LBA602 Background: The increasing detection of renal masses presents a significant patient management challenge. Diagnostic options include cross-sectional imaging, which cannot reliably differentiate benign and malignant renal masses, and biopsy, which is invasive and subject to sampling errors. These limitations highlight the unmet need for accurate noninvasive techniques to guide patient management. Girentuximab is a monoclonal antibody that targets carbonic anhydrase IX (CAIX), an enzyme highly expressed in clear cell renal carcinoma (ccRCC). Radiolabeled 89 Zr-DFO-girentuximab (TLX250-CDx) is highly specific for CAIX and can aid differentiation between ccRCCs and other renal lesions. The ZIRCON study evaluated the performance of TLX250-CDx PET/CT for detection of ccRCC in adult patients with indeterminate renal masses (IDRM). Methods: ZIRCON was an open-label, multicenter clinical trial. Patients with an IDRM (≤ 7 cm; tumor stage cT1) who were scheduled for partial nephrectomy within 90 days from planned TLX250-CDx administration were eligible. Enrolled patients received a single dose of TLX250-CDx IV (37 MBq ± 10%; 10 mg girentuximab) on Day 0 and underwent PET/CT imaging on Day 5 (± 2 days) prior to surgery. Blinded central histology review determined ccRCC status. The coprimary objectives were to evaluate both the sensitivity and specificity of TLX250-CDx PET/CT imaging in detecting ccRCC in patients with IDRM, using histology as the standard of truth. Key secondary objectives included sensitivity and specificity of TLX250-CDx PET/CT imaging in the subgroup of patients with IDRM ≤ 4 cm (cT1a). Other secondary objectives included positive and negative predictive values, safety, and tolerability. The Wilson 95% confidence intervals (CI) lower bound for sensitivity and specificity had to be > 70% and 68% respectively for ≥ 2 independent readers to declare the study successful. Results: 300 patients received TLX250-CDx; mean age was 62 ± 12 y; 71% were males. Of 288 patients with central histopathology of surgical samples, 193 (67%) had ccRCC, and 179 (62%) had CT1a; Of 284 evaluable patients included in primary analysis, the average across all 3 readers for sensitivity and specificity was 86% [80%, 90%] and 87% [79%, 92%] respectively for coprimary endpoints; and 85% [77%, 91%] and 90% [79%, 95%] respectively for key secondary endpoints. For all readers, the lower boundaries of 95% CI for coprimary and key secondary endpoints were > 75%. For all evaluable patients, positive and negative predictive values were ≥ 91.7% and ≥ 73.7%, respectively. Of 263 treatment-emergent adverse events (TEAEs), 2 TEAEs were treatment related. Conclusions: This study confirms that TLX250-CDx PET/CT is well tolerated and can accurately and noninvasively identify ccRCC, with promising utility for designing best management approaches for patients with IDRM. Clinical trial information: NCT03849118 .
To evaluate the sensitivity and specificity of PET/CT findings in PMR and generate a diagnostic algorithm utilizing a minimum number of musculoskeletal sites. Steroid-naive patients with newly diagnosed PMR (2012 EULAR/ACR classification criteria) were prospectively recruited to undergo whole-body 18F−FDG PET/CT. Each PMR case was age- and sex-matched to four PET/CT controls. Control scan indication, diagnosis and medical history were extracted from the clinical record. Qualitative and semi-quantitative scoring (maximum standardized uptake value [SUVmax]) of abnormal 18F-FDG uptake at 21 musculoskeletal sites was undertaken for cases and controls. Results informed the development of a novel PET/CT diagnostic algorithm using a classification and regression trees (CART) method. Thirty-three cases met the inclusion criteria and were matched to 132 controls. Mean age was 68.6 ± 7.4 years for cases compared with 68.2 ± 7.3 for controls, and 54.5% were male. Median CRP was 49 mg/L (32–65) and ESR 41.5 mm/h (24.6–64.4) in the PMR group. The predominant control indication for PET/CT was malignancy (63.6%). Individual musculoskeletal sites proved insufficient for diagnostic purposes. A novel algorithm comprising 18F-FDG uptake ≥ 2 adjacent to the ischial tuberosities in combination with either abnormalities at the peri-articular shoulder or interspinous bursa achieved a sensitivity of 90.9% and specificity of 92.4% for diagnosing PMR. The presence of abnormal 18F-FDG uptake adjacent to the ischial tuberosities together with findings at the peri-articular shoulder or interspinous bursa on whole-body PET/CT is highly sensitive and specific for a diagnosis of PMR. Clinical Trial Registration: Australian New Zealand Clinical Trials Registry,
http://www.anzctr.org.au
, ACTRN1261400696695
