Chondrosarcomas are rare tumors and, historically, investigation of these tumors has been limited to small series and single-institution studies. There have been no studies that evaluated the identification or comparison of differences in prognostic factors between the five known non-conventional chondrosarcoma subtypes (myxoid, juxtacortical, clear-cell, mesenchymal, and dedifferentiated). The purpose of this paper was to determine the demographic, clinical, incidence, and tumor characteristics of all five known non-conventional chondrosarcoma subtypes, determine the 1-, 5-year, and median survival differences between these subtypes, and to determine the demographic and clinical variables that are significant prognostic indicators for each chondrosarcoma subtypes. We retrospectively reviewed the SEER database for all patients with non-conventional chondrosarcoma. χ 2 testing was used for correlations between clinical variables. Kaplan-Meier and Cox proportional hazard analysis were used to compare survival of the subtypes, and to assess the prognostic value of age group, race, sex, grade, anatomic location, and metastatic involvement. Several demographic characteristics including gender, race, age, and grade varied between chondrosarcoma subtypes. The tumor characteristics showed marked differences in presence of metastasis on presentation between the subtypes with increasing order of rate of metastasis with juxtacortical (2.1%), clear cell (5.7%), myxoid (7.6%), mesenchymal (10.6%), and the highest in dedifferentiated (19.8%). One-, 5-year, and median survival differed significantly between chondrosarcomas subtypes. The highest median survival was found in the juxtacortical subtype (97 months), followed by clear cell (79 months), myxoid (60 months), mesenchymal (33.5 months), and lowest in dedifferentiated (11 months). The only prognostic variable that was shown to significantly impact the survival of each non-conventional chondrosarcoma subtype was a metastatic disease at diagnosis (p = 0.03 to p < 0.001). Subtyping classification of chondrosarcoma should be made whenever possible, given differences in survival and prognostic factors between chondrosarcoma subtypes.
Background: During cancer progression, immunosuppressive cells, such as those of myeloid and lymphoid origin, are recruited to the tumor microenvironment (TME) through interactions between chemokines and chemokine receptors (CKRs). CCR2 and CCR5 are CKRs expressed on both myeloid and T-cell infiltrates in the TME and have been shown to mediate the migration of monocyte/myeloid-derived suppressor cells (MDSCs) and polymorphonuclear MDSCs (PMN-MDSCs), respectively, from bone marrow to the blood and TME. CCR5 can also recruit regulatory T cells to the TME, potentiate PMN-MDSC immunosuppressive function via arginase-1, and polarize tumor-associated macrophages into an immunosuppressive M2 phenotype. Engagement of CCR2 or CCR5 promotes an immunosuppressive environment and prevents antitumor immunity; this has been preclinically validated in multiple tumor types, including pancreatic and colorectal. Preliminary data also support the utility of combination with PD-(L)1 inhibition. Clinically, CCR2- and CCR5-selective antagonists have separately shown proof of mechanism in combination with chemotherapy in pts with pancreatic and colorectal cancers, respectively (1, 2). These encouraging studies support further investigation of CCR2/5 dual antagonism in providing greater benefit to pts than CCR2- or CCR5-selective inhibition when combined with chemotherapy. Here we describe the design of a phase 1b/2, nonrandomized, open-label study of BMS-813160 (small-molecule CCR2/5 dual antagonist) as monotherapy or in combination with chemotherapy or nivolumab in pts with advanced pancreatic or colorectal cancer (NCT03184870). Methods: Approximately 260 pts aged ≥ 18 years with an ECOG PS of ≤ 1, adequate marrow and organ function, and the ability to undergo pre- and on-treatment biopsies will be enrolled. Exclusion criteria include prior treatment with CCR2 and/or CCR5 inhibitors, requirement for corticosteroids/other immunosuppressive medications, CNS metastases, autoimmune diseases, and symptomatic interstitial lung disease. In part 1, pts will receive BMS-813160 monotherapy safety lead-in for 2 weeks followed by combination with chemotherapy (5-fluorouracil + leucovorin + irinotecan [colorectal cancer] or nab-paclitaxel + gemcitabine [pancreatic cancer]) or nivolumab. In part 2, pts will receive either the same regimens (without a monotherapy lead-in) or BMS-813160 monotherapy. Primary outcomes are safety, tolerability, objective response rate, median duration of response, and progression-free survival rate at 24 weeks. Secondary outcomes are pharmacokinetics and pharmacodynamics of BMS-813160 and immunogenicity of nivolumab. References 1. Nywening TM, et al. Lancet Oncol 2016;17:651-662. 2. Halama N, et al. Cancer Cell 2016;29:587-601. Citation Format: Dung Le, Martin E. Gutierrez, Mansoor Saleh, Eric Chen, Atrayee Basu Mallick, Michael J. Pishvaian, Jürgen Krauss, Peter O'Dwyer, Ignacio Garrido-Laguna, Qihong Zhao, Anke Kippel, Xiaoli Wang, Yali Liu, Allyson Pollack, Ashwin Sama, Heinz-Josef Lenz. A phase Ib/II study of BMS-813160, a CC chemokine receptor (CCR) 2/5 dual antagonist, in combination with chemotherapy or nivolumab in patients (pts) with advanced pancreatic or colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT124.
