To investigate the activity and safety of afatinib in the preoperative treatment of squamous cell carcinoma of the head and neck (SCCHN).
This study was an open-label, randomized, multicenter, phase ...II window of opportunity trial. Treatment-naïve SCCHN patients selected for primary curative surgery were randomized (5 : 1 ratio) to receive afatinib during 14days (day –15 until day –1) before surgery (day 0) or no treatment. Tumor biopsies, 2-fluorine-18-fluoro-2-deoxy-d-glucose positron emission tomography (FDG-PET), and magnetic resonance imaging (MRI) were carried out at diagnosis and just before surgery. The primary end point was metabolic FDG-PET response (according to EORTC guidelines). Other end points included response assessment based on the Response Evaluation Criteria In Solid Tumors (RECIST) v1.1, dynamic contrast-enhanced (DCE)-MRI, diffusion weighted (DW)-MRI, safety, and translational research (TR).
Thirty patients were randomized: 25 to afatinib and 5 to control arm. Of the 23 eligible patients randomized to afatinib, 16 (70%; 95% CI: 47% to 87%) patients had a partial metabolic FDG-PET response (PMR). Five patients (22%; 95% CI: 8% to 44%) showed a partial response by RECISTv1.1. Responses assessed via DCE-MRI and DWI-MRI did not show a strong association with PMR or RECIST. One patient discontinued afatinib after 11days for grade 3 diarrhea with subsequent renal failure and 24days delay in surgery. No grade 4 toxicities or surgical comorbidities related to afatinib were reported. TR results indicated that PMR was more frequent in the tumors with high Cluster3-hypoxia score expression and with TP53 wild type.
Afatinib given for 2weeks to newly diagnosed SCCHN patients induces a high rate of FDG-PET partial metabolic response and partial response according to RECISTv1.1. Afatinib can be safely administered before surgery. Although exploratory, the hypoxic gene signature needs further investigations as a predictive biomarker of afatinib activity.
ClinicalTrials.gov: NCT01538381
Background: To assess the safety and preliminary efficacy of concurrent radiotherapy, capecitabine, and cetuximab in the preoperative treatment of patients with rectal cancer. Patients and methods: ...Forty patients with rectal cancer (T3–T4, and/or N+, endorectal ultrasound) received preoperative radiotherapy (1.8 Gy, 5 days/week for 5 weeks, total dose 45 Gy, three-dimensional conformal technique) in combination with cetuximab initial dose 400 mg/m2 intravenous given 1 week before the beginning of radiation followed by 250 mg/m2/week for 5 weeks and capecitabine for the duration of radiotherapy (650 mg/m2 orally twice daily, first dose level; 825 mg/m2 twice daily, second dose level). Results: Four and six patients were treated at the first and second dose level of capecitabine, respectively. No dose-limiting toxicity occurred. Thirty additional patients were treated with capecitabine at 825 mg/m2 twice daily. The most frequent grade 1/2 side-effects were acneiform rash (87%), diarrhea (65%), and fatigue (57%). Grade 3 diarrhea was found in 15%. Three grade 4 toxic effects were recorded: one myocardial infarction, one pulmonary embolism, and one pulmonary infection with sepsis. Two patients (5%) had a pathological complete response. Conclusions: Preoperative radiotherapy in combination with capecitabine and cetuximab is feasible with some patients achieving pathological downstaging.
•OS was numerically longer with pembrolizumab in all subgroups.•PFS was similar between treatment arms in all subgroups.•More patients receiving pembrolizumab versus SOC had an objective ...response.•Responses with pembrolizumab were durable.•Results suggest benefit from pembrolizumab regardless of recurrence pattern.
In the phase 3 KEYNOTE-040 study, pembrolizumab prolonged OS versus chemotherapy in previously treated recurrent or metastatic (R/M) HNSCC. We present a post hoc subgroup analysis by disease recurrence pattern: recurrent-only, recurrent and metastatic (recurrent-metastatic), and metastatic-only HNSCC.
Patients had HNSCC that progressed during or after platinum-containing treatment for R/M disease or had recurrence or progression within 3–6 months of previous platinum-containing definitive therapy for locally advanced disease. Patients were randomly assigned (1:1) to pembrolizumab 200 mg Q3W or investigator’s choice of standards of care (SOC): methotrexate, docetaxel, or cetuximab. Outcomes included OS, PFS, ORR, and DOR. The data cutoff was May 15, 2017.
There were 125 patients (pembrolizumab, 53; SOC, 72) in the recurrent-only subgroup, 204 in the recurrent-metastatic subgroup (pembrolizumab, 108; SOC, 96), and 166 in the metastatic-only subgroup (pembrolizumab, 86; SOC, 80). The hazard ratio (95% CI) for death for pembrolizumab versus SOC was 0.83 (0.55–1.25) in the recurrent-only, 0.78 (0.58–1.06) in the recurrent-metastatic, and 0.74 (0.52–1.05) in the metastatic-only subgroups. PFS was similar between treatment arms in all subgroups. ORR was 22.6% for pembrolizumab versus 16.7% for SOC in the recurrent-only, 10.2% versus 6.3% in the recurrent-metastatic, and 15.1% versus 8.8% in the metastatic-only subgroups. DOR was numerically longer with pembrolizumab in all subgroups.
