Abstract / Summary
Introduction: Pemetrexed, an antifolate, is a standard therapy for lung adenocarcinoma (LUAD). Since folic acid is vital for nucleic acid metabolism, disrupting its pathway affects both tumor cells and regenerating healthy cells. The PemToxTrial examined the impact of pemetrexed on severe hematotoxicity and mortality. Methods: This retrospective analysis included 136 LUAD patients (UICC8 stage IVA/B) receiving palliative treatment. Ninety-two patients received pemetrexed-based therapy, while 44 received pemetrexed-free treatment (68 and 38 with immune-checkpoint inhibitors). Bone metastasis (BM) was present in 47 patients in the pemetrexed group and 22 in the comparison group. The primary endpoint was grade III–V hematotoxicity; secondary endpoints included mortality, progression-free survival (PFS), and overall survival (OS). Hematologic outcomes following a subsequent change in clinical practice were prospectively assessed in a post-implementation cohort of 15 patients with bone-metastatic LUAD receiving pemetrexed-free regimens. Results: Median age was 66 years, 59.6% were male and median follow-up was 13.5 months. Grade III-V hematotoxicity was most frequent (81%) in patients with BM receiving pemetrexed (n = 47), significantly higher than in other subgroups (p < 0.0001). Mortality was also increased in this group (66% vs. 29%, p < 0.0001), with hematotoxicity directly contributing to death in 42% versus 11.5% of cases. PFS was significantly inferior (5.2 vs. 8.6 months). Multivariable analysis identified BM as the only independent predictor of severe hematotoxicity and mortality. Only a mutational burden of ≥4 potential driver alterations was associated with inferior PFS. Bone-derived total lesion glycolysis (TLG) on PET-CT strongly correlated with high-grade hematotoxicity (p < 0.0001). Conclusions: The PemToxTrial identified a strong association between pemetrexed exposure, bone metastases, and severe hematotoxicity, supporting further prospective evaluation of bone metastasis status as a potential clinical risk factor for treatment-associated hematotoxicity.