Cancer Background and Evolution

Oncology has developed into the biggest therapy class in terms of revenues for the pharmaceutical industry.¹ A better understanding of cancer cell mechanisms, innovative biologic drugs with good clinical data and strong demographic fundamentals have been driving the high growth rates of the oncology market. However, this might have been just the beginning. New advancements in the area of immuno-oncology, innovative cancer drug technologies and combination therapy may lead to a transformation of how cancer will be treated. While these new treatments are not a “cure,” they represent a material improvement in ways of lengthening and bettering the quality of life for many patients. The complexity of cancer biology means it is highly unlikely that a single “golden bullet” will be found to cure the disease; rather several approaches will be needed and potentially will be used together. The good news is that early stage research continues to open new avenues of investigation.

According to the World Health Organization (WHO), over 14 million new cases of cancer occurred globally in 2012 and 8.8 million cancer deaths in 2015. Despite great strides made in diagnosis and treatment, cancer remains a leading cause of death.² Age is a significant risk factor for cancer; as global life expectancy rises, we expect the number of new cancer cases diagnosed to outpace population growth. The WHO further estimated the annual global financial cost of cancer at USD 1.16 trillion in 2010, with the cost and occurrence expected to rise steadily given the ever-aging population worldwide.

In its simplest terms, cancer is uncontrolled cell growth. It starts when cells become abnormal and grow out of control, for genetic, environmental (e.g., sun exposure), life-style (e.g., smoking, diet), or even unknown factors. Some cancers, like leukemias and lymphomas, affect the blood stream and blood-forming organs, while other cancers invade normal tissues and can spread throughout the body. There are over 100 known forms of cancer, each with its own biological and life-altering characteristics. Treatment often requires multiple rounds of various combination therapies – surgery, chemotherapy, immunotherapy, targeted drug therapy, etc. – to modify disease progression, which commonly means increasing life expectancy by a matter of months.

Evolution of Cancer Treatment

Ancient times – Surgery
1900s – Radiation
1940s – Hormone Therapy
1950s – Chemotherapy
1990s – Immunotherapy: Cytokines
2000s – Immunotherapy: MABs
2000s – Targeted Small Molecules: Tyrosine Kinase Inhibitors
2010s – Immunotherapy: Checkpoint Inhibitors
Now – Personalized Immunotherapy (e.g., CAR-Ts)

Cancer treatment evolved relatively slowly until the last two decades, with most advances in surgery, radiotherapy and chemotherapy offering only incremental improvements in survival compared with previous treatments. A better understanding of cancer cell biology and the immune system has led to the development of immuno-oncology, an approach that activates the body’s own defenses against the cancer. We consider this a new era in cancer treatment, with approved immuno-oncology agents already incorporated into the standard of care of advanced lung cancer, melanoma, and others.³ With research advancing at a rapid rate, we are seeing the adoption of earlier-stage treatments for various diseases. The expectation is for broad use of these immunotherapies as more data becomes available. The data will be paramount to determine their scientific and commercial potential, including use in combination therapies to take advantage of underlying synergies via multiple mechanisms of action.

Rise of Immuno-Oncology

Immuno-oncology agents known as checkpoint inhibitors have established their foothold in standards of care through numerous approvals and swift adoption. Some types of tumor cells evade immune recognition by displaying proteins that activate immunosuppressive pathways typically used by normal cells. Checkpoint inhibitors block the interaction of these proteins with receptors on T cells by binding either of the two components. These therapies are monoclonal antibodies, which originate from identical immune cells and can specifically target a single receptor. The first checkpoint inhibitor, ipilumab, was approved by the FDA in 2011,⁴ and the rate of subsequent approvals picked up speed a few years later.

At the end of 2014, the highly-anticipated approvals of the first two PD-1 inhibitors—pembrolizumab and nivolumab—arrived just a few months apart.⁵ PD-1 is a T cell surface protein that acts as a receptor for the protein PD-L1. When a cell bearing PD-L1 on its surface encounters a T cell, the binding of PD-L1 to PD-1 suppresses an immune response. Inhibitors against PD-1 or PD-L1 were therefore developed to activate the immune system against cancer cells that overexpress PD-L1.

