Independent Radiographic Review Research Articles

Abstract B011: Phase 2, multicenter, open-label basket trial of nab-sirolimus for malignant solid tumors harboring pathogenic inactivating alterations in TSC1 and TSC2 (PRECISION I)

Abstract Introduction/objective: PRECISION I (NCT05103358) is an ongoing trial of nab-sirolimus in advanced cancers harboring pathogenic inactivating alterations in TSC1 or TSC2. TSC1 and TSC2 alterations have been observed in patients with various cancers, including the most common cancer of the female reproductive organs, endometrial cancer, where ~3% contain TSC1 and/or TSC2 alterations. nab-Sirolimus, approved in the USA for patients with advanced malignant perivascular epithelioid cell tumor (PEComa), is an albumin-bound mTOR inhibitor (mTORi) that inhibits the mTOR pathway via suppression of the mTORC1 complex. When TSC1 or TSC2 is inactivated via mutation or loss, the mTOR pathway may be aberrantly activated. In an exploratory analysis of AMPECT (NCT02494570), a pivotal trial of nab-sirolimus in advanced malignant PEComa, 64.3% (9/14) of patients with pathogenic inactivating TSC2 or TSC1 alterations had a confirmed response. Most treatment-related adverse events in AMPECT were grade 1/2 (none were grade ≥4) and were consistent with mTORi-class adverse events. Based on the clinical observations from AMPECT and the underlying mechanism of action of nab-sirolimus, the PRECISION I trial was designed to assess the safety and efficacy of nab-sirolimus in a tumor-agnostic study of patients with advanced cancers with TSC1 or TSC2 inactivating alterations. Patients with endometrial cancer are expected to be enrolled based on the frequency of TSC1 and TSC2 inactivating alterations. Methods: Eligible patients are ≥12 years old and mTORi-naïve, possess advanced or metastatic malignant solid tumors with TSC1 or TSC2 inactivating alterations identified using next-generation sequencing (NGS) in tumor tissue or liquid biopsy (confirmed by central review of NGS reports), and have received appropriate standard treatments, per investigator. nab-Sirolimus 100 mg/m2 is given intravenously over 30 min on days 1 and 8 of each 21-day cycle. The primary endpoint is overall response rate per independent radiographic review (IRR) using Response Evaluation Criteria in Solid Tumors v1.1. Other endpoints include duration of response, time to response, progression-free survival by IRR, overall survival, patient-reported quality of life, and safety. Trial Status: Enrollment began in March 2022 and is expedited through collaboration with leading NGS providers; ongoing study access is facilitated through a just-in-time approach to trial location activation. Citation Format: Debra L. Richardson, Gopa Iyer, Li Ding, Anita N. Schmid, Willis Navarro, David Kwiatkowski, Jordi Rodon Ahnert. Phase 2, multicenter, open-label basket trial of nab-sirolimus for malignant solid tumors harboring pathogenic inactivating alterations in TSC1 and TSC2 (PRECISION I) [abstract]. In: Proceedings of the AACR Special Conference on Endometrial Cancer: Transforming Care through Science; 2023 Nov 16-18; Boston, Massachusetts. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(5_Suppl):Abstract nr B011.

PRECISION 1: A phase 2, multicenter, open-label basket trial of nab-sirolimus for malignant solid tumors harboring pathogenic inactivating alterations in TSC1 and TSC2.

TPS585 Background: SEER data report that US patients with advanced gastrointestinal (GI) cancers have a poor prognosis as indicated by low 5-year survival rates in patients with colorectal (15.6%), liver (3.5%), and other GI cancers, highlighting the need for more efficacious treatments. Dysregulation of the mTOR pathway contributes to tumor growth and disease progression in many cancers, including GI cancers. The tumor suppressor genes TSC1 and TSC2 are critical negative regulators of mTOR activity whose inactivation can lead to tumor cell growth. Inactivating TSC1 and TSC2 alterations have been observed in GI cancers with a combined frequency of up to 6.5% in hepatocellular carcinoma, 1.7% in colorectal adenocarcinoma and gastrointestinal stromal tumors, and 1.6% in cholangiocarcinoma. nab-Sirolimus, approved in the US for patients with advanced malignant perivascular epithelioid cell tumor (PEComa), is an albumin-bound mTOR inhibitor (mTORi) that inhibits the mTOR pathway via suppression of the mTORC1 complex. In an exploratory analysis of the pivotal AMPECT trial of nab-sirolimus in advanced malignant PEComa (NCT02494570), 8/9 (89%) and 1/5 (20%) patients with inactivating alterations in TSC2 and TSC1, respectively, had a confirmed response. Most treatment-related adverse events were grade 1/2 (none were grade ≥4) and were consistent with mTORi-class adverse events. Based on the clinical observations from AMPECT and the underlying mechanism of action of nab-sirolimus, the PRECISION 1 trial was designed to assess the safety and efficacy of nab-sirolimus in a tumor-agnostic study of patients with advanced cancers harboring TSC1 or TSC2 inactivating alterations. The trial is open to patients with GI cancers with inactivating alterations in TSC1 or TSC2. Methods: In PRECISION 1 (NCT05103358), eligible patients are ≥12 years old and mTORi-naïve, have advanced malignant solid tumors harboring TSC1 or TSC2 inactivating alterations identified using next-generation sequencing (NGS) of tumor tissue or liquid biopsy (confirmed by central review of NGS reports), and have received appropriate standard treatments, per investigator. nab-Sirolimus 100 mg/m2 is given intravenously over 30 min on days 1 and 8 of each 21-day cycle. The primary endpoint is overall response rate per independent radiographic review (IRR) using Response Evaluation Criteria in Solid Tumors v1.1. Other endpoints include duration of response, time to response, progression-free survival by IRR, overall survival, patient-reported quality of life, and safety. Enrollment began in March 2022. Collaboration with leading NGS vendors is expediting the identification of patients with qualifying TSC1 and TSC2 alterations; ongoing study access is facilitated through a just-in-time approach to trial location activation. Clinical trial information: NCT05103358 .

Abstract LB_B12: Phase 2, multicenter, open-label basket trial of nab-Sirolimus for malignant solid tumors harboring pathogenic inactivating alterations in TSC1 and TSC2 (PRECISION I)

