Panitumumab

In December 2007 the European Medicines Agency (EMEA) approved panitumumab (Vectibix) for the treatment of metastatic colorectal cancer. Panitumumab has a conditional approval as monotherapy for the treatment of patients with EGFR-expressing tumours with non-mutated (wild-type) K-ras genes after failure of standard chemotherapy regimens. This specific subgroup of patients showed a more favourable outcome in a controlled, open-label, randomized phase III study. Patients treated with panitumumab plus best supportive care had a significantly prolonged progression-free survival compared to patients receiving best supportive care alone.     

Pharmacokinetic and pharmacodynamic perspectives on the clinical drug development of panitumumab

Panitumumab is a recombinant, fully human IgG2 monoclonal antibody directed against the epidermal growth factor receptor (EGFR). It is indicated for use as monotherapy in the treatment of patients with EGFR-expressing metastatic colorectal cancer after disease progression with standard chemotherapy. The currently indicated dose is 6 mg/kg given every 2 weeks. Panitumumab is mainly distributed into the vascular space and exhibits nonlinear pharmacokinetics that are consistent with target-mediated drug disposition, involving saturable binding to EGFR and subsequent internalization and degradation inside the cells. Panitumumab is also cleared in a linear fashion by the reticuloendothelial system, similarly to other endogenous immunoglobulins. After single-dose administration of panitumumab as a 1-hour intravenous infusion, the area under the serum concentration-time curve increases in a greater-than-dose-proportional manner as the dose increases from 0.75 to 5 mg/kg; however, at doses above 2 mg/kg, the exposure to panitumumab increases in a dose-proportional manner. Panitumumab pharmacokinetics are not meaningfully affected by the tumour type, EGFR membrane expression, tumour KRAS mutation, sex, age, race or renal or hepatic dysfunction. In addition, irinotecan-containing and paclitaxel/carboplatin-containing chemotherapeutic regimens do not appear to affect panitumumab pharmacokinetics. The results of population pharmacokinetic analyses have shown that bodyweight is the most influential covariate on panitumumab exposure, supporting the current use of bodyweight-adjusted doses (mg/kg). The relationship between the weekly dose of panitumumab and skin rash, an on-target pharmacodynamic effect of EGFR inhibition, reaches a plateau at 2.5 mg/kg, indicating that this is the optimal weekly dose. Two less-frequent dosing regimens (6 mg/kg given every 2 weeks and 9 mg/kg given every 3 weeks) achieve steady-state serum trough concentrations similar to those achieved by 2.5 mg/kg given every week, ensuring maximal EGFR coverage. Anti-panitumumab antibody production is uncommon and does not appear to have an impact on the pharmacokinetics of panitumumab.     

Panitumumab

Panitumumab, previously known as ABX-EGF, is the first fully human monoclonal antibody to be shown to be effective as a treatment for solid-tumor cancers. Its target is the epidermal growth factor receptor (EGFR), which when overactive may contribute to the development and progression of cancer and is expressed in several solid tumors, including colorectal cancer. In a recently reported phase III trial, patients with metastatic colorectal cancer who had failed previous treatment with oxaliplatin- and irinotecan-based therapy were randomized to receive single-agent panitumumab and best-supportive care, or best-supportive care alone. This trial demonstrated a significant improvement in progression-free survival with panitumumab treatment in these patients. A rash similar to that which occurs with the other anti-EGFR antibody, cetuximab, has been observed in up to 100% of patients treated with panitumumab in the various clinical trials. As with other EGFR antagonists, EGFR staining by immunohistochemistry has not been shown to be an effective method of selecting patients for treatment, whereas the severity of the rash appears to be predictive of outcome. Ongoing randomized trials are evaluating the use of panitumumab with combination treatment for the first-line treatment of metastatic colorectal cancer. This review summarizes the rationale for targeting the EGFR and the development of panitumumab in preclinical and early phase trials in several tumor types. Clinical trial results in colorectal cancer, in which the development of this agent is most advanced, will also be discussed, as will the rash associated with treatment.     

