Samy Ammari

High-Throughput Genomics and Clinical Outcome in Hard-to-Treat Advanced Cancers: Results of the MOSCATO 01 Trial

High-throughput genomic analyses may improve outcomes in patients with advanced cancers. MOSCATO 01 is a prospective clinical trial evaluating the clinical benefit of this approach. Nucleic acids were extracted from fresh-frozen tumor biopsies and analyzed by array comparative genomic hybridization, next-generation sequencing, and RNA sequencing. The primary objective was to evaluate clinical benefit as measured by the percentage of patients presenting progression-free survival (PFS) on matched therapy (PFS2) 1.3-fold longer than the PFS on prior therapy (PFS1). A total of 1,035 adult patients were included, and a biopsy was performed in 948. An actionable molecular alteration was identified in 411 of 843 patients with a molecular portrait. A total of 199 patients were treated with a targeted therapy matched to a genomic alteration. The PFS2/PFS1 ratio was >1.3 in 33% of the patients (63/193). Objective responses were observed in 22 of 194 patients (11%; 95% CI, 7%-17%), and median overall survival was 11.9 months (95% CI, 9.5-14.3 months).Significance: This study suggests that high-throughput genomics could improve outcomes in a subset of patients with hard-to-treat cancers. Although these results are encouraging, only 7% of the successfully screened patients benefited from this approach. Randomized trials are needed to validate this hypothesis and to quantify the magnitude of benefit. Expanding drug access could increase the percentage of patients who benefit. Cancer Discov; 7(6); 586-95. ©2017 AACR.See related commentary by Schram and Hyman, p. 552This article is highlighted in the In This Issue feature, p. 539.

Tumor Growth Rate Is an Early Indicator of Antitumor Drug Activity in Phase I Clinical Trials

Purpose: Response Evaluation Criteria in Solid Tumors (RECIST) evaluation does not take into account the pretreatment tumor kinetics and may provide incomplete information about experimental drug activity. Tumor growth rate (TGR) allows for a dynamic and quantitative assessment of the tumor kinetics. How TGR varies along the introduction of experimental therapeutics and is associated with outcome in phase I patients remains unknown. Experimental Design: Medical records from all patients (N = 253) prospectively treated in 20 phase I trials were analyzed. TGR was computed during the pretreatment period (reference) and the experimental period. Associations between TGR, standard prognostic scores [Royal Marsden Hospital (RMH) score], and outcome [progression-free survival (PFS) and overall survival (OS)] were computed (multivariate analysis). Results: We observed a reduction of TGR between the reference versus experimental periods (38% vs. 4.4%; P < 0.00001). Although most patients were classified as stable disease (65%) or progressive disease (25%) by RECIST at the first evaluation, 82% and 65% of them exhibited a decrease in TGR, respectively. In a multivariate analysis, only the decrease of TGR was associated with PFS (P = 0.004), whereas the RMH score was the only variable associated with OS (P = 0.0008). Only the investigated regimens delivered were associated with a decrease of TGR (P < 0.00001, multivariate analysis). Computing TGR profiles across different clinical trials reveals specific patterns of antitumor activity. Conclusions: Exploring TGR in phase I patients is simple and provides clinically relevant information: (i) an early and subtle assessment of signs of antitumor activity; (ii) independent association with PFS; and (iii) it reveals drug-specific profiles, suggesting potential utility for guiding the further development of the investigational drugs. Clin Cancer Res; 20(1); 246–52. ©2013 AACR.

