Non-small cell lung cancer, KRAS-mutated

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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:
*Histology-specific:
**NSCLC, Nonsquamous
**NSCLC, Squamous
*Site-specific:
**NSCLC, CNS metastases
Last updated on 2024-07-23:3 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==
*2022: Singh et al. Therapy for Stage IV Non-Small-Cell Lung Cancer With Driver Alterations: ASCO Living Guideline EuroPMC
==ESMO==
*2024: Lee et al. Pan-Asian adapted ESMO Clinical Practice Guidelines for the diagnosis, treatment and follow-up of patients with oncogene-addicted metastatic non-small-cell lung cancer EuroPMC
*2023: Hendriks et al. Oncogene-addicted metastatic non-small-cell lung cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up EuroPMC
==NCCN==
*NCCN does not currently have guidelines at this granular level; please see NCCN Guidelines - Non-Small Cell Lung Cancer.
=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====
*Adagrasib (Krazati) 600 mg PO twice per day
Continued indefinitely
===References===
#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 EuroPMC 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 PFSMedian PFS: 2.8 vs 3.9 mo(HR 1.08, 95% CI 0.89-1.30)
de Langen et al. 2023 (CodeBreak 200)	2020-06-04 to 2021-04-26	Phase 3 (C) 	Sotorasib 	Shorter PFSMedian PFS: 4.5 vs 5.6 mo(HR 1.52, 95% CI 1.16-1.96)
====Chemotherapy====
*Docetaxel (Taxotere) 75 mg/m2 IV over 60 minutes once on day 1
====Supportive therapy====
*Per JMEI: Dexamethasone (Decadron) 8 mg PO twice per day on days -1 to 2 (3 days)
21-day cycles
===References===
# 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 EuroPMC NCT01362296
# 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 EuroPMC NCT01933932
#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 manuscript have been reviewed by our editors EuroPMC NCT04303780
##PRO analysis: Waterhouse DM, Rothschild S, Dooms C, Mennecier B, Bozorgmehr F, Majem M, van den Heuvel MH, Linardou H, Chul Cho B, Roberts-Thomson R, Tanaka K, Blais N, Schvartsman G, Holmskov Hansen K, Chmielewska I, Forster MD, Giannopoulou C, Stollenwerk B, Obiozor CC, Wang Y, Novello S. Patient-reported outcomes in CodeBreaK 200: Sotorasib versus docetaxel for previously treated advanced NSCLC with KRAS G12C mutation. Lung Cancer. 2024 Oct;196:107921. Epub 2024 Aug 6. link to original article EuroPMC
# 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 	Longer 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====
*Sotorasib (Lumakras) 960 mg PO once per day
Continued indefinitely
===References===
#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 EuroPMC NCT03600883
##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 EuroPMC
##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 EuroPMC
#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 manuscript have been reviewed by our editors EuroPMC NCT04303780
##PRO analysis: Waterhouse DM, Rothschild S, Dooms C, Mennecier B, Bozorgmehr F, Majem M, van den Heuvel MH, Linardou H, Chul Cho B, Roberts-Thomson R, Tanaka K, Blais N, Schvartsman G, Holmskov Hansen K, Chmielewska I, Forster MD, Giannopoulou C, Stollenwerk B, Obiozor CC, Wang Y, Novello S. Patient-reported outcomes in CodeBreaK 200: Sotorasib versus docetaxel for previously treated advanced NSCLC with KRAS G12C mutation. Lung Cancer. 2024 Oct;196:107921. Epub 2024 Aug 6. link to original article EuroPMC
Category:Non-small cell lung cancer regimens
Category:Biomarker-specific pages
Category:Non-small cell lung cancers