The Ubiquity of Immunotherapy: What’s Next?
By Cory Lewis, PhD
With close to 6,000 oncology drugs in development and more than 2,400 different mechanisms of action (MOAs), immunotherapy has been the hottest topic in oncology. Immunotherapies have started to enter the mainstream, with June being immunotherapy awareness month. Newsman Tom Brokaw and former president Jimmy Carter recently spoke about their treatments with this class of drugs, and several 60 Minutes segments covered immunotherapies. The immunotherapy market horizon includes more than 75 drugs in development for oncology. The race is now on for the next FDA-approved immunotherapy in cancer as well as expanded indications for Merck’s and BMS’s approved immunotherapies.
Kantar Health’s newly developed CancerLandscape™ platform identified 8 immunotherapy drugs in Phase 3 clinical trials in the U.S., with 13 in Phase 2 and 17 in Phase 1; 41 drugs that target PD-1 alone are in various stages of development, many in preclinical development that may never make it to clinical trials. The presence of immunotherapies at annual scientific meetings is growing. At the American Society of Clinical Oncology (ASCO) 2015 annual meeting, immunotherapy targets were mentioned in over 850 out of the 5,000 abstracts.1 The American Association for Cancer Research (AACR) 2015 meeting had more than 500 immunotherapy-related abstracts, skewed toward late-stage and approved targets (PD-1, PD-L1 and CTLA-4). However newer targets appear almost daily.
Immunotherapies have the ability to completely change treatment paradigms within a tumor. In melanoma, for example, the best option before immunotherapy was interleukin-2, which had an only 6% complete response rate2 with a very large side-effect profile. The level of unmet need was high, and Yervoy was able to reduce the risk of death by 32% in these patients. Recently, Opdivo showed an overall response rate of 32% in advanced melanoma patients and a one-year survival rate of 73%.3,4 In an indication with very few options and dismal outcomes, immunotherapy is allowing patients to live longer.
Not only are immunotherapies improving clinical outcomes, they also show the potential to affect management of cancer patients in other areas.
With immunotherapies moving further up in lines of therapies and quickly becoming the go-to option over chemotherapies, what will happen to the supportive care market? Supportive care drugs used to combat nasty side effects of chemotherapy could see a shrinking market as patients move to immunotherapies with fewer (or at least different) side effects. For example, some supportive care drugs are aimed at neutropenia, but the current approved immunotherapy drugs don’t show a significant amount of neutropenia. As immunotherapies become more ubiquitous one could see the supportive care market for neutropenia in cancer shrink.
How will immunotherapies change biomarker testing? Specifically, in melanoma, immunotherapy is moving earlier within the treatment paradigm, and treatments are efficacious regardless of BRAF. Will patients still need BRAF testing? If immunotherapy becomes standard of care in first- and second-line in melanoma, where does BRAF testing fit in?
What about histology? Immunotherapies in lung cancer seem equally effective in squamous and non-squamous subsets. If immunotherapies become the major treatment in lung cancer does it become necessary to separate the two by histology? Immunotherapy has the ability to not only completely shift a treatment paradigm within a tumor but also to affect other markets and possibly how patients are diagnosed.
The Ubiquity of Immunotherapy: What’s Next? (cont.)
Unfortunately, there are more questions than answers right now, and time will tell how immunotherapies will shape treatment paradigms. However, treatments that powerful have caught the eyes of most companies – and their pocketbooks.
According to an in-depth analysis using our CancerLandscape™ platform, of nearly 6,000 oncology drugs in development, the number of companies who have immunotherapy drugs in their pipelines has grown to 77 companies. Keeping track of who owns which drug has become a difficult task with what seems to be a different licensing deal or acquisition every day as companies jockey to have the most promising immuno-oncology drug.
The recent acquisition of Therakos Inc. by Mallinckrodt Pharmaceuticals for $1.33 billion underscores the importance of immuno-oncology drugs within pharmaceutical companies’ pipelines.5 However, companies with immunotherapies already in their pipelines are looking to partner with companies that have second-generation immunomodulatory targets. Novartis made a splash recently with a $750 million deal with Aduro Biotech. Other recent deals involving immunotherapy include BMS’s acquisition of Flexus ($800 million with $450 million in milestones); Merck & Co.’s purchase of cCAM ($95 million upfront with $510 million in milestones); Celgene’s paying $1 billion to partner with Juno; and Johnson & Johnson buying global rights to two Alligator Biosciences compounds for up to $750 million.
