Cetuximab, docetaxel, and cisplatin versus platinum, fluorouracil, and cetuximab as first-line treatment in patients with recurrent or metastatic head and neck squamous-cell carcinoma (GORTEC 2014-01 TPExtreme): a multicentre, open-label, randomised, phase 2 trial.

BACKGROUND: Results from a phase 2 trial of the TPEx chemotherapy regimen (docetaxel-platinum-cetuximab) showed promising results, with a median overall survival of 14·0 months in first-line recurrent or metastatic head and neck squamous-cell carcinoma (HNSCC). We therefore aimed to compare the efficacy and safety of the TPEx regimen with the standard of care EXTREME regimen (platinum-fluorouracil-cetuximab) in this setting. METHODS: This was a multicentre, open-label, randomised, phase 2 trial, done in 68 centres (cancer centres, university and general hospitals, and private clinics) in France, Spain, and Germany. Eligible patients were aged 18-70 years with histologically confirmed recurrent or metastatic HNSCC unsuitable for curative treatment; had at least one measurable lesion according to Response Evaluation Criteria in Solid Tumors version 1.1; and had an Eastern Cooperative Oncology Group (ECOG) performance status of 1 or less. Participants were randomly assigned (1:1) using the TenAlea website by investigators or delegated clinical research associates to the TPEx regimen or the EXTREME regimen, with minimisation by ECOG performance status, type of disease evolution, previous cetuximab treatment, and country. The TPEx regimen consisted of docetaxel 75 mg/m2 and cisplatin 75 mg/m2, both intravenously on day 1, and cetuximab on days 1, 8, and 15 (intravenously 400 mg/m2 on day 1 of cycle 1 and 250 mg/m2 weekly subsequently). Four cycles were repeated every 21 days with systematic granulocyte colony-stimulating factor (G-CSF) support at each cycle. In case of disease control after four cycles, intravenous cetuximab 500 mg/m2 was continued every 2 weeks as maintenance therapy until progression or unacceptable toxicity. The EXTREME regimen consisted of fluorouracil 4000 mg/m2 on day 1-4, cisplatin 100 mg/m2 on day 1, and cetuximab on days 1, 8, and 15 (400 mg/m2 on day 1 of cycle 1 and 250 mg/m2 weekly subsequently) all delivered intravenously. Six cycles were delivered every 21 days followed by weekly 250 mg/m2 cetuximab as maintenance therapy in case of disease control. G-CSF support was not mandatory per the protocol in the EXTREME regimen. The primary endpoint was overall survival in the intention-to-treat population; safety was analysed in all patients who received at least one dose of chemotherapy or cetuximab. Enrolment is closed and this is the final analysis. This study is registered at ClinicalTrials.gov, NCT02268695. FINDINGS: Between Oct 10, 2014, and Nov 29, 2017, 541 patients were enrolled and randomly assigned to the two treatment regimens (271 to TPEx, 270 to EXTREME). Two patients in the TPEx group had major deviations in consent forms and were not included in the final analysis. Median follow-up was 34·4 months (IQR 26·6-44·8) in the TPEx group and 30·2 months (25·5-45·3) in the EXTREME group. At data cutoff, 209 patients had died in the TPEx group and 218 had died in the EXTREME group. Overall survival did not differ significantly between the groups (median 14·5 months [95% CI 12·5-15·7] in the TPEx group and 13·4 months [12·2-15·4] in the EXTREME group; hazard ratio 0·89 [95% CI 0·74-1·08]; p=0·23). 214 (81%) of 263 patients in the TPEx group versus 246 (93%) of 265 patients in the EXTREME group had grade 3 or worse adverse events during chemotherapy (p<0·0001). In the TPEx group, 118 (45%) of 263 patients had at least one serious adverse event versus 143 (54%) of 265 patients in the EXTREME group. 16 patients in the TPEx group and 21 in the EXTREME group died in association with adverse events, including seven patients in each group who had fatal infections (including febrile neutropenia). Eight deaths in the TPEx group and 11 deaths in the EXTREME group were assessed as treatment related, most frequently sepsis or septic shock (four in each treatment group). INTERPRETATION: Although the trial did not meet its primary endpoint, with no significant improvement in overall survival with TPEx versus EXTREME, the TPEx regimen had a favourable safety profile. The TPEx regimen could provide an alternative to standard of care with the EXTREME regimen in the first-line treatment of patients with recurrent or metastatic HNSCC, especially for those who might not be good candidates for up-front pembrolizumab treatment. FUNDING: Merck Santé and Chugai Pharma.

Results of API-AI based regimen in osteosarcoma adult patients included in the French OS2006/Sarcome-09 study.