LDK378 Compassionate Use for Treating Carcinomatous Meningitis in an ALK Translocated Non–Small-Cell Lung Cancer

®42-year-old woman, never smoker, complaining of chronic cough, underwent computed tomography that depicted a right lower lung mass and subcarinal lymphadenopathy. Disease was classified as stage IIIA lung adenocarcinoma (cT3N2M0), without an EGFR or KRAS mutation. After neoadjuvant chemotherapy with cisplatin and gemcitabine, the patient underwent surgery comprising a right pneumonectomy and a lymph node dissection. One year and a half later, she was diagnosed with liver metastasis. The patient was treated with carboplatin, pemetrexed, and bevacizumab, achieving a stable disease for 9 months. Fluorescence in situ hybridization was performed, which revealed anaplastic lymphoma kinase (ALK) gene rearrangement. Crizotinib (ALK inhibitor) was started at disease progression. Tolerance was good and a partial response of hepatic lesions was observed. After 38 cycles of crizotinib (114 weeks on therapy), because the patient complained dizziness, full radiological screening showed stable liver lesions but brain magnetic resonance imaging revealed an appearance of carcinomatous meningitis associated with brain metastases. Lumbar punctions could not be performed because the patient refused. LDK378 was obtained for compassionate use and was started at a dose of 750 mg once daily. The treatment was well tolerated apart from nausea grade 2, thus the dose was reduced to 600 mg at day 60. The patient described rapid attenuation of dizziness. After 5 weeks of treatment, magnetic resonance imaging confirmed treatment efficacy with a decrease in brain lesions of 26% and in meningeal contrast (Fig. 1), that is still maintained after 5 and a half months. DISCUSSION

Abstract CT240: Molecular screening for cancer treatment optimization (MOSCATO 01): a prospective molecular triage trial; Interim analysis of 420 patients

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Background: The widespread use of high-throughput molecular techniques has allowed the identification of recurrent and actionable molecular traits across various tumor types. Translating these approaches to bedside may guide the decision-making for cancer patients candidates to early clinical trials. Methods: Patients with advanced solid tumors, refered to our early drug development department (DITEP), were prospectively enrolled in a prospective molecular screening program at Gustave Roussy (France). CT-Scan or ultrasound-guided biopsies were performed in metastatic or primary tumor sites to carry out a comprehensive molecular characterization. DNA was extracted from fresh tumor samples and analyzed by comparative genomic hybridization (CGH) (≥ 30% tumor cells required) and by Next Generation Sequencing (NGS) for up to 74 target genes (≥ 10% tumor cells required). A weekly molecular tumor board reviewed all the profiles to identify actionable traits for which the most relevant targeted therapy may be available through early clinical trials or marketed drugs. Treatment efficacy was evaluated by RECIST 1.1 criteria. Results: From November 2011 to December 2013, 420 heavily pretreated patients were included in the MOSCATO 01 trial. Out of them, a tumor biopsy could be performed in 368 patients (87%). CGH and NGS profiles were assessed in 284 (77%) and 315 (85%) of biopsied patients, respectively, with 283 patients (76% of biopsied patients) being profiled for both CGH and NGS. The median time for delivering results of 20 days. Actionable molecular aberrations were found in 161 patients (44%). Among them, 81 patients (50%) were matched to a targeted therapy and enrolled in ongoing phase I clinical trials. The most relevant genomic aberrations of interest were FGFR or FGF ligand amplification (n=24), PTEN/PI3K/AKT pathway activation (n=22), HER2 amplification (n=11), KRAS/NRAS/HRAS mutation (n=5), BRAF mutation (n=4), cyclin dependent kinase amplification or deletion (n=8), EGFR amplification or mutation (n=7), MET amplification (n=3), androgen receptor amplification (n=2), ALK translocation (n=2), and KIT amplification, MDM2 amplification, IGF1R amplification, and ROS1 rearrangement (all n=1). Out of the 81 patients profiled and treated according to the genomic profiles, we observed at the first tumor evaluation: 1 (1%) complete response (CR), 9 (11%) partial responses (PR), 52 (64%) stable disease (SD) and 14 (17%) progressive disease (PD). Whole exome analyses on selected patients are ongoing (currently n=24) and will be presented at the meeting. Conclusions: High throughput genomic analysis is feasible in daily practice and allows biological-orientation of patients in early clinical trials. The enrichment of phase I trials with patients harboring specific molecular traits leads to promising antitumor activity and is likely to exert a major influence on early drug development. Citation Format: Charles Ferte, Christophe Massard, Ecaterina Ileana, Antoine Hollebecque, Ludovic Lacroix, Samy Ammari, Maud Ngo-Camus, Rastislav Bahleda, Anas Gazzah, Andrea Varga, Sophie Postel-Vinay, Yohann Loriot, Nathalie Auger, Valerie Koubi-Pick, Bastien Job, Thierry De Baere, Frederic Deschamps, Philippe Vielh, Vladimir Lazar, Marie-Cecile Le Deley, Catherine Richon, vincent ribrag, eric deutsch, eric angevin, gilles vassal, Alexander Eggermont, Fabrice Andre, Jean-Charles Soria. Molecular screening for cancer treatment optimization (MOSCATO 01): a prospective molecular triage trial; Interim analysis of 420 patients. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT240. doi:10.1158/1538-7445.AM2014-CT240

