
Non-Sponsored Content
LUNG CANCER
Selpercatinib displays efficacy in RET fusion-positive non-small cell lung cancer
Medical writer: Kirsty LEE | Last updated: 7th September 2020 | In: Chemotherapy, Lung Cancer, Oncology, Targeted Therapies, US FDA Onc\Haem Approvals
Article Keywords
ALK, EGFR, ELM4-ALK, KRAS, NSCLC, RET, RET mutations, selpercatinib
Aberrant RET activation has shown to be a clinical driver of tumour growth and proliferation.1Belli C et al. Clin Cancer Res Off J Am Assoc Cancer Res. Published online July 14, 2020. It is reported that 1-2% of non-small cell lung cancer patients have activating RET fusions.1Belli C et al. Clin Cancer Res Off J Am Assoc Cancer Res. Published online July 14, 2020. Clinical characteristics of these patients are generally younger (<60 years) with minimal or no smoking history, and frequent presentation with brain metastases at diagnosis of advanced disease.1Belli C et al. Clin Cancer Res Off J Am Assoc Cancer Res. Published online July 14, 2020. RET mutations are mutually exclusive with other common lung cancer genetic abberations, such as reported for KRAS, EGFR, and ALK.1Belli C et al. Clin Cancer Res Off J Am Assoc Cancer Res. Published online July 14, 2020.
Selpercatinib is a highly selective receptor tyrosine kinase RET inhibitor that was approved by the United States (US) Food and Drug Administration (FDA) in May 2020 for the treatment of adult patients with metastatic RET fusion-positive NSCLC.2Markham A. Drugs. 2020;80(11):1119-1124. It was also designed to penetrate the central nervous system and has demonstrated anti-tumour activity in the brain in preclinical models.3Drilon A et al. N Engl J Med. 2020;383(9):813-824. Selpercatinib was evaluated in LIBRETTO-001, a phase 1/2 basket clinical trial enrolling adolescent and adult patients with any type of solid tumour with a RET alteration.3Drilon A et al. N Engl J Med. 2020;383(9):813-824. The efficacy and safety of selpercatinib in the subset of patients with RET fusion-positive NSCLC were recently published in the New England Journal Medicine.3Drilon A et al. N Engl J Med. 2020;383(9):813-824.
The Phase 1 portion of the trial consisted of dose-escalation and dose-expansion cohorts, with patients in the former receiving selpercatinib doses ranging from 20mg once daily to 240mg twice daily. Patients who were enrolled in the phase 2 portion received the recommended phase 2 dose (RP2D) of selpercatinib. A total of 144 patients with RET fusion-positive advanced NSCLC were enrolled in the lung cancer subset of the study and received selpercatinib.3Drilon A et al. N Engl J Med. 2020;383(9):813-824. Patients were at least 12 years of age, with a diagnosis of advanced or metastatic solid tumour.3Drilon A et al. N Engl J Med. 2020;383(9):813-824. Of the 144 patients, 105 were at least pretreated with prior platinum-based chemotherapy. RET alteration status was identified through fluorescence in situ hybridisation (FISH) or reverse transcriptase polymerase chain reaction (RT-PCR) assay.3Drilon A et al. N Engl J Med. 2020;383(9):813-824. The primary endpoint was an objective response (complete or partial response), as determined by independent review.3Drilon A et al. N Engl J Med. 2020;383(9):813-824. Secondary endpoints included objective intracranial response, progression-free survival (PFS), duration of response, and safety.3Drilon A et al. N Engl J Med. 2020;383(9):813-824.
Baseline characteristics were generally similar between patients who were previously treated and previously untreated, although previously untreated patients tended to have better performance status and a lower incidence of brain metastases at study enrolment.3Drilon A et al. N Engl J Med. 2020;383(9):813-824. Previously treated patients received a median of 3 previous systemic therapy regimens, 55% had received previous PD-L1 or PD-1 therapies, and 48% had received multitargeted receptor tyrosine kinase therapies with anti-RET activity.3Drilon A et al. N Engl J Med. 2020;383(9):813-824. 36% of patients had brain metastases at baseline.3Drilon A et al. N Engl J Med. 2020;383(9):813-824.
