Prognostic factors and outcome of patients with hematological malignancies in phase I trials: the Gustave Roussy scoring system.

Despite considerable progress in hematological malignancies (HM) biology during the last decades, translation into clinical benefit remains a major challenge. To improve patient selection and identify patients most likely to benefit from phase I trials, we designed and validated, in an independent cohort, a simple prognostic score. Treatment outcome, toxicity, and survival data from 82 consecutive patients enrolled in 14 phase I trials were reviewed (January 2008-February 2012). We validated these results on a prospectively collected cohort (17 phase I trials, February 2012-May 2014, 88 patients). Within a median follow-up of 19.1 months (range: 2.1-43.8 months), the median progression-free and overall survival (OS) were, respectively, 4.1 months [95% confidence interval (CI): 3.0-5.3] and 19.8 months (95% CI: 16.1-36.8). Best overall response and disease control rates were similar to HM salvage regimens (28 and 64%, respectively). Through multivariate analysis of independent prognostic factors, we designed and prospectively validated a simple prognostic score based on histological subtype, performance status, and albumin. Patients with a low-risk score experienced significantly better OS compared with patients with an intermediate or a high score (median OS: 37 vs. 17 vs. 5 months; hazard ratio=11.68, 95% CI: 4.09-33.3). Our data indicate the safety and efficacy of phase I trials in a significant number of relapsed/refractory HM patients, with clinical benefit achieved in more than half of patients. Our simple scoring system offers a valuable selection tool encouraging HM patient inclusions in phase I trials.

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.

Circulating Cell-Free Tumor DNA Analysis of 50 Genes by Next-Generation Sequencing in the Prospective MOSCATO Trial.

PURPOSE: Liquid biopsies based on circulating cell-free DNA (cfDNA) analysis are described as surrogate samples for molecular analysis. We evaluated the concordance between tumor DNA (tDNA) and cfDNA analysis on a large cohort of patients with advanced or metastatic solid tumor, eligible for phase I trial and with good performance status, enrolled in MOSCATO 01 trial (clinical trial NCT01566019). EXPERIMENTAL DESIGN: Blood samples were collected at inclusion and cfDNA was extracted from plasma for 334 patients. Hotspot mutations were screened using next-generation sequencing for 50 cancer genes. RESULTS: Among the 283 patients with tDNA-cfDNA pairs, 121 had mutation in both, 99 in tumor only, 5 in cfDNA only, and for 58 patients no mutation was detected, leading to a 55.0% estimated sensitivity [95% confidence interval (CI), 48.4%-61.6%] at the patient level. Among the 220 patients with mutations in tDNA, the sensitivity of cfDNA analysis was significantly linked to the number of metastatic sites, albumin level, tumor type, and number of lines of treatment. A sensitivity prediction score could be derived from clinical parameters. Sensitivity is 83% in patients with a high score (≥8). In addition, we analyzed cfDNA for 51 patients without available tissue sample. Mutations were detected for 22 patients, including 19 oncogenic variants and 8 actionable mutations. CONCLUSIONS: Detection of somatic mutations in cfDNA is feasible for prescreening phase I candidates with a satisfactory specificity; overall sensitivity can be improved by a sensitivity score allowing to select patients for whom cfDNA constitutes a reliable noninvasive surrogate to screen mutations. Clin Cancer Res; 22(12); 2960-8. ©2016 AACR.

Factors associated with success of image-guided tumour biopsies: Results from a prospective molecular triage study (MOSCATO-01).

