Clinicians see promise but await survival data more than a year out
Moderna’s personalized mRNA vaccine for melanoma delivered a clinical result researchers have spent decades pursuing and a market reaction that fell short of what investors wanted. Details from the drugmaker’s vaccine study, drawn from the National Library of Medicine, Moderna and Merck and reported by The Wall Street Journal, showed that adding the vaccine to immunotherapy reduced the risk of melanoma returning by 42% compared with immunotherapy alone. Adil Daud, director of melanoma research at the University of California, San Francisco, who worked on the trial, called the finding “a massive conceptual breakthrough.” Scientists have been studying cancer vaccines for decades without success, and the results showed that a highly personalized, immune-targeting medication can work.
Investors were not persuaded. Moderna’s stock fell 19% in the days after the results were prematurely released. Evan Seigerman, an analyst with BMO Capital Markets, said investors were looking for a larger margin of benefit. “Investors wanted to see something that was better, something that really pointed to true differentiation,” Seigerman said. The disconnect illustrates how investors’ expectations can outstrip the promise of experimental medicines, including ones scientists say are significant advances in treatment.
The bar any melanoma treatment must clear was set by what is already available. Immunotherapies such as Keytruda and Bristol-Myers Squibb’s Opdivo have substantially reduced the number of deaths attributed to melanoma since being approved over a decade ago, and their efficacy has created a high bar for the treatments that have followed. Wall Street was also concerned that the study results might not persuade doctors to use what is expected to be a costly new combination.
Both developers need the vaccine to produce revenue. Moderna must prove that its mRNA vaccine technology has a future outside infectious diseases, where sales have been declining for years. Merck, a co-developer of the vaccine, must prove it can make up revenue that will be lost when its blockbuster immunotherapy Keytruda goes off patent in about two years. Pharmaceutical companies more broadly are under pressure to show success with new drugs.
The treatment itself involves more steps than a standard immunotherapy infusion. A blood sample and a sample of high-risk melanoma tissue from the patient are sent for genetic sequencing, where computer algorithms scan the cancer’s unique mutational ‘fingerprint’ to pick targets. Those targets are encoded into a personalized mRNA strand packaged in lipid nanoparticles, or LNPs. Once injected, the LNPs protect the mRNA as it enters host cells, the cells alert the immune system to attack cancer cells carrying the pre-defined targets, and the immune system activates and generates T-cells that eliminate remaining or new cancer cells to prevent recurrence.
Cost and manufacturing complexity are part of the adoption question. New cancer drugs are introduced at prices of around $400,000 or more a year, and this therapy requires more complex manufacturing than most. Beth Buchbinder, a medical oncologist at Dana Farber Cancer Institute, said the cost is “definitely a consideration.” “It is a lot easier to, you know, pull a bag of pembrolizumab off the shelf,” Buchbinder said, referring to Keytruda.
A separate study adds to the uncertainty doctors face. That study showed that using Keytruda alone before surgery appeared to produce a similar result to the vaccine in certain melanoma patients. Merck, which partially funded that study, said the two trials are in different patient populations and can’t be compared. Still, the comparison raised questions for doctors.
What the results did establish, on the evidence, is that a cancer vaccine added to Keytruda could be beneficial for some patients; which patients, and exactly how many, remains open. Lisa Tachiki, an oncologist at Fred Hutch Cancer Center, said, “It’s quite an individualized discussion,” with questions ranging from how far a cancer has spread to whether a person can tolerate the side effects of immunotherapy.
It is also too soon to tell how much longer patients will live on the Moderna treatment; that data is not expected for more than a year. Tachiki framed the open question: “Are we actually helping our patients live a little longer? Or are we just delaying something that potentially can still be salvaged with immunotherapy at the time of recurrence.”
Clinicians said the vaccine holds promise, particularly for people with less advanced melanoma who don’t qualify for immunotherapy before surgery because their tumors are less visible. Patient selection, rather than broad applicability, is the question they are working through.
The companies are also studying the vaccine beyond melanoma, and that work has been driving investor enthusiasm. Moderna and Merck are studying it in cancers such as kidney and lung, and the companies are considering other tumor types. Eliav Barr, chief medical officer of Merck, said the drugmakers chose to start with melanoma because it is highly sensitive to immunotherapies. The real question, Barr said, is whether the vaccine is “a melanoma product, or is this one of those new cancer interventions that may have benefit in a diverse set of cancers.”
For now, the result has settled a long-running scientific question and left the commercial ones open: survival data is more than a year away, the pool of patients likely to benefit most is still being defined, and the companies are trying to show that the approach reaches beyond the disease they started with.