Promising Response Rates In Patients Research Articles

AFT-50 EndoMAP: A phase IB/II multicohort study of targeted agents and/or immunotherapy for patients with recurrent or persistent endometrial cancer (EC).

TPS5642 Background: The landscape in the management of recurrent or persistent endometrial cancer (EC) continues to evolve. Anti-PD-1/PD-L1 immune checkpoint inhibitors (ICI) as monotherapy or when combined with the VEGF-targeted tyrosine kinase inhibitor, lenvatinib, have demonstrated promising response rates in patients (pts) with microsatellite instability-high (MSI-H)/mismatch repair-deficient (dMMR) and MS-stable (MSS)/MMR-proficient (MMRp) EC, respectively. Recent studies have also shown a benefit with adding ICI to standard of care chemotherapy in the frontline setting. Pts with MSI-H/dMMR tumors seem to derive the greatest benefit. Approximately, 30% of recurrent EC pts fall into this category. Pairing ICI with targeted therapies carries the potential to elicit prolonged anti-tumor effects. Atezolizumab (Atezo) is a humanized monoclonal PD-L1 inhibitor that has demonstrated monotherapy antitumor activity in relapsed recurrent EC, and other solid tumors (e.g. NSCLC, HCC) as monotherapy and as part of combinatorial therapy. The AFT-50/EndoMAP study is a phase IB/II non-randomized, multicenter, 2-arm, multi-cohort platform trial designed to evaluate the efficacy and safety of biomarker-driven combination regimens, both with Atezo (AFT-50A) and without Atezo (AFT-50B) with biomarker-defined targeted agents in pts with recurrent or persistent EC. Methods: Eligible pts have recurrent or persistent EC with no more than 2 prior lines of therapy. FoundationOne CDx (F1CDx) NGS assay will be used for genomic tumor profiling. In AFT-50A, pts may be eligible for one of the following doublets: Atezo+talazoparib (tumors with genomic loss of heterozygosity (gLOH ≥16%), Atezo+Trastuzumab emtansine (ERBB2/HER2 mutated or amplified tumors), and Atezo+Tiragolumab (MSI-H and/or TMB-H). The Atezo+bevacizumab (biomarker unmatched) and Atezo+ipatasertib (PIK3CA/PTEN/AKT1-altered tumors) cohorts have completed accrual. Each cohort will enroll ~20 pts with potential adjustment to account for statistical and clinical considerations. AFT-50A pts will receive Atezo in addition to a targeted agent (per study-approved dosing schedule) until progression, unacceptable toxicity, pt withdrawal, death, or study termination. AFT-50B pts will be eligible for inavolisib (PIK3CAm/PTEN and AKT1wt-altered tumors) + letrozole or giredestrant + abemaciclib (RB1wt, estrogen receptor positive tumors). The primary endpoint for AFT-50A is confirmed overall response rate (ORR) for each arm, and for AFT-50B is 6-month progression free survival. Secondary endpoints include disease control rate, duration of response, OS, safety and tolerability. As a platform study, additional arms may be added, as supported by evolving understanding of EC and molecular targets. EndoMAP is actively enrolling at 20 sites in the US with a target of 25 sites nationwide. Clinical trial information: NCT04486352 .

Selinexor in Combination with R-GDP/R-ICE Regimen for Refractory Aggressive Large B-Cell Lymphoma Patients with TP53 Alterations

