Thomas Grellety

Use of PD-1 Targeting, Macrophage Infiltration, and IDO Pathway Activation in Sarcomas: A Phase 2 Clinical Trial

Importance There is a strong rationale for treating sarcomas with immunotherapy. Objective To assess the efficacy and safety of programmed cell death protein 1 (PD-1) targeting in combination with metronomic chemotherapy in sarcomas. Design, Setting, and Participants This was an open-label, multicenter, phase 2 study of 4 cohorts of patients with advanced soft-tissue sarcoma (STS), including leiomyosarcoma (LMS), undifferentiated pleomorphic sarcoma (UPS), other sarcomas (others), and gastrointestinal stromal tumor (GIST). All patients received 50 mg twice daily cyclophosphamide 1 week on and 1 week off and 200 mg of intravenous pembrolizumab every 3 weeks. Intervention or Exposure Pembrolizumab in combination with metronomic cyclophosphamide. Main Outcomes and Measures There was a dual primary end point, encompassing both the nonprogression and objective responses at 6 months per Response Evaluation Criteria in Solid Tumours (RECIST) v1.1 for LMS, UPS, and others and 6-month nonprogression for GIST. An objective response rate of 20% and/or a 6-month nonprogression rate of 60% were determined as reasonable objectives for treatment with meaningful effect. Correlative studies of immune biomarkers were planned from patient tumor and plasma samples. Results Between June 2015 and July 2016, 57 patients were included (median [range] age, 59.5 [18.5-84.0] years; 24 women [42%]); 50 patients were assessable for the efficacy end point. Three patients experienced tumor shrinkage, resulting in a partial response in a single solitary fibrous tumor. The 6-month nonprogression rates were 0%, 0%, 14.3% (95% CI, 1.8%-42.8%) for LMS, UPS, and others, respectively, and 11.1% (95% CI, 2.8%-48.3%) for GIST. The most frequent adverse events were grade 1 or 2 fatigue, diarrhea, and anemia. The only patient who experienced partial response was the only one with strong programmed cell death 1 ligand 1–positive staining in immune cell. Strong infiltration by macrophage expressing the inhibitory enzyme indoleamine 2,3-dioxygenase 1 (IDO1) was observed in the majority of cases. Moreover, a significant increase in the kynurenine to tryptophan ratio was observed in patient plasma samples during the study treatment. Conclusions and Relevance We found that PD-1 inhibition has limited activity in selected STS and GIST. This may be explained by an immunosuppressive tumor microenvironment resulting from macrophage infiltration and IDO1 pathway activation. Trial Registration clinicaltrials.gov Identifier: NCT02406781

PRIMA-1(MET) induces death in soft-tissue sarcomas cell independent of p53.

BackgroundThe aim of this study was to explore the efficacy and define mechanisms of action of PRIMA-1MET as a TP53 targeted therapy in soft-tissue sarcoma (STS) cells.MethodsWe investigated effects of PRIMA-1MET on apoptosis, cell cycle, and induction of oxidative stress and autophagy in a panel of 6 STS cell lines with different TP53 status.ResultsCell viability reduction by PRIMA-1MET was significantly observed in 5 out of 6 STS cell lines. We found that PRIMA-1MET was capable to induce cell death not only in STS cells harboring mutated TP53 but also in TP53-null STS cells demonstrating that PRIMA-1MET can induce cell death independently of TP53 in STS cells. We identified an important role of reactive oxygen species (ROS), involved in PRIMA-1MET toxicity in STS cells leading to a caspase-independent cell death. ROS toxicity was associated with autophagy induction or JNK pathway activation which represented potential mechanisms of cell death induced by PRIMA-1MET in STS.ConclusionsPRIMA-1MET anti-tumor activity in STS partly results from off-target effects involving ROS toxicity and do not deserve further development as a TP53-targeted therapy in this setting.

