Citations

607 Background: Immunotherapy (IO) is known to have robust anti-tumor activity in patients with MSI-H solid tumors. However, clinical trials investigating IO activity have used tissue-based testing to determine MSI-H status. Pancreatic tumor biopsy often does not provide sufficient tumor tissue for MSI testing. We investigated if the MSI-H status detected by plasma-based circulating tumor DNA (ctDNA) testing predicts robust response to IO in patients with PC. Methods: Genomic results from a well-validated plasma-based ctDNA assay (Guardant360[G360]) performed as part of routine clinical care between October 1, 2018 and September 7, 2021 in patients with PC were queried to identify patients with MSI-H tumors. Patient characteristics, tumor characteristics, treatment details, and outcomes were reported by ordering clinicians where available. The data cut-off date was September 1, 2021. Results: A total of 52 patients with PC who had MSI-H tumors on G360 were identified. Clinical outcomes data were available for 10/52 (19%) patients who were included for analysis. This patient cohort had a median age of 68 years (range: 56-82); 80% were male and 80% of patients had metastatic disease. 9/10 patients received IO: 3 in the first-line, 3 in the second-line, 3 in the third-line setting; most received pembrolizumab (8/9) while 1 received ipilimumab plus nivolumab. The median duration of IO was 8 months (range: 1-24). The overall response rate was 77% (7/9) and 6 of the 7 responders continue to show response at the time of data cut-off after a median follow-up of 21 months (range:11-33). The median progression-free survival and overall survival were not reached in the IO-treated cohort. Tissue-based MSI testing results were concordant with plasma-based G360 results in 5 of 6 patients (83%) who had tissue-based test results available. The patient with the discordant result was MSI-H by G360 but had intact mismatch repair protein expression by immunohistochemistry. This patient received neoadjuvant IO followed by surgery and the resected specimen confirmed pathological complete response. Conclusions: The detection of MSI-H status by plasma-based ctDNA testing is highly concordant to tissue-based testing and predicts robust and durable response to IO in patients with PC. The use of a well-validated plasma-based ctDNA analysis may expand the identification of MSI-H tumors in patients with PC and enable treatment with IO resulting in improved outcomes.

6076 Background: HCC is a rare subtype of follicular cell thyroid cancer that has been poorly studied in the past. Recent genomic studies have shown the PI3K/Akt/mTOR pathway is frequently altered in HCC. In addition, a phase II study of sorafenib (S) and everolimus (E) showed promising data in HCC. A study to evaluate this was initiated through Alliance and the International Thyroid Oncology Group. Methods: Patients (pts) were randomized to either sorafenib and everolimus (SE) vs. sorafenib alone (S). Inclusion criteria included; (1) diagnosis of HCC (confirmed through central review), no prior S or E, refractory to radioactive iodine, progressive disease by RECIST over prior 14 months. Primary endpoint was a comparison of progression-free survival (PFS) between SE and S using a stratified 1-sided log-rank test with 0.20 significance level and a power of 80%. 28 events were needed at final analysis. Secondary endpoints consisted of overall survival (OS), confirmed response rate (RR), and adverse events. Results: 35 pts were randomized from 10/2014 to 9/2019, 34 of which were evaluable for analysis (17-SE; 17-S) because 1 patient cancelled prior to receiving treatment. Median age was 66.5 years and 74% were male. ECOG performance status (PS) was 0 (47%) and PS 1 (53%). 41% had prior systemic treatment for HCC. No significant differences in baseline characteristics were observed between treatment arms. Median follow-up in 22 alive patients was 39.2 months (range: 15.1-64.9). Seven (21%) patients remain on treatment. PFS was significantly improved in the SE arm as compared to the S arm (HR=0.65 (95% CI: 0.26, 1.57); median PFS: SE=24.7 months (95% CI: 6.1-no upper), S=10.9 months (95% CI: 5.5-no upper); stratified 1-sided p=0.1662). OS was similar between the arms (2-sided p=0.4138). Confirmed response rate was similar between arms as well (SE: 18% (3 partial response (PR) vs. S: 24% (3 PR, 1 complete response)); Fisher’s exact p=1.00). Grade 3 adverse event (AE) rates (regardless of attribution) were similar between arms (SE: 77% vs. S: 77%; p=1.00). Each arm had 1 patient with at least one grade 4 AE (SE patient: cardiac arrest, tracheal obstruction, encephalopathy; S patient: mucositis oral) and no grade 5 AEs. Conclusions: PFS was improved with the addition of E to S in this small randomized multi-institutional phase II study done. Accrual was difficult, but these promising results suggest that this combination should be further studied. Support: U10CA180821, U10CA180882, U24CA196171; https://acknowledgments.alliancefound.org ; Novartis/GSK; ClinicalTrials.gov Identifier: NCT02143726. Clinical trial information: NCT02143726.

