Switch-maintenance gemcitabine after first-line chemotherapy in patients with malignant mesothelioma (NVALT19): an investigator-initiated, randomised, open-label, phase 2 trial
Menés aux Pays-Bas et au Royaume-Uni sur un total de 156 patients atteints d'un mésothéliome (130 cas de mésothéliome malin sans progression de la maladie après une chimiothérapie de première ligne et 26 cas de mésothéliome présentant une déficience du gène BAP1 ou BRCA1), ces 2 essais de phase II ou IIA évaluent respectivement l'efficacité et la toxicité d'un traitement d'entretien par gemcitabine et d'un traitement par rucaparib
Background : Almost all patients with malignant mesothelioma eventually have disease progression after first-line therapy. Previous studies have investigated maintenance therapy,but none has shown a great effect. We aimed to assess the efficacy and safety of switch-maintenance gemcitabine in patients with malignant mesothelioma without disease progression after first-line chemotherapy.
Methods : We did a randomised, open-label, phase 2 trial in 18 hospitals in the Netherlands (NVALT19). We recruited patients aged older than 18 years with unresectable malignant mesothelioma with no evidence of disease progression after at least four cycles offirst-line chemotherapy (with platinum and pemetrexed), who had a WHO performancestatus of 0–2, adequate organ function, and measurable or evaluable disease. Exclusion criteria were active uncontrolled infection or severe cardiac dysfunction, seriousdisabling conditions, symptomatic CNS metastases, radiotherapy within 2 weeks beforeenrolment, and concomitant use of any other drugs under investigation. Patients wererandomly assigned (1:1), using the minimisation method, to maintenance intravenousgemcitabine (1250 mg/m 2 on days 1 and 8, in cycles of 21 days) plus supportive care, or to best supportivecare alone, until disease progression, unacceptable toxicity, serious intercurrentillness, patient request for discontinuation, or need for any other anticancer agent,except for palliative radiotherapy. A CT scan of the thorax or abdomen (or both) andpulmonary function tests were done at baseline and repeated every 6 weeks. The primary outcome was progression-free survival in the intention-to-treat population. Safety was analysed in all participants who received one or more doses of the study drugor had at least one visit for supportive care. Recruitment is now closed; treatment and follow-up are ongoing. This study is registered with the Netherlands Trial Registry,NTR4132/NL3847.
Findings : Between March 20, 2014, and Feb 27, 2019, 130 patients were enrolled and randomly assigned to gemcitabine plus supportive care (65 patients [50%]) or supportive care alone (65 patients [50%]). No patients were lost to follow-up; median follow-up was36·5 months (95% CI 34·2 to not reached), and one patient in the supportive care groupwithdrew consent. Progression-free survival was significantly longer in the gemcitabinegroup (median 6·2 months [95% CI 4·6–8·7]) than in the supportive care group (3·2months [2·8–4·1]; hazard ratio [HR] 0·48 [95% CI 0·33–0·71]; p=0·0002). The benefitwas confirmed by masked independent central review (HR 0·49 [0·33–0·72]; p=0·0002).Grade 3–4 adverse events occurred in 33 (52%) of 64 patients in the gemcitabine groupand in ten (16%) of 62 patients in the supportive care group. The most frequent adverseevents were anaemia, neutropenia, fatigue or asthenia, pain, and infection in thegemcitabine group, and pain, infection, and cough or dyspnoea in the supportive caregroup. One patient (2%) in the gemcitabine group died, due to a treatment-relatedinfection.
Interpretation : Switch-maintenance gemcitabine, after first-line chemotherapy, significantly prolonged progression-free survival compared with best supportive care alone, among patients with malignant mesothelioma. This study confirms the activity of gemcitabine in treating malignant mesothelioma.
The Lancet Respiratory Medicine , résumé, 2020