The data are coming. Novartis’s Lutathera and Pluvicto, approved in 2018 and 2022, respectively, both use the isotope lutetium-177 to deliver beta radiation — a medium-powered, mid-range stream of electrons that can travel 2–10 mm (several dozen cell diameters), cleaving one or both DNA strands. In Lutathera, the beta radiation is directed at the somatostatin type 2 receptor (SSTR2) found across the surface of slow-growing NETs. The ligand is the somatostatin analog oxodotreotide. In Pluvicto, the targeting moiety is vipivotide, a peptide that inhibits prostate-specific membrane antigen (PSMA), expressed on fast-growing prostate cancer cells.

Both drugs significantly improved overall survival relative to standard of care in phase 3 trials in patients with advanced disease. More recently, in the NETTER-2 trial2,3, Lutathera reduced the risk of death or progression by 72% when used as a first line with octreotide (a somatostatin analog) for newly diagnosed GEP-NET. Pluvicto produced more than a doubling of radiographic progression-free survival in the pre-chemotherapy setting; Novartis expects to file for an additional approval for Pluvicto in early-line disease during 2024. Peak sales are forecast at over $2 billion annually.

Novartis now wants to expand these drugs — and a wider radiopharmaceuticals pipeline — across even more tumors and disease stages. It is not alone (Table 2). Venture financing in radiopharmaceuticals more than quintupled in the five years ending 2023, according to data and analytics firm GlobalData.

Many next-generation radiopharmaceuticals harness alpha radiation: powerful, short-range helium nuclei that rip through both strands of in-range DNA4, causing mostly irreparable damage and leaving no room for resistance. Yet, as they penetrate only one or two cell diameters, they leave nearby healthy cells unharmed. Alpha rays will “will blow almost anything apart,” according to Jason Lewis, professor and Emily Tow chair at Memorial Sloan Kettering Cancer Center (MSKCC) in New York, who has consulted for or is on scientific advisory boards at several radiopharmaceuticals companies. Patients who develop ‘radio-resistance’ to beta-emitting Lutathera or Pluvicto as cancer cells’ rapid genomic alterations outmaneuver the toxic rays may benefit from an alpha emitter.

Alpha emitters with the same targets as Lutathera and Pluvicto are among the most advanced pipeline radiopharmaceuticals, positioned as next-line therapies for patients showing signs of disease after treatment with beta radiation. RayzeBio’s (now Bristol Myers Squibb’s) RYZ101 delivers alpha-emitting actinium-225 (Act-225) to SSTR2 receptors; it’s in phase 3 for GEP-NET that no longer responds to Lutathera. Fusion’s (now AstraZeneca’s) lead candidate, acquired in February 2023 from RadioMedix, uses Act-225 to target PSMA. Act-225 also features in clinical programs at Bayer, Convergent Therapeutics and Actinium Pharmaceuticals. Novartis’s Mariana Oncology acquisition brings a preclinical Act-225 lead in small cell lung cancer.

Another alpha advantage relates to its ability to harness the immune system — critical for a durable anti-cancer effect. Hitting tumor cells with any kind of ionizing radiation generates neoantigens5, potentially sensitizing tumors to immunotherapy. Alpha’s short-range, high-energy punch makes it a more effective cancer cell killer — and thus a better neoantigen generator — than the lower-energy beta-radiation.

Another potential advantage of alpha radiation is convenience: patients receiving Lutathera or Pluvicto must stay away from pregnant women and children for at least a week after therapy6, as Lu-177 has a week-long half-life and emits beta and gamma radiation, both of which travel further than alpha particles. Reduced isolation requirements are a “big plus” for alpha emitters, notes Dominik Rüttinger, head of research and early development, oncology at Bayer, which has since 2013 been selling alpha-emitting Xofigo (radium-223 dichloride) for prostate-cancer-linked bone metastases. (Xofigo has no separate ligand: radium, like calcium, finds its way naturally to fast-growing bone cells, just as beta-emitting iodine-131 naturally accumulates in the thyroid; the latter has been used to treat thyroid cancer since the 1940s.)

Almost two dozen clinical trials of alpha-emitting radiopharmaceuticals are underway7, though no targeted alpha therapy using Act-225 or Pb-212 has yet been approved.

Despite the “huge amount of enthusiasm” for alpha-emitters, “there is not much human data,” cautions MSKCC’s Lewis. A phase 1 dose-finding trial of Johnson & Johnson’s Act-225-based prostate cancer candidate, presented at the American Society of Clinical Oncology conference in early June, revealed 4 patient deaths due to treatment-related adverse events among 57 patients who received the drug, alongside “profound and durable” responses among heavily pretreated patients. For Act-225 in particular, “the jury is still out on long-term safety,” says Gericke at isotope-agnostic Ariceum.