Panitumumab the first fully human monoclonal antibody: from the bench to the clinic

Panitumumab (formerly known as ABX-EGF) is the first fully human monoclonal antibody to epidermal growth factor receptor to enter clinical trials for the treatment of solid tumors. Like cetuximab (Erbitux; BMS), it is directed against the extracellular ligand-binding domain of the receptor and results in blockade of the essential downstream signaling pathways that are known to govern apoptosis, proliferation and differentiation of both normal and neoplastic cell types in a wide array of tissues. It has a very high affinity for epidermal growth factor receptor and has been generally well tolerated and associated with very few infusion reactions. As a fully human agent, panitumumab has not been associated with the formation of any antibodies directed against it that has been evidenced by a very reliable pharmacokinetic profile with possible dosing schedules ranging from 1 to 3 weeks. Similar to other agents targeting the epidermal growth factor receptor pathway, a rash has been the primary toxicity and is dose dependent up to 2.5 mg/kg at which dose 100% of all patients have been affected. The anti-tumor activity of panitumumab has been tested in vitro and in vivo, and inhibition of tumor growth has been observed in numerous cancer models, particularly lung, kidney and colorectal. It has been efficacious and well tolerated both as monotherapy and in combination with other chemotherapeutic agents. Several phase I trials, two phase II trials and most recently a phase III trial in pretreated colorectal cancer have been carried out to date. Currently, there is also a randomized phase III trial (Panitumumab Advanced Colorectal Cancer Evaluation Study) investigating the role of panitumumab in the first-line treatment of colorectal cancer. No unfavorable drug-drug interactions have been observed nor has there been any effect on the pharmacokinetics of drugs with which it is being used. Recent progress in preclinical and clinical studies of panitumumab is reviewed.     

Review article: panitumumab - a fully human anti-EGFR monoclonal antibody for treatment of metastatic colorectal cancer

Background  Panitumumab is a fully human monoclonal IgG2 antibody targeting the epidermal growth factor receptor (EGFR).
Aim  To review the efficacy of panitumumab in the treatment of metastatic colorectal cancer (mCRC).
Methods  Available literature identified from PubMed and conference websites was reviewed.
Results  In phase 2–3 studies, panitumumab monotherapy achieved objective response rates (ORRs) of 8–13% in relapsed/refractory EGFR-expressing mCRC. In a randomized phase 3 study (463 patients), panitumumab almost halved the risk of disease progression/death vs. a control group receiving only best supportive care (hazard ratio 0.54; 95% CI: 0.44–0.66; P  <   0.0001). Objective response was achieved in 22/231 (10%) patients randomized to panitumumab – and also in 20/176 (11%) patients assigned to the control group who received panitumumab in a separate crossover protocol after disease progression. Response was confined to patients with tumours harbouring wild-type KRAS (ORR ≈20%). Panitumumab is also being evaluated in earlier lines of treatment. Panitumumab monotherapy is generally well tolerated; the most common toxicities are skin toxicity (≈90%) and diarrhoea (<30%). Development of anti-panitumumab antibodies (0.3% by ELISA) and grade 3–4 infusion reactions (<1%) are rare.
Conclusion  Panitumumab is an effective monotherapy option for patients with relapsed/refractory EGFR-expressing mCRC harbouring wild-type KRAS .     

Panitumumab: the evidence of its therapeutic potential in metastatic colorectal cancer care

Introduction:

Colorectal cancer is the fourth most common malignant disease. Of newly diagnosed patients, 40% have metastatic disease at diagnosis, and approximately 25% of patients with localized disease at diagnosis will ultimately develop metastatic disease. The benefits of systemic chemotherapy in the treatment of metastatic colorectal cancer over best supportive care have been established. Panitumumab (ABX-EGF) is the first fully human monoclonal antibody developed for use in colorectal cancer that targets the extracellular domains of epidermal growth factor receptor.

Aims:

The goal of this article is to review the published evidence for the use of panitumumab in the treatment of metastatic colorectal cancer to define its therapeutic potential.

Evidence review:

The major evidence of panitumumab activity in colorectal cancer has appeared in meeting report abstracts. One phase II study in monotherapy, one in combination with chemotherapy, and one phase III study have included only patients with metastatic colorectal cancer.

Clinical potential:

To date, in phase II clinical studies panitumumab has demonstrated antitumor activity in advanced, refractory colorectal cancer. As monotherapy it resulted in a 10% response rate with 38% of patients having stable disease, and a 36% response rate with 46% stable disease when combined with chemotherapy. A phase III study indicates a clinically significant advantage of panitumumab as third-line monotherapy over best supportive care. Panitumumab appears to have a good tolerability profile, with no maximum tolerated dose yet defined.     

