In May the report, Innovation in Cancer Care and Implications for Health Systems: Global Oncology Trend Report, stated that the global cancer drug market had hit $100 billion in annual sales and predicted that the market would reach $147 billion by 2018. Further, the report forecasts that by 2017, as a therapeutic area, oncology will receive the highest amount of spending by developed nations.
The report also goes on to state that the largest R&D therapeutic focus area is oncology with almost 2,000 products in the pipeline. This focus on oncology can also be seen when looking at the best selling biologics over the past three years (2012-2014) and in recent new drug approvals.
Biologic Cancer Drugs – Top Sellers
While the use of biologics, specifically monoclonal antibodies, in cancer treatment is well established, some therapies have become top sellers. In 2014, four of the top ten best selling biologics were cancer treatments or related cancer drugs – Rituxin (MabThera) at #3, Avastin at #6, Herceptin at #7 and Neulasta/Neupogen at #8. All four of these treatments were also in the top 10 for 2012 and 2013. To view the full table of best selling biologics for 2014, please see our blog, “10 Biologics on Best Selling Drugs List for 2014.”
|Biologic||Expression System||Company||2014 Sales||Approved Indication|
|Rituxan (rituximab, MabThera) includes sales of next generation version of Rituxan -Gazyva||CHO||Roche and Biogen Idec||8.678 billion||Non-Hodgkin’s lymphoma, chronic lymphocytic leukemia, and rheumatoid arthritis|
|Avastin (bevacizumab)||CHO||Roche||6.957 billion||Metastatic colorectal cancer (colon cancer), non–small cell lung cancer, glioblastoma & metastatic kidney|
|Herceptin (trastuzumab)||CHO||Roche||6.793 billion||HER2-positive breast cancer and HER2-positive metastatic gastric cancer|
|Neulasta/Neupogen (pegfilgrastim)||E.coli||Amgen and Kyowa Hakko Kirin||5.857 billion||Neutropenia caused by cancer chemotherapy|
Recent Biologic Cancer Drug Approvals
In 2014, the FDA approved 41 new drugs, nine were cancer treatments or cancer related and four of those were biologics. For a full listing of biologics approved by the FDA in 2014, please see the blog, “2014 FDA New Drug Approvals – 11 Biologics Receive Approval.”
|Drug Name||Active Ingredients||FDA Expedited Pathway||Expression System||Company||Indications|
|Cyramza||ramucirumab||Fast Track, Priority Review||CYRAMZA is produced in genetically engineered mammalian NS0 cells||Eli Lilly and Company||For treatment in advanced stomach cancer or gastroesophageal junction carcinoma|
|Keytruda||pembrolizumab||Breakthrough, Priority Review, Accelerated Approval||Not listed||Merck & Co., Inc.||For treatment of advanced or unresectable melanoma no longer responding to other drugs|
|Blincyto||blinatumomab||Breakthrough, Priority Review, Accelerated Approval||BLINCYTO is produced in Chinese hamster ovary cells.||Amgen, Inc.||Indicated for the treatment of Philadelphia chromosome-negative relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL).|
|Opdivo||nivolumab||Fast Track, Breakthrough, Priority Review, Accelerated Approval||Not listed||Bristol-Myers Squibb||Indicated for the treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor.|
As of July 2015, there have been four cancer drug treatments approved including one monoclonal antibody, Unituxin.
- Pfizer’s Ibrance (palbociclib), a kinase inhibitor for treatment of metastatic breast cancer.
- Eisai’s Lenvima (lenvatinib), a kinase inhibitor for treatment of thyroid cancer.
- Novartis’ Farydak (panobinostat), a histone deacetylase inhibitor for treatment of multiple myeloma.
- United Therapeutics’ Unituxin (dinutuximab), a GD2-binding monoclonal antibody produced in a murine myeloma cell line for treatment of high-risk neuroblastoma.
Increased R&D Fuels Innovative Approaches
The oncology clinical pipeline includes drugs that are non-biologic (small molecules) and drugs that are biologics. With respect to biologics in the oncology clinical pipeline, monoclonal antibodies still represent a significant majority of the biologic candidates. However, there are several novel biologic cancer drug candidates in the pipeline as well. Some of these novel approaches are discussed below.
Antibody-drug conjugates (ADCs) are drugs that consist of an antibody that is bound to cytotoxic drugs using a linker. The ADC targets cancer by utilizing a monoclonal antibody that is designed to bind to specific receptors on cancer cells. The linker is designed to release the cytotoxic drug only after the ADC enters the cancer cell. In this method, cytotoxic drugs are delivered directly to cancer cells, thus reducing non-target effects and systemic toxicity. To learn more about how Antibody-drug conjugates work, please see:
Two ADCs have been approved by the FDA, Seattle Genetics’ Adcetris for treatment of relapsed Hodgkin’s lymphoma and relapsed systemic anaplastic large cell lymphoma and Genentech’s Kadcyla for treatment of HER2 positive breast cancer.
Kadcyla (ado-trastuzumab emtansine), approved by the FDA in 2013, is designed to treat HER2 positive breast cancer by chemically linking the monoclonal antibody trastuzumab to a cytotoxic drug. The antibody is the humanized anti HER2 IgG1, trastuzumab. The cytotoxic drug is DM1, a microtubule inhibitor. Once bound to the HER2 receptor on the cancer cells, the ADC “undergoes receptor mediated internalization and subsequent lysomal degradation, resulting in the intracellular release of DM1”, (from the Kadcyla prescribing information).
