Selpercatinib as the Guardian of the Central Nervous System for Patients With RET Fusion-Positive NSCLC?

The incidences of central nervous system (CNS) metastasis among newly diagnosed treatment-naive patients with RET-positive (+) NSCLC enrolled into the registrational selpercatinib trial (LiBRETTO-001) and in the pivotal phase 2 pralsetinib trial (ARROW) were 23.6% (n = 16 of 69)1Drilon A. Subbiah V. Gautschi O. 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: 385-394Crossref PubMed Scopus (52) Google Scholar and 33% (n = 25 of 75), respectively.2Griesinger F. Curigliano G. Thomas M. et al.Safety and efficacy of pralsetinib in RET fusion-positive non-small-cell lung cancer including as first-line therapy: update from the ARROW trial.Ann Oncol. 2022; 33: 1168-1178Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar Both approved RET-specific tyrosine kinase inhibitors (TKIs), selpercatinib and pralsetinib, achieved high intracranial overall response rate of 85% (95% confidence interval [CI]: 65–96) (n = 22 of 26)1Drilon A. Subbiah V. Gautschi O. 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: 385-394Crossref PubMed Scopus (52) Google Scholar and 70% (95% CI: 35–93) (n = 7 of 10), respectively.2Griesinger F. Curigliano G. Thomas M. et al.Safety and efficacy of pralsetinib in RET fusion-positive non-small-cell lung cancer including as first-line therapy: update from the ARROW trial.Ann Oncol. 2022; 33: 1168-1178Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar The duration of response in selpercatinib-treated patients with measurable CNS metastasis was 9.4 months (95% CI: 7.4–15.3) compared with the overall median progression-free survival (PFS) of 22.0 months (95% CI: 13.8–not reached) among selpercatinib-treated previously treatment-naive patients without baseline CNS metastasis (N = 69). Similarly, for pralsetinib-treated patients, the median CNS duration of response was 10.5 months (95% CI: 5.5–12.6) with the overall median PFS of 13.0 months (95% CI: 9.1–not reached) among patients with pralsetinib-treated previously treatment-naive RET+ NSCLC (N = 75). This leaves approximately 70% of patients newly diagnosed with having treatment-naive advanced RET+ NSCLC who had no CNS metastasis at diagnosis. In their retrospective analysis of cumulative incidence rate (CIR) of CNS metastasis among the three major (ALK, ROS1, RET) RTK fusion+ NSCLC, Drilon et al.3Drilon A. Lin J.J. Filleron T. et al.Frequency of brain metastases and multikinase inhibitor outcomes in patients with RET-rearranged lung cancers.J Thorac Oncol. 2018; 13: 1595-1601Abstract Full Text Full Text PDF PubMed Scopus (126) Google Scholar reported that although ALK+ NSCLC has the highest and unrelenting CIR in patients with CNS metastasis, RET+ NSCLC without baseline CNS metastasis was second with CIR of close to 40% at 4 years and a lifetime CIR of 46% in all patients with stage IV RET+ NSCLC. Brain metastases are still associated with significant morbidity, and their impact on quality of life cannot be discounted. A systematic review of patients with NSCLC with brain metastases revealed that CNS involvement was associated with worse quality of life and shorter PFS and overall survival, particularly in patients receiving whole-brain radiation therapy.4Peters S. Bexelius C. Munk V. Leighl N. The impact of brain metastasis on quality of life, resource utilization and survival in patients with non-small-cell lung cancer.Cancer Treat Rev. 2016; 45: 139-162Abstract Full Text Full Text PDF PubMed Scopus (172) Google Scholar Health care costs also increased after diagnosis of brain metastases, regardless of the treatment modality.4Peters S. Bexelius C. Munk V. Leighl N. The impact of brain metastasis on quality of life, resource utilization and survival in patients with non-small-cell lung cancer.Cancer Treat Rev. 2016; 45: 139-162Abstract Full Text Full Text PDF PubMed Scopus (172) Google Scholar In addition, EGFR+ patients with brain metastases were found to have a statistically significant increase in the number of clinic visits, hospitalizations, emergency room visits, progressive care unit admissions, and hospice admission in the 9 months preceding death or last clinic visit.5Chooback N. Lefrense S. Lau S. Ho C. CNS metastases in epidermal growth factor receptor mutation-positive non-small-cell lung cancer: impact on health resource utilization.J Oncol Pract. 