First experiences with Lu-177 PSMA therapy in combination with Pembrolizumab or after pretreatment with Olaparib in single patients

Prasad, Vikas; Zengerling, Friedemann; Steinacker, J. M.; Bolenz, Christian; Beer, Meinrad; Wiegel, Thomas; Eiber, Matthias; Fleshner, Neil; Beer, Ambros

doi:10.2967/jnumed.120.249029

Cited by 16 publications

(15 citation statements)

References 14 publications

(10 reference statements)

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“…It is well known that the response to PRRT is mediated by overexpression of somatostatin receptors on the tumor cells, which serve as intracellular transporters for the radioactivity [ 11 ]. In this patient with a high density of somatostatin receptors at the only site of active disease as determined by 68 Ga-DOTATATE PET/MR, it is possible that radiation-related cell lysis uncovered antigenic sites that then augmented the activity of immunotherapy, as has been previously demonstrated for external and internal RTs [ 12 , 13 ]. It is also possible that the benefit this patient received from PRRT is directly attributable to the high dose of radiation that was administered, and that the limited activity that has been previously reported in patients with aggressive pituitary tumors who were previously treated with temozolomide is in large part due to patient selection.…”

Section: Discussionmentioning

confidence: 63%

Synergism of Checkpoint Inhibitors and Peptide Receptor Radionuclide Therapy in the Treatment of Pituitary Carcinoma

Lin

Tabar

Young

et al. 2021

Journal of the Endocrine Society

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Introduction Aggressive pituitary tumors that have progressed following temozolomide have limited treatment options. Peptide receptor radionuclide therapy and immunotherapy may have a complementary role in the management of these tumors. Methods We provide follow-up data on a previously reported patient with a hypermutated recurrent tumor. The patient in this report provided written informed consent for tumor sequencing and review of medical records on an institutional review board approved research protocol (NCT01775072). Results This patient with a corticotroph pituitary carcinoma with alkylator induced somatic hypermutation has remained on treatment with ipilimumab and nivolumab for 3.5 years and remains clinically well. After an initial partial response to checkpoint inhibitors, she has had several recurrences that have undergone immunoediting of subclonal mutations, which have been effectively treated with continuation of immunotherapy, surgery, external beam radiation, and 177Lu-DOTATATE. Following external beam RT, she had radiographic evidence of an abscopal response at a distant site of disease suggesting a synergism between checkpoint inhibitors and radiotherapy. Following treatment with 177Lu-DOTATATE, the patient had a partial response with a 61% reduction in volume of the target lesion. Conclusion In patients with aggressive pituitary tumors, treatment with checkpoint inhibitors may trigger an abscopal response from radiotherapy. With appropriate selection, an additional efficacious treatment, 177Lu-DOTATATE, may be available for a limited number of patients with aggressive pituitary adenomas, including patients who have progressed on temozolomide and exhibit increased somatostatin receptor expression on 68Ga-DOTATATE PET.

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Section: Discussionmentioning

confidence: 63%

Synergism of Checkpoint Inhibitors and Peptide Receptor Radionuclide Therapy in the Treatment of Pituitary Carcinoma

Lin

Tabar

Young

et al. 2021

Journal of the Endocrine Society

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“…Recently, a case report showed good tolerance of 177 Lu-PSMA RLT in combination with pembrolizumab or sequentially after olaparib (28), which is currently investigated in ongoing prospective phase 1/2 trials (NCT03874884, NCT03805594). 90 Y has shorter half-life and higher energy per decay as compared to 177 Lu.…”

Section: Discussionmentioning

confidence: 99%

“…Preclinical studies in several cancer types suggest a synergistic effect of FAP targeting and immunotherapy ( 24 – 27 ). Recently, a case report showed good tolerance of 177 Lu-PSMA RLT in combination with pembrolizumab or sequentially after olaparib ( 28 ), which is currently being investigated in ongoing prospective phase 1/2 trials (NCT03874884, NCT03805594).…”

Section: Discussionmentioning

confidence: 99%

Initial clinical experience with ⁹⁰Y-FAPI-46 radioligand therapy for advanced stage solid tumors: a case series of nine patients