11505 Background: AL3818 (Catequentinib, Anlotinib) is a novel, orally administered, small molecule tyrosine kinase inhibitor. The primary objective of this Phase 3 study is to evaluate the efficacy of AL3818 monotherapy in patients (pts) with synovial sarcoma (SS) comparing with dacarbazine in randomization setting. Methods: Patients with a diagnosis of synovial sarcoma requiring second line or further line treatment were eligible for enrollment. The regimen was a 21-day cycle with oral AL3818 administered on 14 days on and 7 days off. This phase 3 trial is randomized in 2:1 ratio of AL3818 comparing to dacarbazine with option of crossover after PD of dacarbazine treatment. Progression free survival (PFS) with Log Rank test is the primary endpoint and this trial for SS is currently completed enrolled in US and Italy. Results: Total 79 pts initiated treatment and are evaluable, 52 received AL3818 as treatment arm (T), and 27 received dacarbazine (D) as control arm (C). Arms T/C median ages were 40.5/42.0 years (range: 18-70+) and 20/16 (38.5%/59.3%) were male. Overall, PFS was 2.89 months (95% CI: 2.73 – 6.87) for AL3818 and 1.64 (95% CI: 1.45 – 2.70) for D. The PFS of study met the primary endpoint with a p-value of 0.0015 and a HR of 0.449 (95% CI: 0.270– 0.744). At the month 4, 6, and 12, the percentages of progression free patients for AL3818 were 48.1%, 42.3% and 26.9%; and for D were 14.85%, 11.1% and 3.7%. For grade 3 treatment-related adverse events, 12(23.1%) of pts experienced for AL3818 and 7(25.9%) of pts experienced for D. The most common AL3818 related grade 3 AEs were diarrhea (5.8%) and hypertension (3.8%). Conclusions: This phase III trial demonstrates improved disease control and superior progression free survival for AL3818 vs dacarbazine in advanced SS. In addition, the study further confirms the acceptable benefit-risk profile of AL3818 from the prior randomized Phase 2b soft tissue sarcoma study (NCT02449343). AL3818 is a meaningful treatment option for pts with advanced SS. Clinical trial information: NCT 03016819 Clinical trial information: NCT03016819.
103 Background: Therapeutic resistance to antiangiogenics in metastatic colorectal cancer (mCRC) inevitably develops via multiple mechanisms including upregulation of the MET kinase pathway. Cabozantinib, an oral multityrosine kinase inhibitor targeting MET, AXL, and VEGFR, demonstrated significant anti-tumor activity in CRC xenograft and cell line models. Methods: A single-arm, two-stage phase II study was conducted at 7 AGICC centers nationwide. 44 patients (pts) with mCRC who had progressed on or were intolerant of standard of care agents were treated with cabozantinib 60 mg daily in q3 wk cycles. The primary endpoint was 12-wk PFS rate. Based on the control arm of phase III CORRECT study, the Kaplan-Meier 12-wk PFS rate estimate was 13% and served as the null hypothesis. This study was powered at 0.906 to detect the alternative hypothesis of 12-wk PFS rate of 33% with a type I error rate of 0.044. Secondary endpoints were safety, RR, OS, and retrospective analysis of PFS and RR based on RAS, BRAF, and PIK3CA mutation status. Results: 44 pts were enrolled and 34 pts were response-evaluable as having undergone at least the first 6-wk restaging scan. 10 pts discontinued treatment prior to the first 6-wk scan due to clinical disease progression. Median number of cycles was 4 and median follow-up was 2.5 months. As of data-cutoff 8/23/2019, 55 Grade 3/4 AEs were reported with the most common being hypertension, fatigue, diarrhea, pain, HFS, nausea, vomiting, and proteinuria. 32 SAEs occurred in 18 pts. 5 Grade 5 AEs were reported: disease progression (3), disseminated intravascular coagulopathy, and bowel perforation. 15 pts (34%) achieved ≥ 12-wk PFS and 8 patients remain on treatment. Best response was 1 PR and 31 SD with a DCR at 6 wks of 72.7%. Of the pts who achieved ≥ 12-wk PFS, 12 had left-sided primary tumors, 5 had a RAS mutation, 1 had a PIK3CA mutation, and all pts were BRAF WT and MSI stable. Conclusions: Cabozantinib was deemed safe and demonstrates encouraging efficacy in a heavily pretreated mCRC pt population. These results support further investigation of cabozantinib in mCRC. Clinical trial information: NCT03542877.