BackgroundTP53 has been identified as one of the most frequently altered gene in large B-cell lymphoma (LBCL). The prognosis of LBCL patients (pts) with TP53 mutations is poor in R-CHOP era, even treated with autologous stem-cell transplantation (ASCT) or anti-CD19 chimeric antigen receptor T-cell (CAR-T) therapy. Furthermore, TP53 mutation rate was much higher in LBCL pts who acquired relapsed or refractory (R/R) disease and associated with therapeutic resistance. Selinexor is a selective inhibitor of nuclear export with promising anti-cancer properties. Several clinical studies have proved selinexor in combination with R-GDP/R-ICE was effective in relapsed/refractory LBCL and preclinical studies reported that selinexor could suppress tumor cells with TP53 mutations. Method Relapsed/refractory LBCL pts with TP53 alterations (including TP53 mutation and/or deletion) were enrolled to be treated with selinexor plus R-GDP/R-ICE since November 2021 in our center. Selinexor was administered orally (40 mg day 1, 8, 15) plus R-GDP (R 375mg/m2 d0, gemcitabine 1g/m2×d1, cisplatin 25mg/m2 d1-d3, dexamethasone 40mg d1-d4) or R-ICE (R 375mg/m2 d0, ifosfamide 1.5g/m2×3d, carboplatin (AUC 5) and etoposide 100mg/m2×3d) every 3 weeks as per physician's choice. Objective response rate (ORR) was evaluated every 3 cycles based on Lugano 2014 criteria and Adverse events (AE) were rated according to the NCI CTCAE 5.0. Results In total, eleven patients treated with at least 3 cycles of selinexor plus R-GDP/R-ICE and were eligible for initial efficacy evaluation. The median age of the 11 pts was 63 years (range 18 to 77), 7 pts (63.6%) were male, 5 pts (45.5%) had stage III-IV disease, 63.6% of patients with IPI intermediate to high risk. The median number of prior regimen was 2 (range, 1-4), with 2 patients (3 L) and 1 patient (4L). 9 pts were refractory to the last regimen. The mutational profile was presented in Figure 1 (7 patients with TP53 mutation, 3 patients with TP53 mutation and deletion, 1 patient with TP53 deletion). Pts received a median of four cycles (range, 3-6) of selinexor 40mg once a week combined with R-GDP/R-ICE (9 patients received selinexor plus R-GDP and 2 received selinexor plus R-ICE) (Table 1). The most common treatment-related adverse events were grade 1 or 2, including nausea (81.8%), fatigue (81.8%), and anorexia (27.3%) and the most common grade 3 or 4 adverse events were hematological toxicities including neutropenia (63.6%), thrombocytopenia (45.5%)，anemia (9.0%). 2 pts after interim evaluation with PR stopped treatment for one month due to gastrointestinal toxicities and had disease progression. Both of them continued to receive their prior regimen (selinexor-RGDP and selinexor-RICE regimen, respectively). Of the ten evaluable patients, the overall and complete response rates at interim evaluation were 100% and 20%, respectively (the left patient will have interim evaluation at the mid of August). ConclusionsTP53 alterations are an established poor outcome marker in LBCL. To our knowledge, this is the first report on TP53-altered relapsed/refractory aggressive B-cell lymphomas treated upon the combination of selinexor and chemotherapy. The new exploration showed promising response rates in patients with relapsed/refractory TP53-altered LBCL and was well tolerated. In addition, clinicians should be cautious to its GI toxicities with more proactive prevention and management measures. Selinexor (40mg qw) with R-GDP/R-ICE is worthy of further study based on the preliminary efficacy results. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Abstract A18: Investigating CDK4/6 inhibition in triple-negative breast cancer

