Publications by authors named "Mustapha Tehfe"

24 Publications

  • Page 1 of 1

First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma (CheckMate 649): a randomised, open-label, phase 3 trial.

Lancet 2021 Jul 5;398(10294):27-40. Epub 2021 Jun 5.

Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Background: First-line chemotherapy for advanced or metastatic human epidermal growth factor receptor 2 (HER2)-negative gastric or gastro-oesophageal junction adenocarcinoma has a median overall survival (OS) of less than 1 year. We aimed to evaluate first-line programmed cell death (PD)-1 inhibitor-based therapies in gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma. We report the first results for nivolumab plus chemotherapy versus chemotherapy alone.

Methods: In this multicentre, randomised, open-label, phase 3 trial (CheckMate 649), we enrolled adults (≥18 years) with previously untreated, unresectable, non-HER2-positive gastric, gastro-oesophageal junction, or oesophageal adenocarcinoma, regardless of PD-ligand 1 (PD-L1) expression from 175 hospitals and cancer centres in 29 countries. Patients were randomly assigned (1:1:1 while all three groups were open) via interactive web response technology (block sizes of six) to nivolumab (360 mg every 3 weeks or 240 mg every 2 weeks) plus chemotherapy (capecitabine and oxaliplatin every 3 weeks or leucovorin, fluorouracil, and oxaliplatin every 2 weeks), nivolumab plus ipilimumab, or chemotherapy alone. Primary endpoints for nivolumab plus chemotherapy versus chemotherapy alone were OS or progression-free survival (PFS) by blinded independent central review, in patients whose tumours had a PD-L1 combined positive score (CPS) of five or more. Safety was assessed in all patients who received at least one dose of the assigned treatment. This study is registered with ClinicalTrials.gov, NCT02872116.

Findings: From March 27, 2017, to April 24, 2019, of 2687 patients assessed for eligibility, we concurrently randomly assigned 1581 patients to treatment (nivolumab plus chemotherapy [n=789, 50%] or chemotherapy alone [n=792, 50%]). The median follow-up for OS was 13·1 months (IQR 6·7-19·1) for nivolumab plus chemotherapy and 11·1 months (5·8-16·1) for chemotherapy alone. Nivolumab plus chemotherapy resulted in significant improvements in OS (hazard ratio [HR] 0·71 [98·4% CI 0·59-0·86]; p<0·0001) and PFS (HR 0·68 [98 % CI 0·56-0·81]; p<0·0001) versus chemotherapy alone in patients with a PD-L1 CPS of five or more (minimum follow-up 12·1 months). Additional results showed significant improvement in OS, along with PFS benefit, in patients with a PD-L1 CPS of one or more and all randomly assigned patients. Among all treated patients, 462 (59%) of 782 patients in the nivolumab plus chemotherapy group and 341 (44%) of 767 patients in the chemotherapy alone group had grade 3-4 treatment-related adverse events. The most common any-grade treatment-related adverse events (≥25%) were nausea, diarrhoea, and peripheral neuropathy across both groups. 16 (2%) deaths in the nivolumab plus chemotherapy group and four (1%) deaths in the chemotherapy alone group were considered to be treatment-related. No new safety signals were identified.

Interpretation: Nivolumab is the first PD-1 inhibitor to show superior OS, along with PFS benefit and an acceptable safety profile, in combination with chemotherapy versus chemotherapy alone in previously untreated patients with advanced gastric, gastro-oesophageal junction, or oesophageal adenocarcinoma. Nivolumab plus chemotherapy represents a new standard first-line treatment for these patients.

Funding: Bristol Myers Squibb, in collaboration with Ono Pharmaceutical.
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http://dx.doi.org/10.1016/S0140-6736(21)00797-2DOI Listing
July 2021

Eastern Canadian Gastrointestinal Cancer Consensus Conference 2019.

Curr Oncol 2021 May 26;28(3):1988-2006. Epub 2021 May 26.

Queen Elizabeth II Health Sciences Centre, Halifax, NS B3H 2Y9, Canada.

The annual Eastern Canadian Gastrointestinal Cancer Consensus Conference 2019 was held in Morell, Prince Edward Island, 19-21 September 2019. Experts in medical oncology, radiation oncology, and surgical oncology who are involved in the management of patients with gastrointestinal malignancies participated in presentations and discussion sessions for the purpose of developing the recommendations presented here. This consensus statement addresses multiple topics in the management of anal, colorectal, biliary tract, and gastric cancers, including: radiotherapy and systemic therapy for localized and advanced anal cancer; watch and wait strategy for the management of rectal cancer; role of testing for dihydropyrimidine dehydrogenase (DPD) deficiency prior to commencement of fluoropyrimidine therapy; radiotherapy and systemic therapy in the adjuvant and unresectable settings for biliary tract cancer; and radiotherapy and systemic therapy in the perioperative setting for early-stage gastric cancer.
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http://dx.doi.org/10.3390/curroncol28030185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8161825PMC
May 2021

Outcomes of Older Patients with Resectable Colorectal Liver Metastases Cancer (CRLM): Single Center Experience.

Curr Oncol 2021 May 18;28(3):1899-1908. Epub 2021 May 18.

Department of Medicine, Hematology-Oncology Division, Centre Hospitalier de l'Université de Montréal (CHUM), Montréal, QC H2X 0C1, Canada.

