CYRAMZA (COLORECTAL CANCER) – FORECAST …The following figure illustrates the global sales for Cyramza in the CRC markets by region during the forecast period. Sales for Cyramza

REFERENCE CODE GDHC476DFR | PUBLICAT ION DATE NOVEMBER 2014

CYRAMZA (COLORECTAL CANCER) – FORECAST AND MARKET ANALYSIS TO 2023

Cyramza (Colorectal Cancer) – Forecast and Market Analysis to 2023 2 © GlobalData. This report is a licensed product and is not to be copied, reproduced, shared or resold in any form.


Executive Summary

Table below presents the key metrics of Cyramza

for colorectal cancer (CRC) in the eight major

pharmaceutical markets (8MM) (US, France,

Germany, Italy, Spain, UK, Japan, and China)

during the forecast period from 2013–2023.

Cyramza: Key Metrics in the 7MM and China for Colorectal Cancer, 2013-2023

Key events (2013-2023) Level of Impact

Launch of Cyramza (ramucirumab) in the second-line Avastin pre-treated metastatic setting in 2016

↑↑

2023 Market Sales

US $ 130.5m

5EU $ 39.9m

Japan $ 23.9m

Total $194.3m Source: GlobalData 7MM= US, France, Germany, Italy, Spain, the UK, Japan and China 5EU = France, Germany, Italy, Spain, and the UK

Sales for Cyramza in the Colorectal Cancer Market

GlobalData estimates that sales of Cyramza for

CRC markets were $25.2 million in the year 2016

when it will be launched. By 2023, the end of the

forecast period, GlobalData projects Cyramza

sales at $194.3 million in the 8MM.

Major drivers of the growth of Cyramza in the CRC

market over the forecast period include:

Eli Lilly’s experience commercializing oncology

products.

Demonstrated statistically significant efficacy

benefit with FOLFIRI compared to FOLFIRI

alone in a Phase III study.

Prescribed with FOLFIRI, a common second-

line chemotherapy regimen.

Has demonstrated single-agent activity in

another GI cancer (gastric cancer), a disease

where Avastin failed to demonstrate clinical

benefit.

Major barriers to the growth of Cyramza in the

CRC market will include:

Not being investigated as a single-agent in

CRC.

Restrictive eligible patient population of Avastin

+ FOLFOX pre-treated patients only.

Lack of available clinical data.

The following figure illustrates the global sales for

Cyramza in the CRC markets by region during the

forecast period.

Sales for Cyramza by Region, 2023

67%

21%

12%

2023Total: $194.3m

US

5EU

Japan

Source: GlobalData



Executive Summary

What Do the Physicians Think?

Key Opinion Leaders (KOLs) do not expect results

from the FIRE-3 study comparing Erbitux and

Avastin in the first-line KRAS wild-type metastatic

setting to have a major impact on prescribing

behavior.

“I am not sure [the results from the FIRE-3 study]

are going to make a huge difference. I think, in

practice at least, in the US, for patients who are

KRAS wild-type, the choice of Erbitux vs. Avastin

has really been something that the physician has

chosen on their own. I think there are some

physicians who really like to use Erbitux, and use it

up front, and other people who always prescribed

Avastin and either don’t use Erbitux at all or really

use it more at a later stage.”

US Key Opinion Leader

“Avastin is the standard of care for both KRAS

wild-type and KRAS mutated patients. This is the

perception right now for the US as a whole. There

are pockets, perhaps, where people probably are

moving to Erbitux plus FOLFIRI, but I would say

majority is still Avastin frontline.”


“The reason for using Avastin as a first-line

treatment is due to the side-effect profile compared

to Erbitux, rather than the efficacy. The side effect

of most concern with Erbitux is the rash.”


Interviewed KOLs expect Zaltrap and Cyramza

(ramucirumab) to struggle to garner much uptake

in the second-line metastatic setting.

“In second-line [setting] you have Avastin, Zaltrap,

and now, [potentially,] ramucirumab. For

ramucirumab, to be honest, I think it will come

down to what the survival data looks like. If it’s only

as good as or worse than the other two, then,

being the third player to join the party, I don’t think

it has much chance of becoming a standard of

care…”

OUS Key Opinion Leader

“In my view there is no probable advantage [of

Zaltrap] over Avastin continuation, and [in my

experience] there seems to be more side effects

with Zaltrap than Avastin; so I really don’t prefer to

use Zaltrap at this time.”


Interviewed experts reported high unmet need for

targeted treatments for KRAS and BRAF mutation-

positive CRC patients.

