Background

Ripretinib is a switch-control kinase inhibitor that broadly inhibits KIT- and PDGFRA-mutated kinases by regulating the kinase switch pocket and activation loop.

Methods

Patients (pts) with advanced GIST who received prior treatment with at least imatinib, sunitinib, and regorafenib were enrolled. Pts were randomized 2:1 to ripretinib 150 mg QD or placebo (P) and stratified by 3 v ≥ 4 prior therapies and ECOG 0 v 1-2. Patients with a PD on 150 mg QD were allowed to dose escalate and patients on P arm crossed over to ripretinib at PD. The primary end point was PFS per blinded independent central review. Secondary end points included objective response rate (ORR; key end point) and OS.

Results

129 pts were randomized as ITT. In the double-blind period, ripretinib improved median PFS over P (6.3 v 1 mo; HR = 0.15; 95%CI: 0.09,0.25; P < 0.0001). PFS rates at 6 mo were 51% (95%CI: 39.4,61.4) for ripretinib and 3.2% (95%CI: 0.2,13.8) for P. Analysis of PFS in pt subgroups assessed favored ripretinib. ORR was 9.4% for ripretinib and 0% for P (P = 0.0504; median duration not reached). Ripretinib demonstrated an improvement over P in median OS (15.1 v 6.6 mo; HR = 0.36; 95%CI: 0.20,0.62; nominal P = 0.0004). OS rates at 12 mo were 65.4% (95%CI: 51.6,76.1) for ripretinib and 25.9% (95%CI: 7.2,49.9) for P. Ripretinib was generally well tolerated. Any dose reductions were in 7 pts (8.2%) in ripretinib arm v 1 (2.3%) in P arm; interruptions were in 18 pts (21.2%) in ripretinib v 8 (18.6%) in P arm. TEAE-related dose modifications are in the table below.Table:

LBA87

Conclusions

Ripretinib improved PFS over P in advanced GIST patients after progression on standard treatments. Ripretinib was associated with a favorable tolerability profile. Ripretinib is a novel therapy in a population with no other approved therapy and may represent a new standard of care.

Clinical trial identification

NCT03353753.

Editorial acknowledgement

Medical writing assistance was provided by Laura Jung, PharmD, of ETHOS Health Communications in Yardley, Pennsylvania, and financially supported by Deciphera Pharmaceuticals, Inc.

Legal entity responsible for the study

Deciphera Pharmaceuticals, LLC.

Funding

Deciphera Pharmaceuticals, LLC.

