Moderna: Considering The Cancer Vaccine Angle (NASDAQ:MRNA)

Topline Summary

Moderna (NASDAQ:MRNA) is obviously best known as a vaccine company, with much of its success in recent years owed to their COVID-19 vaccines. Of course, this isn’t the only story they’re working on, and arguably one of the more fascinating and exciting projects they have in the works relates to their oncology program, in particular the recent news they’ve divulged regarding vaccine-based treatment of head and neck cancer.

Caveat – This Article on MRNA is not a Comprehensive Investment Thesis

In this article, I want to drill down more specifically on their cancer programs, offer what insights are available, as well as how the data we’ve seen so far stack up against the standard of care. Analyzing the science is more my wheelhouse, rather than considering the fundamentals and their many non-oncology platforms. For those kinds of analyses, I invite and encourage you to check out the recent articles from Edmund Ingham and The Value Portfolio.

Edmund gave his thoughts more related to the viral vaccines, and what is needed financially for MRNA to make sense as an investment thesis. The Value Portfolio offers an optimistic take on the near-term potential for MRNA. For balance, I would also encourage you to consider the cautious take from late February by Mark Holder, offering a bearish thesis supported by disappointing forecasts and a challenging respiratory virus market.

What I hope to do in this article is provide a clearer picture about the cancer program in particular, and whether I think this project has legs. For the long term, this has the potential to be a major pillar for MRNA, but there are historical challenges to overcome here, and a lot of hype that can build prematurely. Let’s take a look.

Getting a Sense of Moderna’s Oncology Pipeline

MRNA has a pretty wide range of therapeutic vaccines in development for cancer. They have several targets they’re trying to exploit using the mRNA vaccine platform, including KRAS, OX40, and IDO. For our purposes today, I’m going to focus only on the vaccines that have had clinical trial data presented.

mRNA-4157 (personalized neoantigen vaccine)

In oncology, the arguable juggernaut that MRNA is building is mRNA-4157. This is a personalized immunotherapy that relies on the following general procedure:

1. Obtain the patient’s tissue sample (either a biopsy or resection specimen)
2. Perform sequencing to identify “neoantigens” (i.e., mutations that are expected to lead to changes in proteins that are shown to the immune system, but that are unique to the tumor)
3. Incorporate up to 34 of these neoantigens into an mRNA vaccine (which should prime the immune system to recognize this mutational signature that is unique to the tumor)
4. Manufacture the vaccine for the patient
5. Administer the vaccine and follow the outcomes

The process takes approximately six weeks, and as you can imagine, the end goal is to generate a bespoke immunotherapeutic that is unique to each cancer case. In the sequencing step of the process, the patient’s normal tissue DNA and RNA are also sequenced to help exclude overlap between tumor and normal tissue.

This is, in fact, the same platform used to develop their SAR-CoV2 vaccine back in 2020, which was highly effective at generating antiviral immune responses against that particular strain of COVID-19. Controversies around the long-term utility of that vaccine notwithstanding, the adaptability of this platform is clear to see, and MRNA hopes that it can be trained against a wide variety of different tumor types.

The first major readout we saw for mRNA-4157 was in the KEYNOTE-942 study at AACR 2023, which randomly assigned patients with advanced, resectable cutaneous melanoma after complete resection to receive either pembrolizumab (one of the standard of care options after surgery) or pembrolizumab plus mRNA-4157.

The combination was well tolerated, with no major increase of concerning toxicities observed in the report (compared with pembrolizumab alone, that is).

Meanwhile, the primary endpoint (recurrence-free survival) was significantly improved for the combination, with 78.6% and 62.2% of patients in the combination and control arms, respectively, having no disease recurrence at 18 months. The Kaplan-Meier analysis demonstrated a ~44% reduction in the relative hazard of recurrence by adding the neoantigen vaccine to pembrolizumab.

For reference, these findings with pembrolizumab alone were consistent with those from KEYNOTE-054 (the study leading to approval of pembrolizumab in this post-surgery setting), which showed a 2-year recurrence-free survival rate of 68.3% for pembrolizumab alone. So it didn’t appear as though pembrolizumab was performing unusually poorly in this study, lending credibility to the early readout of recurrence-free survival.

In another analysis, this benefit appeared to be consistent regardless of whether tumor mutational burden was present. In another analysis presented at ASCO 2023, patients in the combination arm appeared to have a higher rate of elimination of measurable residual disease as assessed by ctDNA positivity (14.4% vs 5.7%), and elimination of this minimal disease corresponded with better recurrence-free survival. This prognostic value of ctDNA was further characterized by a presentation from Jeff Weber as ESMO 2023.

