Targeted therapies in Gastroesophageal Malignancies

Dawn of a new eraManish A. Shah, MD

Associate Professor of MedicineWeill Cornell Medical College of Cornell University

New York-Presbyterian HospitalDirector, Gastrointestinal OncologyCenter for Advanced Digestive Care

ObjectivesDiscussion of abstracts:

• LBA6 – Suntharalingam and colleagues• RTOG 0436 – phase III study of chemo/RT (cisplatin

and paclitaxel) with and without cetuximab for esophageal cancer treated without surgery

• LBA7 – Wilke and colleauges: • RAINBOW – phase III study of paclitaxel with or without

ramucirumab in 2nd line gastric/GEJ adenocarcinoma

The Initial Report of RTOG 0436: A Phase III Trial evaluating the addition of Cetuximab to Paclitaxel, Cisplatin, and Radiation for Patients with Esophageal Cancer Treated

without Surgery

Suntharalingam M, Winter K, Ilson D, Dicker A, Kachnic L, Konski A, Chakravarthy B, Anker C, Thakrar

H, Horiba N, Kavadi V, Deutsch M, Raben A, Roof K,Videdic G, Pollock J, Crane C

Abstract LBA6 - BackgroundRTOG 0436 – Cetuximab in Esophageal CA

• Why paclitaxel / Cisplatin?

Ajani J A et al. RTOG 0113: Phase II randomized trial of two nonoperative regimens of chemoradiation in localized esophageal CA. JCO 2008;26:4551-4556

Cisplatin + Paclitaxel with radiation was equivalent to cisplatin/FU + radiation, but with less toxicity.

(enrollment 2001-2005)

Abstract LBA6 - BackgroundRTOG 0436 – Cetuximab in Esophageal CA

• Context in the CROSS preoperative studyEligibility: T1N1 – T2-3Nx (stage 1-3)Treatment: Radiation 4140 cGy + weekly taxol (50 mg/m2) and

Carboplatin (AUC 2)

van Hagen P et al. Preoperative chemoradiotheapy for esophageal or junctional cancer. NEJM 2012;366:2074-84.

• Why cetuximab?– Cetuximab: a chimeric (mouse/human) monoclonal

antibody against epidermal growth factor receptor (EGFR)

– EGFR expression in ~80% (30-90%) esophageal cancer, ~40% gastric cancer

– EGFR expression correlates with prognosis in esophagogastric ACA and SCC

– KRAS mutations occur in ~2% (0-9%) of esophageal cancers

Mukaida. Cancer 1991; Itakura. Cancer 1994; Yacoub. Mod Pathol 1997; Torzewski. Anticancer Res 1997; Koyama. J Cancer Res Clin Oncol 1999; Lea. Carcinogenesis 2006

Abstract LBA6 - BackgroundRTOG 0436 – Cetuximab in Esophageal CA

Ove

rall S

urviv

al (%

)

0

25

50

75

100

Months from Randomization0 3 6 9 12 15 18 21 24

Patients at RiskRT+Chemo+CetuxRT+Chemo

159169

139158

124141

108121

94102

8283

6568

5454

5149

Failed97110

Total159169

Stratified log-rank p-value = 0.70

HR= 0.92 (0.70,1.21)RT+Chemo+CetuxRT+Chemo

RTOG 0436: Overall Survival

Median follow-up for alive patients = 24.3 months (0.1-60.7)

(n=328)

2-Year Rates:

44.0%41.7%

• Well designed and performed study,

• Reasonable stratification

• No survival difference

Comment• Cetuximab does not improve survival or response

when combined with chemotherapy for localized unresectable esophageal cancer.

• Consistent with previous results in metastatic disease.

Phase III studies EGFR Ab inhibitors are metastatic disease

Comment• Cetuximab does not improve survival or response

when combined with chemotherapy for localized unresectable esophageal cancer.

• Consistent with previous results in metastatic disease.

• These data are definitive.

• Would the results be different in a pre-operative setting. Likely not!