In the OS2006 study, patients younger than 18 years were treated with a methotrexate-based regimen (MTX), patients older than 25 years with a doxorubicin-cisplatin-ifosfamide-based regimen (API-AI), whereas patients aged 18-25 years received either API-AI or MTX. We herein report the prespecified subgroup analysis of the outcome of 106 patients treated with API-AI. Preoperative chemotherapy combined three doxorubicin-ifosfamide-cisplatin (API) and two doxorubicin-ifosfamide (AI) courses. Postoperative chemotherapy was assigned by risk group: localised patients with a good histological response (<10% viable cells) received two AI and two cisplatin-ifosfamide (PI) courses; patients with synchronous metastases, poor histological response or unresectable primary received five cycles of etoposide-ifosfamide (EI). Of the 106 patients, 61 were randomised to receive or not zoledronate. Median age was 30 years (range 18-67), 66 (62%) patients were >25 years. The primary tumours were axial in 28 patients (26%), and 28 (26%) presented with metastases. Ninety-six patients (91%) had surgery, conservative in 82 (85%); 36 patients (38%, 95% CI 28-48%) were good responders. Toxicity was manageable, with no significant difference in severe acute toxicity between patients aged >25 years and those younger. With a median follow-up of 4.8 years, the 5-year event-free survival and overall survival rates were 46% (95% CI 36-56) and 57% (95% CI 47-67), respectively. The primary tumour size and initial metastases correlated with a higher risk of event. In these 106 osteosarcoma adult patients, API-AI proved feasible with no excess of toxicity, and favourable activity despite poor-prognosis factors.

Circulating Tumor Cells as a Prognostic Factor in Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma: The CIRCUTEC Prospective Study.

BACKGROUND: This prospective multicenter study evaluated the prognostic value of circulating tumor cells (CTCs) in relapsing nonoperable or metastatic head and neck squamous cell carcinoma (rHNSCC) treated by chemotherapy and cetuximab. METHODS: In 65 patients suitable for analyses, peripheral blood was taken at day 0 (D0) D7, and D21 of treatment for CTC detection by CellSearch®, EPISPOT, and flow cytometry (FCM). Progression-free survival (PFS) was assessed with the Kaplan-Meier method and compared with the log-rank test (P < 0.05). RESULTS: At D0, CTCs were detected with EPISPOT, CellSearch, and FCM in 69% (45/65), 21% (12/58), and 11% (7/61) of patients, respectively. In the patients tested with all 3 methods, EPISPOT identified 92% (36/39), 92% (35/38), and 90% (25/28) of all positive samples at D0, D7, and D21, respectively. Median PFS time was significantly lower in (a) patients with increasing or stable CTC counts (36/54) from D0 to D7 with EPISPOTEGFR (3.9 vs 6.2 months; 95% CI, 5.0-6.9; P = 0.0103) and (b) patients with ≥1 CTC detected with EPISPOT or CellSearch® (37/51) (P = 0.0311), EPISPOT or FCM (38/54) (P = 0.0480), and CellSearch or FCM (11/51) (P = 0.0005) at D7. CONCLUSIONS: CTCs can be detected before and during chemotherapy in patients with rHNSCC. D0-D7 CTC kinetics evaluated with EPISPOTEGFR are associated with the response to treatment. This study indicates that CTCs can be used as a real-time liquid biopsy to monitor the early response to chemotherapy in rHNSCC. CLINICALTRIALSGOV IDENTIFIER: NCT02119559.

Cetuximab pharmacokinetic/pharmacodynamics relationships in advanced head and neck carcinoma patients.

AIMS: Cetuximab associated with cisplatin and 5-fluorouracil is used to treat patients with inoperable or metastatic head and neck squamous cell carcinomas (HNSCC) up until disease progression or unacceptable toxicities. To date, no biomarkers of efficacy are available to select patients who will benefit from treatment. METHODS: An ancillary pharmacokinetics (PK) exploration was performed in the context of a prospective study investigating circulating-tumour cells vs progression-free survival (PFS). Cetuximab plasma concentrations were analysed according to a population PK model. Individual exposure parameters were confronted with soluble epidermal growth factor receptor (sEGFR) concentrations, tumour response and PFS. RESULTS: PK data (28 patients, 203 observations) were best described by a two-compartment model with linear elimination. Performance status (PS) significantly correlated to both cetuximab clearance and central volume of distribution with both parameters increasing by 33.3% (95% CI 1-65.6) for each 1-point increase of PS compared to PS = 0. Univariate analysis showed that patients with higher trough cetuximab concentrations at Day 7 (Cmin,D7 ) had better tumour response (P = 0.03) and longer PFS (P = 0.035). However, multivariate analysis revealed that only PS and tumour size at baseline remained significantly associated with PFS. Levels of sEGFR increased during cetuximab treatment but were not associated with PFS in the multivariate analysis. CONCLUSIONS: Our study prospectively indicates that PS is likely a confounding factor in the relationship between cetuximab PK and PFS, patients with a poor PS having lower cetuximab plasma exposure and lower PFS.

Safety and efficacy of regorafenib in patients with advanced soft tissue sarcoma (REGOSARC): a randomised, double-blind, placebo-controlled, phase 2 trial.

