Leakage of sensitive data. Massive stock decline.
under the surrounding chaos moderna and MerckThe latest data on personalized cancer vaccines has led oncologists to say something else: an important milestone in melanoma treatment.
The companies on Thursday announced detailed results from Phase 3 trials of the mRNA-based shot, after partial data was leaked on social media platforms earlier in the day.
The vaccine, known as Intismeran autogenic, reduced the risk of melanoma recurrence or death by 42% when used in combination with Merck’s immunotherapy Keytruda compared to Keytruda alone. The combination therapy also reduced the risk of cancer spreading to distant parts of the body and death by 38% compared to immunotherapy alone, according to a study of about 1,100 patients who had their tumors surgically removed.
The stock market reaction contrasted with the assessment of six melanoma specialists who told CNBC that the results were a clinically meaningful advance and could eventually become the standard of care for patients who initially undergo surgery and do not receive immunotherapy before surgery.
“This could be a major advance in melanoma treatment, and indeed in cancer immunotherapy in general, opening the door to even greater outcomes for patients,” said Se-kwon Jang, Ph.D., a melanoma expert at Inova Schar Cancer and principal investigator at one of the trial’s U.S. sites.
“This is the first time we’ve seen that adding something to an immunotherapy actually increases its effectiveness,” added Dr. Janice Mehnert, a skin cancer specialist and study investigator at New York University Langone.
It may not be long before this vaccine is first on the market and could reach melanoma patients. Moderna CEO Stephane Bancel said in an interview ahead of the earnings release that the company is completing regulatory filings with the aim of getting the drug fully approved next year.
“It’s a very, very happy moment for both the staff and the patients,” he said.
Major advances in melanoma
Immunotherapy like Keytruda wakes up the immune system to detect and attack cancer cells. Unlike preventive vaccines, which protect against infections that can cause cancer, Moderna and Merck’s treatments serve as a blueprint for training the immune system to recognize and track remaining cancer cells based on specific mutations within an individual patient’s tumor.
Doctors say the importance of phase 3 data goes beyond just delaying recurrence. Melanoma can be much more difficult to treat if it comes back after surgery and spreads to distant parts of the body, such as the lungs, brain, or liver. Patients with advanced disease may require additional treatments such as immunotherapy, radiation therapy, or further surgery, but there is no guarantee that these methods will be effective.
If cancer can be stopped from coming back, patients may never face the risks and complexities of metastatic disease.
“If we can essentially cure more patients with early-stage melanoma and not have to deal with unresectable metastatic disease, that would be a great advance,” said Dr. Michael Postow, director of the melanoma service at Memorial Sloan Kettering Cancer Center and an investigator on the trial.
Ideally, patients might be able to undergo surgery and receive the vaccine and Keytruda in the future without needing further melanoma treatment, Postow told CNBC.
Still, questions remain about whether this combination will ultimately help patients live longer, what the long-term benefits will be, and which patients will benefit most.
The results also leave open the question of where personalized vaccines fit into the changing melanoma treatment landscape, some experts said.
The trial tested the vaccine after surgery in combination with Keytruda, rather than against an immunotherapy regimen given before surgery. This is an approach increasingly used in eligible patients with resectable melanoma, where the primary tumor can be removed. The data do not show that using a vaccine approach is more or less effective than receiving immunotherapy before surgery.
The medical community will get further clarity after Moderna and Merck present detailed results at Saturday’s European Society of Medical Oncology conference.
Opinions were divided between investors and doctors.
Moderna shares fell as much as 25% on Thursday, but briefly rebounded after some trial data was leaked on social media. Despite the positive results, the decline highlighted the gap between the therapy’s clinical expectations and investors’ expectations of its commercial potential. Moderna’s stock has also risen nearly 600% this year on optimism about its cancer prevention benefits, making Wall Street’s disappointment even more likely.