Strong clinical performance and diverse indications of PD-1 and PD-L1 inhibitors have led to widespread use. In 2017, PD-1/PD-L1 inhibitors were used to treat nearly 150,000 patients, across 23 tumor types, with broad efficacy.⁶ Their remarkable rate of adoption stems from an increasing number of approved PD-1/PD-L1 inhibitors and the expansion of each into additional indications. Nivolumab and pembrolizumab have each received numerous approvals, and three PD-L1 inhibitors—atezolizumab, avelumab, and durvalumab—received first and subsequent approvals from 2016 to 2018.⁶ In 2017, pembrolizumab became the first approval based on biomarkers rather than tumor location.⁷ The groundbreaking approval was indicated for the treatment of unresectable or metastatic solid tumors exhibiting certain genetic features, regardless of tissue type.

Recent years have also witnessed breakthroughs in another class of immunologic agents, CAR T cell therapies. This treatment begins with collection of the patient’s T cells, which are then genetically engineered to express chimeric antigen receptors (CARs) on their surface. The modified T cells are reintroduced into the patient, where their synthetic receptors facilitate recognition and binding of an antigen on tumor cells. Once in the body, the modified T cells multiply, earning CAR T cell its title of the first “living drug.” ⁸ As a result, a single dose of the T cells can produce enduring, and even increasing, effects. In August of 2017, FDA approval of tisagenlecleucel for acute lymphoblastic leukemia marked the first CAR T cell immunotherapy for cancer.⁹ The treatment was associated with remission for 83 percent of trial patients after single administration. Since then, approvals of both a second indication for tisagenlecleucel¹⁰ and a second CAR T cell therapy¹¹ have continued the growth of this class of immunotherapy.

Although immuno-oncology agents exhibit strong clinical performance and have dramatically impacted the treatment landscape, the therapy is currently viewed as a supplement to, rather than a replacement of, existing treatments. In interviews conducted by our team, numerous experts stressed the importance of combining immuno-oncology agents with other therapeutic classes. At present, the experts interviewed agree that a multi-pronged attack remains the most favorable approach to treat most cancers.

Recent Pipeline Trends

A growing emphasis on biomarkers over tumor site has resulted in a paradigm shift in the classification of cancer. Tumors have become increasingly segmented based on their genetic features, stratifying patient populations into niche groups.¹² The trend toward more specialized characterizations is reflected in the oncology therapeutic landscape. In 2017, eighty-seven percent of cancer drugs were used by under 10,000 patients.⁶ Attention has turned from high-incidence tumor types to smaller, more specialized tumors with larger unmet need. Looking forward, this trend may eventually lead to the levels of patient-specific tailoring modeled by precision medicine.

Biomarker use has also gained traction in clinical trials via companion diagnostic tests, which predict a patient’s response to targeted therapy. The tests inform patient selection for trials by identifying subpopulations more likely to benefit from the therapy. Between 2010 and 2017, the proportion of oncology trials using biomarkers for patient preselection or stratification increased from 24 to 34 percent. Furthermore, targeted therapies constituted 90 percent of cancer drugs undergoing development in 2017.⁶ Adoption of companion diagnostics is expected to continue in upcoming years, particularly as biomarker research progresses.

The increasingly crowded pipeline for oncology therapeutics impacts approved drugs as well. The product life cycle for oncology medicines is now almost five times shorter than it was in the 1990, with pipeline competitors existing for 80 percent of compounds being developed.¹² As a result many therapies are now replaced within a few years, often by drugs with similar efficacy.¹³ Such fast-moving and cutthroat competition diminishes the feasibility of extended periods of exclusivity, requiring rapid and continued innovation.

Future of Care

Our research combined with consensus forecasts suggest the new wave of therapies could add up to 20% in market value over the next few years.¹ This will increase the size of the market to $160B by 2022. With the rapid pace of innovation and development of therapies under investigation, these new technologies will create four opportunities in the market to improve treatment standards for patients: earlier detection, combination therapies, personalization, and improved monitoring.

With a rise in the capacity of gene-sequencing tools, it is easier to obtain relevant genetic information which fuels the argument for personalized medicine. Additionally, advancement in technologies like liquid biopsy will provide a push in the direction of personalized medicine by offering a minimally invasive way to measure circulating tumor cells and DNA.  It also reduces the risks compared to a standard biopsy and fewer samples are needed. This technology has the potential to track minimal residual disease and biomarkers for improved monitoring. Grail is a leader in this field and was established recently to bring early cancer diagnosis closer to a reality when a patient is still asymptomatic.¹⁴ These advancements provide an opportunity to improve prognosis for patients and, together with electronic health records, will shift value in our healthcare model. Immunotherapies continue to make the headlines, especially when used in combination therapies. However, there is a significant unmet need for the majority of patients who do not have a durable response with PD-1 or PD-L1. Therapies based on other checkpoint inhibition targets like CTLA-4 and co-stimulatory effects are being tested in clinical trials all over the country. Some examples include interferon-induced adaptive immune response and activation of associated Janus kinases.