Surgery is the only potential curative option of CRLM if resectable. The curative approach in patients over 70 years old is challenging mainly because of comorbidities and other geriatric syndromes. Herein, we report outcomes of older patients with resectable CRLM in our center. We retrospectively analyzed characteristics and outcomes of older patients with CRLM operated at "Centre Hospitalier de l'Université de Montréal" (CHUM) between 2010 and 2019. We identified 210 patients aged ≥70 years with a median age of 76 (range: 70-85). CRLM were synchronous in 56% of patients. Median disease-free survival (DFS) was 41.3 months. Median overall survival (OS) was 62.2 months and estimated 5-year survival rate was 51.5% similar to those of younger counterparts. Patients with metachronous CRLM had a trend to a higher OS compared to those with synchronous disease (67.2 vs. 58.7 months; = 0.42). Factors associated with lower survival in the multivariate analysis were right-sided tumors and increased Charlson Comorbidity index (CCI). Survival outcomes of patients aged ≥70 years were comparable to those of younger patients and those reported in the literature. Age should not be a limiting factor in the curative management of older patients with resectable CRLM.
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http://dx.doi.org/10.3390/curroncol28030176DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8161835PMC
May 2021

Improvement of EGFR Testing over the Last Decade and Impact of Delaying TKI Initiation.

Curr Oncol 2021 Feb 26;28(2):1045-1055. Epub 2021 Feb 26.

Hematology and Medical Oncology Service, Centre Hospitalier Universitaire de Montreal, University of Montreal, Montreal, QC H2X 3E4, Canada.

Background: Epidermal growth factor receptor (EGFR) is the most common oncogenic mutation in lung adenocarcinoma and tyrosine kinase inhibitors (TKIs) have been considered standard treatment for more than a decade. However, time to initiation of TKIs (TTIT) from diagnosis is often delayed and represents a challenge for clinicians. We aimed to assess the impact of TTIT on clinical outcomes and complications.

Method: TTIT was defined as the time between confirmed advanced diagnosis and the initiation of a TKI. Complications during this pre-TKI period were retrospectively collected from all patients with EGFR-mutant non small cell lung cancer (NSCLC) in our institution.

Results: 102 patients were diagnosed with EGFR mutated NSCLC between 2006 and 2019. The median PFS and OS were 12.9 and 22.5 months, respectively. TTIT was 5.7 months (95% CI 3.4-8) with a significant decrease in the latter years of this cohort. During the pre-TKI period, 23 patients received chemotherapy as first line treatment, of which 5 developed severe adverse events and 3 were not fit to receive TKI thereafter. Additionally, 29 patients had rapid clinical deterioration before initiation of first line TKI and 16 had to be hospitalized. Among the patients presenting a performance status deterioration, their prognosis was markedly affected compared to the remainder of the cohort ( = 0.01).

Conclusion: Our real-world evidence study supports the concept that a delay to treat EGFR mutant NSCLC with TKIs is associated with adverse events, patient progression, hospitalization, and decreased overall survival. Rapid molecular diagnosis, including access to ctDNA technology may circumvent these deleterious delays.
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http://dx.doi.org/10.3390/curroncol28020102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8025752PMC
February 2021

Survival Impact of Aggressive Treatment and PD-L1 Expression in Oligometastatic NSCLC.

Curr Oncol 2021 01 20;28(1):593-605. Epub 2021 Jan 20.

Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montreal, QC H2X 0A9, Canada.

Background: Studies have shown that aggressive treatment of non-small cell lung cancer (NSCLC) with oligometastatic disease improves the overall survival (OS) compared to a palliative approach and some immunotherapy checkpoint inhibitors, such as anti-programmed cell death ligand 1 (PD-L1), anti-programmed cell death protein 1 (PD-1), and T-Lymphocyte-associated antigen 4 (CTLA-4) inhibitors are now part of the standard of care for advanced NSCLC. However, the prognostic impact of PD-L1 expression in the oligometastatic setting remains unknown.

Methods: Patients with oligometastatic NSCLC were identified from the patient database of the Centre hospitalier de l'Université de Montréal (CHUM). "Oligometastatic disease" definition chosen is one synchronous metastasis based on the M1b staging of the eight IASLC (The International Association for the Study of Lung Cancer) Classification (within sixth months of diagnosis) or up to three cerebral metastasis based on the methodology of the previous major phase II randomized study of Gomez et al. We compared the OS between patients receiving aggressive treatment at both metastatic and primary sites (Group A) and patients receiving non-aggressive treatment (Group B). Subgroup analysis was performed using tumor PD-L1 expression.

Results: Among 643 metastatic NSCLC patients, we identified 67 patients with oligometastasis (10%). Median follow-up was 13.3 months. Twenty-nine patients (43%) received radical treatment at metastatic and primary sites (Group A), and 38 patients (57%) received non-aggressive treatment (Group B). The median OS (mOS) of Group A was significantly longer than for Group B (26 months vs. 5 months, = 0.0001). Median progression-free survival (mPFS) of Group A was superior than Group B (17.5 months vs. 3.4 months, = 0.0001). This difference was still significant when controlled for primary tumor staging: stage I ( = 0.316), stage II ( = 0.024), and stage III ( = 0.001). In the cohort of patients who were not treated with PD-L1 inhibitors, PD-L1 expression negatively correlated with mOS.

Conclusions: Aggressive treatments of oligometastatic NSCLC significantly improve mOS and mPFS compared to a more palliative approach. PD-L1 expression is a negative prognostic factor which suggests a possible role for immunotherapy in this setting.
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http://dx.doi.org/10.3390/curroncol28010059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7924378PMC
January 2021

Implementing DPYD*2A Genotyping in Clinical Practice: The Quebec, Canada, Experience.