Abstract BACKGROUND. nab-Sirolimus, approved in the US for patients with advanced malignant PEComa, is a novel albumin-bound mTOR inhibitor (mTORi) that inhibits the mTOR pathway via suppression of the mTORC1 complex. When TSC1 or TSC2 is inactivated via mutation or loss, the mTOR pathway may be aberrantly activated. Clinically, in an exploratory analysis of the pivotal AMPECT trial of nab-sirolimus in advanced malignant PEComa (NCT02494570), 8/9 (89%) and 1/5 (20%) patients with inactivating alterations in TSC2 and TSC1, respectively, had confirmed response (Wagner, J Clin Oncol, 2021). TSC1 and TSC2 alterations have been observed in patients with various cancers. Most treatment-related adverse events in AMPECT were grade 1/2 (none were grade ≥4) and were consistent with mTORi-class adverse events. Based on the clinical observations from AMPECT and the underlying mechanism of action of nab-sirolimus, the PRECISION I trial (NCT05103358) was designed to assess the safety and efficacy of nab-sirolimus in a tumor-agnostic study of advanced cancers with TSC1 or TSC2 inactivating alterations. METHODS. Eligible patients are ≥12 years old and mTORi-naïve, possess advanced malignant solid tumors with TSC1 or TSC2 inactivating alterations identified using next-generation sequencing (NGS) in tumor tissue or liquid biopsy (confirmed by central review of NGS reports), and have received appropriate standard treatments, per investigator. nab-Sirolimus 100 mg/m2 will be given intravenously over 30 min on Days 1 and 8 of each 21-day cycle. The primary endpoint is overall response rate per independent radiographic review (IRR) using RECIST v1.1. Other endpoints include duration of response, time to response, progression-free survival by IRR, overall survival, patient-reported quality of life, and safety. Enrollment began March 2022. Collaboration with leading NGS vendors will expedite the identification of patients with qualifying TSC1 and TSC2 mutations; ongoing study access is facilitated through a just-in-time approach to trial location activation. Based on the prevalence of TSC1 and TSC2 inactivating alterations, the most frequent tumor types expected are bladder, hepatobiliary, endometrial, soft tissue sarcoma, ovarian, and esophagogastric. Citation Format: Candace Haddox, Gopa Iyer, Michael J. Demeure, Li Ding, Anita N. Schmid, Willis H. Navarro, David J. Kwiatkowski, Jordi Rodon Ahnert. Phase 2, multicenter, open-label basket trial of nab-Sirolimus for malignant solid tumors harboring pathogenic inactivating alterations in TSC1 and TSC2 (PRECISION I) [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr LB_B12.

Phase 2, multicenter, open-label basket trial of nab-sirolimus for patients with malignant solid tumors harboring pathogenic inactivating alterations in TSC1 or TSC2 genes (PRECISION I).

TPS3168 Background: nab-Sirolimus is a novel albumin-bound mTOR inhibitor (mTORi) approved in the US for adult patients with malignant PEComa. In an exploratory analysis of the pivotal AMPECT trial of nab-sirolimus in advanced malignant PEComa (NCT02494570), 8/9 (89%) and 1/5 (20%) patients with inactivating alterations in TSC2 and TSC1, respectively, had confirmed response (Wagner, J Clin Oncol, 2021). TSC1 and TSC2 alterations have been observed in patients with a broad variety of cancers. Most treatment-related adverse events in AMPECT were grade 1/2 (none were grade ≥4) and were consistent with mTORi class adverse events. Methods: PRECISION I (NCT05103358) will evaluate efficacy and safety of nab-sirolimus in patients with TSC1 (Arm A) and TSC2 (Arm B) alterations. Eligible patients are ≥12 y old and mTORi-naïve, possess malignant solid tumors with TSC1/TSC2 inactivating alterations (confirmed by central review of sequencing reports), and have received appropriate standard treatments, per investigator. nab-Sirolimus 100 mg/m2 will be given weekly intravenously over 30 min on Days 1 and 8 of each 21-d cycle. The primary endpoint is overall response rate per independent radiographic review (IRR) using RECIST v1.1. Other endpoints include duration of response, time to response, progression-free survival by IRR, overall survival, patient-reported quality of life, and safety. Enrollment began March 2022. Collaboration with leading next-generation sequencing vendors will expedite the identification of patients with qualifying TSC1/TSC2 mutations; study access will be facilitated through a just-in-time approach to trial location activation. Based on the prevalence of TSC1/TSC2 inactivating alterations, the most frequent tumor types expected are bladder, hepatobiliary, endometrial, soft tissue sarcoma, ovarian, and esophagogastric (Table). Clinical trial information: NCT05103358 . [Table: see text]

Sintilimab plus chemotherapy for patients with EGFR-mutated non-squamous non-small-cell lung cancer with disease progression after EGFR tyrosine-kinase inhibitor therapy (ORIENT-31): second interim analysis from a double-blind, randomised, placebo-controlled, phase 3 trial

In the first interim analysis of the ORIENT-31 trial, compared with chemotherapy alone, sintilimab plus bevacizumab biosimilar IBI305 plus chemotherapy (pemetrexed and cisplatin) significantly improved progression-free survival in patients with EGFR-mutated non-squamous non-small-cell lung cancer (NSCLC) who progressed on EGFR tyrosine-kinase inhibitor treatment. However, the benefit of anti-PD-1 or PD-L1 antibody added to chemotherapy in this patient population remains unclear, with no prospective evidence from phase 3 trials globally. We report the results from the prespecified second interim analysis of progression-free survival between sintilimab plus chemotherapy and chemotherapy alone, the updated results of sintilimab plus IBI305 plus chemotherapy, and preliminary overall survival results. This double-blind, randomised, placebo-controlled, phase 3 trial was done at 52 centres across China and included patients aged 18-75 years with locally advanced or metastatic (stage IIIB, IIIC, or IV according to the American Joint Committee on Cancer, eighth edition) EGFR-mutated non-squamous NSCLC, disease progression after EGFR tyrosine-kinase inhibitor treatment (according to the Response Evaluation Criteria in Solid Tumours version 1.1 [RECIST 1.1]), and at least one measurable lesion (according to RECIST 1.1). Patients were randomly assigned (1:1:1), using an interactive web response system, to receive sintilimab (200 mg) plus IBI305 (15 mg/kg) plus pemetrexed (500 mg/m2) and cisplatin (75 mg/m2), sintilimab plus chemotherapy, or chemotherapy alone on day 1 of each 3-week cycle for four cycles, followed by maintenance therapy of sintilimab, IBI305, and pemetrexed. All study drugs were administered intravenously. The primary endpoint was progression-free survival in the intention-to-treat population assessed by an independent radiographic review committee. Data cutoff was March 31, 2022, unless otherwise specified. The study is registered at ClinicalTrials.gov, NCT03802240 (ongoing). Between July 11, 2019, and March 31, 2022, 1011 patients were screened and 476 were randomly assigned (158 to the sintilimab plus IBI305 plus chemotherapy group, 158 to the sintilimab plus chemotherapy group, and 160 to the chemotherapy alone group). The median follow-up duration for progression-free survival was 12·9 months (IQR 8·2-17·8) in the sintilimab plus IBI305 plus chemotherapy group, 15·1 months (8·0-19·5) in the sintilimab plus chemotherapy group, and 14·4 months (9·8-23·8) in the chemotherapy alone group. Sintilimab plus chemotherapy significantly improved progression-free survival compared with chemotherapy alone (median 5·5 months [95% CI 4·5-6·1] vs 4·3 months [4·1-5·3]; hazard ratio [HR] 0·72 [95% CI 0·55-0·94]; two-sided p=0·016). Significant progression-free survival benefit was sustained with sintilimab plus IBI305 plus chemotherapy compared with chemotherapy alone (median 7·2 months [95% CI 6·6-9·3]; HR: 0·51 [0·39-0·67]; two-sided p<0·0001). As of data cutoff (July 4, 2022), the median overall survival was 21·1 months (95% CI 17·5-23·9) for sintilimab plus IBI305 plus chemotherapy (HR 0·98 [0·72-1·34]) and 20·5 months (15·8-25·3) for sintilimab plus chemotherapy group (HR 0·97 [0·71-1·32]) versus 19·2 months (15·8-22·4) for chemotherapy alone; after adjusting for crossover, the HR for sintilimab plus IBI305 plus chemotherapy to chemotherapy alone ranged from 0·79 (0·57-1·09) to 0·84 (0·61-1·15) and the HR for sintilimab plus chemotherapy to chemotherapy alone ranged from 0·78 (0·57-1·08) to 0·84 (0·61-1·16). The safety results were generally consistent with those in the first interim analysis; in particular, treatment-related adverse events of grade 3 or worse occurred in 88 (56%) of 158 patients in the sintilimab plus IBI305 plus chemotherapy group, 64 (41%) of 156 patients in the sintilimab plus chemotherapy group, and 79 (49%) of 160 patients in the chemotherapy alone group. This is the first prospective phase 3 trial to show the benefit of anti-PD-1 antibody plus chemotherapy in patients with EGFR-mutated NSCLC who progressed on treatment with tyrosine-kinase inhibitors. Compared with chemotherapy alone, sintilimab combined with pemetrexed and cisplatin showed significant and clinically meaningful improvement of progression-free survival with an optimal safety profile. Sintilimab plus IBI305 plus chemotherapy continued to show progression-free survival benefit compared with chemotherapy alone in this second interim analysis with an additional 8-month follow-up. National Natural Science Foundation of China, Shanghai Municipal Science & Technology Commission Research Project, and Innovent Biologics. For the Chinese translation of the abstract see Supplementary Materials section.

