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"Guide Adjuvant Chemotherapy Decisions with Confidence"

For decades, the standard of care for resected stage I NSCLC,

and in particular stage IA, has been watchful waiting. That standard was built on three assumptions:

1) that a TNM stage I designation reliably identifies low-risk patients,

2) that stage I patients, and particularly stage IA patients, do not benefit from adjuvant chemotherapy, and

3) that chemotherapy can potentially harm stage I NSCLC patients.

These assumptions have been rendered obsolete by over a decade of retrospective, prospective, and now randomized clinical trial data.

You can now reliably identify the stage I patients who will benefit from chemotherapy, avoiding recurrence, and saving more lives.

MYTH VS. REALITY

The 1st Myth vs. The Reality

MYTH 1

TNM staging reliably identifies low-risk patients.

REALITY

35-40% of stage I patients as defined by TNM suffer a recurrence.

What Changed: NCCN Guidelines and the Missing Tool

Since 2004, NCCN guidelines have suggested that medical oncologists consider adjuvant chemotherapy for high-risk, very early-stage NSCLC patients. That guidance reflected a recognition that TNM staging lumps together in each of stages I-IIA patients who were cured in the operating room with a large proportion of patients who, based on their eventual recurrences, must have harbored occult, undetectable metastasis at the time of resection. But this guideline has also been very difficult to implement, particularly because the high mortality extends all the way to stage IA, which should be the lowest risk patients. Stage IB, by definition, is higher risk than all of stage IA, and since older studies failed to document a benefit from adjuvant therapy when all of unsegregated stage IB was treated, NCCN urged clinicians instead to try to home in on a subpopulation of “high-risk” stage IB patients, but offered only conventional criteria that had no prognostic or predictive validation. This approach failed entirely to address the unacceptable mortality even in stage IA. A tool was needed to implement the imperative to identify and treat truly high-risk patients in stage I NSCLC – clearly reflected in, but poorly supported by, NCCN guidelines.

RiskReveal is that tool.

Multiple high-quality studies published in leading journals such as The Lancet and JAMA, involving over 1,700 patients dating back to 2012, 2013, 2018, and 2021, have shown that 14-gene expression profiling applied to resected tumor tissue, (i.e., RiskReveal®), accurately stratifies all early-stage NSCLC patients into molecular risk categories that are independent of TNM stage and independent of EGFR mutation status.

MYTH VS. REALITY

The 2nd Myth vs. The Reality

MYTH 2

Stage I patients do not benefit from chemotherapy.

REALITY

Extensively validated risk stratification is available that identifies the subpopulation of conventional stage I-IIA non-squamous NSCLC patients who benefit substantially from adjuvant chemotherapy, now verified by randomized predictive evidence.

High-Risk Patients Benefit From and Deserve Treatment

As NCCN guidelines have reflected for over 20 years, patients at high risk of recurrence deserve potentially life-saving intervention. Although the 14-gene assay has been available for effective, highly validated risk stratification since 2012, a lingering concern remained that the patients effectively identified by this assay as high-risk stage I-IIA might be resistant to the benefit of adjuvant therapy seen in later stages of NSCLC. These concerns stemmed from the results of seminal, now outdated studies of adjuvant therapy for NSCLC, which did not demonstrate a benefit for unsegregated stage I-IIA patients and even raised concern for potential, although also not firmly established, harm. The documentation of benefit from simple adjuvant therapy for these 14-gene molecular high-risk patients was obtained and published in a progressive, stepwise fashion. First, results of a preliminary, non-randomized single center study of 250 patients published in 2018 and 2021 suggested that 14-gene molecular high-risk, stage IA-IIA patients were not unusually resistant to adjuvant chemotherapy, and that they might benefit even more from adjuvant therapy than stage IIB-III patients due to their very low, often microscopic burden of disease.

Built upon the overwhelming benefit observed in this single center, non-randomized study (>80% reduction in recurrence risk with adjuvant therapy for molecular high-risk patients), a multicenter, international, prospective randomized study, the AIM-HIGH Trial, was designed and executed. Since the ability of the 14-gene assay to prognostically segment high- and low-risk patients in stage IA-IIA had already been definitively demonstrated, the singular imperative, overarching goal of the AIM-HIGH study was simply to provide randomized predictive confirmation that these molecular high-risk patients would not resist the treatment benefit expected from adjuvant intervention.