Abstract The purpose of our study is to investigate the immunologic effects of CDK4/6 inhibitors in triple-negative breast cancer (TNBC), a highly aggressive breast cancer subtype for which there are no targeted therapies. CDK4/6 inhibitors, including the recently FDA approved abemaciclib, show promising response rates in patients with advanced stage hormone receptor-positive (HR+) breast cancer. Our previous report established that CDK4/6 inhibitors promote antitumor immunity by inducing tumor cell antigen presentation by activating tumor endogenous retroviral elements, which induce type III interferon production and MHC-I upregulation (Goel, DeCristo, et al., Nature 2017). In addition, CDK4/6 inhibitors decrease T regulatory cell proliferation without affecting cytotoxic CD8 T-cell numbers. TNBC has been considered a poor candidate for CDK4/6 inhibitor therapy, as tumors often lose Rb protein expression, which is critical for CDK4/6 inhibitor-induced cell cycle arrest. However, reports show around 50%-70% TNBC still has intact RB. We found murine and human TNBC cell lines that express Rb to varying extents and decrease proliferation in vitro in response to abemaciclib. In our preclinical model of TNBC, abemaciclib induced tumor regression. Consistent with previous findings, TNBC tumor cells upregulated MHC-I upon abemaciclib treatment, suggesting increased antigen presentation. Tumor cell-surface PD-L1 was also increased with abemaciclib both in vitro and in vivo, as assessed by flow cytometry and RT-qPCR. These results are encouraging, since a recent trial evaluating αPD-L1 therapy (atezolizumab) reported enhanced progression-free survival in patients with PD-L1+ tumors. These data suggest the potential efficacy of CDK4/6 inhibitors in combination with αPD-L1 in the treatment of TNBC, as we previously reported in our Her2+ model. Abemaciclib also increased total CD8+ and CD4+ T cells and decreased PD1+ CD8 and CD4 cells in the spleen. Furthermore, total numbers of naive CD8+ and CD4+ T cells increased with abemaciclib treatment in the spleen, suggesting a favorable antitumor systemic immunologic effect. CDK4/6 inhibitors might therefore show efficacy in treating TNBC. Deeper analysis of the mechanisms involved in regulating PD-L1 and enhancing naive T cells should enable us to evaluate combination therapies using CDK4/6 inhibitors for this particularly deadly breast cancer subtype. Citation Format: Qiuchen Guo, Gregory J. Goreczny, Adam Maynard, Milos Spasic, Sandra S. McAllister. Investigating CDK4/6 inhibition in triple-negative breast cancer [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr A18.

Efficiency and safety of autologous chimeric antigen receptor T-cells therapy used for patients with lymphoma: A systematic review and meta-analysis.

Chimeric antigen receptor (CAR) T-cell therapy has produced promising response rates in patients with B cell malignancies. However, previous meta-analyses have demonstrated that CAR T-cell efficacy is unsatisfactory in patients with lymphoma unlike in patient with other hematological malignancies, but these studies included insufficient numbers of studies and patients with lymphoma. Furthermore, clinicians are interested in the effects of infusion dose, CAR structure, interleukin-2 (IL-2), and conditioning therapy regimen. All clinical trials administering autologous CAR T-cell therapy in lymphoma patients were searched in medical databases. A traditional meta-analysis was performed to assess the safety and efficacy of CAR T-cells in lymphoma treatment. Subgroup analysis was performed to determine the relationships between potential factors and efficacy. The best overall response rate (ORR), 6 month ORR (6m ORR), and severe cytokine release syndrome (sCRS) rate were calculated by Stata 14.0. A total of 411 patients across all the studies were included. Our analysis showed a best ORR of 0.71, a 6m ORR of 0.63, and an overall CRS (grade ≥ 3) rate of 0.18. The subgroup analysis showed that increased response rates and reduced CRS (grade ≥ 3) rates were associated with a low dose of CAR T-cells. No IL-2 administration and the use of a fludarabine-containing lymphodepletion regimen led to improved efficacy, while anti-CD19 CAR T cells led to a more successful outcome than anti-CD20 CAR T cells. In addition, 2nd- and 3rd-generation CAR T cells exhibited increased effectiveness in clinical studies, and no significant effect diversity was found between the 2nd- and 3rd-generation CAR T cells. sCRS was associated with a high dose of infused CAR T cells when IL-2 and fludarabine were excluded from the positive factors for sCRS. CAR T cells are promising in the treatment of relapsed or refractory lymphoma. Doses lower than 10/m, no IL-2 administration, fludarabine administration, and anti-CD19 CAR T cells were related to improved efficacy and safety.

Oral Azacitidine (CC-486) Plus R-CHOP in Patients with High-Risk or Previously Untreated Diffuse Large B-Cell Lymphoma, Grade 3B Follicular Lymphoma, or Transformed Lymphoma (AFT-08)

Oral Azacitidine (CC-486) Plus R-CHOP in Patients with High-Risk or Previously Untreated Diffuse Large B-Cell Lymphoma, Grade 3B Follicular Lymphoma, or Transformed Lymphoma (AFT-08)

Zuma-6: Phase 1-2 multicenter study evaluating safety and efficacy of axicabtagene ciloleucel (axi-cel; KTE-C19) in combination with atezolizumab in patients with refractory diffuse large b-cell lymphoma (DLBCL).

