Precision medicine and theranostics using radiopharmaceuticals in oncology

Abstract

The recent themed issue of the Journal on precision medicine-based drug treatment individualization in oncology (Volume 87, Issue 2) discusses a wide range of aspects of the precision medicine approach, including pharmacogenomics and therapeutic drug monitoring. To add to this discussion, substantial progress has been made in theranostics using radiopharmaceuticals. Theranostics, a portmanteau of the words therapeutics and diagnostics, is essentially the combined use of diagnostic and therapeutic ligands with the same molecular target, enabling accurate patient selection, targeted therapy and prediction of treatment response.1 Ligands linked to isotopes emitting γ radiation or positrons (such as 123I and 68Ga), targeting specific pathophysiologic processes in malignant tissues, can be visualized in vivo using gamma cameras and PET scanners and thus used for diagnostic imaging. Similar ligands linked to isotopes emitting β radiation (such as 131I and 177Lu) or α radiation (such as 225Ac) will also target those tissues and deliver highly localized therapeutic radiation with only minimal radiation of surrounding normal tissues.2 An α particle has higher linear energy transfer than β particles (leading to more irreparable double-strand DNA breaks in tumour cells), while the tissue range is shorter (limiting normal tissue toxicity), but β-emitting radionuclides are more widely available. Accordingly, visualization of the diagnostic radioligand can confirm presence and anatomic location of a specific molecular target in order to select patients for targeted therapy with the therapeutic radioligand and to exclude patients who are unlikely to have a response to such therapy, which is the very essence of precision medicine. This concept of theranostics is not new. Combinations of diagnostic and therapeutic iodine isotopes 123I and 131I have been used for decades in the treatment of hyperthyroidism (including Graves' disease, toxic adenoma and toxic multinodular goitre) and differentiated thyroid cancer. Also, the radioligands [123I]I-MIBG and [131I]I-MIBG have been used in the diagnosis and treatment of pheochromocytoma, paraganglioma and neuroblastoma. In recent years, the theranostic approach has been successfully applied to neuroendocrine tumours and prostate cancer. Somatostatin is a peptide hormone produced by the hypothalamus, pancreas, gastro-intestinal tract and other tissues that inhibits release of growth hormone and many other hormones and secretory proteins. Somatostatin receptors are overexpressed in most neuroendocrine tumours3 and are therefore suitable targets for theranostics. Diagnostic PET-CT imaging with the somatostatin analogue [68Ga]Ga-DOTATATE has demonstrated high sensitivity for detection of primary and metastastic neuroendocrine tumours, superior to conventional scintigraphy, CT and MR imaging.4 The therapeutic ligand [177Lu]Lu-DOTATATE was evaluated in a phase III trial in patients with inoperable locally advanced or metastasized midgut neuroendocrine tumours, who were randomly assigned to receive [177Lu]Lu-DOTATATE or high dose octreotide LAR.5 Expression of somatostatin receptors on target lesions was confirmed with somatostatin receptor imaging prior to randomization. Treatment with [177Lu]Lu-DOTATATE resulted in markedly longer progression-free survival and a significantly higher response rate than high-dose octreotide LAR with clinically significant myelosuppression occurring in less than 10% of patients. Approval for clinical use of [177Lu]Lu-DOTATATE was granted by the EMA in 2017 and the FDA in 2018. Prostate-specific membrane antigen (PSMA) is a type II transmembrane protein found in the normal prostate, which is significantly overexpressed in most prostate cancer cells, increasing with higher tumour grade and hormone-refractory disease,6 and is therefore an excellent target for theranostics. Diagnostic PET-CT imaging with PSMA ligands has demonstrated high accuracy for identifying pelvic nodal or distant metastatic disease at primary staging of high-risk prostate cancer,7 as well as high rates of lesion detection at biochemical recurrence8 (Figure 1), far superior to conventional diagnostic imaging with CT and bone scintigraphy. The therapeutic ligand [177Lu]Lu-PSMA-617 was evaluated in a recent phase II trial in patients with metastatic castration-resistant prostate cancer with progressive disease after standard treatment (including taxane-based chemotherapy and second-generation anti-androgens).9 Prior to treatment, [68Ga]Ga-PSMA-11 imaging was performed to confirm high PSMA expression at metastatic sites. Treatment with [177Lu]Lu-PSMA-617 resulted in a PSA decline of 50% or more in 57% of patients, with a low toxicity profile, and improved quality-of-life parameters especially in patients with pain. Another recent phase II trial compared [177Lu]Lu-PSMA-617 with cabazitaxel in patients with metastatic castration-resistant prostate cancer with progressive disease after treatment with docetaxel.10 Declines in PSA levels larger than 50% were more frequent in the [177Lu]Lu-PSMA-617 group than in the cabazitaxel group (66% versus 37% by intention to treat and 66% versus 44% by treatment received) with fewer grade 3 or 4 adverse events. A phase III randomized controlled trial comparing [177Lu]Lu-PSMA-617 with best standard of care (VISION trial, NCT03511664) has recently completed enrolment. Novartis announced that the study met both primary endpoints, with [177Lu]Lu-PSMA-617 significantly improving overall survival and radiographic progression-free survival, which will be included in upcoming US and EU regulatory submissions.11 These phase II and III trials included patients with advanced progressive disease, but several ongoing studies are evaluating earlier disease stages, such as hormone-naive metastatic (NCT04343885) and oligometastatic (NCT04443062) stages or neoadjuvant setting prior to prostatectomy (NCT04297410 and NCT04430192). First clinical experience with the therapeutic ligand [225Ac]Ac-PSMA-617 has demonstrated promising antitumour activity and may prove especially advantageous in patients with diffuse bone marrow infiltration or poor response to [177Lu]Lu-PSMA-617 therapy.12 Theranostics directed against other targets such as neurotensin, B7-H3, CXCR-4 and CA19-9 have shown promising preclinical and initial clinical results.13, 14 Another potential target is fibroblast activation protein, a type II transmembrane glycoprotein expressed on the surface of cancer-associated fibroblasts that plays a complex role in modulating stromal components of various tumours.15 Diagnostic PET-CT imaging with the fibroblast activation protein inhibitor [68Ga]Ga-FAPI-04 has demonstrated remarkably high uptake of the ligand in several cancers, including breast, oesophageal, lung, pancreatic, head and neck and colorectal cancer.16 Thus, clinical indications for theranostics may rapidly expand to include some highly prevalent cancer types, thereby further advancing clinical pharmacology of cancer treatment. There are no competing interests to declare.

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