Pembrolizumab provided numerically longer OS and durable responses in all subgroups compared with SOC, suggesting that patients with previously treated R/M HNSCC benefit from pembrolizumab regardless of recurrence pattern.
Preclinical studies suggest that insulin-like growth factor-1 receptor (IGF-1R) blockage could be a promising therapeutic target in squamous cell carcinoma of the head and neck (SCCHN). Therefore, we ...investigated the efficacy and toxicity of figitumumab, an anti-IGF-1R monoclonal antibody, in palliative SCCHN.
Patients with palliative SCCHN progressing after platinum-based therapy were treated with figitumumab i.v. 20 mg/kg, every 3 weeks. The primary end point was the disease control rate at 6–8 weeks after treatment initiation. Tumor biopsies and plasma samples were collected before and after figitumumab administration to monitor the molecular response.
Seventeen patients were included. Only two patients achieved stable disease at 6–8 weeks. Median overall survival and progression-free survival were 63 and 52 days, respectively. The main grade 3–4 adverse event was hyperglycemia (41%). Translational research showed that figitumumab downregulated IGF-1R at the surface of tumor cells with activation of the epidermal growth factor receptor (EGFR) pathway, as shown by the upregulation of p-EGFR in tumor cells (P = 0.016), and an increase in the plasma level of tumor growth factor-alpha (P = 0.006).
Figitumumab monotherapy has no clinically significant activity in unselected palliative SCCHN.
half of anticancer drugs are predominantly excreted in urine. Dosage adjustment in renal insufficiency (RI) is, therefore, a crucial issue. Moreover, patients with abnormal renal function are at high ...risk for drug-induced nephrotoxicity. The Belgian Renal Insufficiency and Anticancer Medications (BIRMA) study investigated the prevalence of RI in cancer patients, and the profile/dosing of anticancer drugs prescribed.
primary end point: to estimate the prevalence of abnormal glomerular filtration rate (GFR; estimated with the abbreviated Modification of Diet in Renal Disease formula) and RI in cancer patient. Secondary end point: to describe the profile of anticancer drugs prescribed (dose reduction/nephrotoxicity). Data were collected for patients presenting at one of the seven Belgian BIRMA centres in March 2006.
a total of 1218 patients were included. The prevalence of elevated SCR (> or =1.2 mg per 100 ml) was 14.9%, but 64.0% had a GFR<90 ml min(-1) per 1.73 m(2). In all, 78.6% of treated patients (n=1087) were receiving at least one drug needing dosage adjustment and 78.1% received at least one nephrotoxic drug. In all, 56.5% of RI patients receiving chemotherapy requiring dose reduction in case of RI did not receive dose adjustment.
the RI is highly frequent in cancer patients. In all, 80% of the patients receive potentially nephrotoxic drugs and/or for which dosage must be adjusted in RI. Oncologists should check the appropriate dose of chemotherapeutic drugs in relation to renal function before prescribing.
Cetuximab in combination with platinum and 5-fluorouracil is the standard of care in the first-line treatment of patients with recurrent/metastatic head and neck squamous cell carcinoma (HNSCC). ...Cetuximab and taxane combinations have shown promising activity. This study evaluated the efficacy and safety of four cycles of docetaxel associated with cisplatin and cetuximab (TPEx), followed by maintenance with cetuximab every 2 weeks.
Patients with a histologically confirmed HNSCC with metastasis or recurrence unsuitable for locoregional curative treatment received docetaxel and cisplatin (75 mg/m2 both) at day 1 and weekly cetuximab 250 mg/m2 (loading dose of 400 mg/m2), repeated every 21 days for four cycles, followed by maintenance cetuximab 500 mg/m2 every 2 weeks until progression or unacceptable toxicity. Prophylactic administration of granulocyte colony-stimulating factor was done systematically after each chemotherapy cycle. Patients had a good general status (performance status ≤1) and were under 71 years. Prior total doses of cisplatin exceeding 300 mg/m2 were not allowed. The primary end point was objective response rate (ORR) after four cycles.
Fifty-four patients were enrolled. The primary end point was met with an ORR of 44.4% (95% CI 30.9–58.6). Median overall and progression-free survivals were, respectively, 14 months (95% CI 11.3–17.3) and 6.2 months (95% CI 5.4–7.2). The most common grade 3/4 adverse events were skin rash (16.6%) and non-febrile neutropenia (20.4%). There were one pulmonary embolism and two infectious events leading to death.