Abstract CT057: Phase 2, multicenter open-label basket trial of nab-sirolimus for patients with inactivating alterations in TSC1 or TSC2 (PRECISION I)

Abstract nab-Sirolimus is a novel albumin-bound mTOR inhibitor (mTORi) approved in the US for adult patients with malignant PEComa. In an exploratory analysis of the pivotal AMPECT trial of nab-sirolimus in advanced malignant PEComa (NCT02494570), 8/9 (89%) and 1/5 (20%) patients with inactivating alterations in TSC1 and TSC2, respectively, had confirmed response (Wagner, J Clin Oncol, 2021). TSC1 and TSC2 alterations have been observed in patients with a broad variety of cancers. Most treatment-related adverse events in AMPECT were grade 1/2 (none were grade ≥4) and were consistent with long-term treatment of nab-sirolimus. PRECISION I (NCT05103358) will evaluate efficacy and safety of nab-sirolimus in patients with TSC1 (Arm A) and TSC2 (Arm B) alterations. Eligible patients are ≥12 years old and mTORi-naïve, possess malignant solid tumors with TSC1 or TSC2 inactivating alterations (confirmed by central review of sequencing reports), and have received appropriate standard treatments, as determined by the investigator. nab-Sirolimus 100 mg/m2 will be given weekly intravenously over 30 minutes on Days 1 and 8 of each 21-day cycle. The primary endpoint is overall response rate per independent radiographic review (IRR) using RECIST v1.1. Other endpoints include duration of response, time to response, progression-free survival by IRR, overall survival, patient-reported quality of life, and safety. Enrollment began March 2022. Collaboration with leading next-generation sequencing vendors will expedite the identification of patients with qualifying TSC1 or TSC2 mutations; study access will be facilitated through a “just-in-time” approach to trial location activation. Based on the prevalence of TSC1 or TSC2 inactivating alterations, the most frequent tumor types expected are bladder, hepatobiliary, endometrial, soft tissue sarcoma, ovarian, and esophagogastric (Table). Est incidence of patients with TSC1 or TSC2 alterations available for 1L therapy in 2030 Tumor Type TSC1 Mutations, %a TSC2 Mutations, %a Eligible TSC1 or TSC2 Combined, % Bladder 6.33 1.70 8.03 Hepatobiliary 1.27 3.31 4.58 Endometrial 2.10 1.22 3.32 Soft tissue sarcoma 1.28 1.71 2.99 Ovarian 1.85 0.92 2.77 Esophagogastric 0.65 1.46 2.11 Colorectal carcinoma 0.99 0.39 1.38 Pancreatic 0.57 — 0.57 Note: Estimated incidence of patients in the United States with definite impact TSC1 or TSC2 alterations available for 1L therapy in 2030. All gastrointestinal tumors (bolded) with known incidence of TSC1 or TSC2 and tumor types with combined incidence of TSC1 or TSC2 alterations of &amp;gt;2% are listed. aThe proportion of patients with definite impact mutations (ie, mutations known to have a biological impact, including frameshift, nonsense, and splice-site mutations and deep deletions) was derived from the NIH NCI Genomic Data Commons Data Portal (NIH NCI Genomic Data Commons). 1L, first-line. Citation Format: Jordi Rodon Ahnert, Brian Schulte, Michael J. Demeure, Dustin Deming, Noah Federman, Meredith A. McKean, Elizabeth Lee, Alexander Spira, David J. Kwiatkowski, Maen Hussein, Erlinda Gordon, David Crockett, Kristen Ganjoo, Lee D. Cranmer, Anita N. Schmid, Willis H. Navarro, Loretta M. Itri, Gopa Iyer. Phase 2, multicenter open-label basket trial of nab-sirolimus for patients with inactivating alterations in TSC1 or TSC2 (PRECISION I) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT057.

Phase 2, multicenter, open-label basket trial of nab-sirolimus for patients with malignant solid tumors harboring pathogenic inactivating alterations in TSC1 or TSC2 genes (PRECISION I).

TPS597 Background: Albumin-bound ( nab)-sirolimus, a novel mTOR inhibitor (mTORi) that utilizes nanoparticle technology to preferentially target tumors, is approved in the US for the treatment of adults with malignant PEComa. In an exploratory analysis of the AMPECT registrational trial of nab-sirolimus in advanced malignant PEComa (NCT02494570), 8/9 (89%) and 1/5 (20%) patients with TSC1 and TSC2 inactivating alterations, respectively, had confirmed response (Wagner, J Clin Oncol. 2021). Importantly, both TSC1 and TSC2 alterations have been observed in patients with various gastrointestinal cancers (Table). Overall, most treatment-related adverse events (TRAEs) in AMPECT were grade 1/2 and manageable for long-term treatment; no grade ≥4 TRAEs occurred. Methods: PRECISION I (NCT05103358) is a phase 2, open-label, multi-institutional basket trial evaluating efficacy and safety of nab-sirolimus in patients with alterations in TSC1 (Arm A) and TSC2 (Arm B). Patients ≥12 years old with malignant solid tumors harboring pathogenic inactivating alterations in TSC1 or TSC2 (confirmed by central review of next-generation sequencing reports) who have progressed on standard therapies and are mTORi-naïve are eligible. nab-Sirolimus 100 mg/m2 will be administered weekly as an intravenous infusion over 30 minutes on Days 1 and 8 of each 21-day cycle. The primary endpoint is overall response rate determined by independent review using RECIST v1.1; other endpoints include duration of response, disease control rate, time to response progression-free survival by independent radiographic review, overall survival, patient-reported quality of life, and safety. Enrollment is ongoing. The most frequent tumor types expected in this tissue-agnostic trial are bladder, hepatobiliary, endometrial, soft tissue sarcoma, ovarian, and esophagogastric based on the prevalence of TSC1 or TSC2 alterations (Table). Clinical trial information: NCT05103358 . [Table: see text]

Phase 2, multicenter, open-label basket trial of nab-sirolimus for patients with malignant solid tumors harboring pathogenic inactivating alterations in TSC1 or TSC2 genes (PRECISION I).

