Denis Soulières - Academia.edu (original) (raw)

Papers by Denis Soulières

Journal of Clinical Oncology, Jun 1, 2023

Background: The efficacy of immunotherapy targeting the PD-1/PD-L1 pathway has previously been de... more Background: The efficacy of immunotherapy targeting the PD-1/PD-L1 pathway has previously been demonstrated in metastatic head and neck squamous cell carcinoma (HNSCC). Stereotactic Body Radiotherapy (SBRT) aims at ablating metastatic lesions and may play a synergistic role with immunotherapy. The purpose of this study is to assess the safety and efficacy of triple treatment combination (TTC) consisting of the administration of durvalumab and tremelimumab in combination with SBRT in metastatic HNSCC. Method: This is a phase I/II single arm study that will include 35 patients with 2-10 extracranial metastatic lesions. Patients will receive durvalumab (1500 mg IV every 4 weeks (Q4W)) and tremelimumab (75 mg IV Q4W for a total of 4 doses) until progression, unacceptable toxicity or patient withdrawal. SBRT to 2-5 metastases will be administered between cycles 2 and 3 of immunotherapy. The safety of the treatment combination will be evaluated through assessment of TTC-related toxicities, defined as grade 3-5 toxicities based on Common Terminology Criteria for Adverse Events (v 4.03), occurring within 6 weeks from SBRT start, and that are definitely, probably or possibly related to the combination of all treatments. We hypothesize that dual targeting of PD-L1 and CTLA-4 pathways combined with SBRT will lead to < 35% grade 3-5 acute toxicities related to TTC. Progression free survival (PFS) will be the primary endpoint of the phase II portion of this study and will be assessed with radiological exams every 8 weeks using the RECIST version 1.1 criteria. Discussion: The combination of synergistic dual checkpoints inhibition along with ablative radiation may significantly potentiate the local and systemic disease control. This study constitutes the first clinical trial combining effects of SBRT with dual checkpoint blockade with durvalumab and tremelimumab in the treatment of metastatic HNSCC. If positive, this study would lead to a phase III trial testing this treatment combination against standard of care in metastatic HNSCC.

Oral Oncology, Feb 1, 2022

Annals of Oncology, Sep 1, 2014

ABSTRACT Aim: A high sunitinib area under the curve is associated with more toxicity, and a bette... more ABSTRACT Aim: A high sunitinib area under the curve is associated with more toxicity, and a better response rate (RR), progression free (PFS) and overall survival (OS). Retrospective data (Urol Oncol 2014;32:480) show poorer PFS and OS in mRCC patients (pts) with minimum toxicity on the standard 28 day (d)/14 d schedule vs. pts with toxicity leading to schedule and/or dose changes. We hypothesized that toxicity (mucositis, diarrhea, hand foot syndrome, fatigue, hematological) could serve as a surrogate to individualize therapy (Rx) to optimize drug exposure and manage toxicity for each pt. Methods: A prospective phase II study (same eligibility criteria as EFFECT trial) will enter 110 pts with the primary endpoint of improving PFS from 8.5 (EFFECT) to 14 Months. Pts start on a 50 mg dose with the intent to treat for 28 d with the Rx break reduced to 7 d for all Rx schedules. Pts with grade-2 toxicity by d 28 stay on the 28 d schedule. Patients with > grade-2 toxicity on d 28 on the first course continue Rx on a 50 mg dose with the number of d on Rx individually reduced aiming for ≤ grade-2 toxicity. Dose is reduced to 37.5 mg in pts that cannot tolerate 50 mg for at least 7 d and to 25 mg in pts that cannot tolerate 37.5 mg for at least 7 d with individualized duration of Rx based on toxicity. Pts with minimum toxicity on d 28 on the first course are dose escalated to 62.5 mg and then 75 mg on a 14 d /7 d schedule. Results: With 73 pts on study, dose and schedule data are available for 69 pts with 13 pts (18.8%) dose escalated to 62.5 mg (9 pts) and 75 mg (4 pts). In 33 pts (47.8%), that would have been dose reduced by standard criteria, a 50 mg dose was continued but for fewer d (7-16 d) and 13 pts (18.8%) stayed on a 28d/7d schedule. Dose was reduced to 37.5 mg in 6 pts (8.7% vs. 36 - 63% in 4 large trials) and to 25 mg in 4 pts (5.8 % vs. 15 - 19% in 4 trials). Rx was discontinued due to toxicity in 3 pts (4.3% vs. 15-19% in 4 trials). In 61 evaluable pts, we found complete responses (CR) in 3 pts, partial responses (PR) in 27 pts, stable disease (SD) > 3 months in 23 pts ( Conclusions: Individualized sunitinib dosing is safe and feasible in a multicenter setting and associated with improved dose intensity and a good response rate. Disclosure: G.A. Bjarnason: Pfizer - membership on an advisory board - Pfzer-sponsored research - Support to attend meetings; B. Naveen, C. Canil, S. North, D. Heng, P. Zalewski, D. Soulieres, D.J. Ruether, M.N. Reaume and A. Kapoor: Pfizer member on advisory boards; P. Venner: Pfizer member on advisory boards and sponsored research; C.K. Kollmannsberger: Pfizer membership on an advisory board; B.J. Eigl: Pfizer: consultancy, honoraria, research funding; J. Knox: Pfizer grant support. All other authors have declared no conflicts of interest.

