Background

Approved TKIs primarily inhibit either the KIT ATP binding pocket (exon 13/14) or a subset of activation loop mutations (exon 17/18) and do not demonstrate activity across both regions known to cause imatinib resistance in GIST. This leaves significant liabilities in inhibitory coverage of known KIT resistance mutations. DCC-2618 is a potent kinase switch control inhibitor active across a broad range of mutations which emerge on treatment with approved TKIs.

Methods

This is a dose-escalation study of oral DCC-2618 (QD or BID q28 days) followed by an expansion cohort in pre-treated TKI resistant GIST. During the escalation phase, FDG-PET scans were performed at baseline and after 3 wks of therapy; CT scans every 2 cycles. Next generation sequencing (NGS) of plasma cell-free (cf) DNA was performed throughout the study to quantify KIT, PDGFRa and other molecular alterations. Concordance of mutational status between plasma cfDNA and tumor tissue was assessed.

Results

33/42 pts enrolled had KIT (30) or PDGFRa- (3) driven GIST and received daily doses ranging from 40-400 mg. Mean prior lines of therapy was 4.8. The dose selected for expansion was 150 mg QD. Safety for all 42 pts was as follows: grade (G) 3/4 adverse effects (regardless of attribution, occurring in > 1 pt) included anemia (15), asymptomatic lipase increase () (7), hypertension (4), creatine phosphokinase (CPK) (2), lower GI hemorrhage (2). Two of the G3/4 lipase at 100 mg BID and 200 mg BID and one CPK at 150 mg QD were DLTs. Of 19 pts with KIT mutant GIST assessed by FDG PET, 15 (79%) had a partial metabolic response per EORTC criteria. 2 out of 23 evaluable patients showed RECIST partial responses (PRs) and 6 out of 11 evaluable patients at doses of ³100 mg/d had RECIST progression free survival of > 6 months (5 pts on therapy at ³Cycle 10). NGS of plasma cfDNA revealed a reduction of mutation allele frequency (MAF) in exons 9, 11, 13, 14, 17 and 18.

Conclusions

DCC-2618 showed encouraging disease control with objective responses and prolonged stable disease in heavily pre-treated GIST patients. The notable decreases in MAF of resistance mutations across all exons supports the use of DCC-2618 beyond imatinib resistance.

Clinical trial identification

NCT02571036

Legal entity responsible for the study

Deciphera

Funding

Deciphera

Disclosure

F. Janku: Research funding: Deciphera; Scientific Advisory Board: Deciphera. D. Flynn, M. Kaufman: Full-time employee of Deciphera Pharmaceuticals. J. Pitman, B. Smith: Full-time employee of Deciphera Pharmaceuticals, stock options at Decipher Pharmaceuticals. All other authors have declared no conflicts of interest.

Background

In 2004, we started an inter-group randomized trial of adjuvant imatinib versus no further therapy after R0-R1 surgery in localized, high/intermediate-risk GIST patients. Interim analyses results were published in 2015 upon recommendation from an independent data review committee. We now report on the final outcome of the study.

Methods

This was a randomized, open label, multicenter phase III trial performed at 112 hospitals in 12 countries. Patients were randomized to 2 years (yrs) of imatinib, 400 mg daily, or no further therapy after surgery. The primary end-point was imatinib failure-free survival (IFFS), while relapse-free survival (RFS), relapse-free interval (RFI), overall survival (OS) and toxicity were secondary end-points. Adjusting for the interim analyses, results on IFFS will be assessed on a 4.3% significance levels; for the other endpoints 5% was used.