Disclosure

M. von Mehren: Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Deciphera Pharmaceuticals, LLC; Advisory / Consultancy, Research grant / Funding (institution): Blueprint Medicines; Research grant / Funding (institution): Arog Pharmaceuticals; Research grant / Funding (institution): Gradalis; Advisory / Consultancy: Exelixis; Leadership role, Chair of the Soft Tissue Sarcoma Panel: NCCN; Research grant / Funding (institution): Genmab; Research grant / Funding (institution): Novartis. C. Serrano: Advisory / Consultancy, Research grant / Funding (self): Deciphera Pharmaceuticals, LLC; Advisory / Consultancy, Speaker Bureau / Expert testimony: Blueprint Medicines; Speaker Bureau / Expert testimony, Research grant / Funding (self), Travel / Accommodation / Expenses: Bayer Healthcare; Research grant / Funding (self), Travel / Accommodation / Expenses: Pfizer; Travel / Accommodation / Expenses: Pharmamar; Travel / Accommodation / Expenses: Novartis; Travel / Accommodation / Expenses: Eli Lilly and Company. S. Bauer: Honoraria (self), Advisory / Consultancy, Research grant / Funding (self), Research grant / Funding (institution): Novartis; Honoraria (self): Pfizer; Honoraria (self), Advisory / Consultancy: Bayer; Honoraria (self), Advisory / Consultancy: Pharmamar; Advisory / Consultancy, Research grant / Funding (institution): Blueprint Medicines; Advisory / Consultancy: ADC Therapeutics; Honoraria (self), Advisory / Consultancy: Eli Lilly and Company; Advisory / Consultancy: Daiichi Sankyo; Advisory / Consultancy: Plexxikon; Advisory / Consultancy: Nanobiotix; Advisory / Consultancy: Deciphera Pharmaceuticals, LLC; Advisory / Consultancy: Exelixis; Advisory / Consultancy: Janssen-Cilag; Advisory / Consultancy: Roche; Research grant / Funding (institution): Incyte; Non-remunerated activity/ies, External advisory board member : Federal Ministry of Health (Bundesgesundheitsministerium). H. Gelderblom: Research grant / Funding (institution): Daiichi Sankyo; Research grant / Funding (institution): Five Prime Therapeutics; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Deciphera Pharmaceuticals, LLC; Research grant / Funding (institution): Eli Lilly and Company; Research grant / Funding (institution): Roche; Research grant / Funding (institution): Eisai Co, Ltd; Research grant / Funding (institution): Debio; Research grant / Funding (institution): Boehringer Ingelheim; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Amgen; Research grant / Funding (institution): Teva. S. George: Advisory / Consultancy, Research grant / Funding (institution): Blueprint Medicines; Advisory / Consultancy, Research grant / Funding (institution): Deciphera Pharmaceuticals, LLC; Advisory / Consultancy: Eli Lilly and Company; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Bayer; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Daiichi Sankyo; Advisory / Consultancy: Exelixis; Leadership role: Alliance Foundation; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Novartis; Shareholder / Stockholder / Stock options: Abbott Laboratories; Shareholder / Stockholder / Stock options: Allergan; Licensing / Royalties, UpToDate: Wolters Kluwer Health. M. Heinrich: Advisory / Consultancy, Speaker Bureau / Expert testimony, Licensing / Royalties, Expert testimony: Novartis; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Deciphera Pharmaceuticals, LLC; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Blueprint Medicines; Advisory / Consultancy: MolecularMD. P. Schöffski: Advisory / Consultancy, Research grant / Funding (institution), Advisory/consultancy is institutional support: Plexxikon; Advisory / Consultancy, Research grant / Funding (institution), Advisory/consultancy is institutional support: Eisai Co, Ltd; Advisory / Consultancy, Advisory/consultancy is institutional support: Loxo Oncology, Inc; Advisory / Consultancy, Research grant / Funding (institution), Advisory/consultancy is institutional support: Blueprint Medicines; Advisory / Consultancy, Advisory/consultancy is institutional support: Ellipses Pharma; Advisory / Consultancy, Advisory/consultancy is institutional support: Deciphera Pharmaceuticals, LLC; Advisory / Consultancy, Advisory/consultancy is institutional support: Merck & Co.; Advisory / Consultancy, Advisory/consultancy is institutional support: Servier; Advisory / Consultancy, Advisory/consultancy is institutional support: Genmab; Advisory / Consultancy, Advisory/consultancy is institutional support: Adaptimmune; Advisory / Consultancy, Advisory/consultancy is institutional support: Intellisphere LLC; Advisory / Consultancy, Advisory/consultancy is institutional support: Transgene; Research grant / Funding (institution): Boehringer Ingelheim; Research grant / Funding (institution): CoBioRes NV; Advisory / Consultancy, Research grant / Funding (institution), Advisory/consultancy is institutional support: Eli Lilly and Company; Research grant / Funding (institution): Exelixis; Research grant / Funding (institution): G1 Therapeutics; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Pharmamar. J. Zalcberg: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Merck Serono; Honoraria (self), Research grant / Funding (institution): Specialized Therapeutics; Honoraria (self), Advisory / Consultancy: Targovax; Honoraria (self), Advisory / Consultancy: Halozyme; Honoraria (self): Gilead Sciences; Advisory / Consultancy, Travel / Accommodation / Expenses: MSD; Advisory / Consultancy: Sirtex Medical; Advisory / Consultancy: Lipotek; Advisory / Consultancy: