Sophie Cousin

Molecular Pathways: Immune Checkpoint Antibodies and their Toxicities

The emergence of immune checkpoint inhibitors for solid tumor treatments represents a major oncologic advance. Since the approval of ipilimumab, a cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) antibody, for the treatment of metastatic melanoma, many drugs, especially those targeting PD-1/PD-L1, have demonstrated promising antitumor effects in many types of cancer. By reactivating the immune system, these immunotherapies have led to the development of new toxicity profiles, also called immune-related adverse events (irAE). IrAEs can involve many organ systems, and their management is radically different from that of cytotoxic drugs; irAEs require immunosuppressive treatments, such as corticoids or TNFα antibody. In addition, the occurrence of irAEs has raised significant questions. Here, we summarize progress that has been made toward answering these questions, focusing on (i) the impact of immunotherapy dose on irAE occurrence, (ii) the correlation between irAE and patient outcome, (iii) the safety of immune checkpoint inhibitors in patients already treated for autoimmune disease, and (iv) the suspected effect on tumor growth of steroids used for the management of irAEs. Clin Cancer Res; 22(18); 4550–5. ©2016 AACR.

Growth modulation index as metric of clinical benefit assessment among advanced soft tissue sarcoma patients receiving trabectedin as a salvage therapy

BACKGROUNDnThe growth modulation index (GMI) is the ratio of time to progression with the nth line (TTP(n)) of therapy to the TTP(n)(-1) with the n-1th line. GMI >1.33 is considered as a sign of activity in phase II trials.nnnPATIENTS AND METHODSnThis retrospective analysis evaluated the concordance between the GMI and the efficacy outcomes in 279 patients with advanced soft tissue sarcoma (ASTS) treated with trabectedin 1.5 mg/m² (24-h infusion every 3 weeks) in four phase II trials.nnnRESULTSnOne hundred and forty-two (51%) patients received one prior line and 137 ≥ 2 lines. The median TTP(n) was 2.8 months (range 0.2-26.8), whereas the median TTP(n)(-1) was 4.0 months (0.3-79.5). The median GMI was 0.6 (0.0-14.4). Overall, 177 patients (63%) had a GMI <1; 21 (8%) a GMI equal to 1-1.33 and 81 (29%) a GMI >1.33, which correlated with the median overall survival in those patients (9.1, 13.9 and 23.8 months, respectively, P = 0.0005). A high concordance rate between the GMI and response rate (P < 0.0001) and progression-free survival (PFS, P < 0.0001) was observed. Good performance status (PS) was the only factor associated with GMI >1.33 (PS = 0; P < 0.04).nnnCONCLUSIONSnA high GMI was associated with favorable efficacy outcomes in patients treated with trabectedin. Further research is needed to assess GMI as an indicator in this setting.BACKGROUNDnThe growth modulation index (GMI) is the ratio of time to progression with the nth line (TTPn) of therapy to the TTPn-1 with the n-1th line. GMI >1.33 is considered as a sign of activity in phase II trials.nnnPATIENTS AND METHODSnThis retrospective analysis evaluated the concordance between the GMI and the efficacy outcomes in 279 patients with advanced soft tissue sarcoma (ASTS) treated with trabectedin 1.5 mg/m² (24-h infusion every 3 weeks) in four phase II trials.nnnRESULTSnOne hundred and forty-two (51%) patients received one prior line and 137 ≥2 lines. The median TTPn was 2.8 months (range 0.2-26.8), whereas the median TTPn-1 was 4.0 months (0.3-79.5). The median GMI was 0.6 (0.0-14.4). Overall, 177 patients (63%) had a GMI <1; 21 (8%) a GMI equal to 1-1.33 and 81 (29%) a GMI >1.33, which correlated with the median overall survival in those patients (9.1, 13.9 and 23.8 months, respectively, P = 0.0005). A high concordance rate between the GMI and response rate (P < 0.0001) and progression-free survival (PFS, P < 0.0001) was observed. Good performance status (PS) was the only factor associated with GMI >1.33 (PS = 0; P < 0.04).nnnCONCLUSIONSnA high GMI was associated with favorable efficacy outcomes in patients treated with trabectedin. Further research is needed to assess GMI as an indicator in this setting.

