Immunotherapy has led a revolution in cancer medicine, starting with the approval of ipilimumab for metastatic melanoma 5 years ago. Since then, newer generations of immune checkpoint inhibitor, especially drugs like Opdivo [Bristol-Myers Squibb (NYSE:BMY)] and Keytruda [Merck & Co (NYSE:MRK)], have extended the benefit of this strategy much further. Now, the far-ranging potential of immunotherapy has been realized in hard-to-treat tumors like metastatic melanoma, non-small cell lung cancer, renal cancer, and resistant Hodgkin lymphoma. In this article, I'd like to explain how Incyte Corporation's (NASDAQ:INCY) entry into this space may impact cancer care.
Despite the promise of contemporary immunotherapy, many challenges remain. One, how do we identify patients who will benefit from immunotherapy? Two, what can we do for patients who develop resistance to immunotherapy? These questions have led researchers down a path of intense investigation into alternate therapies that will boost immunotherapy, including small molecules like epacadostat, which may circumvent resistance and deliver a knockout to the tumor.
What drives immunotherapy resistance?
While molecules like Keytruda and Opdivo yield good response rates and very durable response, when used on their own, a little under half of the patients who are given these therapies see any benefit at all. Moreover, for those patients who stop responding, there is little therapeutic recourse.
Understanding how resistance to immunotherapy develops is the first important step in combating it. As you might expect, the tumors have a host of mechanisms that it can use to continue dodging the immune system despite treatment with immune checkpoint inhibitors.
1) Lack of antigenicity
Many tumors have a low mutational burden, which means they are harder for the body to detect as foreign. This is especially true when you're not dealing with lung cancer, melanoma, and other forms of cancer that often arise from environmental damage. Tumors that don't have many mutations can be difficult to mount an effective immune response against.
2) Poor recruitment of immune cells
Some tumors find themselves in the lucky position of being non-inflammatory or in a tissue site that is not particularly amenable to infiltration by immune cells. It has been well known for a long time, even before the emergence of immune checkpoint inhibitors, that infiltration by immune cells into the tumor correlates with good prognosis. This carries over into response of tumors to immunotherapy.
And this makes sense. In order for the body to mount an immune response, we need to be able to get immune cells into the tumor itself to learn about the tumor cell biology.
3) Poor tumor microenvironment
The nontumor cells that surround tumor tissue can play an equal, if not more important role in determining response to therapy. Research into how the tumor interacts with its surrounding is aggressive, and it may hold the key to a lot of future development. Tumor cells can promote expression of other immune checkpoint pathways (note there are roughly 13 non-PD-1 immune checkpoints), or they can secrete anti-immune cytokines like TGF-beta to downregulate immune cells right in the tumor niche.
One molecule that's made by the tumor and is important for this discussion is called indoleamine 2,3-dioxygenase (IDO), which basically allows tumors to eat tryptophan in the surrounding environment. Immune cells need tryptophan in particular to continue functioning, which is useful to prevent autoimmune overreaction by the immune system. However, tumor cells can subvert this pathway and produce IDO to ramp up tryptophan metabolism in the tumor microenvironment, suppressing nearby immune cells. Overexpression of IDO has been identified in metastatic melanoma and other tumors.
Due to its important function in dodging the immune system, IDO has emerged as an attractive target for oncology drug development. Leading the pack is Incyte's epacadostat, which is now in clinical trials for a variety of indications. Epacadostat blocks the function of IDO in an effort to improve the function of immune cells in the surrounding tumor microenvironment.
This agent is now being explored both alone and in combination with other immunotherapies, such as Aduro Biotech's CRS-207, atezolizumab, pembrolizumab. Moreover, a Phase 1/2 study of epacadostat combined with ipilimumab in melanoma has recently reached full accrual.
This latter study, epacadostat combined with ipilimumab, has yielded early safety and efficacy data of this strategy. At ASCO 2014, the findings from 12 enrolled patients were presented. In total, this combination yielded a response rate of 41.7%, which compares favorably with historical experience using ipilimumab (response rate of 5.7% to 10.9%, according to prescribing information).
Importantly, epacadostat did not substantially increase the risk of immune-related adverse events. This is a crucial point that interested parties should pay attention to. One of the biggest barriers to using combination immunotherapy is the increase in toxicity. Many times, adding more agents to immune checkpoint inhibitors has proved too costly to patients, resulting in suspension of a number of trials.
It remains to be seen whether these findings hold up in randomized assessment. Moreover, the durability of the responses will need to be presented. However, it is clear that epacadostat represents a promising agent for combination with immunotherapy, and I will definitely be watching these studies for further developments.
The bottom line
Epacadostat has yielded some promising early stage efficacy, and investigations using this agent are aggressive and far-ranging, including a variety of other therapies and tumor areas. Should you invest based on this information? At this time, it is obviously premature to put money into Incyte based solely on its foray into oncology. However, this is a successful company with the resources to see its promising projects through. So on its own, Incyte is not a pure speculative investment.
Moreover, the potential reward from finding a therapy that can help circumvent resistance to immune checkpoint inhibition is huge. This could be a treatment provided to patients who do not respond to initial treatment, which can be the majority of cases in some tumor types. As such, epacadostat, if proven effective, could enter the standard of care and become a critical targeted therapy to potentiate the ever-expanding portfolio of immunotherapies.
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Disclosure: I/we have no positions in any stocks mentioned, and no plans to initiate any positions within the next 72 hours.