2018; 14: e612-e620Crossref PubMed Scopus (6) Google Scholar Furthermore, at a personal level, brain metastasis even when controlled serves as a constant psychological albatross in a patient with stage IV NSCLC. Given the current efficacy of next-generation TKI against RTK+ NSCLC, the ability to delay or prevent CNS metastasis to minimize the morbidity associated with any treatment of CNS metastasis and to maximize CNS metastasis-free interval in most patients who do not have CNS metastasis at baseline is paramount in treatment decision. Indeed, lorlatinib set the standard as "guardian of the CNS" in the recent CROWN update where the CIR of patients with ALK+ NSCLC without baseline brain metastasis was 1% at a median of 36.7 months follow-up time with only one patient of 112 advanced ALK+ NSCLC without baseline CNS metastasis suffered disease progression in the brain.6Solomon B.J. Bauer T.M. Mok T.S.K. et al.Efficacy and safety of first-line lorlatinib versus crizotinib in patients with advanced, ALK-positive non-small-cell lung cancer: updated analysis of data from the phase 3, randomised, open-label CROWN study.Lancet Respir Med. 2023; 11 (doi:10.1016/S2213-2600(22)00437-4): 354-366Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar In this issue of the Journal of Thoracic Oncology, Murciano-Goroff et al.7Murciano-Goroff Y.R. Falcon C.J. Lin S.T. et al.Central nervous system disease in patients with RET fusion-positive non-small cell lung cancer treated with selpercatinib.J Thorac Oncol. 2023; 18: 620-627Abstract Full Text Full Text PDF Scopus (5) Google Scholar reported an amazingly low CIR of 0% at 36 months among 31 patients with advanced RET+ NSCLC treated with selpercatinib at the Memorial Sloan Kettering Cancer Center. All 31 patients received regular magnetic resonance imaging scans at approximately every 8 weeks during the first year of treatment and extended to every 12 weeks thereafter. This CIR is consistent with the low estimated 2-year probability of CIR of 0.7% among 178 patients with advanced RET+ NSCLC without baseline CNS metastasis at LIBRETTO-001 study entry.1Drilon A. Subbiah V. Gautschi O. 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: 385-394Crossref PubMed Scopus (52) Google Scholar The estimated CIR in the pralsetinib-treatment patients in the ARROW trial has not been reported.2Griesinger F. Curigliano G. Thomas M. et al.Safety and efficacy of pralsetinib in RET fusion-positive non-small-cell lung cancer including as first-line therapy: update from the ARROW trial.Ann Oncol. 2022; 33: 1168-1178Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar In patients with EGFR+ NSCLC, prolonged CNS control associated with osimertinib as compared to older-generation EGFR TKIs with limited CNS activity was translated to lower resource utilization and better clinical outcomes.8Simionato F. Pancheri F. Scarparo S. et al.P48.07 Real-world impact of upfront osimertinib in reducing health resource utilization by preventing brain metastases.J Thorac Oncol. 2021; 16: S1108-S1109Abstract Full Text Full Text PDF Google Scholar The delay or prevention of intracranial progression and the health care resources associated with it may justify the cost of continuing selpercatinib. Selpercatinib is being compared with platinum-based chemotherapy (with or without pembrolizumab) in an ongoing pivotal randomized phase 3 trial (LIBRETTO-431, NCT04194944) with CNS outcome as a secondary end point.9Solomon B.J. Zhou C.C. Drilon A. et al.Phase III study of selpercatinib versus chemotherapy ± pembrolizumab in untreated RET positive non-small-cell lung cancer.Future Oncol. 2021; 17: 763-773Crossref PubMed Scopus (26) Google Scholar Although we cannot prevent brain metastasis in ∼25% of the newly diagnosed RET+ NSCLC patients already presented with CNS metastasis at diagnosis, it will be important to follow whether the CNS efficacy reported by Murciano-Goroff et al.7Murciano-Goroff Y.R. Falcon C.J. Lin S.T. et al.Central nervous system disease in patients with RET fusion-positive non-small cell lung cancer treated with selpercatinib.J Thorac Oncol. 