Also at ASCO 2023, the authors presented positive findings on a key secondary endpoint: prevention of metastatic disease. This also appeared to be favored in the combination arm, with 91.8% of patients “distant metastasis-free” at 18 months, compared with 76.8% in the pembrolizumab alone arm.

mRNA-4157 plus pembrolizumab (in high-risk, resected melanoma) currently has Breakthrough Therapy designation with the US FDA, and PRIME designation in the EMA, opening avenues for accelerated approvals as the data continue to mature.

MRNA is also pushing the nascent frontiers further into other tumor areas. At SITC 2023, a veritable who’s-who of authors across many tumor types (including melanoma, lung cancer, prostate cancer, and others) presented a poster highlighting T-cell responses observed when using mRNA-4157 either alone or in combination with pembrolizumab. A few patients with non-small cell lung cancer continue to be followed, suggesting possible activity there.

But the most recent update for mRNA-4157 came at AACR 2024, where Dr. Bauman, et al presented a poster highlighting early findings for the vaccine plus pembrolizumab in patients with unresectable, HPV-negative head and neck carcinoma. 22 patients were included in the analysis, of whom five had available patient samples that could be analyzed longitudinally to confirm that immune responses to the neoantigens were occurring and appeared to be sustained.

In all, six of the 22 patients (27.3%) achieved an objective response, with 14 (63.6%) achieving some level of disease control. These findings justify further exploration of the neoantigen vaccine in the head and neck space, a treatment setting of serious unmet need.

mRNA-2752 (targeting OX40)

2752 is actually one of the first of these programs we heard rumblings about, from back in November 2021 at SITC. In 2022, a poster highlighting the preliminary clinical findings for intratumoral delivery of this vaccine was presented at the SITC meeting. This report showed preliminary evidence of tumor shrinkage with mRNA-2752 in combination with intravenous durvalumab (Imfinzi) for patients with melanoma or triple-negative breast cancer.

At AACR 2024, Ryan Sullivan presented an oral presentation highlighting further developments in this study. In total, 33% of patients achieved disease control with this combination, with five of 88 patients having a confirmed objective response to treatment. Analysis of peripheral cytokines was consistent with immune responses expected with mRNA-2752 treatment, and T cell recruitment into the tumor microenvironment was also encouraging.

Strengths and Risks

The most obvious limitation of this analysis, no matter how rosy it may seem, is that there is so much to consider with respect to a multifocal company like MRNA. When you’re sitting at an almost $43 billion market cap, even successful development of these cancer programs could fail to move the needle if other areas of the business underperform. So you need to take on a more holistic view of the company, which I feel one article is not going to be able to convey in a succinct format.

Moreover, I want to emphasize that this is not the first major attempt at a neoantigen vaccine approach in cancer. Many companies have tried, and so far, none have even really gotten close. Arguably, the recent approval of Lifileucel for melanoma was an arguable step toward neoantigen therapy (in a sense), but we’ve seen a lot of failures over the years. MRNA has highlighted in its presentations at scientific conferences that this platform is, in fact, the first neoantigen-based approach to demonstrate efficacy, which is very exciting.

But there’s still more work to do (and risk to take on) before we see anything materialize into a full-fledged product. For starters, the field of melanoma is starting to move past using pembrolizumab alone after surgery. Most notably, if you consider findings from the SWOG S1801 study from last year, it is now known that giving some pembrolizumab before surgery is better than giving all of it after surgery (for those who care: 3 cycles before and 15 cycles after had better event-free survival than 18 cycles after surgery).

SWOG S1801 was a phase 2 trial, and it has not really led to formal shifts in the treatment landscape (“neoadjuvant” pembrolizumab is not currently approved by the FDA), but key opinion leaders are definitely considering it among the options, and neoadjuvant therapy has also made its way into the NCCN guidelines.

This is a critical consideration for the neoadjuvant vaccine, which relies on getting the tumor sample before beginning any therapy. You could imagine that if mRNA-4157 doesn’t really look convincingly better than giving off-the-shelf neoadjuvant immune checkpoint inhibitors, then many doctors won’t bother pursuing that costly, time-intensive approach (recall that the process takes around six weeks to manufacture).

However, even if the neoantigen vaccine does not trigger a change in the standard of care for melanoma, in particular, having the proof of concept means it’s more worthwhile exploring in other tumor spaces that have greater unmet needs. That kind of clinical validation would make it easier to start up bigger studies in other tumor types.

Bottom-Line Summary

It’s easy to lose sight of the oncology program that MRNA is building at this time, buried under the infectious disease platforms. However, if you’re a prospective investor in this company, I think it’s worth seriously considering the oncology platform, given that this is the first clear demonstration of clinical activity for a neoantigen-based immunotherapy, despite decades of (failed) efforts using many different vehicles.

I would not say that the oncology platform alone makes MRNA a clear buy. As I stated above, this analysis was limited to providing details of just this platform, and not the continued viability of their infectious disease programs and ongoing financial challenges. For that, you have plenty of other reading material on Seeking Alpha, and I hope that this writeup has provided one key piece of the puzzle for you.