TPS818 Background: Albumin-bound ( nab)-sirolimus, a novel mTOR inhibitor (mTORi) that utilizes nanoparticle technology to preferentially target tumors, is approved in the US for the treatment of adults with malignant PEComa. In an exploratory analysis of the AMPECT registrational trial of nab-sirolimus in advanced malignant PEComa (NCT02494570), 8/9 (89%) and 1/5 (20%) patients with TSC1 and TSC2 inactivating alterations, respectively, had confirmed response (Wagner, J Clin Oncol. 2021). Importantly, both TSC1 and TSC2 alterations have been observed in patients with various gastrointestinal cancers (Table). Overall, most treatment-related adverse events (TRAEs) in AMPECT were grade 1/2 and manageable for long-term treatment; no grade ≥4 TRAEs occurred. Methods: PRECISION I (NCT05103358) is a phase 2, open-label, multi-institutional basket trial evaluating efficacy and safety of nab-sirolimus in patients with alterations in TSC1 (Arm A) and TSC2 (Arm B). Patients ≥12 years old with malignant solid tumors harboring pathogenic inactivating alterations in TSC1 or TSC2 (confirmed by central review of next generation sequencing reports) who have progressed on standard therapies and are mTORi-naïve are eligible. nab-Sirolimus 100 mg/m2 will be administered weekly as an intravenous infusion over 30 minutes on Days 1 and 8 of each 21-day cycle. The primary endpoint is overall response rate determined by independent review using RECIST v1.1; other endpoints include duration of response, disease control rate, time to response, progression-free survival by independent radiographic review, overall survival, patient-reported quality of life, and safety. Enrollment is ongoing. The most frequent tumor types expected in this tissue-agnostic trial are bladder, hepatobiliary, endometrial, soft tissue sarcoma, ovarian, and esophagogastric based on the prevalence of TSC1 or TSC2 alterations (Table). Clinical trial information: NCT05103358 . [Table: see text]

A Phase 1 Study of ADI-001: Anti-CD20 CAR-Engineered Allogeneic Gamma Delta1 (γδ) T Cells in Adults with B-Cell Malignancies

Introduction: ADI-001 is a first-in-class allogeneic gamma delta (γδ) CAR T cell therapy targeting the B-cell antigen CD20. ADI-001 has both adaptive and innate cytotoxic effector functions to complement CAR targeting, potentially enhancing efficacy and reducing the possibility of tumor escape due to antigen loss. ADI-001 expresses MHC-independent γδ T cell receptors, thus lowering the risk of graft-versus-host disease (GvHD) without the need for gene editing. Methods: This multicenter phase 1 clinical trial is evaluating ADI-001 in adults with relapsed / refractory B-cell lymphoma. Eligibility criteria included the presence of measurable lesions, expression of CD20 on tumor cells and ≥ 2 prior systemic therapies. All patients received conditioning therapy with fludarabine and cyclophosphamide. ADI-001 can be administered at four dose levels (DL) (DL1:3E7, DL2:1E8, DL3:3E8 and DL4:1E9 CAR+ cells) in a 3+3 dose-escalation scheme. Patients who completed the 28-day DLT period were considered evaluable. In DL3, patients could receive a second course of conditioning therapy and be re-dosed with ADI-001 if there was no DLT during the first 28 days, no progressive disease on PET/CT assessment on Day 28, and have recovered from cytopenias. Treatment-emergent adverse events were graded by CTCAE v5.0, and Immune Effector Cell Associated Neurologic Syndrome (ICANS) and Cytokine Release Syndrome (CRS) assessments were performed per ASTCT criteria. Objective response rates (ORR) were evaluated by independent radiographic review per Lugano 2014 criteria. Results: As of 15 July 2022, 11 patients were enrolled and nine were evaluable. Of these nine patients, six (67%) were male and the median age was 62 years (range 45-75). Eight patients had large B-cell lymphoma (LBCL) and one had mantle cell lymphoma (MCL). Of the eight patients with LBCL, five had diffuse-large B-cell lymphoma (DLBCL), two had high-grade B-cell lymphoma (HGBCL) with double/triple hit, and one had HGBCL not otherwise specified. At baseline, the median IPI score was four (range 2-4); the median tumor burden was 2,974 (150-7,919) mm2, and 89% (8/9) had stage III/IV disease. The median number of prior therapies was four (range 2-5). Four patients had prior anti-CD19 CAR T cell therapy (two Liso-cel and two Axi-cel). Among nine evaluable patients, three patients were treated at each of DL1, DL2, and DL3. Two patients at DL3 were re-dosed with a second course of ADI-001. Two patients developed CRS: one Grade 1 and one Grade 2. One patient developed a Grade 1 ICANS which resolved within 24 hours. There were no ≥ Grade 3 CRS or ICANS. The only related SAEs were Grade 2 CRS, Grade 1 ICANS and Grade 3 adenoviraemia. There was no reported GvHD or protocol-defined DLT events. The best ORR was 78% (7/9), and the complete response (CR) rate was 78% (7/9). For the four patients who had prior CD19 CAR T therapies, the ORR was 100% (4/4) and CR rate was also 100%. As of the data cut-off date, of the seven patients who had achieved CR, two patients progressed, one died while in complete remission and four were still in CR and in active follow-up, with a range of follow-up time between 1.2 and 8.8 months. CAR+ γδ T cell kinetics improved in a dose-dependent manner with peak cell expansion occurring between Days 7 and 10 at DL3 based on flow cytometry. Conclusions: ADI-001 γδ CAR T cells maintained a favorable safety profile. Preliminary efficacy showed encouraging CR rate and sustained durability in patients, including those previously exposed to CAR T therapy. Additional data will be presented at the meeting. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Final overall survival data of sintilimab plus pemetrexed and platinum as First-Line treatment for locally advanced or metastatic nonsquamous NSCLC in the Phase 3 ORIENT-11 study

ObjectivesIn ORIENT-11, first-line sintilimab + pemetrexed-platinum significantly improved PFS compared with placebo + pemetrexed-platinum in patients with advanced metastatic nonsquamous non-small-cell lung cancer (AMnsqNSCLC). The study met the primary endpoint of PFS as of 15November2019. Here we report final survival analysis from ORIENT-11 (NCT03607539) using a 15September2021 data cutoff. MethodsPatients with treatment-naïve locally AMnsqNSCLC without sensitizing EGFR or ALK genomic tumor aberrations were randomly assigned to sintilimab + pemetrexed-platinum (n = 266) or placebo + pemetrexed-platinum (n = 131). Patients were stratified by PD-L1 expression, platinum-chemotherapy, and gender. Treatment continued until PD, unacceptable toxicity, or a maximum of 24 months. Patients in the placebo + pemetrexed-platinum arm could be sequenced to second-line sintilimab monotherapy, contingent upon PD. Response was assessed (RECISTv.1.1) by blinded independent radiographic review committee. Primary endpoint was PFS. OS was a secondary endpoint and defined from date of randomization to date of death due to any cause. Final OS analysis was defined as approximately 2 years after last patient randomized or when approximately 65 % of patients died, whichever first. ResultsAt data cutoff of final OS analysis, median study follow-up was 30.8 months. Of 397 patients, 243 OS events were observed (sintilimab + pemetrexed-platinum:151[57 %];placebo + pemetrexed-platinum:92 [70 %]). Of the patients in placebo + pemetrexed-platinum arm, 47 % crossed over to sintilimab monotherapy per protocol. Median OS was 24.2 months in sintilimab + pemetrexed-platinum arm and 16.8 months in placebo + pemetrexed-platinum arm (HR:0.65[95 % CI:0.50,0.85]). Estimated 2-year OS rates were 50 %(sintilimab + pemetrexed-platinum) and 32 %(placebo + pemetrexed-platinum). After adjusting for the crossover effect, OS treatment effect was more pronounced with HR 0.52 (95 % CI:0.38,0.69). OS benefit across all prespecified subgroups was largely consistent with that observed in the ITT population. ConclusionsIn the ORIENT-11 final OS analysis, sintilimab + pemetrexed-platinum demonstrated improved OS compared to placebo + pemetrexed-platinum when administered as first-line therapy in AMnsqNSCLC without EGFR or ALK genomic tumor aberrations.