2023; 18: 620-627Abstract Full Text Full Text PDF Scopus (5) Google Scholar will be validated in a similar and dramatic fashion as lorlatinib's CNS efficacy in ALK+ NSCLC patients in the CROWN trial.6Solomon B.J. Bauer T.M. Mok T.S.K. et al.Efficacy and safety of first-line lorlatinib versus crizotinib in patients with advanced, ALK-positive non-small-cell lung cancer: updated analysis of data from the phase 3, randomised, open-label CROWN study.Lancet Respir Med. 2023; 11 (doi:10.1016/S2213-2600(22)00437-4): 354-366Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar A similarly designed pivotal randomized phase 3 trial comparing pralsetinib versus platinum-based chemotherapy (with or without pembrolizumab) as first-line treatment of RET+ NSCLC (AcceleRET-Lung, NCT04222972) will allow pralsetinib to showcase its CNS activity also. It is unlikely that chemotherapy will confer the same CNS efficacy as selpercatinib or pralsetinib. Third, the report of Murciano-Goroff et al.7Murciano-Goroff Y.R. Falcon C.J. Lin S.T. et al.Central nervous system disease in patients with RET fusion-positive non-small cell lung cancer treated with selpercatinib.J Thorac Oncol. 2023; 18: 620-627Abstract Full Text Full Text PDF Scopus (5) Google Scholar offers some insight on the molecular profile of the patients with brain metastases. There was no association between RET fusion partners and brain metastases. Nevertheless, patients with baseline brain metastases had higher rates of co-mutations in MET, TP53, and TERT, indicating more aggressive tumor biology. Molecular determinants of CNS tropism of actionable driver mutation are an underinvestigated area of thoracic oncology. Additionally, an ongoing randomized placebo-controlled, double-blinded phase 3 trial comparing 3 years of selpercatinib versus placebo in resected IB to IIIA RET+ NSCLC (LIBRETTO-432, NCT04819100) is ongoing.10Tsuboi M. Goldman J.W. Wu Y.L. et al.LIBRETTO-432, a phase III study of adjuvant selpercatinib or placebo in stage IB-IIIA RET fusion-positive non-small-cell lung cancer.Future Oncol. 2022; 18: 3133-3141Crossref PubMed Scopus (8) Google Scholar Primary end point of LIBRETTO-432 is magnetic resonance imaging of the brain scheduled every 6 months for the first 5 years and then annually after 5 years. CNS relapse rate is a prespecified secondary end point. In this cohort of patients treated with curative intent, CNS relapses may be catastrophic and is an equally important end point in addition to event-free survival and overall survival. The results of LIBEBRETTO-432 will likely further affirm the results reported by Murciano-Goroff et al.7Murciano-Goroff Y.R. Falcon C.J. Lin S.T. et al.Central nervous system disease in patients with RET fusion-positive non-small cell lung cancer treated with selpercatinib.J Thorac Oncol. 2023; 18: 620-627Abstract Full Text Full Text PDF Scopus (5) Google Scholar Currently, no such similarly designed adjuvant pralsetinib trial is registered in ClinicalTrials.gov. LIBRETTO-432 trial design is similar to ADAURA, which revealed that the benefit of 3 years of adjuvant osimertinib significantly improved disease-free survival, particularly in preventing CNS relapses.11Wu Y.L. Tsuboi M. He J. et al.Osimertinib in resected EGFR-mutated non-small-cell lung cancer.N Engl J Med. 2020; 383: 1711-1723Crossref PubMed Scopus (969) Google Scholar Updated ADAURA results with a median follow-up time of 44.2 months (similar to the median follow-up time of 45 mo for the no baseline CNS cohort in the study of Murciano-Goroff et al.7Murciano-Goroff Y.R. Falcon C.J. Lin S.T. et al.Central nervous system disease in patients with RET fusion-positive non-small cell lung cancer treated with selpercatinib.J Thorac Oncol. 