Jérôme Fayette

Prospective Multicentric Randomized Phase III Study of Imatinib in Patients With Advanced Gastrointestinal Stromal Tumors Comparing Interruption Versus Continuation of Treatment Beyond 1 Year: The French Sarcoma Group

PURPOSE Imatinib is the standard treatment of advanced GI stromal tumors (GISTs). It is not known whether imatinib may be stopped in patients in whom disease is controlled. METHODS This prospective, randomized, multicentric phase III study was designed to compare continuous (CONT) compared with interrupted (INT) imatinib beyond 1 year of treatment in patients with advanced GIST. The primary end point was progression-free survival. Secondary end points included overall survival, response rate after reinitiation of imatinib, and quality of life. Early stopping rules in cases of rapid progression of disease were defined, with preplanned interim analyses. RESULTS Between May 2002 and April 2004, 182 patients with advanced GIST were enrolled. Between May 2003 and April 2004, 98 patients in response or stable disease under imatinib reached more than 1 year of follow-up. Forty were not eligible for randomization, and 58 patients were randomly assigned, 32 and 26 patients in the INT and CONT arms, respectively. As of October 15, 2005, eight of 26 patients in the CONT group and 26 of 32 patients in the INT group had documented disease progression (P < .0001). Twenty-four of 26 patients with documented progression in the INT arm responded to imatinib reintroduction. No differences in overall survival or imatinib resistance were observed between the two arms. Quality of life evaluated 6 months after random assignment using the 30-item Quality of Life Questionnaire was not significantly different between the two groups of randomly assigned patients. CONCLUSION Imatinib interruption results in rapid progression in most patients with advanced GIST, and cannot be recommended in routine practice unless patient experience significant toxicity

Afatinib versus methotrexate as second-line treatment in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck progressing on or after platinum-based therapy (LUX-Head & Neck 1): an open-label, randomised phase 3 trial

BACKGROUND Patients with recurrent or metastatic squamous-cell carcinoma of the head and neck (HNSCC) progressing after first-line platinum regimens have a poor prognosis and few treatment options. Afatinib, an irreversible ERBB family blocker, has shown efficacy in a phase 2 study in this setting. We aimed to assess the efficacy and safety of afatinib compared with methotrexate as second-line treatment in patients with recurrent or metastatic HNSCC progressing on or after platinum-based therapy. METHODS In this open-label, phase 3, randomised controlled trial conducted in 101 centres in 19 countries, we enrolled patients aged 18 years or older with histologically or cytologically confirmed HNSCC that was recurrent, metastatic, or both who had progressed on or after first-line platinum-based therapy, were not amenable for salvage surgery or radiotherapy, and who had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Previous treatment with more than one systemic regimen in this setting was not allowed; previous treatment with EGFR-targeted antibody therapy (but not EGFR-targeted tyrosine-kinase inhibitors) was allowed. We randomly assigned eligible patients in a 2:1 ratio to receive oral afatinib (40 mg/day) or intravenous methotrexate (40 mg/m(2) per week), stratified by ECOG performance status and previous EGFR-targeted antibody therapy for recurrent or metastatic disease. Randomisation was done centrally with an interactive voice or web-based response system. Clinicians and patients were not masked to treatment allocation; independent review of tumour response was done in a blinded manner. The primary endpoint was progression-free survival as assessed by an independent, central imaging review committee. Efficacy analyses were done in the intention-to-treat population and safety analyses were done in patients who received at least one dose of study drug. This ongoing study is registered with ClinicalTrials.gov, number NCT01345682. FINDINGS Between Jan 10, 2012, and Dec 12, 2013, we enrolled 483 patients and randomly assigned 322 to afatinib and 161 to methotrexate. After a median follow-up of 6·7 months (IQR 3·1-9·0), progression-free survival was longer in the afatinib group than in the methotrexate group (median 2·6 months [95% CI 2·0-2·7] for the afatinib group vs 1·7 months [1·5-2·4] for the methotrexate group; hazard ratio [HR] 0·80 [95% CI 0·65-0·98], p=0·030). The most frequent grade 3 or 4 drug-related adverse events were rash or acne (31 [10%] of 320 patients in the afatinib group vs none of 160 patients in the methotrexate group), diarrhoea (30 [9%] vs three [2%]), stomatitis (20 [6%] vs 13 [8%]), fatigue (18 [6%] vs five [3%]), and neutropenia (1 [<1%] vs 11 [7%]); serious adverse events occurred in 44 (14%) of afatinib-treated patients and 18 (11%) of methotrexate-treated patients. INTERPRETATION Afatinib was associated with significant improvements in progression-free survival and had a manageable safety profile. These findings provide important new insights into the treatment of this patient population and support further investigations with irreversible ERBB family blockers in HNSCC. FUNDING Boehringer Ingelheim.