Tumor hypoxia and angiogenesis are implicated in tumor growth and metastases, and anti-angiogenic therapies have an important role in treating patients with metastatic colorectal cancer. However, the prevalence of hypoxia has not been fully evaluated in colorectal liver metastases, and hypoxic response to anti-angiogenic therapy has not been clearly established. The aims of the study were to evaluate the changes seen on 18F-FMISO and 18F-FDG PET scans in patients treated with anti-angiogenic therapy, and to correlate these measures of hypoxia and metabolism with clinical outcomes, and blood biomarkers of angiogenesis.Patients with metastatic colorectal carcinoma planned for treatment with bevacizumab and chemotherapy received routine staging investigations prior to any treatment, including a FDG PET scan. A FMISO PET scan was performed within 4 weeks of staging tests, with blood specimens collected at that time for serum VEGF and osteopontin measurement. Follow-up FDG and FMISO scans were performed after 1 cycle of treatment. Results were compared to response (RECIST), progression free survival (PFS), and overall survival (OS).A total of 15 patients were recruited into this prospective trial, of which 13 patients were evaluable for assessment of treatment follow-up. Baseline FDG uptake was higher than FMISO uptake, and there was a significant decrease in FDG uptake (SUVmax and TGV) but not FMISO uptake (SUVmax and TNR) after treatment. There was a positive correlation between FDG and FMISO SUVmax on both baseline and post-treatment PET scans. Blood biomarkers of serum VEGF and osteopontin were significantly correlated with the FDG and FMISO PET parameters.This study shows that hypoxia in metastatic colorectal cancer, assessed by FMISO PET, shows minor changes following initial treatment with anti-angiogenic therapy, but is associated with therapeutic response. FDG PET uptake changes (SUVmax, TLG) are also associated with response to anti-angiogenic therapy. These findings demonstrate the interplay between tumor metabolism and hypoxic regulation following anti-angiogenic treatment of metastatic colorectal cancer.
The field of nuclear medicine has seen a polarising change in practice over the past two decades. Nuclear medicine has traditionally been characterised by the use of different radiopharmaceuticals to assess the physiologic nature of diseases afflicting various organs non-invasively, applying quantitative analysis of tracer uptake and distribution. Through this approach, alterations in organ function, early detection and monitoring of disease (before the onset of anatomical abnormalities) and measurement of changes in body physiology have been possible. The advent of three-dimensional (3D) imaging known as single photon emission computed tomography (SPECT) and positron emission tomography (PET), and the integration of this 3D imaging with anatomical imaging provided by computed tomography (CT) and magnetic resonance imaging (MRI), has revolutionised the acquisition and interpretation of functional nuclear medicine images. This includes imaging for myocardial ischaemia and viability, ventilation/perfusion lung scans for the diagnosis of pulmonary embolism and preoperative quantitation of regional lung function, cerebral perfusion studies for neurodegenerative disease and imaging of endocrine diseases. 18F-fluorodeoxyglucose (18F-FDG) PET/CT imaging has become integral in the staging, restaging and monitoring of therapy response in many solid and haematological malignancies, and several indications are now funded by Australian Medicare. While the most commonly used radiotracer in PET in oncology is 18F-FDG, many other radiotracers are available, which are able to assess the biochemical and metabolic hallmarks of cancer described by Hanahan.1 In neurodegenerative disorders, there are new radiotracers which are able to assess amyloid and tau deposition in Alzheimer disease, and differentiate this from other types of dementia.2, 3 Newer applications of radiotracers for SPECT and PET have also resulted in more accurate diagnosis of inflammation and infection, neurologic conditions and myocardial reserve. Personalised medicine is now an essential part of the management of patients with lymphoma, with worldwide consensus on standards of PET acquisition and reporting, which has enabled PET to be the imaging biomarker for treatment response assessment in these patients.4-6 However, there have been clinical trials that support PET-related personalised management of lymphoma, to de-escalate chemotherapy, or to perform more selective radiotherapy. There are clinical trials underway to assess the role of PET to eliminate consolidation radiotherapy in patients with diffuse large B-cell lymphoma and primary mediastinal B-cell lymphoma. In Hodgkin lymphoma, there are several trials that have established