A total of 14 adult patients with rGBM treated with ACTT were identified. Their characteristics are summarized in Tables 1 and 2. All patients were diagnosed as GBM with IDH1-wt and TERTp-mut. The median age at tumor recurrence was 55.0 years (range: 28.0-71.0y); 50% (7/14) of them were male. The tumor locations were the parietal lobe (n = 5, 35.7%), frontal lobe (n =4, 28.6%), occipital lobe (n = 2, 14.3%), cerebellum (n = 2, 14.3%), and basal ganglia region (n = 1, 7.1%). All patients received gross total resection at initial surgery followed by concurrent chemoradiotherapy and TMZ adjuvant chemotherapy. All 14 patients were treated with ACTT for the first-line therapy after tumor recurrence. After 2 months of ACTT, CR occurred in 5 patients, PR in 2 patients, SD in 6 patients, and PD in 1 patient. The ORR was 50.0% (7/14), DCR was 92.9% (13/14). There were 3 patients had AEs, and no treatment-related death.
The median treatment cycle of ACTT was 6.0 cycles (1.0-15.0 cycles). We were highly vigilant of pseudo progression when making a diagnosis of tumor recurrence, especially for patients with tumor progression within 3 months. The distinction between tumor recurrence and pseudo progression based on the extent of resection at initial operation, recurrence time, molecular pathological features, and multiple MRI and MRS examinations. Tumor recurrence is determined by the neurosurgeons, oncologists, and radiologists based on patient's clinical symptoms and examination results. For patients suspected of short-term recurred, we chose dynamic observation, and then dynamic examination of MRI and MRS were performed. And subsequently repeated MRI showed tumor enlargement, and MRS showed the Cho/NAA ratio in the region of interest was higher than that in the first suspected recurrence, and the Cho/NAA ratio >2.0. These patients were eventually identified as GBM recurrence. In addition, the symptoms of those patients had improved after ACTT, the tumor volume decreased and the Cho/NAA ratio in the region of interest decreased, these findings also confirmed that these patients should be diagnosed as GBM recurrence rather than pseudo progression. The interval of MRI and MRS was 1-3 months, and the time point of efficacy evaluation was 2 cycles after the therapy (approximately 2 months after tumor recurrence).
Survival comparison of ACTT and different treatment regimens
The follow-up time ranged from 2.0 to 24.0 months. The 6-month and 1-year of PFS rate were 78.6% and 42.9%, respectively. The 1-year survival rate was 50.0%. And the median PFS and OS were 11.0 and 13.0 months, respectively (Table 3). And then we compared survival outcome for ACTT with other treatment regimens (Tables 2). The Median PFS in Bev-group after GBM recurrence was 4.0 months, which was significantly shorter than that in ACTT group (median PFS: 4.0 vs. 11.0 months, P<0.001, Figure 1A). And the Median OS between these two groups was significantly different (median OS: 8.0 in BEV group vs. 13.0 months in ACTT group, P<0.001, Figure 1B). Twenty-eight patients (without considering IDH1 status) received re-operation after tumor recurrence, with the median OS being 12.0 months, this survival outcome was similar with ACTT group (Figure 1C). However, for the IDH1-wt GBM patients, the ACTT group had prolonged OS than that in re-operation group (median OS: 7.0 vs. 13.0 months, Figure 1D). The median OS in re-irradiation TMZ monotherapy, and supportive care groups were 4.0, 4.0 and 5.0 months, which were worse than that in ACTT group (Figure 1E-G). And compared to all the other treatment groups, the patients treated with ACTT had the best survival (Figure 1H).
A 65-year-old female presented with 1-month history of headache. The MRI showed a ring-enhanced right parietal occipital lobe lesion with peritumoral edema and the midline shift (Figure 2A). After admission, a gross total resection of lesion was performed, and the mass was confirmed as GBM. Immunohistochemical results showed that IDH1 (-), TERT C250T promoter (+), Ki67 index was 30%, GFAP (+), ATRX (+), Oligo2 (+), P53 (+), MGMT (+), MGMT promoter unmethylation. Direct gene sequencing showed IDH1 was wild-type and TERT C250T promoter mutation. The patients received concurrent chemoradiotherapy and temozolomide adjuvant chemotherapy after surgery. However, the MRI suggested the tumor recurrence 6 months later (Figure 2B). And then she received anlotinib combined with temozolomide therapy. Two months after treatment, the enhanced lesion basically disappeared on MRI (Figure 2C), and she achieved complete remission. She continued to receive ACTT, and after tumor recurrence 4, 6, 7, 9, 11 and 13 months, the lesions had completely disappeared and the disease was stable (Figure 2D-I). Unfortunately, the MRI suggested that the tumor recurred again after 15 months treatment (Figure 2J), and the Cho/NAA ratio in the region of interest increased(Figure 2K). She continued to receive ACTT and survived with symptom-free 21 months after tumor recurrence, despite a progressive increase in tumor volume (Figure 2L-N).
A 66-year-old woman with a chief complain of headache for 2 weeks was admitted to our department. Brain MRI showed a right parietal occipital lobe lesion with heterogeneous enhanced (Figure 3A). She received gross total resection of lesion, and the lesion was confirmed as GBM. Immunohistochemistry showed that IDH1 (-), TERT C228T promoter (+), Ki67 index 30%, GFAP (+), ATRX (+), Oligo2 (+), P53 (+), MGMT (-), and MGMT promoter unmethylation. IDH1 wild-type and TERT C250T promoter mutation was confirmed by gene sequencing. Postoperative she received concurrent chemoradiotherapy and TMZ adjuvant chemotherapy. Four months after surgery, the MRI suggested tumor recurrence with the Cho/NAA ratio increased on MRS (Figure 3B, K), and ACTT was initiated. After 2 months of treatment, the lesion was stable without progression (Figure 3C). She continued to receive ACTT, and the disease was stable at 4, 6, 8, 10, 13, 15 and 18 months after tumor recurrence (Figure 3D-J). Although there was no significant change in tumor volume, a gradual decreasing in CHO/NAA ratio in region of interest was observed (Figure 3L, M), and she remained symptom-free survival for 19 months.
According to the Phase III clinical study of ALTER0303 and the Adverse reaction Management Manual of antlotinib, the adverse effects of antlotinib mainly include fatigue, gastrointestinal reaction, oral mucitis, hypertension, rash, proteinuria, hypothyroidism, bone marrow suppression, abnormal liver and kidney function, dyslipidemic, etc. There were 3 patients had AEs in our study, nasal bleeding and mental symptom in 1 patient; pain, blisters, and cerebral hemorrhage in 1 patient; and mild abnormal liver function in 1 patient. These AEs were assessed as grade 1 based on NCI-CTCAE 4.03. All the AEs could be tolerated after symptomatic treatment. Although the AEs were mild, 2 patients refused to continue ACTT. There was no treatment-related deaths in the study.