What oncology drugs have been approved to date? How much time and money was spent in their development? How much revenue did they bring? How much OS and PFS did they increase (in absolute months)? How many patients develop resistance? What pathways do they hit and are these pathways the answer to resistant mechanisms (Do we need to hit 2 pathways or different pathways?). How many of these have companion biomarkers? How many patients did not respond to treatment - Is this because of lack of better patient stratification? Should we spend more time on phase I? How many of these drugs could treat across different cancers - what are the common altered pathways in different cancers (e.g. HER2 amplification in Lung Cancer)? Should we focus more on earlier stage? If I could fund 10 clinical trials today, how to select them - possibly the ones on earlier stage? or should I fund the later stage? I would choose the drug that would give me more return / or the drug that saves more people?
Outcomes for effects are measured in life years (LYs) which represent the average number of years of life per patient. This is measured by the area under the survival curve. LYs are weighted by estimates of health related quality of life represented by ‘utility’ values to produce quality adjusted life years (QALYs). Cost outcomes are measured as average cost per patient. The final cost- effectiveness outcome measure is the difference in costs divided by the difference in effects (cost per QALY); this is referred to as the incremental cost-effectiveness ratio (ICER). In the UK the threshold ICER for an intervention being cost-effective has been estimated to be up to £30,000.
The problem with many of oncology drugs is the high cost compared to their benefits. The ratio cost-benefit is not ideal. Few agents have been proven to be cost-effective, such as Gleevec, imatinib (IM), trastuzumab, but other drugs have not (https://www.nejm.org/doi/full/10.1056/NEJMsb1607705).
A particular good example is in Chronic Myeloid Leukimia, Bower et al have shown that a dramatic improvement in the survival of patients with chronic myeloid leukemia (CML) occurred after the introduction of imatinib mesylate, the first tyrosine kinase inhibitor (TKI). IM is considered a 'personalised drug' because it addresses the underlying cause of CML. In CML there is chromosomal translocation that results in a active tyrosine kinase called BCR-ALBP1. IM targets this oncoprotein. For instance, the life expectancy of a 55-year old male CML patient would be ~3.5years in 1980's but is is after IM increased by 27.3 years in 2010 (IM was introduced around 2000). Ohm et al (https://www.tandfonline.com/doi/full/10.3109/10428194.2014.953141?scroll=top&needAccess=true)evaluated clinical outcome and cost-effectiveness, using Swedish registry data based on patients with CML diagnosed 1973–2008. Outcome from three time periods (I: 1973–1979; II: 1991–1997; III: 2002–2008) and concluded that over the past 4 decades there was a dramatically improved survival in CML, paralleled by incremental cost-effectiveness ratio (ICER) levels. Median survival was 1.9, 4.0 and 13 years during the respective time periods. The ICER between periods III and II was €52700 per quality-adjusted life year (QALY) gained.
Another cited example is Trastuzumab (TR). Metastatic breast cancer (MBC) is rarely curable at present, although some women live with it for many years; the median overall survival (OS) ranges from 18 to 24 months. Around 25% of over-express HER2. TR is a monoclonal antibody approved by EMA in 2000 and one of the first examples of “targeted therapy”, is indicated to treat HER2 positive breast cancer. Cost-effective studies don't always agree on the benefit of TR. For instance, the latest draft guidance on trastuzumab emtansine reverses a previous recommendation issued last December in which NICE said that the drug was too expensive (https://www.bmj.com/content/357/bmj.j2930). The cost of £90 000 (€103 000; $115 000) for an average course of treatment (14.5 months) gives trastuzumab a cost per quality adjusted life year (QALY) of £166 000, which was well above the normal threshold for drugs used at the end of life.