TPS7572 Background: Approximately 1/3 of patients with DLBCL, the most common type of B-cell lymphoma, will become refractory to standard combination chemotherapy and have uniformly poor clinical outcomes (Crump, ASCO 2016). Axi-cel (autologous anti-CD19 chimeric antigen receptor [CAR] T cell therapy) has shown promising response rates in patients with refractory DLBCL compared with standard approaches, although some patients do not respond or progress after an initial response (Locke, Mol Ther 2016). Expression of PD-L1 on DLBCL cells and activation-dependent expression of PD-1 on CAR T cells after infusion led to the hypothesis that PD-1 pathway blockade may augment the activity of axi-cel and result in improved clinical outcomes. This study will evaluate safety and efficacy of axi-cel when given with atezolizumab (anti–PD-L1 antibody), delivered sequentially, in patients with refractory DLBCL. Methods: Phase 1 will enroll ~3-9 patients to estimate the incidence of dose-limiting toxicities. Phase 2 will enroll ~22 patients to evaluate safety and efficacy, with a primary endpoint of complete response (CR) rate (Cheson 2007). Secondary endpoints include key efficacy outcomes such as objective response rate (CR+partial response [PR]), duration of response, progression-free and overall survival, and safety and biomarker outcomes. Eligible adult patients will have received prior adequate therapy (including anti-CD20 monoclonal antibody and an anthracycline-based regimen) and have an ECOG PS of 0-1 and adequate bone marrow and organ function. Patients with a history of Richter transformation, transformed follicular lymphoma, CNS disease, or active infection are not eligible. Patients will receive fludarabine 30 mg/m2/d and cyclophosphamide 500 mg/m2/d × 3 d, followed by a single infusion of axi-cel (target dose, 2 × 106anti-CD19 CAR T cells/kg) followed by atezolizumab 1200 mg given every 21 d for 4 doses (phase 1, first dose to occur 21, 14, and 1 d after axi-cel infusion in cohorts 1, 2, and 3, respectively). The study opened to accrual in September 2016. Clinical trial information: NCT02926833.

Polatuzumab Vedotin Combined with Bendamustine (B) and Rituximab (R) or Obinutuzumab (G) in Patients with Relapsed or Refractory (R/R) Follicular Lymphoma (FL) or Diffuse Large B-Cell Lymphoma (DLBCL): Preliminary Results of a Phase Ib/II Dose-Escalation Study

Polatuzumab Vedotin Combined with Bendamustine (B) and Rituximab (R) or Obinutuzumab (G) in Patients with Relapsed or Refractory (R/R) Follicular Lymphoma (FL) or Diffuse Large B-Cell Lymphoma (DLBCL): Preliminary Results of a Phase Ib/II Dose-Escalation Study

Cabozantinib: a MET, RET, and VEGFR2 tyrosine kinase inhibitor.

Cabozantinib is a receptor tyrosine kinase inhibitor with activity against MET, VEGFR2, FLT3, c-KIT, and RET. Activity of cabozantinib toward a broad range of tumor models could be detected in several preclinical studies. Of note, cabozantinib decreases metastasis potential and tumor invasiveness when compared with placebo or agents that target VEGFR and have no activity against MET. Clinical phase I and II studies with cabozantinib have been conducted in various malignancies including medullary thyroid cancer (MTC), NSCLC, breast, ovarian, pancreatic, and prostate cancer. In MTC, gain of function mutations of RET are central for tumorigenesis. Hereditary forms of MTC (MEN II) are caused by germline mutations of RET, in sporadic MTC in up to 50% of cases RET mutations occur. Additionally, activating molecular changes in VEGFR and MET pathways have also been implicated in MTC progression. Clinical responses with cabozantinib in MTC could be observed in early clinical trials, and following confirmation of clinical benefit in a randomized phase III trial, cabozantinib gained FDA approval for first-line treatment of advanced MTC in 2012. In prostate cancer models, MET expression increases with androgen ablation and clinical progression of bone and lymph node metastasis. A phase II trial with cabozantinib also showed very promising response rates in patients with metastatic prostate cancer. Therefore, randomized phase III studies are currently ongoing to validate the efficacy of cabozantinib in heavily pretreated prostate cancer patients.