Oncologist 2021 04 23;26(4):e597-e602. Epub 2020 Dec 23.

Centre Hospitalier de l'Université de Montréal (CHUM), Montreal, Quebec, Canada.

Background: Fluoropyrimidines are used in chemotherapy combinations for multiple cancers. Deficient dihydropyrimidine dehydrogenase activity can lead to severe life-threatening toxicities. DPYD*2A polymorphism is one of the most studied variants. The study objective was to document the impact of implementing this test in routine clinical practice.

Methods: We retrospectively performed chart reviews of all patients who tested positive for a heterozygous or homozygous DPYD*2A mutation in samples obtained from patients throughout the province of Quebec, Canada.

Results: During a period of 17 months, 2,617 patients were tested: 25 patients tested positive. All were White. Twenty-four of the 25 patients were heterozygous (0.92%), and one was homozygous (0.038%). Data were available for 20 patients: 15 were tested upfront, whereas five were identified after severe toxicities. Of the five patients confirmed after toxicities, all had grade 4 cytopenias, 80% grade ≥3 mucositis, 20% grade 3 rash, and 20% grade 3 diarrhea. Eight patients identified with DPYD*2A mutation prior to treatment received fluoropyrimidine-based chemotherapy at reduced initial doses. The average fluoropyrimidine dose intensity during chemotherapy was 50%. No grade ≥3 toxicities were observed. DPYD*2A test results were available in an average of 6 days, causing no significant delays in treatment initiation.

Conclusion: Upfront genotyping before fluoropyrimidine-based treatment is feasible in clinical practice and can prevent severe toxicities and hospitalizations without delaying treatment initiation. The administration of chemotherapy at reduced doses appears to be safe in patients heterozygous for DPYD*2A.

Implications For Practice: Fluoropyrimidines are part of chemotherapy combinations for multiple cancers. Deficient dihydropyrimidine dehydrogenase activity can lead to severe life-threatening toxicities. This retrospective analysis demonstrates that upfront genotyping of DPYD before fluoropyrimidine-based treatment is feasible in clinical practice and can prevent severe toxicities and hospitalizations without delaying treatment initiation. This approach was reported previously, but insufficient data concerning its application in real practice are available. This is likely the first reported experience of systematic DPYD genotyping all over Canada and North America as well.
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http://dx.doi.org/10.1002/onco.13626DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8018309PMC
April 2021

Durvalumab therapy following chemoradiation compared with a historical cohort treated with chemoradiation alone in patients with stage III non-small cell lung cancer: A real-world multicentre study.

Eur J Cancer 2021 01 24;142:83-91. Epub 2020 Nov 24.

Centre de Recherche Du Centre Hospitalier de L'Université de Montréal (CRCHUM), 900, Rue Saint-Denis, Pavillon R, H2X 0A9, Montreal, Quebec, Canada; Cedars Cancer Center, McGill University Healthcare Center (MUHC), 1001, Boulevard Décarie, H4A 3J1, Montreal, Quebec, Canada; Segal Cancer Center, Jewish General Hospital, 3755, Chemin de La Côte-Sainte-Catherine, H3T 1E2, Montreal, Quebec, Canada. Electronic address:

Background: The PACIFIC trial demonstrated that durvalumab therapy following chemoradiation (CRT) was associated with improved overall survival (OS) in patients with stage III non-small cell lung cancer (NSCLC). It is unclear whether the results obtained as part of randomised controlled trials are a reflection of real-world (RW) data. Several questions remain unanswered with regard to RW durvalumab use, such as optimal time to durvalumab initiation, incidence of pneumonitis and response in PD-L1 subgroups.

Methods: In this multicentre retrospective analysis, 147 patients with stage III NSCLC treated with CRT followed by durvalumab were compared with a historical cohort of 121 patients treated with CRT alone. Survival curves were estimated using the Kaplan-Meier method and compared with the log-rank test in univariate analysis. Multivariate analysis was performed to evaluate the effect of standard prognostic factors for durvalumab use.

Results: Median OS was not reached in the durvalumab group, compared with 26.9 months in the historical group (hazard ratio [HR]: 0.56, 95% confidence interval [CI]: 0.37-0.85, p = 0.001). In the durvalumab group, our data suggest improved 12-month OS in patients with PD-L1 expression ≥50% (100% vs 86%, HR: 0.25, 95% CI: 0.11-0.58, p = 0.007). There was no difference in OS between patients with a PD-L1 expression of 1-49% and patients with PD-L1 expression <1%. Delay in durvalumab initiation beyond 42 days did not impact OS. Incidence of pneumonitis was similar in the durvalumab and historical groups. In the durvalumab group, patients who experienced any-grade pneumonitis had a lower 12-month OS than patients without pneumonitis (85% vs 95%, respectively; HR: 3.3, 95% CI: 1.2-9.0, p = 0.006).

Conclusions: This multicentre analysis suggests that PD-L1 expression ≥50% was associated with favourable OS in patients with stage III NSCLC treated with durvalumab after CRT, whereas the presence of pneumonitis represented a negative prognostic factor.
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http://dx.doi.org/10.1016/j.ejca.2020.10.008DOI Listing
January 2021

Tepotinib Efficacy in a Patient with Non-Small Cell Lung Cancer with Brain Metastasis Harboring an HLA-DRB1-MET Gene Fusion.