Journal of Clinical Oncology

PURPOSE Pembrolizumab and pembrolizumab-chemotherapy demonstrated efficacy in recurrent/metastati... more PURPOSE Pembrolizumab and pembrolizumab-chemotherapy demonstrated efficacy in recurrent/metastatic head and neck squamous cell carcinoma in KEYNOTE-048. Post hoc analysis of long-term efficacy and progression-free survival on next-line therapy (PFS2) is presented. METHODS Patients were randomly assigned (1:1:1) to pembrolizumab, pembrolizumab-chemotherapy, or cetuximab-chemotherapy. Efficacy was evaluated in programmed death ligand 1 (PD-L1) combined positive score (CPS) ≥ 20, CPS ≥ 1, and total populations, with no multiplicity or alpha adjustment. RESULTS The median study follow-up was 45.0 months (interquartile range, 41.0-49.2; n = 882). At data cutoff (February 18, 2020), overall survival improved with pembrolizumab in the PD-L1 CPS ≥ 20 (hazard ratio [HR], 0.61; 95% CI, 0.46 to 0.81) and CPS ≥ 1 populations (HR, 0.74; 95% CI, 0.61 to 0.89) and was noninferior in the total population (HR, 0.81; 95% CI, 0.68 to 0.97). Overall survival improved with pembrolizumab-chemotherapy in ...

Current Oncology, 2022

Background: 5-FU-based chemoradiotherapy (CRT) could be associated with severe treatment-related ... more Background: 5-FU-based chemoradiotherapy (CRT) could be associated with severe treatment-related toxicities in patients harboring at-risk DPYD polymorphisms. Methods: The studied population included consecutive patients with locoregionally advanced oropharyngeal carcinoma treated with carboplatin and 5-FU-based CRT one year before and after the implementation of upfront DPYD*2A genotyping. We aimed to determine the effect of DPYD genotyping on grade ≥3 toxicities. Results: 181 patients were analyzed (87 patients before and 94 patients following DPYD*2A screening). Of the patients, 91% (n = 86) were prospectively genotyped for the DPYD*2A allele. Of those screened, 2% (n = 2/87) demonstrated a heterozygous DPYD*2A mutation. Extended genotyping of DPYD*2A-negative patients later allowed for the retrospective identification of six additional patients with alternative DPYD variants (two c.2846A>T and four c.1236G>A mutations). Grade ≥3 toxicities occurred in 71% of the patients be...

