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

P + FOLFOX

FOLFIRI

C + FOLFIRI

B + FOLFOX/XELOX

FOLFOX/XELOX

FOLFIRI

FOLFOX

P + FOLFOX

FOLFIRI

C + FOLFIRI

B + FOLFOX/XELOX

FOLFOX/XELOX

FOLFIRI

FOLFOX

P + FOLFOX

FOLFIRI

C + FOLFIRI

B + FOLFOX/XELOX

FOLFOX/XELOX

FOLFIRI

FOLFOX

P + FOLFOX

FOLFIRI

C + FOLFIRI

B + FOLFOX/XELOX

FOLFOX/XELOX

FOLFIRI

FOLFOX

P + FOLFOX

FOLFIRI

C + FOLFIRI

B + FOLFOX/XELOX

FOLFOX/XELOX

FOLFIRI

FOLFOX

P + FOLFOX

FOLFIRI

C + FOLFIRI

B + FOLFOX/XELOX

FOLFOX/XELOX

FOLFIRI

FOLFOX

P + FOLFOX

FOLFIRI

C + FOLFIRI

B + FOLFOX/XELOX

FOLFOX/XELOX

FOLFIRI

FOLFOX

P + FOLFOX

FOLFIRI

C + FOLFIRI

B + FOLFOX/XELOX

FOLFOX/XELOX

FOLFIRI

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

N = 180 (3 PTs)

IA Epi + PO Tegafur

IA Epi + IV Epi

IV Epi

Surgery

Adjuvant Rx

N = 180 (3 PTs)

IA Epi + PO Tegafur

IA Epi + IV Epi

IV Epi

Surgery

Adjuvant Rx

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.

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).

CRT Arm FFCD Study

CTx Arm FFCD Study

CTx Arm ECOG Study

CRT Arm ECOG Study

Continued CTx Arm

CRT Arm GERCOR

CRT Arm FFCD Study

CTx Arm FFCD Study

CTx Arm ECOG Study

CRT Arm ECOG Study

Continued CTx Arm

CRT Arm GERCOR

CRT Arm FFCD Study

CTx Arm FFCD Study

CTx Arm ECOG Study

CRT Arm ECOG Study

Continued CTx Arm

CRT Arm GERCOR

CRT Arm FFCD Study

CTx Arm FFCD Study

CTx Arm ECOG Study

CRT Arm ECOG Study

Continued CTx Arm

CRT Arm GERCOR

CRT Arm FFCD Study

CTx Arm FFCD Study

CTx Arm ECOG Study

CRT Arm ECOG Study

Continued CTx Arm

CRT Arm GERCOR

CRT Arm FFCD Study

CTx Arm FFCD Study

CTx Arm ECOG Study

CRT Arm ECOG Study

Continued CTx Arm

CRT Arm GERCOR

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)

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

Ramucirumab

BSC II

Ramucirumab

BSC II

Ramucirumab

BSC II

Ramucirumab

BSC II

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

asco 2014 update in gi cancer

Health & Medicine