Disease Analysis: Colorectal Cancer
Author: Tom Tyler
Publisher: Datamonitor Healthcare
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Overview
Colorectal (or bowel) cancer refers to carcinomas arising in the epithelium of the large intestine at any point between the cecal valve and the anus. CRC typically develops through the proliferation of mucosal epithelial cells of the gastrointestinal (GI) wall, eventually forming a polyp or adenoma. As with many other cancers of the GI tract, the vast majority (>95%) are adenocarcinomas. Colorectal cancers may be broadly divided between the two major regions of the large intestine. Though some disagreement exists on precisely where the boundary between the colon and the rectum exists, it is generally agreed that a primary tumor <15cm from the anal margin may be defined as rectum cancer and more distal tumors defined as colon cancer. Though colon cancers are more common than rectal cancers, when considered together, CRC stands as the third deadliest and fourth most diagnosed form of cancer worldwide.
Latest key takeaways
- Datamonitor Healthcare estimates that in 2018, there were 1.80 million incident cases of colorectal cancer (CRC) worldwide, and expects that number to increase to 1.95 million incident cases by 2027.
- CRC may be subdivided into two distinct categories based on the anatomical origin of the primary tumor – rectal cancer and colon cancer.
- The majority of CRC diagnoses (60.9%) worldwide are colon cancer, ranging from 57.3% to 68.5% across regions.
- Colon cancer is fairly evenly distributed between sexes, with males accounting for 52.5% of global colon cancer diagnoses in 2018, whereas rectum cancer is more common among men, who made up 61.0% of diagnoses in 2018.
- Although systemic therapy is administered in locoregional disease, typically as adjuvant treatment, such regimens consist of genericized chemotherapies. All branded agents are confined to metastatic, unresectable CRC.
- Conventional targeted treatments in CRC are angiogenesis inhibitors typically acting through the receptor tyrosine kinase (RTK) superfamily, including EGFR antagonists, such as Erbitux and Vectibix, and VEGFR antagonists, such as Cyramza, Zaltrap, and Avastin (the latter two inhibit VEGFR through its ligand, VEGF). Additionally, Stivarga is a polyspecific tyrosine kinase inhibitor (TKI) simultaneously targeting VEGFR, PDGFR, and EGFR in addition to non-tyrosine kinases c-KIT and RAF.
- Treatment for mCRC is heavily dependent on gene expression, with many drugs being prescribed only for specific tumor profiles.
- First- and particularly second-line metastatic CRC have become very crowded treatment settings, with multiple combinations of chemotherapies and targeted agents competing for the same patient subsets.
- Avastin, the first targeted agent launched in the indication, is the traditional standard of care and remains widely prescribed in both first- and second-line disease and across tumor profiles. However, the branded drug is approaching the end of its lifecycle and the recent launch of bevacizumab biosimilars will significantly erode its market share.
- Despite biosimilar erosion of branded Avastin, bevacizumab’s potential incorporation into new, highly active combination therapies in first- and second-line mCRC stands to cement the drug’s status as a standard of care.
- Tumors that are RAS/BRAF WT and EGFR+ are among the most common gene expression profiles, accounting for approximately 40% of CRCs. The EGFR antagonist Erbitux, among the first targeted agents launched in CRC alongside Avastin, remains the most commonly prescribed therapy for this subset of patients, despite the more recent addition of Vectibix in the same setting.
- Erbitux has recently found a new use in a doublet with the RAF kinase inhibitor Braftovi for BRAF V600E mutants. The combination is highly active, but only 12–15% of CRCs are BRAF V600E+ and the regimen is currently confined to second-line use.
- Anti-PD-1 checkpoint inhibitors Opdivo and Keytruda have seen initial success in microsatellite instability-high/defective mismatch repair (MSI-H/dMMR) mCRCs, although these comprise only 15% of patients.
