Monga, Varun

Abstract Background Pembrolizumab is approved for advanced cutaneous melanoma (aCM). Cabozantinib, an oral multi‐tyrosine kinase inhibitor, has demonstrated antitumor activity as monotherapy or in combination with anti‐PD‐1 therapy in malignancies. The objective of this study was to determine the safety and efficacy of cabozantinib and pembrolizumab for patients with aCM. Methods This phase 1b/2 study enrolled 28 patients with unresectable aCM. In phase 1b, escalating dose levels of cabozantinib (20 mg, 40 mg, and 60 mg) were administered concurrently with pembrolizumab 200 mg intravenously every 3 weeks using a 3 + 3 design to determine recommended phase 2 dose (RP2D). In phase 2, patients received cabozantinib at RP2D in combination with pembrolizumab using a Simon 2 stage design. Primary end point of phase 2 was overall response rate (ORR). Secondary end points included disease control rate, progression‐free survival (PFS), and overall survival (OS). Results Phase 1b enrolled eight patients, cabozantinib 40 mg daily dose level was selected as RP2D. Response rate in stage 1 exceeded predefined criteria for proceeding to expansion phase; however, phase 2 was terminated after 20 patients due to low accrual in the setting of evolving standard of care. Among all treated patients, the most common grade ≥3 toxicities were hypertension ( n = 10, 36%), hypokalemia ( n = 5, 18%), hypophosphatemia ( n = 4, 14%), and ALT elevation ( n = 4, 14%). Among 20 patients treated in phase 2, ORR was 45%, median PFS was 6.6 months, and median OS was 29.5 months. Conclusions Cabozantinib and pembrolizumab combination was explored in treatment‐naive aCM. Toxicity was consistent with known profiles, but discontinuation rates were notable.

11504 Background: Surgery & radiation therapy (RT) yield high local control rates for soft tissue sarcoma (STS) of the extremity and limb girdle. However, patients (pts) with high-grade stage III STS are at significant risk for developing metastasis. Median survival for pts with metastatic STS is < 2 years. SARC028 (NCT02301039) evaluated the efficacy of pembrolizumab (pembro) for metastatic STS, showing 20% and 8.7% response rates in undifferentiated pleomorphic sarcoma (UPS) and pleomorphic/dedifferentiated liposarcoma (LPS), respectively. We hypothesized that neoadjuvant pembro with concurrent RT followed by surgery and adjuvant pembro for stage III UPS, including myxofibrosarcoma, or LPS would stimulate an anti-tumor immune response to eliminate micrometastatic disease & improve disease-free survival (DFS). SU2C-SARC032 (NCT03092323) is a multi-institutional, international, randomized phase 2 trial evaluating the safety and efficacy of adding pembro to standard of care (SOC) RT & surgery for pts with stage III UPS or LPS. Methods: Pts aged > 12 yo with stage III (FNCLCC grade 2 or 3) UPS or LPS of the extremity and limb girdle were enrolled. Pts were randomized (1:1, stratified by grade) to neoadjuvant RT (50 Gy/25 fx) then surgery (SOC arm) or neoadjuvant pembro and RT then surgery & adjuvant pembro (EXP arm). Pembro was given 200 mg IV Q3 wk for 3 doses (before, during & after RT) & up to 14 adjuvant cycles. The primary endpoint was 2-yr DFS. Secondary endpoints included local recurrence-free survival (LRFS), distant disease-free survival (DDFS), & overall survival (OS). Target enrollment of 126 evaluable patients (max 144 total) provided 80% power (1-sided α = 0.05) to distinguish between a null hypothesis of 50% 2-yr DFS rate & alternative hypothesis of 75% 2-yr DFS rate by log-rank test, with initial analysis at 45 DFS events. Cox models were stratified by grade; primary analysis was a one-sided stratified log-rank test. Results: Between July 2017-November 2023, 143 patients were enrolled, predominantly with UPS (85%) & grade 3 (64%) histology. Median follow-up for alive patients is 24.1 mo. DFS in the EXP arm is significantly higher than the SOC arm (p = 0.023; HR 0.57, 90% CI: 0.35, 0.91). Estimated 2-yr DFS is 53% (90% CI: 43, 66%) for SOC vs 70% (90% CI: 61, 81%) for EXP arm. Currently, there is no statistically significant difference in LRFS (HR 0.55, 95% CI: 0.21, 1.42), DDFS (HR 0.57, 95% CI: 0.32, 1.01), or OS (HR 0.39, 95% CI: 0.14, 1.12). Pts with grade 3 sarcomas had improved DFS with pembro (HR 0.47, 95% CI: 0.25, 0.89), but no difference in DFS was observed in grade 2 tumors (HR 1.21, 95% CI: 0.35, 4.18). The proportion of patients with grade 3+ adverse events was significantly higher in EXP (52%) vs SOC arm (26%) (p = 0.002). Conclusions: Theaddition of neoadjuvant & adjuvant pembro to RT and surgery significantly improves DFS for pts with stage III UPS and LPS of the extremity and limb girdle. Clinical trial information: NCT03092323 .

