Merck’s Keytruda aces another cancer trial as results dazzle researchers

The News:

Hot on the heels of the final presentation at ASCO’s 4-day conference in Chicago, a small, new study is causing jaws to drop after it found that a cancer drug from Merck & Co. (Kenilworth NJ) helped tremendously to shrink or eradicate tumors in patients whose cancer had resisted every other form of treatment.

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The study, which was published in the journal Science, followed 86 patients who had advanced cancer of the pancreas, prostate, uterus, or bone. The patients were given pembrolizumab (also called Keytruda) and the results were extraordinarily promising. Sixty-six patients had tumors that shrank significantly and stabilized; among them were 18 patients whose tumors disappeared completely and haven’t returned.

The patients all carried genetic mutations that prevented their cells from fixing damaged DNA.

“Our study results may lead to a new standard-of-care that includes ‘mismatch repair deficiency’ testing to help identify a wider group of patients who have failed other therapies but may benefit from immunotherapy drugs,” says Dung Le, MD, oncologist at the Johns Hopkins Bloomberg~Kimmel Institute, who led the clinical trial.

Mismatch repair (MMR) defects are part of a system that helps cells recognize and correct mistakes during DNA replication. For more than two decades, defective MMR genes have been linked to inherited and non-inherited (or sporadic) forms of colon cancer  and used as biomarkers for diagnostic screening and chemotherapy treatment planning.

Pembrolizumab is known as a PD-1 blocker, an emerging type of immunotherapy drug that helps the immune system find cancer cells and attack tumors.

The study was small, and there was no control group (i.e., a group that didn’t receive pembrolizumab that scientists could compare results against), but the results were so striking that the FDA has already approved pembrolizumab for patients whose cancer comes from this particular genetic abnormality.

According to The New York Times, this is the first time a drug has been approved for use against tumors that share a particular genetic profile, regardless of where they appear in the body.

Steve’s Take:

What’s truly mind-boggling about this fantastic news is tens of thousands of cancer patients each year could benefit from Merck’s treatment.

“This is absolutely brilliant,” said Dr. José Baselga, physician in chief at Memorial Sloan Kettering Cancer Center in New York, which has just hired the study’s lead investigator, Dr. Luis A. Diaz Jr.

The drug is already on the market for select patients with a few types of advanced lung, melanoma and bladder tumors. It is expensive, costing $156,000 a year, says the Times. A test for the mutations targeted by the drug also is available for $300 to $600.

It’s true that just 4% of cancer patients have the type of genetic aberration susceptible to pembrolizumab. But that tallies up to as many as 60,000 each year in the US alone, the study’s investigators estimated.

Researchers have been saying for years that what matters was the genetic mutation causing the tumors, not necessarily by their location in the body. Patients have been diagnosed with lung cancer, for example, or brain cancer. At first, they were certain they would be able to cure cancers with drugs that zeroed in on the mutations, wherever the tumors were lodged.

The new study was based on a different idea. The immune system can recognize cancer cells as foreign and destroy them. But tumors deflect the attack by shielding proteins on their surface, making them invisible to the immune system.

The median point of survival without disease progression and overall survival has not yet been reached in the Keytruda trial. However, the scientists estimate that disease-free survival at one and two years is 64% and 53%, respectively. Without immunotherapy, patients with advanced, treatment-refractory cancers can expect to live less than six months.

“We still do not understand why only half of the patients in the study responded and half did not,” says Drew Pardoll, MD, PhD, director of the JHBKI) and a co-author of the report. “But in testing for MMR deficiency, we essentially married genetic biomarkers with an immunotherapy drug to find patients we thought would be more likely to respond to this increasingly-used drug, and we believe it’s a terrific example of the future of precision immunotherapy.”

He added, “the hope is that other immunotherapy drugs can be aligned with genetic factors to further increase success,” according to Medical Express.

Bottom Line: John Carroll at Endpoints says Merck’s strat­egy on de­vel­op­ing its PD-1 check­point drug Keytruda could be sum­ma­rized as: If we have any kind of a shot at a le­git­i­mate tar­get, we’re going to take it. Then we’ll start a combo trial ASAP.

Now it’s moved into an early-stage study in what’s impending as the next big chal­lenge that will ei­ther dis­tin­guish the lead­ers or set up the next great pit­fall: A PD-(L)1/CTLA-4 combo.

Merck’s lat­est early-stage combo matches its in-house CTLA-4 drug MK-1308 (pdf) with Keytruda.

“(T)here is a dif­fer­en­ti­a­tion that we’re hop­ing for. And it is a mol­e­cule that was ob­tained in part ex­ter­nally and re­fined in­ter­nally,” Merck R&D chief Roger Perl­mut­ter told Bernstein’s Tim Anderson. “We’ve been work­ing on it for some time.”

What would make the study “easier to justify,” in Anderson’s opinion? Simultaneously launching another combination trial, this one marrying Keytruda and Bristol’s CTLA4 med, Yervoy–the only one currently on the market. This way, as he sees it, if Bristol or Astra succeed with their trials, “Keytruda would remain relevant” in the nearer-term setting, FiercePharma reports.

“As long as Merck generates clinical data like this, physicians would likely feel comfortable mixing-and-matching” Merck and BMS’ products, he theorizes. “Then, Merck has more time to eventually come in with a CTLA4 of its own.”

Investors and payers will more likely get a better handle on the situation later this year when AstraZeneca should have its CTLA4 combo data in hand. Bristol likely won’t have its own results until 2018, thanks to a January decision to pass up an accelerated filing for its Opdivo-Yervoy duo.

Each combo strategy will take its own path either to promising, even successful, results or a dud. With so much at stake for patients, their families and drug developers, the frantic nature of the scientific investigations and evolution of clinical data will only accelerate.

Steve's Take: CAR-T therapies should be covered by #healthinsurance Click To Tweet

As evidenced at the recent ASCO meeting in Chicago, the wildly successful progress and soaring cost of CAR-T therapies, which entail personalized medicine, are invoking questions of just who can afford these medicines. Simple answer? Ask the payers.

These potential cures for cancer will only be available to everyone when we all have health insurance and the insurers won’t be losing money paying for them. But this will require much less expensive generic and biosimilar versions of such meds, and that day is a long way off.