“Unmet needs in overall survival are greater for

KRAS mutated patients. We need to have new

drugs to try to increase overall survival in this

population. [Overall], I think now we need to have a

different strategy for KRAS and for BRAF patients.

It’s important to have different strategy.”

OUS Key Opinion Leader



Executive Summary

“BRAF mutant-positive colorectal cancer patients

are a subset with very poor prognosis; most

patients really have a very rapid and progressive

course and it is a pretty nasty disease. But, I think

his is probably the area where in the area of

targeted therapies we may see perhaps the most

exciting developments in the next few years for

colorectal cancer”


Interviewed KOLs are excited about the potential of

kinase inhibitor combinations, such as BRAF/MEK

with EGFR inhibitors for BRAF mutation-positive

disease, and the immune checkpoint inhibitors,

such as the anti-PD1/PDL1 antibodies.

“The high level question is the comparison

between the doublet BRAF/EGFR combinations to

some of the potential triplet BRAF/MEK/EGFR or

BRAF/PI3K/EGFR combinations. If they are

tolerable, I really think that those triplets are going

to be the better way to go. I am hopeful we could

see some, potentially, really exciting advances in

the ‘oncogene-addiction’ treatment category.”


“The PD1 and PDL1 inhibitors are exciting, and so

far, in CRC, they have only been tested in a very

small number of patients. But I think there is

enough there to warrant the [further] exploration of

this space in colorectal cancer. It remains to be

seen what happens, but I know there is a lot of

excitement about that.”



Table of Contents


1 Table of Contents

1 Table of Contents ....................................................................................................................... 5

1.1 List of Tables ...................................................................................................................... 8

1.2 List of Figures ..................................................................................................................... 8

2 Introduction ................................................................................................................................. 9

2.1 Catalyst ............................................................................................................................... 9

2.2 Related Reports ................................................................................................................ 10

2.3 Upcoming Related Reports ............................................................................................... 11

3 Disease Overview ..................................................................................................................... 12

3.1 Etiology and Pathophysiology ........................................................................................... 12

3.1.1 Etiology ......................................................................................................................... 12

3.1.2 Pathophysiology ............................................................................................................ 14

3.2 Clinical Staging ................................................................................................................. 15

3.3 Symptoms ......................................................................................................................... 16

4 Disease Management ............................................................................................................... 18

4.1 Diagnosis and Treatment Overview .................................................................................. 18

4.1.1 Screening and Diagnosis .............................................................................................. 18

4.1.2 Treatment Guidelines and Leading Prescribed Drugs ................................................... 21

4.1.3 Clinical Practice ............................................................................................................. 25

5 Competitive Assessment .......................................................................................................... 32

5.1 Overview ........................................................................................................................... 32

6 Unmet Need and Opportunity ................................................................................................... 34


Table of Contents


6.1 Overview ........................................................................................................................... 34

6.2 Therapies That Provide Substantial Overall Survival Benefit for Metastatic Patients ......... 35

6.2.1 Unmet Need .................................................................................................................. 35

6.2.2 Gap Analysis ................................................................................................................. 37

6.2.3 Opportunity ................................................................................................................... 37

6.3 Targeted Treatments for KRAS and BRAF Mutaton-Positive Patients ............................... 39

6.3.1 Unmet Need .................................................................................................................. 39

6.3.2 Gap Analysis ................................................................................................................. 40

6.3.3 Opportunity ................................................................................................................... 40

6.4 Effective Neoadjuvant/Adjuvant Therapies for High Risk Resectable Disease .................. 41

6.4.1 Unmet Need .................................................................................................................. 41

6.4.2 Gap Analysis ................................................................................................................. 42

6.4.3 Opportunity ................................................................................................................... 42

6.5 Tolerable Later-Line Therapies For Chemotherapy-Resistant Patients ............................. 43

6.5.1 Unmet Need .................................................................................................................. 43

6.5.2 Gap Analysis ................................................................................................................. 43

6.5.3 Opportunity ................................................................................................................... 44

7 Pipeline Assessment................................................................................................................. 45

7.1 Overview ........................................................................................................................... 45

7.2 Promising Drugs in Clinical Development .......................................................................... 46

8 Cyramza (Ramucirumab) .......................................................................................................... 48

8.1 Overview ........................................................................................................................... 48

8.2 Efficacy ............................................................................................................................. 51


Table of Contents


8.3 Safety ............................................................................................................................... 51