Abstract Purpose: Pharmacologic ascorbate (P-AscH−) is hypothesized to be an iron (Fe)-dependent tumor-specific adjuvant to chemoradiation in treating glioblastoma (GBM). This study determined the efficacy of combining P-AscH− with radiation and temozolomide in a phase II clinical trial while simultaneously investigating a mechanism-based, noninvasive biomarker in T2* mapping to predict GBM response to P-AscH− in humans. Patients and Methods: The single-arm phase II clinical trial (NCT02344355) enrolled 55 subjects, with analysis performed 12 months following the completion of treatment. Overall survival (OS) and progression-free survival (PFS) were estimated with the Kaplan–Meier method and compared across patient subgroups with log-rank tests. Forty-nine of 55 subjects were evaluated using T2*-based MRI to assess its utility as an Fe-dependent biomarker. Results: Median OS was estimated to be 19.6 months [90% confidence interval (CI), 15.7–26.5 months], a statistically significant increase compared with historic control patients (14.6 months). Subjects with initial T2* relaxation &lt; 50 ms were associated with a significant increase in PFS compared with T2*-high subjects (11.2 months vs. 5.7 months, P &lt; 0.05) and a trend toward increased OS (26.5 months vs. 17.5 months). These results were validated in preclinical in vitro and in vivo model systems. Conclusions: P-AscH− combined with temozolomide and radiotherapy has the potential to significantly enhance GBM survival. T2*-based MRI assessment of tumor iron content is a prognostic biomarker for GBM clinical outcomes. See related commentary by Nabavizadeh and Bagley, p. 255

11505 Background: Potentiation of chemotherapy, without increased toxicity, to improve outcome is an area of interest. Preclinical and clinical evidence shows simultaneous utilization of antiangiogenic agents and chemotherapy have a synergistic effect. We hypothesized that the dual targeting of VEGF and c-MET pathways with cabozantinib (CAB) would result in clinical benefit for patients with soft tissue sarcoma (STS) when combined with temozolomide (TMZ), an alkylating agent. Utilization of CAB/TMZ is anticipated to produce a synergistic antitumor effect worthwhile to explore in STS. Methods: A multicenter phase II study of CAB/TMZ in patients with unresectable/metastatic leiomyosarcoma (LMS) and other STS was conducted by the Midwest Sarcoma Trials Partnership. Age ≥ 18, adequate performance status, organ function, measurable disease (RECIST 1.1), and 0-5 prior chemotherapy regimens were required. CAB 40 mg PO daily plus TMZ 150-200 mg/m2 PO 1-5 days were given in 28-day cycles until disease progression or unacceptable toxicity. Patients enrolled in 2 cohorts: 1. Uterine and non-uterine LMS 2. Other STS. The first 14 subjects to be enrolled in the study in either cohort served as a safety lead in. The primary endpoint was progression-free rate (PFR) at 12 weeks for cohort 1. Secondary endpoints include overall response rate (ORR), clinical benefit rate, median progression-free survival (PFS), overall survival, and safety and tolerability. The exploratory endpoint was to estimate the correlation of PFR and OS to expression levels of VEGF, amongst others. A Simon 2-stage design was used. Results: A total of 42 patients were enrolled in Cohort 1, and 30 in Cohort 2, across 5 sites. For Cohort 1, median age was 59 years (range 35-86), 85.7% were non-Hispanic, 73.8% were female, 61.9% had ECOG of 0. The PFR at 12 weeks was 45.9% (for 37 evaluable patient) with a median PFS of 6.4 months (95% CI 4.6-6.7). Five PR were observed for an ORR of 13.5%. For Cohort 2, median age was 63 (20-86), 83.3% were non-Hispanic, 36.7% were female, 53.3% had ECOG of 0. The PFR at 12 weeks was 50% (for 28 evaluable patients) with a median PFS of 3.2 months (95% CI 1.4-4.6). One PR was observed. Reported grade 3-4 adverse events attributed to one or both intervention drugs affecting ≥10% of patients (n = 70) included hypertension (10%), decreased neutrophils (18.7%), decreased platelets (31%). Conclusions: The combination therapy of CAB/TMZ in patients with unresectable or metastatic LMS exceeded its primary endpoint with a PFR at 12 weeks > 39%. The PFS of 6.4 months in Cohort 1 exceeds rates achieved with second line tyrosine kinase inhibitors (TKIs) and alkylators in LMS patients. Treatment was feasible and did not reveal any previously unreported toxicities. The combination with CAB with TMZ demonstrated meaningful clinical benefit and is worth further exploration in LMS. Clinical trial information: NCT04200443 .