With every wave of innovation there are barriers that must be overcome to change the scope of the oncology market. Complex regulatory hurdles provide bottlenecks at certain points of the drug development process. These problems stem from technical issues to understanding the complex nature of combination products and devices. Regulators need to establish guidance on the national standards for combination products currently in pre-clinical/clinical development. This means assigning specific divisions to handle the review of specific combinations, including biologic-biologic, biologic-small molecule, and drug combinations with medical devices. Additionally, the reimbursement landscape is currently lagging to embrace the pace of innovation. Rising drug costs is a legitimate concern for payers and the low efficacy of certain drugs in specific patient populations limits the overall effectiveness of the payer landscape. A move toward value- and outcome- based healthcare will affect both the reimbursement of these therapies as well as the adoption. Real world data (RWD) and real world evidence (RWE) seem to be on the cutting edge of solving these complex challenges. Regulatory agencies will use RWD and RWE to monitor post-market safety and adverse events to make decisions. The health care community will use this data to support reimbursement decisions and to develop guidelines for use in clinical practice. The 21^st Century Cures act, passed in 2016, places additional focus on the use of these types of data to support decision making processes.

New technologies will enable personalization of treatment specific to each individual patient. With the improvement of diagnostics, we will be able to stratify patients and monitor treatment response in order to tune drug regimens based on the patient condition and circumstance. Reduced regulatory and reimbursement burdens will mean patients will have better access to life-saving medications. This goes beyond the traditional mantra of finding the right drug at the right dose for the right patient at the right time.

Works Cited

1. “EvaluatePharma World Preview 2017, Outlook to 2022.” http://info.evaluategroup.com/rs/607-YGS-364/images/ WP17.pdf.
2. Health statistics and information systems. http://www.who.int/cancer/resources/keyfacts/en/.
3. https://www.cell.com/cancer-cell/pdf/S1535-6108(17)30206-4.pdf
4. “Yervoy, a Melanoma Drug, Wins F.D.A. Approval.” https://www.nytimes.com/2011/03/26/business/26drug.html.
5. “Merck Tightens Its Grip on the Lung-Cancer Market.” https://www.bloomberg.com/gadfly/articles/2018-04-16/lung-cancer-drug-trial-data-keytruda-tops-opdivo-again.
6. “Global Oncology Trends 2018.” https://www.iqvia.com/institute/reports/global-oncology-trends-2018.
7. “FDA Approves First Cancer Treatment for Any Solid Tumor with a Specific Genetic Feature.” https://www.fda.gov/newsevents/newsroom/pressannouncements/ucm560167.htm.
8. “CAR T Cells: Engineering Immune Cells to Treat Cancer.” https://www.cancer.gov/about-cancer/treatment/research/car-t-cells.
9. “FDA Approves Tisagenlecleucel for B-Cell ALL and Tocilizumab for Cytokine Release Syndrome.” https://www.fda.gov/drugs/informationondrugs/approveddrugs/ucm574154.htm.
10. “FDA Approves Tisagenlecleucel for Adults with Relapsed or Refractory Large B-Cell Lymphoma.” https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm606540.htm.
11. “Approved Drugs – FDA Approves Axicabtagene Ciloleucel for Large B-Cell Lymphoma.” https://www.fda.gov/drugs/informationondrugs/approveddrugs/ucm581296.htm.
12. “The Next Wave of Innovation in Oncology.” https://www.mckinsey.com/~/media/mckinsey/our%20people/bjorn%20albrecht/mckinsey%20cancer%20center_next%20wave%20of%20innovation%20in%20oncology.ashx.
13. “Global Oncology Trends 2017.” https://morningconsult.com/wp-content/uploads/2017/06/QuintilesIMS-Institute-Oncology-Report.pdf.
14. “Clinical Liquid Biopsy Explained: Applications, Techniques and Players.” https://www.lek.com/sites/default/files/insights/pdf-attachments/2003_Liquid_Biopsy_LEK_Executive_Insights.pdf.