What if your body's immune system fought off deadly cancer cells just like it protects you from germs you encounter every day?
That's the goal of an emerging class of treatments called immuno-oncology, or I-O, drugs, which Barclays analyst Geoff Meacham says could become a $25 billion market by 2025. Products from Merck (MRK), Bristol-Myers Squibb (BMY) and Roche Holding (RHHBY) already are approved by the FDA to treat melanoma and lung cancer.
Leerink analyst Seamus Fernandez estimates some 1,000 trials are underway in the I-O stratosphere. Those include drug trials by the likes of AstraZeneca (AZN), Incyte (INCY) and a slew of others to treat kidney, bladder, urothelial and head and neck cancers.
Results are still very preliminary, says Tim Reilly, development lead for Bristol-Myers' early I-O pipeline.
"That 'cure' is a tough word," he told IBD. "We are seeing indications that we can at least reset the patient's immune system to normal homeostasis. ... Our hope is we can bring patients who have an official diagnosis of cancer back to that homeostatic place."
Bristol-Myers stock rose 0.6% to 54.58 in stock market trading Friday. Merck shares rose a small fraction, to 65.38, while Roche shares inched up 2 cents, to 30.53. Incyte ended the day up 0.3%.
Though preliminary, the I-O thesis played out for Bristol-Myers and Merck in Q4. Bristol-Myers tacked on $1.57 billion in sales of its I-O drugs Opdivo and Yervoy. Yervoy sales were flat, but Opdivo sales grew 176% from a year earlier. Merck's Keytruda grew 125% to $483 million in sales. (See a list of the major immuno-oncology drugs cleared so far by the U.S. FDA and their approved uses.)
How New Cancer Drugs Trick The Immune System
Cancer cells are constantly occurring in everyone, Reilly says.
"Every time we get out in the sunlight and get some UV exposure, there's a mutation to a cell that is technically now a mutated cell and is, technically, cancer," he said. "But our body eradicates that cell."
That's what a healthy immune system does. But, in some cases, aberrant cells evolve to outpace or outsmart the system, throwing off the body's natural homeostasis. Those cells then grow, becoming a cancerous tumor.
IBD'S TAKE: Wall Street was nervous entering the Q4 earnings season as biotechs took political heat for high drug prices. But biotech Incyte is riding high on a plethora of potential blockbusters, including those in the I-O sector. Head to IBD's The New America article to get a deep dive on Incyte's vast opportunities.
Chemotherapy — pumping the body full of poison to kill cancer cells — is the standard of care. In the early 2000s, targeted therapies changed the growth rates of tumors. After that, drugmakers looked at combining therapies to improve results.
Immuno-oncology drugs — more precisely checkpoint inhibitors — are completely different, Meacham says.
Merck's Keytruda and Bristol-Myers' Opdivo are both PD-1 inhibitors. Both were first approved in 2014 to treat melanoma. Since then, they've tacked on a slew of indications including lung cancer and head and neck cancer. Yervoy is Bristol-Myers' CTLA-4 inhibitor. It was approved in 2011 for advanced melanoma.
"A lot of these drugs basically train the immune system to see the difference between a regular cell and a tumor cell, and use the immune system to fight the tumor off," Meacham said.
Immune system T cells patrol the body for aberrant cells. When a T cell encounters another cell, it probes the surface looking for proteins that would indicate a cancerous cell. Upon finding a cancer cell, the T cells attack, calling forth additional molecules to prevent the battle from injuring regular tissue.
These additional molecules are checkpoint inhibitors, explained a July 6, 2016, blog post from the Dana-Farber Cancer Institute. But a cancerous cell can trick a T cell by wearing the proteins of a normal cell, evading detection and destruction.
"Checkpoint inhibitors block these normal proteins on cancer cells, or the proteins on T cells that respond to them," Dana-Farber wrote. "The result is to remove the blinders that prevented T cells from recognizing the cells as cancerous and leading an immune-system assault on them."
