Non-small cell lung cancer, RET-positive

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Eric K. Singhi, MD
MD Anderson Cancer Center
Houston, TX, USA

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Amit Kulkarni, MBBS
University of Minnesota
Minneapolis, MN, USA

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Note: these are regimens tested in biomarker-specific populations, please see the main NSCLC page for other regimens.
There are several related dedicated pages:

Last updated on 2024-07-23:
7 regimens on this page
7 variants on this page


Guidelines

Given the rapid change in evidence in many areas of hematology/oncology, readers are encouraged to consider any guideline published 5+ years ago to be for historical purposes, only.



NCCN


Advanced or metastatic disease, first-line therapy

Carboplatin & Pemetrexed

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Zhou et al. 2023 (LIBRETTO-431) 2020-03 to 2022-08 Phase 3 (C) Selpercatinib Inferior PFS

Chemotherapy

21-day cycles

References

  1. LIBRETTO-431: Zhou C, Solomon B, Loong HH, Park K, Pérol M, Arriola E, Novello S, Han B, Zhou J, Ardizzoni A, Mak MP, Santini FC, Elamin YY, Drilon A, Wolf J, Payakachat N, Uh MK, Rajakumar D, Han H, Puri T, Soldatenkova V, Lin AB, Lin BK, Goto K; LIBRETTO-431 Trial Investigators. First-Line Selpercatinib or Chemotherapy and Pembrolizumab in RET Fusion-Positive NSCLC. N Engl J Med. 2023 Nov 16;389(20):1839-1850. Epub 2023 Oct 21. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors PubMed NCT04194944
    1. Subgroup analysis: Pérol M, Solomon BJ, Goto K, Park K, Nadal E, Bria E, Martin C, Bar J, Williams JN, Puri T, Li J, Uh MK, Lin BK, Zhou C. CNS Protective Effect of Selpercatinib in First-Line RET Fusion-Positive Advanced Non-Small Cell Lung Cancer. J Clin Oncol. 2024 Jul 20;42(21):2500-2505. Epub 2024 Jun 3. link to original article PubMed


Carboplatin, Pemetrexed, Pembrolizumab

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Zhou et al. 2023 (LIBRETTO-431) 2020-03 to 2022-08 Phase 3 (C) Selpercatinib Inferior PFS

Chemotherapy

Immunotherapy

21-day cycles

References

  1. LIBRETTO-431: Zhou C, Solomon B, Loong HH, Park K, Pérol M, Arriola E, Novello S, Han B, Zhou J, Ardizzoni A, Mak MP, Santini FC, Elamin YY, Drilon A, Wolf J, Payakachat N, Uh MK, Rajakumar D, Han H, Puri T, Soldatenkova V, Lin AB, Lin BK, Goto K; LIBRETTO-431 Trial Investigators. First-Line Selpercatinib or Chemotherapy and Pembrolizumab in RET Fusion-Positive NSCLC. N Engl J Med. 2023 Nov 16;389(20):1839-1850. Epub 2023 Oct 21. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors PubMed NCT04194944
    1. Subgroup analysis: Pérol M, Solomon BJ, Goto K, Park K, Nadal E, Bria E, Martin C, Bar J, Williams JN, Puri T, Li J, Uh MK, Lin BK, Zhou C. CNS Protective Effect of Selpercatinib in First-Line RET Fusion-Positive Advanced Non-Small Cell Lung Cancer. J Clin Oncol. 2024 Jul 20;42(21):2500-2505. Epub 2024 Jun 3. link to original article PubMed


Cisplatin & Pemetrexed

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Zhou et al. 2023 (LIBRETTO-431) 2020-03 to 2022-08 Phase 3 (C) Selpercatinib Inferior PFS