Given the ongoing and substantial loss of life to “very early stage” NSCLC, the AIM-HIGH Trial was specifically designed to provide definitive evidence of benefit to this group of patients at the earliest possible time point, so that lingering concern regarding complete resistance to benefit would no longer result in the potentially preventable deaths of thousands in the US and tens of thousands worldwide that has been occurring on an annual basis.

The AIM-HIGH Phase 3 Randomized Trial

Published in The Lancet Respiratory Medicine, 2025
The multicenter, international, prospective, randomized AIM-HIGH trial addressed the limitations of the preliminary studies by enrolling and randomizing patients across 45 sites in the US and Europe. 14-gene molecular high-risk stage IA–IIA non-squamous NSCLC patients were randomized to adjuvant platinum-doublet chemotherapy (4 cycles) or resection alone. The primary endpoint was Disease Free Survival (DFS). A prespecified interim analysis was designed specifically to achieve the study’s critical objective: definitive randomized confirmation that these patients were not for some reason resistant to the benefit of adjuvant therapy.

Key Outcomes

Population Untreated (DFS) Treated (DFS) Risk Reduction
High-risk stage IA-IIA
79%
96%
78% (HR 0.22)
High-risk IA only
78%
98%
85% (HR 0.15)

This confirmation dispels any lingering questions regarding the imperative to treat these stage IA-IIA patients, who can now be scientifically identified as high-risk and in need of an available, effective intervention. While the exact magnitude of the benefit and other scientifically interesting aspects of this treatment will be further addressed in several years by the final analysis of the study, which continues to collect longer-term data, the randomized confirmation of a profound 24-month improvement in DFS, almost identical to that demonstrated in the preliminary, non-randomized studies, now removes any justification for delaying application of this potentially life-saving strategy to the tens of thousands of American patients who will otherwise die of stage IA-IIA NSCLC while those longer-term data are being collected, as the relative shortcomings of the interim analysis could not reasonably explain away all of the profound benefit that was observed.

CLINICAL APPLICATION

What the Randomized Data Clarified

Relation to EGFR Status

In the AIM-HIGH study, molecular risk was independent of EGFR mutation status. High-risk patients benefited from adjuvant chemotherapy regardless of EGFR status, an important consideration for patients for whom targeted therapy is not an option or has failed.

Timing

The benefit of adjuvant therapy has long been understood to depend on timely intervention after resection. In the AIM-HIGH study, post-hoc analysis indicated that all recurrences in the treated high-risk group occurred when chemotherapy was initiated more than 3.5 months after histological diagnosis of NSCLC (p=0.042). RiskReveal results are guaranteed within 10 business days — and often within 2-3 — placing the decision squarely within the actionable treatment window.

The idea that stage IA-IIA patients cannot benefit from adjuvant therapy has now been contradicted in multiple published prospective studies and is outdated.

The data from 20-year-old seminal studies in non-risk-stratified stage IA-IIA patients that suggested that these patients do not benefit from the adjuvant therapy that is well-documented to benefit stage IIB-III patients have been rendered obsolete by the ability of RiskReveal to segregate stage IA-IIA patients who were likely cured in the operating room from those more likely to harbor occult disease and who therefore stand to benefit from intervention, just as do patients in stages IIB-III.

RiskReveal is the scientific implementation of what NCCN has been recommending since 2004. With the recent advent of randomized confirmation of the substantial benefit derived by molecular high-risk patients from adjuvant chemotherapy, molecular risk stratification now allows you to act on that guidance with full confidence.

MYTH VS. REALITY

The 3rd Myth vs. The Reality

MYTH 3

Chemotherapy is harmful to stage I patients.

REALITY

Chemotherapy is well-tolerated in segregated high-risk stage I patients.

Addressing the Stage IA Hesitation

A historically held view, reinforced by older meta-analyses from 2004–2008, suggested that stage IA patients derived no benefit from adjuvant chemotherapy and may even be harmed. Again, those data are now obsolete.

74%
Completed all 4 cycles of adjuvant chemotherapy.
87%

Completed ≥3 cycles of adjuvant chemotherapy.

1%

Chemotherapy-related mortality, consistent with established platinum-doublet safety profiles.

There were a total of 6 deaths across both arms. In the chemotherapy group (n=2), there was 1 chemotherapy-related death and 1 death from disease recurrence. In the untreated group (n=4), there were 3 deaths from disease recurrence and 1 death from myocardial infarction.