Oncologist 2020 11 8;25(11):916-920. Epub 2020 Sep 8.

Thoracic Oncology Unit, Le Centre Hospitalier de l'Université de Montréal, Montreal, Canada.

Alterations in c-MET, a tyrosine kinase receptor encoded by the MET gene, have been reported in approximately 3% of non-small cell lung cancer (NSCLC) cases and carry important treatment implications. The best studied genetic alterations are exon 14 skipping and gene amplification; however, gene rearrangement has also been described, and multiple fusion partners have been reported. Recently, in METex14-mutated NSCLC, multitarget tyrosine kinase inhibitors (TKIs), such as crizotinib and cabozantinib, as well as MET-selective TKIs, such as tepotinib and capmatinib, have demonstrated durable responses. In this study, we present the case of a 41-year-old woman with advanced NSCLC harboring an HLA-DRB1-MET gene fusion. The patient was offered successively two different MET multikinase inhibitors, crizotinib and cabozantinib, and the selective inhibitor tepotinib. Each time, including under tepotinib, the patient experienced rapid and complete responses associated with a tremendous improvement in her physical function. KEY POINTS: To our knowledge, this is the first report of a patient with non-small cell lung cancer harboring an HLA-DRB1-MET gene fusion demonstrating a clinical response to multiple MET inhibitors, including tepotinib. This finding illustrates the efficacy and rationale to targeting MET regardless of fusion partner and gives insight to pooling of patients with different MET fusion products in trials assessing safety and efficacy of novel molecules.
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http://dx.doi.org/10.1634/theoncologist.2020-0502DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7648335PMC
November 2020

Arterial thrombosis and coronavirus disease 2019 in a patient with cancer.

Eur J Cancer 2020 07 18;134:1-2. Epub 2020 May 18.

Centre Hospitalier de l'Université de Montréal, Canada. Electronic address:

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http://dx.doi.org/10.1016/j.ejca.2020.05.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7231757PMC
July 2020

Efficacy of immune checkpoint inhibitors in older patients with non-small cell lung cancer: Real-world data from multicentric cohorts in Canada and France.

J Geriatr Oncol 2020 06 14;11(5):802-806. Epub 2020 Jan 14.

Centre de recherche du Centre hospitalier de l'Université de Montréal (CRCHUM), Division of Oncology, Department of Medicine Montréal, QC, Canada; Centre Hospitalier de l'Université de Montréal (CHUM), Hematology-Oncology Division, Department of Medicine, Montréal, QC, Canada. Electronic address:

Background: Age-related immune remodelling is thought to be associated with resistance to immune checkpoint inhibitors (ICIs) in cancer. Patients older than 70 years, representing >50% of the population with non-small cell lung cancer (NSCLC) according to SEER database, are underrepresented in clinical trials exploring ICIs. The objective of this study was to determine if patients with NSCLC older than ≥70 years had inferior clinical outcomes with ICIs.

Methods: We conducted a retrospective analysis of 381 patients treated with anti-PD-(L)1 ICI for advanced NSCLC at the Dijon Cancer Center (n = 177), University of Montreal Hospital (n = 106) and Quebec Heart and Lung Institute (n = 98). Age was considered as a categorical variable. Patients' baseline characteristics were compared using the Chi-squared test. Survival curves were estimated by the Kaplan-Meier method and compared with the Log-rank test in a univariate analysis. Multivariate cox regression model was used to determine hazard ratios and 95% confidence intervals for progression-free survival (PFS) and overall survival (OS) between the groups, adjusting for other clinicopathologic features.

Results: Among 381 patients included, 335 (88%) received ICI after platinum chemotherapy. The median age was 66 (range 37-89) and 33% were older than 70 years of age. Considering age as a categorical variable, differences in age were not associated with PFS or OS. Subgroup analysis and multivariate cox regression did not reveal significant interaction of age with outcomes. ECOG performance status was the only significant factor in the three cohorts.

Conclusions: Unlike previously described in the era of chemotherapy, age was not associated with outcomes in NSCLC patients treated with ICI.
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http://dx.doi.org/10.1016/j.jgo.2020.01.002DOI Listing
June 2020

Phase I/II trial of Durvalumab plus Tremelimumab and stereotactic body radiotherapy for metastatic head and neck carcinoma.

BMC Cancer 2019 Jan 14;19(1):68. Epub 2019 Jan 14.

Department of Radiation Oncology, Centre Hospitalier de l'Université de Montréal, 1051 Sanguinet Street, Montreal, QC, H2X 3E4, Canada.

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.

Trial Registration: NCT03283605 . Registration date: September 14, 2017; version 1.
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http://dx.doi.org/10.1186/s12885-019-5266-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6332607PMC
January 2019

Ramucirumab in HER-2-positive gastroesophageal adenocarcinoma: an argument for overcoming trastuzumab resistance.

Future Oncol 2018 02 10;14(3):223-228. Epub 2018 Jan 10.

Department of Medical Oncology, University of Naples 'Luigi Vanvitelli', NA 80138, Italy.

Aim: Patients with advanced gastric cancer have a relatively poor prognosis with few therapeutic alternatives beyond first-line therapy. The purpose of this manuscript is to highlight the potential for prolonged responses in patients with HER-2-positive disease. Patients, materials & methods: We analyzed the data of patients diagnosed with HER-2-positive-advanced gastric cancer who progressed on trastuzumab-based combination therapy and subsequently received second-line therapy consisting of ramucirumab in combination with paclitaxel.