BackgroundERCC1, a component of nucleotide excision repair pathway, is known to repair DNA breaks induced by platinum drugs. We sought to ascertain if ERCC1 expression dynamics and a single nucleotide polymorphism (SNP) rs11615 are biomarkers of sensitivity to oxaliplatin therapy in patients with colorectal cancer (CRC).MethodsWestern blot and qPCR for ERCC1 expression was performed from PBMCs isolated from patients receiving oxaliplatin-based therapy at specified timepoints. DNA was also isolated from 59 biorepository specimens for SNP analysis. Clinical benefit was determined using progression free survival (PFS) for metastatic CRC.ResultsERCC1 was induced in PBMC in response to oxaliplatin in 13/25 patients with mCRC (52%). Median PFS with ERCC1 induction was 190d compared to 237d in non-induced patients (HR 2.35, CI 1.005-5.479; p=0.0182). ERCC1 rs11615 SNP analysis revealed that 43.3% harbored C/C, 41.2%-T/C and 15.5%-T/T genotype. Median PFS was significantly lower with C/C or T/C (211 and 196d) compared to T/T (590d; p=0.0310).ConclusionsERCC1 was induced in a sub-population of patients undergoing oxaliplatin treatment, which was associated with poorer outcome, suggesting this could serve as a marker of oxaliplatin response. C/C or C/T genotype in ERCC1 rs11615 locus decreased benefit from oxaliplatin.
Chondrosarcomas are the second most common primary bone malignancy. Chondrosarcomas are characterized by the production of cartilaginous matrix and are generally resistant to radiation and chemotherapy and the outcomes are overall poor. Hence, there is strong interest in determining mechanisms of cancer aggressiveness and therapeutic resistance in chondrosarcomas. There are metabolic alterations in chondrosarcoma that are linked to the epigenetic state and tumor microenvironment that drive treatment resistance. This review focuses on metabolic changes in chondrosarcoma, and the relationship between signaling via isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2), hedgehog, PI3K-mTOR-AKT, and SRC, as well as histone acetylation and angiogenesis. Also, potential treatment strategies targeting metabolism will be discussed including potential synergy with immunotherapies.
TPS11081 Background: AAS is an aggressive soft tissue sarcoma (STS) of endothelial cell origin with an expected median overall survival of 8-12 months. Pazopanib (P) is approved for treatment of advanced STS following progression on chemotherapy. In a retrospective study of 40 AAS patients treated with single agent P the median PFS was 3.1 months and median OS 9.9 months with no complete responses. Endoglin is an essential angiogenic receptor expressed on AAS that is upregulated following VEGF inhibition, and TRC105, an endoglin antibody, given with P produced durable complete responses in AAS patients with median PFS of 5.6 months in refractory patients including those receiving prior P. The TAPPAS trial is the first randomized Phase 3 trial performed in AAS, and was initiated following protocol assistance from the EMA and Special Protocol Assessment from the FDA. Methods: TAPPAS is a randomized multicenter study of TRC105/P vs P alone in the United States and Europe that is actively enrolling cutaneous and non-cutaneous AAS patients and incorporates an adaptive enrichment design. Key inclusion criteria: 0, 1 or 2 prior lines of therapy, ECOG ≤ 1. Primary endpoint is PFS and secondary endpoints include ORR and OS. The initial sample size of 124 patients, followed until 95 PFS events, provides more than 80% power to detect a hazard ratio of 0.55. At the time of interim analysis, projected to occur upon the occurrence of 40 events in approximately 70 patients, the result will be classified as belonging to either the favorable, promising, enrichment or unfavorable zones, based on conditional power. The sample size and PFS events will be unchanged in the favorable and unfavorable zones, and will be increased to a total of 200 patients followed for 170 PFS events in the promising zone. The trial will enroll 100 additional patients, with cutaneous disease only, in the enrichment zone and will follow them until 110 events are observed in the total cutaneous population. An independent DMC will follow the trial for safety and futility. The adaptive design requires the enrollment of fewer patients, preserves type-1 error, and protects power to detect a clinically meaningful survival benefit. (NCT 02979899). Clinical trial information: NCT02979899.
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