the role of interim PET performed during the chemotherapy regimen which allows modification of chemotherapy requirements in patients, depending on their tumour metabolic response to treatment as assessed by the PET scans (response-adapted therapy).7, 8 In follicular lymphoma, PET has been shown to be a reliable predictor of outcome in patients treated with rituximab and chemotherapy, and prospective trials to test PET-guided therapy in this disease are underway.9 Over the past decade, there has been increasing use of the term ‘theranostics’ in medicine, which is simply described as the concept of Therapy guided by Diagnostics. This concept has been used for over 70 years in the treatment of thyroid cancer with radioiodine, with the therapeutic dose guided by pre-treatment diagnostic radioiodine scans. More recently, there has been remarkable progress in the application of theranostics to other tumour types, in particular, neuroendocrine tumours (NET) and prostate cancer. Somatostatin receptor (SSTR) PET/CT using somatostatin analogues labelled with gallium-68 (68Ga) is now accepted as the most accurate imaging test for the evaluation of patients with SSTR-expressing neuroendocrine neoplasms. This translates into additional therapy options with increasing evidence that peptide receptor radionuclide therapy (PRRT) may be the treatment of choice for advanced or progressive NET. Prospective trials of PRRT in NET patients have shown improved progression-free and overall survival, as well as marked symptomatic improvement. The pivotal study to date has been a phase III study of 229 patients with progressive midgut NET treated with high-dose, long-acting somatostatin analogue (Sandostatin-LAR) or a somatostatin analogue labelled with a radionuclide, lutetium-177 (177Lu-DOTATATE). In this study, the median progression-free survival in patients treated with 177Lu-DOTATATE and Sandostatin-LAR had not been reached, compared with 8.4 months in patients undergoing high-dose Sandostatin-LAR treatment alone.10 This treatment option is now integrated into multidisciplinary guidelines for this tumour type (e.g. National Comprehensive Cancer Network, European Neuroendocrine Tumour Society), and is now licensed for use in Europe and the United States. Whilst this treatment is available in Australia, this is primarily in trial settings, and is currently not reimbursed through Medicare, although imaging of SSTR in NET with 68Ga-DOTATATE PET is likely to receive Medicare funding in the near future. Another area of increasing theranostic use is in the evaluation and treatment of patients with metastatic castrate-resistant prostate carcinoma using radiolabelled prostate-specific membrane antigen (PSMA).11 PSMA is a transmembrane protein that is markedly overexpressed in prostate carcinoma.12 Numerous radiopharmaceuticals have emerged over the last few years to target PSMA for both diagnostic imaging and therapy.13 There is a growing body of evidence for the use of PSMA imaging for both primary staging of intermediate to high risk prostate cancer, and to use this information to treat patients with radioligand therapy. A prospective multicentre trial in Australia showed that 68Ga-PSMA PET/CT scans detected previously unsuspected disease in both primary staging and restaging of patients with biochemical recurrence in a high proportion of patients with prostate cancer, and there was a change in management in 51% of patients.14 The impact was greater in the group of patients with biochemical failure after definitive surgery or radiation treatment, in whom management changed in 62% compared with 21% of patients undergoing primary staging.14 By identifying sites of target overexpression, PSMA PET permits selection of patients eligible to receive personalised PSMA radioligand therapy, which has been found to be feasible, safe and effective in appropriately selected patients.15 In the primary staging of prostate cancer, there is an increasing body of evidence that more accurate staging of patients at the time of initial diagnosis may also change the natural history of the disease and the rate of biochemical recurrence,11 but this remains to be proven, with a prospective multicentre trial in Australia underway at the moment to address these questions. In the contemporary practice of nuclear medicine, access to new diagnostic radiotracers, and theranostics of molecular targets leading to new therapeutic approaches to disease, has transformed the specialty to integrate imaging techniques into personalised molecular medicine. The authors acknowledge Associate Professor Fred Khafagi (The University of Queensland) for his advice on this editorial, and thank him for his more than 20 years in the role as Nuclear Medicine Editor for the Internal Medicine Journal.