Comment• Why didn’t this work? (now or previously)Are esophageal cancers driven by EGFR signaling?

Dulak AM et al. Whole-exome and whole-genome sequencing of esophageal adenocarcinoma identifies recurrent driver events and mutational complexity. Nat Genet. 2013;45(5):478-=86.

TP53CDKN2AEYSARID1ASMAD4PIC3CA

EGFR mutations did not occur as top mutations. But it is more complicated –EGFR amplification did occur frequently.

Comment• What have we learned?

• Clinical response to chemo/RT is prognostic.

Ove

rall S

urviv

al (%

)

0

25

50

75

100

Months from Randomization0 3 6 9 12 15 18 21 24

Patients at RiskcCRResidual Disease

10485

10479

9871

8759

7649

6541

5234

4427

4024

Failed6162

Total10485 HR= 1.59 (1.11,2.26)

cCRResidual Disease

Ove

rall S

urviv

al (%

)

0

25

50

75

100

Months from Randomization0 3 6 9 12 15 18 21 24

Patients at RiskcCRResidual Disease

7043

7034

6225

5619

5116

4512

387

307

297

Failed2835

Total7043 HR= 3.67 (2.22,6.07)

cCRResidual Disease

Implications:Our best approach to improving survival in this disease is to improve response to therapy.

– PET directed therapyCALGB 80803: PET directed chemo + chemo/RT

– Targeted therapy RTOG 1010: Trastuzumab with chemo/RT

– Improve our understanding of tumor biology RTOG 0436: 85% tissue collected

RAINBOW: A Global, Phase 3, Randomized, Double-Blind Trial of Ramucirumab and Paclitaxel (PAC) Versus Placebo

and PAC in the Treatment of Metastatic Gastric or Gastroesophageal Junction (GEJ) Adenocarcinoma

Following Disease Progression on First-Line Platinum- and Fluoropyrimidine-Containing Combination Therapy

H. Wilke* Eric Van Cutsem, Sang Cheul Oh, György Bodoky,

Yasuhiro Shimada, Shuichi Hironaka, Naotoshi Sugimoto, Oleg Lipatov, Tae You Kim, David Cunningham, Atsushi Ohtsu, Philippe

Rougier, Michael Emig, Roberto Carlesi, Kumari Chandrawansa, Kei Muro

*On behalf of the RAINBOW Investigators

LBA7

Treat until disease

progression or

intolerable toxicity

• Important inclusion criteria: - Metastatic or loc. adv. unresectable gastric or GEJ* adenocarcinoma - Progression after 1st line platinum/fluoropyrimidine based chemotherapy• Stratification factors: - Geographic region, - Measurable vs non-measurable disease, - Time to progression on 1st line therapy (< 6 mos vs. ≥ 6 mos)

Ramucirumab 8 mg/kg day 1&15+ Paclitaxel 80 mg/m2 day 1,8 &15

of a 28-day cycleN = 330

Placebo day 1&15 + Paclitaxel 80 mg/m2 day 1,8 &15

N = 335

SCREEN

RANDOMIZE

Survival and safety

follow-up

RAINBOW: Study Design

* GEJ= gastroesophageal junction; gastric and GEJ will be summarized under the term GC

1:1

RAINBOW: Overall Survival

0 2 4 6 8 10 12 14 16 18 20 22 24 26 280.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

RAM+PAC

PBO+PAC

Months

Ove

rall

Sur

viva

l Pro

babi

lity

HR (95% CI) = 0.807 (0.678, 0.962)Stratified log rank p-value = 0.0169

RAM + PAC PBO + PACPatients / Events 330 / 256 335 / 260Median(mos) (95% CI) 9.63 (8.48, 10.81) 7.36 (6.31,

8.38) 6-month OS 72% 57%12-month OS 40% 30%

RAM + PAC 330 308 267 228 185 148 116 78 60 41 24 13 6 1 0PBO + PAC 335 294 241 180 143 109 81 64 47 30 22 13 5 2 0

No. at risk

Censored

Δ mOS = 2.3 months

Comment

• Well performed international study – kudos to the investigators and to Lilly.