Fojo et al 2014 has investigated FDA-approved oncology therapies and their limited survival progress against major cancers from 2002 to 2014 (https://jamanetwork.com/journals/jamaotolaryngology/article-abstract/1891387?redirect=true ). 71 cancer drugs were approved, 52 were targeted therapies. For 23 drugs only progression free survival (PFS) is available - no Overall survival (OS). The increase of median progression-free survival was of 2.5 months, and overall survival of 2.1 months. The guidelines to consider survival improvements as 'clinically significant' vary from cancer to cancer. For instance, for pancreatic cancer (where the current OS is 10-14 months), an improvement of 4 months in OS is considered significant. For lung cancer (current survival is 13 months), 3.25 months is considered significant; and for metastatic triple-negative breast cancer (survival is 18 months), at least an additional 4.5 months is considered a significant improvement in survival. Only 30 of the 71 cancer drugs meet these guidelines. Howard et al., 2015 analysed the trends in the launch prices for 58 anticancer drugs approved between 1995 and 2013 by the FDA in the United States. They find that the average launch price of anticancer drugs, adjusted for inflation and health benefits, increased by 10% annually—or an average of $8,500 per year—from 1995 to 2013. We paid $54,100 per year of life in 1995, $139,000 in 2005 and $207,00 in 2013 (https://www.elsevier.com/books/realizing-the-promise-of-precision-medicine/cerrato/978-0-12-811635-7)
Median monthly cost of cancer drugs at time of approval by FDA has increased over the years:
Similar findings have been reported regarding EMA. From 2009 to 2013, the EMA approved the use of 48 cancer drugs for 68 indications with a magnitude of the overall survival benefit ranged from 1.0 to 5.8 months (median 2.7 months) (https://www.bmj.com/content/359/bmj.j4530). At time of market approval, according to the EPARs, there was significant prolongation of survival in just over a third (24/68, 35%) of all drug indications (including 3/17 drugs to treat haematological malignancies and 21/51 drugs to treat solid tumours). For the 44 (65%) remaining drug indications, there was no conclusive evidence at time of market authorisation that the drugs offered survival benefits, either as add on treatment or compared with placebo or existing treatment options in their authorised use.
There is a progressive decline in the number of new drugs per billion US dollars of R&D spending (~80-fold) (https://www.nature.com/articles/nrd3681).
The data in the figure below show that the number of new FDA-approved drugs per billion US dollars of R&D spending in the drug industry has halved approximately every 9 years since 1950, in inflation-adjusted terms. Part of the contrast between Moore’s Law and Eroom’s Law is related to the complexity and limited current understanding of biological systems versus the relative simplicity and higher level of understanding of solid-state physics but, as discussed by the authors, there are other important causes which the authors summarise as ‘better than the Beatles’ problem; the ‘cautious regulator’ problem; the ‘throw money at it’ tendency; and the ‘basic research–brute force’ bias. - good read!
The Cancer Research Institute (CRI) published the most comprehensive assessment ever (https://academic.oup.com/annonc/advance-article/doi/10.1093/annonc/mdx755/4693829) of the state of research and development for immunotherapies. This report identified a staggering 2,004 immunotherapies in development or on the market across the world.
A team at the Anna-Maria Kellen Clinical Accelerator of the Cancer Research Institute (CRI) in New York have published an important new paper in the Annals of Oncology (https://academic.oup.com/annonc/article/29/1/84/4693829) (doi:10.1093/annonc/mdx755) – helping the cancer community to stay informed of the current immuno-oncology (IO) landscape and identifying a number of key trends.
Illustrating the rapid progress in the immuno-oncology field over the last 30 years, the authors highlight that since the approval of the first immunotherapy (interferon-α), a further 25 agents have followed - and an impressive 17 types of cancer now have at least one agent approved as a treatment option.
We have witnessed a transformation in the IO landscape - starting with the approval of ipilimumab for advanced melanoma in 2011. In the past three years alone, eight new immunotherapies were approved - which in most cases, provide desperately-needed new options for patients with advanced, refractory or relapsed cancers.
However, with this success brings a new challenge. With huge investment from industry in and a plethora of companies entering the field, there is now an unprecedented number of new immunotherapy agents at various stages in the drug development pipeline. And this makes it difficult – and potentially overwhelming - to keep track of what’s going on! For cancer patients, this means there are more experimental I-O drugs than ever before that hold hope for more effective treatment. But there's also a downside to having so many drugs being researched.
To help address this, the team set out to curate a much-needed comprehensive overview of this rapidly evolving landscape. Collecting information from a number of trusted and publicly available sources (up to a cut-off date of September 2017), they have created two new databases tracking:
- A total of 2,004 immuno-oncology agents (940 in clinical stage and 1,064 in pre-clinical testing). Of the 2,004 I-O drugs in development, 940 were in clinical testing with humans or already approved after having completed clinical testing. The remaining 1,064 drugs were in preclinical testing. These drugs target 303 specific types of cancer. That might seem like an extraordinarily high number, but there are often many types of genetic mutations that cause one broader type of cancer.