Chemotherapy

21-day cycles

References

  1. LIBRETTO-431: Zhou C, Solomon B, Loong HH, Park K, Pérol M, Arriola E, Novello S, Han B, Zhou J, Ardizzoni A, Mak MP, Santini FC, Elamin YY, Drilon A, Wolf J, Payakachat N, Uh MK, Rajakumar D, Han H, Puri T, Soldatenkova V, Lin AB, Lin BK, Goto K; LIBRETTO-431 Trial Investigators. First-Line Selpercatinib or Chemotherapy and Pembrolizumab in RET Fusion-Positive NSCLC. N Engl J Med. 2023 Nov 16;389(20):1839-1850. Epub 2023 Oct 21. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors PubMed NCT04194944
    1. Subgroup analysis: Pérol M, Solomon BJ, Goto K, Park K, Nadal E, Bria E, Martin C, Bar J, Williams JN, Puri T, Li J, Uh MK, Lin BK, Zhou C. CNS Protective Effect of Selpercatinib in First-Line RET Fusion-Positive Advanced Non-Small Cell Lung Cancer. J Clin Oncol. 2024 Jul 20;42(21):2500-2505. Epub 2024 Jun 3. link to original article PubMed


Cisplatin, Pemetrexed, Pembrolizumab

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Zhou et al. 2023 (LIBRETTO-431) 2020-03 to 2022-08 Phase 3 (C) Selpercatinib Inferior PFS

Chemotherapy

Immunotherapy

21-day cycles

References

  1. LIBRETTO-431: Zhou C, Solomon B, Loong HH, Park K, Pérol M, Arriola E, Novello S, Han B, Zhou J, Ardizzoni A, Mak MP, Santini FC, Elamin YY, Drilon A, Wolf J, Payakachat N, Uh MK, Rajakumar D, Han H, Puri T, Soldatenkova V, Lin AB, Lin BK, Goto K; LIBRETTO-431 Trial Investigators. First-Line Selpercatinib or Chemotherapy and Pembrolizumab in RET Fusion-Positive NSCLC. N Engl J Med. 2023 Nov 16;389(20):1839-1850. Epub 2023 Oct 21. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors PubMed NCT04194944
    1. Subgroup analysis: Pérol M, Solomon BJ, Goto K, Park K, Nadal E, Bria E, Martin C, Bar J, Williams JN, Puri T, Li J, Uh MK, Lin BK, Zhou C. CNS Protective Effect of Selpercatinib in First-Line RET Fusion-Positive Advanced Non-Small Cell Lung Cancer. J Clin Oncol. 2024 Jul 20;42(21):2500-2505. Epub 2024 Jun 3. link to original article PubMed


Selpercatinib monotherapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Zhou et al. 2023 (LIBRETTO-431) 2020-03 to 2022-08 Phase 3 (E-switch-ooc) 1a. Carboplatin & Pemetrexed
1b. Carboplatin, Pemetrexed, Pembrolizumab
1c. Cisplatin & Pemetrexed
1d. Cisplatin, Pemetrexed, Pembrolizumab
Superior PFS (primary endpoint)
Median PFS: 24.8 vs 11.2 mo
(HR 0.46, 95% CI 0.31-0.70)

Targeted therapy

21-day cycles

References

  1. LIBRETTO-431: Zhou C, Solomon B, Loong HH, Park K, Pérol M, Arriola E, Novello S, Han B, Zhou J, Ardizzoni A, Mak MP, Santini FC, Elamin YY, Drilon A, Wolf J, Payakachat N, Uh MK, Rajakumar D, Han H, Puri T, Soldatenkova V, Lin AB, Lin BK, Goto K; LIBRETTO-431 Trial Investigators. First-Line Selpercatinib or Chemotherapy and Pembrolizumab in RET Fusion-Positive NSCLC. N Engl J Med. 2023 Nov 16;389(20):1839-1850. Epub 2023 Oct 21. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors PubMed NCT04194944
    1. Subgroup analysis: Pérol M, Solomon BJ, Goto K, Park K, Nadal E, Bria E, Martin C, Bar J, Williams JN, Puri T, Li J, Uh MK, Lin BK, Zhou C. CNS Protective Effect of Selpercatinib in First-Line RET Fusion-Positive Advanced Non-Small Cell Lung Cancer. J Clin Oncol. 2024 Jul 20;42(21):2500-2505. Epub 2024 Jun 3. link to original article PubMed


Advanced or metastatic disease, all lines of therapy

Pralsetinib monotherapy

Regimen

Study Dates of enrollment Evidence
Gainor et al. 2021 (ARROWRET-NSCLC) 2017-2020 Phase 1/2 (RT)

Note: this trial is denoted as ARROWRET-NSCLC to distinguish from other arms of this basket trial. This was the phase 2 dosing.

