Merck’s checkpoint inhibitor Keytruda (pembrolizumab) has been approved for 21 indications, but you’d better keep up, because it seems the drug is approved for some new indication or combination just about every week.
There are currently more than 1,000 clinical trials ongoing involving Keytruda in a variety of cancers and treatment settings. It is presently approved for a range of indications in melanoma, non-small cell lung cancer, small cell lung cancer, head and neck cancer, classical Hodgkin Lymphoma, primary mediastinal large B-cell lymphoma, urothelial carcinoma, microsatellite instability-high (MSI-H) cancer, gastric cancer, esophageal cancer, cervical cancer, hepatocellular carcinoma, Merkel Cell Carcinoma, and renal cell carcinoma.
The drug is foundational for the company, bringing in $2.27 billion alone in the first quarter of 2019, hitting $2.63 billion for the second quarter, exceeding Wall Street projections of about $2.5 billion.
Although there are other checkpoint inhibitors on the market, they are a distant second place to Keytruda. For example, Bristol-Myers Squibb’s Opdivo (nivolumab) brought in $1.823 billion in this year’s second quarter and Roche/Genentech’s Tecentriq (atezolizumab) brought in $450 million.
In June, BioSpace interviewed Scot Ebbinghaus, Merck Research Laboratories’ vice president and therapeutic area head, Oncology Clinical Research, ahead of the American Society of Clinical Oncology (ASCO) Annual Meeting, where the company was presenting a whopping 140 abstracts on 25 different cancer types.
“I’ve been working on the Keytruda program almost since there was one,” Ebbinghaus said. “I joined in 2012, and then we had about 50 or so melanoma patients on Keytruda, which looked really interesting. It was first used in humans in 2011. And over the past eight years, since the first time Keytruda was given to a human, we have had tremendous growth in the program, which really underscores how transformational the anti-PDL1 drugs in general and Keytruda specifically have been for the treatment of cancer.”
How Checkpoint Inhibitors Work
Tumors have a surface protein called PD-L1. T-cells, a type of immune cell, have a surface protein called PD1. Tumor cells use PD-L1 to essentially trigger PD1 to tell T-cells to leave them alone. Checkpoint inhibitors act by blocking the function of either PD-L1 (Keytruda, for example) or PD1 (Opdivo). In other words, the checkpoint inhibitors prevent the cancer cells from hiding from the immune system.
Checkpoint inhibitors are used by themselves in some cases, as monotherapies, but often in combination with other drugs and immunotherapies. Sometimes, as was recently announced for Roche’s Tecentriq, the checkpoint inhibitor is used in combination with traditional chemotherapy. Another example is the results of Merck’s KEYNOTE-062 Phase III clinical trial that evaluated Keytruda alone and in combination with chemotherapy (cisplatin and either 5-flurouracil or capecitabine) for the first-line treatment of advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma.
Ebbinghaus told BioSpace, “The way the trial is designed, we evaluated Keytruda compared to chemotherapy for what’s called non-inferiority, which means in lay terms, as good or better than chemotherapy as first-line treatment for stomach cancer and in patients with low-level PDL1 expression, and that’s what it showed. In patients with higher levels of PDL1 expression, the overall survival data looked even better.”
He went on to say, “Why that’s important is that two-drug chemotherapy for stomach cancer can be pretty toxic. Some patients aren’t necessarily great candidates for chemotherapy, so if this were to be approved by the FDA and other agencies around the world, it could represent another option for patients with gastric cancer that’s at least as good as chemotherapy but with a less toxic profile.”
Sometimes checkpoint inhibitors are used with immunotherapies that stimulate the immune system, a combination that is like simultaneously taking the foot off the brake while stomping on the gas. Research has been conducted on using checkpoint inhibitors in combination with CAR-T therapies, for example.
Sometimes checkpoint inhibitors don’t work, and it’s not fully understood why, although researchers are making strides in figuring it out. Recent research out of the University of Colorado Cancer Center working with mouse models of B-cell lymphoma found evidence that another set of proteins called the major histocompatibility complex (MHC), which transport antigens from inside the cell to the cell surface—such as PD-L1—may sometimes be downregulated by certain cancers, causing them not to interact with anti-PD-1 drugs. This may provide yet another avenue of research for combination therapies with Keytruda and other checkpoint inhibitors.
The Future of Keytruda
Investors and analysts have expressed some concern that Merck is too dependent on Keytruda. The company has a market capitalization of about $217 billion, and much of that is related to Keytruda sales, which hit $7 billion in 2018, and is expected to beat out AbbVie’s Humira by 2024 as the world’s top-selling drug.
Merck is aware of this, of course, but views oncology as a promising growth market. In addition to its internal programs, which are quite significant, the company recently acquired Peloton Therapeutics and Tilos Therapeutics, both oncology-focused biotech companies. Those companies’ pipelines are expected to provide new revenue for the company over time, and it also has numerous partnerships in oncology related to Keytruda. But in addition, it has a partnership with AstraZeneca on the PARP inhibitor Lynparza, which they expect will be approved after recent strong Phase III results in pancreatic cancer.
The company is also focused on vaccines and its HIV program. It recently picked up an approval for Zerbaxa for hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia (HABP/VABP).
But Keytruda will remain a strong foundation for the company’s success.
Ebbinghaus outlined the two different pathways Merck expects to build on what they have to date. The first, he said, is to further evaluate and improve on the foundation they’ve laid with Keytruda in the company’s combination program. “We have a very large program to evaluate combinations and signal-finding and have collaborated with a number of industry partners to do signal-finding in a variety of combinations and a variety of diseases. A number of those are starting to show interesting results and we’re moving into registration development.”
The second pathway is to evaluate Keytruda in earlier stages of disease. As Ebbinghaus points out, the trials discussed in the context of the ASCO meeting were in cancer that has metastasized. “What we would like to do,” he said, “is use Keytruda in an earlier setting, for example after cancer surgery, to reduce the risk of cancer coming back.”
To date they’ve had one study in melanoma, KEYNOTE-54, read out. It evaluated Keytruda in Stage 3 melanoma post-operatively and showed a clinical relapse-free survival benefit that led to its approval in the U.S., Europe, Japan and other countries. Ebbinghaus said, “We’ve expanded on that concept and have a large portfolio of studies in the adjuvant, neoadjuvant or locally advanced disease setting…. So that’s a second important direction with our Keytruda program.”
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