Epidermal growth factor receptor monoclonal antibodies for the treatment of metastatic colorectal cancer

Treatment of metastatic colorectal disease has evolved over the last decade. Two epidermal growth factor receptor (EGFR) monoclonal antibodies--cetuximab and panitumumab--have been developed in an effort to provide yet another therapeutic option. The EGFR is a transmembrane glycoprotein, expressed constitutively throughout the body and found on many epithelial tissues. The monoclonal antibodies bind to and inhibit the activation of the receptor in the body. This inhibition prevents tumor cell growth, angiogenesis, invasion, and metastasis, and induces apoptosis. Cetuximab and panitumumab exhibit nonlinear pharmacokinetics. Both monoclonal antibodies are approved for the treatment of refractory metastatic colorectal cancer. Cetuximab in combination with irinotecan has significantly better response rates and progression-free survival compared with those of cetuximab or irinotecan alone. Cetuximab and panitumumab as monotherapy have shown significantly better response rates and progression-free survival compared with best supportive care in patients refractory to irinotecan and oxaliplatin. In the Cetuximab Combined with Irinotecan in First Line Therapy for Metastatic Colorectal Cancer (CRYSTAL) trial, treatment-na?ve patients received cetuximab in combination with the chemotherapy regimen infusional leucovorin, fluorouracil, and irinotecan (FOLFIRI) or FOLFIRI alone; the difference in progression-free survival was statistically significant but suggested only a modest benefit over FOLFIRI alone (8.9 vs 8 mo, p=0.036). Results of a preplanned analysis of the first 231 events in the Panitumumab Advanced Colorectal Cancer Evaluation (PACCE) trial favored the control group (chemotherapy regimen with folinic acid [leucovorin], fluorouracil, and oxaliplatin [FOLFOX] plus bevacizumab) instead of the control group plus panitumumab. For clinical consideration, many trials have shown that the intensity or absence of EGFR expression is not a clinically significant predictor of outcomes. Development and intensity of a rash are suggested to be a positive predictor of outcomes in patients. The most common adverse events of EGFR monoclonal antibody therapy are rash, diarrhea, and hypomagnesemia. Other serious but not common adverse events include hypersensitivity reactions and pulmonary toxicity. The availability of EGFR monoclonal antibodies has provided another weapon in the arsenal to treat refractory metastatic colorectal cancer. They have shown safety and efficacy in combination with other chemotherapy regimens and as monotherapy; however, their use as metastatic colorectal cancer therapy needs to be further explored.     

Cetuximab: in the treatment of metastatic colorectal cancer

Cetuximab is a chimeric monoclonal antibody highly selective for the epidermal growth factor receptor (EGFR), which is over-expressed by 25-80% of colorectal cancer tumours and associated with advanced disease. Cetuximab induces a broad range of cellular responses in tumours expressing EGFR, enhancing sensitivity to radiotherapy and chemotherapeutic agents. In a large, randomised, open-label, multicentre study in adult patients with irinotecan-refractory, metastatic colorectal cancer expressing EGFR, cetuximab 400 mg/m2 initial dose followed by 250 mg/m2 weekly plus irinotecan (various doses) produced a greater rate of partial response and disease control (partial response plus stable disease), and increased time to disease progression, compared with cetuximab monotherapy; survival was similar in both groups. The same dosage of cetuximab combined with irinotecan, fluorouracil and folinic acid (various regimens) produced partial responses in 43-58% of patients, a complete response in 5% of patients (one study only) and stable disease in 32-52% of patients with treatment-naive metastatic colorectal cancer expressing EGFR in three small, open-label trials. The most common grade 3/4 adverse events associated with cetuximab monotherapy were acne-like rash, asthenia, abdominal pain and nausea/vomiting. In patients receiving cetuximab plus irinotecan, these were diarrhoea, asthenia, leucopenia and neutropenia.     

