Non-small cell lung cancer, KRAS-mutated

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Eric K. Singhi, MD
MD Anderson Cancer Center
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Amit Kulkarni, MBBS
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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:

3 regimens on this page
3 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.

ASCO

ESMO

NCCN

Advanced or metastatic disease, subsequent lines of therapy

Adagrasib monotherapy

Regimen

FDA-recommended dose
Study Dates of enrollment Evidence
Jänne et al. 2022 (KRYSTAL-1NSCLC) 2020-01 to 2020-12 Phase 1/2 (RT)

Biomarker eligibility criteria

  • KRAS p.G12C mutation

Targeted therapy

Continued indefinitely

References

  1. KRYSTAL-1NSCLC: Jänne PA, Riely GJ, Gadgeel SM, Heist RS, Ou SI, Pacheco JM, Johnson ML, Sabari JK, Leventakos K, Yau E, Bazhenova L, Negrao MV, Pennell NA, Zhang J, Anderes K, Der-Torossian H, Kheoh T, Velastegui K, Yan X, Christensen JG, Chao RC, Spira AI. Adagrasib in Non-Small-Cell Lung Cancer Harboring a KRASG12C Mutation. N Engl J Med. 2022 Jul 14;387(2):120-131. Epub 2022 Jun 3. link to original article PubMed NCT03785249

Docetaxel monotherapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Blumenschein et al. 2015 (GSK 114653) 2011-2012 Randomized Phase 2 (C) Trametinib Did not meet primary endpoint of PFS
Jänne et al. 2017 (SELECT-1) 2013-2016 Phase 3 (C) Docetaxel & Selumetinib Did not meet primary endpoint of PFS
de Langen et al. 2023 (CodeBreak 200) 2020-06-04 to 2021-04-26 Phase 3 (C) Sotorasib Inferior PFS

Chemotherapy

Supportive therapy

21-day cycles

References

  1. GSK 114653: Blumenschein GR Jr, Smit EF, Planchard D, Kim DW, Cadranel J, De Pas T, Dunphy F, Udud K, Ahn MJ, Hanna NH, Kim JH, Mazieres J, Kim SW, Baas P, Rappold E, Redhu S, Puski A, Wu FS, Jänne PA. A randomized phase II study of the MEK1/MEK2 inhibitor trametinib (GSK1120212) compared with docetaxel in KRAS-mutant advanced non-small-cell lung cancer (NSCLC). Ann Oncol. 2015 May;26(5):894-901. Epub 2015 Feb 26. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors PubMed NCT01362296
  2. SELECT-1: Jänne PA, van den Heuvel MM, Barlesi F, Cobo M, Mazieres J, Crinò L, Orlov S, Blackhall F, Wolf J, Garrido P, Poltoratskiy A, Mariani G, Ghiorghiu D, Kilgour E, Smith P, Kohlmann A, Carlile DJ, Lawrence D, Bowen K, Vansteenkiste J. Selumetinib plus docetaxel compared with docetaxel alone and progression-free survival in patients with KRAS-mutant advanced non-small cell lung cancer: The SELECT-1 randomized clinical trial. JAMA. 2017 May 9;317(18):1844-1853. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT01933932
  3. CodeBreak 200: de Langen AJ, Johnson ML, Mazieres J, Dingemans AC, Mountzios G, Pless M, Wolf J, Schuler M, Lena H, Skoulidis F, Yoneshima Y, Kim SW, Linardou H, Novello S, van der Wekken AJ, Chen Y, Peters S, Felip E, Solomon BJ, Ramalingam SS, Dooms C, Lindsay CR, Ferreira CG, Blais N, Obiozor CC, Wang Y, Mehta B, Varrieur T, Ngarmchamnanrith G, Stollenwerk B, Waterhouse D, Paz-Ares L. Sotorasib versus docetaxel for previously treated non-small-cell lung cancer with KRAS. Lancet. 2023 Mar 4;401(10378):733-746. Epub 2023 Feb 7. link to original article dosing details in abstract have been reviewed by our editors PubMed NCT04303780
  4. KRYSTAL-12: NCT04685135