Patterns of responses in metastatic NSCLC during PD-1 or PDL-1 inhibitor therapy: Comparison of RECIST 1.1, irRECIST and iRECIST criteria

BACKGROUND Immune checkpoint inhibitors are an important tool in the therapeutic strategy against metastatic non-small cell lung cancer (NSCLC); however, radiological evaluation is challenging due to the emergence of atypical patterns of responses. Several evaluation criteria have been proposed, such as the Response Evaluation Criteria in Solid Tumours (RECIST), version 1.1, immune -related RECIST (irRECIST) and iRECIST, but have not been systematically compared in a homogeneous population. PATIENTS AND METHODS We conducted a monocentric retrospective analysis of consecutive advanced NSCLC patients treated with an anti-programmed cell death-1 or anti-program death-ligand 1. Response patterns and the discordance between RECIST 1.1, irRECIST and iRECIST guidelines were described, and associations of response patterns and clinical outcome were explored. RESULTS Overall, 160 patients treated between February 2013 and October 2016 were included. Atypical responses were observed in 20 patients (13%), including eight pseudoprogressions (PsPDs) (5%) and 12 dissociated responses (8%). Thirteen of the 20 patients demonstrated clinical benefit. Per the RECIST 1.1, 37 patients (23%) showed an objective response or stable disease, and 123 patients (77%) exhibited progression. Eighty progressive patients were assessable for irRECIST and iRECIST: 15 patients were assessed differently; however, only three (3.8%) mismatches with a theoretical impact on the therapeutic decision were identified. Patients with PsPD or dissociated response had higher overall survival than patients with true progression. CONCLUSION Atypical responses (PsPD/dissociated response) occurred in 13% of NSCLC patients under immune checkpoint inhibitors. Based on survival analyses, the RECIST 1.1 evaluation underestimated the benefit of immune checkpoint inhibitors in 11% of the progressive patients. Immune-related RECIST and iRECIST identified these unconventional responses, with a 3.8% discrepancy rate.

Reversible Posterior Leukoencephalopathy Syndrome Induced by Axitinib

Reversible posterior leukoencephalopathy syndrome (RPLS) is a clinicoradiological syndrome that might be caused by anti-vascular endothelial growth factor (VEGF)-targeted compounds such as bevacizumab, sunitinib, and sorafenib. We report herein the first case of RPLS induced by axitinib, a multi-VEGF receptor tyrosine kinase inhibitor, with antiangiogenic activity. Because diastolic blood pressure was proposed as a predictive biomarker of axitinib efficacy, oncologists should be aware of this rare complication, because rapid stopping of the drug is key for complete recovery.

A radiomics approach to assess tumour-infiltrating CD8 cells and response to anti-PD-1 or anti-PD-L1 immunotherapy: an imaging biomarker, retrospective multicohort study