BACKGROUND: Regorafenib is a multikinase inhibitor with proven activity in refractory gastrointestinal stromal tumours and chemotherapy-refractory advanced colorectal cancers. We assessed this agent's efficacy and safety in patients with metastatic soft tissue sarcomas previously treated with anthracycline. METHODS: In this randomised, double-blind, phase 2 trial undertaken in France and Austria, we enrolled patients aged 18 years and older with advanced soft tissue sarcomas who had received previous doxorubicin or other anthracycline treatment. These patients were randomly assigned (1:1) into one of the following four cohorts: liposarcoma, leiomyosarcoma, synovial sarcoma, and other sarcomas. Participants were treated with oral regorafenib (160 mg per day 3 weeks on and 1 week off) or matched placebo. Patients receiving placebo were offered optional crossover in case of centrally confirmed disease progression. The random allocation schedule was computer-generated with permuted blocks of four patients, with two stratification factors: country (France or Austria) and previous exposure to pazopanib (yes or no). Eligibility criteria included patients with histologically proven advanced and inoperable soft tissue sarcomas with intolerance or failure to doxorubicin or other anthracycline-based chemotherapy and at least one unidimensionally or bidimensionally measurable lesion according to Response Evaluation Criteria in Solid Tumors (RECIST; version 1.1). The primary endpoint was RECIST-based progression-free survival after central radiological review in the intention-to-treat population. Patients, physicians, and radiologists of the panel were masked to treatment allocation. This study is still open for recruitment for an additional stratum (patients previously treated with pazopanib) and registered with ClinicalTrials.gov, NCT01900743. FINDINGS: From Aug 5, 2013, to Nov 26, 2014, 182 patients were randomly assigned to one of four cohorts and included in the final analysis. At the cutoff date (Jan 7, 2016), the number of required events was reached for the four cohorts. In the liposarcoma cohort, progression-free survival was 1·1 months (95% CI 0·9-2·3) with regorafenib versus 1·7 months (0·9-1·8) with placebo (HR 0·89 [95% CI 0·48-1·64] p=0·70). In the leiomyosarcoma cohort, progression-free survival was 3·7 months (95% CI 2·5-5·0) with regorafenib versus 1·8 (1·0-2·8) months with placebo (HR 0·46 [95% CI 0·46-0·80] p=0·0045). In the synovial sarcoma cohort, progression-free survival was 5·6 months (95% CI 1·4-11·6) with regorafenib versus 1·0 (0·8-1·4) with placebo (HR 0·10 [95% CI 0·03-0·35] p<0·0001). In the other sarcoma cohort, progression-free survival was 2·9 months (95% CI 1·0-7·8) with regorafenib versus 1·0 (0·9-1·9) with placebo (HR 0·46 [95% CI 0·25-0·81] p=0·0061). Before crossover, the most common clinically significant grade 3 or higher adverse events were arterial hypertension (17 [19%] events in the 89 patients in the regorafenib group vs two [2%] events in the 92 patients in the placebo group), hand and foot skin reaction (14 [15%] vs no events) and asthenia (12 [13%] vs six [6%]). One treatment-related death occurred in the regorafenib group due to liver failure. INTERPRETATION: Regorafenib has an important clinical antitumour effect in non-adipocytic soft tissue sarcomas, improving progression-free survival. Regorafenib should be further evaluated in this setting, and its therapeutic role has to be defined in the context of the growing therapeutic armamentarium, already including one approved multikinase inhibitor, pazopanib. FUNDING: Bayer HealthCare.

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.

Ombrabulin plus cisplatin versus placebo plus cisplatin in patients with advanced soft-tissue sarcomas after failure of anthracycline and ifosfamide chemotherapy: a randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: Ombrabulin (AVE8062) disrupts the vasculature of established tumours and has shown preclinical synergistic anti-tumour activity when combined with cisplatin. In this phase 3 trial, we aimed to assess the efficacy and safety of ombrabulin plus cisplatin compared with placebo plus cisplatin in patients with advanced soft-tissue sarcomas. METHODS: We did this multinational, randomised, double-blind, placebo-controlled phase 3 study at 44 centres in ten countries. Patients aged 18 years and older with metastatic soft-tissue sarcomas, an Eastern Cooperative Oncology Group performance status of 0-2, and who had previously received treatment with anthracycline and ifosfamide were randomly assigned (1:1) to intravenous infusion of ombrabulin 25 mg/m(2) plus cisplatin 75 mg/m(2) or intravenous infusion of placebo plus cisplatin 75 mg/m(2) every 3 weeks. Patients were allocated to treatment using a permuted blocks randomisation scheme (block size of four) via an interactive voice-response system, and stratified by histological subtype. Patients, medical staff, study investigators, and individuals who handled and analysed the data were masked to treatment assignment. Our primary endpoint was median progression-free survival in the intention-to-treat population. Safety analyses were done on all randomised patients who received at least one dose of study drug. This trial is now closed, and is registered with ClinicalTrials.gov, number NCT00699517. FINDINGS: Between June 13, 2008, and April 26, 2012, we randomly assigned 355 patients to ombrabulin plus cisplatin (n=176) or placebo plus cisplatin (n=179). Median duration of follow-up was 27·9 (IQR 20·9-33·2) in the placebo group and 30·5 months (20·7-37·6) in the ombrabulin group. Progression-free survival was slightly, but significantly, improved in the ombrabulin group compared with the placebo group (median 1·54 months [95% CI 1·45-2·69] vs 1·41 [1·38-1·58] months; hazard ratio 0·76 [95% CI 0·59-0·98]; p=0·0302). Grade 3 or 4 adverse events occurred more frequently in individuals in the ombrabulin group than in those in the placebo group and included neutropenia (34 [19%] in the ombrabulin group vs 14 [8%] in the placebo group) and thrombocytopenia (15 [8%] vs six [3%] for placebo). Adverse events leading to death occurred in 18 patients in the ombrabulin group and 10 patients in the placebo group. INTERPRETATION: The combination of ombrabulin and cisplatin significantly improved progression-free survival; however, it did not show a sufficient clinical benefit in patients with advanced soft-tissue sarcomas to support its use as a therapeutic option. Predictive biomarkers are needed for the rational clinical development of tumour vascular-disrupting drugs for soft-tissue sarcomas. FUNDING: Sanofi.