Results: Most patients had a stable disease after ramucirumab-based therapy (50%, 5/10), median duration to disease control was 8 months.

Conclusion: The prolonged duration of response that we observed indicates that an interaction between the EGF pathway and the angiogenesis pathway requires further clinical investigations.
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http://dx.doi.org/10.2217/fon-2017-0434DOI Listing
February 2018

Management of stage III non-small cell lung cancer.

Semin Oncol 2017 06 18;44(3):163-177. Epub 2017 Oct 18.

Medical Oncology Department, Centre Hospitalier de l'Université de Montréal, Montréal, QC, Canada. Electronic address:

Optimal management of patients with locally advanced non-small cell lung cancer remains challenging in the context of this heterogeneous disease. Despite aggressive therapeutic approaches, survival benefits are still unsatisfactory for what might be viewed as a localized malignancy. A combined modality approach offers patients superior outcomes, especially because technological advances and refined surgical procedures now provide better results with fewer complications. Nevertheless, several features of therapy remain controversial and lack formal prospective data. Traditional cytotoxic chemoradiation therapy may have reached a plateau and future perspectives opting to integrate molecularly targeted agents and immunotherapy might be the way to improve outcomes in this disease subset.
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http://dx.doi.org/10.1053/j.seminoncol.2017.10.009DOI Listing
June 2017

Rilotumumab plus epirubicin, cisplatin, and capecitabine as first-line therapy in advanced MET-positive gastric or gastro-oesophageal junction cancer (RILOMET-1): a randomised, double-blind, placebo-controlled, phase 3 trial.

Lancet Oncol 2017 11 25;18(11):1467-1482. Epub 2017 Sep 25.

Royal Marsden Hospital, London and Surrey, UK. Electronic address:

Background: Rilotumumab is a fully human monoclonal antibody that selectively targets the ligand of the MET receptor, hepatocyte growth factor (HGF). We aimed to assess the efficacy, safety, and pharmacokinetics of rilotumumab combined with epirubicin, cisplatin, and capecitabine, and to assess potential biomarkers, in patients with advanced MET-positive gastric or gastro-oesophageal junction adenocarcinoma.

Methods: This multicentre, randomised, double-blind, placebo-controlled, phase 3 study was done at 152 centres in 27 countries. We recruited adults (aged ≥18 years) with unresectable locally advanced or metastatic gastric or gastro-oesophageal junction adenocarcinoma, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, MET-positive tumours (≥25% of tumour cells with membrane staining of ≥1+ staining intensity), and evaluable disease, who had not received previous systemic therapy. Eligible patients were randomly assigned (1:1) via a computerised voice response system to receive rilotumumab 15 mg/kg intravenously or placebo in combination with open-label chemotherapy (epirubicin 50 mg/m intravenously; cisplatin 60 mg/m intravenously; capecitabine 625 mg/m orally twice daily) in 21-day cycles for up to ten cycles. After completion of chemotherapy, patients continued to receive rilotumumab or placebo monotherapy until disease progression, intolerability, withdrawal of consent, or study termination. Randomisation was stratified by disease extent and ECOG performance status. Both patients and physicians were masked to study treatment assignment. The primary endpoint was overall survival, analysed by intention to treat. We report the final analysis. This study is registered with ClinicalTrials.gov, number NCT01697072.

Findings: Between Nov 7, 2012, and Nov 21, 2014, 609 patients were randomly assigned to rilotumumab plus epirubicin, cisplatin, and capecitabine (rilotumumab group; n=304) or placebo plus epirubicin, cisplatin, and capecitabine (placebo group; n=305). Study treatment was stopped early after an independent data monitoring committee found a higher number of deaths in the rilotumumab group than in the placebo group; all patients in the rilotumumab group subsequently discontinued all study treatment. Median follow-up was 7·7 months (IQR 3·6-12·0) for patients in the rilotumumab group and 9·4 months (5·3-13·1) for patients in the placebo group. Median overall survival was 8·8 months (95% CI 7·7-10·2) in the rilotumumab group compared with 10·7 months (9·6-12·4) in the placebo group (stratified hazard ratio 1·34, 95% CI 1·10-1·63; p=0·003). The most common grade 3 or worse adverse events in the rilotumumab and placebo groups were neutropenia (86 [29%] of 298 patients vs 97 [32%] of 299 patients), anaemia (37 [12%] vs 43 [14%]), and fatigue (30 [10%] vs 35 [12%]). The frequency of serious adverse events was similar in the rilotumumab and placebo groups (142 [48%] vs 149 [50%]). More deaths due to adverse events occurred in the rilotumumab group than the placebo group (42 [14%] vs 31 [10%]). In the rilotumumab group, 33 (11%) of 298 patients had fatal adverse events due to disease progression, and nine (3%) had fatal events not due to disease progression. In the placebo group, 23 (8%) of 299 patients had fatal adverse events due to disease progression, and eight (3%) had fatal events not due to disease progression.

Interpretation: Ligand-blocking inhibition of the MET pathway with rilotumumab is not effective in improving clinical outcomes in patients with MET-positive gastric or gastro-oesophageal adenocarcinoma.

Funding: Amgen.
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http://dx.doi.org/10.1016/S1470-2045(17)30566-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5898242PMC
November 2017

Single-center comparison of multiple chemotherapy regimens for concurrent chemoradiotherapy in unresectable stage III non-small-cell lung cancer.

Cancer Chemother Pharmacol 2017 Feb 12;79(2):381-387. Epub 2017 Jan 12.