Given this flurry of Big Pharma investment in smaller companies, the definition of immuno-oncology has broadened. Some of it is warranted, such as natural killer cells and other forms of innate immunity. However, others have attached the “immunotherapy” label to their drug to gain publicity or obtain higher prices for licensing deals. Weeding through the relevant targets has now become the job of scientists as well as dealmakers.
While current approvals for immuno-oncology agents are as monotherapies, researchers are actively investigating whether the dramatic improvements seen with the monotherapies will be additive or synergistic if used in combination. Some trials pair immuno-oncology drugs with other immuno-oncology targets (such as the CTLA4 inhibitor Yervoy with the PD-1 inhibitor Opdivo), while others combine immuno-oncology drugs with non-immunotherapy targets (such as PD-1 inhibitor atezolizumab with VEGF inhibitor Avastin). Currently 142 clinical trials contain immunotherapy combinations. Combining immunotherapies raises safety and tolerability concerns, but work is being done to determine the proper combinations. Not only are combinatorial trials being looked at, but the sequences in which immunotherapies are given are actively being investigated. The possibilities are endless, which points to the value for proven biomarkers for immuno-oncology drugs. With so many clinical trials available, how does a physician know which trial to recommend to their patients? Biomarkers could help with that decision in the future.
CTLA4 and PD-1 have been shown to work as targets; now we are waiting to see what will be next: OX40, LAG-3 or second-generation immuno-oncology agents such as cyclic dinucleotides directed toward the stimulator of interferon genes receptor (STING). These second-generation compounds provide many more possibilities, with many to investigate and many indications to investigate them in. Agents designed to target natural killer cells and macrophages are in early stages and a new take on immunotherapy drugs in cancer. Will these be able to match the PD-1 data? It will be a fun ride in which some are sure to rise to the top while others may be geared toward niche patient populations. One thing is for sure: immunotherapy will have a long-lasting effect on oncology pipelines.
- Booth, Bruce. ASCO 2015: Abstract Thoughts On Cancer And Competition. Life Sci VC. 29 May 2015. http://lifescivc.com/2015/05/asco-2015-abstract-thoughts-on-cancer-and-competition/
- Atkins MB, Kunkel L, Sznol M, Rosenberg SA. High-dose recombinant interleukin-2 therapy in patients with metastatic melanoma: long-term survival update. Cancer J Sci Am. 2000 Feb; 6 suppl (1):S11-4.
- Bristol-Myers Squibb Company. (2014). Opdivo [package insert]. Princeton, NJ: Bristol-Myers Squibb Company.
- Bristol-Myers Squibb Company. (2015). Press release June 19. Princeton, NJ: Bristol-Myers Squibb Company.
- Noles, Cory. Mallinckrodt to buy immunotherapy company for $1.33 billion. St. Louis Business Journal. 10 Aug 2015. http://www.bizjournals.com/stlouis/blog/health-care/2015/08/mallinckrodt-to-buy-immunotherapy-company-for-1-33.html
About the Contributor
Cory Lewis, Ph.D., is an Analyst in Clinical and Scientific Assessment at Kantar Health.
Kantar Health is a leading global healthcare advisory firm and trusted advisor to the world’s largest pharmaceutical, biotech, and medical device and diagnostic companies. It combines evidence-based research capabilities with deep scientific, therapeutic and clinical knowledge, commercial development know-how, and marketing expertise to help clients launch products and differentiate their brands in the marketplace.
CancerLandscape™ is a web-based platform that allows users to quickly review more than 7,500 cancer drugs simultaneously. It combines multiple primary and secondary data sources so users can quickly navigate product opportunities within the cancer landscape. Kantar Health leverages internal methodological expertise and our structured molecular pathway analysis to provide clients with a systematic and scientific set of criteria to rank molecular agents. In addition to these methods we apply and layer in our clinical, commercial and scientific assessments to create valuable insights that can help prioritize which tumors or mechanisms may be of greatest interest for investment or resource deployment.
If you would like us to act as catalysts for you, contact us at www.kantarhealth.com/contactus.