The TPEx regimen showed promising activity as first-line treatment in fit patients with recurrent/metastatic HNSCC. Further studies are needed to compare the TPEx versus EXTREME regimen in this population.
NCT01289522.
Purpose
The purpose of the trial was to assess the efficacy and tolerability of Sym004, a novel 1:1 mixture of two chimeric monoclonal antibodies (992 and 1024) targeting non-overlapping epitopes of ...the anti-epidermal growth factor receptor (EGFR), in patients with squamous cell carcinoma of the head and neck (SCCHN).
Methods
Incurable, recurrent and/or metastatic SCCHN patients with acquired resistance to anti-EGFR monoclonal antibody-containing treatment received weekly infusions of 12 mg/kg Sym004 until disease progression or unacceptable toxicity.
Results
Among the 26 patients treated with Sym004, the proportion of patients alive without disease progression at 6 months was 12 % (95 % CI 1–39 %). The median duration of progression-free survival was 82 days (95 % CI 41–140 days). Of 19 patients evaluable for response, eight showed a decrease in the sum of the largest diameter in their target lesions (median 11 %; range 7–27 %). The best overall response was stable disease in 13 patients (50 %). Paired biopsies showed a significant down-regulation of EGFR in both skin and tumors following exposure to Sym004. All patients had EGFR-related adverse events, including grade 3 skin toxicities and grade ≥3 hypomagnesemia reported in 13 (50 %) and 10 (38 %) of 26 patients, respectively. One event fulfilling the protocol-defined criteria for infusion-related reactions (grade 2) was reported. No anti-drug antibodies were detected.
Conclusions
The marked EGFR down-regulation shown in target tissues supports the proposed mechanism of action of Sym004. This trial revealed modest anti-tumor activity of Sym004 in extensively pretreated advanced SCCHN patients.
Background: Preoperative radiotherapy has been shown to decrease the local recurrence rate of patients with locally advanced rectal cancer. Capecitabine and oxaliplatin are both active anticancer ...agents in the treatment of patients with advanced colorectal cancer and have radiosensitizing properties. Therefore, these drugs would be expected to improve effectiveness of preoperative radiotherapy in terms of local control and prevention of distant metastases. Patients and methods: Forty patients with rectal cancer (T3–T4 and/or N+) received radiotherapy (1.8 Gy, 5 days a week over 5 weeks, total dose 45 Gy, 3D conformational technique) in combination with intravenous oxaliplatin 50 mg/m2 once weekly for 5 weeks and oral capecitabine 825 mg/m2 twice daily on each day of radiation. Surgery was performed 6–8 weeks after completion of radiotherapy. The main end points were safety and efficacy as assessed by the pathological complete response (pCR). Results: The most frequent grade 3/4 adverse event was diarrhea, occurring in 30% of patients. pCR was found in five (14%) patients. According to Dworak's classification, good regression was found in six (18%) additional patients. Conclusions: Combination of preoperative radiotherapy with capecitabine and oxaliplatin is feasible for downstaging rectal cancer.
In this phase Ib, dose-escalation study, the oral irreversible ErbB family blocker afatinib (BIBW 2992) was combined with cisplatin (Cadila Healthcare Ltd, Ahmedabad, India) 50 or 75 mg/m2/paclitaxel ...(Bristol-Myers Squibb Pharmaceuticals Ltd, New York, USA) (Taxol)175 mg/m2 (regimen A) or cisplatin 75–100 mg/m2/5-fluorouracil 750–1000 mg/m2 (regimen B) in patients with advanced solid tumors.
The primary objective was to assess dose-limiting toxicities (DLTs) during cycle 1 for each regimen, from which the maximum tolerated dose (MTD) was determined. Patients received once daily oral afatinib 20, 30, 40 or 50 mg in 21-day cycles (3 + 3 design).
The MTD for afatinib in regimens A (n = 26) and B (n = 21) was determined as 20 mg and 30 mg following DLTs in five and four patients in cycle 1, respectively. Most frequent adverse events (AEs, any grade) were diarrhea and nausea. Disease control was observed in 54% and 29% of patients in regimens A and B, respectively. Plasma sampling suggested no relevant pharmacokinetic interaction between afatinib and the chemotherapeutic agents.
The MTD of afatinib was 20 mg with cisplatin–paclitaxel and 30 mg with cisplatin–5-fluorouracil. Pre-emptive management of side-effects is important to maintain adequate safety and tolerability. Both combinations showed antitumor activity across tumor types and lines of prior treatment.
•This ESMO–EURACAN Clinical Practice Guideline provides key recommendations for managing salivary gland cancer.•The guideline covers clinical and pathological diagnosis, staging and risk assessment, ...treatment and follow-up.•Treatment algorithms for parotid, submandibular, sublingual and minor salivary gland cancer are provided.•The author group encompasses a multidisciplinary group of experts from different institutions and countries in Europe.•Recommendations are based on available scientific data and the authors’ collective expert opinion.
PDF