Trabectedin in combination with doxorubicin for first-line treatment of advanced uterine or soft-tissue leiomyosarcoma (LMS-02): a non-randomised, multicentre, phase 2 trial.

BACKGROUND: Metastatic leiomyosarcomas of uterine or soft-tissue origin have poor prognosis and moderate chemosensitivity. Trabectedin has shown activity in pretreated leiomyosarcoma. We did a single-group, multicentre, phase 2 trial (LMS-02) to assess the effect of first-line doxorubicin and trabectedin combination on disease control and survival. METHODS: Adults (18 years to physiological age ≤70 years) with measurable metastatic or unresectable uterine leiomyosarcoma or soft-tissue leiomyosarcoma who had not received any previous chemotherapy were enrolled at 19 centres in France. Treatment consisted of 60 mg/m(2) intravenous doxorubicin followed by 1·1 mg/m(2) trabectedin in a 3 h intravenous infusion on day 1, both by the central venous route, and 6 mg subcutaneous pegfilgrastim on day 2, repeated every 3 weeks for up to six cycles. Surgery for residual disease was permitted. The primary endpoint was the proportion of patients achieving disease control, defined as complete or partial response or stable disease. Stratification was done by anatomical site and analyses were per protocol. This study is registered with ClinicalTrials.gov, number NCT02131480. FINDINGS: Between July 28, 2010, and May 10, 2013, 109 patients were enrolled and treated, of whom 108 were assessable for response: 47 in the uterine leiomyosarcoma group and 61 in the soft-tissue leiomyosarcoma group. 32 (68%) patients in the uterine leiomyosarcoma group and 45 (74%) in the soft-tissue leiomyosarcoma group received all six cycles of treatment. Of 47 patients with uterine leiomyosarcoma, 28 (59·6%, 95% CI 44·3-73·6) achieved a partial response and 13 (27·7%, 15·6-42·6) stable disease; 41 (87·2%, 74·3-95·2) patients achieved disease control. Of 61 patients with soft-tissue leiomyosarcoma, two (3·3%, 95% CI 0·4-11·7) achieved a complete response, 22 (36·1%, 25·0-50·8) had a partial response, and 32 (52·5%, 40·8-67·3) had stable disease; 56 (91·8%, 81·9-97·3) of patients achieved disease control. The most common grade 3-4 treatment-associated adverse events were neutropenia (84 [78%] of 108 patients), increased alanine aminotransferase concentration (42 [39%]), thrombocytopenia (40 [37%]), anaemia (29 [27%]), febrile neutropenia (26 [24%]), and fatigue (21 [19%]). INTERPRETATION: Despite expected but manageable toxic effects, these results support the activity of doxorubicin plus trabectedin as first-line treatment for uterine leiomyosarcoma and soft-tissue leiomyosarcoma. This combination should be developed further in a phase 3 trial against the present standard of care. FUNDING: Pharmamar and Amgen.

Primary localized rectal/pararectal gastrointestinal stromal tumors: results of surgical and multimodal therapy from the French Sarcoma group.

BACKGROUND: Rectal and pararectal gastrointestinal stromal tumors (GISTs) are rare. The optimal management strategy for primary localized GISTs remains poorly defined. METHODS: We conducted a retrospective analysis of 41 patients with localized rectal or pararectal GISTs treated between 1991 and 2011 in 13 French Sarcoma Group centers. RESULTS: Of 12 patients who received preoperative imatinib therapy for a median duration of 7 (2-12) months, 8 experienced a partial response, 3 had stable disease, and 1 had a complete response. Thirty and 11 patients underwent function-sparing conservative surgery and abdominoperineal resection, respectively. Tumor resections were mostly R0 and R1 in 35 patients. Tumor rupture occurred in 12 patients. Eleven patients received postoperative imatinib with a median follow-up of 59 (2.4-186) months. The median time to disease relapse was 36 (9.8-62) months. The 5-year overall survival rate was 86.5%. Twenty patients developed local recurrence after surgery alone, two developed recurrence after resection combined with preoperative and/or postoperative imatinib, and eight developed metastases. In univariate analysis, the mitotic index (≤5) and tumor size (≤5 cm) were associated with a significantly decreased risk of local relapse. Perioperative imatinib was associated with a significantly reduced risk of overall relapse and local relapse. CONCLUSIONS: Perioperative imatinib therapy was associated with improved disease-free survival. Preoperative imatinib was effective. Tumor shrinkage has a clear benefit for local excision in terms of feasibility and function preservation. Given the complexity of rectal GISTs, referral of patients with this rare disease to expert centers to undergo a multidisciplinary approach is recommended.

The off-label use of targeted therapies in sarcomas: the OUTC'S program.

BACKGROUND: Few targeted therapies (TTs) are registered for sarcoma treatment despite numerous phase II studies and yet there are potential treatment options for patients after standard treatment escape. The French Sarcoma Group - Bone Tumor Study Group (GSF-GETO) created a national registry to evaluate the outcome of patients treated with off-label TTs. METHODS: Every consecutive sarcoma-patient receiving an off-label TT outside a clinical trial was included. The objective was to describe this patient efficacy and safety data in routine practice. RESULTS: From October 2008 to October 2011, 249 patients in 24 centers received 278 treatment lines with TTs. Twenty-five histological subtypes were included: most frequent were leiomyosarcoma (n=48, receiving sorafenib in 63%, and sunitinib in 27%), GIST (n=39, receiving sorafenib in 79%), and angiosarcoma (n=18, receiving sorafenib in 78%). The overall response rate to TTs was 15% (95% CI [10,6-20,2]), the disease control rate at 2 months was 59%. The median progression-free survival was 4,1 months (IC 95% [3,2-4,8]). Three complete responses were observed. No toxic death occurred, grade 3 and 4 toxicities were reported in 74 (27%) and 14 patients (5%) respectively. CONCLUSION: Off-label TTs can be used for sarcoma patients in routine practice with an acceptable toxicity profile and efficacy similar to that reported in non-randomized clinical trials.

