Strong results from a phase 2 trial pairing Moderna’s experimental mRNA-based therapeutic cancer vaccine (mRNA-4157) with Merck’s monoclonal antibody drug Keytruda to treat adjuvant melanoma represents a potential inflection point for oncology. Assuming mRNA-4157 shows similar safety and efficacy in a confirmatory trial before earning FDA approval, this news will have significant implications for biopharma research and development, drug manufacturing and, of course, patients.
However, many key questions—and barriers to adoption—remain. In this article, we’ll discuss the implications of last month’s announcement, address the most pressing barriers to adoption and scale and, most importantly, offer a call to action for biopharmas.
The full implications of any scientific leap emerge only in the fullness of time, but there are four key reasons to believe this breakthrough represents a potential inflection point in the treatment of cancer.
It's highly effective. Moderna’s mRNA-4157 isn’t the world’s first cancer vaccine, or even the first in the U.S.; that honor goes to prostate cancer vaccine Provenge, which has been available since 2010 but whose impact has been minimal due to limited efficacy. In its phase 2 trial, meanwhile, Moderna and Merck's vaccine led to a 44% reduction in recurrence or death from melanoma—and that’s on top of Keytruda’s strong track record against melanoma. Moreover, serious adverse treatment-related events occurred in just 14% of patients, compared with 10% of patients treated with Keytruda alone. This kind of result holds the potential to transform standards of care.
It's fully personalized. While CAR-T therapies are personalized in that they enlist a patient’s own T cells to fight their cancer, they’re all trained to attack a finite set of markers found on cancer cells. mRNA-4157, on the other hand, involves the individual sequencing of a patient’s tumor to develop an n-of-1 treatment based on their tumor’s unique mutational signature. This takes personalization a step further than CAR-T and should elicit a superior patient response.
It's AI-supercharged. Based on information in the public domain, Moderna and Merck's vaccine candidate uses a proprietary algorithm to analyze a patient’s tumor to identify the mutations most likely to cause cancer to return and then creates a custom vaccine mRNA-encoded with up to 34 neoantigens meant to build tailored adaptive immunity. Most importantly, they’re able to do this in just eight weeks from the time a patient’s tumor is surgically resected, allowing the company to deliver an exceedingly fast personalized vaccine to patients at high risk of recurrence or death.
It's scalable—with caveats. Unlike CAR-T, which must be administered in highly specialized and accredited centers of excellence, mRNA-4157—if approved—will be administered at local infusion centers where Keytruda is already being given. While the operational burden posed by delivering a personalized vaccine means this won’t be a fully outpatient therapy, at least at first, the promise of greater scale is real—but only if manufacturers can perfect workflows that allow for pinpoint coordination of just-in-time surgery, specimen sequencing and vaccine manufacture, shipping, storage and infusion. It’s a daunting “if.”
While this new treatment modality pairing a therapeutic vaccine with an immune checkpoint inhibitor holds tremendous promise, it will need to clear several hurdles before transforming the standard of care for melanoma—where it may first appear—or any of the other cancer types with active trials exploring similar targets. Other barriers to adoption may emerge between now and a hypothetical launch, but here are the five most significant right now.
Unconventional trial design. Some researchers have raised questions about the trial’s use of a one-sided efficacy endpoint to demonstrate clinical superiority. Although Merck and Moderna made this design decision at the trial’s outset, some have wondered if a larger confirmatory trial will yield such favorable results.
Indirect mechanism of action. There’s a clinical rationale for pairing a personalized mRNA-based vaccine with an immune checkpoint inhibitor such as Keytruda: They both work by supercharging the immune system’s ability to fight cancer. However, unlike a CAR-T, where the modified immune cell interacts directly with the cancer, Merck and Moderna's vaccine produces tumor-specific proteins and presents them to the patient's immune system for processing. While a common and proven method for preventive care, it's a somewhat roundabout mechanism of action for treating existing cancers, which may lead some to question its true efficacy.
Complex logistics. Like Moderna’s COVID-19 vaccine, mRNA-4157 must be kept frozen from the time of its manufacture through a patient’s six-plus month treatment regimen. While the pandemic pushed labs and providers to develop capabilities for cold-chain shipping and storage, it didn’t require the end-to-end individualized ordering, tracking and storage required of a personalized medicine. Luckily, the advance and growing adoption of CAR-T therapies means the model for a fully personalized supply chain, from initial collection through medicine manufacture and infusion, already exists. However, neither Merck nor Moderna has a CAR-T in its portfolio, and neither do the other companies vying to be first in this space.