O1-028 - ASP3026, a Selective ALK Inhibitor, Induces Tumor Regression against Crizotinib Resistant EML4-ALK-Dependent Tumor Models in Mice

ABSTRACT EML4-ALK translocation has been validated as a therapeutic target in a subset of non-small-cell lung cancer (NSCLC) patients. In clinical settings, crizotinib has shown promising response rates in patients with EML4-ALK-positive NSCLC. However, disease relapse has been observed after an initial favorable response and several resistance mechanisms, including the gatekeeper L1196M mutation, have been reported to date. We have discovered ASP3026, a selective inhibitor for the ALK kinase. ASP3026 potently inhibited ALK kinase activity with an IC50 value of 3.5 nmol/L and showed more selective inhibition in a Tyr-kinase panel than crizotinib. Using NCI-H2228, a human NSCLC cell line endogenously expressing EML4-ALK, we determined the anti-proliferative effect of ASP3026. ASP3026 inhibited the in vitro proliferation with an IC50 value of 64.8 nmol/L and induced dose-dependent anti-tumor effects starting at 1 mg/kg with marked regression at 10, 30 and 100 mg/kg in a subcutaneous tumor model. Body weights were unaffected. ASP3026 at 100 mg/kg also showed tumor regression against EML4-ALK-driven tumor model with gatekeeper mutation while crizotinib at 100 mg/kg was ineffective. In an NCI-H2228 orthotopic lung model, ASP3026 at 30 mg/kg induced sustained tumor regression during the experimental period. In contrast, crizotinib at 30 mg/kg induced initial regression during the first 7 days but regrowth of the tumor was observed despite continuous crizotinib administration. After tumor regrowth had been established in crizotinib-treated mice, substantial tumor regression was achieved by subsequent administration of ASP3026 at 30 mg/kg. Taken together, these results suggest that ASP3026 in the non-clinical setting shows superior efficacy to crizotinib in crizotinib-resistant models.

Abstract 866: ASP3026, a selective ALK inhibitor, induces tumor regression in a crizotinib-refractory model and prolongs survival in an intrapleurally xenograft model

Abstract EML4-ALK translocation has been validated as a therapeutic target in a subset of non-small cell lung cancer (NSCLC) patients. In clinical settings, crizotinib has shown promising response rates in patients with EML4-ALK positive NSCLC, while disease relapse has been observed in several sites, including the lungs. Our previous studies found that ASP3026, a selective ALK inhibitor, had higher kinase selectivity than crizotinib and induced regression of tumors expressing EML4-ALK with a gate-keeper mutation that confers resistance to crizotinib. Here, we evaluated the antitumor activity of ASP3026 and crizotinib against orthotopic lung and intrapleural tumors in mice using luciferase-expressing NCI-H2228, a human NSCLC tumor cell line endogenously expressing EML4-ALK. In an orthotopic lung model, implanted cells were monitored using bioluminescent imaging (BLI) of the chest area. ASP3026 and crizotinib were administered orally at once daily doses ranging from 3 to 30 mg/kg (starting after confirmation of tumor growth). ASP3026 at 30 mg/kg induced tumor regression by 27 days after the start of administration; in contrast, crizotinib at 30 mg/kg induced regression during the first 7 days of administration, although tumors subsequently regrew despite continuous drug administration. After tumor regrowth had been established by the first cycle treatment of crizotinib, substantial regression was achieved by subsequent administration of ASP3026 at 30 mg/kg against the crizotinib-refractory tumors. In an intrapleural xenograft model, disease-related mortality was observed in tested animals, with a median survival time (MST) of 39 days in vehicle-treated control mice and 71 days in crizotinib-treated animals at 30 mg/kg. In contrast, no mice receiving ASP3026 treatment at 30 mg/kg died during the experimental period (90 days). These effects were accompanied by change in the bioluminescent emissions, with crizotinib-treated mice showing increased emissions following the initial reduction, while ASP3026-induced reduction continuing throughout the experimental period. The mean bioluminescent emission in the group treated with ASP3026 was significantly lower than in the crizotinib-treated group, indicating that ASP3026-treated animals exhibited lower tumor burden than crizotinib-treated ones.Taken together, these results suggest that ASP3026 is effective in producing shrinkage of tumors refractory to crizotinib and shows superior efficacy to crizotinib against intrapleural metastatic tumors with respect to prolonging survival. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 866. doi:1538-7445.AM2012-866

IN5 What's new in myelodysplastic syndromes?