A phase 1 study of ADI-001: Anti-CD20 CAR-engineered allogeneic gamma delta (γδ) T cells in adults with B-cell malignancies.

7509 Background: ADI-001 is a first-in-class allogeneic gamma delta (γδ) CAR T-cell therapy targeting the B-cell antigen CD20. ADI-001 also has both adaptive and innate cytotoxic effector functions to complement CAR targeting, potentially enhancing efficacy and reducing the possibility of tumor escape due to antigen loss. ADI-001 expresses MHC independent γδ T cell receptors, thus lowering the risk of graft versus host disease (GvHD) without the need for gene-editing. Methods: This phase 1 trial evaluates ADI-001 in adults with relapsed/refractory advanced B-cell lymphoma. Eligibility criteria included presence of measurable lesions, expression of CD20 and ≥ 2 prior systemic therapies. All patients received conditioning therapy with fludarabine and cyclophosphamide. ADI-001 is administered at 3 flat dose levels (DL; DL1:3E7, DL2:1E8, or DL3:3E8 cells) in a 3 + 3 dose-escalation scheme. Dose-limiting toxicities (DLT) were monitored during the initial 28-days post-treatment. Patients who completed the 28-day DLT period were considered evaluable. Treatment-emergent adverse events were graded by CTCAE v5.0, and immune effector cell toxicity assessment and grading were performed per ASTCT criteria. Objective response rates (ORR) were evaluated by independent radiographic review per Lugano 2014 criteria. Results: As of 14 February 2022, eight patients were enrolled and six were evaluable. Of these six patients, 2/6 were female (33%) and the median age was 62 years (range 45-75). The median number of prior therapies was 3.5 (range 2-5) and median IPI score was 3.5 (range 2-4). One patient received prior anti-CD19 CAR T cells therapy with lisocabtagene maraleucel. There were five patients with large B-cell lymphoma and one with mantle cell lymphoma. Among the six evaluable patients, three were treated on DL1 and three on DL2. Most related AEs (78%) were of grade 1/2. There were three AESI: two CRS (one grade 1 and one grade 2) and one grade 1 ICANS, and the only related SAEs were the grade 2 CRS and grade 1 ICANS. There was no reported GvHD and no protocol defined DLT events. At day 28, the ORR based upon PET/CT was 67% (4/6 patients) and the CR rate was 67% (4/6 patients). Both patients with ≥ 3 months post-treatment follow-up remained in CR. Additional data will be presented at the meeting. Conclusions: ADI-001 γδ CAR T cells were well tolerated, with a favorable safety profile and encouraging preliminary efficacy. Patients who achieved CR at day 28 appeared to be disease free during further follow-up at month-3. Clinical trial information: NCT04735471.

Comparison of Existing and New Total Knee Arthroplasty Implant Systems From the Same Manufacturer: A Prospective, Multicenter Study.

Introduction:This study evaluated total knee arthroplasty (TKA) outcomes for an Existing-TKA versus New-TKA from the same manufacturer.Methods:TKA outcomes for 752 with Existing-TKA versus 1129 subjects with New-TKA were followed through 2 years using patient-reported outcome measures (PROMs). Responders were assessed per Outcome Measures in Rheumatology-Osteoarthritis Research Society International criteria. Kaplan-Meier implant survivorship was estimated. Radiographs had an independent radiographic review.Results:Two-year follow-up was 84.6% (636/752) for Existing-TKA and 82.5% (931/1129) for New-TKA. Two-year PROMs mean outcomes for New-TKA versus Existing-TKA at 2 years were: Knee Injury and Osteoarthritis Outcome Score (ADL: 89.0 versus 86.8, P = 0.005; pain: 88.9 versus 87.1, P = 0.019; symptoms: 84.1 versus 82.2, P = 0.017; Sport/Rec: 63.9 versus 58.8, P = 0.001; and QOL: 77.0 versus 73.5, P = 0.003), Patient's Knee Implant Performance (overall: 76.5 versus 73.5, P = 0.003; confidence: 8.4 versus 8.1, P = 0.004; stability: 8.6 versus 8.3, P = 0.006; satisfaction: 8.3 versus 8.1, P = 0.042; and modifying activities: 6.6 versus 6.4, P = 0.334), Oxford Knee Score (41.9 versus 41.1, P = 0.027), and EQ5D-3L (0.88 versus 0.88, P = 0.737). Two-year responder rates using WOMAC were 93.9% versus 90.6% (P = 0.018) for New-TKA versus Existing-TKA. Independent radiographic review showed that tibial and femoral radiolucencies ≥2 mm were similar (P ≥ 0.05) or favored New-TKA. Implant survivorship was similar between groups (log-rank P = 0.9994).Discussion:New-TKA versus Existing-TKA demonstrated slightly better PROMs with similar radiographic and implant survivorship outcomes.

VP9-2021: ORIENT-31: Phase III study of sintilimab with or without IBI305 plus chemotherapy in patients with EGFR mutated nonsquamous NSCLC who progressed after EGFR-TKI therapy

Treatment option for nonsquamous non-small cell lung cancer (nsqNSCLC) with epidermal growth factor receptor mutations (EGFRm) is limited upon progression after tyrosine kinase inhibitors (TKIs). ORIENT-31 is a randomized, double-blind, phase 3 study of sintilimab (sint, anti-PD-1 antibody) with or without IBI305 (bevacizumab biosimilar) plus chemotherapy (chemo) in patients (pts) with EGFRm nsqNSCLC who progressed after EGFR TKI therapy (NCT03802240). Pts with EGFRm nsqNSCLC who had progressed afterEGFR-TKI therapy were randomized (1:1:1) to Arm A (sint + IBI305 + chemo), Arm B [sint + placebo 2 (pb2) + chemo] or Arm C (pb1 + pb2 + chemo), stratified by sex (male vs female) and brain metastasis (yes vs no). Sint / pb1 (200 mg), IBI305 / pb2 (15 mg/kg), pemetrexed (500 mg/m2) and cisplatin (75 mg/m2) were administered IV Q3W for 4 cycles, followed by maintenance treatment of sint / pb1, IBI305 / pb2 and pemetrexed. Conditional crossover to sint monotherapy was allowed for pts in Arm C. Primary endpoint is progression-free survival (PFS) by independent radiographic review committee (IRRC). By data cutoff (31 Jul, 2021, median follow up of 9.8m) of first interim analysis, 444 pts were randomized (Arm A / B / C 148 / 145 / 151). Median age was 57 y. 36.0% pts had brain metastasis. Previously, 63.7% pts received 1st or 2nd generation (G) TKI with T790M-, 28.2% pts received 1st or 2nd and then 3rd G TKI with T790M+, 8.1% pts received first-line 3rd G TKI. Median PFS (95%CI) by IRRC was 6.9m (6.0, 9.3) in Arm A, 5.6m (4.7, 6.9) in Arm B, 4.3m (4.1, 5.4) in Arm C. PFS was significantly prolonged in Arm A vs. Arm C (HR 0.464, 95%CI: 0.337, 0.639; p<0.0001). Arm B showed trend of PFS benefit vs. Arm C (HR 0.750, 95%CI: 0.555, 1.013; p=0.0584). The futility analysis of Arm A vs. B did not cross the futility boundary (HR 0.726, 95%CI: 0.528, 0.998). Confirmed ORR were 43.9%, 33.1% and 25.2% in Arm A, B and C respectively. Incidence of grade ≥3 treatment-emergent AEs were 54.7%, 39.3% and 51.0% respectively. In pts with EGFRm nsqNSCLC who progressed after EGFR-TKIs, sint combined with IBI305 and chemo has significantly improved PFS compared with chemo alone.

