The notion that a systemically administered source of radiation can be usefully directed towards a tumor has been exploited since the 1940s, when radioiodine was introduced as a treatment for thyroid cancer. In the 1990s, Quadramet® (samarium-153) and Metastron® (strontium-89 chloride), both formulations of radionuclides which are taken up by bone lesions, were approved for the relief of pain arising from metastatic prostate cancer.
Monoclonal antibodies, with their exquisite specificity for tumor-associated antigens, were explored in the early 1990s as a practical means of delivering radionuclides, leading to approval of the first antibody-directed radiotherapy, Zevalin® (anti-CD20 conjugated to yttrium-90) for the treatment of non-Hodgkin’s lymphoma in 2002, followed by Bexxar® (anti-CD20 conjugated to iodine-131) a year later.
Clinical effectiveness and opinion leader enthusiasm did not translate into sales 1. Bexxar® was withdrawn by GSK in 2014, with only 75 patients treated in 2012. Spectrum Pharmaceuticals booked Zevalin® sales of just $7 million in 2018, with the company divesting the product the following year 2.
Much has been written about the failure of these innovative and much-needed treatments. Poor marketing, lack of clarity regarding clinical study data and patient selection, and a paucity of post-approval studies are cited, along with the sheer complexity of the prescribing process, with oncologists in private practice having to refer patients to nuclear medicine specialists, while navigating a complex reimbursement path.
Lack of commercial success did not completely curb industry interest in targeted radiotherapy. Bayer acquired Algeta in 2014, adding Xofigo®, a treatment for metastatic prostate cancer (and the first alpha-emitting radiopharmaceutical to secure regulatory approval) to its portfolio. The development candidate BAY 2315497, comprising an antibody directed against prostate-specific membrane antigen (PSMA) conjugated to the alpha-emitter thorium-227, was acquired from Progenics Pharmaceuticals in 2016.
Novartis has likewise built its targeted radiotherapy portfolio through acquisition, beginning with Advanced Accelerator Applications in 2017, bringing Lutathera®, a lutetium-177 conjugated somatostatin analogue for the treatment of neuroendocrine tumours and three early-stage radiotherapy candidates. Lutathera® posted respectable sales for a rare tumour treatment of $445 million in 2020.
Novartis has now chalked up another success with the FDA approval of Pluvicto®, a lutetium-177 PMSA radioconjugate, an asset acquired with the purchase of of Endocyte in 2018 3. Pluvicto® achieved impressive results compared with best standard of care in previously treated metastatic prostate cancer patients, with respect to overall survival and radiographic progression-free survival. Approval of an Locametz®, a gallium-68 PMSA-specific imaging agent, was granted on the same day and is the first radioactive diagnostic agent approved for patient selection in the use of a targeted radiotherapy.
This “seek and treat” theranostic strategy is a key factor in the renaissance of targeted radiotherapy, allowing accurate disease assessment and monitoring, and optimization of patient selection, with better outcomes and improved cost-effectiveness. Almost all current industrial efforts integrate diagnostic imaging with therapeutic product development.
Annual peak sales estimates for Pluvicto® are in the range of $600 million to over $1 billion, although Novartis faces future competition from PSMA antibody-targeted radiotherapies under development by Bayer, Telix Pharmaceuticals and Convergent Therapeutics, and PSMA small molecule-targeted radiotherapies from Point Biopharma, Clarity Pharmaceuticals and Cancer Targeted Technologies. Potential Lutathera® challengers from Ipsen, ITM Solucin, Clarity Pharmaceuticals and Orano Med are under evaluation in neuroendocrine tumors.
While external beam radiotherapy will remain a pillar of cancer treatment, targeted radiotherapy offers significant advantages, which include the minimal irradiation of healthy tissues and low systemic radiation exposure and, importantly, the ability to target small numbers of cancer cells which have migrated from the primary tumor. Targeted radiotherapies are generally associated with low toxicity and shorter treatment cycles and may be better tolerated by frail patients than are conventional therapies.
Unlike targeted cancer drug treatments, the efficacy of targeted radiotherapy is independent of the presence or activation of key signaling or phenotype driving pathways. Growing evidence indicates that a synergy exists between external or targeted radiotherapy and cancer drug efficacy, including that of the immune checkpoint inhibitors. A variety of drug-radiotherapy combination studies are ongoing 4.
Several of the challenges which curtailed uptake of earlier targeted radiotherapies remain, notably the limited number of nuclear medicine specialist and radiopharmacies, and comprehensive reimbursement of the spectrum of activities required for theranostic-based disease management. Despite commercial optimism, the relative complexity of targeted radiotherapy may force prescribers to opt for simpler, next best, options.
Radionuclide supply is now less of a limiting factor, and several specialist service companies now support targeted radiotherapy development efforts. Supply could be greatly tested should Pluvicto® and other close to market products achieve real world clinical success: a European Commission survey has estimated that near-term approvals might result in a ten-fold increase in radionuclide requirement over current medical use 5.
But, for now, the targeted radiotherapy sector is booming, with clinical-stage companies such as Telix Pharmaceuticals, Actinium Pharmaceuticals and Fusion pharmaceuticals all looking to make their mark in treatments for rare and common cancers. Targeted radiotherapy is once again investable: start-ups RayzeBio and Aktis Oncology attracted investments of $108 million and $72 million, respectively, in 2021, with two clinical-stage players, Clarity Pharmaceuticals and Radiopharm Theranostics going public in 2021. Twenty years on from the approval of Zevalin®, success for Novartis could precipitate a scramble for targeted radiotherapy assets among large players looking to broaden their current oncology portfolios.
References
1 Users Fear that Lymphoma Drugs Will Disappear. Garber Ken. Journal of the National Cancer Institute, Volume 99, Issue 7, 4 April 2007, Pages 498–501. https://tinyurl.com/ycwhskf2
2 Zevalin® was developed and initially marketed by Idec Pharmaceutical, then Biogen Idec following merger, with Bayer owning ex-US rights. Cell Therapeutics acquired Zevalin® in 2007 and entered a US co-marketing agreement with Spectrum Pharmaceuticals in 2008. Spectrum acquired US rights in 2008, and ex-US rights from Bayer in 2012. Japanese rights were acquired from Spectrum by Mundipharma in 2015. Spectrum divested Zevalin® to Acrotech Biopharma in 2019
3 FDA approves Pluvicto for metastatic castration-resistant prostate cancer. FDA press release online 23rd March 2022. https://tinyurl.com/mr33pjv7
4 Combination radionuclide therapy: A new paradigm. Suman SK et al. Nucl Med Biol. 2021 Jul-Aug;98-99:40-58. DOI: https://doi.org/10.1016/j.nucmedbio.2021.05.001
5 Study on sustainable and resilient supply of medical radioisotopes in the EU, Goulart De Medeiros, M. and Joerger, A. editor(s), EUR 30690 EN, Publications Office of the European Union, Luxembourg. https://tinyurl.com/2p9fpzva
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