New treatment options are urgently needed for patients with relapsed multiple myeloma (MM) who are refractory to thalidomide, lenalidomide, and bortezomib therapy. Pomalidomide, a second-generation immunomodulatory agent, has been shown to exert direct antiproliferative actions on MM cells, effects on the bone-marrow microenvironment, and immunomodulation. In phase I clinical trials, pomalidomide has demonstrated promising response rates in patients with relapsed and/or refractory MM, with manageable toxicity. In phase II trials pomalidomide, 2–4 mg/daily, given continuously or on days 1–21 of a 28-day cycle, in combination with dexamethasone, has been associated with high quality and durable clinical responses in patients who are refractory to lenalidomide, bortezomib, or both. Pomalidomide appears to be well tolerated; hematologic toxicities are the most commonly reported adverse events and peripheral neuropathy is rare. Phase III trials are currently underway to determine the optimal dose and combination regimen of pomalidomide in the treatment of MM.

Treatment of brain metastases from lung cancer: chemotherapy

Brain metastases are a frequent complication in patients suffering from Lung cancer, and a significant cause of morbidity and mortality. Brain metastases are found in about 10% of patients at the time of diagnosis, and approximately 40% of all patients with lung cancer develop brain metastases during the course of their disease. The prognosis of these patients is rather poor. The standard treatment for brain metastases, so far, has been whole-brain radiation therapy and surgery focussing on symptom palliation. The use of chemotherapy for the treatment of brain metastases has been limited because of a presumed lack of effectiveness due to the blood-brain barrier. However, the importance of the blood-brain barrier is probably overrated in the case of macroscopic metastases or relapsed disease as the blood-brain barrier has already been disrupted at this stage resulting from the newly developed blood vessels not provided with the physiological properties of the common blood-brain barrier. Chemotherapeutic agents initially lipid-insoluble or liquor-impermeable can also penetrate into the brain and, therefore, trigger action against tumour cells. A number of clinical trials have demonstrated that brain metastases resulting from both small-cell lung cancer and non-small-cell lung cancer are susceptible to systemic chemotherapy. In small-cell lung cancer, cerebral response rates up to 50% were observed even in the second-line situation and were comparable to the response rates observed in the primary tumour. In non-small-cell lung cancer, similar results were achieved. Therefore, it seems justified to further evaluate the significance of chemotherapy compared to whole-brain radiation therapy. Whether chemotherapy alone is superior to whole-brain radiation therapy, or whether the combination of both therapeutic modalities should be preferred for the management of brain metastases, has not yet been proven, and further randomised phase-III studies are clearly needed. Based on the current available data, and the promising response rates in patients with lung cancer, chemotherapy should be considered for the management of brain metastases as part of a multimodality (or "interdisciplinary") treatment concept.

IMC-C225, an anti-epidermal growth factor receptor monoclonal antibody for treatment of head and neck cancer.

