Definitions: Minimal or molecular residual disease (MRD) and “monitoring” as referenced in this blog include the assessment of ctDNA levels or ctDNA load to determine prognosis, serially monitor response to treatment, or serially monitor for molecular signatures of relapse and recurrence.

Introduction

2020 and 2021 have proven to be incredibly exciting and pivotal times for ctDNA MRD and monitoring: multiple companies noted intentions to enter the MRD / monitoring space, existing competitors reached key commercial milestones including new product launches and reimbursement, and the clinical evidence surrounding the utility of MRD / monitoring continued to grow across cancers. It is becoming evident that MRD and ctDNA monitoring will be an integral part of patient care, and that NGS will be the technology of choice.

See the timeline below for select key events and milestones in the MRD and monitoring space, color-coded by competitor and structured by event type.

Figure 1: Timeline of Select Events – MRD & ctDNA-based Monitoring

Activity in the MRD / monitoring space expected to accelerate

Looking forward, we expect that activity in the MRD / monitoring space will continue to accelerate, due to a combination of factors:

1. High revenue potential, given serial testing (e.g., treatment response monitoring, recurrence monitoring) and multiple use cases across the patient journey
2. Initial study data and Natera’s Local Coverage Decision / draft LCD de-risking investment in a still relatively new and unproven technology
3. Biopharma interest in stratifying high-risk patients and monitoring response, including potential to demonstrate improved drug efficacy by stratifying patients (e.g., Genentech’s IMvigor bladder cancer trial)
4. Increasing attractiveness in a “one-stop-shop” or end-to-end play in oncology diagnostics (i.e., offerings across early detection, therapy selection, MRD, monitoring)

Competitors – Pioneers have paved the way for a wave of fast followers, with most companies taking a tumor-informed approach

Since Natera Signatera first launched in 2017, 10+ companies have at minimum expressed intentions to enter the space. Most products are still in development and in the coming years, we expect this place to become competitive and crowded like the comprehensive genomic profiling (CGP) space. In addition to these key players, many additional start-ups and early cancer diagnostics / oncology diagnostics companies are evaluating the space.

However, unlike the CGP space, in MRD, technology and approach (e.g., tumor-informed vs. tumor-naïve, panel size) may be highly differentiating for use cases that require superior sensitivity. While most competitors are betting on tumor-informed assays to achieve this required sensitivity, it is still too early to tell which approach will “win out”. Tumor-informed and tumor-naïve approaches each have benefits and drawbacks and preference likely will be defined by the unique needs of each indication and MRD / monitoring use case.

Figure 2: MRD Approaches – Key Differentiators and Competitors

Note: For products in development, competitors are categorized based on our best estimates. The MRD space is dynamic and we may have missed your company. If you would like to see your company or another company added to this list, please let us know and we will update this table

Cancer Types – MRD companies steadily expanding beyond key battlegrounds of early stage colorectal and NSCLC; Natera covers the most cancers with proof-of-concept data while competitors remain more focused in scope

So far, MRD and monitoring activity have largely been concentrated in a few key cancers – primarily colorectal (being the main cancer type for MRD adoption in the clinic, driven by Natera and Guardant), secondarily lung (driven by Invitae/Archer and Inivata), followed by growing activity in breast and bladder. With the commercial launch of both Natera Signatera and Guardant Reveal in the past year, we’ve seen the first gradual growth of MRD adoption in the clinic and expect this to greatly accelerate in the coming years as (1) reimbursement becomes better established, (2) ongoing trials provide further validation for these technologies, and (3) the utility of MRD is proven in a larger number of cancer types and use cases.

Additionally, as the pioneer for the MRD space, Natera has taken a very broad approach to generating proof of concept data across cancer types, including renal cell carcinoma, pancreatic cancer, gastroesophageal cancer, hepatocellular carcinoma, melanoma, ovarian cancer, and multiple myeloma. Although many of these studies are small and retrospectively conducted, and thus generally not sufficient to drive clinicians to adopt, such data can be particularly attractive to biopharma stakeholders who are evaluating the addition of MRD in clinical trials and de-risks a technology that is still relatively unproven.

Figure 3: Key Competitors by Select Cancer Type and MRD and ctDNA Monitoring Use Case

Note: Competitors are categorized based on our best estimates and publicly announced studies and results. The MRD space is dynamic and this table is not comprehensive. Please feel free to provide feedback so we can update this table

Use Cases – primarily early stage settings, with growing activity in late stage monitoring

Adjuvant therapy selection has clear potential actionability for clinicians and provides greater potential for biopharma partnerships as targeted and I/O therapies attempt to move into early-stage settings. Additionally, though the adjuvant stratification use case itself is a relatively small, single-timepoint opportunity, the ability to serial monitoring and surveillance downstream can lock-in a much more sizeable opportunity for a company, assuming that a patient is likely to use the same assay across the MRD and monitoring timeframe.

Surveillance for molecular relapse or recurrence is also perceived to be a highly attractive use case that is well aligned with the strengths of ctDNA-based testing overall – sensitivity and the potential for non-invasive serial testing. From a commercial standpoint, this is also expected to be the largest opportunity due to serial testing over a number of years on a relatively large patient population (a significant portion of the often quoted $15B U.S. TAM opportunity is expected to be attributed to this use case). However, the ability to realize such an opportunity will depend on proof of actionability and utility (i.e., does rising ctDNA levels mean a patient can and should be treated before recurrence is detected radiographically?).

Finally, late-stage monitoring of response to therapy is another growing use case, particularly with the launch of new assays from the 2 biggest late-stage NGS vendors – FoundationOne Tracker and Guardant360 Response. Clinically, a more sensitive approach to informing when alternative treatments should be considered is enticing, particularly in indications such as lung where multiple therapeutic options are available. For payors, monitoring response to I/O in particular is expected to be compelling from a cost-benefit standpoint. However this is still early days, and similar to the surveillance use case, actionability and utility will have to be demonstrated.

Conclusion

Overall, the MRD / monitoring space is still in the relatively early stages of research, development, and clinical adoption today. It still has much to prove as a novel diagnostic modality. However, significant runway remains, with the potential to be incredibly impactful in the fine-tuning of oncology patient care. We at DeciBio (and I, personally) will continue to track this dynamic space closely and are excited to see developments in this exciting field poised to positively affect patient outcome.

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