Phase II study of second-line oxaliplatin, irinotecan and mitomycin C in patients with advanced or metastatic colorectal cancer

The aim of this phase II study was to investigate the therapeutic value of second-line treatment with oxaliplatin, irinotecan (CPT-11) and mitomycin C (MMC) in patients with metastatic colorectal cancer pretreated with 5-fluorouracil (5-FU)-based chemotherapy. A total of 10 patients with metastatic colorectal cancer, all of whom had developed progressive disease from advanced or metastatic colorectal cancer while receiving or within 6 months after discontinuing first-line chemotherapy with 5-FU and leucovorin, were entered in this study. At the time of relapse, cytotoxic chemotherapy consisting of oxaliplatin 80 mg/m2 plus CPT-11 80 mg/m2 given i.v. on therapeutic day 1, and MMC 6 mg/ m2 given i.v. on day 15, respectively, was initiated. Treatment courses were repeated every 4 weeks for a total of six courses unless there was prior evidence of progressive disease. The overall response rate was 30% with three partial responses for all 10 assessable patients. Two additional patients (20%) had stable disease and five patients (50%) progressed. The median overall survival duration has not been reached yet and is longer than 7.1 months (range 2-23.5+) from the beginning of second-line therapy. Four patients are currently alive with progressive disease. The tolerance of second-line treatment was generally mild to moderate and easy to treat. Our data suggest that the combination of oxaliplatin, CPT-11 and MMC in patients with metastatic colorectal cancer pretreated with 5-FU-based chemotherapy is feasible and has substantial antitumor activity. Further evaluation of this regimen seems warranted.     

Sunitinib

Sunitinib and its active metabolite (SU012662) are selective inhibitors of multiple receptor tyrosine kinases associated with tumour growth and angiogenesis. The clinical efficacy of oral sunitinib has been demonstrated in patients with advanced gastrointestinal stromal tumours (GIST). In a phase III, randomised, double-blind, placebo-controlled, multicentre trial in patients with metastatic and/or unresectable GIST following unsuccessful imatinib therapy, the median time to tumour progression and median progression-free survival time were > or =4-fold longer in patients receiving sunitinib 50 mg/day than in those receiving placebo, in 6-week cycles consisting of 4 weeks of treatment followed by a 2-week rest period. Sunitinib also exhibited antitumour activity in patients with advanced renal cell carcinoma (RCC) following unsuccessful cytokine therapy. In two multicentre, single-arm, phase II clinical trials in patients with cytokine-refractory metastatic RCC, partial responses were reported in 40% and 43% of patients receiving sunitinib 50 mg/day for 4 weeks followed by 2 weeks without treatment in 6-week cycles; 27% and 22% of patients achieved stable disease for > or =3 months. Sunitinib was more effective than interferon-alpha as a first-line therapy in patients with metastatic RCC. In a large, well designed, phase III trial in previously untreated patients, progression-free survival was significantly longer in patients receiving sunitinib 50 mg/day in 6-week cycles (4 weeks of treatment followed by a 2-week rest period) compared with those receiving interferon-alpha 9MU three times weekly (47.3 vs 24.9 weeks). In general, sunitinib was well tolerated in patients with GIST and RCC, with adverse events usually being of mild or moderate severity.     

Docetaxel in hormone-refractory metastatic prostate cancer

The taxoid analogue docetaxel is a potent inhibitor of microtubular depolymerisation and, in hormone-refractory metastatic prostate cancer, it also counters the effects of the anti-apoptotic protein Bcl-2. Overall survival was significantly increased in patients with hormone-refractory metastatic prostate cancer receiving intravenous docetaxel every 3 weeks plus oral prednisone or estramustine, compared with patients receiving intravenous mitoxantrone every 3 weeks plus prednisone in two large phase III trials (TAX 327 and SWOG [Southwest Oncology Group] 9916). In the TAX 327 study, patients receiving docetaxel 75 mg/m(2) every 3 weeks plus prednisone had a median overall survival duration of 18.9 months; in the SWOG 9916 study, median overall survival duration was 17.5 months with docetaxel 60 mg/m(2) every 3 weeks plus estramustine 280 mg three times daily on days 1-5. The median overall survival duration for the control arm of mitoxantrone 12 mg/m(2) every 3 weeks plus prednisone was 16-17 months. Compared with mitoxantrone plus prednisone, docetaxel plus prednisone improved prostate specific antigen response rate, pain and health-related quality of life, and docetaxel plus estramustine increased progression-free survival. Adverse events were more common with docetaxel- than mitoxantrone-based treatment regimens, but most events associated with docetaxel were mild-to-moderate in severity.     