Manufacturers will need to master the logistics not only of identifying qualified patients, coordinating surgical resection of their tumors and then submitting samples for genetic sequencing but also of manufacturing a personalized vaccine, scheduling patients for infusion the moment their treatment is ready and managing personalized cold storage over an extended period. While CAR-T manufacturers have already learned to clear most of these logistical hurdles, operationalizing the delivery of this personalized therapy will require providers to hire and train staff with specialized capabilities they don’t currently have. No one should underestimate the scope of the scale-up challenge this therapy will entail.
Uncertain reimbursement. We don’t know how much this treatment will cost, assuming it’s approved. However, given its level of personalization and logistical complexities, it’s reasonable to assume it won’t be inexpensive. While clinical trial results are promising, there’s no guarantee payers will embrace another potentially pricey combination treatment—especially one indicated for an early line. As with CAR-Ts, securing single-case agreements can be time-consuming and resource-intensive, and not every provider will have the capacity to do so for every patient. Companies seeking to combine a therapeutic vaccine such as mRNA-4157 with an immune-oncology drug such as Keytruda will face headwinds given the current environment, especially in key markets like Germany, where the government recently tightened drug pricing and reimbursement rules.
Strong alternatives. From chemotherapy agents and cytokines to new next-generation combinations with checkpoint inhibitors, there’s no dearth of treatment options for melanoma. This will create a high bar for Merck and Moderna.
Whether or not this technology follows CAR-T as a true jump forward in cancer treatment, biopharma executives would be wise to assume it will and plan accordingly. We see potentially far-reaching implications across three broad areas.
1. Drug development’s new status quo
Moderna says it needs just eight weeks to sequence a tumor’s gene, identify the proteins most likely to cause recurrence and manufacture a custom vaccine based on the results. For patients, this cycle time would be highly transformative and disruptive—in a good way. For other drug manufacturers, it represents a brazen challenge to the status quo. Our recommendation: If you’re working with precision therapies for aggressive forms of cancer, shortening needle-to-needle time will become a key competitive necessity. If creating a personalized treatment on this timeframe isn’t feasible given your current capabilities, it may be time to look at your target identification and discovery programs. Cost pressures spurred by new regulatory hurdles, especially in cell and gene, will push the industry to shrink development and manufacturing times to make the financial math work. Get there early, not late.
2. A warning shot to incumbents
If Moderna’s vaccine platform is especially well suited to tag-teaming with a PD-1 inhibitor, companies in other solid tumor areas should be on alert. For those with a checkpoint inhibitor in their portfolio, a combination like Merck and Moderna’s may represent a new frontier for generating real-world evidence or for bolstering pipelines with similar programs. Meanwhile, companies operating in different modalities in diseases for which this combination is being tested should closely monitor emerging vaccine options to see which patient subtypes and lines of therapy are being targeted. Separating new competition from merely adjacent options will be key. Phase 1 and phase 2 trials are already underway for vaccines with a similar mechanism of action to treat colorectal cancer, head and neck squamous cell carcinoma, non-small cell lung cancer, pancreatic cancer and more. If these trials show similar efficacy as Moderna and Merck’s melanoma treatment, then this new modality has the potential to disrupt standard of care substantially across a variety of tumor areas.
3. NGS’s growing stature
Next-generation sequencing (NGS) is a critical building block for numerous therapies, from targeted chemotherapy to the treatment of genetic disorders. Oncology players, particularly those with biomarker-directed therapies, are already considering the strategic role NGS plays in optimizing diagnosis and selecting treatment options. For a therapeutic vaccine such as mRNA-4157, NGS isn’t just used to determine patient eligibility; it’s integral to the manufacturing process. This creative new way to leverage NGS underscores the field’s vitality and invites new opportunities for mutually beneficial partnerships with biopharma.
For companies with an existing CAR-T, it’s time to explore therapies of this nature because they have the commercial infrastructure to scale this kind of treatment in solid tumors. For companies with immuno-oncology drugs, the promise of mRNA-4157 offers a path forward in areas with remaining unmet need. And for companies with personalized vaccines in the pipeline, do your homework on the logistics for CAR-T because operationalizing at scale won’t be easy.
Oncology has been one of the richest sources of scientific breakthroughs, leading to life-altering clinical results for untold patients and driving outsize commercial success for manufacturers. Meanwhile, the scope of what’s possible with personalized medicine is expanding, and the pace at which it’s evolving is accelerating. We recommend exploring how to introduce vaccines into your portfolio plan and pipeline development because this latest advance represents a powerful sign of cancer vaccines’ transformative potential and a novel path forward for cancer treatment.