Sintilimab Plus Platinum and Gemcitabine as First-Line Treatment for Advanced or Metastatic Squamous NSCLC: Results From a Randomized, Double-Blind, Phase 3 Trial (ORIENT-12)

IntroductionThe standard chemotherapy for squamous NSCLC (sqNSCLC) includes platinum plus gemcitabine. Sintilimab, an anti–programmed cell death protein 1 antibody, plus platinum and gemcitabine (GP) has revealed encouraging efficacy as first-line therapy for sqNSCLC in a phase 1b study. We conducted a randomized, double-blind, phase 3 study to further compare the efficacy and safety of sintilimab with placebo, both in combination with GP. MethodsORIENT-12, a randomized, double-blind, phase 3 study, was conducted at 42 centers in the People’s Republic of China (ClinicalTrials.gov, number NCT03629925). Patients with locally advanced or metastatic sqNSCLC and without EGFR-sensitive mutations or ALK rearrangements were enrolled in the study. The stratification factors included clinical stage, choice of platinum, and programmed death-ligand 1 tumor proportion score. The patients, investigators, research staff, and sponsor team were masked to treatment assignment. Eligible patients were randomized 1:1, using an integrated web-response system, to receive sintilimab 200 mg or placebo plus GP every 3 weeks for four or six cycles, followed by sintilimab or placebo as maintenance therapy until disease progression or 2 years. The primary end point was progression-free survival (PFS), assessed by an independent radiographic review committee. ResultsBetween September 25, 2018 and July 26, 2019, a total of 543 patients were screened, of whom 357 patients were randomized to the sintilimab-GP group (n = 179) and the placebo-GP group (n = 178). After a median follow-up period of 12.9 months, sintilimab-GP continued to reveal a meaningful improvement in PFS than placebo-GP (hazard ratio = 0.536 [95% confidence interval: 0.422–0.681], p < 0.00001). Treatment-emergent adverse events of grade 3 or worse occurred in 86.6% patients in the sintilimab-GP group and in 83.1% in the placebo-GP group. The incidence of treatment-emergent adverse event leading to death was 4.5% and 6.7% in the two treatment groups, respectively. ConclusionsRegarding PFS, sintilimab plus GP reveals clinical benefit than GP alone as first-line therapy in patients with locally advanced or metastatic sqNSCLC. The toxicity was acceptable, and no new unexpected safety signals were observed.

LBA2 Sintilimab plus bevacizumab biosimilar vs sorafenib as first-line treatment for advanced hepatocellular carcinoma (ORIENT-32)2

ORIENT-32 is a randomized, open-label, multi-center phase II/III study to evaluate the efficacy and safety of sintilimab (anti-PD-1 antibody) plus a bevacizumab biosimilar (anti-VEGF antibody), versus sorafenib as first-line treatment for advanced hepatocellular carcinoma (HCC). The phase II part has demonstrated an acceptable safety of this combination. Here we report the result of phase III part (NCT03794440). Patients (pts) with unresectable or metastatic, systemic treatment naive HCC were enrolled and randomized (2:1) to receive sintilimab (200 mg IV Q3W) plus bevacizumab biosimilar (15 mg/kg IV Q3W) (SinBev arm) or sorafenib (400 mg orally, BID) (Sor arm). Stratification factors were macrovascular invasion and/or extrahepatic metastasis (presence vs absence), baseline alpha fetoprotein level (< 400 vs ≥400 ng/mL) and ECOG PS (0 vs 1). The primary endpoints were OS and PFS by independent radiographic review committee (IRRC) per RECIST 1.1. As data cutoff date (Aug 15, 2020), 571 pts were enrolled to SinBev arm (n=380) and Sor arm (n=191). The baseline characteristics were well balanced between two arms, with most pts had hepatitis B infection (94.2%) and 4.2% of pts with Child-Pugh B. With a median follow-up of 10.0 m, median OS was significantly longer in SinBev arm than that in Sor arm (NE vs. 10.4 m, HR 0.57, 95%CI: 0.43-0.75, P<0.0001). Median PFS was significantly improved in SinBev arm as compared with Sor arm (4.5 m vs. 2.8 m, HR 0.57, 95%CI: 0.46-0.70, P<0.0001). The superior OS and PFS benefits with SinVev over Sor were generally consistent across all relevant subgroups. Among pts with evaluable tumor assessment at baseline, the confirmed ORR by IRRC per RECIST 1.1 was 20.3% (74/364, 95%CI: 16.3%-24.8%) in SinBev arm and 4.1% (7/172, 95%CI: 1.7%-8.2%) in Sor arm. Of pts receiving at least one drug dose, the incidences of treatment related adverse events were 88.7% in SinBev arm (n=380) and 93.5% in Sor arm (n=185). Grade 3-4 TRAEs occurred in 33.7% and 35.7% of pts, respectively. Sintilimab plus bevacizumab biosimilar as first-line treatment was associated with significantly improved clinical benefits than sorafenib in pts with advanced HCC.

Independent Radiographic Review of Joint Space Following First Metatarsophalangeal Synthetic Cartilage Implantation: Is There an Association Between Joint Space and Outcomes?

Category:Midfoot/Forefoot; OtherIntroduction/Purpose:Synthetic cartilage implants for first metatarsophalangeal osteoarthritis have been used for nearly a decade with Level 1 clinical evidence showing 84.9% of implants remain in place at a mean follow-up of 5.8 years. In contradiction to these positive results, however, some recent publications have shown higher revision rates and attempted to correlate the need for revision with the postoperative joint space interval. Most of these studies performed assessments based off of routine anterior-posterior (AP) radiographs using hand drawn measurements without image calibration or scaling. The purpose of this independent radiographic review was to further explore any relationship between joint space integrity and the need for revision surgery.Methods:An independent radiographic review by two board-certified, fellowship-trained, practicing musculoskeletal radiologists with no competing financial interests was conducted for 15 subjects from a previously concluded Level 1 clinical trial looking at outcomes of a synthetic cartilage implant. Ten (10) subjects with positive outcomes and 5 who required revision were selected at random for evaluation. Weight-bearing AP and lateral radiographs at baseline, 2 weeks, 6, 12, 24, and 60 months were reviewed. Using previously validated Quantitative Motion Analysis software, joint space was measured in the medial, central, and lateral locations on AP radiographs and dorsal, central, and plantar locations on lateral radiographs (Coughlin et al. 2003). Measurements were normalized to the proximal phalanx width in the relevant view (AP or lateral) to adjust for lack of image scaling or calibration. Normalized joint spaces at each interval and changes from the 2-week visit, the earliest with the implant in place, were evaluated.Results:In this pilot study, no relationship between mean normalized joint space and implant removal was found at any time point over the 60-month follow-up. Scatterplots were used to determine if movement in different directions impacted mean values. There was significant overlap for the two groups in joint space at each subject’s final visit with the implant in place and the change from the 2-week visit to the final visit (Figure 1). The majority of subjects in both groups experienced changes in joint space of less than 10% across all measurements. The maximum change from the 2-week visit in the revision group was less than 15%, compared to over 25% for subjects in the retention group.Conclusion:Neither joint space at final follow-up nor joint space change from initial postoperative assessment were associated with revision. The maximum observed decrease in the revision group was less than 15%, or 0.5 mm in a joint space of 3 mm. Both the clinical relevance of this minimal decrease and whether or not it can be reliably assessed remain unclear. Future studies could examine patient factors other than joint space to determine success or failure of this implant. These preliminary results suggest joint space integrity evaluated from plain film is a weak indicator of clinical efficacy with this synthetic cartilage implant.