• Why did it work?

AvagastOverall Survival : Cis/Cape +/- Bevacizumab

XP + Placebo

XP + Bev

HR = 0.8795% CI 0.73–1.03 p = 0.1002

Survival rate

3 9 15 18 21 240

0.0

0.10.2

0.3

0.4

0.5

0.6

0.70.8

0.9

1.0

6 12Study month

10.1

12.1

Bevacizumab plus CT for Advanced Gastroesophageal Adenocarcinoma (GC): Combined U.S. experience*

Smyth, et al. ASCO 2011 (Abstract 4056)

Tumor Characteristics

US cohortAVAGAST

Chemo + Bev arm p valuen % n %

SiteGastric 64 (41) 333 (86)

<0.0001GEJ 92 (59) 54 (14)Lauren's Classification* Diffuse 42 (27) 176 (46)

<0.0001**Intestinal 81 (52) 155 (40)Mixed 35 (9)Not reported 33 (21)Liver metastasis 81 (52) 130 (34) <0.0001

*Data from 4 investigator initiated U.S. phase II studies of chemotherapy plus bevacizumab for the treatment of metastatic/unresectable gastric cancer were pooled. Sites involved were: 1) Memorial Sloan-Kettering Cancer Center, 2) Dana-Farber/Harvard Cancer Center, 3)Yale Cancer Center, and 4) Stanford Comprehensive Cancer Center.

Patient characteristics by region AVAGAST Study

Characteristic, % Asia Europe Pan-AmericaAge <65 72 68 77

≥65 28 32 23ECOG PS 0–1 97 91 96

≥2 3 9 4Primary site Stomach 94 78 84

GEJ 6 22 16Disease status Metastatic 99 95 92

Locally advanced 1 5 8Prior gastrectomy Yes 32 23 27

No 68 77 73Measurable lesion Yes 73 88 77

No 27 12 23Liver metastasis Yes 27 37 42

No 73 63 58

*1 additional patient had an ECOG PS of 4 There was an imbalance of >10% between the regions

Avagast vs. RamicirumabAvagast Rainbow

Study Design 1st line 2nd lineBackbone chemotherapy

Cisplatin/ capecitabine Paclitaxel

Demographics N = 774 N = 665Asia 376 (49%) 223 (33.5%)

Non-Asia 398 (51%) 442 (66.5%)Results OS

Asia 12.1 13.9 mo HR 0.97 (0.75-1.25)

10.5 12.1 moHR 0.99 (0.73-1.34)

Non-Asia 7.3 11.4 moHR 0.67 (0.52-0.88)

5.9 8.5 moHR 0.73 (0.59-0.91)

Results PFSAsia 5.6 6.7 (HR 0.92) 2.8 5.5 (HR 0.63)

Europe 4.4 6.9 (HR 0.71)2.9 4.2 (HR 0.64)

Pan-America 4.4 5.9 (HR 0.65)

Avagast vs. RamicirumabAvagast Rainbow

Study Design 1st line 2nd lineBackbone chemotherapy

Cisplatin/ capecitabine Paclitaxel

Demographics N = 774 N = 665Asia 376 (49%) 223 (33.5%)

Non-Asia 398 (51%) 442 (66.5%)Results OS

Asia 12.1 13.9 mo HR 0.97 (0.75-1.25)

10.5 12.1 moHR 0.99 (0.73-1.34)

Non-Asia 7.3 11.4 moHR 0.67 (0.52-0.88)

5.9 8.5 moHR 0.73 (0.59-0.91)

Results PFSAsia 5.6 6.7 (HR 0.92) 2.8 5.5 (HR 0.63)

Europe 4.4 6.9 (HR 0.71)2.9 4.2 (HR 0.64)

Pan-America 4.4 5.9 (HR 0.65)