Clinical advances with topoisomerase I inhibitors in gastrointestinal malignancies

Phase III studies have shown irinotecan prolongs survival significantly when compared with either best supportive care or best infusional 5-fluorouracil (5-FU)-based chemotherapy in patients with 5-FU-resistant colorectal cancer. Phase I/II studies are investigating the combination of irinotecan with 5-FU, with thymidylate synthase inhibitors, notably raltitrexed, and with the oral fluoropyrimidines. Preliminary results suggest irinotecan and raltitrexed can safely be combined in the clinic and that this combination is active. The combination of irinotecan with the oral fluoropyrimidines also has produced promising results. A phase I study of irinotecan plus 5-FU/folinic acid showed high activity in first-line metastatic disease and further trials using the doses of 80 mg/m2 irinotecan plus 2 g 5-FU weekly are recommended. The combination of irinotecan with the De Gramont 5-FU regimen is feasible and active in patients with 5-FU-resistant metastatic disease. Alternating exposure to irinotecan and 5-FU may be as active as either treatment alone, and has been associated with overall response rates (ORRs) greater than 30% and encouraging median survival. The combination of irinotecan with oxaliplatin is also feasible and levels of response rates are in the region of 50% (especially with a 2-weekly administration schedule). In patients with advanced gastric cancer (including those with pretreated disease) ORRs of around 50% have been reported following administration of either cisplatin plus irinotecan or cisplatin plus docetaxel.     

Capecitabine: a review of its pharmacology and therapeutic efficacy in the management of advanced breast cancer

Capecitabine is an orally administered prodrug of fluorouracil which is indicated in the US and Europe, in combination with docetaxel, for the treatment of patients with metastatic breast cancer failing anthracycline therapy, and as monotherapy for metastatic breast cancer resistant to paclitaxel and anthracycline therapy (US) or failing intensive chemotherapy (Europe). Capecitabine is also approved for use in metastatic colorectal cancer. Capecitabine is metabolically activated preferentially at the tumour site, and shows antineoplastic activity and synergy with other cytotoxic agents including cyclophosphamide or docetaxel in animal models. Bioavailability after oral administration is close to 100%. In patients with pretreated advanced breast cancer, capecitabine is effective as monotherapy and also in combination with other agents. Combination therapy with capecitabine 1,250 mg/m(2) twice daily for 2 weeks of every 3-week cycle plus intravenous docetaxel 75 mg/m(2) on day one of each cycle was superior to intravenous monotherapy with docetaxel 100 mg/m(2) on day one of each cycle. Capecitabine plus docetaxel significantly reduced the risks of disease progression and death by 35% (p = 0.0001) and 23% (p < 0.05), respectively, and significantly increased median survival (p < 0.05) and objective response rates (p < 0.01). Efficacy has also been demonstrated with capecitabine monotherapy and combination therapy in previously untreated patients in preliminary trials. The most common adverse effects occurring in patients receiving capecitabine monotherapy include lymphopenia, anaemia, diarrhoea, hand-and-foot syndrome, nausea, fatigue, hyperbilirubinaemia, dermatitis and vomiting (all >25% incidence). While gastrointestinal events and hand-and-foot syndrome occurred more often with capecitabine than with paclitaxel or a regimen of cyclophosphamide, methotrexate and fluorouracil (CMF), neutropenic fever, arthralgia, pyrexia and myalgia were more common with paclitaxel, and nausea, stomatitis, alopecia and asthenia were more common with CMF. The incidence of adverse effects and hospitalisation was similar in patients receiving capecitabine plus docetaxel and those receiving docetaxel monotherapy. In conclusion, capecitabine, an oral prodrug of fluorouracil which is activated preferentially at the tumour site, is an effective and convenient addition to the intravenous polychemotherapeutic treatment of advanced breast cancer in pretreated patients, and also has potential as a component of first-line combination regimens. Combined capecitabine plus docetaxel therapy resulted in similar rates of treatment-related adverse effects and hospitalisation to those seen with docetaxel monotherapy. Capecitabine is also effective as monotherapy in pretreated patients and phase II data for capecitabine as first-line monotherapy are also promising. While gastrointestinal effects and hand-and-foot syndrome occur often with capecitabine, the tolerability profile was comparatively favourable for other adverse effects (notably, neutropenia and alopecia).     

