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On Target

Gastric and oesophageal cancers are relatively rare indications that originate in the portion of the digestive tract between the larynx and the duodenum. Across the top eight markets (the US, UK, France, Germany, Italy, Spain, Japan and Canada), gastric cancer is estimated to be prevalent in 380,000 patients, while some 132,000 are suffering from oesophageal cancer (including gastro-oesophageal junction cancer).

Poor Outcomes

Historically, the outlook for these indications has been poor, with the overall relative five-year survival rates for gastric and oesophageal cancers estimated at 28% and 18%, respectively (1). Recent efforts to develop targeted therapies and improve patient outcomes have been met with a modest level of success, resulting in a significant clinical opportunity for the entry of a superior product.

As with other cancers, the stage of disease progression at diagnosis is the most important factor in the patient’s prognosis. The five-year relative survival for gastric cancer is 64% for patients diagnosed when the tumour is localised, decreasing to just 4% where distant metastasis has occurred; likewise, the survival rate for localised pancreatic cancers is 40%, also decreasing to 4% where there are distant metastases (1).

Additionally, due to the often late presentation of symptoms in these two indications, they are frequently undiagnosed until the tumour has already metastasised. This is the case in 35% of gastric cancers and 37% of oesophageal cancers (1).

Chemotherapy and radiation therapy together have been found to substantially improve survival in the early stages of gastric cancer – compared to surgery alone – and can add six months to the lifespan of advanced gastric cancer patients. However, no definitive conclusion can be drawn as to whether the same approach adds a survival benefit for oesophageal cancer patients in either setting.

The persistently poor outcomes for these indications, in spite of interventions and in addition to the very poor tolerability of chemotherapy regimens, leave a strong unmet need which research efforts into targeted therapies in oncology indications have specifically aimed to address.

Monoclonal Antibody Therapies

In other, larger oncology indications, such as breast and colorectal cancers, the therapeutic properties of monoclonal antibodies (mAbs) have enabled strong clinical improvements over chemotherapies and targeted small-molecule approaches. Due to favourable market conditions, these products have also been very strong commercial successes, with mAbs such as Herceptin (trastuzumab) generating $6.5 billion in revenues worldwide in 2013, and Avastin (bevacizumab) making $6.7 billion in the same year.

Two mAbs, Herceptin and Cyramza (ramucirumab), are currently marketed for the treatment of advanced gastric and gastro-oesophageal junction cancers. Both are recent additions to these markets, with Herceptin originally approved for the two indications in the US in 2010 (after having been marketed for breast cancer since 1998), and Cyramza in the US in June 2014.

mAbs are immunoglobulin proteins that bind strongly and with great specificity to a particular extracellular or cell membrane-bound target. Although small-molecule targeted therapies are able to pass through the cell membrane and are therefore able to target specific intracellular molecules, mAbs generally have a far higher degree of specificity for their targets, leading to fewer offtarget effects and particularly potent target inactivation. They can also be conjugated to highly cytotoxic agents to act as delivery vehicles.

Herceptin binds to the human epidermal growth factor-2 (HER-2) receptor tyrosine kinase, a growth factor receptor that acts as a potent initiator of cell proliferation, and is overexpressed in 15-25% of gastric cancers and 6-35% of carcinomas of the gastro-oesophageal junction (2,3). It is only approved for use in patients who overexpress the receptor and have not had prior chemotherapy. Although, commercially speaking, the primary indication of Herceptin is breast cancer, its FDA approval for the treatment of gastric and oesophageal cancers represents a substantial source of revenue outside breast cancer.

Cyramza is a vascular endothelial growth factor receptor-2 (VEGFR-2) antagonist which, similarly to HER-2, is a receptor tyrosine kinase. However, instead of driving cell proliferation, VEGFR-2 mediates the process of angiogenesis – the process by which a growing tumour stimulates the formation of blood vessels in its microenvironment. This is believed to be necessary for the tumour to reach a large size, and has been shown to be indispensable for a tumour to metastasise (4). In contrast with Herceptin, it is only approved for use in patients who have had prior chemotherapy.

No Targeted Treatment

Both of these mAbs are approved for the treatment of metastatic cancer alone, meaning that there are currently no targeted therapies for localised gastric or oesophageal cancers. Additionally, there are no targeted therapies for the treatment of oesophageal cancers residing above the gastro-oesophageal junction, excluding the majority of the advanced oesophageal cancer population.

The therapeutic benefits of these two products in advanced gastric cancers and gastro-oesophageal junction carcinomas are moderate at best, with an overall survival (OS) benefit of approximately 2.2 months for ramucirumab plus paclitaxel, and 2.4 months for Herceptin plus chemotherapy, versus paclitaxel and chemotherapy alone, respectively (5,6). In spite of this, both drugs are highly priced; the monthly cost of Herceptin in the US is about $4,500, and Cyramza entered the US market at a similar price point of $4,000-$9,000 per month. Compared to chemotherapy, the available targeted therapies are, therefore, both expensive and lacking in efficacy.

However, adverse events associated with these treatments are far milder than those associated with chemotherapy, rendering the drugs much more tolerable and exerting less of a negative impact on the patient’s quality of life.

Overall, the level of competition in this indication from both conventional and targeted therapies is very low, and there is a strong unmet need owing to the disappointing standard of efficacy among available treatments.

Pipelines of Promise

As of November 2014, there were 167 pipeline products in development for gastric cancer, and 85 for oesophageal cancer (including gastro-oesophageal junction cancer for each). Although small-molecules have the largest share of each of the pipelines, mAbs occupy a substantial fraction of them – with some 36% of the gastric cancer and 40% of the oesophageal cancer pipeline consisting of mAbs – representing a particularly high level of research interest in these indications.

