Clinical trial results with immune checkpoint blockers/inhibitors, such as Yervoy (ipilimumab) from Bristol-Myers Squibb (NYSE:BMY), have almost guaranteed that many of these immune-stimulating antibodies will eventually receive FDA approval to treat cancer. But with so many checkpoint inhibitors potentially coming to market, how will drug companies differentiate their drugs from one another? One strategy that companies have already begun to employ is to combine checkpoint blockers with other cancer immunotherapies. Finding the right combination of cancer immunotherapies may not only improve survival in patients, but could give drug companies a significant edge over competitors.
In 2011, BMY launched the first and so far only checkpoint blocker on the market, Yervoy, to treat metastatic melanoma. Yervoy blocks a receptor on the surface of T cells known as CTLA-4, which suppresses T cell killing of tumor cells. About 11 percent of melanoma patients treated with Yervoy respond to the treatment, and the median overall survival rate for Yervoy-treated patients is 10 months versus 6.4 months in control patients. Sales for the melanoma market as a whole exceeded $1 billion in 2012, and analysts predict that annual sales could be over $2 billion by 2021, with Yervoy alone forecasted to sell over $1 billion.
Several major drug companies are nowdeveloping newer checkpoint blockers that appear to be better than Yervoy (see Table 1). BMY has an antibody in the pipeline called nivolumab, which targets PD-1, a receptoron T cells that functions similarly to CTLA-4. Analysts expect that nivolumab will be approved for lung cancer as early as 2015. Merck (NYSE:MRK) also has a PD-1 antibody in development called MK-3475 (formerly lambriluzumab). MRK’s PD-1 antibody received breakthrough status from the FDA, and MRK anticipates completing a BLA for melanoma in the first half of 2014 based on only a single Phase 1 study.
With FDA priority review, MK-3475 may be able to leap frog and beat nivolumab to the market and get an approval later this year. Roche (ROG.VX)/Genentech, AstraZeneca (NYSE:AZN)/MedImmune, and Merck KGaA (MRK.DE)/EMD Serono also have immune checkpoint blockers in their pipelines, but are a bit behind BMY and MRK. ROG.VX is developing a checkpoint blocker called MPDL3280A, an antibody targeting PD-L1, which is found on tumor cells and binds to PD-1 to turn off T cell activity. MPDL3280A is currently in a Phase 3 trial to treat lung cancer and will likely get approved around 2018. AZN has a CTLA-4 antibody called tremilimumab that is in a Phase 2 trial for mesothelioma andalso a PD-L1 antibody, MEDI4736, in Phase 1 trials for solid tumors. MRK.DE also has a PD-L1 antibody called MSB0010718C that is also Phase 1 trials for solid tumors.
Table 1. Summary of checkpoint blockers
|Merck KGaA/EMD Serono||MRK.DE||MSB0010718C||PD-L1||2020+|
With several checkpoint blockers coming down the pipeline, drug companies are desperately looking for ways to “get a leg up” on their competitors. One strategy has been to combine checkpoint blockers with other cancer immunotherapies. BMY, for example, is combining nivolumab with Yervoy, since the company has both a CTLA-4 and a PD-1 antibody. Early results have been extremely promising: about half of advanced melanoma patients had tumor reductions of 80 percent or more. With such promising results from BMY’s combination of Yervoy and nivolumab, BMY’s competitors with checkpoint blockers are now having to play a little bit of catch-up.AZN has both a CTLA-4 and PD-1 antibody, but tremilimumab and MEDI4736 are still relatively early in development, and it will be challenging to compete with Yervoy and nivolumab once the BMY combination has been entrenched.
Companies without a CTLA-4 antibody are likely looking at different cancer immunotherapies to combine. For example, MRK’s MK-3475 will likely get approved soon, but the Yervoy plus nivolumab combination will probably become the standard of care when it gets on the market. Since MRK does not have access to a CTLA-4 antibody at the moment, the company has been very aggressive in finding alternative immunotherapies to combine with its PD-1 antibody. MRK recently announced collaborations with Pfizer, Incyte, and Amgen to combine MK-3475 with a variety of cancer immunotherapies. ROG.VX and MRK.DE are in similar situations and must also find the right combination of immunotherapies to compete with BMY.
One approach is to combine checkpoint blockers with cancer vaccines. By first priming tumor-specific T cells with a cancer vaccine, it is believed that the checkpoint blockers can “take the brakes off” of these T cells to specifically target tumor cells and improve survival. Agenus (NASDAQ:AGEN), for example, is running a Phase 2 trial combining Yervoy with its cancer vaccine, Prophage, to treat melanoma.
Another alternative is combining checkpoint blockers with tumor infiltrating lymphocytes (TILs), which are being developed by Lion Biotechnologies (OTC:LBIO). This combination might be the most effective of all. TILs alone are one of the most promising treatments for metastatic melanoma currently in development, being able to reduce tumors by 50 percent or more in half of patients and completely eliminating tumors without any surgical intervention in about 1 in 10 patients — similar results compared to the Yervoy plus nivolumab combination. TILs are already primed to target multiple tumor antigens, and adding a checkpoint inhibitor should theoretically unleash their activity.
A clinical trial combining TILs with Yervoy in melanoma patients has already been initiated, and a trial with TILs and a PD-1/PD-L1 antibody should begin by the end of the year. Combining TILs with PD-1/PD-L1 is expected to significantly exceed the combination of Yervoy and nivolumab and, as a result, could make TILs and PD-1/PD-L1 the eventual standard of care.
While companies are employing various strategies, such as the use of predictive biomarkers, to differentiate their checkpoint blockers, finding the most effective combination of cancer immunotherapies to use with checkpoint blockers will be critical to compete. Ultimately, combinations with the best survival and safety will most likely be the winners. Investors should keep an eye on not only the checkpoints blockers alone, but also what other immunotherapies that are partnered with them.