Squamous cell carcinoma of the head and neck remains a clinical challenge because of the high rate of locoregional disease recurrence. The importance of the epidermal growth factor receptor (EGFR) in the development and progression of many solid tumors, including squamous cell carcinoma of the head and neck, is well understood; increased expression is associated with enhanced tumor invasiveness, resistance to chemotherapy, and a lower patient survival rate. Several approaches have been developed to achieve EGFR blockade as an anticancer treatment strategy, including the anti-EGFR monoclonal antibody IMC-C225, which competitively binds to the extracellular receptor site and prevents binding by the natural EGFR ligands EGF and transforming growth factor-alpha. Preclinical studies to evaluate IMC-225 in human cancer cell lines in vitro and human tumor xenografts in vivo have shown its potent antitumor activity. Clinical efficacy of IMC-C225 appears to involve multiple mechanisms, including inhibition of cell cycle progression, induction of apoptosis, inhibition of angiogenesis, inhibition of metastasis, and enhancement of the response to chemotherapy and radiation therapy. Phase I studies of IMC-C225 combined with chemotherapy or radiation showed promising response rates in patients with recurrent or refractory squamous cell carcinoma of the head and neck. Phase II and III trials to examine the efficacy and safety of these combinations are currently underway. To date, IMC-C225 has been well tolerated, with skin rashes and allergic reactions being the most clinically important adverse events reported. IMC-C225 displays dose-dependent elimination characteristics and a half-life of approximately 7 days. Current recommendations for dosing include a 400 mg/m(2) loading dose, followed by weekly infusions at 250 mg/m(2).

IMC-C225, an anti-epidermal growth factor receptor monoclonal antibody for treatment of head and neck cancer

Squamous cell carcinoma of the head and neck remains a clinical challenge because of the high rate of locoregional disease recurrence. The importance of the epidermal growth factor receptor (EGFR) in the development and progression of many solid tumors, including squamous cell carcinoma of the head and neck, is well understood; increased expression is associated with enhanced tumor invasiveness, resistance to chemotherapy, and a lower patient survival rate. Several approaches have been developed to achieve EGFR blockade as an anticancer treatment strategy, including the anti-EGFR monoclonal antibody IMC-C225, which competitively binds to the extracellular receptor site and prevents binding by the natural EGFR ligands EGF and transforming growth factor–alpha. Preclinical studies to evaluate IMC-225 in human cancer cell lines in vitro and human tumor xenografts in vivo have shown its potent antitumor activity. Clinical efficacy of IMC-C225 appears to involve multiple mechanisms, including inhibition of cell cycle progression, induction of apoptosis, inhibition of angiogenesis, inhibition of metastasis, and enhancement of the response to chemotherapy and radiation therapy. Phase I studies of IMC-C225 combined with chemotherapy or radiation showed promising response rates in patients with recurrent or refractory squamous cell carcinoma of the head and neck. Phase II and III trials to examine the efficacy and safety of these combinations are currently underway. To date, IMC-C225 has been well tolerated, with skin rashes and allergic reactions being the most clinically important adverse events reported. IMC-C225 displays dose-dependent elimination characteristics and a half-life of approximately 7 days. Current recommendations for dosing include a 400 mg/m 2 loading dose, followed by weekly infusions at 250 mg/m 2. Semin Oncol 29 (suppl 14):18-30. Copyright 2002, Elsevier Science (USA). All rights reserved.

High-dose cis-platinum combination chemotherapy in advanced nonseminomatous malignant germ cell tumours with emphasis on nephrotoxicity

High-dose cis-platinum treatment (180 mg/m2 per cycle) in combination with VP16 and bleomycin was given to 14 patients with highly advanced nonseminomatous malignant germ cell tumours (total: 31 cycles). Cis-platinum was administered in infusions of 0.9% NaCl given daily for 3 days with 3-week intervals. An intensive hydration regimen (71 NaCl/day) provided a urinary output of at least 1000 ml/4 h. The response and side effects were evaluated. Ultimately 11 of 12 patients evaluable for treatment effect were rendered tumour-free and are alive with NED. All 14 patients were evaluable for toxicity; 2 developed life-threatening lung edema during the initial prehydration period and did not continue the high-dose cis-platinum schedule. After one to four cycles of high-dose cis-platinum treatment the 131I-Hippuran clearance was reduced by 28%. Decreased kidney function evaluated by 131I-Hippuran clearance was the reason for discontinuation of treatment in 5 patients. Patients with ureteric obstruction represented a high-risk group for reduction of kidney function. High-dose cis-platinum therapy is an intensive treatment demanding a high level of investment of resources, which has promising response rates in patients with highly advanced malignant germ cell tumours. Short-term clinically significant reduction of the kidney function can be avoided by intensive hydration of the patient.