1667O - Results of the TAPPAS trial: An adaptive enrichment phase III trial of TRC105 and pazopanib (P) versus pazopanib alone in patients with advanced angiosarcoma (AS)

BackgroundPazopanib (P) is approved for refractory advanced STS refractory. A retrospective study of 40 AS patients treated with P, reported a median progression-free survival (PFS) of 3.1 months and median overall survival (OS) 9.9 months (Kollar et al, Acta Oncol, 2017). Endoglin is an essential angiogenic receptor expressed on AS cells that is upregulated following VEGF inhibition. TRC105, an endoglin antibody, combined with P produced a median PFS of 7.8 months in chemotherapy-refractory and P-naïve patients enrolled on a phase I-II trial. MethodsTAPPAS was a randomized multicenter trial of TRC105/P vs P that enrolled cutaneous and non-cutaneous AS patients and incorporated an adaptive enrichment design. Key inclusion criteria: 0-2 prior lines of therapy, ECOG ≤ 1. The primary endpoint was PFS by RECIST 1.1 by independent radiographic review (+ cutaneous lesions by photography) (IRR). Secondary endpoints included PFS by investigator review (INV) and OS. An interim analysis to determine the final sample size was conducted following enrollment of 123 patients. ResultsOf 123 pts (TRC105/P, 62; P, 61), 60% were female, 89% were white; median age was 68 years (range: 24-82); 46% were ECOG PS 0; 50% had cutaneous disease; and 28% had no prior treatment. TRC105/P did not prolong median PFS or OS compared to P (Table). Most common all-grade adverse events (AEs) in TRC105/P vs P: fatigue (61% vs 55%); headache (64% vs 23%), diarrhea (57% vs 51%), nausea (48% vs 49%), vomiting (38% vs 23%), anemia (44% vs 9.4%), epistaxis (56% vs 3.8%) & hypertension (36% vs.55%).Table1667OTablePTRC105/PMedian PFS, mo (95% CI), IRR4.3 (2.9-NE)4.2 (2.8-8.3)HR (95% CI)0.98 (0.52-1.8)p-value0.95Median PFS, mo (95% CI), Investigator2.9 (2.6-4.1)3.9 (2.6-5.5)HR (95% CI)0.77 (0.46-1.78)p-value0.31Median PFS, cutaneous, mo (95% CI), IRR5.6 (2.6-5.6)4.2 (2.8-8.3)HR (95% CI)1.07 (0.43, 2.7)p-value0.89Overall Survival, mo (95% CI)8.7 (7.4, NE)NE (6.8, NE)Odds ratio (95% CI)0.90 (0.46, 1.74)p-value0.74Overall Survival, cutaneous, mo (95% CI)8.0 (6.7, NE) NE (6.8, NE)Odds ratio (95% CI)0.68 (0.25, 1.84)p-value0.45NE: not estimable; CI: confidence interval; mo: months ConclusionsTRC105 did not demonstrate activity when combined with P in angiosarcoma. This was the 1st randomized phase III trial in angiosarcoma. These data provide a benchmark of the activity of P in 1st + 2nd-line setting in AS. A number of patients derived durable benefit from the combination schedule, indicating the heterogeneity of angiosarcomas. Clinical trial identificationNCT 02979899. Legal entity responsible for the studyTracon Pharmaceuticals, Inc. FundingTracon Pharmaceuticals, Inc. DisclosureR.L. Jones: Advisory / Consultancy: Tracon; Advisory / Consultancy: Adaptimmune; Advisory / Consultancy: Blueprint; Advisory / Consultancy: Clinigen; Advisory / Consultancy: Deciphera; Advisory / Consultancy: Daichii; Advisory / Consultancy: Eisai; Advisory / Consultancy: Epizyme; Advisory / Consultancy: PharmaMar; Advisory / Consultancy: Lilly; Advisory / Consultancy: Merck. L. Liu: Full / Part-time employment: Tracon. C. Theuer: Full / Part-time employment: Tracon. All other authors have declared no conflicts of interest.

Five-year Outcomes of a Synthetic Cartilage Implant for the First Metatarsophalangeal Joint in Advanced Hallux Rigidus

Category: Midfoot/Forefoot Introduction/Purpose: Hallux rigidus is the most common arthritic condition of the foot. A prospective, randomized, non-inferiority clinical trial of first metatarsophalangeal joint (MTPJ) hemiarthroplasty with a synthetic polyvinyl alcohol hydrogel implant, for moderate to severe hallux rigidus, demonstrated maintenance of MTPJ active dorsiflexion motion and excellent pain relief; additionally, the trial showed functional outcomes and safety equivalent to first MTPJ arthrodesis at 24 months (Baumhauer et al. 2016; FAI:37(5):457-469). Recognizing that many hemiarthroplasty and total toe implants have initially good results that deteriorate over time, the purpose of this study was to prospectively assess the safety and efficacy outcomes for the synthetic cartilage implant population and to determine if the excellent outcomes were maintained at &gt;5 years. Methods: One hundred and fifty-two patients underwent implant hemiarthroplasty in the original trial; 14 underwent implant removal and conversion to fusion and 3 were lost to follow-up during the first 24 months, leaving 135 eligible for this study. One hundred patients were evaluated at 5+ years; 5 could not be reached for follow-up. Thirty are pending consent, follow-up, and/or data entry; their status will be available for inclusion at the conference presentation. Patients completed a pain visual analogue scale (VAS) and Foot and Ankle Ability Measure (FAAM) Sports and Activities of Daily Living (ADL) scores, preoperatively and at 2, 6, 12, 26, 52, 104 and 260 weeks postoperatively. Minimal clinically important differences are: =30% difference for pain VAS, 9 points for FAAM Sports, and 8 points for FAAM ADL. Great toe active dorsiflexion, weight-bearing radiographs, secondary procedures, and safety parameters were evaluated. Results: Of 100 synthetic cartilage implant hemiarthroplasty patients available at mean 5.8 years follow-up (SD ±0.7; range: 4.4- 7.4), 5 underwent implant removal and conversion to fusion in years 2-5 (Figure 1), and 2 underwent subsequent surgical interventions during the pivotal trial and were censored, leaving 93 patients for evaluation. Pain and function outcomes observed at 5.8 years were similar to those at 2 years (Figure 1). VAS Pain and FAAM Sports Scores were maintained or improved at 5.8 years follow-up, but these differences were not clinically significant. Joint motion was maintained at 5.8 years. No evidence of avascular necrosis, device migration or fragmentation was observed upon independent radiographic review. Eighty-six percent of patients agreed their overall well-being had improved, and 92% would have the procedure again. Conclusion: Clinical and safety outcomes of patients having undergone synthetic cartilage implant hemiarthroplasty for the surgical treatment of hallux rigidus were previously demonstrated to be non-inferior to the gold standard treatment, MTPJ fusion, at 2 years. Prospectively determined outcomes for 100/135 of these implant hemiarthroplasty patients at 5.8 years are similar to those reported at 2 years. Longer-term results demonstrate that clinical and safety outcomes for synthetic cartilage implant hemiarthroplasty are durable, and that the implant remains a viable treatment option to decrease pain, improve function and maintain motion for advanced hallux rigidus.

