Selpercatinib for RET fusion-positive non-small cell lung cancer

Background:
Lung cancer is the fifth most common cancer in Australia and the most common cause of cancer-related death. Non-small cell lung cancer (NSCLC) is the most common form, often presenting as locally advanced or metastatic disease, with poor prognosis. Standard treatments include immune checkpoint inhibitors and chemotherapy (e.g. pembrolizumab with a platinum-based drug and/or pemetrexed).^1,2

Mutations in the RET (rearranged during transfection) gene, a gene that encodes a transmembrane receptor tyrosine kinase, promote cancer growth and present opportunities for targeted therapy.² RET gene fusions occur in approximately 1 to 2% of patients with NSCLC and are associated with a high risk of central nervous system (CNS) metastases.^3,4

Mechanism of action:
Selpercatinib is a novel, highly selective and potent small-molecule RET kinase inhibitor with CNS penetration.

Clinical trials:
The decision to provisionally approve selpercatinib for RET fusion-positive NSCLC was based on interim analysis from a phase 1–2 multicentre, open-label, single-arm clinical study (LIBRETTO-001)^2-4 that has since been completed.⁵ Phase 1 established a selpercatinib dosage of 160 mg twice daily for evaluating anti-tumour activity in phase 2.

The LIBRETTO-001 study included 247 patients with RET fusion-positive NSCLC who were previously treated with at least platinum-based chemotherapy, and 69 patients with RET fusion-positive NSCLC who were treatment-naive.^4,5 Baseline characteristics of the 2 groups were similar, except for CNS metastases which were found in 31.2% of previously treated patients and 23.2% of treatment-naive patients. The median participant ages were 61 and 63 years, respectively. Both groups had a slightly higher proportion of females and nearly 70% of patients had never smoked. The primary outcome was the objective response rate. Secondary outcomes included duration of response, progression-free survival, overall survival, and safety. Outcomes at a median follow-up of approximately 40 months, are summarised in Table 1.⁵

Table 1. Outcome data from the LIBRETTO-001 study of selpercatinib in patients with RET fusion-positive non-small cell lung cancer [NB1]⁵

	Previously treated patients (n=247)	Treatment-naive patients (n=69)
Objective response rate	61.5%	82.6%
Complete response rate	8.1%	7.2%
Time to response (median)	1.9 months (range 0.7 to 44.2)	1.8 months (range 0.7 to 10.8)
Progression-free survival (median)	26.2 months	22.0 months
Overall survival (median)	47.6 months	Not reached [NB2]
NB1: Outcomes were assessed by a blinded independent review committee following Response Evaluation Criteria in Solid Tumours (RECIST v1.1) guidelines. NB2: Median overall survival was not able to be calculated for treatment-naive patients, as 52.3% were still alive at final follow-up.5

In 26 patients with measurable brain metastases at baseline, the response rate was 85% (complete response rate 27%) and median duration of response was 9.4 months.⁵

The efficacy of selpercatinib was confirmed in the interim data analysis from an ongoing phase 3 randomised controlled trial (LIBRETTO-431).¹ This study compared selpercatinib to pemetrexed with platinum-based therapy with or without pembrolizumab. Selpercatinib demonstrated significantly longer progression-free survival (24.8 months versus 11.2 months) and higher response rate (84% versus 65%) than the comparator.¹

Adverse effects:
Common adverse effects with grade 3 severity or higher in the LIBRETTO-001 study were hypertension (19.6%), decreased lymphocyte count (17.6%), hypothyroidism (15.4%), raised alanine aminotransferase (ALT) (10.7%), raised aspartate aminotransferase (AST) (9.7%), diarrhoea (5%) and prolonged QT interval (4.8%).⁶ Pneumonia occurred in 4% of patients and interstitial lung disease and/or pneumonitis in 2.2%.⁶ Grade 3 or 4 haemorrhagic events occurred in 3% of patients.^5,6

Most toxicities were manageable with dose modification and standard clinical care.^1,5 Dose reduction occurred in up to 51% of patients, and 4% of patients discontinued treatment because of selpercatinib-associated adverse effects.^1,4,6

Dosage and administration:
The standard dosage of selpercatinib is 160 mg orally twice daily. For patients who weigh less than 50 kg the dose is reduced to 120 mg twice daily.⁶ No dose adjustment is required in renal impairment or in mild to moderate hepatic impairment.