et al. 2021

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Introduction: Fibroblast activation protein (FAP) is overexpressed in several solid tumors and therefore represents an attractive target for radiotheranostic applications. Recent investigations demonstrated rapid and high uptake of small-molecule inhibitors of FAP ( 68 Ga-FAPI-46) for PET imaging. Here, we report our initial experience in terms of feasibility and safety of 90 Y-labelled FAPI-46 ( 90 Y-FAPI-46) for radioligand therapy (RLT) of extensively pretreated patients with solid tumors. Methods: Patients were considered for 90 Y-FAPI-46 therapy in case of (a) exhaustion of all approved therapies based on multidisciplinary tumor board decision and (b) high FAP expression, defined as SUVmax ≥ 10 in more than 50% of all lesions. If tolerated, posttherapeutic 90 Y-FAPI-46 bremsstrahlung scintigraphy was performed to visually confirm systemic distribution and focal tumor uptake, and 90 Y-FAPI-46 PET scans at multiple timepoints were performed to determine absorbed dose. Blood-based dosimetry was used to determine bone-marrow absorbed dose. Adverse Events were graded using CTCAE v.5.0. Results: Nine patients with either metastatic soft tissue or bone sarcoma (N = 6) and pancreatic cancer (N = 3) were treated between June 2020 and March 2021. Patients received a median of 3.8 (IQR 3.25-5.40) GBq for the first cycle and three patients received subsequent cycles with a median of 7.4 (IQR 7.3-7-5) GBq. Post-therapy 90 Y-FAPI-46 bremsstrahlung scintigraphy demonstrated sufficient 90 Y-FAPI-46 uptake in tumor lesions in 7 of 9 patients (78%). Mean absorbed dose was 0.52 Gy/GBq (IQR 0.41-0.65) in kidney, 0.04 Gy/GBq (IQR 0.03-0.06) in bone marrow and below 0.26 Gy/GBq in the lung and liver. Measured tumor lesions received up to 2.28 Gy/GBq (median 1.28Gy/GBq). Hematologic G3/G4 toxicities were noted in four patients (44%), of which

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“…Radiosensitizing agents, immune modulators, high-dose vitamin C and polyadenosine-diphosphate-ribose polymerase (PARP) inhibitors may have synergistic effects when combined with PSMA-targeted radioligands [ 63 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 ]. The mechanism of action of radiosensitizing agents may be to dysregulate the cell cycle, resulting in oxygenated stress and thereby inducing cytotoxicity and inhibiting DNA repair mechanisms [ 74 ].…”

Section: Pharmacodynamics Of Psma-based Radioligand Therapymentioning

confidence: 99%

Pharmacological Optimization of PSMA-Based Radioligand Therapy

et al. 2022

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Prostate cancer (PCa) is the most common malignancy in men of middle and older age. The standard treatment strategy for PCa ranges from active surveillance in low-grade, localized PCa to radical prostatectomy, external beam radiation therapy, hormonal treatment and chemotherapy. Recently, the use of prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT) for metastatic castration-resistant PCa has been approved. PSMA is predominantly, but not exclusively, expressed on PCa cells. Because of its high expression in PCa, PSMA is a promising target for diagnostics and therapy. To understand the currently used RLT, knowledge about pharmacokinetics (PK) and pharmacodynamics (PD) of the PSMA ligand and the PSMA protein itself is crucial. PK and PD properties of the ligand and its target determine the duration and extent of the effect. Knowledge on the concentration–time profile, the target affinity and target abundance may help to predict the effect of RLT. Increased specific binding of radioligands to PSMA on PCa cells may be associated with better treatment response, where nonspecific binding may increase the risk of toxicity in healthy organs. Optimization of the radioligand, as well as synergistic effects of concomitant agents and an improved dosing strategy, may lead to more individualized treatment and better overall survival.

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First experiences with Lu-177 PSMA therapy in combination with Pembrolizumab or after pretreatment with Olaparib in single patients

Cited by 16 publications

References 14 publications

Synergism of Checkpoint Inhibitors and Peptide Receptor Radionuclide Therapy in the Treatment of Pituitary Carcinoma

Synergism of Checkpoint Inhibitors and Peptide Receptor Radionuclide Therapy in the Treatment of Pituitary Carcinoma

Initial clinical experience with ⁹⁰Y-FAPI-46 radioligand therapy for advanced stage solid tumors: a case series of nine patients

Pharmacological Optimization of PSMA-Based Radioligand Therapy

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First experiences with Lu-177 PSMA therapy in combination with Pembrolizumab or after pretreatment with Olaparib in single patients

Cited by 16 publications

References 14 publications

Synergism of Checkpoint Inhibitors and Peptide Receptor Radionuclide Therapy in the Treatment of Pituitary Carcinoma

Synergism of Checkpoint Inhibitors and Peptide Receptor Radionuclide Therapy in the Treatment of Pituitary Carcinoma

Initial clinical experience with 90Y-FAPI-46 radioligand therapy for advanced stage solid tumors: a case series of nine patients

Pharmacological Optimization of PSMA-Based Radioligand Therapy

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Initial clinical experience with ⁹⁰Y-FAPI-46 radioligand therapy for advanced stage solid tumors: a case series of nine patients