Hematology - Oncology Division, Department of Medicine, Centre Hospitalier de l'Université de Montréal (CHUM), Montreal, QC, Canada.

Purpose: To date, the best chemotherapy regimen to combine with concurrent radiotherapy in stage III non-small-cell lung cancer remains undetermined. We compared the survival outcomes and toxicities in patients who were treated with etoposide-cisplatin (EP), paclitaxel-carboplatin (PC), or vinblastine-cisplatin (VP) in one large cancer referral center.

Methods: We enrolled patients who received concurrent chemoradiotherapy at our university-affiliated hospital between January 1, 2009 and December 31, 2013. Demographic and clinical characteristics were identified. Progression-free survival (PFS) and overall survival (OS) between the different treatment groups were compared using Kaplan-Meier and Cox proportional hazards regression models. Treatment-related toxicities were also compared.

Results: A total of 107 patients were treated with EP (31.8%), PC (32.7%) or VP (35.5%). Treatment with VP was significantly superior to PC, both in terms of median PFS [29.2 vs. 10.5 months; hazard ratio (HR) 0.43; 95% CI 0.21-0.85; p = 0.01] and in terms of median OS [40.7 vs. 17.8 months; (HR) 0.42; (0.21-0.84); p = 0.01]. However, there was no survival difference between EP and either one of the other regimens, but there was significantly more toxicities reported with the use of EP (73.5%) compared to PC (44.7%) or VP (37.1%); (p = 0.001). The most frequent non-hematologic toxicities for the entire cohort were esophagitis (28%), fatigue (22.4%), pneumonitis (14%), and nephrotoxicity (9.3%).

Conclusion: Although the present study is limited by its small cohort and its retrospective nature, the results suggest that VP might be superior to PC and is less toxic than EP.
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http://dx.doi.org/10.1007/s00280-016-3226-0DOI Listing
February 2017

Biomarker analyses in REGARD gastric/GEJ carcinoma patients treated with VEGFR2-targeted antibody ramucirumab.

Br J Cancer 2016 10 13;115(8):974-982. Epub 2016 Sep 13.

The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 426, Houston, Texas 77030, USA.

Background: Angiogenesis inhibition is an important strategy for cancer treatment. Ramucirumab, a human IgG1 monoclonal antibody that targets VEGF receptor 2 (VEGFR2), inhibits VEGF-A, -C, -D binding and endothelial cell proliferation. To attempt to identify prognostic and predictive biomarkers, retrospective analyses were used to assess tumour (HER2, VEGFR2) and serum (VEGF-C and -D, and soluble (s) VEGFR1 and 3) biomarkers in phase 3 REGARD patients with metastatic gastric/gastroesophageal junction carcinoma.

Methods: A total of 152 out of 355 (43%) patients randomised to ramucirumab or placebo had ⩾1 evaluable biomarker result using VEGFR2 immunohistochemistry or HER2, immunohistochemistry or FISH, of blinded baseline tumour tissue samples. Serum samples (32 patients, 9%) were assayed for VEGF-C and -D, and sVEGFR1 and 3.

Results: None of the biomarkers tested were associated with ramucirumab efficacy at a level of statistical significance. High VEGFR2 endothelial expression was associated with a non-significant prognostic trend toward shorter progression-free survival (high vs low HR=1.65, 95% CI=0.84,3.23). Treatment with ramucirumab was associated with a trend toward improved survival in both high (HR=0.69, 95% CI=0.38, 1.22) and low (HR=0.73, 95% CI=0.42, 1.26) VEGFR2 subgroups. The benefit associated with ramucirumab did not appear to differ by tumoural HER2 expression.

Conclusions: REGARD exploratory analyses did not identify a strong potentially predictive biomarker of ramucirumab efficacy; however, statistical power was limited.
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http://dx.doi.org/10.1038/bjc.2016.293DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5061911PMC
October 2016

nab-Paclitaxel Plus Gemcitabine Versus Gemcitabine in Patients with Metastatic Pancreatic Adenocarcinoma: Canadian Subgroup Analysis of the Phase 3 MPACT Trial.

Adv Ther 2016 05 16;33(5):747-59. Epub 2016 Apr 16.

Celgene Corporation, Summit, NJ, USA.

Introduction: The phase III MPACT trial in patients with metastatic pancreatic cancer (MPC) demonstrated superior efficacy of nab-paclitaxel (nab-P) plus gemcitabine (Gem) compared with Gem monotherapy, including the primary endpoint of overall survival (OS; median 8.7 vs. 6.6 months; hazard ratio [HR] 0.72; P < 0.001). A significant treatment difference favoring nab-P + Gem over Gem was observed for OS in patients treated in North America. The majority of patients were from the US (88%) with only 12% from Canada. Healthcare systems and treatment patterns are different between the 2 countries, and there is limited published information on outcomes of Canadian patients treated with first-line nab-P + Gem. This analysis evaluated efficacy and safety outcomes in Canadian patients in the MPACT trial.

Methods: Treatment-naive patients with MPC (N = 861) received either nab-P 125 mg/m(2) + Gem 1000 mg/m(2) on days 1, 8, and 15 every 4 weeks or Gem 1000 mg/m(2) weekly for the first 7 of 8 weeks (cycle 1) and then on days 1, 8, and 15 every 4 weeks (cycle ≥2).