Safety and Activity of Brentuximab Vedotin (BV) Plus Ifosfamide, Carboplatin, and Etoposide (ICE) for Relapsed/Refractory (Rel/Ref) Classical Hodgkin Lymphoma (cHL): Initial Results of a Phase I/II Trial

Background: When initial therapy for cHL fails, the standard approach is multiagent salvage chemotherapy followed by autologous stem cell transplant (ASCT). The success of ASCT can be predicted by achievement of complete remission (CR) by fluorodeoxyglucose positron emission tomography (PET) following salvage chemotherapy (Moskowitz, et al. Blood 2012;119:1665-70). Unfortunately, about half of patients (pts) are unable to achieve CR with first salvage. The anti-CD30 antibody-drug conjugate BV is effective as a single agent in rel/ref cHL (Younes, et al. JCO 2012;30:2183-9). Pre-ASCT salvage chemotherapy combinations with BV have been explored (LaCasce, et al. ASH 2015, #293; Garcia-Sanz, et al. ASH 2015, #582), as has a PET-adapted sequential approach with BV then ICE (Moskowitz, et al. Lancet Oncol 2015;16:284-92). We hypothesized that concurrent therapy with BV and ICE would be safe and produce high CR rates. We also sought to explore inflammatory microenvironment prognostic factors. (ClinicalTrials.gov #NCT02227199)Methods: Pts ≥ 18 years old with first relapse or primary refractory CD30+ cHL were eligible. Key inclusion criteria were ≥ 1 FDG-avid site of disease ≥ 1 cm; adequate marrow, hepatic, and renal function; and HIV-. Key exclusions were any prior BV; chemotherapy ≤ 3 weeks of enrollment; and pre-existing neuropathy > NCI-CTCAE Grade 1. All pts signed IRB-approved informed consent forms. Treatment included BV on Days 1 and 8, ifosfamide and mesna 5 g/m2 each on Day 2, carboplatin AUC 5 (capped at 800 mg) on Day 2, and etoposide 100 mg/m2daily on Days 1-3. A 3+3 dose-escalation schema for BV was used to determine the maximum tolerated dose (MTD) with ICE: starting dose was 1.2 mg/kg on Days 1 and 8, escalated to 1.5 mg/kg on Days 1 and 8 or de-escalated to 1.2 mg/kg on Day 1 only, based on rate of dose-limiting toxicity (DLT). Once MTD of BV was established, subsequent pts received this dose. 2 21-day cycles were given with G-CSF support. PET was performed after Cycle 2, with response assigned per Cheson 2007. Stem cells were collected after Cycle 2 at discretion of treating investigator. Peripheral blood (PB) pre- and post-treatment, stem cell (PBSC) product, and (when available) archived formalin-fixed paraffin-embedded tissue from presentation and relapse were collected for correlative studies. Pre-treatment PB PD-L1 levels were measured by ELISA.Results: To date, 16 pts have enrolled and completed study treatment. Median age was 32 (range, 23-60). All received ABVD-based initial chemotherapy, and 5 (31%) received radiation. 11 (69%) did not obtain CR with initial therapy. Grade 3-4 neutropenia, lymphopenia, and anemia was seen in 2 (12%) pts each; thrombocytopenia in 4 (25%) pts. 6 (38%) pts experienced Grade 3-4 non-heme toxicity, but no single toxicity occurred in > 1 pt. Neuropathy was seen in 5 (31%) pts: 4 Grade 1, and 1 Grade 3. 1 DLT (sepsis) was observed in the 9 pts treated in the dose-escalation phase, defining 1.5 mg/kg on Days 1 and 8 as the MTD of BV with ICE.Overall response rate for all enrolled patients was 94% (n=14), with 88% (n=14) and 69% (n=11) achieving CR by investigator and central independent radiographic review, respectively. 15 (94%) pts underwent PBSC collection, all of which were successful. 12 (75%) pts proceeded to ASCT immediately following this treatment. With a median follow-up of 6.5 (range, 2-20) months, there have been 3 (19%) relapses (2 were in CR after BV-ICE) and no deaths.Counts of CD68+ macrophages (15%, 14%), granzyme+ cytotoxic cells (6.2%, 8.7%), and CD20+ B cells (24%, 14%) by immunohistochemistry were not significantly different between presentation and relapse (respectively). Levels of PD-L1 were below the limit of detection (500 pg/mL) in all pts.Conclusions: Pts with rel/ref cHL can safely receive BV up to 1.5mg/kg on Days 1 and 8 per cycle of ICE. Apart from generally-mild neuropathy, adding BV does not appreciably change the toxicity profile of ICE. Observed response rates by PET are very encouraging. Inflammatory cell composition appears similar at presentation and relapse. Without more sensitive testing, circulating levels of PD-L1 are unlikely to be of use in this setting. Enrollment is ongoing, and updated clinical and correlative data, including the use of next-generation sequencing-based detection of lymphoma-specific DNA sequence as a novel method of response assessment, will be presented at the meeting. DisclosuresGopal:Seattle Genetics: Research Funding.

Ultraporous &amp;b.beta;-Tricalcium Phosphate Alone or Combined with Bone Marrow Aspirate for Benign Cavitary Lesions

Ultraporous β-tricalcium phosphate (TCP) synthetic graft material (Vitoss; Orthovita) persists for a year or longer in some cases. In this study, we prospectively examined healing of cavitary defects filled with TCP versus TCP and bone marrow aspirate (TCP/BM) with the hypothesis that bone-marrow aspirate speeds incorporation of bone graft substitute. Fifty-five patients with a benign bone lesion undergoing surgical curettage were randomized to receive TCP (N = 26; mean duration of follow-up [and standard deviation], 20.2 ± 7.2 months) or TCP/BM (N = 29; mean duration of follow-up, 18.0 ± 7.7 months). There were no significant differences between the groups with regard to demographic or defect parameters. Clinical and radiographic evaluations were done at 1.5, three, six, twelve, eighteen, and twenty-four months, and computed tomography [CT] scans were performed at twelve months. An independent radiographic review was done to evaluate six parameters. There was a significant (p < 0.001) increase in trabeculation through the defect and graft resorption with decreases in the persistence of the graft in both soft tissue and the defect as well as a decreased radiolucent rim around the graft over time. No significant differences were observed between the TCP and TCP/BM groups in terms of any radiographic parameter. No complications related to the graft material or BM were identified. While significant improvements in radiographic parameters were observed in both TCP groups over two years of follow-up, the addition of BM was not found to provide any significant benefit. Results should not be extrapolated to other bone graft substitutes used for this purpose.