Current Oncology, 2021

The tyrosine receptor kinase (TRK) inhibitors larotrectinib and entrectinib were recently approve... more The tyrosine receptor kinase (TRK) inhibitors larotrectinib and entrectinib were recently approved in Canada for the treatment of solid tumours harbouring neurotrophic tyrosine receptor kinase (NTRK) gene fusions. These NTRK gene fusions are oncogenic drivers found in most tumour types at a low frequency (<5%), and at a higher frequency (>80%) in a small number of rare tumours (e.g., secretory carcinoma of the salivary gland and of the breast). They are generally mutually exclusive of other common oncogenic drivers. Larotrectinib and entrectinib have demonstrated impressive overall response rates and tolerability in Phase I/II trials in patients with TRK fusion cancer with no other effective treatment options. Given the low frequency of TRK fusion cancer and the heterogeneous molecular testing landscape in Canada, identifying and optimally managing such patients represents a new challenge. We provide a Canadian consensus on when and how to test for NTRK gene fusions and when t...

Journal of Clinical Oncology, 2020

6580 Background: The combination of carboplatin and 5-fluorouracil (5-FU) is effective when used ... more 6580 Background: The combination of carboplatin and 5-fluorouracil (5-FU) is effective when used concurrently with radiotherapy for locoregionally advanced oropharyngeal carcinomas (Calais et al. 1999). DPYD polymorphisms can be associated with an increased risk of severe toxicity to fluoropyrimidines (Deenen et al. 2016). Upfront screening for the DPYD*2A allele is available in the province of Québec, Canada since March 2017. This study aimed to determine the effect of upfront genotyping on grade ≥3 toxicities. Methods: The studied population included all consecutive cases of oropharyngeal carcinomas treated with 5-FU based chemoradiotherapy one year before and after the implementation of upfront DPYD*2A genotyping. All patients were treated at the Centre Hospitalier de l’Université de Montréal (CHUM) between March 2016 and April 2018. Clinical data were extracted from chart review. Extended screening for 3 supplemental at-risk DPYD variants was also retrospectively performed in Au...

The Lancet, 2019

Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or meta... more Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-048) KEYNOTE-048 Investigators;

Journal for ImmunoTherapy of Cancer, 2019

Two phase III clinical trials (CheckMate 141 and KEYNOTE 040) have independently demonstrated tha... more Two phase III clinical trials (CheckMate 141 and KEYNOTE 040) have independently demonstrated that overall survival (OS) in recurrent and/or metastatic head and neck squamous cell carcinoma (R/M HNSCC) patients, who have failed platinum-based therapy, can be improved with anti-PD1 monotherapy. Treatment with nivolumab or pembrolizumab in R/M HNSCC patients led to an improved OS with a hazards ratio (HR) of 0.70 (95%CI 0.51-0.96; p = 0.01) and HR of 0. 80 (95%CI 0.65-0.98, p = 0.0161), respectively, as compared to standard of care (SOC) chemo monotherapy regimens (specifically, cetuximab, docetaxel, or methotrexate). The gain in OS was similar in both studies, underscoring the role of anti-PD1 drugs in R/M HNSCC patients. One of the striking discrepancies between CheckMate 141 and KEYNOTE 040 was the OS observed in the control SOC arms (6.9 months median in KEYNOTE 040 versus 5.1 months in CheckMate 141), which inadvertently set a higher threshold in the bio-statistical analysis of KEYNOTE 040 so that the clinical outcome of every patient was influential in the analysis. We perform a comparative analysis of the two studies to identify potential factors in the control arm that can impact clinical trial bio-statistical outcomes and which may have implications for future immunotherapy clinical trial designs.