Results: The MPACT trial enrolled 63 patients in Canada. Baseline characteristics were well balanced and comparable with those of the intent-to-treat population. Both OS (median 11.9 vs. 7.1 months; HR 0.76; P = 0.373) and progression-free survival (median 7.2 vs. 5.2 months; HR 0.65; P = 0.224) were numerically longer and overall response rate (27% vs. 17%; P = 0.312) was numerically higher with nab-P + Gem vs. Gem. The most common grade ≥3 adverse events with nab-P + Gem vs. Gem were neutropenia (22% vs. 10%), fatigue (34% vs. 33%), and neuropathy (25% vs. 0%).

Conclusion: This subanalysis confirmed that nab-P + Gem is an efficacious treatment option and has a manageable safety profile in patients with MPC treated in Canada.

Trial Registration: ClinicalTrials.gov identifier, NCT00844649.

Funding: Celgene Corporation, Summit, NJ, USA.
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http://dx.doi.org/10.1007/s12325-016-0327-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4882352PMC
May 2016

Metastatic gastric cancer treatment: Second line and beyond.

World J Gastroenterol 2016 Mar;22(11):3069-77

Marwan Ghosn, Hampig Raphael Kourie, Hematology-Oncology Department, Faculty of Medicine, Saint Joseph University, Beirut 166830, Lebanon.

Advanced gastric cancer (aGC), not amenable to curative surgery, is still a burdensome illness tormenting afflicted patients and their healthcare providers. Whereas combination chemotherapy has been shown to improve survival and tumor related symptoms in the frontline setting, second-line therapy (SLT) is subject to much debate in the scientific community, mainly because of the debilitating effects of GC, which would impede the administration of cytotoxic therapy. Recent data has provided sufficient evidence for the safe use of SLT in patients with an adequate performance status. Taxanes, Irinotecan and even some Fluoropyrimidine analogs were found to provide a survival advantage in this subset of patients. Most importantly, quality of life measures were also improved through the use of adequate therapy. Even more pertinent were the findings involving antiangiogenic agents, which would add measurable improvements without significantly jeopardizing the patients' well-being. Further lines of therapy are cause for much more debate nowadays, but specific targeted agents have shown considerable promise in this context. We herein review noteworthy published data involving the use of additional lines of the therapy after failure of standard frontline therapies in patients with aGC.
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http://dx.doi.org/10.3748/wjg.v22.i11.3069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4789984PMC
March 2016

Anti-EGFR Therapy for Metastatic Colorectal Cancer in the Era of Extended RAS Gene Mutational Analysis.

BioDrugs 2016 Apr;30(2):95-104

Hematology-Oncology Division, Department of Hematology Oncology, Hôpital Notre Dame, Centre Hospitalier de l'Université de Montréal, 1560 Sherbrooke Street East, Montréal, QC, H2L 4M1, Canada.

Colorectal cancer (CRC) is one of the leading causes of cancer-related mortality worldwide. In the past 2 decades, advances in cancer therapeutics allowed for a remarkable improvement in terms of survival for patients with metastatic CRC. The advent of targeted therapy, coupled with more efficient chemotherapy regimens, was the pillar achievement that contributed to the success of CRC therapy. Cetuximab and panitumumab, monoclonal antibodies targeting the epidermal growth factor receptor pathway, are the focus of this review since their mechanism of action and efficiency are closely related to the mutational status of a predictive biomarker, the Kristen rat Sarcoma viral oncogene (KRAS). More recently, another biomarker, the neuroblastoma rat sarcoma viral oncogene (NRAS), was found to be as valuable for the refinement of this targeted therapy. The arguments for the use of extended analysis of the RAS gene are thoroughly reviewed because they directly affect the choice of targeted agents and potentially the choice of backbone chemotherapy.
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http://dx.doi.org/10.1007/s40259-016-0166-5DOI Listing
April 2016

Phase 2, randomized, open-label study of ramucirumab in combination with first-line pemetrexed and platinum chemotherapy in patients with nonsquamous, advanced/metastatic non-small cell lung cancer.

Cancer 2015 Mar 6;121(6):883-92. Epub 2014 Nov 6.

University of Colorado Anschutz Medical Campus, Aurora, Colorado.

Background: Vascular endothelial growth factor (VEGF)-mediated angiogenesis plays an important role in non-small cell lung cancer (NSCLC). Ramucirumab is a human immunoglobulin G1 monoclonal antibody that inhibits VEGF receptor 2. This phase 2 study investigated ramucirumab in combination with first-line pemetrexed and platinum chemotherapy in advanced/metastatic NSCLC.

Methods: Eligible stage IV nonsquamous NSCLC patients with no prior chemotherapy for metastatic disease were randomized 1:1 to pemetrexed and carboplatin (or cisplatin) or ramucirumab (10 mg/kg) plus pemetrexed and carboplatin (or cisplatin) once every 3 weeks. Treatment was given for 4 to 6 cycles, and this was followed by a maintenance phase with pemetrexed or ramucirumab and pemetrexed. The primary endpoint was progression-free survival (PFS) with a sample size of sufficient power to detect an increase from 7 to 10.4 months.

Results: From October 2010 to October 2011, 140 patients were randomized (pemetrexed-platinum arm, 71; ramucirumab-pemetrexed-platinum arm, 69), and most baseline characteristics were similar for the 2 treatment arms. The median PFS was 5.6 months for the pemetrexed-platinum arm and 7.2 months for the ramucirumab-pemetrexed-platinum arm (hazard ratio, 0.75; P = .132). The objective response rates were 38.0% and 49.3% for the pemetrexed-platinum and ramucirumab-pemetrexed-platinum arms, respectively (P = .180). The disease control rate was 70.4% for the pemetrexed-platinum arm and 85.5% for the ramucirumab-pemetrexed-platinum arm (P = .032). The grade 3 or higher adverse events occurring in 10% or more of patients were thrombocytopenia, neutropenia, fatigue, anemia, nausea, back pain, and hypertension.