Sotorasib monotherapy

Regimen

FDA-recommended dose
Study Dates of enrollment Evidence Comparator Comparative Efficacy
Hong et al. 2020 (CodeBreaK100NSCLC) 2018-2020 Phase 1/2 (RT)
de Langen et al. 2023 (CodeBreak 200) 2020-06-04 to 2021-04-26 Phase 3 (E-switch-ooc) Docetaxel Superior PFS (primary endpoint)
Median PFS: 5.6 vs 4.5 mo
(HR 0.66, 95% CI 0.51-0.86)

Note: this was the dose used in the expansion cohort of CodeBreaK100.

Biomarker eligibility criteria

  • KRAS p.G12C mutation

Targeted therapy

Continued indefinitely

References

  1. CodeBreaK100NSCLC: Hong DS, Fakih MG, Strickler JH, Desai J, Durm GA, Shapiro GI, Falchook GS, Price TJ, Sacher A, Denlinger CS, Bang YJ, Dy GK, Krauss JC, Kuboki Y, Kuo JC, Coveler AL, Park K, Kim TW, Barlesi F, Munster PN, Ramalingam SS, Burns TF, Meric-Bernstam F, Henary H, Ngang J, Ngarmchamnanrith G, Kim J, Houk BE, Canon J, Lipford JR, Friberg G, Lito P, Govindan R, Li BT. KRASG12C Inhibition with Sotorasib in Advanced Solid Tumors. N Engl J Med. 2020 Sep 24;383(13):1207-1217. Epub 2020 Sep 20. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors PubMed NCT03600883
    1. Update: Skoulidis F, Li BT, Dy GK, Price TJ, Falchook GS, Wolf J, Italiano A, Schuler M, Borghaei H, Barlesi F, Kato T, Curioni-Fontecedro A, Sacher A, Spira A, Ramalingam SS, Takahashi T, Besse B, Anderson A, Ang A, Tran Q, Mather O, Henary H, Ngarmchamnanrith G, Friberg G, Velcheti V, Govindan R. Sotorasib for Lung Cancers with KRAS p.G12C Mutation. N Engl J Med. 2021 Jun 24;384(25):2371-2381. Epub 2021 Jun 4. link to original article link to PMC article PubMed
    2. Update: Dy GK, Govindan R, Velcheti V, Falchook GS, Italiano A, Wolf J, Sacher AG, Takahashi T, Ramalingam SS, Dooms C, Kim DW, Addeo A, Desai J, Schuler M, Tomasini P, Hong DS, Lito P, Tran Q, Jones S, Anderson A, Hindoyan A, Snyder W, Skoulidis F, Li BT. Long-Term Outcomes and Molecular Correlates of Sotorasib Efficacy in Patients With Pretreated KRAS G12C-Mutated Non-Small-Cell Lung Cancer: 2-Year Analysis of CodeBreaK 100. J Clin Oncol. 2023 Jun 20;41(18):3311-3317. Epub 2023 Apr 25. link to original article link to PMC article PubMed
  2. CodeBreak 200: de Langen AJ, Johnson ML, Mazieres J, Dingemans AC, Mountzios G, Pless M, Wolf J, Schuler M, Lena H, Skoulidis F, Yoneshima Y, Kim SW, Linardou H, Novello S, van der Wekken AJ, Chen Y, Peters S, Felip E, Solomon BJ, Ramalingam SS, Dooms C, Lindsay CR, Ferreira CG, Blais N, Obiozor CC, Wang Y, Mehta B, Varrieur T, Ngarmchamnanrith G, Stollenwerk B, Waterhouse D, Paz-Ares L. Sotorasib versus docetaxel for previously treated non-small-cell lung cancer with KRAS. Lancet. 2023 Mar 4;401(10378):733-746. Epub 2023 Feb 7. link to original article dosing details in abstract have been reviewed by our editors PubMed NCT04303780