Novella; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Roche; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution), Travel / Accommodation / Expenses: AstraZeneca; Research grant / Funding (institution): Baxalta/Shire; Research grant / Funding (institution): Eli Lilly and Company; Research grant / Funding (institution): Boehringer Ingelheim; Travel / Accommodation / Expenses: Deciphera Pharmaceuticals, LLC; Travel / Accommodation / Expenses: Sirtex; Shareholder / Stockholder / Stock options: GW Pharmaceuticals; Shareholder / Stockholder / Stock options: Aimmune; Shareholder / Stockholder / Stock options: Vertex; Shareholder / Stockholder / Stock options: Bluebird Bio; Shareholder / Stockholder / Stock options: Alnylam; Shareholder / Stockholder / Stock options: Biomarin; Shareholder / Stockholder / Stock options: Sage Therapeutics; Shareholder / Stockholder / Stock options: Dova Pharmaceuticals; Shareholder / Stockholder / Stock options: Therapeutics MD; Shareholder / Stockholder / Stock options: Juno Therapeutics; Shareholder / Stockholder / Stock options: Kite Pharma; Shareholder / Stockholder / Stock options: Kiadis Pharma; Shareholder / Stockholder / Stock options: CSL Limited; Shareholder / Stockholder / Stock options: Cochlear; Non-remunerated activity/ies, Chair: Australian Clinical Trials Alliance; Non-remunerated activity/ies, Co-Chair: National Oncology Alliance; Non-remunerated activity/ies, Co-Chair: All.Can Australia. P. Chi: Advisory / Consultancy, Research grant / Funding (institution), Clinical research support: Deciphera Pharmaceuticals, LLC; Advisory / Consultancy: Exelixis; Research grant / Funding (institution), Clinical research support: Novartis; Research grant / Funding (institution), Clinical research support: Array Biopharma. R.L. Jones: Honoraria (self), Advisory / Consultancy: Adaptimmune; Honoraria (self), Advisory / Consultancy: Blueprint Medicines; Honoraria (self), Advisory / Consultancy: Clinigen; Honoraria (self), Advisory / Consultancy: Eisai Co., Ltd; Honoraria (self), Advisory / Consultancy: Epizyme; Honoraria (self), Advisory / Consultancy: Daiichi Sankyo; Honoraria (self), Advisory / Consultancy: Deciphera Pharmaceuticals, LLC; Honoraria (self), Advisory / Consultancy: Immune Design Corp; Honoraria (self), Advisory / Consultancy: Eli Lilly and Company; Honoraria (self), Advisory / Consultancy: Merck; Honoraria (self), Advisory / Consultancy: Pharmamar; Honoraria (self), Advisory / Consultancy: UpToDate; Advisory / Consultancy: TRACON Pharmaceuticals; Research grant / Funding (institution), Clinical trial: MSD Pharmaceuticals. P. Reichardt: Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Novartis; Advisory / Consultancy, Speaker Bureau / Expert testimony: Pfizer; Advisory / Consultancy, Speaker Bureau / Expert testimony: Bayer; Advisory / Consultancy, Speaker Bureau / Expert testimony: Pharmamar; Advisory / Consultancy, Speaker Bureau / Expert testimony: Eli Lilly and Company; Speaker Bureau / Expert testimony: Amgen; Advisory / Consultancy: Clinigen; Advisory / Consultancy: Deciphera Pharmaceutcials, LLC; Advisory / Consultancy: Roche. S. Attia: Research grant / Funding (self): Desmoid Tumor Research Foundation; Research grant / Funding (institution): AB Science; Research grant / Funding (institution): TRACON Pharmaceuticals; Research grant / Funding (institution): CytRx Corp; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Daiichi Sankyo; Research grant / Funding (institution): Eli Lilly and Company; Research grant / Funding (institution), Travel / Accommodation / Expenses: Immune Design; Research grant / Funding (institution): Karyopharm Therapeutics; Research grant / Funding (institution): Epizyme; Research grant / Funding (institution): Blueprint Medicines; Research grant / Funding (institution): Genmab; Research grant / Funding (institution): CBA Pharma; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Philogen; Research grant / Funding (institution): Gradalis; Research grant / Funding (institution): Deciphera Pharmaceuticals, LLC; Research grant / Funding (institution): Takeda; Research grant / Funding (institution): Incyte; Research grant / Funding (institution): Springworks; Research grant / Funding (institution): Adaptimmune; Research grant / Funding (institution): Advenchen Laboratories; Research grant / Funding (institution): Bavarian Nordic; Research grant / Funding (institution): BTG; Research grant / Funding (institution): PTC Therapeutics; Research grant / Funding (institution): GlaxoSmithKline; Research grant / Funding (institution): FORMA Therapeutics. G. D’Amato: Advisory / Consultancy, Speaker Bureau / Expert testimony: Eli Lilly and Company; Advisory / Consultancy: Blueprint Medicines; Advisory / Consultancy, Speaker Bureau / Expert testimony: Janssen; Speaker Bureau / Expert testimony: Eisai Co., Ltd. J. Meade: Shareholder / Stockholder / Stock options, Full / Part-time employment: Deciphera Pharmaceuticals, LLC. K. Shi: Shareholder / Stockholder / Stock options: Alnylam; Shareholder / Stockholder / Stock options: Immunogen; Full / Part-time employment: Deciphera Pharmaceuticals, LLC. R. Ruiz-Soto: Shareholder / Stockholder / Stock options, Full / Part-time employment: Deciphera Pharmaceuticals, LLC. J. Blay: Honoraria (self), Honoraria (institution), Advisory / Consultancy: Novartis; Honoraria (self), Honoraria (institution), Advisory / Consultancy: Bayer; Honoraria (self), Honoraria (institution), Advisory / Consultancy: Pfizer; Honoraria (self), Honoraria (institution), Advisory / Consultancy: Deciphera Pharmaceuticals, LLC; Honoraria (self), Honoraria (institution), Advisory / Consultancy: Roche.