Docetaxel and gemcitabine combination in 133 advanced soft-tissue sarcomas: A retrospective analysis

Advanced soft‐tissue sarcomas are usually resistant to cytotoxic agents such as doxorubicin and ifosfamide. Antitumor activity has been observed for gemcitabine and docetaxel combination. We conducted a retrospective study on 133 patients (58 males/75 females) with unresectable or metastatic soft‐tissue sarcoma. The median age at diagnosis was 51.7 (18–82), with 76 patients with leiomoyosarcoma and 57 patients with other histological subtypes. The initial localizations were limb (44), uterine (32), retroperitoneal (23) and organs or bone (34). Patients received 900 mg/m2 of gemcitabine (days 1 and 8) over 90 min plus 100 mg/m2 of docetaxel (day 8), intravenously every 21 days. Gemcitabine/docetaxel combination was well tolerated with an overall response of 18.4% and with no clear statistical difference between leiomyosarcomas and other histological subtypes (24.2% versus 10.4% (p = 0.06)). No difference was found between uterine soft‐tissue sarcomas versus others. The median overall survival was 12.1 months (1–28). Better overall survival was correlated with leiomyosarcoma (p = 0.01) and with the quality of the response, even for patients with stable disease (p < 10−4). No statistical difference was found for the initial localization. Response to treatment and overall survival were better for patients in World Health Organization (WHO) performance status classification (PS) 0 at baseline versus patients in WHO PS‐1, 2 or 3 (p = 0.023 and p < 10−4, respectively). Gemcitabine/docetaxel combination was tolerable and demonstrated better response and survival for leiomyosarcoma, especially for patients in WHO PS‐0 at baseline. For the other histological subtypes, the response was not encouraging, but the survival for patients in response or stable suggests further investigation.

Phase III, randomized trial (CheckMate 057) of nivolumab (NIVO) versus docetaxel (DOC) in advanced non-squamous cell (non-SQ) non-small cell lung cancer (NSCLC).

LBA109 Background: Options for advanced non-SQ NSCLC patients (pts) who progress after platinum-based doublet chemotherapy (PT-DC) are limited, with minimal improvement in overall survival (OS). We report results from a randomized, global phase III study of NIVO, a fully human IgG4 programmed death-1 (PD-1) immune checkpoint inhibitor antibody, vs DOC in pts with advanced non-SQ NSCLC after failure of PT-DC and tyrosine kinase inhibitor, if eligible. METHODS Pts were randomized to NIVO 3 mg/kg Q2W (n=292) or DOC 75 mg/m2 Q3W (n=290) until progression or discontinuation due to toxicity/other reasons. Primary objective was OS; Secondary objectives were investigator-assessed objective response rate (ORR; per RECIST v1.1), progression-free survival (PFS), efficacy by PD-L1 expression, quality of life, and safety. RESULTS NIVO demonstrated superior OS (HR=0.73; 96% CI: 0.59, 0.89; P=0.00155) and improved ORR (19.2% vs 12.4%; P=0.0235). HR for PFS was 0.92 (95% CI: 0.77, 1.11; P=0.393). PD-L1 expression was associated with benefit from NIVO (Table). In PD-L1+ pts, NIVO showed improved efficacy across all endpoints at predefined 1%, 5%, and 10% cut- points. Grade 3-5 drug-related AEs occurred in 10.5% (30/287) of NIVO and 53.7% (144/268) of DOC pts. No deaths were related to NIVO vs 1 DOC-related death. After discontinuation, 42.1% of NIVO and 49.7% of DOC pts received subsequent systemic therapy. CONCLUSIONS NIVO demonstrated superior OS vs DOC in pts with advanced non-SQ NSCLC after failure of PT-DC. The safety profile of NIVO 3 mg/kg Q2W was favorable vs DOC. NIVO demonstrated survival benefit across histologies in two randomized phase III trials. CLINICAL TRIAL INFORMATION NCT01673867. [Table: see text].

A randomized, phase II study of afatinib versus cetuximab in metastatic or recurrent squamous cell carcinoma of the head and neck.