International Journal of Radiation Oncology*Biology*Physics, 2018

used to compare rates of failure. CTCAE v4, and EORTC QLQ-C30 and H&N35 are used to assess toxici... more used to compare rates of failure. CTCAE v4, and EORTC QLQ-C30 and H&N35 are used to assess toxicity and quality of life (QOL). Results: At time of analysis, 31 of the planned 80 patients have completed treatment: 15 randomized to boost and 16 to standard therapy. At a median follow-up of 13.3 months, there were 7 (22.6%) locoregional failures (LRFs) in all patients: 5 (31.2%) in the 70-Gy arm and 2 (13.3%) in the 80-Gy arm (HR 0.36, P Z .218). There were 6 (19.4%) distant failures (DFs): 4 (25%) in the 70-Gy arm and 2 (13.3%) in the 80-Gy arm (HR 0.46, P Z .365). Rates of HPV positivity were 56.2% and 66.7% in the 70-Gy and 80-Gy arms, respectively (P Z .567). In HPV (+) patients, there were 2 (10.5%) LRFs: 2 (22.2%) in the 70-Gy arm and 0 in the 80-Gy arm (HR 0.19, P Z .211). There were 3 (15.8%) DFs: 2 (22.2%) in the 70-Gy arm and 1 (10%) in the 80-Gy arm (HR 0.41, P Z .463). In HPV (-) patients, there were 5 (41.7%) LRFs: 3 (42.8%) in the 70-Gy arm and 2 (40%) in the 80-Gy arm (HR 0.60, P Z .586). There were 3 (15.8%) DFs: 2 (22.2%) in the 70-Gy arm and 1 (20%) in the 80-Gy arm (HR 0.59, P Z .670). On univariate analysis, HPV positivity (HR 0.22, P Z .073), as well as pretreatment hypermetabolic (HFDG) (HR 1.57, P Z .079) and union of HP, RD, and HFDG (HR 2.15, P Z.046) volumes were significant or marginally significant correlates of LRF. There were no significant differences in acute toxicity between arms. "Lost-Weight" QOL scores were worse in the boost arm at baseline and at 4 weeks posttreatment, although the difference at 4 weeks was of lesser magnitude than at baseline. At 72 weeks, "Cough" scores were worse in the boost arm at 2 versus 1.2 on a 4-point scale (P Z .010). Conclusion: In this interim analysis of MRI-guided boost in poor-prognosis HNC, there were not yet significant differences in outcomes between arms. However, the HR for LRF was encouraging as it was consistent with the value used to calculate power for the study. Boost was associated with no increased acute toxicity and minimal difference in QOL.

International Journal of Cancer, 2017

The purpose of this study was to determine the prognostic value and oncogenic pathways associated... more The purpose of this study was to determine the prognostic value and oncogenic pathways associated to miRNA expression in squamous cell carcinoma of the oral tongue and to link these miRNA candidates with potential gene targets. We performed a miRNA screening within our institutional cohort (n 5 58 patients) and reported five prognostic targets including a cluster of four co-expressed miRNAs (miR-18a, miR-92a, miR-103, and miR-205). Multivariate analysis showed that expression of miR-548b (p 5 0.007) and miR-18a (p 5 0.004, representative of co-expressed miRNAs) are independent prognostic markers for squamous cell carcinoma of the oral tongue. These findings were validated in The Cancer Genome Atlas (TCGA) cohort (n 5 131) for both miRNAs (miR-548b: p 5 0.027; miR-18a: p 5 0.001). Bioinformatics analysis identified PTEN and ACTN4 as direct targets of the four co-expressed miRNAs and miR-548b, respectively. Correlations between the five identified miRNAs and their respective targeted genes were validated in the two merged cohorts and were concordantly significant (miR-18a/

International Journal of Radiation Oncology*Biology*Physics, 2016

Purpose-To determine the relationship between p16 status and the regional response of patients wi... more Purpose-To determine the relationship between p16 status and the regional response of patients with node-positive oropharynx cancer treated on NRG Oncology RTOG 0129. Methods and Materials-Patients with N1-N3 oropharynx cancer and known p16 status who underwent treatment on RTOG 0129 were analyzed. Pathologic complete response (pCR) rates in patients treated with a postchemoradiation neck dissection (with p16-positive or p16-negative cancer) were compared by Fisher exact test. Patients managed expectantly were compared with those treated with a neck dissection. Results-Ninety-nine (34%) of 292 patients with node-positive oropharynx cancer and known p16 status underwent a posttreatment neck dissection (p16-positive: n = 69; p16-negative: n = 30). The remaining 193 patients with malignant lymphadenopathy at diagnosis were observed. Neck dissection was performed a median of 70 (range, 17-169) days after completion of