RBC Capital Markets analyst Chun Huynh said in a note Thursday that investors had hoped the vaccine and Keytruda would replicate results from an earlier Phase 2 trial that showed a roughly 49% reduction in the risk of recurrence or death after five years. Huynh said the Phase 3 results were clinically meaningful and likely supported regulatory approval, but said the primary efficacy results met the lower end of investors’ expectations.
However, there were important differences in the studies. Dr. George Anstas, head of the melanoma division at Washington University in St. Louis, said the phase 3 trial included patients with a broader risk profile than those enrolled in the earlier phase 2 trial, including those at lower risk of recurrence. This result may have been somewhat attenuated because patients considered to be at low risk are less likely to have a recurrence in the first place.
“This is actually great data. It’s overall consistent with what we’ve seen in the Phase 2 trial,” said Anstas, who was also involved in the Phase 2 trial.
The companies said the combination showed little difference from Keytruda alone during the first six months of treatment. However, a separate analysis of phase 3 data provided more encouraging signals about treatment efficacy after 6 months. The vaccine and Keytruda reduced the risk of subsequent recurrence or death by 58% compared to Keytruda alone.
The 42% figure was derived from the primary analysis, which included patient outcomes throughout the study’s follow-up period. Median follow-up at the time of analysis was approximately 2 years, so the results reflect the overall treatment effect, not just what happened before and after 6 months.
Anstas said it could take several months before the benefits of personalized cancer vaccines become apparent. Each shot must be custom-made, a process that can take about six weeks, during which patients begin receiving Keytruda. Even after vaccination begins, it takes time for the immune system to mount a response against the tumor, and repeated doses are required.
Anstas said this timeline may help explain why the group that received the combination therapy experienced even greater benefits around six months. Still, this explanation does not prove when the vaccine’s effectiveness begins and is only a hypothesis.
Dr. Hussein Tobi, a melanoma expert and trial investigator at the University of Texas MD Anderson Cancer Center, also emphasized the relatively mild side effects associated with the vaccine, such as injection site reactions, as a positive.
Keytruda and other cancer treatments can cause serious immune-related side effects. Detailed safety results released Saturday should help clarify the trade-offs of adding the vaccine to immunotherapy regimens.
There’s more to do
For Moderna, the stakes extend beyond melanoma. Merck is bracing for the eventual loss of patent protection on Keytruda as the company works to build its business beyond coronavirus vaccines.
Companies face several hurdles, including selling personalized therapies at scale that take weeks to create for patients.
“I think the downside is that it’s very labor-intensive and you have to make the vaccine for each person, so you can’t just stockpile a million vaccines and ship them out when someone needs it,” said Dr. Adil Daud, a melanoma specialist and professor of medicine at the University of California, San Francisco, who is the lead investigator on the Phase 3 trial. “It’s going to take time and money and probably cost a lot of money.”
Moderna and Merck have not provided details about the manufacturing costs of their vaccines.
He added that most people who come into the clinic with tumors that have not been surgically removed may insist on receiving Keytruda before surgery. That’s because “that approach is easier and doesn’t put patients through delays in creating a vaccine,” he added.
Dowd said he expects the combination vaccine to be used primarily as an adjuvant therapy after surgery, rather than replacing established immunotherapy regimens given before surgery. He said a vaccine combination could be another option for patients who receive immunotherapy before surgery but have little response, but it would likely be for a small number of patients.
Moderna and Merck will need to test their approaches in other cancers, including non-small cell lung cancer, bladder cancer, and renal cell cancer. Success in melanoma does not automatically guarantee that the approach will work in other tumors.
“You can dream of building a log cabin, but we also got a piece of wood and just felled a tree,” Merck Research Institute President Dean Lee said in an interview ahead of the results. “You don’t get a hut or a village by just knocking down one tree.”
Moderna’s Bancel said he sees a bright future for the vaccine and believes it can eventually help “literally thousands, then tens of thousands, then hundreds of thousands of people with different tumors around the world.”
