Silverman, Joshua S.

2090 Background: A subset of meningiomas has an aggressive clinical course requiring multimodal therapies. Yet, treatment options beyond surgery and radiation are limited. Somatostatin receptor 2 (SSTR2) is uniformly expressed in meningiomas and can be targeted by the radiopharmaceutical agent [ 177 Lu]Lu-DOTA-TATE ( 177 Lu-Dotatate). [ 68 Ga]Ga-DOTA-TATE ( 68 Ga-Dotatate) PET is emerging as a promising imaging modality to assess treatment response in SSTR2-expressing tumors. However, prospective clinical data supporting the use of 177 Lu-Dotatate and 68 Ga-Dotatate in treatment-refractory meningiomas is limited. Methods: In this multicenter, open-label, phase 2 clinical study (NCT03971461), adult patients with progressive intracranial meningiomas received 177 Lu-Dotatate at 7.4 GBq (200 mCi) every 8 weeks for 4 doses. The primary endpoint was 6-month progression-free survival (PFS-6). Up to 5 meningioma lesions per patient were assessed by gadolinium-enhanced T1 MRI every 12 weeks. 68 Ga-Dotatate PET was obtained before/after 177 Lu-Dotatate treatments. Lesional 68 Ga-Dotatate PET activity was assessed relative to liver/spleen or superior sagittal sinus (SSS). Results: 32 patients (female = 21, male = 11) with progressive meningiomas (WHO grade 1 = 7, grade 2 = 24, grade 3 = 1) were enrolled. Median age was 65.5 (range 41-78) years. All patients had at least one prior tumor surgery and at least one course of radiation. Overall, 177 Lu-Dotatate was well tolerated and the most common grade 3/4 adverse events were transient cytopenia in 15 patients (47%). One patient (3%) discontinued treatment due to grade 4 thrombocytopenia. PFS-6 was reached in 22 patients (69%), which includes 5 of 7 (71%) with grade 1 and 17 of 24 (71%) with grade 2 meningiomas. Best radiographic response by MRI was partial response (PR) in 5 (16%) and stable disease (SD) in 20 (63%) patients. Eight patients (16 lesions) were evaluable by paired MRI and 68 Ga-Dotatate PET pre- and post-treatment. Referenced to SSS, 68 Ga-Dotatate avidity reduced by ≥50% in 2 lesions (PR), 25-49% (minor response, MR) in 3 lesions and remained stable ( < 25% reduction and < 25% increase) in 11 lesions. Using liver/spleen as a reference (6 patients, 14 lesions), 68 Ga-Dotatate uptake was reduced in 9 lesions and stable in 5 lesions. 68 Ga-Dotatate PET assessments were generally concordant with MRI-based treatment response assessments. Conclusions: The primary endpoint (PFS-6) was met in this phase 2 study with 69% of patients achieving PFS-6, thereby surpassing established historical benchmarks. 177 Lu-Dotatate was generally well tolerated and deserves further study in patients with advanced meningiomas. Exploratory 68 Ga-DOTATATE PET studies showed decreased uptake in a subset of lesions and bears promise as an imaging biomarker to assess treatment response. Clinical trial information: NCT03971461 .

Abstract BACKGROUND [68Ga]Ga-DOTA-TATE (68Ga-Dotatate) PET is a promising imaging modality for post-operative meningioma delineation and outcome assessments following stereotactic radiosurgery. However, its utility for response assessment following other meningioma therapies, including somatostatin receptor 2 (SSTR2) targeting [177Lu]Lu-DOTA-TATE (177Lu-Dotatate) therapy is insufficiently understood. Here we report the 68Ga-Dotatate PET results, prospectively obtained in patients with treatment-refractory meningioma who enrolled in a phase 2, open-label clinical trial (NCT03971461) evaluating the radiopharmaceutical 177Lu-Dotatate. METHODS Patients underwent 68Ga-Dotatate PET during screening and 24±2 weeks following treatment with 177Lu-Dotatate at 7.4 GBq (200 mCi) every 8 weeks for 4 doses. Up to 5 meningioma lesions per patient were assessed by gadolinium-enhanced T1 MRI and 68Ga-Dotatate PET using lesional Krenning score and lesional to superior sagittal sinus (SSS) maximum standardized uptake value (SUVmax) ratio (SUVR (lesion/SSS)). RESULTS Eight patients with 16 lesions were assessed. By RANO criteria, the best radiographic response was stable disease (SD) in 7 patients (14 lesions) and partial response (PR) in 1 patient (2 lesions). Krenning score was assessed in 14 lesions (Krenning 4/3/2/1 in 3/4/5/2 lesions). Following 177Lu-Dotatate, Krenning score was reduced by ≥1 point in 9 and remained stable in 5 lesions. SUVR (lesion/SSS) was evaluated in 16 lesions. Compared to baseline, SUVR (lesion/SSS) at 6 months was partially reduced (PR, ≥50%) in 2 lesions, minimally reduced (MR, &lt;50% and ≥25%) in 3 lesions, and stable (SD, &lt;25% reduction and &lt;25% increase) in 11 lesions. CONCLUSIONS 68Ga-Dotatate PET is a promising imaging biomarker in patients with advanced meningioma. Treatment with 177Lu-Dotatate led to substantial reduction in SUVR (lesion/SSS) in a subset of patients. In contrast to other reports, 68Ga-Dotatate assessments were generally concordant with post-gad T1 based MRI assessments per RANO. Updated results in an expanded group of patients will be presented.

