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European Biopharmaceutical Review

Cancer Concerns

With increasing prevalence and high morbidity rates, cancer has always presented a signifi cant challenge to the medical research community. In spite of major improvements in cancer therapeutics in the last few decades, many types of cancers still do not fully respond to treatment. While oncology continues to be a key therapeutic area for research, many of the approved drugs fail to extend survival times by more than a few months for patients with the deadliest of cancers.

However, oncology still attracts vast amounts of research funding, with the recent trends in drug approvals reflecting this heavy investment by the pharmaceutical industry. In 2011, the US Food and Drug Administration (FDA) approved 30 new products – eight of which were oncology drugs. In 2012, 39 new drugs were approved by the FDA, of which 11 drugs were for the treatment of cancer. The same trend is expected to continue in the future, as strong pipelines are evident for many oncology indications.

Advancing Treatments

Until the advent of radiation therapy in the 1920s, surgery was the only form of effi cient treatment. Surgery continues to dominate this area as a preferred treatment option for localised primary tumours as it is often the most effective form. In the 1940s, chemotherapy gained prominence, and since then all three forms of treatment have been used either in conjunction or to complement each other. Platinum-based chemotherapies – such as cisplatin and carboplatin – are still dominant chemotherapeutic regimens for many cancers, despite first entering the market more than 30 years ago. Most other approved drugs are administered as adjuvant treatments or as a second-line option in platinumresistant cancer.

Cancer therapy is dominated by cytotoxic chemotherapy, which causes the death of rapidly dividing cancerous cells, along with some healthy cells. Even if a chemotherapy drug is directly targeted at cancerous cells, there is the possibility that the cells will develop the ability to mutate and become drugresistant. However, with rapid advances in cancer genetics research, the latest therapies are able to target the specific cancer cells, and handle mutations and the microenvironment that these cancer cells need to thrive.

Targeting Molecules

Currently, molecular targeting in cancer therapeutics is achieved mainly by monoclonal antibodies (mAb) or small molecules. mAbs operate by blocking the growth factor receptor interactions of cancer cells, while small molecules target the growth signals and block them. Examples of these targeted therapies and their mechanisms of action include Herceptin (trastuzumab, anti-human epidermal receptor type-2) and Erbitux (cetuximab, anti-epidermal growth factor receptors (EGFR)).

Targeted therapies are expected to play key roles in indications such as nonsmall-cell lung cancer (NSCLC), where some of the treated patients may not respond to first-line treatment due to various mutations – EGFR mutations or anaplastic lymphoma kinase (ALK) or Kirsten rat sarcoma (KRAS). Boehringer Ingelheim's Gilotrif (afatinib) was approved as a first-line treatment for lung cancer patients with EGFR mutations by the FDA in July 2013 and by the European Medicines Agency (EMA) in September 2013. Gilotrif – an EGFR tyrosine kinase inhibitor (TKI) – is expected to overcome acquired resistance after prior treatment with another TKI. Afatinib has already been granted orphan status for the treatment of EGFR mutation-positive NSCLC.

Earlier in 2011, Xalkori (crizotinib) was approved for NSCLC patients with ALK mutations, while Roche’s Tarceva (erlotinib) is another drug that is extensively used in treating NSCLC patients with EGFR mutations. However, one of the challenges of targeted agents is that they need companion diagnostic tests. Should these diagnostics require approval by a different regulatory body, the process is further complicated, often delaying drug development. Although targeted therapies and mAbs caused a high level of interest and excitement in the pharmaceutical industry, they are yet to deliver on their full promised potential.

Antibody Drug Conjugates

Antibody drug conjugates (ADCs) are among the other latest technologies which seem to be most favourable. ADCs consist of a cytotoxic component to kill cancer cells – an antibody to direct the drug to a cancer cell marker and another component to connect these two. As ADCs help to deliver the chemotherapy drug directly to cancer cells, they provide better efficacy with fewer side-effects as there is a lower chance that healthy cells will be damaged.

The first ADC approved by the FDA for any solid tumour is Kadcyla (adotrastuzumab emtansine), developed by Roche, which is given to metastatic breast cancer patients along with cytotoxic agent DM-1, developed by Immunogen and Herceptin. The drug was approved in February 2013 and is currently in regulatory review in Europe and Japan. Herceptin is already approved as a first-line treatment for breast cancer and is a blockbuster drug. Roche/Genentech hope to develop Kadcyla as a gold-standard monotherapy for metastatic breast cancer.

