Halperin7e_CH29

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C H A P T E R 2 9  Radioimmunotherapy and Unsealed Radionuclide Therapy

Zevalin arm were treated with an activity of 0.4 mCi/kg; a maximum activity of 32 mCi was allowed. Although two doses of rituximab (250 mg/m 2 ) were used, an 111 In biodistribution scan was not required. The data were analyzed with a median follow-up of 3.5 years. Zevalin consolidation resulted in a median progression-free survival (PFS) advantage of 36.5 ver- sus 13.3 months in the control arm ( P < .0001). The PFS ben- efit was maintained in the Zevalin arm regardless if patients achieved a PR (29.3 vs. 6.2 months; P < .0001) or CR (53.9 vs. 29.5 months; P = .0154). The benefit of Zevalin consolidation was maintained across all Follicular Lymphoma International Prognostic Index (FLIPI) subgroups. In patients with a PR after induction chemotherapy, 77% were further converted to a CR when treated with Zevalin. This resulted in a final CR rate of 87% in the treatment arm, and this result com- pares well with established data. In the treatment arm, 90% of patients who were Bcl-2 positive converted to a negative status (90% molecular CR). Toxicity was well managed and primarily hematologic. A total of 8% of patients experienced a grade 3 to grade 4 infection. There were no treatment-related deaths. The FIT trial has been updated and with a median follow-up of 7.3 years 90 Y-ibritumomab consolidation results in a 3-year benefit in median PFS (41% vs. 22%; P < .001) and improves time to next treatment by 5.1 years ( P < .001). Second malignancies were not statistically different. 49 Peptide receptor radionuclide therapy (PRRT) has been suc- cessfully used for greater than a decade to treat advanced NETs expressing somatostatin receptors. The most common PRRT agents are 177 Lu–DOTATATE and 90 Y–DOTATOC. 19,20 A phase III trial (NETTER-1) was performed, which random- ized 229 patients with metastatic midgut NETs to either 177 Lu– DOTATATE (Lutathera) versus octreotide LAR (long-acting repeatable). The 177 Lu–DOTATATE was administered at an activity of 7.4 GBq (200 mCi) per infusion, every 8 weeks for a total of 4 doses.The 177 Lu–DOTATATE group exhibited a signif- icant progression-free survival ( P < .001) and overall survival ( P = .004).Toxicity was acceptable. 50 Lutathera gained US FDA approval for somatostain receptor positive gastroenteropan- creatic neuroendocrine tumors on 1/26/2018. Lung cancer remains the leading cause of cancer mortal- ity in the world. Clearly, new strategies are required to help improve local and systemic control. There are data to sup- port the concept of targeting necrotic and hypoxic regions of tumors. 51 The selective targeting of dead or dying cells will allow a cytotoxic event of nearby malignant cells by the bystander and crossfire effect. Additionally, only one type of targeting construct needs to be manufactured to target many different types of malignancies. If the cell surface antigen does not internalize to any significant degree, then a typical targeting construct will remain on the cell surface. Because dead and dying cells (undergoing apoptosis) exhibit disrup- tion of their cell membrane, constructs that target intracel- lular products of apoptosis will then be able to gain access to the cell cytoplasm and nucleus. Although several “dead cancer cell antigens” are under investigation, tumor necrosis therapy or treatment (TNT) has been investigated in human trials. TNT is an IgG 2a mAb that targets nuclear histones. 52 A pivotal trial of iodine-131–chimeric tumor necrosis treatment ( 131 I-chTNT) in advanced lung cancer patients was performed. 53 A total of 107 patients ( n = 97, non–small cell; n = 10, small cell) were enrolled from 1999 to 2002. All patients had failed at least one prior therapeutic regimen (mean = 3; range = 1 to 5), and 86.9% of the patients had stage III to stage IV disease at study entry. In all cases, the patients received two instillations of 131 I-chTNT administered SOLID TUMOR TRIALS AND APPROVED THERAPEUTICS

