The U.S. Food and Drug Administration’s Oncology Center of Excellence (OCE) launched Project Frontrunner to shift the paradigm in oncology drug development. Traditionally, novel oncology drugs gain approval for use in patients with later-stage disease and who have exhausted other treatment options. Project Frontrunner challenges this model by encouraging sponsors to pursue initial drug approvals in the earliest feasible disease setting, particularly first-line or treatment-naïve populations.

The conventional late-line strategy for oncology drug development offers fewer regulatory hurdles and facilitates faster enrollment. However, it delays access to potentially life-extending or curative therapies for patients with early-stage disease. Moreover, the biology of tumors in heavily pretreated patients often differs significantly from earlier stages, limiting generalizability. Project Frontrunner seeks to reverse this trend, thereby aligning trial design with patient-centric outcomes.

Here, I discuss the key elements of Project Frontrunner, the statistical complexities of first-line trial design, and the potential impact on sponsors.

Key elements of Project Frontrunner

• First-line indication targeting: Encourages drug developers to pursue marketing applications based on trials in treatment-naïve populations, not just refractory or relapsed disease settings.
• Regulatory support and early engagement: The FDA offers early scientific engagement with sponsors through Type B and Type C meetings, helping optimize development plans for first-line indications.
• Use of randomized controlled trials (RCTs): Promotes the use of RCTs in early-stage disease rather than single-arm studies in late-stage patients, aiming for more robust and generalizable evidence.
• Expedited programs compatibility: Supports use of breakthrough therapy designation, priority review, and accelerated approval, even when targeting earlier lines of therapy.

Practical implications for trialists

• Trial design complexity: Sponsors must design larger, more rigorous trials, often needing comparator arms, which may increase cost and duration but improve scientific robustness.
• Patient recruitment considerations: Recruiting treatment-naïve patients can be more competitive and ethically challenging, requiring careful protocol development and site coordination.
• Strategic endpoint selection: Trialists must select endpoints that reflect long-term clinical benefit (e.g., progression-free survival, overall survival), rather than short-term surrogate markers typically used in late-line settings.

Statistical complexities in first-line trial design

Designing oncology trials for first-line indications — as encouraged by Project Frontrunner — brings increased statistical and methodological complexity compared to traditional late-line trials. The rigor demanded by earlier-stage settings requires careful planning to ensure validity, power, and regulatory acceptability.

Randomized comparators and control integrity

Trials typically require active control arms rather than historical controls. Selecting an appropriate standard-of-care comparator and maintaining blinding (where feasible) becomes essential to minimize bias and strengthen inference.

Longer time horizons for endpoints

In first-line disease, progression-free survival (PFS) and overall survival (OS) require longer follow-up, increasing risk of loss to follow-up and requiring more robust methods for censoring and handling missing data.

Multiplicity adjustments and hierarchical testing

With multiple endpoints — such as PFS, OS, objective response rate (ORR), and quality of life — multiplicity becomes a critical issue. Sponsors may need hierarchical testing strategies or gatekeeping procedures to control Type I error.

Interim analysis and adaptive design considerations

Sponsors may wish to incorporate group-sequential designs or adaptive features (e.g., sample size re-estimation), but these add statistical complexity and must be pre-specified with strong rationale to be acceptable to regulators.

Subgroup analyses and biomarker stratification

Treatment-naïve populations may be heterogeneous. Stratification by biomarkers or disease subtype may be necessary, but raises statistical power concerns and increases the risk of false discovery if not pre-specified and adjusted.

Likely impact on sponsors

Project Frontrunner presents both opportunities and challenges for drug developers aiming to target earlier lines of oncology treatment. Below are key advantages and disadvantages for sponsors engaging with this program:

Advantages

• Market leadership and differentiation: Gaining approval for a first-line indication can position a therapy as the standard of care, offering strategic advantage over drugs only approved for late-line use.
• Extended commercial exclusivity: Earlier approval typically translates into longer duration of market exclusivity, enhancing revenue potential before generics or biosimilars enter the market.
• Clinical value and branding: Drugs proven effective in first-line settings may be perceived as more effective and versatile, strengthening the sponsor’s brand and clinical reputation across stakeholders, including physicians and payers.

Disadvantages

• Higher development costs and risk: Trials in earlier-stage patients typically require larger sample sizes, randomized designs, and longer follow-up, increasing overall trial costs and investment risk.
• Increased regulatory scrutiny: Early-line trials are subject to higher evidentiary standards, with greater emphasis on demonstrating long-term clinical benefit (e.g., overall survival), making approval more difficult.
• Competitive recruitment environment: Enrolling treatment-naïve patients is often slower and more competitive, as these patients may have multiple treatment options and may be hesitant to join experimental arms.

Final thoughts

Project Frontrunner represents a bold step by the FDA to reshape oncology drug development. While it demands more rigorous trial designs and greater investment from sponsors, it aligns closely with patient-centric goals: bringing promising therapies to those who need them most, earlier in their disease journey. For sponsors willing to embrace these challenges, the program offers a chance to lead in an increasingly competitive oncology landscape.

James Matcham, VP Strategic Consulting, and Pranav Yajnik, Senior Consultant, will be hosting a Cytel webinar on August 20, 2025, where they will provide an overview of Project Frontrunner and its implications for oncology drug development. They will also explore, using a case study, how innovative trial design strategies can lead to faster, more robust pathways to market for oncology therapies.

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