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Journal of Clinical Oncology, Vol 23, No 7 (March 1), 2005: pp. 1538-1547 © 2005 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.06.108 Pivotal Study of Iodine-131–Labeled Chimeric Tumor Necrosis Treatment Radioimmunotherapy in Patients With Advanced Lung CancerFrom the Zhongshan Hospital and Tumor Hospital, Fudan University, Shanghai; Nanjng Chest Hospital Oncology Department, Nanjing; Zhujiang Hospital Oncology Center, First Military Medical University, Guangzhou; Second Hospital, Zhejiang University Medical School, Hangzhou; Department of Oncology, Liaoning Tumor Hospital, Shenyang; 309 Hospital Oncology Department, Beijing; Shanghai MediPharm Biotech Co Ltd, Shanghai, China; and University of Southern California Keck School of Medicine, Los Angeles, CA Address reprint requests to Dian Wen Ju, MD, Shanghai MediPharm Biotech Co Ltd, Bldg 72-2F, 887 Zu Chong Zhi Road, Zhangjiang HiTech Park, Shanghai 201203, China; e-mail: jud{at}vip.sina.com
PURPOSE: Tumor necrosis treatment (TNT) uses degenerating tumor cells and necrotic regions of tumors as targets for radioimmunotherapy. Previous studies in animal tumor models and clinical trials have demonstrated that when linked to the therapeutic radionuclide iodine-131, recombinant chimeric TNT antibody (131I-chTNT) can deliver therapeutic doses to tumors regardless of the location or type of malignancy. Therapeutic efficacy and toxicity of 131I-chTNT in advanced lung cancer patients were studied in this pivotal registration trial. PATIENTS AND METHODS: Patients with advanced lung cancer were treated with systemic or intratumoral injection of 131I-chTNT in eight oncology centers in China. The objective response rate (ORR) was assessed as the primary end point. RESULTS: All 107 patients who were entered onto the study and completed therapy had experienced treatment failure after prior radiotherapy or chemotherapy a mean of three times. The results showed an ORR of 34.6% (complete response, 3.7%; partial response, 30.8%; no change, 55.1%; and progressive disease, 10.3%) in all patients and 33% in 97 non–small-cell lung cancer patients. A biodistribution study demonstrated excellent localization of the radioactivity in tumors in both systemically and intratumorally injected patients. The most obvious adverse side effect was mild and reversible bone marrow suppression. CONCLUSION: Radioimmunotherapy with 131I-chTNT was well tolerated and can be used systemically or locally to treat refractory tumors of the lung.
Lung cancer has a worldwide incidence of 12.3% of all cancers, with an estimated 1.2 million new cases in 2000.1 As such, it is the most common form of cancer in the world. Etiologically, tobacco smoking is responsible for 80% to 90% of the incidence of lung cancer.2 Although the prevalence of smoking is decreasing in the United States, in China and East Europe there is an epidemic of smoking which will result in tens of millions of new cases of lung cancer in the future.1,3,4 Despite improvements in therapy, approximately 90% of lung cancer patients will die from their disease. In 2000, it was estimated that lung cancer resulted in 1.1 million deaths worldwide, or 17.8% of all cancer deaths.1 Because chemotherapy has added little to improve these grim statistics, only surgery with or without extended-field radiotherapy is a viable treatment option if warranted by the stage of the disease. In recent years, targeted radiotherapy using radiolabeled monoclonal antibodies has emerged as a new treatment option, especially for the treatment of radiosensitive lymphomas.5-10 For solid tumors, however, which tend to be more radioresistant in nature, radioimmunotherapy has not yielded significant results largely due to insufficient dosing to the tumor.11-13 In the last several years, a new antibody targeting methodology has been developed for the targeting of solid tumors. Designated tumor necrosis therapy (TNT), this approach targets necrotic regions found in tumors but absent from normal tissues and organs.14-17 Unlike other antibody targeting approaches that bind to cell surface antigens expressed on viable tumor cells, TNT antibodies recognize nonviable zones found principally in hypoxic areas of the tumor, regions that represent 30% to 80% of the tumor mass.18,19 Normal tissues, which are policed by the reticuloendothelial system consisting of fixed tissue and circulating phagocytic cells, do not contain necrotic areas and hence cannot bind TNT antibodies, as shown by tissue biodistribution studies,14,20 