INTRODUCTION: MOSCATO-01 is a molecular triage trial based on on-purpose tumour biopsies to perform molecular portraits. We aimed at identifying factors associated with high tumour cellularity. MATERIAL AND METHODS: Tumour cellularity (percentage of tumour cells in samples defined at pathology) was evaluated according to patient characteristics, target lesion characteristics, operators' experience and biopsy approach. RESULTS: Among 460 patients enrolled between November, 2011 and March, 2014, 334 patients (73%) had an image-guided needle biopsy of the primary tumour (N = 38) or a metastatic lesion (N = 296). Biopsies were performed on liver (N = 127), lung (N = 72), lymph nodes (N = 71), bone (N = 11), or another tumour site (N = 53). Eighteen patients (5%) experienced a complication: pneumothorax in 10 patients treated medically, and haemorrhage in 8, requiring embolisation in 3 cases. Median tumour cellularity was 50% (interquartile range, 30-70%). The molecular analysis was successful in 291/334 cases (87%). On-going chemotherapy, tumour origin (primary versus metastatic), lesion size, tumour growth rate, presence of necrosis on imaging, standardised uptake value, and needle size were not statistically associated with cellularity. Compared to liver or lung biopsies, cellularity was significantly lower in bone and higher in other sites (P < 0.0001). Cellularity significantly increased with the number of collected samples (P < 0.0001) and was higher in contrast-enhanced ultrasound-guided biopsies (P < 0.02). In paired samples, cellularity in central samples was lower than in peripheral samples in 85, equal in 68 and higher in 89 of the cases. CONCLUSION: Image-guided biopsy is feasible and safe in cancer patients for molecular screening. Imaging modality, multiple sampling of the lesion, and the organ chosen for biopsy were associated with higher tumour cellularity.

From Uniplex to Multiplex Molecular Profiling in Advanced Non-Small Cell Lung Carcinoma.

Non-small cell lung carcinoma is a leading cause of cancer death worldwide. Understanding the molecular biology of survival and proliferation of cancer cells led to a new molecular classification of lung cancer and the development of targeted therapies with promising results. With the advances of image-guided biopsy techniques, tumor samples are becoming smaller, and the molecular testing techniques have to overcome the challenge of integrating the characterization of a panel of abnormalities including gene mutations, copy-number changes, and fusions in a reduced number of assays using only a small amount of genetic material. This article reviews the current knowledge about the most frequent actionable molecular abnormalities in non-small cell lung carcinoma, the new approaches of molecular analysis, and the implications of these findings in the context of clinical practice.

Targeting FGFR Signaling in Cancer.

The fibroblast growth factor signaling pathway (FGFR signaling) is an evolutionary conserved signaling cascade that regulates several basic biologic processes, including tissue development, angiogenesis, and tissue regeneration. Substantial evidence indicates that aberrant FGFR signaling is involved in the pathogenesis of cancer. Recent developments of deep sequencing technologies have allowed the discovery of frequent molecular alterations in components of FGFR signaling among several solid tumor types. Moreover, compelling preclinical models have demonstrated the oncogenic potential of these aberrations in driving tumor growth, promoting angiogenesis, and conferring resistance mechanisms to anticancer therapies. Recently, the field of FGFR targeting has exponentially progressed thanks to the development of novel agents inhibiting FGFs or FGFRs, which had manageable safety profiles in early-phase trials. Promising treatment efficacy has been observed in different types of malignancies, particularly in tumors harboring aberrant FGFR signaling, thus offering novel therapeutic opportunities in the era of precision medicine. The most exciting challenges now focus on selecting patients who are most likely to benefit from these agents, increasing the efficacy of therapies with the development of novel potent compounds and combination strategies, and overcoming toxicities associated with FGFR inhibitors. After examination of the basic and translational research studies that validated the oncogenic potential of aberrant FGFR signaling, this review focuses on recent data from clinical trials evaluating FGFR targeting therapies and discusses the challenges and perspectives for the development of these agents.

Prior long response to androgen deprivation predicts response to next-generation androgen receptor axis targeted drugs in castration resistant prostate cancer.