Abstract Glioblastoma (GBM) is the most frequent and lethal primary brain neoplasm. EphA3 is a tumor restricted antigen expressed in 38–40% of GBM and 100% of the tumor vasculature. Ifabotuzumab is a non-fucosylated IgG1κ antibody targeting EphA3 receptor. A Phase 1 study of ifabotuzumab in haematological malignancies was well tolerated and clinically active. Here we report on a Phase I dose escalation and biodistribution study of ifabotuzumab in recurrent glioblastoma. DESIGN The primary objective is to determine the toxicity and recommended phase II dose of Ifabotuzumab in GBM patients (pts). Secondary objectives are to determine the biodistribution and pharmacokinetics (PK) of 89Zr-Ifabotuzumab, the frequency of EphA3 positive GBM and response rates. Eligible pts received a trace (5mg) dose of zirconium-89 labelled ifabotuzumab (89Zr-ifab) on day 1 followed by sequential PET imaging over 1 week to determine its biodistribution, frequency of in situ EphA3 expression and tumor uptake. Safety and PK assessments were undertaken. On Day 8, pts commenced weekly ifabotuzumab infusions until PD. Three cohorts are planned (3.5mg/kg, 5.25 mg/kg, 7.9 mg/kg). On day 36, pts received both 89Zr-ifab and Ifabotuzumab, to assess receptor occupancy. Response rate (RANO) and survival data were collected. RESULTS: To date, 7 of 12 pts have enrolled (6 at 3.5 mg/kg,1 at 5.25 mg/kg; Mean age: 55 years (±12.6), 4 are male). Treatment emergent AEs included infusion reactions, seizures, cerebral oedema, rash, pruritis, headaches, eye disorder. Most were considered related to study drug, seizures and infusion reactions were readily managed with increased premedications after the first occurrence. Best response in cohort 1 is SD for 23 weeks. 89Zr-ifab PET/CT scans showed rapid, specific targeting at all known tumor sites and in all pts, but no normal tissue uptake. MRI scans showed predominant T2/FLAIR changes, occasionally marked, which were consistent with treatment effect on tumor vasculature.
Abstract BACKGROUND Preclinical data demonstrates that tumor volumes predicted response to the anti-EGFR ADC Depatuxizumab mafadotin (Depatux-M) because of reduced drug delivery in large tumors. We investigated the impact of tumor volumes on outcomes with Depatux-M in the EORTC randomized phase 2 Intellance 2 study on recurrent glioblastoma (NeuroOncol 22(5):684). METHODS 260 patients were randomized to Depatux-M, Depatux-M with temozolomide, or control treatment (lomustine/temozolomide). Manual segmentation of enhancing tumor on baseline MRI scans was performed and compared with OS and PFS using SPSS Version 29.0: Kaplan-Meier survival analysis including log rank test and Cox regression analyses; categorical data were compared with Fishers’ exact test; correlation between 2D and 3D measurements with Pearson’s correlation. RESULTS MRI scans and data from 240/260 (92%) patients were available. Firstly, we confirmed that tumor volumes were a significant prognostic variable. Significant differences were seen in OS between the 0-20 vs 20-40 ml groups (321 vs 216 days, p<0.001) and between the 20-40ml vs 40+ groups (216 vs 150 days, p<0.001) with corresponding differences in PFS. Tumor volumes were also predictive of benefit from Depatux-M, with only patients with smaller tumors benefiting from Depatux-M. Patients in the 0-20 ml and 20-40 ml group group had superior OS when treated with Depatux-M compared to controls (356 vs 309 days, p=0.011 and 229 vs 178 days, p=0.028 respectively). Conversely, the 40 ml + group had no benefit (146 vs 152 days, p=0.875) as predicted. The benefit was maximal in the combination arm, with OS improvement in the 0-20 ml group (437 vs 309 days, p=0.007) and 20-40ml groups (225 vs 178 days, p=0.009). The impact of tumor volumes was confirmed in multi-variate analysis and superior to similar analysis with 2D RANO measurements. CONCLUSIONS Tumor volumes are an important prognostic variable in recurrent glioblastoma and modulate survival to large molecules like Depatux-M.