autoradiography,21 and imaging studies15,22 performed in both experimental animals and humans.14,15 From 1999 to 2001, 62 patients with lung cancer, glioblastoma, lymphoma, head and neck cancer, colorectal carcinoma, hepatocellular carcinoma, and other malignant solid tumors were treated with iodine-131–labeled recombinant chimeric TNT monoclonal antibody (131I-chTNT). From these initial studies, it became clear that lung cancer was an excellent candidate to study the clinical efficacy of TNT radioimmunotherapy. From 2001 to 2002, these clinical trials were continued in an additional 45 patients. The results of this pivotal registration clinical trial were presented to the Chinese State Food and Drug Administration and on June 13, 2003, 131I-chTNT was approved for the treatment of advanced lung cancer in China, making it the second of three approved radiolabeled antibodies (ibritumomab [Zevalin; Biogen Idec, San Diego, CA] and tositumomab [Bexxar; GlaxoSmithKline, Philadelphia, PA]) and the first for the treatment of solid tumors worldwide. Currently, additional trials are ongoing in China to expand the utility of this product for the treatment of brain cancer, hepatocellular carcinoma, and other solid tumors, and trials are ongoing in the United States for both systemic (gastrointestinal tumors) and intratumoral use (recurrent glioblastoma). We report the clinical data obtained during this pivotal trial as part of an international collaboration that began in the late 1980s and early 1990s when TNT was originally developed as a new approach for the targeting of solid tumors.
Patient Selection This study enrolled 107 patients from January 1, 1999, to June 30, 2002. Eligible patients were required to have a histologically or cytologically confirmed diagnosis of lung cancer, to be between the ages of 18 and 80 years, and to have experienced treatment failure after chemotherapy or radiotherapy. In addition, patients were required to have an anticipated survival time of at least 3 months according to the judgment of the clinicians. Other entry criteria included no radiotherapy for 2 months or chemotherapy for 1 month before study entry, and all patients had to demonstrate progressing and measurable disease as shown by thoracic radiograph or computed tomography (CT) scans. Finally, patients were required to have a WBC count more than 4,000/µL, an absolute neutrophil count more than 2,000/µL, a platelet count more than 100,000/µL, normal hepatic and renal function, a Karnofsky performance score of at least 60, no serum human antimouse antibodies (HAMA) or human antichimeric antibodies (HACA), and no serious concomitant illnesses. Follow-up was assured to the extent of allowing assessment of the short-term effects of the treatment. The study was approved by the Chinese State Food and Drug Administration and the Research Ethics Committee of Zhongshan Hospital, Fudan University, Shanghai. Informed consent was obtained for all of the enrolled patients.
Preparation of 131I-chTNT
Therapeutic Regimen
Response Criteria and Evaluation
Imaging and Biodistribution
Evaluation of Toxicity
Statistical Analysis
Patient Characteristics A total of 107 patients with advanced lung cancer were entered onto the trial and completed treatment from January 1999 to June 2002. The main demographic and clinical characteristics of the cohort are listed in Table 1. All patients had experienced treatment failure after prior therapies (mean, three times; range, 1 to 5 times). These prior therapies included radiotherapy, irinotecan-based chemotherapy, platinum-containing regimen, or other combined chemotherapy regimens. The median age was 60 years (range, 30 to 77 years). Ninety-three of the patients (86.9%) had stage III or IV disease. Ten of the patients (9.3%) had a diagnosis of small-cell lung carcinoma and 97 of the patients (90.7%) had a diagnosis of non–small-cell lung cancer.
Clinical Efficacy Eight different oncology centers in China participated in the pivotal study. All patients received two doses of TNT radioimmunotherapy either by systemic (0.8 mCi/kg of body weight) or intratumoral (0.8 mCi/cm3 of tumor size) administration at 2- or 4-week intervals. Assessments of objective response used WHO criteria and responses were observed regardless of type or number of prior radiotherapy or chemotherapy regimens. As shown in Table 2, among the 107 patients, four patients (3.7%) achieved a CR, 33 patients (30.8%) had a PR, 59 patients (55.1%) had NC, and 11 patients (10.3%) had PD. The overall therapeutic efficacy ORR (CR plus PR) was therefore 34.6%.