BACKGROUND Because responses of patients with cancer to immunotherapy can vary in success, innovative predictors of response to treatment are urgently needed to improve treatment outcomes. We aimed to develop and independently validate a radiomics-based biomarker of tumour-infiltrating CD8 cells in patients included in phase 1 trials of anti-programmed cell death protein (PD)-1 or anti-programmed cell death ligand 1 (PD-L1) monotherapy. We also aimed to evaluate the association between the biomarker, and tumour immune phenotype and clinical outcomes of these patients. METHODS In this retrospective multicohort study, we used four independent cohorts of patients with advanced solid tumours to develop and validate a radiomic signature predictive of immunotherapy response by combining contrast-enhanced CT images and RNA-seq genomic data from tumour biopsies to assess CD8 cell tumour infiltration. To develop the radiomic signature of CD8 cells, we used the CT images and RNA sequencing data of 135 patients with advanced solid malignant tumours who had been enrolled into the MOSCATO trial between May 1, 2012, and March 31, 2016, in France (training set). The genomic data, which are based on the CD8B gene, were used to estimate the abundance of CD8 cells in the samples and data were then aligned with the images to generate the radiomic signatures. The concordance of the radiomic signature (primary endpoint) was validated in a Cancer Genome Atlas [TGCA] database dataset including 119 patients who had available baseline preoperative imaging data and corresponding transcriptomic data on June 30, 2017. From 84 input variables used for the machine-learning method (78 radiomic features, five location variables, and one technical variable), a radiomics-based predictor of the CD8 cell expression signature was built by use of machine learning (elastic-net regularised regression method). Two other independent cohorts of patients with advanced solid tumours were used to evaluate this predictor. The immune phenotype internal cohort (n=100), were randomly selected from the Gustave Roussy Cancer Campus database of patient medical records based on previously described, extreme tumour-immune phenotypes: immune-inflamed (with dense CD8 cell infiltration) or immune-desert (with low CD8 cell infiltration), irrespective of treatment delivered; these data were used to analyse the correlation of the immune phenotype with this biomarker. Finally, the immunotherapy-treated dataset (n=137) of patients recruited from Dec 1, 2011, to Jan 31, 2014, at the Gustave Roussy Cancer Campus, who had been treated with anti-PD-1 and anti-PD-L1 monotherapy in phase 1 trials, was used to assess the predictive value of this biomarker in terms of clinical outcome. FINDINGS We developed a radiomic signature for CD8 cells that included eight variables, which was validated with the gene expression signature of CD8 cells in the TCGA dataset (area under the curve [AUC]=0·67; 95% CI 0·57-0·77; p=0·0019). In the cohort with assumed immune phenotypes, the signature was also able to discriminate inflamed tumours from immune-desert tumours (0·76; 0·66-0·86; p<0·0001). In patients treated with anti-PD-1 and PD-L1, a high baseline radiomic score (relative to the median) was associated with a higher proportion of patients who achieved an objective response at 3 months (vs those with progressive disease or stable disease; p=0·049) and a higher proportion of patients who had an objective response (vs those with progressive disease or stable disease; p=0·025) or stable disease (vs those with progressive disease; p=0·013) at 6 months. A high baseline radiomic score was also associated with improved overall survival in univariate (median overall survival 24·3 months in the high radiomic score group, 95% CI 18·63-42·1; vs 11·5 months in the low radiomic score group, 7·98-15·6; hazard ratio 0·58, 95% CI 0·39-0·87; p=0·0081) and multivariate analyses (0·52, 0·35-0·79; p=0·0022). INTERPRETATION The radiomic signature of CD8 cells was validated in three independent cohorts. This imaging predictor provided a promising way to predict the immune phenotype of tumours and to infer clinical outcomes for patients with cancer who had been treated with anti-PD-1 and PD-L1. Our imaging biomarker could be useful in estimating CD8 cell count and predicting clinical outcomes of patients treated with immunotherapy, when validated by further prospective randomised trials. FUNDING Fondation pour la Recherche Médicale, and SIRIC-SOCRATE 2.0, French Society of Radiation Oncology.

Anti-PD-1 Vasculitis of the central nervous system or radionecrosis?

Commentary on « Cerebral vasculitis mimicking intracranial metastatic progression of lung cancer during PD-1 blockade » by Läubli H et al., J Immunother Cancer. 2017;5:46.The authors diagnosed a cerebral tumor-like lymphocytic vasculitis associated with anti-endothelial cell auto-antibodies secondary to anti-PD-1 therapy, treated by surgical resection and corticosteroids. We thought that this diagnosis should be discussed for at least two reasons. First, etiological explorations were not sufficient. Second, the diagnostic of radionecrosis should also be discussed.