Treatment is continuous until disease progression or unacceptable toxicity.⁷ Some adverse effects may be managed with dose modifications (interruption or dose reduction in 40 mg decrements).⁶

Precautions and practice points:
Hepatic transaminase levels should be measured before starting selpercatinib, every 2 weeks for the first 3 months, monthly for the following 3 months, and as clinically indicated.⁶ Hypertension should be controlled before starting selpercatinib and blood pressure monitored regularly during treatment.⁶ Electrocardiogram and serum electrolyte monitoring is recommended before starting selpercatinib, after 1 week of treatment, monthly for the first 6 months, and as clinically indicated. Caution is advised when co-administering drugs that prolong the QT interval and in patients predisposed to arrhythmias.⁶ Monitoring for symptoms of interstitial lung disease or pneumonitis during therapy is advised.

Selpercatinib is a substrate of cytochrome P450 (CYP) 3A4 and P-glycoprotein. Co-administration with CYP3A4 or P-glycoprotein inducers or inhibitors should be avoided. Selpercatinib can inhibit CYP2C8, CYP3A4 and P-glycoprotein, affecting sensitive substrates.⁶ Selpercatinib’s solubility is pH dependent. Patients taking a proton pump inhibitor should be advised to take selpercatinib with food. Doses of selpercatinib should be spaced from histamine-2 (H2) receptor antagonists and locally acting antacids.⁶

Use in pregnancy:
There are limited data on the safety of selpercatinib in pregnancy. It is classified as Therapeutic Goods Administration pregnancy category D.⁶ Women of childbearing potential, and men with female partners of childbearing potential, should be advised to use effective contraception during treatment and for at least 1 week after the last dose.⁶

Place in therapy:
Selpercatinib provides a potential benefit over platinum-based chemotherapy and may be considered for first- or second-line therapy for patients with RET fusion-positive NSCLC.² The clinical trials demonstrated rapid and durable responses with selpercatinib, including intracranial activity, irrespective of prior treatment.^1,3,4

This new drug comment was finalised on 17 June 2025.

At the time this new drug comment was prepared, the Australian Public Assessment Report was available from the Therapeutic Goods Administration. The sponsor did not provide the Clinical Evaluation Report.

 

References

1. Zhou C, Solomon B, Loong HH, Park K, Perol M, Arriola E, et al. First-Line Selpercatinib or Chemotherapy and Pembrolizumab in RET Fusion-Positive NSCLC. N Engl J Med 2023;389:1839-50.
2. Therapeutic Goods Administration. Australian Public Assessment Report for Retevmo. Department of Health, Disability and Ageing; 2024. [cited 2025 Jun 24]
3. Drilon A, Oxnard GR, Tan DSW, Loong HHF, Johnson M, Gainor J, et al. Efficacy of Selpercatinib in RET Fusion-Positive Non-Small-Cell Lung Cancer. N Engl J Med 2020;383:813-24.
4. Drilon A, Subbiah V, Gautschi O, Tomasini P, de Braud F, Solomon BJ, et al. Selpercatinib in Patients With RET Fusion-Positive Non-Small-Cell Lung Cancer: Updated Safety and Efficacy From the Registrational LIBRETTO-001 Phase I/II Trial. J Clin Oncol 2023;41:385-94.
5. Gautschi O, Park K, Solomon BJ, Tomasini P, Loong HH, De Braud F, et al. Selpercatinib in RET Fusion-Positive Non-Small Cell Lung Cancer: Final Safety and Efficacy, Including Overall Survival, From the LIBRETTO-001 Phase I/II Trial. J Clin Oncol 2025;43:1758-64.
6. Therapeutic Goods Administration. Australian Product Information - RETEVMO selpercatinib 40 mg immediate release capsules. Department of Health, Disability and Ageing; 2023. [cited 2025 Jun 24]
7. eviQ. Cancer Institute NSW; [cited 2025 Jun 2]

 

The new drug comments in Australian Prescriber are prepared by the editors and reviewed by the Editorial Advisory Committee. Some of the views expressed on newly approved products should be regarded as preliminary, as there may be limited published data at the time of publication, and little experience in Australia of their safety or efficacy. Before new drugs are prescribed, it is important that more detailed information is obtained from the approved product information, a medicines information centre or some other appropriate source.

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