Marie Alt

Hyperprogression during anti-PD-1/PD-L1 therapy in patients with recurrent and/or metastatic head and neck squamous cell carcinoma

BackgroundnPembrolizumab and nivolumab are immune checkpoint inhibitors targeting PD-1 that have recently been approved in pretreated recurrent and/or metastatic head and neck squamous cell carcinoma (R/M HNSCC) patients. In the clinic, some patients seem not only not to benefit from anti-PD-L1/PD-1 agents but rather to experience an acceleration of tumor growth kinetics (TGK).nnnPatients and methodsnWe retrospectively compared TGK on immunotherapy and TGK on last treatment in patients with R/M HNSCC treated with PD-1/PD-L1 inhibitors in four French centers. The TGK ratio (TGKR, ratio of the slope of tumor growth before treatment and the slope of tumor growth on treatment) was calculated. Hyperprogression was defined as a TGKR ≥ 2.nnnResultsnFrom September 2012 to September 2015, 34 patients were identified. Patterns of recurrence included exclusive loco-regional recurrence in 14 patients, exclusive distant metastases in 11 patients, and both in 9 patients. No pseudo-progression was observed. Hyperprogression was observed in 10 patients (29%), including 9 patients with at least a locoregional recurrence, and only 1 patient with exclusively distant metastases. Hyperprogression significantly correlated with a regional recurrence (TGKR ≥ 2: 90% versus TGKR < 2: 37%, Pu2009=u20090.008), but not with local or distant recurrence. Hyperprogression was associated with a shorter progression-free survival (PFS) according to RECIST (Pu2009=u20090.003) and irRECIST (Pu2009=u20090.02), but not with overall survival (Pu2009=u20090.77).nnnConclusionsnHyperprogression was observed in 29% of patients with R/M HNSCC treated with anti-PD-L1/PD-1 agents and correlated with a shorter PFS. It occurred in 39% of patients with at least a locoregional recurrence and 9% of patients with exclusively distant metastases. No pseudo-progressions were reported. Mechanisms and causality of hyperprogression should further be assessed through prospective controlled studies.

Randomized phase II trial comparing molecularly targeted therapy based on tumor molecular profiling versus conventional therapy in patients with refractory cancer: cross-over analysis from the SHIVA trial

BackgroundnSeveral studies used the ratio of progression-free survival (PFS) on genotype-matched treatment to PFS on genotype-unmatched treatment to assess the efficacy of therapy guided by patients tumor molecular profiling. We evaluated the PFS ratio from patients who cross-over in the SHIVA trial.nnnPatients and methodsnThe primary end point of the SHIVA trial was to compare PFS on molecularly targeted agents (MTAs) based on tumor molecular profiling and treatment at physicians choice (TPC) in patients with any kind of cancer who had failed standard-of-care therapy. The experimental treatment included only marketed MTAs given outside their indications according to a pre-specified treatment algorithm. Patients were allowed to cross-over at disease progression in both arms. Response was evaluated according to RECIST 1.1 at randomization and at cross-over. We evaluated the ratio of PFS on MTA (PFSMTA) to PFS on TPC (PFSTPC) in patients who crossed-over.nnnResultsnAmong 741 patients enrolled in the SHIVA trial, 197 were randomized, and 95 crossed-over, including 70 patients from the TPC to the MTA arm and 25 patients from the MTA to the TPC arm. Two patients crossed-over in the TPC arm without disease progression. The PFSMTA/PFSTPC ratio exceeded 1.3 in 37% of patients who crossed-over from the TPC to the MTA arm. The PFSMTA/PFSTPC ratio exceeded 1.3 in 61% of patients who crossed-over from the MTA arm to the TPC arm.nnnConclusionsnThe cross-over analysis of the SHIVA trial identified 37% of patients who crossed-over from TPC to MTA with a PFSMTA/PFSTPC ratio exceeding 1.3.