Patterns of care and outcomes of patients with METAstatic soft tissue SARComa in a real-life setting: the METASARC observational study

BackgroundWell-designed observational studies of individuals with rare tumors are needed to improve patient care, clinical investigations, and the education of healthcare professionals.MethodsThe patterns of care, outcomes, and prognostic factors of a cohort of 2225 patients with metastatic soft tissue sarcomas who were diagnosed between 1990 and 2013 and documented in the prospectively maintained database of the French Sarcoma Group were analyzed.ResultsThe median number of systemic treatments was 3 (range, 1–6); 27% of the patients did not receive any systemic treatment and 1054 (49%) patients underwent locoregional treatment of the metastasis. Half of the patients who underwent chemotherapy (nu2009=u2009810) received an off-label drug. Leiomyosarcoma was associated with a significantly better outcome than the other histological subtypes. With the exception of leiomyosarcomas, the benefit of a greater than third-line regimen was very limited, with a median time to next treatment (TNT) and overall survival (OS) ranging between 2.3 and 3.7xa0months and 5.4 and 8.5xa0months, respectively. The TNT was highly correlated with OS. Female sex, leiomyosarcoma histology, locoregional treatment of metastases, inclusion in a clinical trial, and treatment with first-line polychemotherapy were significantly associated with improved OS in the multivariate analysis.ConclusionsThe combination of doxorubicin with a second drug, such as ifosfamide, represents a valid option, particularly when tumor shrinkage is expected to provide clinical benefits. After failure of the second-line therapy, best supportive care should be considered, particularly in patients with non-leiomyosarcoma histology who are not eligible to participate in a clinical trial. Locoregional treatment of metastasis should always be included in the therapeutic strategy when feasible. TNT may represent a useful surrogate endpoint for OS in clinical studies.

High-grade soft-tissue sarcoma: optimizing injection improves MRI evaluation of tumor response

ObjectivesTo determine the acquisition delay after gadolinium-chelate injection that optimizes the prediction of the histological response during anthracycline-based neoadjuvant chemotherapy (NAC) for locally advanced high-grade soft-tissue sarcomas (STS).MethodsThirty patients (mean age 62 years) were included in this IRB-approved study. All patients received 5-6 cycles of NAC followed by surgery. A good response was defined as ≤ 10% viable cells on histological analysis of the surgical specimen. DCE-MRI was performed before treatment (MRI0) and after two cycles (MRI1). Images were obtained every 8 s. Change in contrast enhancement (CE) between MRI0 and MRI1 was calculated for each acquisition delay ‘t’ on the whole tumor volume. Area under the receiver-operating characteristics curves (AUROC) for change in CE was calculated at each acquisition delay, as well as the accuracy of the Choi criteria.ResultsThere were 22 (73.3%) poor responders. Acquisition delay had a significant effect on change in CE and on the response status according to Choi (p = 0.0014 and 0.0270, respectively). The highest AUROC was obtained at t = 58 s (0.792) with an optimal threshold of a -30.5% decrease in CE. At t = 58 s, accuracy to predict a poor response was 82.8% above this threshold, while it was 72.4% and 70% with no objective response according to the Choi criteria and RECIST1.1, respectively.ConclusionOptimization of acquisition delay after injection to estimate change in CE improves the prediction of histological response. For STS undergoing NAC, a 60-s delay can be recommended with MRI.Key points• Accuracy of response criteria based on contrast enhancement, like the Choi criteria, is dependent on the acquisition delay after gadolinium-chelate injection.• DCE-MRI helps determine the optimal acquisition delay after gadolinium-chelate injection for improving evaluation of tumor response.• In soft tissue sarcoma, an acquisition delay at 60 s optimizes the evaluation of the response and accuracy of the Choi criteria.

Homogeneous myxoid liposarcomas mimicking cysts on MRI: A challenging diagnosis

OBJECTIVESnMyxoid liposarcoma (M-LPS) is the second most frequent subtype of liposarcoma. Foci of fat on MRI are strongly suggestive of this diagnosis. The aims of this study are to (i) assess the prevalence of perfectly homogeneous M-LPS-mimicking cyst and characterize their associated clinical and pathological features and to (ii) identify helpful clues to prevent misdiagnosis when encountered with a cyst-like lesion in soft tissue parts.nnnMETHODSnMR images from 32 consecutive pathologically proven M-LPS and round cell liposarcomas (RC-LPS) were retrospectively reviewed independently by two radiologists at our institution. Location, morphology, signals, lesion architecture, heterogeneity, margins and periphery were systematically assessed in each case. Medical records were checked for initial and definitive histopathological diagnosis, therapeutic managements and outcomes. Histopathological specimens of cyst-like M-LPS were reviewed for the study.nnnRESULTSnWe have identified seven perfectly homogeneous well-defined cyst mimickers (21.9%) located on the limbs, all but one being deep-seated. These tumors were significantly smaller than the conventional M-LPS (pu202f=u202f0.0005). Six lesions were initially diagnosed as benign; 4 patients underwent marginal surgical resection without prior diagnosis and 2 cases were put under medical surveillance, one of which progressed towards classical RC-LPS on follow-up MRI. No specific pathological features could be identified nor were any clinical adverse outcomes recorded.nnnCONCLUSIONnCyst on MRI, without pathological adjacent joint, necessitates ultrasonography with Doppler and intravenous Gadolinium agent injections as subsets of M-LPS can mimic cyst on MRI. Cyst-like M-LPS, due to their smaller size and relative favorable outcome, could have better prognosis.