The treatment of sarcoma necessitates a collaborative approach, given its rarity and complex management. At a single institution, multidisciplinary teams of specialists determine and execute treatment plans involving surgical, radiation, and medical management. Treatment guidelines for systemic therapies in advanced or nonresectable soft tissue sarcoma have advanced in recent years as new immunotherapies and targeted therapies become available. Collaboration between institutions is necessary to facilitate accrual to clinical trials. Here, we describe the success of the Midwest Sarcoma Trials Partnership (MWSTP) in creating a network encompassing large academic centers and local community sites. We propose a new model utilizing online platforms to expand the reach of clinical expertise for the treatment of advanced soft tissue sarcoma.

80 Background: Incidence of colorectal cancer (CRC) among adolescents and young adults (AYA) is increasing. A significant proportion of adolescents and young adults (AYA) with colorectal cancer (CRC) lack traceable genetic risk factors. We sought to study the impact of lifestyle-related risk factors on the incidence and mortality of CRC in these patients. Methods: We extracted data on crude incidence and mortality rates of CRC (reported per 100,000 population) for ages 15-39 years in all 50 U.S. states and District of Columbia from the Center for Disease Control (CDC) WONDER database (1999-2018). Data on risk factors such as obesity, physical activity, alcohol and tobacco abuse and nutrition were obtained from the Behavioral Risk Factor Surveillance System (BRFSS, 2020). Correlations were analyzed using Pearson’s co-efficient. p < 0.05 was considered statistically significant. Statistical analysis was performed using VassarStats. Results: Median crude incidence and mortality rates of CRC in AYA in the US from 1999-2018 were 3.8 (IQR 3.2, 4.4) and 0.7 (IQR 0.5,0.9) per 100,000 population respectively. States with higher age-adjusted prevalence of obesity per 100,000 had higher incidence (r = 0.36, p = 0.01) and mortality rates (r = 0.49, p = 0.0002) of CRC in AYA population. States with a higher age-adjusted prevalence of adherence to recommended weekly aerobic activity had lower incidence (r = -0.4515, p = 0.001) and mortality (r = -0.569, p < 0.0001) rates. While states with higher age-adjusted prevalence of tobacco abuse had higher incidence rate of CRC (r = 0.33, p = 0.02), there was no correlation with mortality rates (r = 0.24, p = 0.09). Higher prevalence of alcohol consumption was associated with decreased mortality rate (r = -0.44, p = 0.001), with no impact on incidence rate (r = -0.16, p = 0.26). States with lower daily consumption of fruits had higher incidence (r = 0.37, p = 0.01) and mortality rates (r = 0.59, p < 0.0001). No correlation of daily consumption of vegetables with incidence (r = -0.1516, p = 0.29) and mortality (r = 0.18, p = 0.22) rates was noted. Conclusions: In the current analysis, higher prevalence of obesity, lower rates of aerobic activity and lower daily consumption of fruits were strongly associated with increased incidence and mortality rates. The impact of tobacco abuse and alcohol consumption was more variable. Apart from improving access to genetic testing and counseling, efforts aimed at mitigating the rise of CRC incidence among AYA should also focus on traditional lifestyle-related risk factors.