Designs of preoperative biomarkers trials in oncology: a systematic review of the literature

BACKGROUNDnThe identification of predictive and pharmacodynamics (PD) biomarkers of efficacy of anticancer-targeted therapies is not always straightforward. To address this problem, preoperative trials have been set up. The present study aimed at evaluating how these trials are designed.nnnDESIGNnWe retrieved all preoperative oncology trials, defined as preoperative trials having a PD end point.nnnRESULTSnOnly 56 trials met our selection criteria. Of these, 27 trials (48%) were randomized. Forty-nine trials (88%) evaluated at least a noncytotoxic agent. In 37 trials (66%), a single agent was administered. The most prevalent tumor type was breast cancer (59%). Median duration of accrual was 28 months (range: 9-98). In these trials, there was a mean of two patients included per month (range: 0-7). The date of surgery was fixed before study entry in 35 trials (62%), while surgery was set up after preoperative therapy in the remaining 21 trials (38%). In the former trials, median duration of preoperative therapy was 17 days (range: 1-112), whereas in the latter trials it ranged from 4 to 29 weeks. The primary end point was a PD end point in 26 of the 45 trials (58%) in which it was mentioned. One percent of patients could not undergo surgery as per protocol due to an adverse event. Statistically significant predictive and PD biomarkers were identified in 17 (30%) and 27 trials (48%), respectively.nnnCONCLUSIONnPreoperative biomarkers trials are infrequent but safe and feasible. These trials often permit the identification of predictive and PD biomarkers.

Challenges for the implementation of high-throughput testing and liquid biopsies in personalized medicine cancer trials

During recent decades, major advances in the comprehension of biology and in biotechnologies have paved the way for what is commonly named personalized medicine. For cancer therapy, personalized medicine represents a paradigm shift in which patient treatment is based on biology in addition to histology and tumor location. Here, we report the major personalized medicine trials in oncology that are either based on molecular alterations from tumor tissue or from circulating blood markers. We next review important challenges facing the implementation of personalized medicine in daily clinical practice, including tumor heterogeneity, reliability of high-throughput technologies, the key role of bioinformatics and the assessment of biomarkers and synthetic models, in order to use big data in actual cancer biology.

Immunotherapy in head and neck cancers: a new challenge for immunologists, pathologists and clinicians

Cancer occurrence can be understood as the result of dysfunctions in immune tumoral microenvironment. Here we review the recent understandings of those microenvironment changes, regarding their causes and prognostic significance in head and neck (HN) carcinoma. We will focus on HN squamous cell cancer (SCC) and nasopharyngeal carcinomas (NPC). Their overall poor prognosis may be improved with immunotherapy in a subset of patients, as supported by current clinical trials. However, finding reliable markers of therapeutic response is crucial for patient selection, due to potential severe adverse reactions and high costs. Half of HNSCC exhibit PD-L1 expression, this expression being higher in HPV-positive tumors. In recent clinical trials, a better therapeutic response to anti-PD-1 was obtained in patients with higher PD-L1 expression. The Food and Drug Administration (FDA) approved the use of these therapeutics without stating a need for patient selection regarding PD-L1 status. Activation status, density and localization of TIL as well as PD-L2, γ-interferon, inflammatory cytokines, epithelial-mesenchymal transition phenotype and mutational burden may all be potential therapeutic response markers. In Epstein-Barr Virus (EBV)-induced nasopharyngeal non-keratinizing cancer, PD-L1 is over-expressed compared to EBV-negative tumors. A 22% response rate has been observed under anti-PD-1 treatment among PD-L1-positive NPC patients. A better understanding of immune checkpoint regulation processes may allow patients to benefit from these promising immunotherapies.

First-in-Human Phase I Study of Single-agent Vanucizumab, A First-in-Class Bispecific Anti-Angiopoietin-2/Anti-VEGF-A Antibody, in Adult Patients with Advanced Solid Tumors