- The exploratory CheckMate 9X8 regimen of bevacizumab, Opdivo, and FOLFOX in front-line disease, currently in Phase II/III investigation, has the potential to both introduce a highly active combination to the CRC treatment landscape and also expand PD-1 inhibitor use to the wider patient population who are MSI normal/MMR proficient.
- A suite of trial suspensions has shrunk the late-stage CRC pipeline. Current Phase III drugs include the MEK inhibitor Mektovi, the CDK antagonist Cosela, the KRAS inhibitor adagrasib, the novel folate Modufolin, the PARP inhibitor Lynparza, and the novel VEGFR inhibitor fruquintinib.
CONTENTS
7 OVERVIEW
7 Latest key takeaways
9 DISEASE BACKGROUND
9 Definition
9 Risk factors
10 Symptoms
10 Diagnosis
10 Prognosis
11 Patient segmentation
14 TREATMENT
14 Locoregional disease
14 Metastatic disease
15 Front-line therapy for unresectable metastatic disease
16 Second-line therapy for unresectable metastatic disease
17 Subsequent-line therapy for unresectable metastatic disease
18 Branded drugs summary
22 EPIDEMIOLOGY
22 Incidence methodology
28 MARKETED DRUGS
34 PIPELINE DRUGS
49 KEY REGULATORY EVENTS
49 Henlius Submits NDA For HLX04 To China’s NMPA
49 Amneal Takes A Step Forward On Biosimilars
49 Tislelizumab Chinese Supplemental BLA Accepted
49 NICE Recommends Keytruda As First-Line Treatment Option For Colorectal Cancer
50 Bio-Thera Follows EU Bevacizumab Biosimilar Filing With FDA Goal Date
50 Keytruda & Bavencio Win EU Nod For More Cancers
51 PROBABILITY OF SUCCESS
52 LICENSING AND ASSET ACQUISITION DEALS
52 Zai Lab Gets Greater China Rights To Mirati’s Adagrasib
52 MD Anderson Inks New Cancer Collaboration With Mirati
52 Servier, Celsius Team To Seek Novel Colorectal Cancer Targets
52 Biomm Backs Bio-Thera’s Brazilian Bevacizumab
53 Solasia Gets Japanese Rights To Isofol’s Colorectal Cancer Therapy
53 Chi-Med, Lilly Update Partnership For Elunate In China
54 CLINICAL TRIAL LANDSCAPE
55 Sponsors by status
56 Sponsors by phase
57 Recent events
60 DRUG ASSESSMENT MODEL
65 MARKET DYNAMICS
66 FUTURE TRENDS
66 Bevacizumab to remain standard of care in first- and second-line disease
66 PD-1 inhibitor market share is stunted by competition and restrictive approvals, but a trial of Opdivo in the broader
population presents a rare opportunity for expansion
67 Biosimilar erosion to increase payer pressure
67 Substantial opportunity for next-generation chemotherapies
69 CONSENSUS FORECASTS
72 RECENT EVENTS AND ANALYST OPINION
72 Multiple Drugs for Colorectal Cancer (June 4, 2021)
72 Stivarga for Colorectal Cancer (June 4, 2021)
74 Xpovio for Colorectal Cancer (June 4, 2021)
75 Napabucasin for Colorectal Cancer (February 9, 2021)
76 MRTX849 for Colorectal Cancer (October 25, 2020)
77 Keytruda for Colorectal Cancer (May 31, 2020)
79 CYAD-101 for Colorectal Cancer (May 30, 2020)
80 Enhertu for Colorectal Cancer (May 29, 2020)
82 Lumakras for Colorectal Cancer (May 29, 2020)
83 Onvansertib for Colorectal Cancer (May 29, 2020)
85 RGX-202 for Colorectal Cancer (May 29, 2020)
86 Keytruda for Colorectal Cancer (April 2, 2020)
89 KEY UPCOMING EVENTS
90 KEY OPINION LEADER INSIGHTS
91 BIBLIOGRAPHY
92 APPENDIX
LIST OF FIGURES