Abstract BACKGROUND Most meningiomas are considered benign tumors, however, a subset of meningiomas are characterized by a more aggressive clinical course and require multimodal treatment. Beyond surgery and radiation, there are no effective medical treatments available. Somatostatin receptor 2 (SSTR2) is expressed by the majority of meningiomas. [177Lu]Lu-DOTA-TATE (177Lu-Dotatate) is a SSTR2-targeting radioligand therapeutic agent that has been successful in other oncological entities, including neuroendocrine tumors. Here we report the results of a phase 2 clinical trial (NCT03971461) evaluating 177Lu-Dotatate in patients with advanced and treatment-refractory intracranial meningiomas. METHODS In this multicenter, open-label, phase 2 study, adults with advanced intracranial meningiomas received 177Lu-Dotatate at 7.4 GBq (200 mCi) every eight weeks for four doses. [68Ga]Ga-DOTA-TATE (68Ga-Dotatate) PET was performed before and at the end of treatment. The primary endpoint was progression-free survival at 6 months (PFS-6). Correlative studies evaluated the association of PFS-6, objective response rate, progression-free survival, overall survival with radiographic tumor measurements, and 68Ga-Dotatate uptake on PET. RESULTS Thirty-two patients (F=21, M=11) with progressive meningiomas (WHO 1=7, WHO 2=24, WHO 3=1) were enrolled. Median age was 65.5 (range 41-78) years. All patients previously underwent tumor resection and at least one course of radiation. Three patients (9%) had received medical therapy. Treatment with 177Lu-Dotatate was well tolerated, no treatment-limiting toxicities were observed. Of 29 evaluable patients at the data cutoff, 19 patients (66%) had achieved PFS-6 (WHO 1=4, WHO 2=15). Radiographically, the best response was partial response (PR) in 2 patients (6%) and stable disease (SD) in 20 patients (63%). CONCLUSIONS Treatment with SSTR2-targeting 177Lu-Dotatate is well tolerated and 66% of patients achieved PFS-6, comparing favorably to historical benchmarks, 177Lu-Dotatate therefore may be a useful new therapeutic modality for patients with advanced meningiomas and will be further explored in MOMENTUM-1 (NCT#06955169), an open-label, randomized, phase 2 trial.

BACKGROUND AND OBJECTIVES: Gynecological cancers represent 10% to 15% of cancers in women, but brain metastases (BM) are uncommon, with limited evidence regarding their management. This study investigates the role of stereotactic radiosurgery (SRS) for BM from primary gynecological cancers. METHODS: Institutions of the International Radiosurgery Research Foundation participated in this study. Inclusion criteria required histological diagnosis of epithelial ovarian, cervical, or endometrial cancer, SRS between 2000 and 2020, and at least 1 imaging or clinical follow-up. RESULTS: A total of 276 patients having SRS for 977 BM were included. Median age at SRS was 62 years (IQR, 55-70). Primary cancer origin was ovarian in 128 (46%), cervical in 43 (16%), and endometrial in 105 patients (38%). Median Karnofsky Performance Scale was 80%, and systemic disease was active in 124 (45%) of patients. A median of 1 metastasis was treated (IQR, 1-3) per patient. Median individual metastasis volume was 0.27 cc (IQR, 0.05-1.59 cc). The majority (91%) received single-fraction SRS, using a median margin dose of 18 Gy (IQR, 16-20 Gy). Actuarial overall survival was 77%, 65%, and 44% at 6, 12, and 24 months, respectively. Predictors of worsened survival included older age, cervical and endometrial primary, previous whole-brain radiation therapy (WBRT), active systemic disease, worsened Karnofsky Performance Scale, absence of subsequent surgery, and increasing number of BM. Actuarial local control was 94% at 6 months, 89% at 12 months, and 78% at 24 months. Previous SRS or WBRT, tumor bed treatment, and cervical histology increased the risk of local failure. New remote BM and leptomeningeal dissemination occurred in 44% and 11% of patients, respectively. Adverse radiation effects (ARE) occurred in 13% of cases but were symptomatic in only 3%. Previous WBRT or SRS and increased tumor diameter increased the risk of ARE. CONCLUSION: SRS is an effective management for BM from gynecological cancers with low risks of symptomatic ARE.