Purpose: Vanucizumab is an investigational antiangiogenic, first-in-class, bispecific mAb targeting VEGF-A and angiopoietin-2 (Ang-2). This first-in-human study evaluated the safety, pharmacokinetics, pharmacodynamics, and antitumor activity of vanucizumab in adults with advanced solid tumors refractory to standard therapies. Experimental Design: Patients received escalating biweekly (3–30 mg/kg) or weekly (10–30 mg/kg) intravenous doses guided by a Bayesian logistic regression model with overdose control. Results: Forty-two patients were treated. One dose-limiting toxicity, a fatal pulmonary hemorrhage from a large centrally located mediastinal mass judged possibly related to vanucizumab, occurred with the 19 mg/kg biweekly dose. Arterial hypertension (59.5%), asthenia (42.9%), and headache (31%) were the most common toxicities. Seventeen (41%) patients experienced treatment-related grade ≥3 toxicities. Toxicity was generally higher with weekly than biweekly dosing. A MTD of vanucizumab was not reached in either schedule. Pharmacokinetics were dose-linear with an elimination half-life of 6–9 days. All patients had reduced plasma levels of free VEGF-A and Ang-2; most had reductions in KTRANS (measured by dynamic contrast-enhanced MRI). Two patients (renal cell and colon cancer) treated with 30 mg/kg achieved confirmed partial responses. Ten patients were without disease progression for ≥6 months. A flat-fixed 2,000 mg biweekly dose (phamacokinetically equivalent to 30 mg/kg biweekly) was recommended for further investigation. Conclusions: Biweekly vanucizumab had an acceptable safety and tolerability profile consistent with single-agent use of selective inhibitors of the VEGF-A and Ang/Tie2 pathway. Vanucizumab modulated its angiogenic targets, impacted tumor vascularity, and demonstrated encouraging antitumor activity in this heterogeneous population. Clin Cancer Res; 24(7); 1536–45. ©2017 AACR.

Relevance of a molecular tumour board (MTB) for patients’ enrolment in clinical trials: experience of the Institut Curie

Background High throughput molecular screening techniques allow the identification of multiple molecular alterations, some of which are actionable and can be targeted by molecularly targeted agents (MTA). We aimed at evaluating the relevance of using this approach in the frame of Institut Curie Molecular Tumor Board (MTB) to guide patients with cancer to clinical trials with MTAs. Patients and methods We included all patients presented at Institut Curie MTB from 4 October 2014 to 31 October 2017. The following information was extracted from the chart: decision to perform tumour profiling, types of molecular analyses, samples used, molecular alterations identified and those which are actionable, and inclusion in a clinical trial with matched MTA. Results 736 patients were presented at the MTB. Molecular analyses were performed in 442 patients (60%). Techniques used included next-generation sequencing, comparative genomic hybridisation array and/or other techniques including immunohistochemistry in 78%, 51% and 58% of patients, respectively. Analyses were performed on a fresh frozen biopsy in 91 patients (21%), on archival tissue (fixed or frozen) in 326 patients (74%) and on both archival and fresh frozen biopsy in 25 patients (6%). At least one molecular alteration was identified in 280 analysed patients (63%). An actionable molecular alteration was identified in 207 analysed patients (47%). Forty-five analysed patients (10%) were enrolled in a clinical trial with matched MTA and 29 additional patients were oriented and included in a clinical trial based on a molecular alteration identified prior to the MTB analysis. Median time between date of specimen reception and molecular results was 28 days (range: 5–168). Conclusions The implementation of an MTB at Institut Curie enabled the inclusion of 10% of patients into a clinical trial with matched therapy.

1379PCLINICO-BIOLOGICAL CHARACTERISTICS OF PATIENTS SURVIVING MORE THAN TWO YEARS WITH RECURRENT AND/OR METASTATIC (R/M) CANCER: RESULTS OF A TRANSVERSAL NATIONAL MULTICENTRIC SURVEY

ABSTRACT Aim: R/M cancer patients may have prolonged survival, and R/M cancer can be considered as a chronic disease. To our knowledge, there are few data describing these patients. The main goal of the present study was to describe the clinico-biological features of patients surviving more than two years with R/M cancer. Methods: During 4 months, we conducted a national multicentric survey about patients aged ≥ 18 with R/M cancer for more than 24 months. Clinico-biological data were collected in 39 French centers. Preliminary results of the first 200 patients are presented. Results: Most of them were women (70%) with breast cancer (44%) but a wide variety of other cancers were represented. Median age at diagnosis was 58 [range: 20-85]. Median time between primary tumor and R/M disease was 19 months [range: 0-312] with 39% of patients with a R/M disease at presentation. Median time from R/M disease was 46 months [range: 24-241]. At the time of R/M diagnosis, 72% of patients were not single; 48% were working while 37% were retired. At data collection, 88% of non-single patients were not separated, but only 32% of working patients were still working. At the time of R/M diagnosis, patients presented with good performance status (ECOG performance status of 0 or 1 in 88% of cases), without malnutrition (Body Mass Index Conclusions: Our preliminary results suggest that an important proportion of R/M cancer patients who live more than 2 years have been treated with a targeted therapy and have participated in a clinical trial. However, a majority of them have stopped their job and few of them received palliative care. Disclosure: All authors have declared no conflicts of interest.