Background The CeTeG/NOA-09 trial assessed in a randomized phase 3 setting, whether combined treatment of lomustine together with temozolomide was superior to temozolomide treatment alone in newly diagnosed MGMT (O(6)-methylguanine-DNA-methyltransferase) promoter methylated glioblastoma patients. Survival was significantly improved from 31.4 months with temozolomide alone to 48.1 months with the combination of lomustine plus temozolomide. In view of this encouraging data - suggesting this combination could have a significant impact on the survival of newly diagnosed glioblastoma patients - we were curious to assess safety and efficacy of this regimen under real-life conditions. Material and Methods We collected clinical and radiographic data from adult newly diagnosed MGMT promoter methylated IDH (isocitrate dehydrogenase) wildtype glioblastoma patients treated at five neuro-oncology centers in Germany. As a requirement for inclusion, first-line treatment with lomustine plus temozolomide had to be performed for at least six weeks (one course). The available radiographic data was independently reviewed by an experienced board-certified neuro-radiologist. Results In total, 70 patients were included. Median progression-free survival of the full cohort was 14.4 months and median overall survival was 36.0 months. Patients who received TTFields (Tumor Treating Fields) treatment for eight weeks or longer together with the combination of lomustine plus temozolomide (n=22, 31%) had a prolonged progression-free survival compared to those patients who received TTFields treatment less than eight weeks or did not receive treatment with TTFields (n=48, 69%) (21.5 months versus 11.2 months; HR: 2.118, 95% CI: 1.245-3.605; p=0.0105). In a multivariable Cox regression analysis the use of TTFields for eight weeks or longer together with the combination of lomustine plus temozolomide as well as the application of at least five courses of CeTeG therapy emerged as independent prognostic factors for progression-free survival and overall survival. Pseudoprogression occurred in n=16 (33%) of the patients. We observed no treatment related deaths and high-grade hematotoxicity in n=31 (44%) of the patients. Conclusion The results from this multicentric trial that investigated newly diagnosed MGMT promoter methylated IDH wildtype glioblastoma under real-life conditions indicate toxicity and survival estimates comparable to the CeTeG/NOA-09 trial. The use of TTFields for at least eight weeks in combination with this regimen was independently associated with extended progression-free and overall survival.

Background The EF-14 phase III trial demonstrated improved survival for patients with newly diagnosed glioblastoma (nGBM) when TTFields therapy was added to adjuvant temozolomide chemotherapy. TTFields at 200 kHz are applied to the tumor utilizing arrays on the patients’ scalp. In preclinical studies, a synergistic inhibiting effect on glioblastoma cell proliferation was found for the combination of TTFields and radiotherapy. Based on these findings, we conduct the phase I/II PriCoTTF trial in adult nGBM patients to investigate the safety and efficacy of TTFields therapy initiated prior and concomitant to radiochemotherapy. Material and Methods Per study protocol, TTFields therapy is initiated following surgery and completed wound healing. Continuing throughout radiochemotherapy and adjuvant chemotherapy, TTFields therapy is used for approximately 9 months in total with TTFields rechallenge allowed at recurrence. Radiotherapy is conducted with arrays applied on the patients’ scalp. A total recruitment of 33 patients was sought, with 20 patients in arm A receiving normo-fractionated radiotherapy, and 13 elderly patients in arm B receiving hypo-fractionated radiotherapy. Safety and tolerance are the study’s primary endpoint, analyzed by a selection of pre-specified treatment-limiting toxicities (TLTs). Results A total of 33 patients have been enrolled. Patients' characteristics were mostly typical for glioblastoma, except for a rather low fraction of patients with gross total resection (GTR, 22.5%). The distribution of adverse events of common toxicity criteria (CTC) grade 3 or higher was comparable to that of established glioblastoma trials. Notably, skin toxicity of CTC grade 3 or higher was quite uncommon (n=2, 6%). As no patient developed TLTs, the study's primary endpoint was met. Median TTFields treatment duration was 8.4 months. Overall survival data was not mature enough (event rate 48%) to allow for a definite conclusion. Notably, on multivariable Cox regression, the number of days with TTFields adherence of more than 23 hours was independently associated with overall survival (HR 0.96, 95% confidence interval 0.93 - 0.99, p=0.008). Conclusion The PriCoTTF trial met its primary endpoint indicating that combined TTFields and radiotherapy is safe and well tolerated. High-grade skin toxicity was quite uncommon and the patients with high TTFields adherence seem to perform particularly well. An extended follow-up is required to provide first estimates regarding putative efficacy. At that point in time, the reduced overall TTFields duration and fraction of patients with GTR need to be factored in.