BACKGROUND Afatinib is an oral, irreversible ErbB family blocker that has shown activity in epidermal growth factor receptor (EGFR)-mutated lung cancer. We hypothesized that the agent would have greater antitumor activity compared with cetuximab in recurrent or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) patients, whose disease has progressed after platinum-containing therapy. PATIENTS AND METHODS An open-label, randomized, phase II trial was conducted in 43 centers; 124 patients were randomized (1 : 1) to either afatinib (50mg/day) or cetuximab (250mg/m2/week) until disease progression or intolerable adverse events (AEs) (stage I), with optional crossover (stage II). The primary end point was tumor shrinkage before crossover assessed by investigator (IR) and independent central review (ICR). RESULTS A total of 121 patients were treated (61 afatinib, 60 cetuximab) and 68 crossed over to stage II (32 and 36 respectively). In stage I, mean tumor shrinkage by IR/ICR was 10.4%/16.6% with afatinib and 5.4%/10.1% with cetuximab (P = 0.46/0.30). Objective response rate was 16.1%/8.1% with afatinib and 6.5%/9.7% with cetuximab (IR/ICR). Comparable disease control rates were observed with afatinib (50%) and cetuximab (56.5%) by IR; similar results were seen by ICR. Most common grade ≥3 drug-related AEs (DRAEs) were rash/acne (18% versus 8.3%), diarrhea (14.8% versus 0%), and stomatitis/mucositis (11.5% versus 0%) with afatinib and cetuximab, respectively. Patients with DRAEs leading to treatment discontinuation were 23% with afatinib and 5% with cetuximab. In stage II, disease control rate (IR/ICR) was 38.9%/33.3% with afatinib and 18.8%/18.8% with cetuximab. CONCLUSION Afatinib showed antitumor activity comparable to cetuximab in R/M HNSCC in this exploratory phase II trial, although more patients on afatinib discontinued treatment due to AEs. Sequential EGFR/ErbB treatment with afatinib and cetuximab provided sustained clinical benefit in patients after crossover, suggesting a lack of cross-resistance.Afatinib, an oral irreversible ErbB family blocker, showed comparable activity to cetuximab in patients with recurrent/metastatic head and neck squamous cell carcinoma in this phase II trial. Further, sequential EGFR/ErbB treatment provided sustained clinical benefit in some patients, suggesting a lack of cross-resistance.

Neoadjuvant imatinib in patients with locally advanced non metastatic GIST in the prospective BFR14 trial

BackgroundThe role of surgery in the management of patients with advanced gastrointestinal stromal tumors (GIST) in the era of imatinib mesylate (IM) remains debated. We analyzed the outcome of patients with non metastatic locally advanced primary GIST treated with IM within the prospective BFR14 phase III trial.MethodsThe database of the BFR14 trial was searched for patients with no metastasis at time of inclusion. Patients treated for recurrent disease were excluded. Twenty-five of 434 patients met these criteria.ResultsFifteen of 25 patients (60%) had a partial response to IM. Nine of the 25 patients (36%) underwent surgical resection of their primary tumor after a median of 7.3 months of IM treatment (range 3.4-12.0). Per protocol patients received continuous IM treatment in the post resection period, in an adjuvant setting. With a median follow-up of 53.5 months, there was a significant improvement in progression-free survival (PFS) and overall survival (OS) for patients who underwent surgical resection versus those who did not (median not reached vs 23.6 months, p = 0.0318 for PFS and median not reached vs 42.2 months, p = 0.0217 for OS). In the group of patients who underwent resection followed by IM, the 3-year PFS and OS rates were 67% and 89% respectivelyConclusionsFollowing neoadjuvant IM for non metastatic locally advanced GIST 9 of 25 patients (36%) were selected for resection of the primary tumor. OS and PFS figures were close to those of localised intermediate or high risk GIST (70% at 5 years) in the subgroup of operated patients, while the outcome of the non-operated subgroup was similar to that of metastatic GIST.