Biomarker eligibility criteria

  • RET fusion positive

Targeted therapy

Continued indefinitely

References

  1. ARROWRET-NSCLC: Gainor JF, Curigliano G, Kim DW, Lee DH, Besse B, Baik CS, Doebele RC, Cassier PA, Lopes G, Tan DSW, Garralda E, Paz-Ares LG, Cho BC, Gadgeel SM, Thomas M, Liu SV, Taylor MH, Mansfield AS, Zhu VW, Clifford C, Zhang H, Palmer M, Green J, Turner CD, Subbiah V. Pralsetinib for RET fusion-positive non-small-cell lung cancer (ARROW): a multi-cohort, open-label, phase 1/2 study. Lancet Oncol. 2021 Jul;22(7):959-969. Epub 2021 Jun 9. Erratum in: Lancet Oncol. 2021 Aug;22(8):e347. link to original article PubMed NCT03037385
    1. Update: Griesinger F, Curigliano G, Thomas M, Subbiah V, Baik CS, Tan DSW, Lee DH, Misch D, Garralda E, Kim DW, van der Wekken AJ, Gainor JF, Paz-Ares L, Liu SV, Kalemkerian GP, Houvras Y, Bowles DW, Mansfield AS, Lin JJ, Smoljanovic V, Rahman A, Kong S, Zalutskaya A, Louie-Gao M, Boral AL, Mazières J. 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 Nov;33(11):1168-1178. Epub 2022 Aug 13. link to original article PubMed


Selpercatinib monotherapy

Regimen

FDA-recommended dose
Study Dates of enrollment Evidence
Drilon et al. 2020 (LIBRETTO-001NSCLC) 2017-2018 Phase 1/2 (RT)

Biomarker eligibility criteria

  • RET fusion positive

Targeted therapy

  • Selpercatinib (Retevmo) by the following weight-based criteria:
    • Less than 50 kg: 120 mg PO twice per day
    • 50 kg or more: 160 mg PO twice per day

Continued indefinitely

References

  1. LIBRETTO-001NSCLC: Drilon A, Oxnard GR, Tan DSW, Loong HHF, Johnson M, Gainor J, McCoach CE, Gautschi O, Besse B, Cho BC, Peled N, Weiss J, Kim YJ, Ohe Y, Nishio M, Park K, Patel J, Seto T, Sakamoto T, Rosen E, Shah MH, Barlesi F, Cassier PA, Bazhenova L, De Braud F, Garralda E, Velcheti V, Satouchi M, Ohashi K, Pennell NA, Reckamp KL, Dy GK, Wolf J, Solomon B, Falchook G, Ebata K, Nguyen M, Nair B, Zhu EY, Yang L, Huang X, Olek E, Rothenberg SM, Goto K, Subbiah V. Efficacy of Selpercatinib in RET Fusion-Positive Non-Small-Cell Lung Cancer. N Engl J Med. 2020 Aug 27;383(9):813-824. link to original article link to PMC article PubMed NCT03157128
    1. PRO analysis: Minchom A, Tan AC, Massarelli E, Subbiah V, Boni V, Robinson B, Wirth LJ, Hess LM, Jen MH, Kherani J, Olek E, McCoach CE. Patient-Reported Outcomes with Selpercatinib Among Patients with RET Fusion-Positive Non-Small Cell Lung Cancer in the Phase I/II LIBRETTO-001 Trial. Oncologist. 2022 Feb 3;27(1):22-29. link to original article link to PMC article PubMed
    2. Update: Drilon A, Subbiah V, Gautschi O, Tomasini P, de Braud F, Solomon BJ, Shao-Weng Tan D, Alonso G, Wolf J, Park K, Goto K, Soldatenkova V, Szymczak S, Barker SS, Puri T, Bence Lin A, Loong H, Besse B. 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 Jan 10;41(2):385-394. Epub 2022 Sep 19. link to original article link to PMC article PubMed