Merck Vs. Bristol-Myers In Combination Drug Therapies
Monotherapies like Merck's Keytruda and Bristol's Opdivo block the interaction between the PD-1 protein on a T cell surface and the PD-L1 protein on the surface of the cancer cell. Doing so allows the T cell to see the cancer cell for what it is.
Bristol's CTLA-4 antibody Yervoy works in a similar fashion.
More than 1,000 clinical trials are exploring different inhibitors, Leerink's Fernandez wrote in a Jan. 20 note. Firms are also looking at checkpoint modulators that would stimulate T cell activation.
Merck's Keytruda and Bristol-Myers' Opdivo have myriad indications as solo therapies. Both are indicated in advanced lung cancer and head and neck cancer. Opdivo is also approved to treat melanoma, renal cell carcinoma and Hodgkin lymphoma. Bristol-Myers' Yervoy is indicated in melanoma.
Near-term excitement, though, is on the potential for I-O combinations. That's where Merck might have a slight lead. In January, the Food and Drug Administration accepted Merck's supplemental filing for accelerated approval of a Keytruda plus chemo combination to treat non-small-cell lung cancer.
Less than two weeks later, Bristol-Myers said it wouldn't seek accelerated approval for its combination of Opdivo and Yervoy in non-small-cell lung cancer, confirming Merck will have a lead in that market. Bristol-Myers is studying that combo in its Phase 3 trial CheckMate-227.
In the aftermath, Wall Street is awaiting the results of AstraZeneca's Mystic trial with bated breath. Like Opdivo and Yervoy, AstraZeneca's durvalumab and tremelimumab are PD-1 and CTLA-4 antibodies, respectively, Barclays' Meacham says.
"That trial is a leading indicator of what could happen with 227," he told IBD. "It's a similar mechanism to Bristol-Myers' Yervoy and Opdivo. ... There are a lot of subtleties between the (Mystic) trial and the 227 study, but I think overall people want to see if the idea worked."
Meanwhile, Merck is testing out Keytruda with Incyte's epacadostat in first-line melanoma, advanced lung cancer, renal cell carcinoma, head and neck cancer, and bladder cancer. Epacadostat belongs to another class of checkpoint inhibitors working to target IDO enzymes.
'The Cancer Will Kill The Patient'
CTLA-4 antibodies were among the first I-O antibodies approved. In 2011, when it was first approved, Yervoy "was a pretty toxic drug," Meacham said. But drugmakers pushed forward upon the discovery of "eye-popping" efficacy when combining CTLA-4 and PD-1 antibodies.
Finding the right dosages of both drugs requires "a bit of trial and error," Bristol-Myers' Reilly said. Through that testing, Bristol-Myers has cut down on the toxicity of its Opdivo and Yervoy combo to ensure the benefits outweigh the risks.
"We don't want to bring toxicity to patients," he said. "But we know one thing for sure: The cancer will kill the patient. We want to be sure we're bringing the benefit and that the Opdivo plus Yervoy combination will bring that benefit."
Reilly expects future cancer treatment to focus on segments of patients who share a diagnosis and similar biomarkers. In the distant future, treatment combinations could potentially be tailored to specific patients based on their body's chemical makeup, said Merck's Dr. Roy Barnes.
Barnes is the senior vice president of global clinical development for Merck Research Laboratories. Like Reilly, he won't call I-O a cure for cancer. But he notes impressive results from patients who've been on Yervoy, one of the first approvals, for years without progressing.
"A lot of patients have started coming off of the drugs after three or four years," he said. "When they come off, there have been very few relapses. It's early days, but it's quite encouraging."
RELATED:
Merck Keytruda Sales Lag Without $40 Million In Deferred Revenue: Analyst
Bristol-Myers Topples On 2017 Guidance Cut Amid Merck I-O Competition
Could Merck's 'Meaningful' Keytruda Royalty Give Bristol-Myers A Leg Up?