BACKGROUND: There is an urgent need for qualified predictive biomarkers of sensitivity for the treatments used in patients with castration-resistant prostate cancer (CRPC). We attempted to identify ready-to-use clinical predictors of improved outcome in metastatic CRPC (mCRPC) patients treated with next generation androgen receptor (AR) axis targeted drugs. PATIENTS AND METHODS: We reviewed a cohort of patients who received AR axis targeted drugs for CRPC at two major French cancer centres. The predictive role of several clinical, biological and radiological parameters on progression-free survival (PFS) was studied. RESULTS: The study cohort consisted of 173 patients. Median duration of response to initial androgen deprivation therapy (ADT) (time to castration resistance, TTCRPC) was 17.8 months. The 50% prostate-specific antigen (PSA) response rate to AR axis targeted drugs was 16% (95% confidence interval (CI): 6-27) and 41% (95% CI: 30-47) in patients with TTCRPC of under and over 12 months respectively (p=0.005). Median PFS was 2.8 months (95% CI: 2.1-3.9) and 5.8 (95% CI: 4.6-7.8; HR: 0.58, p=0.002). In patients treated with post-docetaxel enzalutamide (n=57), median PFS was 2.8 months and 8.6 months, (Hazard ratio (HR)=3.1; 95% CI: 1.6-5.8, p=0.0016) according to TTCRPC, whereas no difference was observed in placebo-treated patients (n=27). The 50% PSA response rate to enzalutamide was 8% (95% CI: 0-38) and 58% (95% CI: 42-73) in patients with a TTCRPC of under and over 12 months respectively (p<0.001). CONCLUSION: The previous duration of response to ADT is a predictor of sensitivity to next generation AR axis targeted drugs in patients with mCRPC.

Incorporating immune-checkpoint inhibitors into systemic therapy of NSCLC.

Despite current therapeutic options metastatic non- small-cell lung cancer (NSCLC) remains incurable. Targeted therapies have opened new opportunities for several molecular subtypes, but virtually all patients treated will ultimately develop progressive disease by treatment resistance. Recent clinical trials have shown that immune-checkpoint blockade can result in striking and durable responses in metastatic NSCLC. These impressive results are yet to be confirmed in following trials; nonetheless, NSCLC therapeutic strategies will most likely need to integrate immune-checkpoint inhibitors in the near future. Interestingly, conventional therapies are capable of modulating the immune system and can therefore interact directly or indirectly with immunotherapies. This suggests that some combinations might have synergistic activity and lead to improved efficacy. Conventional and targeted therapies can induce rapid tumor lysis, and immune-checkpoint blockade can then help to induce a sustained immune-mediated tumor control. Moreover, the distinctive toxicity profile associated with immune-checkpoint modulators makes them good candidates for combination strategies. Here we summarize the results of immune-checkpoints trials in NSCLC, and also report how current therapeutic options can modulate the immune system. We provide a rationale and identify potential challenges for immune-checkpoint blockade combinations with conventional therapeutics in NSCLC.

[Immune-checkpoints: the new anti-cancer immunotherapies]. / Immune-Checkpoints: les nouvelles immunothérapies anticancéreuses.

The immune system plays a dual role against cancer: it prevents tumor cell outgrowth and also sculpts the immunogenicity of the tumor cells. Cancer cells are able to escape from the immune system by inhibiting T lymphocytes activation. New immunotherapies have been developped to target these T lymphocytes activation modulators: the immune checkpoints. These novel therapies are showing promising results with durable objective responses in some patients. Ipilimumab (anti-CTLA4) was the first of these new therapeutics to be approved by the FDA in March 2011 for advanced melanoma and other immunomodulators trials are ongoing in other cancers with similar encouraging results like with the anti PD-1/PD-L1. These drugs are already challenging our future practice like for evaluation of tumor response or for management of immune related toxicities. Many immune checkpoints have been identified and could potentially be targeted. Future studies will help to identify predictive factors but also to coordinate these new immunotherapies with our classic treatment strategies.

Surgical resection of liver non-small cell lung cancer metastasis: a dual weapon?

Liver resection for metastases from a colorectal cancer is well established and it is considered the treatment of choice. However, for patients with liver metastases from other carcinomas, the value of resection is incompletely defined and still debated. We report two cases of partial hepatectomies for liver metastases from non-small cell lung cancer leading to different outcomes. A review of the literature suggests that although early reports of similar procedures were not favorable, hepatic resection became a safe procedure, which can sometimes offer a long-term survival and should be considered in selected cases.