BMC Cancer, 2015

Background: Increasing evidence suggests a close relationship between systemic inflammation and c... more Background: Increasing evidence suggests a close relationship between systemic inflammation and cancer development and progression. The neutrophil to lymphocyte ratio (NLR) has been shown to be an independent prognostic indicator in various advanced and localized cancers. We investigated the influence of markers of systemic inflammation such as leucocyte counts and metabolic co-morbidities on overall survival (OS) after radiotherapy for localized prostate cancer. Methods: We conducted a retrospective study of patients with localized prostate cancer treated with definitive external beam radiotherapy or brachytherapy. Univariate and multivariate cox proportional hazards models were used to investigate the influence of the following factors on OS: age, neutrophil and lymphocyte counts, neutrophil-to-lymphocyte ratio (NLR), Cancer of the Prostate Risk Assessment (CAPRA) score as well as comorbidities associated with inflammation such as cardiac history, diabetes and use of a statin. A stepwise selection of variable based on the Akaike information criterion (AIC) was used for multivariate analysis. Results: In total, 1772 pts were included; blood count data was available for 950 pts. Median age was 68 years (44-87). Actuarial 5 years OS and biochemical recurrence-free survival (BRFS) for the 1772 patients were 93 % and 95 %, respectively, with a median follow-up of 44 months (1-156). On univariate analysis, neutrophil count (p = 0.04), cardiac history (p = 0.008), age (p = 0.001) and CAPRA (p = 0.0002) were associated with OS. Lymphocytes, NLR and comorbidities other than cardiac history were not associated with mortality. On multivariate analysis, neutrophil count (HR = 1.18, 95 % CI: 1.017-1.37, p = 0.028), age (HR = 1.06, 95 % CI: 1.01-1.1, p = 0.008) and CAPRA (HR = 1.16, 95 % CI: 1.03-1.31, p = 0.015) were independent predictors of OS. Conclusion: Neutrophil count, as a possible marker of systemic inflammation, appear to be an independent prognostic factor for overall mortality in localized prostate cancer. A validation cohort is needed to corroborate these results.

Radiotherapy and Oncology, 2013

British journal of cancer, Jan 25, 2012

The relationship between progression-free survival and time to progression (PFS/TTP) and overall ... more The relationship between progression-free survival and time to progression (PFS/TTP) and overall survival (OS) has been demonstrated in a variety of solid tumours but not in metastatic renal cell carcinoma (mRCC). A systematic literature search was conducted to identify controlled trials of cytokine or targeted therapies for mRCC reporting information on treatment effects on PFS/TTP and OS for one or more comparison. The associations between treatment effects on PFS/TTP and OS were analysed using linear regression. Thirty-one studies representing 10943 patients, 75 treatment groups, and 41 comparisons were identified. The correlation coefficient between the negative log of the hazard ratio (HR) for PFS/TTP (-ln HR(PFS/TTP)) vs the negative log of the HR for OS (-ln HR(OS)) was 0.80 (P<0.0001). In linear regression, the coefficient on -ln HR(PFS/TTP) vs -ln HR(OS) was 0.64 (95% confidence interval (CI): 0.470.81; R(2)=0.63), suggesting each 10% relative risk reduction (RRR) for PF...

Current Oncology, 2010

Survival of patients with metastatic CRC (mCRC) has improved steadily over the past several decad... more Survival of patients with metastatic CRC (mCRC) has improved steadily over the past several decades, due largely to the development of new combinations of standard chemotherapy, as well as to the introduction of new targeted therapies. Among the available targeted therapies are two monoclonal antibodies that target the epidermal growth factor receptor (EGFR)—cetuximab and panitumumab—which have demonstrated efficacy in the treatment of mCRC. These therapies are associated with a unique set of toxicities and costs, prompting the need for tools to select patients who are most likely to derive a benefit from them. Mutations in the KRAS oncogene have consistently been shown to predict non-response to cetuximab and panitumumab. The role of KRAS as a marker of efficacy of anti-EGFR therapies is reviewed.