Angiogenesis Factors

Anti-angiogenesis treatments also demonstrated promise in cancer treatment with anti-angiogenesis agents, such as Pfizer’s Sutent (sunitinib) or Roche’s Avastin (bevacizumab), which regulate various angiogenesis factors to starve the cancer cells and prevent tumour expansion.

Targeted angiogenesis factors include vascular endothelial growth factor, platelet-derived growth factor and interleukin-8.

Cancer stem cell therapy and immunotherapy also hold promise in oncology treatment and are attracting significant research investments. Immunotherapy triggers the patient’s immune system to tackle cancer cells and is therefore less toxic than a cytotoxic chemotherapy. One example includes an immunotherapy for stage 4 melanoma with a highdose interleukin-2 and/or Yervoy (ipilimumab) – a mAb targeting cytotoxic T-lymphocyte antigen-4 (CTLA-4). The binding of CTLA-4 with a mAb can interfere with the inhibition of T-cell activation against tumour antigens, thereby allowing the activation of a tumour-specific immunity. Bristol-Meyer Squibb’s Yervoy was approved in March 2011 for metastatic, surgically unresectable melanoma by the FDA and as a second-line treatment by the EMA in November 2012.

Recent Approvals

In spite of recent advances, the quest for drugs with improved safety and efficacy profiles will continue to drive the oncology therapeutics landscape. Some cancers, such as ovarian cancer, experience a high rate of recurrence (up to 75 per cent) with no existing curative therapies. This, combined with poor survival rates, signifies a substantial unmet need. Recent approvals – for example, Avastin – and pipeline drugs, such as Votrient (pazopanib), do not demonstrate much improvement in safety and efficacy in comparison to the existing gold-standard for first-line chemotherapy and maintenance treatment of Gemzar (gemcitabine). Recently, AstraZeneca's olaparib – a poly ADP-ribose polymerase 1 or 2 (PARP1/2) inhibitor – has posted promising Phase 3 results as maintenance therapy for platinum-sensitive ovarian cancer patients with breast cancer mutations and is under investigation as a firstline therapy. PARP inhibitors act by manipulating existing mutations to induce cell death upon inhibition of a second target.

Other Disease Types

As with ovarian cancer, pancreatic cancer has some of the lowest survival rates in the oncology segment and signifies a very high unmet need. Pancreatic cancer also has limited treatment options with just Gemzar and Tarceva as the standard treatment options, with the recent approvals of Pfizer's Sutent and Novartis' Afinitor (everolimus) limited to a small subset of pancreatic neuroendocrine tumours.

Other cancer types, such as bladder cancer, are also underserved, with the existing treatments lacking in efficacy and presenting limited options for patients. The standard treatment option of Bacillus Calmette-Guérin immunotherapy for non-muscleinvasive bladder cancer remains unchallenged even though this cancer exhibits high relapse rates. In oncology therapeutics, most of the investment dollars are funnelled toward highly lucrative indications, such as breast cancer and lung cancer, which have high prevalence and treatment populations. This means that there are still untapped opportunities and unchartered clinical pathways in the oncology landscape, in spite of the high level of interest demonstrated by the pharmaceutical industry.

Looking Forward

One of the major disadvantages of the cancer treatment landscape is the high cost of drugs. Although oncology is still a high investment area and drug approvals are increasing, it still does not translate into vastly improved access to treatment in some indications because of the high treatment prices.

Recently, one major cancer care centre in the US –Sloan-Kettering – caused ripples by deciding not to use one of the latest drugs, Zaltrap (ziv-aflibercept), due to its prohibitive cost and similarity in efficacy with the existing drug Avastin. This saw Sanofi reducing the price of Zaltrap as a result. Even when cancer patients are covered by insurance systems, the burden of treatment is often shared by the patient, and the prohibitive cost of some drugs makes them inaccessible to the neediest of patients.

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About the author

Vijaya Vulapalli works as a Senior Analyst with GBI Research. She has industry research experience within the life sciences and healthcare space at Satyam and Deloitte. Vijaya holds an MBA degree from the University of Bradford and a Bachelor’s degree in Life Sciences from Osmania University in Hyderabad. She also attended a one-year Executive Business Management Programme at the Indian Institute of Management, Calcutta.
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