Background

REGOBONE, a non-comparative phase II, double-blind, PL-controlled trial was designed to evaluate the activity of REG, an oral multikinase inhibitor, in four parallel independent bone sarcomas cohorts: osteosarcoma, Ewing sarcoma, chondrosarcoma, and chordoma. REG demonstrated promising activity in the osteosarcoma cohort (Lancet Oncol 2019). We report here the CS cohort results.

Methods

Eligible CS pts were randomized (2:1) to receive either REG (160 mg/d, 21/28 d) or PL with optional cross-over at the time of centrally confirmed progressive disease (PD). Key-eligibility criteria were age ≥10 years, histologically confirmed diagnosis of CS, confirmed measurable PD not amenable to curative-intent, 1-2 previous chemotherapy (CT) regimen(s) for relapsed disease, ECOG 0-1. 24 pts were planned in the REG arm based on a A’Hern’s single-stage design for phase II trials (1-sided a = 0.05, and 80% power) to detect a 25% improvement in the progression-free rate (PFR) at 12 weeks (P₀=50%) as evaluated by central review per RECIST1.1. Major secondary endpoints were PFS, OS and safety.

Results

From September 2014 to February 2019, 46 CS pts were included. Six pts were not eligible for efficacy analysis. Of 40 efficacy-evaluable pts (16 in PL arm and 24 in REG arm); 25 were men, median age was 61 (20-75) years. 13 pts (54.2%; one-sided CI95% = [35.8-[) were non-progressive at 12 weeks in the REG arm vs. 6 (37.5%; CI95% = [17.8-[) in the PL arm. Median PFS was 19.4 (CI95% = 11.4-35) vs. 8 (CI95%= 4.3-23.4) weeks for REG and PL arms, respectively. At the time of the analysis there is not enough event to describe OS. 14 pts crossed-over to REG after PD on PL. The most common Gr3-5 REG-related AEs during the double-blind period were hypertension (12%), cutaneous toxicity (8%), asthenia (8%), diarrhea (8%), thrombocytopenia (8%), and 1 fatal liver cytolysis.

Conclusions

Despite a PFR at 12 weeks lower than expected, this randomized non comparative study shows a promising signal of benefit of REG in relapsed CS, with a median of PFS of 19 weeks and, an acceptable toxicity.

Clinical trial identification

EudraCT: 2013-003910-42, NCT02389244.

Legal entity responsible for the study

UNICANCER.

Funding

Bayer HealthCare SAS.

Disclosure

F. Duffaud: Honoraria (self), Advisory / Consultancy: Bayer; Honoraria (self), Advisory / Consultancy: Roche; Advisory / Consultancy: Lilly; Travel / Accommodation / Expenses: Pharmamar; Travel / Accommodation / Expenses: Leo Pharma. J. Blay: Honoraria (self), Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): Bayer; Honoraria (self), Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): Novartis; Honoraria (self), Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): GSK. O. Mir: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options: Amgen; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options: AstraZeneca; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options: Bayer; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options: Blueprint Medicines; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options: BMS; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options: Eli-Lilly; Honoraria (self), Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options: Incyte; Honoraria (self), Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options: Ipsen; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options: Lundbeck; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options: MSD; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options: Novartis; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options: Pfizer; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options: Roche; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options: Servier; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options: Vifor Pharma. P. Boudou Rouquette: Honoraria (self): BMS; Honoraria (self): Roche; Travel / Accommodation / Expenses: Pharmamar; Travel / Accommodation / Expenses: Pfizer; Travel / Accommodation / Expenses: Novartis. All other authors have declared no conflicts of interest.

Background

Pazopanib (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.

Methods

TAPPAS 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.

Results

Of 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%).Table:

1667O

Conclusions

TRC105 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 identification

NCT 02979899.

Legal entity responsible for the study

Tracon Pharmaceuticals, Inc.

Funding

Tracon Pharmaceuticals, Inc.

Disclosure

R.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.

