to 5FU and platinum based regimen in first line does addition ramucirumab to second line therapy with paclitaxel improve survival?
Abstract: 4005
RAINBOW: OVERVIEW
A Global, Phase III, Randomized, Double-Blind Study of Ramucirumab Plus Paclitaxel versus Placebo Plus Paclitaxel in the Treatment of Metastatic Gastroesophageal Junction and Gastric Adenocarcinoma Following Disease Progression on First-Line Platinum- and Fluoropyrimidine-Containing Combination Therapy: Efficacy Analysis in Japanese and Western Patients.
Background: AVAGAST study failed to show OS benefit from bevacizumab (median PFS & RR improved).
Japanese (0lder, better PS, doublet 1st Rx, gastric): more TEAEs !
Ohtsu et al. JCO 2011; Ciombor et al. CCR 2013
RAINBOW TRIAL: RESULTS
More Japanese pts (75% v. 35%) received PDT.
Adjusted PDT trends same.
RAINBOW: PAST & PRESENT
BSC v. Salvage ChemoRx (Docetaxel or Irinotecan): 5.3 v. 3.8 m (P = 0.007)
BSC
Salvage Chemotherapy: Docetaxel/Irinotecan
Ramucirumab
BSC II
REGARD: BSC v. Ram. 5.2 v. 3.8 m (P = 0.047)
New standard of care.
Kang et al. JCO 2012; Fuchs et al. Lancet 2014
RAINBOW: PAST & PRESENT
BSC v. Salvage ChemoRx (Docetaxel or Irinotecan): 5.3 v. 3.8 m (P = 0.007)
BSC
Salvage Chemotherapy: Docetaxel/Irinotecan
Ramucirumab
BSC II
REGARD: BSC v. Ram. 5.2 v. 3.8 m (P = 0.047)
New standard of care.
Kang et al. JCO 2012; Fuchs et al. Lancet 2014
RAINBOW: PAST & PRESENT
BSC v. Salvage ChemoRx (Docetaxel or Irinotecan): 5.3 v. 3.8 m (P = 0.007)
BSC
Salvage Chemotherapy: Docetaxel/Irinotecan
Ramucirumab
BSC II
REGARD: BSC v. Ram. 5.2 v. 3.8 m (P = 0.047)
New standard of care.
Kang et al. JCO 2012; Fuchs et al. Lancet 2014
RAINBOW: PAST & PRESENT
BSC v. Salvage ChemoRx (Docetaxel or Irinotecan): 5.3 v. 3.8 m (P = 0.007)
BSC
Salvage Chemotherapy: Docetaxel/Irinotecan
Ramucirumab
BSC II
REGARD: BSC v. Ram. 5.2 v. 3.8 m (P = 0.047)
New standard of care.
Kang et al. JCO 2012; Fuchs et al. Lancet 2014
RAINBOW: PAST & PRESENT
BSC v. Salvage ChemoRx (Docetaxel or Irinotecan): 5.3 v. 3.8 m (P = 0.007)
BSC
Salvage Chemotherapy: Docetaxel/Irinotecan
Ramucirumab
BSC II
REGARD: BSC v. Ram. 5.2 v. 3.8 m (P = 0.047)
New standard of care.
Kang et al. JCO 2012; Fuchs et al. Lancet 2014
RAINBOW: LESSONS LEARNED!
Ramucirumab + Paclitaxel improves PFS/OS in 2nd-line mG/GEJ cancers refractory to 5FU and Platinum therapy.
✤ ? Is this similar to the story of Bevacizumab (AVAGAST).
✤ ? Why 2nd-line & not 1st-line efficacy.
✤ ? Chemotherapy backbone matters.
✤ ? Validity across populations.
✤ Very heterogenous disease.
✤ Future: Biomarker analysis and comparative angiogenic efficacy!
✤ PDT can confound OS. Choice of control arm critical in studies with OS endpoint.
✤ 1st-line Ramu. + FOLFOX-6: Negative for PFS (HR 0.98).
✤ Apatinib 3rd-line study (v. BSC) (N = 273): OS benefit (HR 0.7) (P = 0.0149)
DISCUSSION