For the 10 patients with small-cell lung cancer, the ORR was 50%, with one CR and four PRs. For the 97 patients with non–small-cell lung cancer, the ORR was 33%, with three CRs and 29 PRs. Among the 39 non–small-cell lung cancer patients with squamous cancer, one patient had a CR and 17 patients had a PR, with an ORR of 46.2%. For the 50 non–small-cell lung cancer patients with adenocarcinoma, the ORR was 24%, with two CRs and 10 PRs. Patients with different stages of disease at entry onto the study had different therapeutic responses. In 14 patients with stage II disease, the ORR for six patients was 25%, and in 62 patients with stage III disease, the ORR was 37.1%. In contrast, in 31 patients with stage IV disease, one patient achieved a CR and seven patients achieved a PR, with an ORR of 25.8%. Sixty-two patients received systemic administration of 131I-chTNT; two of the systemically treated patients achieved a CR and 20 patients achieved a PR, with an ORR of 35.5%. Forty-five of the cancer patients were treated with intratumoral injection of 131I-chTNT, and in this group two patients achieved a CR and 13 patients achieved a PR, with an ORR of 33.3%. In 58 patients evaluated for overall survival, median survival time was 11.7 months and the 1-year survival rate was 41.4% (Fig 1). Determination of therapeutic efficacy of this radioimmunotherapy was based mainly on ORR without evidence of an effect on overall survival.
Imaging and Biodistribution of 131I-chTNT in Patients Imaging was conducted in all 131I-chTNT–treated patients. Figures 2A to 2G show whole-body images of representative patients after systemic or intratumoral administration of 131I-chTNT. Data in Figures2A to 2D demonstrated visual uptake of 131I activity in the tumor obtained at 0.5 and 5 hours, and 2 and 8 days after systemic administration of 131I-chTNT. These images reveal the remarkable retention of radiolabeled antibody in the vicinity of the tumor mass over time. Figures 2E to 2G show whole-body scintigraphy of a lung cancer patient at 5 (Fig 2E), 15 (Fig 2F), and 25 days (Fig 2G) after intratumoral administration of 131I-chTNT, demonstrating minimal diffusion of radioactivity from tumor site of injection. To demonstrate that the location of the radiolabel coincides with the anatomic position of the tumor, fusion images consisting of transaxial, coronal, and sagittal CT and single-photon emission CT, and x-ray (scout view) and single-photon emission CT of the lung tumor were prepared (Figs 2H to 2K) in a patient receiving intratumoral injection of 131I-chTNT 5 days previously. These images again demonstrated excellent localization of the radiolabel in the tumor, with little evidence of diffusion over time. The biodistribution of 131I radioactivity in the tumor versus nontumor areas (normal lung fields, T-to-NT ratio) was measured in 11 patients in each group. As shown in Figure 3, the average absorbed doses for tumor and normal lung tissue were 8.45 and 2.35 Gy in patients receiving systemic radioimmunotherapy. For patients receiving intratumoral injection, the average absorbed doses for tumor and normal lung tissue were 30.0 and 2.65 Gy, respectively. The T-to-NT ratio was 3.8:1 for systemically administered antibody and 16.1:1 for intratumorally injected reagent.
Radiation-absorbed dose estimation for 131I-chTNT was performed using sequential whole-body images and the MIRDOSE 3.0 software program. The data for both systemic and intratumoral administration are shown in Table 3. As expected, most organs except for the lungs (site of intratumoral injection), received about half of the dose of those patients receiving intratumoral injection compared with those administered systemic 131I-chTNT.
Adverse Experiences Toxicity was graded according to the WHO toxicity criteria. As listed in Table 4, the major site of adverse effects was the bone marrow. All-grade platelet toxicity was found in 59.7% of systemically treated patients and 24.4% of intratumorally treated patients. For patients receiving systemic administration, 11.3% and 8.1%, respectively, experienced grade 3 or 4 platelet toxicity compared with 4.4% and 0% for patients receiving intratumoral injection. Grade 1 to 4 neutrophil toxicity was found in about one third of all patients, and for patients receiving systemic administration, 8.1% and 1.6%, respectively, had grade 3 and 4 neutrophil toxicity compared with 2.2% and 0% for those patients receiving intratumoral injection. All-grade hemoglobin toxicity was found in 41.9% of systemically treated patients and 20% of intratumorally treated patients. Only two patients receiving systemic therapy and one patient receiving intratumoral therapy had grade 3 hemoglobin toxicity, and no patient was reported with grade 4 hemoglobin toxicity.