Current oncology (Toronto, Ont.), 2012

Non-small-cell lung cancer (nsclc) tumours with activating mutations of the epidermal growth fact... more Non-small-cell lung cancer (nsclc) tumours with activating mutations of the epidermal growth factor receptor (efgr) tyrosine kinase are highly sensitized to the effects of oral tyrosine kinase inhibitors such as gefitinib and erlotinib, suggesting the possibility of targeted treatment of nsclc based on EFGR mutation status. However, no standardized method exists for assessing the EGFR mutation status of tumours. Also, it is not known if available methods are feasible for routine screening. To address that question, we conducted a validation study of methods used for detecting EGFR mutations in exons 19 and 21 at molecular laboratories located in five specialized Canadian cancer centres. The screening methods were first optimized using cell lines harbouring the mutations in question. A validation phase using anonymized patient samples followed. The methods used at the sites were highly specific and sensitive in detecting both mutations in cell-line dna (specificity of 100% and sensit...

Canadian Urological Association Journal, 2013

Background: Hereditary renal cell cancer (RCC) is an ideal model for germline genetic testing. We... more Background: Hereditary renal cell cancer (RCC) is an ideal model for germline genetic testing. We propose a guideline of hereditary RCC specific criteria to suggest referral for genetic assessment.Methods: A review of the literature and stakeholder resources for existing guidelines or consensus statements was performed. Referral criteria were developed by expert consensus.Results: The criteria included characteristics for patients with RCC (age ≤45 years, bilateral or multifocal tumours, associated medical conditions and non-clear cell histologies with unusual features) and for patients with or without RCC, but a family history of specific clinical or genetic diagnoses.Conclusions: This guideline represents a practical RCC-specific reference to allow healthcare providers to identify patients who may have a hereditary RCC syndrome, without extensive knowledge of each syndrome. RCC survivors and their families can also use the document to guide their discussions with healthcare provid...

International Journal of Otolaryngology, 2013

Background. RAS gene mutations have an impact on treatment response and overall prognosis for cer... more Background. RAS gene mutations have an impact on treatment response and overall prognosis for certain types of cancer.Objectives. To determine the prevalence and impact of K-RAS codons 12 and 13 mutations in patients with locally advanced HNSCC treated with primary or adjuvant chemo-radiation.Methods. 428 consecutive patients were treated with chemo-radiation therapy and followed for a median of 37 months. From these, 199 paraffin embedded biopsy or surgical specimens were retrieved. DNA was isolated and analyzed for K-RAS mutational status.Results. DNA extraction was successful in 197 samples. Of the 197 specimens, 3.5% presented K-RAS codon 12 mutations. For mutated cases and non-mutated cases, complete initial response to chemoradiation therapy was 71 and 73% (P=0.32). LRC was respectively 32 and 83% (P=0.03), DFS was 27 and 68% (P=0.12), distant metastasis-free survival was 100 and 81% (P=0.30) and OS was 57 and 65% (P=0.14) at three years. K-Ras codon 13 analysis revealed no mu...

Journal of Clinical Oncology, 2003

Purpose: A multi-institution phase II study was undertaken by National Cancer Institute of Canada... more Purpose: A multi-institution phase II study was undertaken by National Cancer Institute of Canada–Clinical Trials Group to evaluate the efficacy and toxicity of intravenous troxacitabine (Troxatyl; Shire Pharmaceuticals Plc, Laval, Quebec, Canada), in patients with renal cell carcinoma. Patients and Methods: Between June 1999 and March 2000, 35 patients (24 male) with a mean age of 60 years who had advanced and/or metastatic disease were treated with troxacitabine given as an intravenous infusion over 30 minutes at a dose of 10 mg/m2 intravenously, once every 3 weeks. Results: Of the 33 of 35 patients evaluable for response, there were two confirmed partial responses, 21 patients had stable disease (median duration, 4.4 months), and 10 patients had progressive disease. Eight patients remained stable for more than 6 months, of whom six remain free of progression. The most common drug-related nonhematologic toxicities observed were skin rash (77.1%), hand-foot syndrome (68.6%), alopec...