Background. This study investigates the use of 18F-fluoromisonidazole (FMISO) PET-guided radiotherapy dose painting for potentially overcoming the radioresistant effects of hypoxia in head and neck squamous cell carcinoma (HNSCC). Material and methods. The study cohort consisted of eight patients with HNSCC who were planned for definitive radiotherapy. Hypoxic subvolumes were automatically generated on pre-radiotherapy FMISO PET scans. Three radiotherapy plans were generated for each patient: a standard (STD) radiotherapy plan to a dose of 70 Gy, a uniform dose escalation (UDE) plan to the standard target volumes to a dose of 84 Gy, and a hypoxia dose-painted (HDP) plan with dose escalation only to the hypoxic subvolume to 84 Gy. Plans were compared based on tumor control probability (TCP), normal tissue complication probability (NTCP), and uncomplicated tumor control probability (UTCP). Results. The mean TCP increased from 73% with STD plans to 95% with the use of UDE plans (p < 0.001) and to 93% with HDP plans (p < 0.001). The mean parotid NTCP increased from 26% to 44% with the use of UDE plans (p = 0.003), and the mean mandible NTCP increased from 2% to 27% with the use of UDE plans (p = 0.001). There were no statistically significant differences between any of the NTCPs between the STD plans and HDP plans. The mean UTCP increased from 48% with STD plans to 66% with HDP plans (p = 0.016) and dropped to 37% with UDE plans (p = 0.138). Conclusion. Hypoxia-targeted radiotherapy dose painting for head and neck cancer using FMISO PET is technically feasible, increases the TCP without increasing the NTCP, and increases the UTCP. This approach is superior to uniform dose escalation.
Radioimmunoconjugates consist of a monoclonal antibody (mAb) linked to a radionuclide. Radioimmunoconjugates as theranostics tools have been in development with success, particularly in hematological malignancies, leading to approval by the US Food and Drug Administration (FDA) for the treatment of non-Hodgkin’s lymphoma. Radioimmunotherapy (RIT) allows for reduced toxicity compared to conventional radiation therapy and enhances the efficacy of mAbs. In addition, using radiolabeled mAbs with imaging methods provides critical information on the pharmacokinetics and pharmacodynamics of therapeutic agents with direct relevance to the optimization of the dose and dosing schedule, real-time antigen quantitation, antigen heterogeneity, and dynamic antigen changes. All of these parameters are critical in predicting treatment responses and identifying patients who are most likely to benefit from treatment. Historically, RITs have been less effective in solid tumors; however, several strategies are being investigated to improve their therapeutic index, including targeting patients with minimal disease burden; using pre-targeting strategies, newer radionuclides, and improved labeling techniques; and using combined modalities and locoregional application. This review provides an overview of the radiolabeled intact antibodies currently in clinical use and those in development.