Adapted EXTREME regimen in the first-line treatment of fit, older patients with recurrent or metastatic head and neck squamous cell carcinoma (ELAN-FIT): a multicentre, single-arm, phase 2 trial.

BACKGROUND: A standard treatment for fit, older patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) is yet to be established. In the previous EXTREME trial, few older patients were included. We aimed to evaluate the efficacy and tolerance of an adapted EXTREME regimen in fit, older patients with recurrent or metastatic HNSCC. METHODS: This single-arm, phase 2 study was done at 22 centres in France. Eligible patients were aged 70 years or older and assessed as not frail (fit) using the ELAN Geriatric Evaluation (EGE) and had recurrent or metastatic HNSCC in the first-line setting that was not eligible for local therapy (surgery or radiotherapy), and an Eastern Cooperative Oncology Group performance status of 0-1. The adapted EXTREME regimen consisted of six cycles of fluorouracil 4000 mg/m2 on days 1-4, carboplatin with an area under the curve of 5 on day 1, and cetuximab on days 1, 8, and 15 (400 mg/m2 on cycle 1-day 1, and 250 mg/m2 subsequently), all intravenously, with cycles starting every 21 days. In patients with disease control after two to six cycles, cetuximab 500 mg/m2 was continued once every 2 weeks as maintenance therapy until disease progression or unacceptable toxicity. Granulocyte colony-stimulating factor was systematically administered and erythropoietin was recommended during chemotherapy. The study was based on the two-stage Bryant and Day design, combining efficacy and toxicity endpoints. The primary efficacy endpoint was objective response rate at week 12 after the start of treatment, assessed by central review (with an unacceptable rate of ≤15%). The primary toxicity endpoint was morbidity, defined as grade 4-5 adverse events, or cutaneous rash (grade ≥3) that required cetuximab to be discontinued, during the chemotherapy phase, or a decrease in functional autonomy (Activities of Daily Living score decrease ≥2 points from baseline) at 1 month after the end of chemotherapy (with an unacceptable morbidity rate of >40%). Analysis of the coprimary endpoints, and of safety in the chemotherapy phase, was based on the per-protocol population, defined as eligible patients who received at least one cycle of the adapted EXTREME regimen. Safety in the maintenance phase was assessed in all patients who received at least one dose of cetuximab as maintenance therapy. The study is registered with ClinicalTrials.gov, NCT01864772, and is completed. FINDINGS: Between Sept 27, 2013, and June 20, 2018, 85 patients were enrolled, of whom 78 were in the per-protocol population. 66 (85%) patients were male and 12 (15%) were female, and the median age was 75 years (IQR 72-79). The median number of chemotherapy cycles received was five (IQR 3-6). Objective response at week 12 was observed in 31 patients (40% [95% CI 30-51]) and morbidity events were observed in 24 patients (31% [22-42]). No fatal adverse events occurred. Four patients presented with a decrease in functional autonomy 1 month after the end of chemotherapy versus baseline. During chemotherapy, the most common grade 3-4 adverse events were haematological events (leukopenia [22 patients; 28%], neutropenia [20; 26%], thrombocytopenia [15; 19%], and anaemia [12; 15%]), oral mucositis (14; 18%), fatigue (11; 14%), rash acneiform (ten; 13%), and hypomagnesaemia (nine; 12%). Among 44 patients who received cetuximab during the maintenance phase, the most common grade 3-4 adverse events were hypomagnesaemia (six patients; 14%) and acneiform rash (six; 14%). INTERPRETATION: The study met its primary objectives on objective response and morbidity, and showed overall survival to be as good as in younger patients treated with standard regimens, indicating that the adapted EXTREME regimen could be used in older patients with recurrent or metastatic HNSCC who are deemed fit with use of a geriatric evaluation tool adapted to patients with head and neck cancer, such as the EGE. FUNDING: French programme PAIR-VADS 2011 (sponsored by the National Cancer Institute, the Fondation ARC, and the Ligue Contre le Cancer), Sandoz, GEFLUC, and GEMLUC. TRANSLATION: For the French translation of the abstract see Supplementary Materials section.

Cetuximab versus methotrexate in first-line treatment of older, frail patients with inoperable recurrent or metastatic head and neck cancer (ELAN UNFIT): a randomised, open-label, phase 3 trial.