Oral tegafur/uracil

Tegafur is a prodrug of the antineoplastic agent fluorouracil, and is administered in a 1:4 molar ratio with the fluorouracil modulator uracil. Oral tegafur/uracil 300 mg/m(2)/day plus calcium folinate 75 or 90 mg/day for 28 days every 35 days was as effective as intravenous (IV) fluorouracil 425 mg/m(2)/day plus folinic acid 20 mg/m(2)/day for 5 days every 28 or 35 days in the treatment of patients with metastatic colorectal cancer in two large, randomised, nonblind, multicentre trials (n = 816 and 380). Median survival time among patients treated with tegafur/ uracil or fluorouracil was approximately 12 months in both trials. Results from both trials also demonstrated no significant between-group differences in overall response rates among patients treated with oral tegafur/uracil (12 and 11%) or IV fluorouracil (15 and 9%). In elderly patients (aged > or = 70 years) with metastatic colorectal cancer, results from small noncomparative studies showed that treatment with oral tegafur/uracil afforded overall response rates of 12.5 to 29% and was well tolerated. During preoperative treatment with oral tegafur/uracil plus calcium folinate as an adjunct to radiotherapy in patients with stage II or III rectal cancer, the maximum tolerated dosage of tegafur/uracil was 350 mg/m(2)/day (administered 5 days per week for 5 weeks). Among the 15 patients who were followed for 5 to 8 months, three had a complete response to treatment. Treatment with tegafur/uracil was also given postoperatively. The most common adverse events associated with oral tegafur/uracil were anaemia, nausea/vomiting, diarrhoea, thrombocytopenia, mucositis, neutropenia, asthenia, anorexia and abdominal pain. Oral tegafur/uracil was associated with a significantly more favourable tolerability profile than IV fluorouracil in the two large randomised trials. In particular, stomatitis and most adverse haematological events were less frequent.     

Trastuzumab: in HER2-positive metastatic gastric cancer

Trastuzumab is a recombinant humanized IgG? monoclonal antibody directed against the extracellular domain of the human epidermal growth factor receptor type 2 (HER2) that inhibits HER2-dependent tumour cell proliferation and survival. Proliferation of gastric cancer cells overexpressing HER2 is inhibited by trastuzumab in vitro and in vivo. HER2-positive expression (defined as immunohistochemistry 3+ or fluorescence in situ hybridization-positive) was observed in 22.1% of almost 4000 metastatic gastric cancers in patients who were screened for randomization in the open-label, multicentre, phase III ToGA trial. In patients with HER2-positive metastatic gastric cancer (n?=?584), median overall survival (primary endpoint) was significantly longer for recipients of intravenous trastuzumab plus chemotherapy (comprising cisplatin and either fluorouracil or capecitabine) than in those receiving chemotherapy alone in the ToGA trial. Furthermore, the overall response rate was significantly higher and the median time to disease progression and median time of progression-free survival were also significantly longer with trastuzumab plus chemotherapy than with chemotherapy alone. In general, combination therapy with trastuzumab and chemotherapy was relatively well tolerated in patients with metastatic gastric cancer with no reports of new or unexpected adverse events.     

Prospective multicenter phase II study of irinotecan as third-line therapy in metastatic colorectal cancer and progression after bolus and infusional 5-fluorouracil