The avoidance of adjuvant chemotherapy in stage IA has stemmed entirely from relatively small study populations in which accurate risk stratification of stage I patients was not available. The studies treated all stage IA patients as a homogeneous group, mixing patients who were cured surgically with a large proportion of patients harboring occult micrometastasis. Even conventional TNM staging suffered in those early studies from the unavailability of modern staging methods such as PET scanning, further limiting the benefit that might have otherwise been observed in better-staged populations. The result was a diluted, inconclusive signal that obscured the benefit for the subgroup who needed treatment most.

AIM-HIGH, along with preliminary prospective clinical studies from 2018 and 2021, demonstrates clearly that molecular high-risk stage IA patients are not resistant to chemotherapy and suggests that the benefit to micrometastasis may be significantly more profound than the treatment of detectable metastasis. When the right patients are identified and treated, the reduction in recurrence risk may be as high as 80%. “Should we treat stage IA patients?” was always the wrong question. The real question is “Which stage IA patients are biologically stage IIB or worse?”

RiskReveal allows you to reliably identify stage I patients who will benefit from adjuvant chemotherapy and allows you to treat them with confidence.

There is now unequivocal evidence to treat molecular high-risk early-stage NSCLC patients. The tool for their identification is strongly validated and available. The data confirming a predictive benefit are randomized, prospective, and published in high-impact journals.  

Treatment reduces the risk of recurrence. In NSCLC, preventing recurrence saves lives.

Each year, approximately 100,000 people diagnosed with stage I-IIA non-squamous NSCLC worldwide are under-staged and under-treated – and die as a result. Each of them and their families deserve access to the best predictive analysis available now, knowing that subsequent treatment is based on strong, current scientific evidence.
CLINICAL RESPONSIBILITY

A Note on Clinical Responsibility

NCCN guidelines have attempted to reconcile the unacceptable outcomes of stage I-IIA NSCLC patients with the hamstringing data from outdated studies that benefit from adjuvant therapy was not observed in this population. Staging is nothing more than a prognostic system. Higher-risk patients, i.e., those in stages IIB-III, were known to benefit from adjuvant intervention. Stage IB is, by definition, higher risk than stage IA. Up until recently, the only available data suggested that at the risk level of unsegregated stage IB, a benefit still had not been observed. NCCN therefore attempted to call out a risk level slightly higher than all stage IB patients, and recommended intervention even in the absence of any predictive data clearly demonstrating a benefit. NCCN has been advocating for 20 years the adjuvant treatment of “high-risk” stage I patients, as best they felt they could try to identify them. RiskReveal now provides an actionable, fully validated decision-support tool that finally enables scientific implementation of the approach reflected in longstanding NCCN guidelines. With Level 1 evidence now available for molecular risk stratification in early-stage NSCLC, the standard of care conversation has shifted.
When a high-risk early-stage patient recurs without having been tested for molecular risk, and without having had the opportunity to receive adjuvant therapy that might have prevented the recurrence, the clinical record will speak for itself.

RiskReveal vs. Blood-Based MRD Testing

Some oncologists are evaluating ctDNA as a post-resection prognostic tool. The evidence base, relative to RiskReveal, warrants direct comparison.
  RiskReveal / AIM-HIGH Clinically Available Blood-Based MRD (ctDNA)
Type of data available
Phase 3, randomized, interventional
Observational, no intervention
Sites per study
45 (US + Europe)
Single center
Number of high-risk stage I patients with outcomes included per study
190
<20
Published
Lancet Respiratory Medicine, 2025
J Thoracic & Cardiovascular Surgery, 2024; J Thoracic Oncology, 2026
Time to actionable assay result
<10 days
2-3 months or greater
Blood-based MRD testing retains clinical utility for post-treatment recurrence surveillance. As a pre-treatment prognostic decision tool for early-stage NSCLC, it fully lacks predictive interventional outcomes data and introduces a delay that is incompatible with the best standard of care adjuvant treatment window.

Ordering & Logistics

Sample Requirements

FFPE tissue block or slides. Razor Genomics provides a shipping kit with preparation and shipping instructions.

Turnaround Time

Results typically available within 10 business days of specimen receipt.

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Physician Portal
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Insurance Coverage & Resources

Insurance & Patient Access

Razor Genomics accepts many forms of insurance. Patients with Medicare have no out-of-pocket cost. For patients with other insurance, Razor Genomics bills directly — coverage depends on the specific plan.
A Patient Assistance Program for qualifying patients.

Questions about insurance or billing:

Billing: 1-844-662-6298 
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