The RP2D was established at selpercatinib 160mg twice daily.3Drilon A et al. N Engl J Med. 2020;383(9):813-824. Among the platinum chemotherapy-pretreated patients, 68% had an objective response.3Drilon A et al. N Engl J Med. 2020;383(9):813-824. A complete response was observed in 2% of patients, and 62% had a partial response.3Drilon A et al. N Engl J Med. 2020;383(9):813-824. Stable disease was observed in 29%, while 4% had progressive disease and 4% could not be evaluated.3Drilon A et al. N Engl J Med. 2020;383(9):813-824. Responses were observed regardless of treatment with previous anti-PD-L1, anti-PD1, or multitargeted kinase inhibitors.3Drilon A et al. N Engl J Med. 2020;383(9):813-824. Median duration of response was 17.5 months, with 63% of responses still ongoing at a median follow-up of 12.1 months.3Drilon A et al. N Engl J Med. 2020;383(9):813-824. Median PFS for this group of patients at one year was 16.5 months.3Drilon A et al. N Engl J Med. 2020;383(9):813-824.
In the subgroup of 105 patients pre-treated with platinum-based chemotherapy, 38 had investigator-assessed central nervous system (CNS) metastasis at baseline, and 11 patients had measurable lesions according to RECIST by independent review.3Drilon A et al. N Engl J Med. 2020;383(9):813-824. Of these 11 patients, 91% had an objective intracranial response, including three complete responses (27%) and seven partial responses (64%). The median CNS duration of response was 10.1 months.3Drilon A et al. N Engl J Med. 2020;383(9):813-824.
In the subgroup of 39 previously untreated patients, 85% had a response according to independent review, and at six months, 90% of the responses were ongoing.3Drilon A et al. N Engl J Med. 2020;383(9):813-824. Median PFS and duration of response were not reached at the median follow-up of 9.2 and 7.4 months, respectively.3Drilon A et al. N Engl J Med. 2020;383(9):813-824.
The most common grade 3 or 4 adverse events (AEs) with selpercatinib were hypertension, increased alanine aminotransferase (ALT) and aspartate aminotransferase (AST), hyponatremia, and lymphopenia.3Drilon A et al. N Engl J Med. 2020;383(9):813-824. Grade 5 adverse events occurred six times, which included sepsis and cardiac arrest, multi-organ dysfunction syndrome, pneumonia, and respiratory failure but were deemed unrelated to selpercatinib treatment.3Drilon A et al. N Engl J Med. 2020;383(9):813-824. Of all 531 patients with any metastatic RET-positive solid tumour in the LIBRETTO-001 trial and who received at least one dose of selpercatinib, 30% warranted a dose reduction due to treatment-related AEs, and 2% discontinued due to treatment-related AEs.3Drilon A et al. N Engl J Med. 2020;383(9):813-824.
Reference
- Belli C et al. Clin Cancer Res Off J Am Assoc Cancer Res. Published online July 14, 2020.
- Markham A. Drugs. 2020;80(11):1119-1124.
- Drilon A et al. N Engl J Med. 2020;383(9):813-824.
Disclaimer
This article is not medical advice. Patients should seek personal assessment by a licenced specialist. Physicians are recommended to read the full publication(s) as cited in the article before making medical decisions. This article does not supersede nor replace the published article(s).
© Copyright 2020 MediPaper Medical Communications Ltd. – Selpercatinib displays efficacy in RET fusion-positive non-small cell lung cancer
YOU MAY ALSO LIKE



































































Venetoclax plus azacitidine, decitabine, or low-dose cytarabine FDA approved in elderly AML patients












































































































© Copyright 2020 MediPaper Medical Communications Ltd. – Selpercatinib displays efficacy in RET fusion-positive non-small cell lung cancer
Leave a Reply
Want to join the discussion?Feel free to contribute!