Irinotecan has proven anti-tumor activity as induction treatment in combination with 5-fluorouracil (5-FU) or as second-line treatment after 5-FU in patients with metastatic colorectal cancer. The aim of the present phase II study was to evaluate irinotecan as third-line chemotherapy in patients with colorectal cancer after sequential treatment with bolus 5-FU followed by an infusional 5-FU regimen. Patients pretreated with bolus 5-FU/folinic acid and the infusional 5-FU/folinic acid regimen were treated with 350 mg/m irinotecan i.v. once every 3 weeks in a multicenter phase II study. Tumor size was measured every cycle and treatment with irinotecan was continued until the occurrence of progressive disease or unacceptable toxicity. A total of 50 pretreated patients were included. Of the 45 evaluable patients, 13.3% [n=6, 95% confidence interval (CI) 5.1-26.8] attained a response (complete/partial response) to treatment lasting 5.6 months (95% CI 4.2-6.3) and in four patients response has been confirmed (8.9%, 95% CI 2.5-21.2). Disease stabilization was noted in 51.1% of the patients (n=23, 95% CI 35.8-66.3). The median duration of response/disease stabilization was 4.2 months (95% CI 3.2-6.0). Median overall survival was 7.9 months (95% CI 6.1-11.1), corresponding to a calculated 1-year survival of 28.3% (95% CI 15.2-41.3). Severe neutropenia occurred in 14% (n=7) and anemia grade III in 6% of the patients (n=3). The most frequent non-hematological toxicity grade III/IV related to treatment was diarrhea in 24% of the patients (n=12), followed by vomiting in 8% (n=4) and constipation as well as infection in two patients each (4%) (evaluable n=50). We conclude single-agent irinotecan is an effective and well-tolerable treatment in pretreated patients with metastatic colorectal cancer after failure of bolus and infusional 5-FU/folinic acid regimens. Elderly patients had the same probability to respond.     

Cetuximab: a review of its use in squamous cell carcinoma of the head and neck and metastatic colorectal cancer

Cetuximab (Erbitux) is a human-mouse chimeric monoclonal antibody, which competitively binds to the accessible extracellular domain of the epidermal growth factor receptor (EGFR) to inhibit dimerisation and, subsequently, inhibit tumour growth and metastasis. In the EU and the US, cetuximab has been approved for use with concomitant radiotherapy in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN) and in combination with irinotecan for the treatment of metastatic colorectal cancer (mCRC) in patients with EGFR-expressing tumours who are refractory to irinotecan-based therapy. In the US, cetuximab has also been approved as monotherapy in patients with recurrent or metastatic SCCHN for whom platinum-based therapy has failed and in patients with mCRC who are intolerant of irinotecan-based regimens.In treatment-naive patients with locoregionally advanced SCCHN, cetuximab plus radiotherapy was more effective than radiation therapy alone in prolonging locoregional disease control. In addition, more limited noncomparative data from a large trial indicated a 13% overall objective response rate (ORR) in platinum-refractory patients with SCCHN. In patients with EGFR-expressing mCRC, cetuximab plus irinotecan improved ORR more than cetuximab monotherapy in a trial in irinotecan-refractory patients; however, there was no difference in overall survival (OS) between cetuximab plus irinotecan and cetuximab monotherapy in oxaliplatin-refractory recipients in another trial. In an ongoing trial, progression-free survival (PFS) exceeded 50% after 12 weeks in irinotecan-refractory patients receiving three different dosages of cetuximab plus irinotecan. In another large trial, cetuximab monotherapy prolonged OS compared with best supportive care (BSC) in heavily pretreated patients. Overall, cetuximab treatment had an acceptable tolerability profile, with the majority of adverse events being mild or moderate in severity and clinically manageable. In particular, cetuximab therapy did not exacerbate toxicities commonly associated with chemo- or radiotherapeutic regimens. Albeit occurring with high incidence, adverse cutaneous reactions appear to be a marker for response. Results of ongoing head-to-head comparative trials comparing cetuximab with other biological agents will help to establish definitively the role of cetuximab in the management of SCCHN and mCRC. In the meantime, cetuximab, with its highly targeted mechanism of action and synergistic activity with current treatment modalities, is a valuable treatment option in patients with SCCHN and mCRC.     

Advanced therapies on BRAF-mutated and KRAS-mutated metastatic colorectal cancer

Colorectal cancer(CRC) is one of the most-diagnosed cancer worldwide, and 30% of patients with CRC have showed a metastatic situation. Monoclonal antibodies(mAbs) that target vascular endothelial growth factor(VEGF) and the epidermal growth factor receptor(EGFR) can achieveantitumor efficacy via antivascular and anticellular effects respectively and have been added into first-line chemotherapy for patients with metastatic colorectal cancer(mCRC). Investigations found that unlike VEGF inhibitors, the efficacy of EGFR inhibitors,such as Cetuximab and panitumumab, is limited to patients with wild-type-KRAS tumors without BRAF mutant. Studies revealed that resistance to EGFR inhibitors result in the poor response to anti-EGFR therapiesthrough acquired mutations of KRAS and BRAF.Considering this situation, in this review, we will focus onresistance mechanism to anti-EGFR therapies and advanced therapies for BRAF-mutated and KRAS-mutated mCRC patients.     