8.4 Dosing and Formulation .................................................................................................... 51

8.5 Potential Clinical and Commercial Positioning................................................................... 52

8.6 SWOT Analysis ................................................................................................................. 53

8.7 Forecast ............................................................................................................................ 54

9 Appendix................................................................................................................................... 55

9.1 Bibliography ...................................................................................................................... 55

9.2 Abbreviations .................................................................................................................... 60

9.3 Methodology ..................................................................................................................... 64

9.4 Forecasting Methodology .................................................................................................. 64

9.4.1 Diagnosed Colorectal Cancer Patients .......................................................................... 64

9.4.2 Percent Drug-Treated Patients ...................................................................................... 65

9.4.3 General Pricing Assumptions ........................................................................................ 65

9.4.4 Average Body Weight and Surface Area Across the 8MM ............................................. 66

9.4.5 Generic Erosion ............................................................................................................ 66

9.4.6 Pricing of Pipeline Agents.............................................................................................. 66

9.5 Primary Research – KOLs Interviewed for this Report ...................................................... 67

9.6 Primary Research – Prescriber Survey ............................................................................. 69

9.7 About the Authors ............................................................................................................. 70

9.7.1 Analyst .......................................................................................................................... 70

9.7.2 Global Head of Healthcare ............................................................................................ 71

9.8 About GlobalData .............................................................................................................. 72

9.9 Disclaimer ......................................................................................................................... 72


Table of Contents


1.1 List of Tables

Table 1: TNM and Staging Classification System for CRC ......................................................................... 16

Table 2: Symptoms of Colorectal Cancer .................................................................................................. 17

Table 3: Treatment Guidelines for CRC ..................................................................................................... 22

Table 4: Most-Prescribed Neoadjuvant/Adjuvant Regimens for Early-Stage CRC in the Global Markets,

2013............................................................................................................................................ 23

Table 5: Most Prescribed Targeted Therapies for Metastatic CRC by Segment in the Global Markets, 2013

................................................................................................................................................... 24

Table 6: Leading Treatments for CRC, 2014 ............................................................................................. 33

Table 7: Unmet Need and Opportunity in CRC .......................................................................................... 35

Table 8: Product Profile – Cyramza ........................................................................................................... 50

Table 9: Cyramza SWOT Analysis, 2014 .................................................................................................. 53

Table 10: Global Sales Forecasts ($m) for Cyramza, 2013-2023 ................................................................. 54

Table 11: Average Body Weight and Surface Area Across the 8MM ............................................................ 66

Table 12: High-Prescribing Physicians (non-KOLs) Surveyed, By Country .................................................. 69

1.2 List of Figures

Figure 1: CRC – Phase III Pipeline ............................................................................................................. 46

Figure 2: Competitive Assessment of Late-Stage Pipeline Agents in CRC, 2013-2023................................ 47

Figure 3: Clinical and Commercial Positioning of Cyramza ......................................................................... 52



Introduction

2 Introduction

2.1 Catalyst

Colorectal cancer (CRC) is the second leading cause of mortality among cancer patients in the

world and is the third most diagnosed cancer globally, and thus represents a huge burden on

healthcare systems. Despite robust screening programs across most of the 8MM (US, France,

Germany, Italy, Spain, UK, Japan, and China), a significant proportion (10-20%) of patients are

diagnosed with stage IV metastatic disease and correspondingly poor prognoses, compared to

resectable early-stage disease. In terms of targeted treatments, the metastatic CRC treatment

landscape is mature, including the branded treatments Avastin (bevacizumab), Erbitux (cetuximab),

and Vectibix (panitumumab), treatments that have extended the survival of metastatic patients

compared to chemotherapy-only regimens. However, high unmet needs remain for the extension of

survival of metastatic patients, and particularly those with KRAS mutation-positive disease, for

whom the epidermal growth factor receptor (EGFR) inhibitors Erbitux and Vectibix are not

recommended.

The CRC market is expected to grow due to the incorporation of five late-stage pipeline agents

during the forecast period, including Mologen’s MGN1703, Eli Lilly’s Cyramza (ramucirumab), and

Boehringer Ingelheim’s nintedanib. These pipeline agents will be utilized across different segments

of the metastatic population, from the first-line maintenance setting (MGN1703) to the second- and

later-line settings (Cyramza and nintedanib). Furthermore, GlobalData expects the label extension

of Stivarga as a first-line adjuvant treatment for metastatic CRC patients with resected liver

metastases. Stivarga is currently approved for the smaller third- or fourth-line, chemotherapy, and

targeted-treatment refractive settings. Ultimately, however, GlobalData expects unmet needs to

remain unfulfilled by these pipeline agents, and anticipates that novel, innovative approaches, such

as those targeting BRAF mutation-positive disease and immune checkpoint inhibitors, will provide

the best opportunity for substantial improvement in the prognosis of advanced CRC patients.



