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Molecular diagnostics for RET inhibition in NSCLC and thyroid cancers

Efficacy of Selpercatinib in RET Fusion-Positive Non-Small Cell Lung Cancer

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Last updated:10th Nov 2021
Published:10th Nov 2021

Efficacy of Selpercatinib in RET Fusion-Positive Non-Small Cell Lung Cancer

Drilon A, Oxnard GR, Tan DSW, Loong HHF, Johnson M J, et al. New England Journal Medicine. 2020;383(9):813–824.

  • RET fusions are presented in up to 2% of all patients with NSCLC
  • Selpercatinib is a highly selective inhibitor of RET kinase that also reports CNS activity
  • This was a Phase I/II study assessing the efficacy and safety of selpercatinib in both chemotherapy-experienced and treatment-naïve patients
  • Selpercatinib demonstrated antitumor activity across both patient groups plus a substantial intracranial response

 

RET fusions are present in 1-2% of patients with non-small cell lung cancer (NSCLC),1–3 accounting for >10,000 new cases each year globally. RET fusions typically occur in a mutually exclusive fashion with other cancer drivers and are associated with a high risk of brain metastases4.

In prospective clinical trials, use of multitargeted kinase inhibitors has demonstrated a measure of RET inhibition. However, treatment outcomes suggest poor pharmacokinetic characteristics, limited clinical benefits,5–7 and dose-limiting off-target toxicity8,9.

Selpercatinib (formerly LOXO-292) is a novel, highly selective, small-molecule inhibitor of RET kinase. Experimental models highlight a nanomolar potency against diverse RET alterations, while mainly sparing non-RET kinases and non-kinase targets10. In addition, preclinical models have demonstrated penetration and antitumour activity within the central nervous system (CNS).

In this international, multicentre, Phase I/II trial (LIBRETTO-001), Drilon and colleagues assessed the efficacy and safety of oral selpercatinib (20–240 mg twice daily in 28-day cycles) in adolescent and adult patients (≥12 years of age) with RET fusion-positive advanced or metastatic NSCLC. Patients with previously treated or untreated brain metastases were also included.

The study included 105 consecutive patients who had received at least platinum-based chemotherapy; 39 treatment-naïve patients were subsequently enrolled. The primary study endpoint was objective response, with secondary endpoints including objective intracranial response, and safety.

In treatment-experienced patients, selpercatinib was associated with an objective response rate of 64%, with a median progression-free survival (PFS) of 16.5 months. In treatment-naïve patients, 85% were reported with an objective response, with 90% of responses ongoing after 6 months.

RET_DigestOCT21_Fig1.png

Figure 1. Waterfall plots of maximum change in tumour size in all target lesions (A), and in intracranial target lesions in previously treated patients (B). Data for 5 patients with platinum-based chemotherapy are not shown; one had non-target lesions only and four did not undergo target lesion measurement after baseline measurement. Dashed lines at 20% and -30% indicate growth and shrinkage of target lesions, respectively. Anti-PD-1, anti-programmed cell death protein 1; anti-PD-L1, anti-programmed cell death ligand 1.

Of the 11 treatment-experienced patients with measurable CNS metastases at baseline, objective intracranial response was 91% (10 of 11 patients) with a median CNS duration of response of 10.1 months.

The most common grade 3 or 4 adverse events across all patients were reported as hypertension (14%), increased alanine aminotransferase level (13%), increased aspartate aminotransferase level (10%), hyponatremia (6%), and lymphopenia (6%).

Overall, these findings establish RET fusions as genuine and clinically actionable drivers in lung cancer. Selpercatinib demonstrated substantial antitumor activity in treatment-experienced and treatment-naïve patients with RET fusion-positive NSCLC. In addition, due to the high lifetime risk of brain metastases in these patients, the intracranial response to selpercatinib is important.

Drilon and colleagues highlighted that the continued implementation of molecular screening strategies that detect RET fusions will be critical for identifying NSCLC patients who may benefit from selpercatinib.

Treating brain metastases
- 91% of patients with baseline CNS metastases had an objective intracranial response following selpercatinib

- Median CNS duration of response of 10.1 months

References

  1. Wang R, Hu H, Pan Y, Li Y, Ye T, Chenguang L, et al. RET fusions define a unique molecular and clinicopathologic subtype of non-small-cell lung cancer. J Clin Oncol. 2012;30:4352–4359.
  2. Tsuta K, Kohno T, Yoshida A, Shimada Y, Asamura H, Furuta K, et al. RET-rearranged non-small-cell lung carcinoma: a clinicopathological and molecular analysis. Br J Cancer. 2014;110:1571–1578.
  3. Takeuchi K. Discovery stories of RET fusions in lung cancer: a mini-review. Front Physiol. 2019;10:216.
  4. Drilon A, Lin JJ, Filleron T, Ni A, Milia J, Bergagnini I, et al. Frequency of brain metastases and multikinase inhibitor outcomes in patients with RET-rearranged lung cancers. J Thorac Oncol. 2018;13:1595–1601.
  5. Gautschi O, Milia J, Filleron T, Wolf J, Carbone DP, Owen D, et al. Targeting RET in patients with RET-rearranged lung cancers: results from the global, multicenter RET registry. J Clin Oncol. 2017;35(13):1403–1410.
  6. Drilon A, Rekhtman N, Arcila M, Wang L, Ni A, Albano M, et al. Cabozantinib in patients with advanced RET-rearranged non-small-cell lung cancer: an open-label, single-centre, phase 2, single-arm trial. Lancet Oncol. 2016;17:1653–1660.
  7. Lee S-H, Lee J-K, Ahn M-J, Kim D-W, Sun J-M, Keam B, et al. Vandetanib in pretreated patients with advanced non-small cell lung cancer-harboring RET rearrangement: a phase II clinical trial. Ann Oncol. 2017;28:292–297.
  8. Drilon A, Hu ZI, Lai GGY, Tan DSW. Targeting RET-driven cancers: lessons from evolving preclinical and clinical landscapes. Nat Rev Clin Oncol. 2018;15(3):151–167.
  9. Ferrara R, Auger N, Auclin E, Besse B. Clinical and translational implications of RET rearrangements in non-small cell lung cancer. J Thorac Oncol. 2018;13(1):27–45.
  10. Subbiah V, Velcheti V, Tuch BB, Ebata K, Busaidy NL, Wirth LJ, et al. Selective RET kinase inhibition for patients with RET-altered cancers. Ann Oncol. 2018;29:1869–1876.
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