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Various PD-1 and PD-L1 checkpoint inhibitors have been approved by U.S. regulators including blockbuster drugs Keytruda, Imfinzi, and Opdivo to treat different types of cancer. But that hasn’t stopped biotechs from advancing their checkpoint inhibitor candidates in the clinic in a bid to beat these approved drugs in both efficacy and safety – the latter of which has been a cause for concern.
According to the Cancer Research Institute, there were 3,674 clinical trials testing the popular checkpoint inhibitors in 2020, a dramatic increase from 215 trials in 2016. By 2032, the market for this class of drugs could reach nearly $189.4 billion, a report by Allied Market Research estimated.
How PD-1 and PD-L1 checkpoint inhibitors work and their clinical evolution
Why have these specific drugs become so popular? Well, checkpoint inhibitors can block mechanisms that tumors use to protect themselves from being attacked by immune cells. The PD-1 receptor is an immune checkpoint on T cells that instructs them not to attack any cell carrying PD-L1. Blocking the interaction between PD-1 and PD-L1 lets T cells attack tumor cells that produce PD-L1 as a mechanism to evade the immune system.
PD-1 and PD-L1 inhibitors are not a wholly new concept. In fact, the first checkpoint inhibitor in the market, Yervoy (ipilimumab) from Bristol Myers Squibb, targeted a different immune checkpoint called CTLA4. But concerns about strong autoimmune reactions to the drug in up to 20% of patients played in favor of the PD-1 and PD-L1 generation.
The first PD-1 inhibitor, Merck’s Keytruda, had impressive effects on patients with metastatic melanoma who were unresponsive to standard therapies. But after the initial excitement, unexpected side effects and some big clinical failures started to bring us back to reality. Checkpoint inhibitors do work, but only in a small percentage of patients. It is not yet known exactly why, though doctors have noticed that the drugs seem to work especially well for patients whose cancer cells have a higher number of mutations.
Biotech and pharma now seem convinced that the solution lies in combining checkpoint inhibitors with other cancer treatments. 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.
Checkpoint inhibitors: Approved therapies and emerging candidates in clinical trials
After Keytruda was greenlit in 2014 to treat melanoma, a type of skin cancer, it has since been cleared for a number of cancer indications, with the latest one obtained last year for advanced malignant pleural mesothelioma (MPM), a rare, aggressive cancer that forms in the lining of the lungs. But other checkpoint inhibitors are being tested in the clinic to dethrone approved ones like Keytruda.
One strong contender is the candidate PM8002, now owned by German vaccine maker BioNTech after its $800 million acquisition of China-based Biotheus. Patients with triple-negative breast cancer who received the bispecific antibody targeting PD-L1 and VEGF-A had a 69.7% overall survival rate at 18 months. While the drug overtook Keytruda in the clinic, the question remains of whether the candidate will reap similar results based on PD-L1 protein levels in a larger trial.
Late last year, California-based Summit Therapeutics also surprised the industry when it reported the success of its checkpoint inhibitor ivonescimab in a phase 3 trial. Patients with lung cancer who were given Summit’s candidate had around 11.1 months before their cancer worsened as opposed to 5.8 months for those who received Keytruda. A 49% decline in risk of progression was observed for ivonescimab compared with Keytruda.
“The findings from the HARMONi-2 study support the use of ivonescimab as a promising first-line treatment option for patients with PD-L1-positive advanced non-small cell lung cancer (NSCLC),” Caicun Zhou, the principal investigator of the study, said in a report published in eCancer.
The safety profiles for both treatments were comparable, according to Zhou, and no new safety signals were linked to ivonescimab.
“These results highlight ivonescimab’s potential as a new standard of care,” Zhou added.
Moreover, cosibelimab passed the U.S. Food and Drug Administration (FDA) checkpoint last month for cutaneous squamous cell carcinoma, a type of skin cancer, making it the first of its kind to treat the disease. Branded as Unloxcyt by Massachusetts-based Checkpoint Therapeutics, its approval came after a 47% response rate in those with metastatic CSCC and 48% in patients with locally advanced disease.
Checkpoint inhibitors: safety and financial concerns loom
The clearance of Unloxcyt came almost exactly a year after it was shot down by the FDA due to little-known concerns brought up at a third-party manufacturing facility. The FDA has actually been fairly cautious about which PDL-1 checkpoint inhibitors it okays. It expressed that it was wary of the broad use of these drugs to treat stomach and esophageal cancers. This was also backed by external investigators back in September, who declared that the benefits of the class of drugs were not convincing enough, citing hazard ratios close to 1, which means that risk is almost the same in the treatment and control groups in trials.
“I’m just not sure we want to let their doctors make this decision when these hazard ratios are almost 1, and there are financial and toxicity impacts for these patients,” said Daniel Spratt, from Case Western Reserve University, in a Fierce Biotech report, after voting against checkpoint inhibitors for stomach cancer.
Bearing in mind that the cost of a checkpoint inhibitor therapy is around $150,000 per year in the U.S. and weighing the benefits of these drugs to the risks, the agency could even narrow existing approvals for Keytruda and Bristol Myers Squibb’s Opdivo.
In fact, a study by Rockefeller University revealed why these drugs may leave patients vulnerable to infections. In patients who have an immune deficiency impacting B cell function, the therapy prevents the body from generating antibodies to fight pathogens since PD-1 is expressed on B cells. Perhaps, monitoring B cell function in patients who receive this treatment could help mitigate infections, according to Stéphanie Boisson-Dupuis, a senior co-author of the study.
“This research started with our discovery of just two families with similar inherited deficiencies, and yet, as a result, we’ve learned that PD-1 and its ligand PD-L1 are physiologically essential for all human B cells to produce antibodies against microbes,” said senior co-author Jean-Laurent Casanova, head of the St. Giles Laboratory of Human Genetics of Infectious Diseases at Rockefeller University.
Moreover, Masoud Tavazoie, co-founder of the immuno-oncology biotech Inspirna, had warned that some biotechs may be jumping into the checkpoint inhibitors space 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,” Masoud Tavazoie told Labiotech, a few years ago. “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 strategy to find rational combinations is testing patients for specific biomarkers. For example, before administering Keytruda, doctors need to test whether the patient’s tumor presents a minimum level of the PD-L1 immune checkpoint. Although this strategy reduces the number of patients that can get the drug, it drives the success rate up.
Biotech startups to look beyond PD-1 and PD-L1 checkpoint inhibitors
Still, despite big pharmas like AstraZeneca, Bristol-Myers Squibb, and Merck, all of whom have a stake in the market, young biotechs are not too fazed by the competition or the FDA’s watchful eye. Just last month, Ottimo Pharma raised over $140 million in series A financing to accelerate Investigational New Drug (IND)-enabling studies for its lead asset Jankistomig, a PD1/VEGFR2 bifunctional antibody.
And, companies like California-based Valora Therapeutics are seeking to develop checkpoint inhibitors beyond PD-1 and PD-L1 – in glycobiology. Focusing on sugar molecules called glycans, which play a pivotal role in regulating immune response, Valora emerged from stealth with its $30 million seed financing to advance its glyco-immune checkpoint platform, AbLec.
As biopharmas hold out on their hopes of beating approved checkpoint inhibitors with their own candidates despite the FDA’s less lenient outlook on these drugs, PD-1 and PD-L1 checkpoint inhibitors are still on the roster and there is room for other immune checkpoint drugs like glyco-immune inhibitors to revolutionize cancer care.
This article was originally published by Clara Rodríguez Fernández in April 2018 and has since been updated.
Nex technologies related to checkpoint inhibitors:
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