Results

908 patients were randomized between December 2004 and October 2008, 454 to imatinib and 454 to observation. 835 patients were eligible. With a median follow-up of 9.1 years, 5 (10)-year IFFS was 87% (75%) in the imatinib arm versus 83% (74%) in the control arm (HR = 0.87, 95.7% CI [0.65; 1.15], p = 0.31); RFS was 70% versus 63% at 5 years and 63% vs 61% at 10 years, (HR = 0.71, 95% CI [0.57; 0.89], p = 0.002); OS was 93% versus 92% at 5 years and 80% versus 78% at 10 years (HR = 0.88, 95% CI [0.65; 1.21], p = 0.43). Among 526 patients with high-risk GIST by local pathology, 10-year IFFS and RFS were 69% versus 61%, and 48% versus 43% respectively.

Conclusions

With 9.1 years of follow-up, a trend toward better long-term IFFS and RFS in Imatinib treated patients was observed in the high risk subgroup. Although not statistically significant, this trend is consistent with the results reported by the Scandinavian/German trial, showing a sustained small but significant long-term OS benefit in high risk GIST patients treated with 3 years adjuvant Imatinib. On the contrary our study discourages the use of Imatinib in patients affected by low risk (as per current standards) GIST, as long term IFFS and RFS are superimposable.

Clinical trial identification

EUDRACT 2004-001810-16, NCT00103168

Legal entity responsible for the study

EORTC HQ

Funding

Novartis

Disclosure

P.G. Casali: Research funds (institution): Amgen, Bayer, Eli Lilly, Daiichi Sankyo, Epizyme, Novartis, Pharmamar. Advisory: Bayer, Blueprint, Eisai, EliLilly, Merck SD, Merck Serono, Nektar Therapeutics, Novartis, Pfizer, Pharmamar. Honoraria: Bayer, Novartis, Pfizer, Pharmamar. A. Le Cesne: Pharmamar, Lilly, Pfizer, Novartis, Amgen Honoraria, myself, compensated. P. Rutkowski: Novartis, BMS, Roche, MSD, GSK, Amgen. P. Hohenberger: Honoraria, consultation fees and research support from Novartis. H. Gelderblom: My institution (LUMC) received study grants form Novartis. D. Goldstein: Research grants to institution, Pfizer, Amgen, Celgene, unremunerated advisory - Celgene, Shire, Pfizer, Bayer. A. Gronchi: Honoraria and compensation for advisory boards from Novartis honoraria from Pfizer compensation for advisory boards from Bayer. J. Zalcberg: Research support from Novartis and Bayer. J-Y. Blay: Research support and honoraria from Novartis, GSK, Bayer, Roche. All other authors have declared no conflicts of interest.

Background

Sarcomas are rare but aggressive diseases. Specialized multidisciplinary management is not implemented for all patients in most countries. We investigated the impact of the surgery in a reference center on relapse and survival in the nationwide NETSARC/RREPS study.

Methods

NETSARC (netsarc.org) is a network of 26 reference sarcoma centers with specialized MDTB, funded by the French National Cancer Institute to improve the outcome of sarcoma patients. Since 2010, presentation to an MDTB and second pathological review are mandatory for sarcoma patients. Patients’ characteristics and follow-up are collected in a database regularly monitored. Uni and multivariate analysis of prognostic factors for local relapse free survival (LRFS), relapse free survival (RFS) and overall (OS) were conducted.

Results

Out of the 9,594 non-metastatic pts aged > =15, with a first diagnosis of soft tissue and visceral sarcoma obtained between Jan 2010 and Dec 2014, 3505 (37%) and 6089 (63%) were operated within vs outside of one of the 26 NETSARC reference center. The former group had worse prognostic characteristics (age, size, grade, depth p < 0.0001 all). In univariate analysis, surgery within a reference center was associated with a better LRFS & RFS (median 60 vs 41 mos, and 25 vs 21 mos, respectively, logrank p < 0.001). LRFS and RFS were significantly better for pts operated in reference centers in all individual subgroups of quality of resection, (R0, R1, R2, R unknown) (p < 0.001). Surgery in reference center was an independent good prognostic factor for LRFS (HR: 0,60), RFS (HR:0,79) as well as OS (HR:0,68) using Cox model (p < 0.001 all).