- The 3,042 active clinical trials – covering all common cancer types and the majority of the less common ones. For those 940 I-O drugs in clinical testing, the CRI is tracking 3,042 active clinical trials. These trials combine for total enrolment of 577,076 patients. Some of the clinical trials have already fully enrolled, while others are either actively enrolling or plan to begin enrolling in the future. These collectively aim to recruit 577,076 patients.
The overview of 2,004 IO agents. 6 classes of IO agents are identified on the basis of different mechanisms of actions. Unspecified tumor associated antigen (Unspecified TAA) is defined as the target of unspecified antigens from either individual patients or cell lines. In this sense, therapies against this target mainly consist of cell line-based vaccines, autologous tumor vaccines, autologous DC vaccines, and tumor infiltrating T cell therapies (TIL). Personalization is defined as the targets discovered by algorithm-based approaches from, e.g., the individual patients’ tumor samples or blood circulating DNA.
While there are a huge number of experimental I-O drugs, only 26 have won regulatory approval so far. The first was interferon-alpha back in 1986. The real turning point, though, came in 2011 when Bristol-Myers Squibb (NYSE: BMY) won approval for checkpoint inhibitor Yervoy in treating advanced melanoma. Checkpoint inhibitors block proteins that interfere with the body's immune cells attacking cancer cells. Another checkpoint inhibitor from Bristol-Myers Squibb, Opdivo, is projected to become the No. 2 cancer drug (https://www.fool.com/investing/2017/07/10/these-5-cancer-drugs-will-be-the-biggest-winners-5.aspx) in the world in sales within the next few years.
The numbers from CRI show where the scientific community seems to think the most potential for fighting cancer lies. CRI found 344 cancer vaccines either in clinical development or on the market. These vaccines target either preventing cancer or treating existing cancer.
There are 224 clinical-stage cell therapy I-O drugs. Cell therapy involves putting cellular material into a patient to fight cancer. Novartis' (NYSE: NVS) Kymriah became the first cell therapy to win regulatory approval in August for treatment of B-cell precursor acute lymphoblastic leukemia (ALL). Gilead Sciences (NASDAQ: GILD), thanks to its acquisition of Kite Pharma, followed closely behind in October with approval of another cell therapy, Yescarta, in treating large B-cell lymphoma.
CRI identified 99 immunomodulators that target T cells in clinical testing or on the market. T cells are immune cells produced in the thymus gland (which is where the "T" comes from in their name). Another 170 clinical-stage immunomodulators are targeting other immune cells or the tumor immune microenvironment.
There was one other thing from the CRI report that stood out to me: Those 2,004 drugs were owned by 864 companies. Even in China, which has been a communist nation for more than 70 years, businesses lead the way in cancer drug development. The report stated that 46 Chinese companies owned 98 clinical-stage immunotherapies focused on CAR-T (chimeric antigen receptor T cell) development.
All of the 26 immunotherapies available to patients today are owned by biopharmaceutical companies. The most promising cancer drugs that could be game changers (https://www.fool.com/investing/2017/07/10/these-5-cancer-drugs-will-be-the-biggest-winners-5.aspx) are being developed by businesses, and most of them are publicly traded corporations. It's no surprise that the stocks of the most innovative biopharmaceutical companies, such as bluebird bio and Juno Therapeutics, rank among the hottest on the market.
It seems that better treatment -- and perhaps one day even a cure (or cures) -- for cancer will ultimately come as a result of capitalism. The pursuit of profit, while attacked by some, is probably the best reason to think that there's hope for a world where one day cancer doesn't kill more than 8 million people every year.
Through analysing these data, they identify some important key trends:
- A large number of overlaps, with companies chasing the same targets
- An avalanche in the number of studies involving anti-PD-1/L1 combinations, many of which are testing the same combinations
- A big increase in small studies, initiated by researchers
Crizotinib (trade name Xalkori, Pfizer): Acts as a acting as an ALK (anaplastic lymphoma kinase) and ROS1 (c-ros oncogene 1) inhibitor. Approved in March 2016 for ROS1-positive non-small cell lung cancer
Vismodegib (Erivedge, Genentech/Roche): Erivedge is a pill taken once a day and works by inhibiting the Hedgehog pathway, a pathway that is active in most basal cell cancers and only a few normal tissues, such as hair follicles. Aproved in January 2012 for metastatic basal cell carcinoma.