The mammary ducts create a favourable microenvironment for xenografting of luminal and molecular apocrine breast tumours

There is a paucity of models for hormone receptor‐positive (HR+) breast cancer because of the difficulty of establishing xenografts from these tumours. We show that this obstacle can be overcome by injecting human tumour cells directly into the mammary ducts of immunodeficient mice. Tumours from 31 patients were infected overnight with a lentiviral vector expressing tdTomato and injected through the nipple into the mammary ducts of NOD‐SCID‐IL2RG−/− mice. Tumours formed in the mice in 77% of cases after the first injection (6/8 luminal A, 15/20 luminal B, and 3/3 molecular apocrine). Four luminal A and one molecular apocrine graft were tested in secondary and tertiary grafts: all were successfully passaged in secondary and 4/5 in tertiary grafts. None of the samples engrafted when injected subcutaneously. The morphology, oestrogen receptor (ER), progesterone receptor (PR), androgen receptor (AR), and Ki‐67 profiles of the clinical samples were maintained in the tertiary grafts. We also show that the intraductal approach can be used to test the response to targeted therapy with fulvestrant and palbociclib, using a genetically defined ER+ model. We conclude that the mammary ducts create a microenvironment that is uniquely favourable to the survival and growth of tumours derived from mammary hormone‐sensing cells. This approach opens the door to testing genomically targeted treatment of HR+ tumours in precision medicine programmes. Copyright

Angiosarcoma associated with a Kasabach-Merritt syndrome: report of two cases treated with paclitaxel.

Angiosarcomas are rare, aggressive vascular malignancies of endothelial cell differentiation. Kasabach-Merritt syndrome is a rare condition defined by the association of thrombocytopenia and consumption coagulopathy with specific vascular tumors, such as tufted angioma or kaposiform hemangioendothelioma. We report here two cases of angiosarcomas complicated by a Kasabach-Merritt syndrome and their outcome after treatment with paclitaxel.

Challenging a dogma: co-mutations exist in MAPK pathway genes in colorectal cancer

Sequencing of genes encoding mitogen-activated protein kinase (MAPK) pathway proteins in colorectal cancer (CRC) has established as dogma that of the genes in a pathway only a single one is ever mutated. We searched for cases with a mutation in more than one MAPK pathway gene (co-mutations). Tumor tissue samples of all patients presenting with CRC, and referred between 01/01/2008 and 01/06/2015 to three French cancer centers for determination of mutation status of RAS/RAF+/−PIK3CA, were retrospectively screened for co-mutations using Sanger sequencing or next-generation sequencing. We found that of 1791 colorectal patients with mutations in the MAPK pathway, 20 had a co-mutation, 8 of KRAS/NRAS, and some even with a third mutation. More than half of the mutations were in codons 12 and 13. We also found 3 cases with a co-mutation of NRAS/BRAF and 9 with a co-mutation of KRAS/BRAF. In 2 patients with a co-mutation of KRAS/NRAS, the co-mutation existed in the primary as well as in a metastasis, which suggests that co-mutations occur early during carcinogenesis and are maintained when a tumor disseminates. We conclude that co-mutations exist in the MAPK genes but with low frequency and as yet with unknown outcome implications.

Encouraging Trends in Modern Phase 1 Oncology Trials

Benefits of Phase 1 Oncology Trials Historically, phase 1 trials have been aimed at defining the toxic effects of an agent. With the advent of targeted therapies and immunotherapies, response rates...

Clinical activity of regorafenib in PDGFRA-mutated gastrointestinal stromal tumor.

Gastrointestinal stromal tumor (GIST) is the most frequent mesenchymal tumor of the gastrointestinal tract and one of the most frequent sarcoma. Mutually exclusive KIT and PDGFRA mutations are central events in GIST pathogenesis, and their understanding is crucial because specific treatment targeting oncogenic KIT and PDGFRA activation (especially imatinib) has become available. The most frequent PDGFRA mutation (D842V) is associated with primary resistance to imatinib. Data related to regorafenib efficacy in PDGFRA-mutated GIST are lacking. We report here a case report of a prolonged response with regorafenib in a patient with a PDGFRA-mutated GIST.