Background

DT are rare tumors arising from musculoaponeurotic tissues. Although benign, they may be locally aggressive, leading to pain and disability, and exceptionally death. ESMO guidelines recommend frontline watchful waiting. Medical treatment includes NSAID’s, anti-estrogens, chemotherapy, antiangiogenics or radiation therapy in progressing tumors. Some pts do not respond for whom there is an unmet need for new treatments. Cryoablation (CA) is an interventional radiology technique that is suitable for DT pts. The procedure is based on repeated cycles of freezing/passive thawing of the tumor, leading to cell death.

Methods

CRYODESMO-01 was the first prospective, open-label, non-randomized, non- comparative, multicentric pilot study assessing CA in non-abdominopelvic progressive DT pts. The primary endpoint was the rate of non-progression at 12 months; secondary endpoints included safety, quality of life (QoL), assessment of pain and functional status. Inclusion criteria were: pts 18 y.o., DT deemed accessible by the operator, measurable lesion (RECIST), progressive disease after at least two lines of adequate medical therapy or with functional symptoms/pain, adequate biological parameters, informed consent and affiliation to social security.

Results

50 pts were enrolled (78% female). Mean age was 41 y.o (range 19-73). The median number of prior treatments was 2.00 [1-4]. Tumor location were limbs (36%); trunk (60%) and cervical area (4%). The median tumor volume was 111cm³ (0.6-1 068). The rate of non-progressing disease +12 months was 86% (CI95% 73%-94%). Grade 1 and 2 toxicity occured in 32.8 and 44.5% of cases, whereas 11 pts (22%) had grade 3 and 4 AEs, all with a favorable outcome. 63% and 83% of pts had better functional status and pain scores, respectively. Female sex (p = 0.046) was correlated to response at + 12 months (90.38% vs: 62.82%).

Conclusions

The study met is primary endpoint with 86% of non-progressive disease at + 12 months, reduced pain and better functional status. CA in the hands of expert interventional radiologists, should be considered in guidelines as a reasonable treatment option for these pts. CA will soon challenge medical therapy as front-line therapy in the forthcoming randomized trial CRYODESMO-02.

Clinical trial identification

NCT02476305.

Legal entity responsible for the study

Hôpitaux Universitaires de Strasbourg.

Funding

French National Cancer Institute (INCa).

Disclosure

J. Kurtz: Travel / Accommodation / Expenses: PharmaMar; Travel / Accommodation / Expenses: Roche; Advisory / Consultancy, Travel / Accommodation / Expenses: Tesaro; Advisory / Consultancy, Travel / Accommodation / Expenses: AstraZeneca. X. Buy: Honoraria (self): Galil BTG. F. Deschamps: Honoraria (self): BTG; Honoraria (self): Medtronic; Honoraria (self): Covidien. A. gangi: Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Canon medical; Licensing / Royalties: Apriomed; Non-remunerated activity/ies: BTG. All other authors have declared no conflicts of interest.

Background

The combination of sunitinib (SU) and nivolumab (NI) showed to be safe in the previous phase I of IMMUNOSARC study. We present the results of the phase II of the combination of SU-NI in the advanced STS (pts) cohort.

Methods

Pretreated progressing pts, ECOG 0-1, with UPS, synovial (SS), clear cell (CCS), angio(AS)/epithelioid hemangioendothelioma (EH), solitary fibrous tumor (SFT), epithelioid sarcoma (ES), extraskeletal myxoid chondrosarcoma (ECM) or alveolar soft part sarcoma (ASPS) were eligible. SU 37.5 mg/d as induction was given days 1-14 and then reduced to 25mg/d continuously. NI was administered at 3 mg/Kg every 2 weeks from week 3. SU-NI was maintained up to progression or intolerance. Primary end-point was progression-free survival rate (PFSR) at 6 months (m) by RECIST. Secondary end-points: overall survival (OS), objective response rate (ORR) by RECIST and CHOI and toxicity.