Other adverse reactions are listed in Table 5 for patients receiving either systemic or intratumoral injection of 131I-chTNT. In general, no adverse effects were detected in the liver or kidneys during the treatment and follow-up periods. Likewise, no patient developed a HACA or HAMA response during the time it was tested. Because absorption of released radionuclide was imaged in the thyroid of some patients undergoing 131I-chTNT therapy, total T3, total T4, free T3, free T4, and thyroid-stimulating hormone before and after radioimmunotherapy were determined. The results demonstrated that total T3, total T4, free T3, and free T4 decreased slightly and thyroid-stimulating hormone increased significantly 1 and 2 months after 131I-chTNT administration. These changes, however, were all within the normal range (data not shown).
To date, only tositumomab6 (131iodine-labeled murine anti-CD20 antibody) and ibritumomab7 (yttrium-90–labeled murine anti-CD20 antibody), and two radiolabeled antibodies for the radioimmunotherapy of human malignant B-cell non-Hodgkin's lymphoma, are approved for use in the United States. Along with 131I-chTNT, now approved for refractory advanced lung cancer in China, these reagents are important new biologics for the radioimmunotherapy of cancer that can lead the way to the identification of new methods to produce longer disease-free intervals and/or survival times for patients with these tumors. In this regard, the results of our study show that 131I-chTNT can be an effective radioimmunotherapeutic reagent when given systemically or intratumorally in patients with resistant lung cancer. Adverse reactions to this therapy are essentially limited to bone marrow suppression due to the circulatory time of the radiolabeled product (passenger effect). As expected, intratumorally administered reagent, which enters the circulation at a slower rate over an extended time frame, has a lower severity of thrombocytopenia and neutropenia than when given intravenously. The results also show that small-cell and non–small-cell tumors are both good targets for this form of therapy. Although most prior studies with radiolabeled antibodies have been performed using systemic administration,5,9 a number of investigators are now focusing on the locoregional use of these reagents to treat identifiable lesions in solid tumor patients. Reasons for this include the low amount of uptake seen in tumors after intravenous injection, poor penetration into larger lesions, and heterogeneity of antibody uptake. Locoregional injection has been used most frequently in studies with malignant glioblastomas, which are tumors that are especially difficult to treat due to local extension of tumor tendrils into the white and gray matter of the brain. One such study by Riva et al24 using radiolabeled antitenascin antibodies found that catheter-directed administrations of 131I-antitenascin antibodies produced an increase in both the duration of remission and survival time in these difficult-to-treat patients, with little or no toxicity. In these studies, the results were dependent on the size of the tumor at the time of treatment. In addition, studies performed at multiple centers in the United States with 131I-chTNT-1 plus biotin produced dramatic results despite the dismal prognosis of these patients. In these studies, an infusion pump was used to deliver the radiolabeled antibody into the tumor over a 20-hour period via a surgically implanted catheter (unpublished observation). The use of the infusion pump to deliver the radiolabeled antibody slowly and forcefully may have improved the effectiveness of locoregional delivery by ensuring a more homogeneous distribution of reagent into the substance of the tumor. Although this may be an important consideration for glioblastoma, the method used in our study appears to have successfully infiltrated the full substance of the tumor, as shown by images taken shortly after infusion of tumor by the radiolabeled antibody (Fig 2). Because of the lower toxicity of this approach and the ability of radiolabeled antibody to infiltrate even large tumor masses effectively, locoregional or intratumoral injection may be a useful method of treating individual lesions such as those seen in glioblastoma or lung cancer, as described in this report. Despite these hopeful findings, the number of complete responders in all the above-described studies was small, indicating that radioimmunotherapy might require additional treatment modalities to be used in combination for this form of therapy to reach its full potential. For example, it may be possible to improve the clinical efficacy of 131I-chTNT if it is used in combination with methods to increase the radiosensitivity of the tumor.25 In addition, as demonstrated by Anderson et al,26 prior treatment of tumors with ablative therapies increases the target size for TNT antibodies. In this study, it was demonstrated that prior radiofrequency ablation therapy of hepatic metastases, which generally produces a 1- to 5-cm zone of necrosis, significantly enhanced 131I-chTNT-1/biotin uptake in the tumor lesions. Anderson et al is the first patient study to take advantage of the basic property of TNT; namely, its proclivity to bind to dead and dying cells. When used in this manner, 131I-chTNT may become an adjuvant to other cytotoxic therapies. Chemotherapeutic drugs may also be used to generate larger areas of necrosis in tumors, and some of these drugs, such as doxorubicin, are also radiosensitizing because of their inhibition of DNA repair mechanisms. In addition, methods such as hormonal therapy used in prostate cancer patients can produce massive tumor destruction in a short period of time, thereby providing an excellent opportunity to test the adjuvant effects of 131I-chTNT in this setting. With the approval of 131I-chTNT radioimmunotherapy for refractory lung cancer in China, it becomes possible for clinicians to study these more advanced concepts with 131I-chTNT radioimmunotherapy. It is hoped that ongoing studies in the United States and China with 131I-chTNT may provide new indications for its use or reveal its role as an adjuvant to current treatment approaches.