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 CT031: The effect of food on the pharmacokinetics (pk) of tazemetostat in patients with cancer

Tazemetostat is a selective oral small molecule inhibitor of enhancer of zeste homolog 2 (EZH2). In preclinical evaluations of tazemetostat in monkeys, oral administration (30 mg/kg) with concomitant food decreased Cmax and AUC by 10- and 5-fold, respectively, relative to the fasted state. Therefore, a food interaction sub-study was performed as part of the ongoing study E7438-G000-101 (NCT01897571). Purpose: To investigate the effect of food on the PK of tazemetostat in patients with advanced solid tumors or B-cell lymphomas. Methods: Patients (n = 13; 5 B-cell lymphoma, 8 solid tumor) received 200 mg tazemetostat fasted and immediately after a high-fat breakfast in a randomized crossover fashion with 7 days between doses. Serial blood samples for analysis of plasma tazemetostat were collected over 24 hours after each dose. Patients received 400 mg twice daily after completing the food effect component of the study. Results: Preliminary tazemetostat PK data (n = 11) are displayed below.n In contrast to results from monkeys, administration of tazemetostat with a high-fat meal decreased AUC(0-?) and Cmax 7% and 28%, respectively, relative to administration in the fasted state. Administration with a high-fat meal resulted in a 4-fold increase in median Tmax relative to the fasted state. Mean t1/2 values were nearly identical after administration in the fed and fasted states. All Cmax and AUC(0-?) values observed after administration of tazemetostat after a high-fat meal were within the range of the respective values observed after administration in the fasted state. Conclusions: The effect of food on the PK tazemetostat observed in monkeys did not predict the results observed in cancer patients, possibly due to inter-species differences in gastric residence time and pH. Administration of tazemetostat with a high fat breakfast results in slower absorption with no clinically relevant effect on systemic disposition or overall systemic exposure. These results support administration of tazemetostat without regards to meals. Citation Format: Benjamin Suttle, Sherri A. Smith, Nigel L. Waters, Vincent Ribrag, Antoine Italiano, Jean-Marie Michot, Sophie Postel-Vinay, Maud Toulmonde, Sophie Cousin, Maria Roche, Patricia Pimentel, Blythe Thomson, Peter Ho. The effect of food on the pharmacokinetics (pk) of tazemetostat in patients with cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT031.

Abstract CT029: The effect of tazemetostat on CYP3A-mediated metabolism of midazolam in patients with solid tumors

Background: Tazemetostat is a selective oral small molecule inhibitor of enhancer of zeste homolog 2 (EZH2). Results from in vitro studies using human liver microsomes, recombinant CYP isoforms, and hepatocytes demonstrated that tazemetostat is an inhibitor, inducer, and substrate of CYP3A4. Previous results indicated that systemic exposure to tazemetostat decreased after multiple dose administration in patients with cancer, consistent with net induction of CYP3A-mediated metabolism. Therefore, a drug-drug interaction sub-study was performed as part of the ongoing study E7438-G000-101 (NCT01897571). Purpose: To investigate the effect of tazemetostat on CYP3A-mediated metabolism in patients with solid tumors using midazolam as a sensitive CYP3A probe substrate. Methods: This was a single-sequence, open-label, crossover study. Patients with solid tumors (n = 13) received a single oral dose of 2 mg midazolam on Day -1 and on Day 15. Tazemetostat 800 mg twice daily (BID) was administered continuously starting on Day 1. Serial blood samples for the analysis of plasma midazolam and metabolites were collected over 24 h on Day -1 (midazolam alone) and Day 15 (midazolam plus tazemetostat). Results: A summary of midazolam pharmacokinetic parameters after administration alone and with tazemetostat 800 mg BID in 12 evaluable patients is presented below:n Plasma midazolam AUC(0-?) and Cmax decreased approximately 40% and 22%, respectively, after administration with tazemetostat 800 mg BID relative to administration of midazolam alone. Geometric mean t1/2 for midazolam decreased approximately 25%, after administration of midazolam with tazemetostat 800 mg BID relative to administration of midazolam alone. Conclusions: Administration of tazemetostat 800 mg BID resulted in net induction of CYP3A-mediated metabolism in patients with cancer. Tazemetostat 800 mg BID resulted in a less than 50% decrease in midazolam AUC and therefore is a weak inducer of CYP3A-mediated metabolism. Citation Format: Sherri Smith, Benjamin Suttle, Nigel L. Waters, Vincent Ribrag, Antoine Italiano, Jean-Marie Michot, Sophie Postel-Vinay, Maud Toulmonde, Sophie Cousin, Maria Roche, Patricia Pimentel, Peter Ho. The effect of tazemetostat on CYP3A-mediated metabolism of midazolam in patients with solid tumors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT029.