11 Figure 1: US colorectal cancer death and incidence rates per 100,000, 1992–2017
24 Figure 2: Trends in incident cases of colorectal cancer, 2018–27
34 Figure 3: Overview of pipeline drugs for colorectal cancer in the US
34 Figure 4: Pipeline drugs for colorectal cancer, by company
35 Figure 5: Pipeline drugs for colorectal cancer, by drug type
35 Figure 6: Pipeline drugs for colorectal cancer, by classification
51 Figure 7: Probability of success in the colorectal cancer pipeline
54 Figure 8: Clinical trials in colorectal cancer
54 Figure 9: Top 10 drugs for clinical trials in colorectal cancer
55 Figure 10: Top 10 companies for clinical trials in colorectal cancer
55 Figure 11: Trial locations in colorectal cancer
56 Figure 12: Colorectal cancer trials status
57 Figure 13: Colorectal cancer trials sponsors, by phase
60 Figure 14: Datamonitor Healthcare’s drug assessment summary for colorectal cancer
65 Figure 15: Market dynamics for colorectal cancer
66 Figure 16: Future trends in colorectal cancer
74 Figure 17: Stivarga for Colorectal Cancer (June 4, 2021): Phase II – w/Opdivo (pMMR/MSS)
79 Figure 18: Keytruda for Colorectal Cancer (May 31, 2020): Phase III – KEYNOTE-177
82 Figure 19: Enhertu for Colorectal Cancer (May 29, 2020): Phase II – DESTINY-CRC01
85 Figure 20: Onvansertib for Colorectal Cancer (May 29, 2020): Phase Ib/II – w/Avastin + FOLFIRI
88 Figure 21: Keytruda for Colorectal Cancer (April 2, 2020): Phase III – KEYNOTE-177
89 Figure 22: Key upcoming events in colorectal cancer
LIST OF TABLES
12 Table 1: TNM staging for colorectal cancer
14 Table 2: Recommended systemic therapy for locally advanced colorectal cancer
16 Table 3: Recommended front-line systemic therapy for unresectable colorectal cancer
17 Table 4: Recommended second-line systemic therapy for unresectable colorectal cancer
18 Table 5: Recommended ≥3rd-line systemic therapy for unresectable colorectal cancer
20 Table 6: Summary of branded drugs available for colorectal cancer
23 Table 7: Incident cases of colorectal cancer, 2018–27
25 Table 8: Proportion of colorectal cancer incident cases by cancer type, 2018
26 Table 9: Incident cases of colon cancer, by gender, 2018
27 Table 10: Incident cases of rectum cancer, by gender, 2018
29 Table 11: Marketed drugs for colorectal cancer
36 Table 12: Pipeline drugs for colorectal cancer in the US
70 Table 13: Historical global sales, by drug ($m), 2016–20
71 Table 14: Forecasted global sales, by drug ($m), 2021–25
72 Table 15: Multiple Drugs for Colorectal Cancer (June 4, 2021)
73 Table 16: Stivarga for Colorectal Cancer (June 4, 2021)
75 Table 17: Xpovio for Colorectal Cancer (June 4, 2021)
76 Table 18: Napabucasin for Colorectal Cancer (February 9, 2021)
77 Table 19: MRTX849 for Colorectal Cancer (October 25, 2020)
78 Table 20: Keytruda for Colorectal Cancer (May 31, 2020)
80 Table 21: CYAD-101 for Colorectal Cancer (May 30, 2020)
81 Table 22: Enhertu for Colorectal Cancer (May 29, 2020)
83 Table 23: Lumakras for Colorectal Cancer (May 29, 2020)
84 Table 24: Onvansertib for Colorectal Cancer (May 29, 2020)
86 Table 25: RGX-202 for Colorectal Cancer (May 29, 2020)
87 Table 26: Keytruda for Colorectal Cancer (April 2, 2020)
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