Vemurafenib (Zelboraf, Roche): Zelboraf is a BRAF inhibitor that is able to block the function of the V600E-mutated BRAF protein. Zelboraf is specifically indicated for the treatment of patients with melanoma whose tumors express a gene mutation called BRAF V600E. Aproved in August 2017 for late stage metastatic melanoma.
Recently approved drugs for the treatment of kidney cancer include sorafenib (2005), sunitinib (2006), temsirolimus (2007), everolimus (2009), bevacizumab (2009) and pazopanib (2009).
Axitinib (Trade name Inlyta, Pfizer). Inlyta works by blocking certain proteins called kinases that play a role in tumor growth and cancer progression. Aproved for late stage renal cell carcinoma in January 2012.
Ruxolitinib (trade names Jakafi and Jakavi, Incyte). Ruxolitinib is a Janus kinase inhibitor with selectivity for subtypes JAK1 and JAK2 of this enzyme. Approved for myelofibrosis in February 2016.
Trastuzumab (Herceptin, Genentech). Trastuzumab works by binding to the HER2 receptor and slowing down cell duplication. Trastuzumab was approved for medical use in the United States in 1998. Trastuzumab can be used in the treatment of metastatic and in early stage (curable) HER2-positive breast cancer. Around 20 companies worldwide, particularly from emerging markets, are developing biosimilar versions of the drug 'Herceptin' after Roche/Genentech's patents expired in 2014 in Europe, and in 2019 in the United States.
Olaparib (trade name Lynparza, KuDOS/AstraZeneca). It is a PARP inhibitor, inhibiting poly ADP ribose polymerase (PARP), an enzyme involved in DNA repair.It acts against cancers in people with hereditary BRCA1 or BRCA2 mutations, which include some ovarian, breast, and prostate cancers. The FDA approval in 2014 is in germline BRCA mutated (gBRCAm) advanced ovarian cancer that has received three or more prior lines of chemotherapy.
Bevacizumab (Avastin, Genentech). Bevacizumab is a recombinant humanized monoclonal antibody that blocks angiogenesis by inhibiting vascular endothelial growth factor A (VEGF-A). In 2004 it became the first clinically used angiogenesis inhibitor. Used in several cancers including Colorectal, Brest, Lung, Renal and eye disease
Cabozantinib (Cabometyx,Exelixis Inc). It is a small molecule inhibitor of the tyrosine kinases c-Met and VEGFR2, and has been shown to reduce tumor growth, metastasis, and angiogenesis. Approved in January 2011. Used to treat metastatic advanced prostate cancer (castration-resistant prostate cancer) (2011), Glioblastoma multiforme and advanced clear renal cell carcinoma (2015).
Gemcitabine, sold under the brand name Gemzar among others, is a chemotherapy medication used to treat a number of types of cancer. This includes breast cancer, non-small cell lung cancer, pancreatic cancer, bladder cancer, and biliary tract cancer.
Denosumab (trade names Prolia and Xgeva, Amgen). Denosumab is used in the treatment of osteoporosis. It is a RANKL inhibitor, which works by preventing the development of osteoclasts which are cells that break down bone. Xgeva is the first drug to significantly increase bone metastasis-free survival in castration-resistant prostate cancer, but was not approved by FDA.
Decitabine (trade name Dacogen), or 5-aza-2'-deoxycytidine, acts as an Nucleic Acid Synthesis Inhibitor.It is a drug for the treatment of myelodysplastic syndromes and for acute myeloid leukemia (AML). Decitabine did not achieve FDA approval for AML, but continues to be used off-label. Current research is focused on further defining subgroups of elderly AML patients who may derive greater benefit from decitabine therapy and combining it with other low-intensity active agents for AML.
Iniparib (from Bipar) was a drug candidate for cancer treatment. It was originally believed to act as an irreversible inhibitor of PARP1 (hence, a PARP inhibitor). It underwent clinical trials for treatment of some types of breast cancer, but was discontinued after phase III clinical trials.