BACKGROUND: At present, there is no established standard treatment for frail older patients with recurrent or metastatic head and neck squamous cell carcinoma. We aimed to compare the efficacy and safety of cetuximab to those of methotrexate (the reference regimen) in this population. METHODS: This randomised, open-label, phase 3 trial was done at 20 hospitals in France. Patients aged 70 years or older, assessed as frail by the ELAN Geriatric Evaluation, with recurrent or metastatic head and neck squamous cell carcinoma in the first-line setting and with an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 were eligible for inclusion. Patients were randomly assigned (1:1) to receive cetuximab 500 mg/m2 intravenously every 2 weeks or methotrexate 40 mg/m2 intravenously every week, with minimisation by ECOG performance status, type of disease evolution, Charlson Comorbidity Index score, serum albumin concentration, and geriatrician consultation. To avoid deterministic minimisation and assure allocation concealment, patients were allocated with a probability of 0·80 to the treatment that most reduced the imbalance. Treatment was continued until disease progression or unacceptable toxicity, whichever occurred first. The primary endpoint was failure-free survival (defined as the time from randomisation to disease progression, death, discontinuation of treatment, or loss of 2 or more points on the Activities in Daily Living scale, whichever occurred first) and was analysed in the intention-to-treat population. 151 failures expected out of 164 patients were required to detect a hazard ratio (HR) of 0·625 with 0·05 alpha error, with 80% power. A futility interim analysis was planned when approximately 80 failures were observed, based on failure-free survival. Safety analyses included all patients who received at least one dose of the study drug. This study is registered on ClinicalTrials.gov (NCT01884623) and was stopped for futility after the interim analysis. FINDINGS: Between Nov 7, 2013, and April 23, 2018, 82 patients were enrolled (41 to the cetuximab group and 41 to the methotrexate group); 60 (73%) were male, 37 (45%) were aged 80 years or older, 35 (43%) had an ECOG performance status of 2, and 36 (44%) had metastatic disease. Enrolment was stopped for futility at the interim analysis. At the final analysis, median follow-up was 43·3 months (IQR 30·8-52·1). At data cutoff, all 82 patients had failure; failure-free survival did not differ significantly between the groups (median 1·4 months [95% CI 1·0-2·1] in the cetuximab group vs 1·9 months [1·1-2·6] in the methotrexate group; adjusted HR 1·03 [95% CI 0·66-1·61], p=0·89). The frequency of patients who had grade 3 or worse adverse events was 63% (26 of 41) in the cetuximab group and 73% (30 of 41) in the methotrexate group. The most common grade 3-4 adverse events in the cetuximab group were fatigue (four [10%] of 41 patients), lung infection (four [10%]), and rash acneiform (four [10%]), and those in the methotrexate group were fatigue (nine [22%] of 41), increased gamma-glutamyltransferase (seven [17%]), natraemia disorder (four [10%]), anaemia (four [10%]), leukopenia (four [10%]), and neutropenia (four [10%]). The frequency of patients who had serious adverse events was 44% (18 of 41) in the cetuximab group and 39% (16 of 41) in the methotrexate group. Four patients presented with a fatal adverse event in the cetuximab group (sepsis, decreased level of consciousness, pulmonary oedema, and death of unknown cause) as did two patients in the methotrexate group (dyspnoea and death of unknown cause). INTERPRETATION: The study showed no improvement in failure-free survival with cetuximab versus methotrexate. Patients with an ECOG performance status of 2 did not benefit from these systemic therapies. New treatment options including immunotherapy should be explored in frail older patients with recurrent or metastatic head and neck squamous cell carcinoma, after an initial geriatric evaluation, such as the ELAN Geriatric Evaluation. FUNDING: French programme PAIR-VADS 2011 (sponsored by the National Cancer Institute, the Fondation ARC and the Ligue Contre le Cancer), GEMLUC, GEFLUC, and Merck Santé. TRANSLATION: For the French translation of the abstract see Supplementary Materials section.

[French national standard for the treatment of squamous cell carcinoma of upper aero-digestive tract - General principles of treatment]. / Référentiel national de traitement des carcinomes épidermoïdes des voies aérodigestives supérieures ­ Principes généraux de traitement.

OBJECTIVES: The management of upper aerodigestive tract cancers is a complex specialty. It is essential to provide an update to establish optimal care. At the initiative of the INCa and under the auspices of the SFORL, the scientific committee, led by Professor Béatrix Barry, Dr. Gilles Dolivet, and Dr. Dominique De Raucourt, decided to develop a reference framework aimed at defining, in a scientific and consensus-based manner, the general principles of treatment for upper aerodigestive tract cancers applicable to all sub-locations. METHODOLOGY: To develop this framework, a multidisciplinary team of practitioners was formed. A systematic analysis of the literature was conducted to produce recommendations classified by grades, in accordance with the standards of the French National Authority for Health (HAS). RESULTS: The grading of recommendations according to HAS standards has allowed the establishment of a reference for patient care based on several criteria. In this framework, patients benefit from differentiated care based on prognostic factors they present (age, comorbidities, TNM status, HPV status, etc.), conditions of implementation, and quality criteria for indicated surgery (operability, resectability, margin quality, mutilation, salvage surgery), as well as quality criteria for radiotherapy (target volume, implementation time, etc.). The role of medical and postoperative treatments was also evaluated based on specific criteria. Finally, supportive care must be organized from the beginning and throughout the patients' care journey. CONCLUSION: All collected data have led to the development of a comprehensive framework aimed at harmonizing practices nationally, facilitating decision-making in multidisciplinary consultation meetings, promoting equality in practices, and providing a state-of-the-art and reference practices for assessing the quality of care. This new framework is intended to be updated every 5 years to best reflect the latest advances in the field.