Randomised Phase II study of oral lapatinib combined with chemoradiotherapy in patients with advanced squamous cell carcinoma of the head and neck: Rationale for future randomised trials in human papilloma virus-negative disease

BACKGROUND This randomised Phase II study assessed the activity and safety of concurrent chemoradiotherapy (CRT) and lapatinib followed by maintenance treatment in locally advanced, unresected stage III/IVA/IVB head and neck cancer. PATIENTS AND METHODS Patients were randomised 1:1 to concurrent CRT and placebo followed by placebo or concurrent CRT and lapatinib followed by lapatinib. Treatment continued until disease progression or study withdrawal. Primary end-point was complete response rate (CRR) by independent review 6 months post-CRT. RESULTS Sixty-seven patients (median age 56 years; 97% Eastern Cooperative Oncology Group performance status ≤1; 82% stage IV) were recruited. CRT dose intensities were unaffected by lapatinib: median radiation dose 70 Gy (lapatinib, placebo), duration 49 (lapatinib) and 50 days (placebo); median cisplatin dose 260 mg/m(2) (lapatinib) and 280 mg/m(2) (placebo). Lapatinib combined with CRT was well-tolerated. Grade 3/4 toxicities during CRT were balanced between arms, with the exception of an excess of grade 3 diarrhoea (6% versus 0%) and rash (9% versus 3%) and two grade 4 cardiac events in the lapatinib arm. CRR at 6 months post-CRT was 53% with lapatinib versus 36% with placebo in the intent-to-treat population. The progression-free survival (PFS) and overall survival rates at 18 months were 55% versus 41% and 68% versus 57% for the lapatinib and placebo arms, respectively. The difference between study arms was greatest in p16-negative disease (median PFS >20.4 months [lapatinib] versus 10.9 [placebo]). CONCLUSION Lapatinib combined with CRT is well-tolerated with numeric increases in CRR at 6 months post-CRT and median PFS in p16-negative disease.

ET-743: a novel agent with activity in soft-tissue sarcomas.

Purpose of review ET-743 (ecteinascidin-743, trabectedin, Yondelis) is a natural marine product that has shown clinical activity in sarcoma. This paper reviews the current knowledge on this compound. Recent findings ET-743 interferes with several transcription factors, traps protein from the nucleotide-excision repair system, thus resulting in DNA damage, modulates gene expression, and blocks cells in the G2–M phase. In the clinical setting, after failure of standard treatment, ET-743 at 1.5 mg/m2 in 24 h continuous infusion every 21 days yielded an overall response rate close to 8% and stabilization rates of 30–40%, some lasting beyond 3 years. Leiomyosarcomas, liposarcomas, and synovial sarcomas may be the more sensitive histotypes. The major toxicities of ET-743 are hepatic – through biliary duct destruction – and hematologic. They are not cumulative and a significant number of patients may receive 12 courses or more. In a randomized Phase II study testing weekly ET-743 with treatment every 3 weeks, an improved progression-free survival rate was observed in the 3-weekly arm; the results of the follow-up Phase III trial should be available at the American Society of Clinical Oncology meeting of 2006. Phase I combination studies are in currently progress. Summary ET-743 is a novel active drug for sarcoma which yields prolonged disease-free survival in subsets of patients.

Bevacizumab and paclitaxel for breast cancer patients with central nervous system metastases: a case series.

Central nervous system (CNS) metastases are a major concern in patients with stage IV breast cancer. Recent studies have shown the efficacy of anti-vascular endothelial growth factor drugs on brain tumors, in particular glioblastoma, but none has explored their efficacy and tolerance in breast cancer patients with CNS metastases. We report 4 cases of patients with CNS metastases treated with bevacizumab and paclitaxel. All but 1 had previous whole-brain radiation therapy, performance status 0-2, and radiographic evidence of progressive CNS metastases. Patients received paclitaxel 80 mg/m2 on days 1, 8, and 15, and bevacizumab 10 mg/kg on days 1 and 15. Response was evaluated according to the World Health Organization criteria. Three patients had brain metastases, and 1 had meningeal lesions. Only 1 patient was chemotherapy-naive. Significant antitumor activity was observed, with 1 complete response and 3 partial responses in the CNS metastases. With a mean follow-up of 9 months, duration of response was 11, 10, 8, and 6 months. No patient had extra-CNS progression. This observed antitumor activity suggests efficiency of the combination of bevacizumab and paclitaxel and warrants further evaluation of this combination as an alternative option for the treatment of multiple CNS metastases in breast cancer.

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

Background Pembrolizumab 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). Patients and methods We 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. Results From 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%, P = 0.008), but not with local or distant recurrence. Hyperprogression was associated with a shorter progression-free survival (PFS) according to RECIST (P = 0.003) and irRECIST (P = 0.02), but not with overall survival (P = 0.77). Conclusions Hyperprogression 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.