Risks and benefits of phase 1 oncology trials in the era of personalized medicine.

e18116Background: Although crucial to developing new anti-cancer treatments, phase I trials in oncology remain ethically controversial. Critics argue that they have no therapeutic intent and offer ...

Abstract C48: BIP (Bergonie Institute profiling) program: Fighting cancer by matching molecular alterations and drugs in early phase trials

Background: BIP is an institution-wide permanent screening program started in 2014 to identify patients (pts) referred to Institut Bergonie (Bordeaux, France) with somatic alterations that can be matched to targeted therapies in early phase clinical trials. Methods: Pts with advanced solid tumors and with ECOG performance status ≤ 2 were eligible. Tumor DNA was isolated from a FFPE archived sample when available or from a fresh tumor biopsy. DNA analysis was performed by next generation sequencing (NGS) using a panel of up to 287 genes and by comparative genomic hybridization (CGH). Results for each patient were discussed during a weekly multidsicplinary molecular tumor board in order to assess the eligibility of the patient to early phase clinical trials. Results: From Jan 1 2014 to June 30 2015, 542 pts were enrolled with median 2 prior treatments for advanced disease (range 0-9). The main tumor types were: lung (19.2%), colorectal (16.2%), breast (13.3%), ovarian (11%), and sarcomas (10%). Median age was 61 years (range 18-84). In 28 cases (5%) molecular analysis failed mainly because of insufficient tissue. The median time from first referral to reporting was 9 weeks (range 1-36). The 20 genes most frequently altered were TP53, CDKN2A,PTEN, CDKN2B, PIK3CA, MYC, ARID1A, KRAS, RB1, EGFR, ERBB2, FGFR1, APC,RICTOR,ZNF703,ATM,BRAF,NF1,FGFR3 and CCND1. Among the patients included between Jan 1 2014 and January 31 2015 (n = 286), 176 patients (68%) of patients had at least one genetic alteration that was considered actionable by the molecular tumor board. 85 patients (29.7%) were included in a clinical trial with a median delay of 17 weeks between first referral and date of treatment onset. The treatment was matched with the tumor profile in 49 cases (17%). The main reasons for non-inclusion in a clinical trial despite the identification of an actionable mutation were: non progressive disease on the current line of treatment (31.5%), general status deterioration (26%), death (13%), clinical trial not available (13%), screening failure (6.5%), lost of follow-up (5.5%), and patient refusal (4.5%). 79 patients were evaluable for response according to RECIST 1.1. The disease control rate (objective response + stable disease) was 47% for patients included in clinical trials matched with the tumor profile versus 53% (p = 0.9) for the group of patients included in other clinical trials The median progression-free survival was 3.6 months (95 CI 1.8-5.3) versus 3.6 months (95 CI 0.9-6.3) (p = 0.5). Conclusions: Extensive molecular profiling by using high-throughput techniques is feasible in routine practice, allow identification of actionable mutations in the majority of cases and can be used to enroll patients in early phase trials matched to their tumor genotype. Citation Format: MAUD TOULMONDE, THOMAS GRELLETY, CELINE AUZANNEAU, YEC9HAN LAIZET, KEVIN TRAN, ANNE FLOQUET, DELPHINE GARBAY, JACQUES ROBERT, ISABELLE HOSTEIN, ISABELLE SOUBEYRAN, ANTOINE ITALIANO. BIP (Bergonie Institute profiling) program: Fighting cancer by matching molecular alterations and drugs in early phase trials. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C48.

Conception, mise en place et fonctionnement d’une RCP dédiée aux essais précoces : l’exemple de l’Institut Bergonié

Nous rapportons l’experience de l’Institut Bergonie dans la mise en place en routine d’un programme de cartographie genomique tumorale au sein d’une reunion de concertation pluridisciplinaire (RCP) dediee. Nous discutons egalement les nombreux defis emergeant dans l’acces a la medecine de precision en oncologie.