All times are listed in CEST (Central European Summer Time)
- Breelyn A. Wilky (Aurora, United States of America)
- Tom Wei-Wu Chen (Taipei City, Taiwan)
1482O - A phase III study comparing methotrexate (M), adriamycin (A) and cisplatin (P) with MAP + ifosfamide (MAP + IF) for the treatment of osteosarcoma: JCOG0905
- Hiroaki Hiraga (Sapporo, Japan)
Abstract
Background
Our previous phase II studies on high-grade osteosarcoma, NECO93J and 95J, suggested that application of Ifosfamide (IF) (16 g/m2 × 6 courses) to patients with a poor response (PrRsp) to preoperative chemotherapy using Methotrexate, Adriamycin, and Cisplatin (MAP) improves their prognosis. The JCOG0905 randomized controlled trial investigated the efficacy and safety of adding IF in patients with PrRsp (> 10% viable tumor cells at surgery).
Methods
Patients ≤ 50 years old with operable, high-grade osteosarcoma (Stage IIA, IIB, III, UICC TNM 6th edition) of the extremities, limb girdles, and thoracic wall were eligible for registration at diagnosis. Eligibility for randomization included: completion of 2 MAP cycles preoperatively, followed by complete resection of the primary tumor and 1 postoperative cycle of Adriamycin and Cisplatin with no disease progression; and known histological response. PrRsp patients were randomized (1:1) to continuation of MAP or MAP + IF (15 g/m2 × 6 courses). The primary endpoint was disease-free survival (DFS), and the secondary endpoints included overall survival (OS) and safety. The planned sample size was 100 with a one-sided alpha of 0.1 and power of 0.7, assuming 3-year DFS of MAP and MAP + IF of 50% and 65%, respectively.
Results
Of the 287 patients registered from Feb. 2010 to Aug. 2020, 51 and 52 patients were randomly assigned to MAP and MAP + IF, respectively. At the second interim-analysis on March 2022, the 3-year DFS was 64.3% (95% confidence interval (CI) 49.4-75.8) in MAP and 64.3% (49.3-75.8) in MAP + IF (hazard ratio (HR) 1.05, 95% CI 0.57-1.91). The 3-year OS was 86.5% (72.4-93.7) in MAP and 78.8% (64.1-88.0) in MAP + IF (HR 1.48, 0.68-3.22). There were no treatment-related deaths in both arms. Nine patients in MAP + IF terminated protocol treatment due to adverse events, whereas none in MAP terminated treatment. Based on the results of this analysis, the Data and Safety Monitoring Committee of JCOG recommended terminating the study since the point estimate of HR was above the pre-specified HR of 1.0.
Conclusions
Evidence from JCOG0905 does not support adding IF in PrRsp patients, even at a total dose of 90 g/m2, which is higher than the dose of 60 g/m2 in EURAMOS-1.
Editorial acknowledgement
Monisha R, MD, Forte Science Communications.
Legal entity responsible for the study
National Cancer Center.
Funding
the National Cancer Center Research and Development Fund (2020-J-3) and the Japan Agency for Medical Research and Development (AMED) under grant number JP20ck0106614.
Disclosure
All authors have declared no conflicts of interest.
1483O - Results of a phase I/II combination regimen with ipilimumab (I), nivolumab (N) and trabectedin (T) as first line therapy for advanced leiomyosarcoma
- Erlinda Gordon (Santa Monica, United States of America)
Abstract
Background
A 5-year phase I/II with an expanded phase II study of 101 patients has been recently reported. A subgroup of patients with advanced leiomyosarcoma (LMS) participated in the study. Hypothesis: Sarcoma tumors are more immunogenic at the onset of disease. Immune checkpoint inhibitors that promote sustained T cell activation would be most effective when given as first line therapy, together with a tumoricidal agent such as Trabectedin that depletes growth promoting macrophages in the tumor microenvironment.
Methods
A subgroup of patients (Total: 101 patients with advanced soft tissue sarcoma) included males or females ≥ 18 years of age with locally advanced unresectable or metastatic LMS and measurable disease by RECIST v1.1. Objectives: Primary: To evaluate the DLT and MTD; Secondary: To evaluate response, PFS and OS and incidence of adverse events. Treatment protocol: (I) mg/kg i.v. q 12 wks, (N) 3 mg/kg i.v. q 2 wks, (T) 1.2 mg/m2 CIV q 3 wks.
Results
Twenty-six of 101 patients enrolled had advanced leiomyosarcoma. Safety Analysis (n=26). 13/26 (50%) had a > Grade 3 TRAE: cellulitis =2; inc. AST=2; inc. ALT = 5; dec. platelet ct =1; dec. WBC =1; fatigue =2; anemia =2; inc. alk phos = 1; dec TSH = 1; inc. TSH = 1; inc. T4 = 1; inc. CK = 1. There was no incidence of alopecia nor cardiac toxicity reported. The MTD for T was 1.2 mg/m2. Efficacy analysis: 22/26 (84.6%) patients were evaluable for efficacy. Phase 1 previously treated (n=3): 3 (100%) had stable disease (SD); Expanded Phase 2, previously untreated (n=19): 2CR, 4PR, 11SD, 2PD. Overall response rate was 31.6%, Disease Control Rate, 89.5%. The median PFS was 7.4 (range: 1.2 - 33.6) months, median OS, 36.1 (range: 1.6 - 45.8) months; 6 month PFS = 63.2%; 6 month OS = 89.5%.
