GI ASCO single slide per page 1-17-15

New anti-angiogenic therapy in mCRC: FOLFIRI +/- Ramucirumab in 2nd line after FOLFOX + Bevacizumab (phase III: RAISE study) or

single agent Famitinib in 3rd line (phase II randomized with placebo)

Wafik El-Deiry, MD, PhD, FACP Deputy Director for Translational Research Co-Leader, Molecular Therapeutics Program

Fox Chase Cancer Center January 17, 2015

Oral Abstract Session: Cancers of the Colon, Rectum, and Anus

Learning Objectives •  Understand current use of anti-angiogenic therapy in mCRC

•  Understand different anti-angiogenic therapeutic targets and agents in mCRC

•  Explain and critique the RAISE phase III trial of Ramicirumab + FOLFIRI used in second line for mCRC

•  Explain and critique the randomized phase II single agent Famitinib trial in 3rd line therapy of mCRC

Presented by: Wafik El-Deiry, MD, PhD, FACP

Outline of Presentation •  Review angiogenesis as a therapeutic target •  Describe approved agents and agents under

investigation •  Critically assess the Ramicirumab and

Famitinib clinical trials in mCRC


Angiogenesis


Clinical Observations in 1960’s

2004

2001-2015

Effectively translated in last two decades

1980’s: VEGF

By 2010, many inhibitors tried in mCRC, most failed


By 2010, there was no progress in angiogenesis inhibition beyond bevacizumab Regorafenib, VEGF-trap, Tie2, bFGF, angiopoietin inhibitors were being tested

Angiogenesis beyond VEGF in mCRC


Phase III CORRECT Trial in mCRC

Phase III VELOUR Trial in mCRC

Regorafenib & Aflibercept approved in 2012 Targets include VEGFRs, Ang-2, PDGFR-β, FGFR

Current NCCN Guidelines for mCRC


NCCN Guidelines now include Ziv-aflibercept in 2nd line and regorafenib in 3rd line regimens

Ramicurimab


•  Ramicurimab is a fully humanized angiogenesis inhibitory antibody that targets VEGFR2 and prevents binding of VEGF

•  Approved by FDA in April 2014 to treat gastric or GE junction cancer after it improved OS

•  Known side-effects include diarrhea and hypertension

VEGFR2


Ramicirumab was approved by the FDA in combination with docetaxel for NSCLC following progression on platinum-based therapy on December 12, 2014

Phase II study of Ramicurimab plus FOLFOX as frontline therapy in mCRC


RAISE Study of Ramicurimab


•  A randomized, double-blind, multicenter phase III of FOLFIRI + Ramicurimab or placebo in patients with mCRC progression during or following FOLFOX + Bevacizumab

N= 536

N= 536

1072 patients

RAISE: Ramicurimab + FOLFIRI in 2nd line mCRC after FOLFOX + Bevacizumab improved OS


•  Lots of patients with WT KRAS (~50%) were eligible in both arms

•  The two arms were well-matched at baseline

•  Addition of Ramicurimab to FOLFIRI prolonged median overall survival by 13.3 months versus 11.7 months for FOLFIRI alone P = 0.0219

•  The most common grade 3/4 adverse events with ramicurimab were neutropenia, fatigue, hypertension and diarrhea

Time (months)

0 3 6 9 12 15 18 21 24 27 30 33 36 39 42

Ove

rall

Surv

ival

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0Ramicurimab increased OS when added to FOLFIRI in 2nd line therapy of mCRC to 13.3 mo vs 11.7 mo for FOLFIRI alone

Ramicurimab also increased PFS when added to FOLFIRI in 2nd line therapy of mCRC to 5.7 mo vs 4.5 mo for FOLFIRI alone (P = 0.0005)

P = 0.0219

536 patients in each arm

3 Studies RAISE, TML, & VELOUR looked at anti-angiogenic therapy in the second line after first line CT + Bev


FOLFOX + Bev ! FOLFIRI -/+ Ramicurimab

FOLFOX or + Bev ! FOLFOX or -/+ Bev FOLFIRI FOLFIRI

FOLFOX -/+ Bev ! FOLFIRI -/+ ziv-Aflibercept

RAISE: TML: VELOUR:

First Line Second Line

TML: Bevacizumab + FOLFIRI in 2nd line mCRC after FOLFOX or FOLFIRI + Bevacizumab improved OS


•  Similar design as RAISE •  Similar outcomes for PFS/OS extension

FOLFIRI FOLFIRI + Ramicurimab

FOLFIRI/FOLFOX

FOLFIRI + bevacizumab

PFS 4.5 5.7 4.1 5.7

OS 11.7 13.3 9.8 11.2

RAISE arms TML arms

PFS and OS: median survival in months

Not exactly the same: In TML patients had either FOLFOX or FOLFIRI in first line + bevacizumab and randomized to FOLFOX or FOLFIRI -/+ bevacizumab beyond progression

TML

TML PFS TML OS

VELOUR: Aflibercept + FOLFIRI in 2nd line mCRC after FOLFOX + Bevacizumab improved OS


•  Similar design as RAISE •  Similar outcomes for OS extension

FOLFIRI FOLFIRI + Ramicurimab

FOLFIRI FOLFIRI + Aflibercept

PFS 4.5 5.7 4.67 6.90

OS 11.7 13.3 12.06 13.5

RAISE arms VELOUR arms

PFS and OS: median survival in months

Not exactly the same: In VELOUR most patients had no prior Bevacizumab which may explain slightly lower PFS numbers in RAISE although it didn’t seem to impact the OS data