There are currently over 30 ADCs in clinical trials for treatment of various types of cancers.
Some examples include:
- Pfizer’s Inotuzumab Ozogamicin in Phase III for treatment of relapsed or refractory acute lymphoblastic leukemia
- Celldex’s glembatumumab vedotin (CDX-011) in Phase II for treatment of metastatic breast cancer and metastatic melanoma.
- Progenics’ PSMA ADC in Phase II for treatment of prostate cancer.
Cancer vaccines can either be preventative or prophylactic meaning they are designed to prevent cancer in healthy individuals or they can be a therapeutic vaccine, which is designed to treat cancer by engaging the immune system to fight the cancer.
Preventative vaccines work by protecting against infectious agents that can cause cancer. Two preventative cancer vaccines that have been approved by the FDA are Gardasil and Cervarix that protect against the human papilloma virus (HPV) types 16 and 18. It has been found that these HPV types are responsible for about 70% of all cervical cancer cases with the remaining 30% caused by other HPV types. Gardasil also offers protection against HPV types 6 and 11.
One example of a therapeutic cancer vaccine is Dendreon’s Provenge. Approved in 2010, Provenge is the first and only therapeutic cancer vaccine to be approved by the FDA. Provenge is a personalized vaccine, custom manufactured for each patient. The first step in manufacturing the vaccine is to take a sample of the patient’s blood and then isolate the blood cells including antigen-presenting cells (APCs). After isolation, the cells are cultured with recombinant prostatic acid phosphatase (PAP), an antigen expressed in more than 95% of prostate cancer cells, and granulocyte-macrophage colony-stimulating factor, which is an immune cell activator that supports APC maturation. As the APCs mature in culture and engulf the recombinant PAP, they begin to express antigen on their surface. After the treated APCs are infused back into the patient, the vaccine activates the patient’s own T cells to recognize and attack the PAP expressing prostate cancer cells. To learn more about cancer vaccines, please see:
Additional therapeutic cancer vaccines are in development. A few examples are listed below:
- Agros Therapeutics’ AGS-003 in Phase III for treatment of metastatic renal cell carcinoma.
- Northwest Biotherapeutics’ DCVax-L in Phase III for treatment of Glioblastoma multiforme.
- Agenus’ Prophage in Phase II for treatment of Glioblastoma multiforme.
Adoptive Cell Transfer Therapy
In one type of adoptive cell transfer therapy, a patient’s own T cells are harvested from their cancer tumor. Researchers then isolate the T cells that have the highest anti-tumor activity and grow large amounts of these cells in the lab. Once sufficient cell numbers are achieved, the cells are infused back into the patient. The idea being that the T cells with the most cancer fighting activity will go on to kill the cancer cells after being infused back into the body.
Another form of adoptive cell transfer therapy is to isolate T cells from a patient’s blood then genetically modify the T cells to create tumor reactive T cells. T cells are modified by inserting a gene for a receptor of a certain antigen specific to that type of cancer cell. This process creates T cells that are tumor-reactive and after expansion in the lab can be infused into patients. The modified T cells once back in the body can now recognize and attack the cancer cells.
There are two types of genetically modified T cell therapies, gene modified T cell receptor (TCR) therapies and chimeric antigen receptor (CAR) therapies. To learn more about Adoptive Cell Therapies, please see:
Several adoptive cell transfer therapies for cancer are in clinical trials, some examples include:
- Novartis’ CTL019 (CAR) T Cell Therapy in Phase II for treatment of pediatric patients with r/r acute lymphoblastic leukemia and for treatment of patients with hard to treat non-Hodgkin’s Lymphoma.
- Juno Therapeutics’ JTCR016 (TCR) T Cell Therapy in Phase I/II for treatment of patients with stage III-IV non-small cell lung cancer or mesothelioma.
- Kite Pharma’s KTE-C19 (CAR) T Cell Therapy in Phase I/II for treatment of patients with refractory aggressive non-Hodgkin’s Lymphoma.
There are currently no gene therapies approved by the FDA, but there are some currently in human clinical trials. The research behind Gene Therapy demonstrates that a missing or defective gene can be replaced by a correct copy. However, since DNA cannot be directly inserted into cells, Gene Therapy requires a carrier or vector, most commonly inactivated viruses.
Gene therapy can either take place outside the patient’s body with patients’ cells collected, expanded, and treated with the vector in the lab prior to infusion back into the patient’s body or patients can also be treated directly with the vector. There are many gene therapies in clinical trials. Most Gene Therapy cancer treatment candidates either focus on attacking cancer cells and inducing cell death or they focus on boosting immune system cells in attacking the cancer.
One Gene Therapy has been approved by the European Commission, although not in cancer treatment. UniQure’s Glybera was approved in November, 2012 for treatment of lipoprotein lipase deficiency (LPL). The therapy is currently the world’s most expensive medicine with costs at close to 1 million dollars for one treatment.
In society’s battle with cancer we have an increasing number of weapons in the arsenal. According to the global oncology trend report, “survival has improved significantly over the past two decades with published research suggesting that 23% of the improvement is due to behavioral changes, 35% is due to screening, 20% to advances in treatment, and the remaining 22% attributed to other factors. While we have had much success, researchers still look for the silver bullet, the ultimate weapon against cancer. It is clear that the commitment to pursuing new therapies has not waned with almost 2,000 in the pipeline. With new therapeutic approaches gaining ground, will one of these drugs in the pipeline be a game changer? Only time and many years of dedicated research will tell.