Conclusions

In this nationwide unselected population, the LRFS and RFS of sarcoma patients is worse than that reported in expert centers series. Surgery in reference center is associated with significant reduction of the risk of relapse and death.

Clinical trial identification

This is not a clinical trial this is a registry of sarcoma approved by the French NCI and competent authorities in France (CNIL)

Legal entity responsible for the study

NetSARC/French Sarcoma Group_GETO

Funding

INCA DGOS

Disclosure

All authors have declared no conflicts of interest.

Background

Giant cell tumor of bone (GCTB) is a progressive osteolytic tumor with proven response to denosumab when unresectable or at high surgical risk. We report on the primary analysis of this phase 2 study.

Methods

Patients (pts) were enrolled with unresectable GCTB (Cohort 1), resectable GCTB with planned high morbidity surgery (Cohort 2), and prior GCTB study pts (Cohort 3). Denosumab was given 120 mg SC every 4 weeks with loading doses on days 8 and 15. The primary endpoint was safety; efficacy endpoints included proportion of Cohort 2 pts without surgery, and progression-free survival for all pts.

Results

Baseline characteristics and key safety results for 532 pts are shown in the Table. Median follow-up was 55 months (IQR 34, 75) in Cohort 1 and 44 months (IQR 26, 59) in Cohort 2. Overall response rates were 99% in Cohorts 1 and 2. Of 267 Cohort 1 pts, 19 (7%) ended denosumab for GCTB progression. Kaplan Meier (KM) estimates (95% CI) for GCTB progression in these pts were 4% (2–7%) at week 49, and 7% (4–10%) at week 98. 135 Cohort 1 pts ended denosumab without GCTB progression, and 34 (25%) recurred with a KM median estimate (95% CI) of 39 (18, NE) months. Of 248 Cohort 2 pts with planned surgery, 63% underwent surgery and 37% continued with denosumab only. Following surgery, 27% pts had a recurrence, higher after curettage than resection (34 vs 12%).

Table:

LBA56

Conclusions

Denosumab was generally well tolerated with excellent long-term disease control in unresectable patients. A 27% recurrence rate following surgery was seen in this high-risk, resectable population (26% had recurrent GCTB at enrollment). Adverse events were consistent with the known profile for denosumab, with no unexpected long-term toxicities. Several cases of misdiagnosed as benign GCTB at enrollment were seen, reinforcing the need for careful expert pathologic evaluation of this rare disease at diagnosis. Denosumab has major, long-lasting antitumor activity in unresectable or metastatic GCTB.

Clinical trial identification

NCT00396279

Legal entity responsible for the study

Amgen Inc.

Funding

Amgen Inc.

Disclosure

E. Palmerini: Amgen advisory board. J-Y. Blay: Research grants from Novartis, Roche, Pharmamar, Bayer, Ignyta, GSK, Lilly and Amgen, and has served as a consultant for Novartis, Roche, Pharmamar, Bayer, Ignyta, GSK, Lilly and Amgen A. Le Cesne: Consulting fees from Novartis, Pfizer, Lilly and Pharmamar. P. Reichardt: Advisory boards for Novartis, Pfizer, Bayer, PharmaMar, Ariad, Amgen, Inc., GlaxoSmithKline, AstraZeneca, Clinigen, and Lilly, and has received honoraria from Novartis, Pfizer, Bayer, PharmaMar, Amgen, Inc., GlaxoSmithKline, and Lilly. P. Rutkowski: Consultant for Amgen, MSD, BMS, Novartis and Roche and served on speaker’s bureaus for Novartis, Pfizer, BMS, MSD and Roche, and advisory board for Blueprint. H. Gelderblom: Institution has received grants and consultancy fees from Amgen. R.J. Grimer: Scientific advisory board for Amgen for this trial. A. Feng: Employee of Amgen during the time that this abstract was written. D. Jandial: Employee and Stockholder of Amgen. S. Chawla: Advisor and consultant for Amgen.