Locally advanced cervical cancer with bladder invasion: clinical outcomes and predictive factors for vesicovaginal fistulae

Objective We report outcomes of cervical cancer patients with bladder invasion (CCBI) at diagnosis, with focus on the incidence and predictive factors of vesicovaginal fistula (VVF). Results Seventy-one patients were identified. Twenty-one (30%) had para-aortic nodal involvement. Eight had VVF at diagnosis. With a mean follow-up time of 34.2 months (range: 1.9 months–14.8 years), among 63 patients without VVF at diagnosis, 15 (24%) developed VVF. A VVF occurred in 19% of patients without local relapses (9/48) and 40% of patients with local relapse (6/15). Two-year overall survival (OS), disease-free survival (DFS) and local control rates were 56.4% (95% CI: 44.1–67.9%), 39.1% (95% CI: 28.1–51.4%) and 63.8% (95% CI: 50.4–75.4%), respectively. Para-aortic nodes were associated with poorer OS (adjusted HR = 3.78, P-value = 0.001). In multivariate analysis, anterior tumor necrosis on baseline MRI was associated with VVF formation (63% vs 0% at 1 year, adjusted-HR = 34.13, 95% CI: 4.07–286, P-value = 0.001), as well as the height of the bladder wall involvement of >26 mm (adjusted-HR = 5.08, 95% CI: 1.38–18.64, P-value = 0.014). Conclusions A curative intent strategy including brachytherapy is feasible in patients with CCBI, with VVF occurrence in 24% of the patients. MRI patterns help predicting VVF occurrence. Methods Patients with locally advanced CCBI treated with (chemo)radiation ± brachytherapy in our institute from 1989 to 2015 were analyzed. Reviews of baseline magnetic resonance imaging (MRI) scans were carried out blind to clinical data, retrieving potential parameters correlated to VVF formation (including necrosis and tumor volume).

Efficacy of histology-agnostic and molecularly-driven HER2 inhibitors for refractory cancers

A targeted therapy is recommended in case of ERBB2 alteration for breast and gastric carcinomas, but miscellaneous other tumor types are ERBB2-altered at low prevalence. Broadening the administration of HER2 inhibitors across tumor types and genomic alterations could benefit to patients with refractory metastatic tumors. Targeted next-generation-sequencing (tNGS) and comparative genomic hybridization array (CGH) have been performed on fresh tumor biopsies of patients included in the MOSCATO-01 and ongoing MOSCATO-02 trials to administrate HER2 inhibitors in case of ERBB2 pathogenic mutation of amplification. Between December 2011 and January 2017 a molecular analysis was performed for 934 patients (759 CGH and 912 tNGS). A novel ERBB2 alteration has been found in 4.7% (n = 44/934), including 1.5% (n = 14/912) ERBB2 mutations, and 4% (n = 30/759) ERBB2 amplifications. A matched HER2 inhibitor was administrated to 70% (31/44) of patients and consisted in trastuzumab plus chemotherapy for 90% of them (28/31). On the 31 evaluable patients, 1 complete response (CR), 10 partial response (PR) and 2 stable disease (SD) >24 weeks were observed accounting for a clinical benefit rate (CBR) of 42% (n = 13/31, 95% CI 25–61%). Besides breast and oesogastric carcinomas, 19 patients affected by 8 different tumor types had a CBR of 25% for ERBB2 mutations (n = 2/8, 95% CI 3%–65%, with 2 PR) and 64% for ERBB2 amplifications (n = 7/11, 95% CI 31%–89%; with 1 CR, 4 PR, 2 SD). ERBB2 genomic alterations were diffuse across metastatic tumor types and signs of efficacy emerged for HER2 targeted treatments, especially in case of ERBB2 amplifications or a p.S310Y ERBB2 mutation.