Conclusions: The primary endpoint of significant prolongation of PFS was not met; however, ramucirumab showed evidence of clinical activity in combination with pemetrexed and platinum in nonsquamous NSCLC patients. The addition of ramucirumab to pemetrexed and platinum did not result in new or unexpected safety findings.
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http://dx.doi.org/10.1002/cncr.29132DOI Listing
March 2015

Mutations in NSCLC and their link with lung cancer-associated thrombosis: a case-control study.

Thromb Res 2014 Jan 6;133(1):48-51. Epub 2013 Nov 6.

Medical Oncologist/Hematologist, Hôpital Notre-Dame, Centre Hospitalier de l'Université de Montréal, Montreal, Quebec, Canada. Electronic address:

Introduction: The association of venous thromboembolic events (VTE) and lung cancer is highly prevalent. Additionally, the occurrence of a VTE with cancer has been associated with a worse prognosis and a poor quality of life. Underlying cancer biological features such as tumour mutations may contribute to VTE risk and cancer prognosis. Since preclinical data suggest a link between thrombosis and KRAS mutations in tumours, we aimed to validate this association in a patient registry cohort.

Methods: A retrospective case control study was performed using the CHUM NSCLC registry. Cases had VTE occurring 6months previous to or after a diagnosis of NSCLC. Diagnosis of VTE (venous thrombosis, pulmonary embolism, and migratory superficial thrombophlebitis) was confirmed by a review of the imaging reports. Controls were patients with NSCLC without thrombosis matched for age and stage (I-IIIA/IIIB-IV). Exclusion criteria included insufficient tissue for KRAS/EGFR mutation analysis or insufficient clinical information.

Results: Between Jan 2000 and Dec 2009 a total of 57 cases with VTE and 102 controls without VTE were included. The OR for thrombosis in KRAS and EGFR mutated NSCLC patients are respectively 2.67 (1.12-6.42; p=0.014) and 0.99 (0.27-3.48; p=0.99).

Conclusions: KRAS mutation is associated with an increased risk of VTE in this NSCLC cohort. These findings are consistent with preclinical studies. Prospective data on VTE rates from clinical trials with molecularly defined NSCLC are needed to confirm these findings.
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http://dx.doi.org/10.1016/j.thromres.2013.10.042DOI Listing
January 2014

Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial.

Lancet 2014 Jan 3;383(9911):31-39. Epub 2013 Oct 3.

Medical Oncology Department Vall d'Hebron University Hospital, UniversitatAutònoma de Barcelona, Barcelona, Spain.

Background: Vascular endothelial growth factor (VEGF) and VEGF receptor-2 (VEGFR-2)-mediated signalling and angiogenesis can contribute to the pathogenesis and progression of gastric cancer. We aimed to assess whether ramucirumab, a monoclonal antibody VEGFR-2 antagonist, prolonged survival in patients with advanced gastric cancer.

Methods: We did an international, randomised, double-blind, placebo-controlled, phase 3 trial between Oct 6, 2009, and Jan 26, 2012, at 119 centres in 29 countries in North America, Central and South America, Europe, Asia, Australia, and Africa. Patients aged 24-87 years with advanced gastric or gastro-oesophageal junction adenocarcinoma and disease progression after first-line platinum-containing or fluoropyrimidine-containing chemotherapy were randomly assigned (2:1), via a central interactive voice-response system, to receive best supportive care plus either ramucirumab 8 mg/kg or placebo, intravenously once every 2 weeks. The study sponsor, participants, and investigators were masked to treatment assignment. The primary endpoint was overall survival. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00917384.

Findings: 355 patients were assigned to receive ramucirumab (n=238) or placebo (n=117). Median overall survival was 5·2 months (IQR 2·3-9·9) in patients in the ramucirumab group and 3·8 months (1·7-7·1) in those in the placebo group (hazard ratio [HR] 0·776, 95% CI 0·603-0·998; p=0·047). The survival benefit with ramucirumab remained unchanged after multivariable adjustment for other prognostic factors (multivariable HR 0·774, 0·605-0·991; p=0·042). Rates of hypertension were higher in the ramucirumab group than in the placebo group (38 [16%] vs nine [8%]), whereas rates of other adverse events were mostly similar between groups (223 [94%] vs 101 [88%]). Five (2%) deaths in the ramucirumab group and two (2%) in the placebo group were considered to be related to study drug.

Interpretation: Ramucirumab is the first biological treatment given as a single drug that has survival benefits in patients with advanced gastric or gastro-oesophageal junction adenocarcinoma progressing after first-line chemotherapy. Our findings validate VEGFR-2 signalling as an important therapeutic target in advanced gastric cancer.

Funding: ImClone Systems.
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http://dx.doi.org/10.1016/S0140-6736(13)61719-5DOI Listing
January 2014

Response to Bernardi and colleagues.

Authors:
Mustapha Tehfe

Curr Oncol 2013 Jun;20(3):e279

Department of Hemato-Oncology, Centre Hospitalier de l'Université de Montréal, Montreal, QC,

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http://dx.doi.org/10.3747/co.20.1374DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3671037PMC
June 2013