Results

From Nov 2017 to Dec 2018, 50 eligible pts were included in 8 centres: (M/F 30/20), median age 45y (19-77). Diagnosis was: SS in 9 (18%), CCS in 7 (14%), SFT in 7 (14%), UPS in 6 (12%), ES in 6 (12%), AS in 5 (10%), ECM in 4 (8%), ASPS in 3 (6%) and other in 3 (6%). With a median FU of 6.1 m (0-13), 23 pts (46%) progressed based on RECIST with a median PFS of 5.9 m (95% IC 2.7-9.1) and 9 pts (18%) died, with median OS not reached yet. PFSR at 3 and 6 m based on local evaluation were 69% and 50% respectively and OS at 3 and 6 m were 86% and 77%. Based on central radiological review (RECIST, 43 evaluable pts), there were 1 CR (2.3%), 3 PR (7%), 26 SD (60%, 12 pts showing shrinkage) and 13 PD (30%). By CHOI (31 evaluable), there were 19 PR (61.3%), 8 SD (25.8%) and 4 PD (13%). Most relevant G3/4 toxicities were: AST increase 6 (11.8%), ALT increase 5 (9.8%), neutropenia 5 (9.8%), fatigue 3 (5,9%), thrombocytopenia 2 (3.9%), diarrhea 2 (3.9%), renal function impairment 2 (3.9%), without toxic deaths.

Conclusions

The trial met its primary endpoint. SU-NI is an active combination for the treatment of advanced selected STS patients, with 50% of patients free of progression at 6m. Further exploration of immunomodulatory strategies is warranted in selected sarcoma subtypes.

Clinical trial identification

NCT03277924.

Legal entity responsible for the study

Grupo Español de Investigación en Sarcomas (GEIS).

Funding

Pfizer and BMS.

Disclosure

J. Martin Broto: Honoraria (self), Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: PharmaMar; Honoraria (self), Speaker Bureau / Expert testimony, Research grant / Funding (institution): Novartis; Honoraria (self): Bayer; Honoraria (self): Amgen; Travel / Accommodation / Expenses: Pfizer; Honoraria (self), Research grant / Funding (institution): Lilly; Research grant / Funding (institution): Eisai; Research grant / Funding (self): GlaxoSmithKline . N. Hindi: Honoraria (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: PharmaMar; Research grant / Funding (institution): Eisai; Research grant / Funding (institution): Novartis. G.E. Grignani: Travel / Accommodation / Expenses: PharmaMar; Travel / Accommodation / Expenses: Lilly; Travel / Accommodation / Expenses: Novartis. A. Redondo: Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche; Advisory / Consultancy, Travel / Accommodation / Expenses: AstraZeneca; Advisory / Consultancy: Tesaro; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: PharmaMar; Advisory / Consultancy: Clovis; Research grant / Funding (institution): Eisai. C. Valverde: Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: PharmaMar; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Lilly; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Novartis; Advisory / Consultancy, Travel / Accommodation / Expenses: Bayer; Advisory / Consultancy, Research grant / Funding (institution): Bluprint; Travel / Accommodation / Expenses: Pfizer; Research grant / Funding (institution): Karyopharm; Research grant / Funding (institution): Decyphera; Research grant / Funding (institution): Incyte. A. Lopez Pousa: Travel / Accommodation / Expenses: PharmaMar. S. Stacchiotti: Research grant / Funding (institution): Pfizer . E. Palmerini: Advisory / Consultancy, Research grant / Funding (institution): Daiichi Sankyo; Advisory / Consultancy: Amgen; Advisory / Consultancy, Travel / Accommodation / Expenses: Lilly; Research grant / Funding (institution): Bristol-Myers Squibb (BMS); Research grant / Funding (institution): Pfizer; Research grant / Funding (institution), Travel / Accommodation / Expenses: PharmaMar; Travel / Accommodation / Expenses: Takeda. D.S. Moura: Research grant / Funding (institution), Travel / Accommodation / Expenses: PharmaMar; Research grant / Funding (institution), Travel / Accommodation / Expenses: Eisai; Research grant / Funding (institution): Novartis. L. D’Ambrosio: Travel / Accommodation / Expenses: PharmaMar; Travel / Accommodation / Expenses: Lilly; Advisory / Consultancy: PSI. J.A. Lopez Martin: Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: MSD; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: BMS; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche; Advisory / Consultancy: Pierre Fabre; Advisory / Consultancy: Celgene; Advisory / Consultancy: Novartis; Advisory / Consultancy: Amgen; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Lilly; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options, Licensing / Royalties: PharmaMar; Advisory / Consultancy: Chobani; Advisory / Consultancy: Pfizer. All other authors have declared no conflicts of interest.

Background

This study (NCT03132922) evaluates safety, tolerability, and antitumor activity of ADP-A2M4, genetically engineered autologous specific peptide enhanced affinity receptor (SPEAR) T-cells directed towards a MAGE-A4 peptide expressed in the context of HLA-A*02. Here, we report on a subset of patients (pts) with synovial sarcoma (SS).