Avagast vs. RamicirumabAvagast Rainbow

Study Design 1st line 2nd lineBackbone chemotherapy

Cisplatin/ capecitabine Paclitaxel

Demographics N = 774 N = 665Asia 376 (49%) 223 (33.5%)

Non-Asia 398 (51%) 442 (66.5%)Results OS

Asia 12.1 13.9 mo HR 0.97 (0.75-1.25)

10.5 12.1 moHR 0.99 (0.73-1.34)

Non-Asia 7.3 11.4 moHR 0.67 (0.52-0.88)

5.9 8.5 moHR 0.73 (0.59-0.91)

Results PFSAsia 5.6 6.7 (HR 0.92) 2.8 5.5 (HR 0.63)

Europe 4.4 6.9 (HR 0.71)2.9 4.2 (HR 0.64)

Pan-America 4.4 5.9 (HR 0.65)

Biomarkers- pVEGFA and NRPCandidate Biomarkers for Bevacizumab Efficacy in Gastric Cancer

Van Cutsem E [Shah MA]. JCO 2012;30:2119-2127

Implications• Targeting the angiogenesis pathway in

gastric/ GEJ adenocarcinoma is now validated

• Ramicirumab + paclitaxel is a viable, safe, effective treatment option following 1st line therapy.

• Is VEGFR2 specific inhibition any different than blocking VEGF-A?

What have we learned• Disease biology is important, as shown by

gastric cancer heterogeneity.

Genetic Risk Environment

Behavior

Family History:CDH1MMRAPCTP53

H. Pylori cag A strain

Tobacco use/ diet (salt) (fruits/vegetables)

Immune SNPsIL1, IL4, etc.

Proximal non

diffuse

Gastric

Cancer

Distal non

diffuse

Gastric CA

Diffuse Gastric CA

Are we at the Dawn of a new era?

Shah MA. Nat Rev Clin Oncol 2014;11:10-11.

Are we at the Dawn of a new era?

Pathway Agent Clinical Trial Randomization Patients

METOrnartuzumab METGASTRIC FOLFOX +/-

ornatuzumab 800

Rilotumumab RILOMET ECX +/- rilotumumab 450

HER2

Pertuzumab JACOB XP-T +/- pertuzumab 780

Trastuzumab HELOISEXP-T (standard) vs.

XP-T (high dose) 400

TDM-1 GATSBYTDM-1 vs taxane

(2nd line) 412

Lapatinib TyTANPaclitaxel +/- lapatinib

(2nd line) 261

EGFRPanitumumab REAL-3 EOX +/- panitumuamb 574

Cetuximab EXPAND XP +/- cetuximab 904

Angiogenesis

Ramucirumab REGARDRamucirumab vs. BSC

(2nd line) 355

Ramicirumab RAINBOWPaclitaxel +/-

Ramucirumab (2nd line) 665

Regorafenib INTEGRATERegorafenib vs BSC

(2nd line) 150

Targeted Successes

Target Study Setting Clinical Benefit

HER2 TOGA 1st line HER2 positive

HR 0.74 (2.7 month)

VEGFR2 REGARD 2nd line monotherapy

HR 0.78 (1.4 month)

RAINBOW 2nd line combination

HR 0.81 (2.3 month)

Dawn of …. more of the same?Target Study Why does it work? Why does it not?

HER2 TOGA HER2 drives tumor growth and proliferation

?

VEGFR2 REGARD Blocks VEGFR2 ?

RAINBOW Blocks VEGFR2 ?

Angiogenesis Bevacizumab Inhibits VEGF-A ?

Mictrotubules Taxanes Arrests cell division

?

DNA Synthesis Fluoropyrimidines Stops DNA /RNA synthesis

?

DNA Damage Platinum Accumulation of DNA damage

?

We are in a New Era !• Greater emphasis on obtaining tissue and

biospecimens• Greater tools at our disposal

– [put your – omic here]Focus our efforts on understanding how therapy works understanding why therapy doesn’t work why therapy stops working

That is our next move….