Selpercatinib may alter the landscape of RET-altered cancers

The novel, next-generation, highly potent and selective RET inhibitor selpercatinib may modify the landscape of another genomic subgroup — RET-altered cancers, according to two early-phase trials investigating the potential of selpercatinib in medullary thyroid cancer (MTC) and non-small-cell lung cancer (NSCLC).

Cabozantinib and vandetanib are multikinase targeted inhibitors approved for metastatic MTC, [J Clin Oncol 2013;31:3639-3646; J Clin Oncol 2012;30:134-141] and investigated for RET fusion-positive LC. [J Clin Oncol 2017;35:1403-1410; Ann Oncol 2017;28:292-297; Lancet Respir Med 2017;5:42-50] However, durability of responses are limited by poor anti-RET activity and pharmacokinetic features, and off-target adverse events (AEs) leading to dose reductions and even permanent discontinuation. [Nat Rev Clin Oncol 2018;15:151-167; J Thorac Oncol 2018;13:27-45]

Currently, there are no selective RET inhibitors approved for RET-altered cancers. Selpercatinib reportedly has nanomolar potency against various RET alterations while sparing non-RET kinases and nonkinase targets, and has antitumour activity in the brain. [Ann Oncol 2018;29:1869-1876]

The phase I/II LIBRETTO-001 trial comprised 531 adolescents and adults with any solid tumour harbouring an activating RET alteration. In phase I (dose-escalation), selpercatinib was delivered at doses ranging from 20 mg QD to 240 mg BID. In phase II, the recommended dose of 160 mg BID was given. Selpercatinib was administered orally continuously in 28-day cycles until disease progression, death, unacceptable toxicity, or withdrawal of consent. Due to treatment-related AEs, 30 percent of participants had dose reductions while 2 percent withdrew treatment.

 

RET-altered thyroid cancer

This study comprised 162 participants from the overall LIBRETTO-001 cohort who had RET-mutant MTCs with (n=55; group A) or without (n=88; group B) prior cabozantinib or vandetanib use, and those with previously treated RET fusion-positive TC including its subtypes* (n=19; group C). [N Engl J Med 2020;383:825-835]

The fractions of participants achieving objective responses (ORs) in groups A, B, and C were 69, 73, and 79 percent, respectively. At 1 year, 86, 91, and 71 percent of these respective responses were ongoing, while 82, 92, and 64 percent of patients in the respective arms remained progression-free.

The most common grade ≥3 AEs were hypertension, increased ALT/AST** levels, and hyponatremia.

“Selpercatinib showed durable efficacy with mainly low-grade toxic effects in patients with MTC with and without previous vandetanib or cabozantinib treatment,” said lead investigator Dr Lori Wirth from the Massachusetts General Hospital in Boston, Massachusetts, US.

RET mutations are tied to more aggressive disease in MTC. [iScience 2019;20:324-336] RET-fusion TCs, though generally rare, are mostly seen in children and young adults than older individuals, and are more likely observed in cases linked to exposure to environmental radiation. [Histopathology 2019;75:890-899; Oncologist 2017;22:255-263; Oncotarget 2016;7:16716-16730]

In trials evaluating cabozantinib and vandetanib for metastatic MTC, the dose-limiting toxicities were attributed to VEGFR2 inhibition. [Cancer Treat Rev 2018;66:64-73; Cancer Treat Rev 2016;42:47-55] “[Moreover,] some patients are simply not eligible for these therapies [due to] unacceptable risk of bleeding or concerns about wound healing,” added Wirth and colleagues.

“[In our study,] the percentage of patients with previously treated RET-mutant MTC who had an OR to selpercatinib appears to exceed the percentage who had an OR to previously approved first-line agents, while potentially offering a better safety profile,” said the investigators. “[Nonetheless,] caution is necessary when interpreting results because comparisons between studies may not take into account important factors that influence the likelihood of response.”

 

RET fusion-positive NSCLC

In this cohort, 144 participants from LIBRETTO-001 with advanced RET fusion-positive NSCLC (n=105 had chemotherapy [CT]; n=39 untreated) were evaluated. [N Engl J Med 2020;383:813-824]

Of those who received CT, 64 percent achieved an OR, 63 percent of which were ongoing at a median follow-up of 12.1 months. Among those who were previously untreated, 85 percent had an OR, 90 percent of which were ongoing at 6 months.

Despite the shorter follow-up in the previously untreated group vs those who had CT, responses continued in most patients beyond 1 year after treatment initiation.

In CT recipients with measurable CNS*** metastasis (n=11), 91 percent had an intracranial OR. “[A]lthough the incidence of brain metastases observed in our trial was lower than that in previous trials … the promising frequency of intracranial response to selpercatinib is important, given the high estimated lifetime risk of brain metastases among patients with RET fusion-positive LC,” noted the study team led by Dr Alexander Drilon from the Memorial Sloan Kettering Cancer Center in New York City, New York, US.

The most common grade ≥3 AEs were the same as those observed in the MTC cohort. “[These] were reversible with dose modifications, [suggesting] that long-term treatment is feasible, particularly in light of the responses observed with selpercatinib at doses as low as 20 mg QD,” they said.

The current findings suggest that selpercatinib had substantial antitumour activity regardless of prior exposure to anti-PD-1/PD-L1 agents or multikinase inhibitors, and among those with brain metastases, and was tied to low-grade toxicities, noted Drilon and colleagues.

The durable efficacy of selpercatinib in the current study surpassed those observed with multikinase inhibitors, [Lancet Oncol 2016;17:1653-1660; Ann Oncol 2017;28:292-297; Lancet Respir Med 2017;5:42-50; Lung Cancer 2019;138:124-130] thus highlighting the potential of selpercatinib in this genetically defined LC subgroup. “These findings established RET fusions as bona fide and clinically actionable drivers in LC,” said the investigators.

 

RET: An attractive therapeutic target

“In both trials, selpercatinib produced durable responses in [most] patients, and only ~3 percent discontinued because of drug-related AEs. [Selpercatinib] offers the potential for improved efficacy and a more satisfactory side-effect profile [in these settings],” said editorialist Dr Razelle Kurzrock from the Division of Hematology-Oncology at the University of California, San Diego in the US.

“RET is thus an attractive therapeutic target … RET abnormalities now join other^# genomic alterations … that warrant molecular screening strategies,” added Kurzrock. Furthermore, employing tailored combination therapy strategies and additional techniques (eg, transcriptome analysis) may help fully understand the molecular landscape of cancer.