Methods

In this first-in-human T-cell dose-escalation study, pts who are HLA-A*02⁺ (excluding *02:05, *02:07), have inoperable or metastatic MAGE-A4⁺ disease, and meet entry criteria are eligible for treatment. Following apheresis, T-cells are isolated, transduced with MAGE-A4^c1032TCR, and expanded. The lymphodepletion chemotherapy increased in intensity as the study progressed, with max dose of 30 mg/m²/d fludarabine x 4 d and 1800 mg/m²/d cyclophosphamide x 2 d. During dose escalation, 3 pts with various tumor types received 0.1x10⁹ (±20%), 1x10⁹ (range: 0.5 – 1.2 × 10⁹), or 5x10⁹ (range: 1.2 – 6 × 10⁹) transduced cells and were monitored for dose-limiting toxicities (DLTs). During expansion, 30 pts (not only SS) will be treated with 1.2 – 10 x 10⁹ transduced cells. Disease is assessed per RECIST by CT/MRI at wk 6, 12, 18, and 24, and every 3 mo for 2 yr, then every 6 mo or until progression. Correlative studies will investigate transduced cell persistence, phenotype, and function, and serum and tumor microenvironment factors.

Results

No DLTs were reported. ADP-A2M4 was well tolerated, with adverse events consistent with chemotherapy or other immunotherapies. 10 pts with SS have been treated in cohort 3 and the expansion phase (30Apr19). Median T-cell dose was 9.7 x 10⁹ (4.49 - 9.98 x 10⁹). 8 pts have post-baseline tumor assessments. There are 3 confirmed partial responses (PR) (-86%, -44%, -54), and 1 unconfirmed PR (-31%) at wk 6. Best response was stable disease in 3 pts (-27% and -15%, ongoing, and +12%, progressed) and progressive disease in 1. 2 pts have yet to be assessed. Ex vivo analysis of transduced cells from peripheral blood and tumor showed cells were cytolytic and activated in an antigen-specific manner.

Conclusions

ADP-A2M4 induced clinical responses in pts with SS. Transduced T-cells expand upon exposure to antigen and are functional. Updated data from this ongoing study will be presented.

Clinical trial identification

NCT03132922, First posted on April 28, 2017.

Editorial acknowledgement

Debra Brocksmith, MB ChB, PhD, of Envision Pharma Group; contracted by Adaptimmune.

Legal entity responsible for the study

Adaptimmune.

Funding

Adaptimmune.

