Improving Everolimus Safety in Oncology: Missed Opportunities in Risk Minimization

Despite two decades of clinical experience with Everolimus in transplant medicine, cancer patients continue to face preventable toxicities and fatal adverse events. While transplant patients benefit from twice-daily dosing and therapeutic drug monitoring, oncologists prescribe Afinitor using a fixed once-daily regimen without blood concentration monitoring.

By Carine Cohen

PhD, Pharmacoepidemiologist 

This discrepancy has resulted in thousands of reported deaths in the US alone. By adopting proven risk minimization strategies from transplantation practice—including dose individualization through the more flexible Zortress/Certican formulation—we could significantly improve both the safety and efficacy of Everolimus in oncology.

The Core Problem: Preventable Toxicity in Cancer Patients

The literature consistently demonstrates that progressive treatment initiation prevents adverse events and subsequent treatment interruptions.^1,2,3,4,5 Yet, fatal adverse events continue to affect several percent of patients receiving Afinitor,⁶ with above five thousand deaths reported in the US FDA database, compared to 143 with the safer Zortress/Certican presentation.⁷ While Novartis attributes Afinitor toxicity to lack of physical exercise,⁸ the evidence points to a more fundamental issue: inadequate dosing strategies and the absence of two critical risk minimization measures that have protected transplant patients for over 20 years.

Twice-Daily Dosing: A Proven Strategy to Minimize Toxicity

The pharmacokinetic rationale for twice-daily dosing is compelling. Expert analysis shows that cancer patients could benefit from the same twice-daily schedule used in transplantation, achieving equivalent drug exposure with approximately 25% lower total daily doses.⁹ This regimen limits the peak blood concentrations that drive adverse events, while preventing the troughs that compromise efficacy.^10,11 This optimal approach directly addresses a primary cause of cancer treatment failure: adverse events triggering interruptions that accelerate resistance development and progression to potentially less effective therapies.¹² 

The Critical Role of Therapeutic Drug Monitoring

Everolimus metabolism exhibits high interindividual genetic variability and can change during treatment.¹³ The relationship between blood concentrations and adverse reactions is linear,^14,15 while the efficacy plateau may start around 10 ng/ml.^16,17,18,19 In transplantation, Novartis mandates close blood concentration monitoring, for safety purposes.²⁰ With a safety threshold around 12 ng/ml (twice-daily dosing), in France, this test costs €20.71 and has been reimbursed since 2006 for all indications. The absence of such monitoring in oncology represents a missed opportunity for personalized dosing that could prevent toxicity to maintain efficacy.²¹

The Zortress/Certican Solution: Flexibility for Individualization 

The current Afinitor formulation (2.5, 5, or 10 mg tablets) lacks the flexibility needed for dose individualization. In contrast, Zortress/Certican tablets (0.25, 0.5, and 1 mg) enable precise adjustments for twice-daily schedules and individual patient needs. Paradoxically, the per-mg cost of Everolimus is lower with Zortress/Certican due to competition in the transplant market. Despite identical pharmacokinetics (same half-life as per labels, and EMA assessments)²² Novartis pretends that these formulations are “not bioequivalent”.²³ Contradicting international regulatory standards,²⁴ this artificial distinction is used since the past two decades to prevent oncologists from accessing a safer schedule, via a more flexible formulation, and safety-driven therapeutic drug monitoring. 

Practical Implementation Strategy 

Besides of a different dosage and, subsequently, no “bioequivalence”, the US label supports switching from Afinitor Disperz (2 mg liquid formulation) to Afinitor (2.5 mg tablets). Hence, for patients currently receiving Afinitor 10 mg or 5 mg daily, the transition process to Certican/Zortress is also straightforward:

1. Measure trough blood concentration before the next dose
2. Split the daily dose into twice-daily administration
3. Repeat measurement after five days
4. Switch to equivalent Zortress/Certican dosing
5. Confirm bioequivalence with repeat measurement after five days
6. Implement appropriate dose reductions, and repeat measurements weekly or every other week

The twice-daily schedule automatically increases trough concentrations by approximately 25% (measured at 11 hours versus 23 hours post-dose), allowing for appropriate dose reductions to preserve safety (and efficacy).²⁵

Additional Safety Measures

Beyond dosing optimization, several precautionary measures can further enhance patient safety:

• Patient education on oxygen saturation monitoring for early pneumonitis detection
• Patient education on regular blood pressure monitoring
• Comprehensive vaccination status review and updates, including influenza, COVID-19, zoster, pertussis, pneumococcal vaccines, and possibly meningococcal vaccines and bronchiolitis²⁶ 

Regulatory and Ethical Considerations 

The systematic exclusion of cancer patients from proven safety measures raises serious ethical questions. Oncologists should consider reporting retrospectively all deaths attributed to Afinitor toxicity, which may have been under-reported due to clinical workload constraints, focusing on their recall for recent years (2024-25).

Conclusion

The evidence overwhelmingly supports adopting transplantation's risk minimization strategies for Everolimus use in oncology. Facilitated by the flexible Zortress/Certican formulation, twice-daily dosing, with safety-driven therapeutic drug monitoring, could prevent thousands of adverse events and deaths while maintaining or even improving efficacy. After 20 years of unnecessary patient harm, it's time to bridge this gap between specialties and provide cancer patients with the same standard of care long established in transplantation.
The question is not whether these measures work—transplant medicine has proven they do. The question is why we continue to deny cancer patients access to these life-saving strategies.

Disclaimer: This article represents the independent analysis of the author and does not reflect the views of the publisher.

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About Author: Carine Cohen, PhD

Carine has 20+ years of experience in big pharma’s. Here, she speaks as a patient, with early Breast Cancer. After an initial response, her prognosis got compromised by disease progression in her lymph node. Indeed, Ribolaris trial aims to replicate at large-scale this acquired resistance phenomenon (escape in the Ki67) triggered by neoadjuvant Ribociclib, impacting 67-73% of the patients in FELINE (Griffiths et al.) and Coralleen trials. Since August 2023, she is struggling with no success to engage with Novartis, asking for their 5-year overall survival data from FELINE trial, hoping to inform and rescue the other victims. In her relentless quest for rescue treatments, she came across another Novartis saga, impairing the safety and ethics of Everolimus, another cancer drug.