PD-1 inhibitors face scrutiny in esophageal cancer: Key takeaways for drug developers

This blog is part of The Regulatory Navigator series, where we explore the evolving regulatory landscape with actionable insight from Parexel's experts, sharing their experience to maximize success for clinical development and patient access.

An FDA advisory committee recommended against using PD-1 inhibitors as first-line treatment for patients with esophageal squamous cell carcinoma (ESCC) who have low or negative PD-L1 expression, during a meeting on September 26th, 2024.¹  

Key takeaways include: 

• The Oncologic Drugs Advisory Committee (ODAC) voted 11-1 that the risk-benefit profile was not favorable for PD-1 inhibitors in ESCC patients with PD-L1 expression <1%. 
• FDA analysis of three pivotal trials (KEYNOTE-590, CHECKMATE-648, RATIONALE-306) showed little to no benefit for PD-1 inhibitors in patients with PD-L1 <1%. 
• Most treatment benefit was seen in patients with PD-L1 ≥1%, with increasing benefit at higher PD-L1 levels. 
• This recommendation could impact the labeling of approved drugs like pembrolizumab (Keytruda) and nivolumab (Opdivo), as well as tislelizumab which is currently under FDA review. 

Highlighting the importance of robust biomarker strategies, early in clinical development 

PD-L1 expression has emerged as a key predictive biomarker for PD-1/PD-L1 inhibitors across multiple tumor types, and drug developers should prioritize its integration into their research plans. Future clinical trials should consider enriching for PD-L1 positive patients, with power calculations accounting for potential differences in treatment effects across biomarker subgroups. This approach could lead to more efficient and targeted studies. 

The variability in PD-L1 testing methods and cutoffs across different drug programs highlights the need for standardized, validated companion diagnostic assays. From an FDA perspective, immunotherapy developers should be prepared to present detailed subgroup analyses by biomarker status to regulatory agencies. The FDA is increasingly focused on optimizing the benefit-risk profile for specific patient populations, and this granular data will be crucial in discussions with the agency. 

Importantly, even if a drug shows overall efficacy in an unselected population, the FDA will, in the future, push for biomarker-restricted labeling if subgroup analyses suggest limited benefit in certain patients.  

This represents a clear policy shift from the FDA, moving away from broader approvals towards more targeted indications based on biomarker status. Drug developers should anticipate this trend and plan their clinical development and regulatory strategies accordingly, focusing on identifying and validating predictive biomarkers that can guide patient selection and optimize treatment outcomes. 

Implications for immunotherapy stakeholders  

• Precision medicine: This decision reinforces the shift towards more precise patient selection in immunotherapy. The era of "one-size-fits-all" approaches is ending, even for broadly active drugs like PD-1 inhibitors. 
• Novel biomarkers: While PD-L1 has proven useful, additional predictive biomarkers are needed. Sponsors should invest in biomarker discovery efforts to identify novel predictors of response or resistance to immunotherapy. 
• Real-world evidence: As labels potentially become more restrictive, real-world evidence may play an important role in understanding outcomes in broader patient populations. Sponsors should consider incorporating real-world data collection through integrated evidence planning.  
• Patient access: More restrictive labeling could limit treatment options for some patients. Developers should be prepared to engage with payers and healthcare systems to ensure appropriate access for eligible patients. 
• Future trial designs: Adaptive trial designs that allow for biomarker-based enrichment or expansion are encouraged, enabling more efficient drug evaluation in biomarker-defined populations. 

Conclusion 

The scrutiny of PD-1 inhibitors in ESCC patients with low PD-L1 expression is part of a broader trend toward more precise use of immunotherapies. Drug developers should anticipate similar analyses across other tumor types and immunotherapy classes in this evolving landscape, and take action: 

• Invest heavily in biomarker discovery and validation 
• Design trials with pre-specified analyses of biomarker-defined subgroups 
• Consider adaptive trial designs that can adjust to emerging biomarker data 
• Develop clear regulatory strategies for biomarker-driven approvals 
• Plan for the development and validation of companion diagnostics 

While this decision may limit the use of PD-1 inhibitors in some ESCC patients, it ultimately aims to optimize patient outcomes by focusing these powerful drugs on those most likely to benefit. By embracing a precision medicine approach, drug developers can create more targeted, effective therapies that stand up to increasing regulatory scrutiny. Additionally, there is the potential increased justification for payers to reimburse the therapy costs in a precisely defined population that would realize greater benefit.  

As a leading global Phase I-IV clinical research organization, Parexel leverages our breadth of regulatory, clinical trial, and therapeutic expertise to optimize clinical development programs. Our team of ex-regulators can help you navigate the requirements of the major regulatory agencies, including an assessment of this new FDA recommendation and its implications for your immunotherapy development program. Please contact us, we are always available for a conversation.  

References: 

U.S Food & Drug Administration (2024, September 26). Oncologic Drugs Advisory Committee (ODAC) meeting: September 26, 2024: Meeting of the Oncologic Drugs Advisory Committee Meeting Announcement - 09/26/2024 | FDA 
[accessed September 26, 2024] 

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