MA 03.02 Timing of B12/Folate Supplementation in NSCLC Patients on Pemetrexed Based Chemotherapy: Final Results of the PEMVITASTART Randomized Trial

Abstract

Vitamin B12 and folic acid supplementation (B12-FAS) reduces the incidence and severity of hematological toxicity [HTox] in pemetrexed-based chemotherapy. It is recommended to initiate B12-FAS 5-7 days before the first cycle. Observational and prospective single-arm studies have not shown any increase in HTox when pemetrexed was started earlier than the recommended duration of B12-FAS. An open-label, randomized trial (PEMVITASTART; NCT02679443) was conducted to evaluate differences in HTox between patients initiated on pemetrexed-platinum chemotherapy following 5-7 days of B12-FAS (Delayed Arm; DA) versus those receiving B12-FAS simultaneously(≤24 hours) with chemotherapy initiation (Immediate Arm; IA). Eligible patients had locally advanced/metastatic non-squamous NSCLC AND ECOG PS=0-2. Block randomization was 1:1 into DA and IA. All enrolled patients received 3-weekly pemetrexed-platinum doublet [500mg/m2 AND cisplatin (65mg/m2) OR carboplatin (AUC 5.0mg/mL/min) each on D1] for maximum of six cycles. Supplementation was 1000μgm FA PO daily and 3-weekly 1000μgm i/m vitamin B12. Primary outcome was any grade HTox while secondary outcomes were grade 3/4 HTox, relative dose intensity (RDI) delivered, inter-cycle delays (ICDs), supportive therapies usage (ESA/G-CSF/PRBC transfusions) and changes in serum levels of B12/FA/homocysteine. Of 161 patients recruited (81 IA, 80 DA), 150 patients (77 IA, 73 DA) received ≥1 cycle and were included in modified ITT analysis. Baseline parameters were matched except for gender (IA=10.4%, DA=23.3%, p=0.03) and baseline thrombocytopenia (IA=7.8%, DA=0%, p=0.03). Baseline anemia (Hb<12gm/dL) was present in 34.7% (IA=32.5%, DA=37.0%; p=0.56). Incidence of any grade anemia, leukopenia, neutropenia and thrombocytopenia was 87.0% vs. 87.7% (p=0.90), 37.7% vs. 28.8% (p=0.25), 20.8% vs. 15.1%(p=0.36) and 31.2% vs. 16.4%(p=0.04) in IA and DA respectively. Grade 3/4 anemia was 18.2% vs. 12.3% (p=0.32) in IA and DA respectively while other cytopenias were similar (<5% in each arm). Supportive therapies usage in IA vs. DA were 22.1% vs. 12.3% for PRBC transfusions (p=0.12), 3.9% vs. 6.8% for G-CSF (p=0.49) and 10.4% vs. 1.4% for ESAs (p=0.03). ICDs occurred in 14.3% of IA vs. 8.2% in DA (p=0.24). RDI delivered (median 93.5% for pemetrexed and 91.0% for platinum) was similar in both arms. Following continued B12-FAS, after C3 (compared to baseline), serum homocysteine was lower (median 10.0μmol/L vs. 17.6μmol/L;p<0.001) while FA (median 17.9ng/ml vs. 5.7ng/ml;p<0.001) and B12 levels (mean 1926.3pg/ml vs. 880.2pg/ml;p<0.001) were higher. In DA, serum FA and B12 on Day1 of C1(following 5-7days of B12-FAS) were significantly higher than baseline but homocysteine levels were similar. Simultaneous B12-FAS initiation with pemetrexed-based chemotherapy is feasible with acceptable HTox profile. Serum homocysteine levels are unaffected by 5-7 days of B12-FAS.