Disclosure

B.A. Van Tine: Research grant / Funding (self): Pfizer; Research grant / Funding (self): Tracon; Research grant / Funding (self): Merck; Advisory / Consultancy: Epizyme; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Lilly; Advisory / Consultancy: CytRX; Advisory / Consultancy, Speaker Bureau / Expert testimony: Janssen; Advisory / Consultancy: Immune Design; Advisory / Consultancy: Daiichi Sankyo; Advisory / Consultancy: Plexxicon; Advisory / Consultancy: Adaptimmune; Speaker Bureau / Expert testimony: Caris. M.O. Butler: Honoraria (self), Advisory / Consultancy: Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Merck; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self): Roche; Advisory / Consultancy: Adaptimmune; Advisory / Consultancy: EMD Serono; Advisory / Consultancy: GSK; Advisory / Consultancy: Immunocore; Advisory / Consultancy: Immunovaccine; Research grant / Funding (institution): Takara Bio. M.L. Johnson: Research grant / Funding (institution): BerGenBio; Research grant / Funding (institution): Lilly; Research grant / Funding (institution), Travel / Accommodation / Expenses: EMD Serono; Research grant / Funding (institution): Janssen; Advisory / Consultancy, Research grant / Funding (institution): Mirati Therapeutics; Research grant / Funding (institution): Genmab; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Pfizer; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses, Additional travel from: Astellas, AstraZeneca, Boehringer Ingelheim, Clovis, Daiichi Sankyo, Bristol-Myers Squibb, Exelixis, Incyte, Merck, Sysmex Inostics, Vapotherm: Genentech; Research grant / Funding (institution): Stemcentrix; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Checkpoint Therapeutics; Research grant / Funding (institution): Array Biopharma; Research grant / Funding (institution): Regeneron; Research grant / Funding (institution): Apexigen; Research grant / Funding (institution), Travel / Accommodation / Expenses: AbbVie; Research grant / Funding (institution): Tarveda; Research grant / Funding (institution): Adaptimmune; Research grant / Funding (institution), Additional advisory for: Gelgene, Boehringer Ingelheim, Sanofi, LOXO, Calithera, Merck, Araxes Pharma, Mersana Therapeutics, BeiGene, Incyte, Guardant Health, Bristol-Myers Squibb, Ribon Therapeutics: Syndax; Research grant / Funding (institution), Additional grant funding from: Boehringer Ingelheim, Sanofi, Hengrui Therapuetics INC, Merck, Daiichi-Sankyo, Lycera, G1 Therapeutics, Dynavax, LOXO, Cytomx, BeiGene, Birdie, Corvus, Incyte, Genocea, Gritstone, Amgen, Bristol-Myers Squibb, Kadmon, Clovis, Acerta, OncoMed, Guardant Health, Takeda, Shattuck Labs, GSK: Neovia. J. Clarke: Research grant / Funding (self): MedPacto; Research grant / Funding (self): Bristol-Myers Squibb; Advisory / Consultancy, Research grant / Funding (self): Eli Lilly; Research grant / Funding (self): Genentech; Research grant / Funding (self): Spectrum; Research grant / Funding (self): Adaptimmune; Research grant / Funding (self): Bayer; Research grant / Funding (self): AbbVie; Research grant / Funding (self): Moderna; Advisory / Consultancy, Speaker Bureau / Expert testimony: Merck; Advisory / Consultancy, Speaker Bureau / Expert testimony: Guardant; Advisory / Consultancy: AstraZeneca. D. Liebner: Advisory / Consultancy: Foundation Medicine; Advisory / Consultancy: Blueprint Medicines. K. Odunsi: Research grant / Funding (self): ITeos Therapeutics. A.J. Olszanski: Advisory / Consultancy, Research grant / Funding (self): Bristol-Myers Squibb; Advisory / Consultancy: Merck; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Array; Advisory / Consultancy, Research grant / Funding (self): EMD Serono; Advisory / Consultancy: Iovance; Advisory / Consultancy: Novartis; Advisory / Consultancy, Research grant / Funding (self): Alkermes; Research grant / Funding (self): Adaptimmune; Research grant / Funding (self): Astellas; Research grant / Funding (self): Boston Biomedical; Research grant / Funding (self): Checkmate Pharmaceutics; Research grant / Funding (self): GSK; Research grant / Funding (self): Immunocore; Research grant / Funding (self): Intensity Therapeutics; Research grant / Funding (self): Kartos; Research grant / Funding (self): Kura; Research grant / Funding (self): Oncoceutics; Research grant / Funding (self): Targovax. S. Basu: Shareholder / Stockholder / Stock options, Full / Part-time employment: Adaptimmune. F. Brophy: Shareholder / Stockholder / Stock options, Full / Part-time employment: Adaptimmune. T. Holdich: Shareholder / Stockholder / Stock options, Full / Part-time employment: Adaptimmune. T. Trivedi: Shareholder / Stockholder / Stock options, Full / Part-time employment: Adaptimmune. R.G. Amado: Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment: Adaptimmune. D.S. Hong: Research grant / Funding (self): AbbVie; Advisory / Consultancy, Research grant / Funding (self): Adaptimmune; Research grant / Funding (self): Amgen; Research grant / Funding (self): AstraZeneca; Advisory / Consultancy, Research grant / Funding (self): Bayer; Research grant / Funding (self): Bristol-Myers Squibb; Research grant / Funding (self): Daiichi-Sankyo; Research grant / Funding (self): Eisai; Research grant / Funding (self): Fate Therapeutics; Advisory / Consultancy, Research grant / Funding (self): Genentech; Research grant / Funding (self), Travel / Accommodation / Expenses: Genmab; Research grant / Funding (self): Ignyta; Advisory / Consultancy, Research grant / Funding (self): Infinity; Research grant / Funding (self): Kite; Research grant / Funding (self): Kyowa; Research grant / Funding (self): Lilly; Research grant / Funding (self), Travel / Accommodation / Expenses: LOXO; Research grant / Funding (self): MedImmune; Research grant / Funding (self): Merck; Research grant / Funding (self), Additional grant funding from: miRNA, Molecular Templates, Mologen, NCI-CTEP, Novartics, Pfizer, Seattle Genetics, Takeda. Additional advisory consulting for: Alpha Insights, Axiom, Baxter, GLG, Group H, Guidepoint Global, Merrimack, Medscape, Numab, Pfizer, Seattle Genetics, Takeda, Trieza Therapeutics, WebMD; Travel support from MiRNA, AACR, ASCO, SITC; ownership interests in Molecular Match, OncoResponse, Presagia Inc: Mirati. All other authors have declared no conflicts of interest.