PURPOSE Patients with progressive or recurrent meningiomas have limited systemic therapy options. Focal adhesion kinase (FAK) inhibition has a synthetic lethal relationship with NF2 loss. Given the predominance of NF2 mutations in meningiomas, we evaluated the efficacy of GSK2256098, a FAK inhibitor, as part of the first genomically driven phase II study in recurrent or progressive grade 1-3 meningiomas. PATIENTS AND METHODS Eligible patients whose tumors screened positively for NF2 mutations were treated with GSK2256098, 750 mg orally twice daily, until progressive disease. Efficacy was evaluated using two coprimary end points: progression-free survival at 6 months (PFS6) and response rate by Macdonald criteria, where PFS6 was evaluated separately within grade-based subgroups: grade 1 versus 2/3 meningiomas. Per study design, the FAK inhibitor would be considered promising in this patient population if either end point met the corresponding decision criteria for efficacy. RESULTS Of 322 patients screened for all mutation cohorts of the study, 36 eligible and evaluable patients with NF2 mutations were enrolled and treated: 12 grade 1 and 24 grade 2/3 patients. Across all grades, one patient had a partial response and 24 had stable disease as their best response to treatment. In grade 1 patients, the observed PFS6 rate was 83% (10/12 patients; 95% CI, 52 to 98). In grade 2/3 patients, the observed PFS6 rate was 33% (8/24 patients; 95% CI, 16 to 55). The study met the PFS6 efficacy end point both for the grade 1 and the grade 2/3 cohorts. Treatment was well tolerated; seven patients had a maximum grade 3 adverse event that was at least possibly related to treatment with no grade 4 or 5 events. CONCLUSION GSK2256098 was well tolerated and resulted in an improved PFS6 rate in patients with recurrent or progressive NF2-mutated meningiomas, compared with historical controls. The criteria for promising activity were met, and FAK inhibition warrants further evaluation for this patient population.

Although checkpoint inhibitors have been approved in multiple cancers, they are still under investigation in soft tissue sarcoma (STS). We conducted a retrospective review to report the safety, efficacy, and prognostic factors related to checkpoint inhibitors in STS. A sequential cohort of metastatic STS patients from four institutions treated with checkpoint inhibitors was assembled. Logistic and Cox regression models were applied to determine the effect of patient characteristics, prior treatment, and baseline factors on achieving the best overall response of complete response (CR), partial response (PR), or stable disease (SD) as determined by the treating physician. Eighty-eight patients with two median prior therapies received checkpoint inhibitors. Treatments included pembrolizumab in 47, nivolumab in 6, ipilimumab in 1, combination ipilimumab/nivolumab in 27, and other combination immunotherapies in 7 patients. Immunotherapy was discontinued in 54 patients—72.2% for progression, 16.7% for toxicity, and 11.1% for other reasons. Median progression-free survival (PFS) was 4.1 months and median overall survival was 19.1 months. One patient with undifferentiated pleomorphic sarcoma (UPS) achieved a CR, while 20 patients had a PR, including 7 UPS, 9 leiomyosarcoma (LMS), and 1 each with alveolar soft part sarcoma, fibroblastic sarcoma, sclerosing epithelioid fibrosarcoma, and myxofibrosarcoma. Forty-five percent (9 of 20) of LMS patients achieved a PR. Twenty-eight patients had SD. Our results confirm the activity and safety of anti-PD-1 therapy in metastatic STS. A notable response rate was observed in UPS and LMS subtypes. This study expands the knowledge base beyond what is currently available from clinical trials involving checkpoint inhibitors in metastatic STS.