2023; 18: 620-627Abstract Full Text Full Text PDF Scopus (5) Google Scholar) for the osimertinib-treated patients, the data revealed that potentially CNS relapse started to increase after completion of 3 years of adjuvant osimertinib with 54% (14 of 25) and 83.3% (15 of 18) of the CNS relapse (or death) in the osimertinib-treated patients and the osimertinib-treated patients on stages II to IIIA, respectively, occurring after completion of osimertinib treatment,12Herbst R.S. Wu Y.L. John T. et al.Adjuvant Osimertinib for Resected EGFR-Mutated Stage IB-IIIA Non-Small-Cell Lung Cancer: Updated Results From the Phase III Randomized ADAURA Trial.J Clin Oncol. 2023; 41 (doi:10.1200/JCO.22.02186): 1830-1840Crossref PubMed Scopus (66) Google Scholar indicating 3 years of adjuvant osimertinib may be insufficient to suppress continual tropism for the CNS in EGFR+ NSCLC and that prolonged or indefinite use of osimertinib may be necessary. It is not unreasonable to expect, on the basis of the report from Murciano-Goroff et al.,7Murciano-Goroff Y.R. Falcon C.J. Lin S.T. et al.Central nervous system disease in patients with RET fusion-positive non-small cell lung cancer treated with selpercatinib.J Thorac Oncol. 2023; 18: 620-627Abstract Full Text Full Text PDF Scopus (5) Google Scholar that LIBRETTO-432 will likely provide us with further evidence that preventing CNS metastasis with adjuvant selpercatinib is the paramount factor in preventing relapse in resected RET+ NSCLC, similar to ADAURA, although duration of selpercatinib treatment may be beyond 3 years until disease progression in the LIBRETTO-431 trial in the stage IV setting. Thus, continual follow-up of the patients in the cohort of Murciano-Goroff et al.7Murciano-Goroff Y.R. Falcon C.J. Lin S.T. et al.Central nervous system disease in patients with RET fusion-positive non-small cell lung cancer treated with selpercatinib.J Thorac Oncol. 2023; 18: 620-627Abstract Full Text Full Text PDF Scopus (5) Google Scholar is necessary to help us understand if the 0% CIR remained intact during prolonged selpercatinib treatment as selpercatinib will be continued in the stage IV setting until disease progression not an arbitrary period in the adjuvant setting. In the meanwhile, bear in mind that 71.4% of the participants in ADAURA were never-smokers11Wu Y.L. Tsuboi M. He J. et al.Osimertinib in resected EGFR-mutated non-small-cell lung cancer.N Engl J Med. 2020; 383: 1711-1723Crossref PubMed Scopus (969) Google Scholar and 69.6% of the treatment-naive participants with RET+ NSCLC in LIBRETTO-001 were also never-smokers.1Drilon A. Subbiah V. Gautschi O. 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: 385-394Crossref PubMed Scopus (52) Google Scholar With likely continual positive results from these ongoing adjuvant TKI trials in resected early stage NSCLC with actionable driver mutation occurring predominantly in never-smokers, a day of reckoning where the necessity of implementing low-dose computed tomography lung cancer screening among never-smokers to achieve an unfathomable yet reachable "holy grail" of curing or indefinitely suppressing lung cancer is inescapable. With this report by Murciano-Goroff et al.7Murciano-Goroff Y.R. Falcon C.J. Lin S.T. et al.Central nervous system disease in patients with RET fusion-positive non-small cell lung cancer treated with selpercatinib.J Thorac Oncol. 2023; 18: 620-627Abstract Full Text Full Text PDF Scopus (5) Google Scholar, selpercatinib has likely joined osimertinib and lorlatinib as agents with activity in the CNS for their respective mutant NSCLC subtypes. We look forward to identifying drugs to join the list of CNS active agents for ROS1+ and HER2 exon20 insertion positive NSCLC. Sally C. M. Lau: Conceptualization, Data curation, Writing—original draft, Writing—review and editing. Sai-Hong Ignatius Ou: Conceptualization, Data curation, Writing—original draft, Writing—review and editing. Central Nervous System Disease in Patients With RET Fusion-Positive NSCLC Treated With SelpercatinibJournal of Thoracic OncologyVol. 18Issue 5PreviewCentral nervous system (CNS) metastases develop in nearly half of patients with RET fusion-positive NSCLCs and cause morbidity and mortality. The selective RET inhibitor selpercatinib treats existing intracranial disease, but no studies have investigated whether early initiation of selpercatinib is associated with decreased development of CNS metastases. Full-Text PDF Open Access