VELOUR: Aflibercept + FOLFIRI in 2nd line mCRC after FOLFOX + Bevacizumab improved OS


In VELOUR less than 1/3 of patients received prior Bevacizumab whereas in RAISE all patients received at least 2 doses of Bevacizumab

RAISE vs TML vs VELOUR summary of outcomes


RAISE: TML: VELOUR:

PFS -/+ OS -/+

4.5/ 5.7 m

11.7/ 13.3 m

4.1/ 5.7 m

9.8/ 11.2 m

4.7/ 6.9 m

12.1/ 13.5 m

•  Outcomes appear similar although designs not exactly the same •  Need randomized comparisons •  ? If there may be benefit from ziv or Ram beyond Bev & Ram or ziv (3rd line) •  ? If it may be worth trying to combine anti-angiogenics

•  Was too toxic in RCC but is this universally true with all agent combinations?

FOLFOX + Bev ! FOLFIRI -/+ Ramicurimab

FOLFOX or + Bev ! FOLFOX or -/+ Bev FOLFIRI FOLFIRI

FOLFOX -/+ Bev ! FOLFIRI -/+ ziv-Aflibercept

First Line Second Line

RAISE Comments: Ramicurimab + FOLFIRI in 2nd line mCRC after FOLFOX + Bevacizumab


•  Ramicurimab is effective to prolong OS in the second line therapy when combined with FOLFIRI after progression on FOLFOX plus Bevacizumab

•  The combination was well-tolerated (with some added toxicities in the combo) •  Recap of some possible future directions:

•  Ramicurimab + FOLFIRI vs Bev + FOLFIRI in 2nd line after FOLFOX + Bev •  Ramicurimab + FOLFIRI in patients with prior FOLFOX without Bev •  Ramicurimab + FOLFIRI vs anti-EGFR + FOLFIRI in 2nd line in WT KRAS

population •  Single agent Ram in patients who can’t tolerate chemo •  Ram or Ram + cape maintenance •  Ram + FOLFIRI vs Aflibercept + FOLFIRI in 2nd line with prior FOLFOX or

FOLFOX + Bev •  Need biomarkers to predict best responders vs those less likely to benefit •  In 2015 need to assess and compare financial toxicities

Ramicurimab in gastric cancer—poster at 2015 GI ASCO


Potential to push dose of Ramicirumab to improve outcomes

A randomized, double-blind, parallel-group, placebo controlled, multi-center, phase II

clinical study of Famitinib in the treatment of advanced metastatic colorectal cancer�

Rui-hua Xu*, Lin Shen*, Ke-ming Wang, Gang Wu, Chun-mei Shi, Ke-feng Ding, Li-zhu Lin, Jin-wan Wang, Jian-ping Xiong, Chang-ping Wu, Jin Li, Yun-peng Liu, Dong Wang,

Yi Ba, Jue-ping Feng, Yu-xian Bai, Jing-Wang Bi, Li-wen MA, Jian Lei and Hao Yu�

*Co-Leading Principle Investigator Abstract No.513�

Presented by: Rui-hua Xu�

Famitinib targets


KDR/VEGFR2

cKit

PDGFR

Anti-angiogenesis

Famitinib targets


Famitinib had efficacy in NPC phase II trial


Famitinib in mCRC


•  154 patients 2:1 randomization; groups well matched •  1.3 mo prolongation of FPS (P = 0.0053) & 59.8% DCR •  Breakdown of prior therapies unclear; FOLFOX, FOLFIRI, cetuximab and

bevacizumab are available in China •  No difference in OS noted •  AEs included proteinuria, neutropenia, HTN, thrombocytopenia, H/F

syndrome and diarrhea

PFS Data:

Regorafenib in mCRC


•  1052 patients 2:1 randomization; groups well matched •  1.9 mo prolongation of FPS and 6.4 mo (Regoraf) vs 5.0 mo (placebo) OS

OS/PFS Data:

•  Subgroup analyses supported impact of Regorafenib on OS including KRAS mutant mCRC

•  Lack of demonstrated effect on OS by Famitinib may be aided if biomarkers are developed or if combined with other agents

Summary: phase III Ramicirumab and phase II Famitinib trials in mCRC

•  Ramicirumab added to FOLFIRI improves OS in second line for mCRC after progression on FOLFOX plus bevacizumab

•  Famitinib does not improve OS in mCRC vs placebo after 2 failed prior regimens but does prolong PFS

•  Need to incorporate biomarkers in trial designs to make more sense of outcomes; are drugs hitting targets/are targets present?

•  Ramicirumab is comparable in 2nd line to other approved options •  Famitinib is not better in 3rd line than approved regimens •  Randomized comparisons or combination regimens may or may not

in the future show improved or better outcomes; ? Pushing doses



From Wehland et al., Int J Mol Sci, 2013

Possible biomarkers in CRC include Serum LDH, IL-8, Angiopoietin-2, CECs Others include VEGF plasma levels, sVEGFR2, VCAM-1 & E-selectin, sKIT, HTN, tumor expression of sensitivity or resistance markers

There are prognostic biomarkers to consider evaluating:


Clarke & Hurwitz, Exp Opin Biol Ther, 2013

The landscape of anti-angiogenic targets would appear to have more opportunities for target exploitation as well as testing of novel sequences and combinations

Comment

GI ASCO single slide per page 1-17-15

Documents

Transcript of GI ASCO single slide per page 1-17-15