TPS366 Background: First-line treatment of mRCC has rapidly changed to include IPI-NIVO or CABO, with clinical benefit of each based on the Checkmate 214 and CABOSUN (A031203) trials. Combination immunotherapy with VEGF therapies has shown benefit over sunitinib in the JAVELIN 101 and KEYNOTE 426 trials. It is yet unclear which patients (pts) benefit most from combination immunotherapy-VEGF inhibitors, and the optimal sequence of drugs. Methods: In an adaptive, randomized, multicenter phase III trial (Alliance A031704, PDIGREE), pts start treatment with induction IPI 1 mg/kg and NIVO 3 mg/kg intravenously (IV) once every 3 weeks. Key inclusion criteria include clear cell mRCC, International Metastatic RCC Database Consortium (IMDC) intermediate or poor risk, Karnofsky performance status >70, and no prior treatments for mRCC. Based on 3-month radiographic assessment (after completing IPI-NIVO combination), pts with complete responses (CR) undergo maintenance NIVO 480 mg IV every 4 weeks; pts with progression of disease (PD) switch to CABO 60 mg oral daily; pts with non-CR/non-PD are randomized to NIVO 480 mg IV every 4 weeks versus NIVO 480 mg IV every 4 weeks with CABO 40 mg oral daily. Randomization is stratified by IMDC risk criteria and presence of bone metastases. The primary endpoint of the study is overall survival (OS). We hypothesize that 3-year OS will improve to 70% for NIVO-CABO compared to 60% for NIVO alone; to achieve 85% power with a two-sided alpha of 0.05 and exponential distribution, 696 patients will be randomized. Accounting for 30% patients with either CR or PD, and 5% dropout from toxicity, up to 1046 pts will be enrolled. Key secondary endpoints include progression-free survival, 12-month CR rate, overall response rate based on RECIST 1.1 and iRECIST criteria, and toxicity profiles. Quality of life will be assessed based on the FKSI-19, PROMIS-fatigue, and EQ5D-5L questionnaires. Biomarkers associated with CR, tissue-based and plasma-based biomarkers will be assessed. Updated enrollment through January 2021 will be presented. Clinical trial information: NCT03793166 .

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 .

TPS5100 Background: First-line treatment of mRCC has rapidly changed to include IPI-NIVO or CABO, with clinical benefit of each based on the Checkmate 214 and CABOSUN (A031203) trials. Combination immunotherapy with VEGF therapies has shown benefit over sunitinib in the JAVELIN 101 and KEYNOTE 426 trials. It is yet unclear which patients (pts) benefit most from combination immunotherapy-VEGF inhibitors, and the optimal sequence of drugs. Methods: In an adaptive, randomized, multicenter phase 3 trial (Alliance A031704, PDIGREE), pts start treatment with induction IPI 1 mg/kg and NIVO 3 mg/kg intravenously (IV) once every 3 weeks. Key inclusion criteria include clear cell mRCC, International Metastatic RCC Database Consortium (IMDC) intermediate or poor risk, Karnofsky performance status > 70, and no prior treatments for mRCC. Based on 3-month radiographic assessment (after completing IPI-NIVO combination), pts with complete responses (CR) undergo maintenance NIVO 480 mg IV every 4 weeks; pts with progression of disease (PD) switch to CABO 60 mg oral daily; pts with non-CR/non-PD are randomized to NIVO 480 mg IV every 4 weeks versus NIVO 480 mg IV every 4 weeks with CABO 40 mg oral daily. Randomization is stratified by IMDC risk criteria and presence of bone metastases. The primary endpoint of the study is overall survival (OS). We hypothesize that 3-year OS will improve to 70% for NIVO-CABO compared to 60% for NIVO alone; to achieve 85% power with a two-sided alpha of 0.05 and exponential distribution, 696 patients will be randomized. Accounting for 30% patients with either CR or PD, and 5% dropout from toxicity, up to 1046 pts will be enrolled. Key secondary endpoints include progression-free survival, 12-month CR rate, overall response rate based on RECIST 1.1 and irRECIST criteria, and toxicity profiles. Quality of life will be assessed based on the FKSI-19, PROMIS-fatigue, and EQ5D-5L questionnaires. Biomarkers associated with CR, tissue-based and plasma-based biomarkers will be assessed. Updated enrollment through May 2020 will be presented. Clinical trial information: NCT03793166 .