11562 Background: Soft tissue sarcoma (STS) is a heterogeneous malignancy of connective tissue. Although mTOR is implicated in STS pathogenesis, clinical activity from mTORC1 inhibitors is modest. M, a potent selective mTORC1/mTORC2 inhibitor, was more effective in STS preclinical models than inhibitors of mTORC1, IGF1R and mTORC1+IGF1R, owing to more complete suppression of PI3K/AKT/mTOR and abrogation of feedback AKT activation. P, an oral multikinase inhibitor, is approved for non-adipocytic STS and often used after progression (PD) on chemotherapy. In phase 1, the RP2D of M was 30 mg weekly. A091304 was to evaluate M as a novel targeted therapy for STS. Methods: In A091304, pts were randomized 1:1 to M 30 mg weekly or P 800 mg daily. Eligibility required Eastern Cooperative Oncology Group PS ≤ 1, progression on ≥ 1 prior chemotherapy and specific STS subtypes (cohort 1: UPS; 2: LMS; 3: MPNST, SS). Crossover to M was allowed after PD on P. 1° endpoint was progression-free survival (PFS). Assuming median PFS of P was 4.6 months (mo), 98 pts yielded 80% power to detect a hazard ratio of 0.66 favoring M [1-sided test, alpha = 0.15] and including 1 planned futility analysis. 2° endpoints were response rate, clinical benefit rate (CBR) at 4 mo and safety. After 4 of the first 12 pts randomized to P experienced ≥ grade (gr) 3 toxicity, the study was amended to begin at P 400 mg, allowing titration to 800 per investigator discretion. Results: After protocol amendment, 114 pt underwent randomization (M: 56, P: 58), and 111 initiated treatment. Median PFS was 2 mo for M and 2.1 mo for P (HR = 1.47; 1-sided 85% upper confidence boundary = 1.85), with 2 partial responses in each arm. CBR was 5.4% for M and 13.8% for P. Median OS was 10.7 mo for M and 13.9 mo for P (HR = 1.41; 95% CI 0.80-2.49). 26/43 pt with PD on P crossed over to M. Median PFS after crossover was 1.8 mo (95% CI 1.5-3.5). Gr 3 drug-related adverse events (AEs) occurred in 36% on M and 41% on P; gr 4 toxicity was rare. AEs were consistent with known effects of M and P. Conclusions: P at 400 mg daily (allowing escalation to 800 mg per investigator discretion) demonstrated a shorter PFS as compared prior randomized studies with P. Despite this, M failed to demonstrate superior clinical activity as compared to P at the interim analysis. Further work will examine activity within histology-specific cohorts and evaluate available tissue samples for evidence of pharmacodynamic activity. Support: U10CA180821, U10CA180882, U10CA180888, UG1CA233324 (SWOG); https://acknowledgments.alliancefound.org . Clinical trial information: NCT02601209 .

11561 Background: Angiosarcoma has a particularly poor prognosis with 5-year overall survival rates of approximately 30-40%. Treatment of locally advanced and metastatic angiosarcoma is inadequate. Data strongly suggest concurrent, potent inhibition of VEGFR and Tie2 represents an attractive therapeutic strategy in angiosarcoma. Regorafenib displays potent VEGFR and Tie2 receptor inhibition and also possesses activity against additional potential targets in angiosarcoma including PDGFRs, RAF, KIT and FGFR, amongst others. Methods: A multicenter phase II study of regorafenib in patients with locally advanced or metastatic angiosarcoma was conducted through the Midwest Sarcoma Trials Partnership. Adequate performance status, organ function, measurable disease (RECIST 1.1) and 1-4 prior therapies were required. Regorafenib 160 mg PO daily was given in 28-day cycles (21 days on, 7 days off) until disease progression (PD) or unacceptable toxicity. The primary endpoint was progression-free survival (PFS), assessed at 16 weeks. Secondary endpoints include overall response rate (ORR), clinical benefit rate (CBR), OS, and safety and tolerability. A Simon 2-stage design was used. Results: After final enrollment of the second stage, a total of 31 pts were enrolled at 6 sites, 23 are evaluable for response. Median age was 65 (range 30-91); 50% were female, 67.7% had metastatic disease. PFS at 4 months is 52.2% with a median PFS and OS of 3.55 and 11.4 months. 1 confirmed CR and 2 PR, 12 SD and 8 PD were observed. ORR and CBR are 14.29 and 65.2%, respectively. No uncommon grade 3-4 adverse events were observed. 6 pts were non-evaluable due to refusal of further therapy and 2 patients progressed prior to first evaluation. Conclusions: Regorafenib was well tolerated in this study of pretreated patients with angiosarcomas and met its primary endpoint with a median PFS > 45% at 4 months. Treatment was feasible and did not reveal any previously unreported toxicities. Efficacy outcomes were complicated by early withdrawals of patients. RECIST responses were encouraging and regorafenib has a clinically meaningful 4-month PFS. Clinical trial information: NCT02048722 .