The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Employment: Qing Fu, Shanghai MediPharm Biotech Co Ltd; Qun Tao, Shanghai MediPharm Biotech Co Ltd; Dan Ye, Shanghai MediPharm Biotech Co Ltd; Dian Wen Ju, Shanghai MediPharm Biotech Co Ltd. Leadership Position: Peisheng Hu, Cancer Therapeutics Labs, MediBiotech Inc; Clive R. Taylor, Cancer Therapeutics Labs, MediBiotech Inc, Peregrine Pharmaceuticals; Alan L. Epstein, Cancer Therapeutics Labs, MediBiotech Inc. Consultant/advisory role: Peisheng Hu, Peregrine Pharmaceuticals; Leslie A. Khawli, Peregrine Pharmaceuticals; Alan L. Epstein, Peregrine Pharmaceuticals. Stock ownership: Peisheng Hu, Cancer Therapeutics Labs, Peregrine Pharmaceuticals; Leslie A. Khawli, Peregrine Pharmaceuticals; Clive R. Taylor, Cancer Therapeutics Labs, Peregrine Pharmaceuticals; Alan L. Epstein, Cancer Therapeutics Labs, Peregrine Pharmaceuticals. For a detailed description of these categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and Disclosures of Potential Conflicts of Interest found in Information for Contributors in the front of each issue.
Supported by MediPharm Biotech Co, Shanghai, China. Authors' disclosures of potential conflicts of interest are found at the end of this article.
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17. Chen FM, Taylor CR, Epstein AL: Tumor necrosis treatment of ME-180 human cervical carcinoma model with 131I-labeled TNT-1 monoclonal antibody. Cancer Res 49:4578-4585, 1989 18. Cooper E: Cell death in normal and malignant tissues. Adv Cancer Res 21:59-120, 1975[Medline] 19. Steel G: Cell loss as a factor in the growth rate of human tumors. Eur J Cancer 3:381-387, 1967 20. Hornick JL, Hu P, Khawli LA, et al: A new chemically modified chimeric TNT-3 monoclonal antibody directed against DNA for the radioimmunotherapy of solid tumors. Cancer Biother Radiopharm 13:255-268, 1998[Medline]
21. Chen FM, Epstein AL, Li Z, et al: A comparative autoradiographic study demonstrating differential intratumor localization of monoclonal antibodies to cell surface (Lym-1) and intracellular (TNT-1) antigens. J Nucl Med 31:1059-1066, 1990 22. Khawli LA, Alauddin MM, Hu P, et al: Tumor targeting properties of 111In-labeled genetically engineered Fab' and F(ab')2 constructs of chTNT-3. Cancer Biother Radiopharm 18:933-942, 2003 23. Gatzemeier U, Shepherd FA, Le Chevalier T, et al: Activity of gemcitabine in patients with non-small cell lung cancer: A multicentre, extended phase II study. Eur J Cancer 32:243-248, 1996 24. Riva P, Franceschi G, Arista A, et al: Local application of radiolabeled monoclonal antibodies in the treatment of high grade malignant gliomas: A six-year clinical experience. Cancer 80:2733-2741, 1997 (suppl)[CrossRef][Medline] 25. Gold DV, Modrak DE, Schutsky K, et al: Combined 90 yttrium DOTA-labeled PAM4 antibody radioimmunotherapy and gemcitabine radiosensitization for the treatment of a human pancreatic cancer xenograft. Int J Cancer 109:618-626, 2004[CrossRef][Medline] 26. Anderson PM, Wiseman GA, Lewis BD, et al: A phase I safety and imaging study using radiofrequency ablation (RFA) followed by 131I-chTNT-1/B radioimmunotherapy adjuvant treatment of hepatic metastases. Cancer Ther 1:297-306, 2003 Submitted June 16, 2004; accepted December 13, 2004.
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
5 mR/h at 1 m). 
