Checkpoint inhibitors, especially those targeting PD-1 and PD-L1, are exploding in popularity. But how much of it is hype?

The pipelines of biotech and pharma are filling up with combination therapies for anti-PD-1 and PD-L1 antibodies. A report by EP Vantage has identified 765 trials testing the popular checkpoint inhibitors, a number that has dramatically increased from the 215 trials that were registered just 18 months ago. By 2025, the market for PD-1 and PD-L1 inhibitors could reach near €30Bn, a massive amount for such a young market.

PD-1 PD-L1 immune checkpoint inhibitors

Why have these specific targets become so popular? Well, checkpoint inhibitors are drugs that can block mechanisms that tumors use to protect themselves from being attacked by immune cells. PD-1 is a receptor present on T cells that instructs them not to attack a cell expressing its ligand, PD-L1. Blocking this interaction lets T cells attack tumoral cells that express PD-L1 as an immune evasion mechanism.

PD-1 and PD-L1 are not a wholly new concept. In fact, the first checkpoint inhibitor in the market, BMS’ Yervoy (ipilimumab), targeted CTLA4 instead. But concerns about adverse side effects from autoimmune reactions in up to 20% of patients played in favor of the PD-1 and PD-L1 generation. The impressive effects of the first PD-1 inhibitor, Keytruda, on some patients with metastatic melanoma that were unresponsive to standard therapies, and the story of how it saved former US President Jimmy Carter from cancer, have driven up the hopes of many.

PD-1 PD-L1 FDA approval immune checkpoint inhibitors

But after the initial hype, unexpected side effects and some big clinical failures started to bring us back to reality. Biotech and pharma now seem convinced that the solution is combinations, and it seems like everyone’s giving it a try, hoping that their own therapies will improve the safety and efficacy of the successful PD-1 and PD-L1 inhibitors.

But many of them might just be jumping in blindly. “Rational combination of clinical strategies should be based on strong biological principles, and we have a lot of clinical trials being done now that may not have that rationale,” said Masoud Tavazoie, CEO of the immuno-oncology biotech Rgenix, during a panel at Labiotech Refresh. “Over the next two to three years we’re gonna start to see the real winners. And the losers, which are likely based on poor combinations.

One example of how some are looking for rational strategies is biomarker testing. Before administering Keytruda, MSD tests that the patient expresses certain levels of PD-L1. This strategy reduces the patient population but drives the success rate up. BMS recently failed a big trial in non-small cell lung cancer that recruited patients with very low PD-L1 expression. As a result, the company fell behind MSD in the checkpoint inhibitor market.

PD-1 PD-L1 immune checkpoint inhibitors indications

According to Dr. Justin Gainor from the Massachusetts General Hospital, there’s an additional concern to the rapidly growing number of combination trials. “We need to do better at identifying predictive biomarkers for who is most likely to respond to these drugs, not only to save people from potential toxicity, but also because these drugs are very expensive,” he told Cancer Therapy Advisor.

That’s right. All these companies erratically testing combinations seem to be oblivious to the cost of not one but two drugs. With the cancer market rapidly growing, many assume there will always be someone willing to pay, but given the huge competition, ignoring this aspect might doom many a not-so-carefully planned combination.

The point is that checkpoint inhibitors are definitely bringing new hope to patients that did not respond to standard treatments, but we shouldn’t let hype and huge market projections blind the decisions that will help scientists continue improving the technology and make it accessible to more and more patients. The same goes for other widely acclaimed therapies like CAR-T, which could be hitting the market as soon as the end of this year.

Images via MSD, Keytruda; Jacob Plieth & Edwin Elmhirst, PD-1 / PD-L1 Combination Therapies (May 2017)

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