Q-TWiST analysis of panitumumab plus FOLFOX4 versus FOLFOX4 alone in patients with previously untreated wild-type RAS metastatic colorectal cancer

Introduction:

Panitumumab plus infusional 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) significantly improved overall survival versus FOLFOX4 alone in patients with previously untreated wild-type RAS metastatic colorectal cancer (mCRC). We applied a quality-adjusted time without symptoms of disease or toxicity (Q-TWiST) analysis to provide an integrated measure of clinical benefit, with the objective of comparing quality-adjusted survival between the two arms. We acknowledge that there are limitations associated with Q-TWIST methodology for crossover trials.

Methods:

For each treatment arm, the truncated mean times spent in the toxicity (TOX: grade 3 or 4 adverse events), time without symptoms of disease or toxicity (TWiST), and relapse (REL: after disease progression) states were estimated by the product-limit method, and adjusted using utility weights derived from patient-reported EuroQol 5-dimension measures. Sensitivity analyses were performed in which utility weights (varying from 0 to 1) were applied to time in the TOX and REL health states.

Results:

Quality-adjusted overall survival time was statistically significantly longer with panitumumab plus FOLFOX4 (20.5 months) than with FOLFOX4 alone (18.2 months) (P?=?0.025).

Conclusion:

In patients with previously untreated wild-type RAS mCRC, panitumumab plus FOLFOX4 significantly improved quality-adjusted survival compared with FOLFOX4 alone.     

Biweekly oxaliplatin plus irinotecan and folinic acid-modulated 5-fluorouracil: a phase II study in pretreated patients with metastatic colorectal cancer

Oxaliplatin (OXA) and irinotecan (IRI) are active drugs for metastatic colorectal cancer, their toxicity profiles are not overlapping, and both drugs have shown at least additivity with folinic acid-modulated 5-fluorouracil (5FU). We carried out this phase II study to assess the activity and toxicity of a biweekly regimen including OXA plus IRI on day 1, and levo-folinic acid (LFA) plus 5FU on day 2 (OXIRIFAFU) in pretreated patients with metastatic colorectal cancer. Forty-one patients, all previously treated with adjuvant and/or palliative 5FU-based chemotherapy (16 of them already exposed to IRI, OXA or both), were enrolled into this trial. On the basis of sensitivity to previous treatment, 19 patients were considered as chemo-resistant and 14 patients as chemo-refractory. OXA 110 mg/m (over 2 h) and IRI 175 mg/m (over 1 h) were delivered on day 1, followed by LFA 250 mg/m (2-h infusion) plus 5FU 800 mg/m as intravenous bolus on day 2. Cycles were repeated every 2 weeks. A total of 348 cycles were delivered, with a median of nine cycles per patient (range, 1-12 cycles per patient). Five complete and 13 partial responses were reported on 40 assessable patients, giving a response rate of 45% [95% confidence interval (CI), 29-62%]; eight of 19 (42%) resistant patients and five of 14 (36%) refractory patients achieved a major response, which was also obtained in four of eight (50%) patients pretreated with IRI and in three of eight (38%) patients pretreated with OXA. Grade 3 or higher neutropenia occurred in 68% of patients, but febrile neutropenia or infections affected only seven (17%) patients. No episodes of grade 3 or higher thrombocytopenia or anemia were recorded. Occurrence of severe non-hematologic toxicities by patients were: diarrhea, 34%; vomiting, 17%; peripheral cumulative neuropathy, 15%; stomatitis, 10%; acute cholinergic syndrome, 7%. Actually delivered dose intensities of all three drugs resulted in about two-thirds of the planned ones. After a follow-up of 39 months, median progression-free survival was 7.5 months. Median overall survival was 14.4 (95% CI, 10.4-18.4) months from the start of OXIRIFAFU and 25.3 (95% CI, 18.1-32.5) months from the diagnosis of metastatic disease. This OXIRIFAFU triplet regimen was highly effective in resistant/refractory colorectal cancer patients. A slight dose reduction of all cytotoxic drugs could be advisable in order to improve the tolerability of this regimen without jeopardizing its activity.