[Unusual association of BRAF and MEK inhibitors: Clinical response of metastatic melanoma treated with dabrafenib-cobimetinib]. / Association inhabituelle d'inhibiteurs de BRAF et de MEK : réponse clinique d'un mélanome métastatique traité par dabrafénib­cobimétinib.

Despite the efficacy of targeted therapies in melanoma, the management of adverse events with BRAFi and MEKi (inhibitors) is one of the limits of these treatments. Close monitoring is required to ensure efficacy and patient safety. In this case study, we report a patient treated for metastatic melanoma with an unusual and innovative combination of dabrafenib (BRAFi) and cobimetinib (MEKi), to manage pyrexia, and lead to complete remission for 19 months. This is the first case ever reported of metastatic melanoma treated with this off-label combination and characterized by the use of therapeutic drug monitoring.

Randomized multicenter and stratified phase II study of gemcitabine alone versus gemcitabine and docetaxel in patients with metastatic or relapsed leiomyosarcomas: a Federation Nationale des Centres de Lutte Contre le Cancer (FNCLCC) French Sarcoma Group Study (TAXOGEM study).

BACKGROUND: This study aimed to evaluate the efficacy and toxicity of single-agent gemcitabine versus gemcitabine plus docetaxel as second-line therapy in patients with uterine and nonuterine leiomyosarcoma (LMS). PATIENTS AND METHODS: Patients had metastatic or unresectable LMS and had received one prior anthracycline-based regimen. A total of 90 patients received either single-agent gemcitabine (arm A; gemcitabine, 1,000 mg/m(2) i.v. for 100 minutes on days 1, 8, and 15 of a 28-day cycle) or a combination of gemcitabine and docetaxel (arm B; gemcitabine, 900 mg/m(2) i.v. for 90 minutes on days 1 and 8, plus docetaxel, 100 mg/m(2) i.v. for 1 hour on day 8 of a 21-day cycle with lenograstim). The primary endpoint was the objective response rate. RESULTS: The objective response rates were 19% and 24% in arm A (gemcitabine) and arm B (gemcitabine plus docetaxel), respectively, for patients with uterine LMS. For patients with nonuterine LMS, the objective response rates were 14% and 5% for arms A and B, respectively. The median progression-free survival times for arms A and B were 5.5 months and 4.7 months, respectively, for patients with uterine LMS. For patients with nonuterine LMS, the median progression-free survival times were 6.3 months and 3.8 months for arms A and B, respectively. One toxic death occurred in arm B. CONCLUSIONS: Both single-agent gemcitabine and gemcitabine plus docetaxel were found to be effective second-line therapies for leiomyosarcomas, with a 3-month progression-free survival rate of 40% for LMS with both uterine and nonuterine sites of origin. Single-agent gemcitabine yielded results similar to those of gemcitabine plus docetaxel in this trial, but patients using single-agent gemcitabine experienced less toxicity.

Sorafenib for patients with advanced angiosarcoma: a phase II Trial from the French Sarcoma Group (GSF/GETO).

BACKGROUND: Angiosarcomas account for <2% of all soft tissue sarcomas. This subtype is one of the most aggressive forms of soft tissue sarcoma. The prognosis for angiosarcoma patients in the advanced phase remains poor with current cytotoxic agents (progression-free survival [PFS] time of ∼4 months and overall survival [OS] time of ∼8 months). We investigated the antitumor activity of sorafenib in patients with metastatic or advanced angiosarcomas in a phase II trial. METHODS: We conducted a stratified phase II trial. The primary endpoint was the progression-free rate (PFR) at 9 months according to the Response Evaluation Criteria in Solid Tumors. A two-stage design (optimal Simon design) was used. Patients received sorafenib (400 mg twice daily) for 9 months until unacceptable toxicity or tumor progression. Central pathological and radiological reviews were performed. Data on stratum A (superficial angiosarcoma) and stratum B (visceral angiosarcoma) are currently available. This trial is registered with ClinicalTrials.gov (identifier, NCT00874874). FINDINGS: Strata A and B recruited 26 and 15 patients, respectively. The median age was 63 years (range, 31-82 years), with 17 male and 24 female patients. Fourteen cases arose in irradiated fields. Thirty patients (73.0%) had been pretreated with conventional chemotherapy. No unexpected toxicity occurred. The PFR at 9 months was 3.8% in stratum A and 0.0% in stratum B. The median PFS times were 1.8 months and 3.8 months, respectively, whereas the median OS times were 12.0 months and 9.0 months, respectively. No responses were observed in chemotherapy-naïve patients, whereas a 40% tumor control rate and 23% response rate were observed in the pretreated population. In this cohort, no activating mutation of the KDR gene (exons 15, 16, 24) was detected. INTERPRETATION: Sorafenib showed limited antitumor activity in pretreated patients only, for both visceral and superficial angiosarcoma, but tumor control was of short duration.

Immune Infiltrate and Tumor Microenvironment Transcriptional Programs Stratify Pediatric Osteosarcoma into Prognostic Groups at Diagnosis.