Abstract Overview: Glioblastoma (GBM) is the most frequent and lethal primary brain neoplasm, with only 10% of patients surviving 5 years (1). EphA3 is a tumor restricted antigen expressed in 38-40% of GBM and 100% of the tumor vasculature (2, 3). Ifabotuzumab is a non-fucosylated IgG1K antibody targeting EphA3 receptor (4). A Phase I study of ifabotuzumab in haematological malignancies showed it was well tolerated and clinically active (5). Here we report on a Phase I dose escalation and biodistribution study of ifabotuzumab in recurrent GBM. Study Design: The primary objective is to determine the toxicity and recommended phase II dose of Ifabotuzumab in GBM patients (pts). Secondary objectives are to determine the biodistribution and pharmacokinetics (PK) of 89Zr-Ifabotuzumab, the frequency of EphA3 positive GBM and response rates. Eligible pts had measurable tumors received a trace (5mg) dose of zirconium-89 labelled ifabotuzumab (89Zr-ifab) on day 1 followed by sequential PET imaging over 1 week to determine its biodistribution, frequency of in situ EphA3 expression and quantitative tumor uptake. Safety assessments and PK sampling was also undertaken. On Day 8, pts commenced weekly Ifabotuzumab infusions over 2 hours. Three cohorts are planned (3.5mg/kg, 5.25 mg/kg, 7.9 mg/kg). On day 36, pts received both 89Zr-ifab and Ifabotuzumab, allowing assessment of receptor occupancy. Response rate (RANO) and survival data were collected. Pts then continued on Ifabotuzumab until progression. Results: To date, 4 of 12 planned pts have enrolled. Their mean age is 53 years (±16.3) and 3 are male. Treatment emergent adverse events included infusion reactions in 4 patients, seizures in 3 pts, cerebral oedema in 1, rash in 1, headaches in 1, eye disorder in 1. Most were considered related to study drug except seizure in 2 pts, headaches and eye disorder. Seizures and infusion reactions were readily managed with increased premedications after the first occurrence. The best response was stable disease for 23 weeks. 89Zr-ifab PET/CT scans showed rapid, specific targeting at all known tumor sites and in all pts, but no normal tissue uptake. MRI scans showed predominant T2/FLAIR changes, occasionally marked, which were consistent with treatment effect on tumor vasculature. The mean ± SD (n=4) PK parameters for first infusion 89Zr-ifab were T½α= 10.63 ± 3.14 hr, T½β = 106.85 ± 40.60 hr, V1 = 3.88 ± 0.88 L, CL= 94.11 ± 36.54 mL/hr. Conclusions: 89Zr-Ifabotuzumab demonstrates sensitive, specific and reproducible targeting of the tumor microenvironment in GBM patients. The imaging changes suggest modulation of the tumor vasculature. Enrolment is on-going. References: 1. Stupp R, et al. Lancet Oncology 10:459-66, 2009 2. Day BW, et al. Cancer Cell 23:238-48, 2013 3. Vail ME, et al. Cancer Research 74:4470-81, 2014 4. Tomasevic N, et al. Growth Factors 32:223-35, 2014 5. Swords RT, et al. Leukemia Research 50:123-131, 2016 Citation Format: Hui Gan, Lawrence Cher, Po Inglis, Zarnie Lwin, Eddie Lau, Christian Wichmann, Uwe Ackermann, Nicole Coombs, Kirsten Remen, Nancy Guo, Sze Ting Lee, Sylvia Gong, Jodie B. Palmer, Kunthi Pathmaraj, Graeme O'Keefe, Fiona Scott, Bryan W. Day, Andrew W. Boyd, Paul Thomas, Cameron Durrant, Andrew M. Scott. Preliminary findings of a Phase I safety and bioimaging trial of KB004 (ifabotuzumab) in patients with glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT063.
'/%3e%3c/defs%3e%3cpath fill='%23012169' d='M0 0h10080v5040H0z'/%3e%3cpath stroke='%23fff' stroke-width='.6' d='m0 0 6 3m0-3L0 3' clip-path='url(%23b)' transform='scale(840)'/%3e%3cpath stroke='%23e4002b' stroke-width='.4' d='m0 0 6 3m0-3L0 3' clip-path='url(%23c)' transform='scale(840)'/%3e%3cpath stroke='%23fff' stroke-width='840' d='M2520 0v2520M0 1260h5040'/%3e%3cpath stroke='%23e4002b' stroke-width='504' d='M2520 0v2520M0 1260h5040'/%3e%3cg fill='%23fff'%3e%3cuse xlink:href='%23d' x='2520' y='3780'/%3e%3cuse xlink:href='%23a' x='7560' y='4200'/%3e%3cuse xlink:href='%23a' x='6300' y='2205'/%3e%3cuse xlink:href='%23a' x='7560' y='840'/%3e%3cuse xlink:href='%23a' x='8680' y='1869'/%3e%3cuse xlink:href='%23e' x='8064' y='2730'/%3e%3c/g%3e%3c/svg%3e)