A large-scale real-world safety analysis has revealed significant differences in adverse event profiles between pembrolizumab combination therapy and chemotherapy alone in lung cancer patients, with the immunotherapy combination showing increased risks of kidney and liver toxicity while extending overall survival benefits.
The comprehensive study analyzed 8,314 lung cancer patients from the FDA Adverse Event Reporting System (FAERS) database between Q2 2017 and Q3 2024, comparing safety profiles of pemetrexed plus platinum chemotherapy alone (2,871 reports) versus the combination with pembrolizumab (5,443 reports). The analysis represents one of the largest real-world safety assessments of this widely-used immunotherapy combination.
Enhanced Nephrotoxicity Risk with Combination Therapy
The study identified a concerning increase in renal and urinary system disorders with pembrolizumab combination therapy compared to chemotherapy alone. Combination therapy significantly elevated the risk of tubulointerstitial nephritis, renal impairment, and renal tubular necrosis, though it did not appear to increase acute kidney injury incidence directly.
"Nephrotoxicity is a challenging and often underestimated safety issue that not only reduces patients' quality of life but also poses a potential negative impact on treatment outcomes," the researchers noted. The findings align with results from the phase 3 KEYNOTE-189 study, which suggested increased nephritis and acute kidney injury risk with combination therapy.
The mechanism behind increased nephrotoxicity involves immune checkpoint inhibitors blocking the PD-1/PD-L1 pathway, which releases cytotoxic T cell inhibition but may trigger autoimmune reactions. PD-L1 expression in renal cells, particularly when upregulated by interferon-gamma, may expose patients to T cell-mediated kidney damage. Additionally, the interaction between pembrolizumab and platinum agents may compound renal toxicity risks.
Respiratory and Hepatic Safety Concerns
Combination therapy also demonstrated increased risks of interstitial lung disease (ILD) and pneumonitis compared to chemotherapy alone. Drug-induced interstitial lung disease, while having a low incidence rate, carries high mortality risk. The study found that PD-1 inhibitors like pembrolizumab pose higher ILD risk than PD-L1 or CTLA-4 inhibitors, with concurrent use of multiple pulmonary toxic drugs potentially increasing DIILD risk.
The analysis revealed significantly elevated hepatobiliary disorder risks with combination therapy, including increased rates of hepatitis and other liver-related adverse events. This finding adds to the growing understanding of immune-related adverse events associated with checkpoint inhibitor therapy.
Gender and Age Disparities in Toxicity Profiles
Subgroup analyses revealed striking gender differences in adverse event susceptibility. Female patients receiving combination therapy showed higher rates of acute kidney injury, tubulointerstitial nephritis, hepatitis, and renal tubular necrosis. This pattern persisted across both treatment regimens for nephrotoxicity, suggesting inherent gender-based susceptibility.
"Renal tubular necrosis is more prevalent in women regardless of chemotherapy alone or combination therapy, suggesting that female patients may be more susceptible to nephrotoxicity," the researchers observed. Cisplatin-induced nephrotoxicity appears more severe in women, possibly due to higher glutathione S-transferase activity and estrogen influence leading to prolonged drug retention.
Conversely, male patients experienced higher rates of life-threatening complications including sepsis, septic shock, and neutropenic sepsis. In the combination therapy group, males showed increased susceptibility to 17 of the 50 most common adverse events.
Age-Related Vulnerability
Elderly patients (≥65 years) demonstrated significantly higher adverse event burdens compared to younger patients (<65 years) across both treatment regimens. The analysis identified four primary factors contributing to this increased vulnerability: age-related decline in hepatic and renal function affecting drug clearance, reduced physiological reserves making organs more susceptible to treatment stress, multiple comorbidities increasing treatment complexity, and immunosenescence affecting immune system interactions with checkpoint inhibitors.
Elderly patients showed particular susceptibility to blood and lymphatic system disorders, renal and urinary disorders, and various immune-related adverse events affecting cardiovascular, pulmonary, and skin systems.
Temporal Patterns and Monitoring Implications
The study revealed important differences in adverse event timing between treatment regimens. Combination therapy extended the median time to adverse event onset from 17 days (chemotherapy alone) to 25 days, with most treatment-related adverse events occurring within three months versus six weeks for chemotherapy alone.
This temporal pattern has significant clinical implications for monitoring protocols. The researchers recommend enhanced surveillance during the initial three months of combination therapy, with specific focus on hematologic adverse events during the first month, respiratory complications in the second month, and renal and urinary adverse events in the third month.
Clinical Practice Implications
Despite increased toxicity risks, the safety profile of pembrolizumab combination therapy remains within acceptable ranges, consistent with clinical trial findings. Common adverse events including anemia, pancytopenia, thrombocytopenia, nausea, and neutropenia showed similar profiles between treatment regimens.
The study's sensitivity analysis, excluding common concomitant medications, confirmed that the vast majority of adverse events retained positive signals, supporting the robustness of the findings. Among the top adverse events with positive signals, life-threatening complications such as febrile neutropenia, sepsis, and septic shock require particular attention for early detection and intervention.
The researchers propose developing intelligent reminder applications based on adverse event timelines to automatically deliver self-assessment questionnaires at key time points, potentially improving patient safety monitoring in real-world practice.
These findings provide crucial real-world evidence complementing clinical trial data, offering healthcare providers enhanced understanding of toxicity patterns to optimize patient selection, monitoring strategies, and personalized treatment approaches for lung cancer patients receiving pembrolizumab combination therapy.