Introduction

2.2 Related Reports

GlobalData (2014). HER2-Positive Breast Cancer – Global Drug Forecast and Market Analysis

to 2023, September 2014, GDHC86PIDR

GlobalData (2014). Non-Hodgkin’s B-Cell Lymphoma – Opportunity Analysis and Forecast to

2018, August 2014, GDHC035POA

GlobalData (2014). Chronic Lymphocytic Leukemia (CLL) – Opportunity Analysis and

Forecasts to 2018, June 2014, GDHC017POA

GlobalData (2014). Non-Small Cell Lung Cancer (NSCLC) – Global Drug Forecast and Market

Analysis to 2022 – Event-Driven Update, April 2014, GDHC002EPIDR

GlobalData (2014). Pancreatic Cancer – Opportunity Analysis and Forecasts to 2017, March

2014, GDHC016POA

GlobalData (2013). Bladder Cancer – Opportunity Analysis and Forecasts to 2017, December

2013, GDHC014POA

GlobalData (2014). Colorectal Cancer – Global Drug Forecast and Market Analysis to 2023,

November 2014, GDHC95PIDR

GlobalData (2014). Colorectal Cancer – US Drug Forecast and Market Analysis to 2023,

November 2014, GDHC257CFR

GlobalData (2014). Colorectal Cancer – 5EU Drug Forecast and Market Analysis to 2023,


GlobalData (2014). Colorectal Cancer – Japan Drug Forecast and Market Analysis to 2023,


GlobalData (2014). Colorectal Cancer – China Drug Forecast and Market Analysis to 2023,


GlobalData. Avastin (Colorectal Cancer) – Forecast and Market Analysis to 2023, November

2014, GDHC469DFR

GlobalData. Erbitux (Colorectal Cancer) – Forecast and Market Analysis to 2023, November

2014, GDHC470DFR



Introduction

GlobalData. Vectibix (Colorectal Cancer) – Forecast and Market Analysis to 2023, November

2014, GDHC471DFR

GlobalData. Stivarga (Colorectal Cancer) – Forecast and Market Analysis to 2023, November

2014, GDHC472DFR

GlobalData. Zaltrap (Colorectal Cancer) – Forecast and Market Analysis to 2023, November

2014, GDHC473DFR

GlobalData. TS-1 (Colorectal Cancer) – Forecast and Market Analysis to 2023, November

2014, GDHC474DFR

GlobalData. Lonsurf (Colorectal Cancer) – Forecast and Market Analysis to 2023, November

2014, GDHC475DFR

GlobalData. Imprime PGG (Colorectal Cancer) – Forecast and Market Analysis to 2023,

November 2014, GDHC477DFR

GlobalData. MGN1703 (Colorectal Cancer) – Forecast and Market Analysis to 2023,


GlobalData. Nintedanib (Colorectal Cancer) – Forecast and Market Analysis to 2023,


GlobalData. Colorectal Cancer – Current and Future Players, November 2014,

GDHC1039FPR

2.3 Upcoming Related Reports

GlobalData (2014). HER2-Negative Breast Cancer – Global Drug Forecast and Market

Analysis to 2023

GlobalData (2014). Malignant Melanoma – Global Drug Forecast and Market Analysis to 2023


Appendix


9.8 About GlobalData

GlobalData is a leading global provider of business intelligence in the Healthcare industry.

GlobalData provides its clients with up-to-date information and analysis on the latest developments

in drug research, disease analysis, and clinical research and development. Our integrated business

intelligence solutions include a range of interactive online databases, analytical tools, reports and

forecasts. Our analysis is supported by a 24/7 client support and analyst team.

GlobalData has offices in New York, Boston, London, India and Singapore.

9.9 Disclaimer

All Rights Reserved.

No part of this publication may be reproduced, stored in a retrieval system or transmitted in any

form by any means, electronic, mechanical, photocopying, recording or otherwise, without the prior

permission of the publisher, GlobalData.

Documents

CYRAMZA (COLORECTAL CANCER) – FORECAST …The following figure illustrates the global sales for Cyramza in the CRC markets by region during the forecast period. Sales for Cyramza