The outcomes of adolescents/young adults with osteosarcoma have not improved in decades. The chaotic karyotype of this rare tumor has precluded the identification of prognostic biomarkers and patient stratification. We reasoned that transcriptomic studies should overcome this genetic complexity. RNA sequencing (RNA-seq) of 79 osteosarcoma diagnostic biopsies identified stable independent components that recapitulate the tumor and microenvironment cell composition. Unsupervised classification of the independent components stratified this cohort into favorable (G1) and unfavorable (G2) prognostic tumors in terms of overall survival. Multivariate survival analysis ranked this stratification as the most influential variable. Functional characterization associated G1 tumors with innate immunity and G2 tumors with angiogenic, osteoclastic, and adipogenic activities as well as PPARγ pathway upregulation. A focused gene signature that predicted G1/G2 tumors from RNA-seq data was developed and validated within an independent cohort of 82 osteosarcomas. This signature was further validated with a custom NanoString panel in 96 additional osteosarcomas. This study thus proposes new biomarkers to detect high-risk patients and new therapeutic options for osteosarcoma. SIGNIFICANCE: These findings indicate that the osteosarcoma microenvironment composition is a major feature to identify hard-to-treat patient tumors at diagnosis and define the biological pathways and potential actionable targets associated with these tumors.

Platinum-based chemotherapy plus cetuximab in head and neck cancer.

BACKGROUND: Cetuximab is effective in platinum-resistant recurrent or metastatic squamous-cell carcinoma of the head and neck. We investigated the efficacy of cetuximab plus platinum-based chemotherapy as first-line treatment in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck. METHODS: We randomly assigned 220 of 442 eligible patients with untreated recurrent or metastatic squamous-cell carcinoma of the head and neck to receive cisplatin (at a dose of 100 mg per square meter of body-surface area on day 1) or carboplatin (at an area under the curve of 5 mg per milliliter per minute, as a 1-hour intravenous infusion on day 1) plus fluorouracil (at a dose of 1000 mg per square meter per day for 4 days) every 3 weeks for a maximum of 6 cycles and 222 patients to receive the same chemotherapy plus cetuximab (at a dose of 400 mg per square meter initially, as a 2-hour intravenous infusion, then 250 mg per square meter, as a 1-hour intravenous infusion per week) for a maximum of 6 cycles. Patients with stable disease who received chemotherapy plus cetuximab continued to receive cetuximab until disease progression or unacceptable toxic effects, whichever occurred first. RESULTS: Adding cetuximab to platinum-based chemotherapy with fluorouracil (platinum-fluorouracil) significantly prolonged the median overall survival from 7.4 months in the chemotherapy-alone group to 10.1 months in the group that received chemotherapy plus cetuximab (hazard ratio for death, 0.80; 95% confidence interval, 0.64 to 0.99; P=0.04). The addition of cetuximab prolonged the median progression-free survival time from 3.3 to 5.6 months (hazard ratio for progression, 0.54; P<0.001) and increased the response rate from 20% to 36% (P<0.001). The most common grade 3 or 4 adverse events in the chemotherapy-alone and cetuximab groups were anemia (19% and 13%, respectively), neutropenia (23% and 22%), and thrombocytopenia (11% in both groups). Sepsis occurred in 9 patients in the cetuximab group and in 1 patient in the chemotherapy-alone group (P=0.02). Of 219 patients receiving cetuximab, 9% had grade 3 skin reactions and 3% had grade 3 or 4 infusion-related reactions. There were no cetuximab-related deaths. CONCLUSIONS: As compared with platinum-based chemotherapy plus fluorouracil alone, cetuximab plus platinum-fluorouracil chemotherapy improved overall survival when given as first-line treatment in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck. (ClinicalTrials.gov number, NCT00122460.)

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

BACKGROUND: The 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. METHODS: The 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. RESULTS: Fifteen 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% respectively CONCLUSIONS: Following 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.

Discontinuation of imatinib in patients with advanced gastrointestinal stromal tumours after 3 years of treatment: an open-label multicentre randomised phase 3 trial.

BACKGROUND: The effect of imatinib discontinuation on progression-free survival and overall survival in long-lasting responders with advanced gastrointestinal stromal tumours (GIST) is unknown. We assessed treatment interruption in patients with non-progressive disease according to the Response Evaluation Criteria In Solid Tumors criteria after 3 years of imatinib in a randomised trial. METHODS: In this open-label national multicentre phase 3 study in France, patients with GIST free of progression after 3 years of imatinib 400 mg/day were randomly assigned to continue or interrupt imatinib. Randomisation was done centrally and independently from other study procedures with computer-generated permuted blocks of two and four patients stratified by participating centre and presence or absence of residual disease on CT scan. The primary endpoint was progression-free survival. An interim analysis was planned after the first 50 randomly assigned patients. Analysis was done according to the intention-to-treat principle-ie, all patients randomly assigned to a study group were included. This study is registered with ClinicalTrial.gov, number NCT00367861. FINDINGS: 434 patients were enrolled in this trial between May 27, 2002, and May 5, 2009. Between June 13, 2005, and May 30, 2007, 50 patients with non-progressive disease who had received 3 years of treatment with imatinib were randomly assigned to continue or interrupt their treatment, 25 patients in each group. By Dec 7, 2009, after a median follow-up of 35 months (95% CI 33-38) after random assignment, 2-year progression-free survival was 80% (95% CI 58-91) in the continuation group and 16% (5-33) in the interruption group (p < 0·0001). There was no difference in adverse events grade 3 or greater (oedema and asthenia) between the two groups. INTERPRETATION: Imatinib interruption after 3 years in responders results in a high risk of rapid progression in patients with advanced GIST. Discontinuation of imatinib is not recommended outside clinical trials unless patients experience significant toxic effects. FUNDING: Conticanet, the Ligue Contre Le Cancer du Rhone, and Novartis.