There is a modest level of developmental activity centered on mAb conjugates, which comprise a small-molecule covalently attached to the immunoglobulin protein making up the mAb, thus enabling targeted delivery of a cytotoxic compound to a tumour.

With 10 pipeline mAbs currently in Phase 3 clinical development across these indications, there is potential for a number to enter the two disease markets during the forecast period. These late-stage pipelines include a number of novel mAbs confirmed to have potential, both clinically and commercially. The most promising drug, Rilotumumab, has shown a median OS benefit of over five months – when combined with chemotherapy – in a large patient subset of both indications in Phase 2 trials (versus chemotherapy alone), and is now undergoing confirmatory Phase 3 trials (7).

Additionally, Theraloc (nimotuzumab), also in Phase 3, has shown a survival benefit of just over two months in oesophageal cancer (8). While this is not entirely compelling, there are currently few options available for the treatment of oesophageal cancer outside the subset that originates in the gastro-oesophageal junction.

Favourable Market Conditions

To conclude, the addition of two new mAbs to the gastric cancer market has not improved the clinical outlook for gastric or oesophageal cancers to any great degree – although the late-stage pipelines have shown signs of potential. A more nuanced understanding of the molecular processes driving gastric and oesophageal cancer development is required in order to facilitate the development of effective targeted products, and replicate the success of targeted therapies seen in other oncology indications.

However, a very strong opportunity and favourable market conditions exist for the development of mAbs to treat these indications. In the US, which is the largest pharma market for these treatment areas, retail prices for speciality pharmaceuticals such as mAbs have consistently and rapidly increased year-on-year, with an annual growth rate of over 7.5% since 2006 (9).

Furthermore, the loss of revenues and premium prices of mAbs compared to biosimilars following patent expiry is predicted to be slow and weak. For example, following the patent expiry of Herceptin in 2014 in the EU and 2019 in the US, the mean retail price is not anticipated to decrease to less than 70% of its original value. Therefore, in contrast to small-molecule drugs that are readily substituted by generics, premium mAbs are anticipated to maintain a high market share and price for a far longer period after the loss of market exclusivity.

In spite of modest late-stage pipelines, a number of factors will drive growth in these mAb markets. Favourable market conditions – in terms of pricing structures in the US, rising disease prevalence in certain geographies, and the anticipated approval of a number of these late-stage pipeline drugs towards the end of the forecast period – are anticipated to boost growth from $256 million in 2012 to $501 million in 2019, at a compound annual growth rate (CAGR) of 10%. The market for mAbs in oesophageal cancer is also anticipated to grow from $137 million in 2012 to $265 million in 2019, at a CAGR of 9.9%.

In order to drive sustainable long-term growth in these markets, independently of favourable conditions, stronger improvements over current therapies are necessary, driven by innovative therapeutic strategies and a deeper understanding of the underlying disease pathophysiologies.

Further analysis of mAbs can be found in GBI Research’s Therapy Analysis reports, including their use in gastric, oesophageal, breast and colorectal cancers.

1. Howlader N et al, SEER cancer statistics review, 1975-2011, 2014. Visit:
2. Gravalos C and Jimeno A, HER2 in gastric cancer: A new prognostic factor and a novel therapeutic target, Annals of Oncology 19(9): pp1,523-1,529, 2008
3. Bang Y, Advances in the management of HER2-positive advanced gastric and gastroesophageal junction cancer, Journal of Clinical Gastroenterology 46(8): pp637-648, 2012
4. Moserle L and Casanovas O, Antiangiogenesis and metastasis: A tumour and stromal cell alliance, Journal of Internal Medicine 273(2): pp128-137, 2013
5. Cutsem E et al, Efficacy results from the ToGA trial: A phase III study of trastuzumab added to standard chemotherapy (CT) in first-line human epidermal growth factor receptor 2 (HER2)-positive advanced gastric cancer (GC), Journal of Clinical Oncology 27(18): LBA4509, 2009
6. Wilke H et al, RAINBOW: A global, phase III, randomized, double-blind study of ramucirumab plus paclitaxel versus placebo plus paclitaxel in the treatment of metastatic gastroesophageal junction (GEJ) and gastric adenocarcinoma following disease progression on first-line platinum- and fluoropyrimidine-containing combination therapy rainbow IMCL CP12-0922 (I4T-IE-JVBE), 2014. Visit:
7. Amgen, Analysis of Rilotumumab (AMG 102) data identifies a potential predictive biomarker for patients with gastric or gastroesophageal cancer, 16 May 2012
8. Ramos-Suzarte M et al, Treatment of malignant, non-resectable, epithelial origin esophageal tumours with the humanized anti-epidermal growth factor antibody nimotuzumab combined with radiation therapy and chemotherapy, Cancer Biology and Therapy 13(8): pp600-605, 2012
9. AARP Public Policy Institute, Rx watchdog report: Brand name drug prices continue to climb despite low general inflation rate, 2010. Visit:

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Dominic Trewartha is a Senior Analyst at GBI Research, a market-leading provider of business intelligence reports to the life sciences industry. He has a strong interest in cellular signaling and molecular biology, and his expertise in this area has filtered through to his involvement in a range of product development initiatives at the company, with a particular focus on developing new data interrogation methodologies and analytical frameworks. Dominic holds a BSc in Medical Biochemistry from the University of Manchester.
Dominic Trewartha
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