over 2 to 4 weeks. Sixty-two patients received IV adminis- trations, and 45 patients received intratumoral injections of 131 I-chTNT. IV administrations were delivered at an activity 0.8 mCi/kg, and intratumoral injections were delivered at an activity of 0.8 mCi/cm 3 of tumor size. In all patients ( n = 107), the ORR was 34.6% (3.7% CR; 30.8% PR; 55.1% no change or stable disease; 10.3% progressive disease). Of the 62 patients receiving a systemic administration of 131 I-chTNT, the ORR was 35.5% (3.2% CR; 32.2% PR). Of the 45 patients receiv- ing intratumoral injection of 131 I-chTNT, the ORR was 33.3% (5% CR; 20.9% PR). In 58 evaluable patients, the median survival was 11.7 months, and the 1-year survival rate was 41.4%. The average absorbed doses for tumor and normal lung were 8.45 and 2.35 Gy for patients receiving systemic 131 I-chTNT and 30.0 and 2.65 Gy for patients receiving intra- tumoral 131 I-chTNT. The major toxicity was hematologic and reversible. As expected, the hematologic toxicity was lower in the intratumoral injection group. In 2003, 131 I-chTNT was approved by the Chinese State Food and Drug Administration to treat refractory bronchogenic carcinoma. A phase III trial was performed randomizing patients with stage II-IIIA non–small cell carcinoma of the lung, requir- ing chemoradiotherapy after surgery. 54 Group A included 49 patients treated with chemotherapy (docetaxel and cis- platin) and external beam radiotherapy. Group B included 47 treated with 131 I-chTNT and percutaneous microwave coagulation therapy (PMCT), with further chemotherapy. Survivals at 1 and 2 years for groups A and B were 80% and 49% versus 83% and 53% ( P < .05). Adverse events and median survival were similar. HCC, or liver carcinoma, represents a significant worldwide malignancy. Resection and orthotopic liver transplantation (OLT) represent the only potential curative options. In 1989, the Radiation Therapy Oncology Group (RTOG) reported its first and only phase III RIT trial comparing EBRT and chemo- therapy to the same treatment plus 131 I antiferritin antibody. None of the patients receiving EBRT and chemotherapy only were converted to a resectable state. In a separate analysis, 11 patients crossing over from the EBRT and chemotherapy arm to further therapy with 131 I antiferritin antibody were converted to resection. There was, however, no significant difference in the initial “intent-to-treat” treatment arms based on response rate and survival. 55 Of course, the most promising role of RIT is in the treatment of minimal residual microscopic disease. Licartin is an antibody fragment, F(ab’) 2 , that targets HAb18G/CD147, a HCC TAA. The safety and pharmacokinetics of Licartin ( 131 I metuximab) have been investigated in phase I/II trials. 56 Realizing that TRT is most suited for treating micro- scopic disease, Licartin was tested in the adjuvant setting for patients with HCC undergoing OLT. 57 A total of 60 patients with HCC who were undergoing OLT were randomized to Licartin (0.42 mCi/kg) for three fractions at 28-day intervals versus pla- cebo. Analysis at 1 year post therapy revealed that the recur- rence rate was significantly decreased by 30.4% ( P = .0174) and the survival rate was significantly increased by 20.6% ( P = .0289) in the Licartin group. No significant toxicities were observed. The Chinese State Food and Drug Administration has approved Licartin as adjuvant therapy after OLT for HCC in 2005. To my knowledge, this trial has not been updated. A phase III trial of radiofrequency ablation (RFA) for unresectable HCC with or without Licartin was performed. 58 Patients received RFA followed by Licartin ( n = 62) or RFA alone ( n = 65). Adverse events were similar and minimal in both arms. The median time to recurrence was 17 and 10 months for the RFA/Licartin group and RFA-alone group, respectively ( P = .03). Currently, the most common antigen targets for CNS malignancies consist of the epidermal growth factor recep- tor (EGFR), tenascin, neural cell adhesion molecule (NCAM), placental alkaline phosphatase (PLAP), and phosphatidyl

Section II