Safety and Efficacy of Immune Checkpoint Inhibitors Monotherapy in Patients Over 85 Years Old – ICIPO-85 Study

Technical Summary: Safety and Efficacy of Immune Checkpoint Inhibitors Monotherapy in Patients Over 85 Years Old (ICIPO-85 Study)

Problem Statement
The global population aged 85 years and older ("oldest-old") is projected to triple by 2050, leading to a proportional surge in solid tumor diagnoses. While Immune Checkpoint Inhibitors (ICIs) have become a standard of care for various malignancies, clinical evidence regarding their safety and efficacy in this specific demographic is scarce. Most geriatric oncology studies and randomized clinical trials predominantly include patients under 65 or 75 years of age, leaving a significant data gap for those over 85. Furthermore, age-related physiological changes, such as immunosenescence, raise questions about whether the antitumor immune response and toxicity profiles of ICIs differ in the oldest-old. Consequently, clinicians often lack evidence-based guidance for treating this vulnerable population, leading to potential underutilization of effective therapies or inappropriate exclusion based solely on chronological age.

Methodology
The ICIPO-85 study is a multicenter, retrospective, observational study conducted between 2015 and 2023 at two tertiary centers in France: Hospices Civils de Lyon (HCL) and the University Hospital of Saint-Étienne (CHUSE).

• Cohort: The study included 114 patients aged ≥85 years (median age 88, range 85–101) with locally advanced or metastatic solid tumors who initiated ICI monotherapy.
• Inclusion Criteria: Patients received at least one injection of an approved ICI (atezolizumab, avelumab, cemiplimab, durvalumab, ipilimumab, pembrolizumab, or nivolumab) as monotherapy. Combination therapies were excluded.
• Data Collection: Researchers collected socio-demographic data, geriatric variables (G8 score, MMSE, ADL/IADL, nutritional status), oncologic history, and treatment details.
• Endpoints:
  • Primary: Safety, defined by the incidence, type, and severity of immune-related adverse events (irAEs) graded according to CTCAE v5.0.
  • Secondary: Overall Survival (OS), Overall Response Rate (ORR) based on RECIST 1.1, and identification of prognostic factors via univariate and multivariate Cox proportional hazard models.
• Statistical Analysis: Survival probabilities were estimated using the Kaplan-Meier method. Multivariate analyses adjusted for covariates including tumor type, polypharmacy, albumin levels, and performance status.

Key Results

• Patient Characteristics: The cohort consisted of 62% males. Primary tumor types were melanoma (40%), non-small cell lung cancer (NSCLC) (27%), and other solid tumors (33%). Most patients (85%) had metastatic disease.
• Safety Profile:
  • irAEs occurred in 35 out of 114 patients (30%), totaling 45 events.
  • The most common irAEs were endocrine (hypothyroidism), hepatic (hepatitis), and cutaneous (rashes).
  • Severity was predominantly low-grade: 71% were Grade 1–2, and 29% were Grade 3. No Grade 4 or 5 irAEs were reported.
  • Management involved topical or systemic corticosteroids; one patient required immunosuppressive therapy for myocarditis.
  • There were no deaths attributed to ICI toxicity.
• Efficacy:
  • The Overall Response Rate (ORR) was 31% (9 Complete Responses, 22 Partial Responses).
  • Median Overall Survival (OS) for the entire cohort was 12.0 months.
  • OS varied significantly by tumor type: Melanoma (17.8 months), Other solid tumors (14.4 months), and NSCLC (3.3 months).
• Prognostic Factors:
  • Multivariate analysis identified NSCLC (HR 2.29) and polypharmacy (≥3 daily medications, HR 2.08) as independent factors associated with poorer OS.
  • Conversely, the occurrence of any grade of irAE was associated with better OS (HR 0.86).
  • Higher albumin levels (>30 g/L) were associated with better survival in univariate analysis.

Key Contributions
This study represents, to the authors' knowledge, the first real-world analysis exclusively focused on patients aged 85 years and older treated with ICI monotherapy across multiple tumor types.

1. Safety Validation: It provides evidence that the oldest-old population can tolerate ICI monotherapy with an acceptable safety profile, showing no signal of increased severe toxicity (Grade ≥4) compared to younger populations.
2. Efficacy Data: It establishes baseline efficacy metrics (ORR and OS) for this specific age group, demonstrating that response rates are consistent with reports from younger populations, though survival varies by tumor histology.
3. Geriatric Insights: The study highlights the impact of polypharmacy and tumor type on survival, suggesting that biological age and comorbidity burden are more predictive of outcomes than chronological age alone.

Significance and Claims
The authors conclude that chronological age alone should not be considered a barrier to initiating ICI monotherapy in carefully selected patients over 85 years old. The study suggests that the "oldest-old" can derive clinical benefit from ICIs with a manageable toxicity profile.

However, the paper maintains a modest tone regarding its claims:

• It acknowledges limitations inherent to retrospective designs, such as potential underreporting of irAEs and the heterogeneity of tumor types which limits tumor-specific statistical power.
• It notes that the poor OS observed in the NSCLC subgroup likely reflects the profound clinical vulnerability of this specific age group rather than a failure of the drug itself.
• The authors explicitly state that while their findings are encouraging, they "suggest—but cannot establish" that age should not preclude treatment.
• They emphasize the need for prospective studies specifically designed for the oldest-old population, incorporating formal geriatric assessments and tumor-specific stratification, to validate these observations and refine patient selection criteria.