Conclusions
Taken together, these data suggest that first-line combinatorial therapy with Ipilimumab, Nivolumab and Trabectedin may be (1) More effective than standard first line therapy, and (2) Safer than standard first line therapy for advanced LMS. Randomized Phase 2 studies are planned to confirm these findings.
Clinical trial identification
NCT03138161.
Legal entity responsible for the study
Sarcoma Oncology Center.
Funding
Bristol Myers Squibb.
Disclosure
All authors have declared no conflicts of interest.
Invited Discussant 1482O and 1483O
- Kjetil Boye (Oslo, Norway)
Q&A
- All Speakers (Lugano, Switzerland)
1485O - Percutaneous uterine needle biopsy with microscopic and array-CGH analyses in patients with suspicious myometrial tumors on MRI: A prospective study
- Jeremy SMADJA (Paris, France)
Abstract
Background
Preoperative diagnosis of uterine tumors is of utmost importance to avoid inadvertent morcellation of leiomyosarcoma (LMS) and unnecessary hysterectomy in childbearing patients. There are no pathognomonic criteria for malignancy on Magnetic Resonance Imaging (MRI). The diagnosis of malignancy includes microscopic and genomic analyses with array-Comparative Genomic Hybridization (CGH). To date, no study has evaluated preoperative percutaneous uterine needle biopsy (PUB) with microscopic examination (M-PUB) and array-CGH analyses (MCGH-PUB).
Methods
This is a prospective single-center cohort study including all consecutive patients who had uterine LMS suspicion on MRI and for whom a PUB was performed. Microscopic and array-CGH analyses with genomic index (GI) count for myometrial tumors were performed in order to guide the therapeutic strategy. Suspicious myometrial tumors after microscopic examination, including STUMP, were assessed malignant with a GI superior to 15. Preoperative diagnoses based on M-PUB and MCGH-PUB were compared to the postsurgical pathological examination or follow-up for non-operated tumors.
Results
A total of 36 patients were included from November 2016 to December 2021. Ten tumors were ultimately sarcomas, 25 were leiomyomas and one was an inflammatory myofibroblastic tumor. Six of the sarcomas and 18 of the benign tumors received surgery. The median follow-up time was 12 months (IQR= 6-35). The diagnostic accuracy, sensitivity, specificity and Negative Predictive Value of MCGH-PUB were 100%. A high GI was significantly associated with malignancy (p<0.001). High GI allowed correct malignancy upgrade for three tumors after suspicious microscopic examination. There was no PUB complication and no dissemination on the biopsy track.
Conclusions
MCGH-PUB is safe and accurate to discriminate pre operatively benign tumors from uterine sarcoma.
Legal entity responsible for the study
S. Bonvalot.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.
1484O - Deep learning predicts patients’ outcome and mutations from H&E slides in gastrointestinal stromal tumor (GIST)
- Raul Perret (Bordeaux, France)
Abstract
Background
Risk assessment according to the AFIP/Miettinen classification and mutational profiling are major tools for patient management. However, the AFIP/Miettinen classification depends heavily on mitotic counts, which is laborious and sometimes inconsistent between pathologists. It has also been shown to be imperfect in stratifying patients. Molecular testing is costly and time consuming, therefore not systematically performed in all countries. New methods to improve risk and molecular predictions are hence crucial to improve the tailoring of adjuvant therapy.
Methods
We have built deep learning (DL) models on digitized H&E-stained whole slide images (WSI) to predict patients’ outcome and mutations. Models were trained with a cohort of 1233 GIST and validated on an independent cohort of 286 GIST.
Results
DL models outperformed the Miettinen classification for relapse-free-survival prediction in localized GIST without adjuvant Imatinib (C-index=0.83 in testing and 0.72 for independent validation). DL splitted Miettinen intermediate risk GIST into high/low risk groups(p value=2.1e-03). DL models achieved an area under the receiver operating characteristic curve (AUC) of 0.81, 0.91 and 0.71 for predicting mutations in KIT, PDGFRA and wild type respectively in testing and 0.84, 0.93 and 0.56 in independent validation. Notably, PDGFRA exon18 D842V mutation which is resistant to Imatinib, was predicted with an AUC of 0.87 and 0.90 in testing and independent validation, respectively. Additionally,
Conclusions
Our results strongly suggest that implementing DL with digitized WSI may represent a reproducible way to improve tailoring therapy and precision medicine for patients with GIST.
Legal entity responsible for the study
Institut Bergonié. Bordeaux, France.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.
Invited Discussant 1485O and 1484O
- Jakob N. Kather (Aachen, Germany)
Q&A
- All Speakers (Lugano, Switzerland)