Non-small cell lung cancer, KRAS-mutated

Section editor transclusions Note: these are regimens tested in biomarker-specific populations, please see the main NSCLC page for other regimens.

3 regimens on this page 3 variants on this page

Guidelines

ASCO

• 2022: Singh et al. Therapy for Stage IV Non-Small-Cell Lung Cancer With Driver Alterations: ASCO Living Guideline

ESMO

• 2023: Hendriks et al. Oncogene-addicted metastatic non-small-cell lung cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up

Advanced or metastatic disease, subsequent lines of therapy

Adagrasib monotherapy

Regimen

FDA-recommended dose

Study	Dates of enrollment	Evidence
Jänne et al. 2022 (KRYSTAL-1) ESMO-MCBS (2)	2020	Phase 2 (RT)

Biomarker eligibility criteria

• KRAS p.G12C mutation

Targeted therapy

• Adagrasib (Krazati) 600 mg PO twice per day

Continued indefinitely

References

1. KRYSTAL-1: 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 Clinical Trial Registry

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

• 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)
• Per Chem et al. 2006: Dexamethasone (Decadron) by the following split schedule:
  • 8 mg PO once per day on days 1, 8, 15; 12 hours prior to Docetaxel (Taxotere)
  • 10 mg IV once per day on days 1, 8, 15; 30 minutes prior to Docetaxel (Taxotere)
  • 8 mg PO once per day on days 1, 8, 15; 12 hours after Docetaxel (Taxotere)

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 contains dosing details in manuscript PubMed Clinical Trial Registry
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 contains dosing details in manuscript link to PMC article PubMed Clinical Trial Registry
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 contains dosing details in abstract PubMed Clinical Trial Registry
4. KRYSTAL-12: Clinical Trial Registry

Sotorasib monotherapy

Regimen

FDA-recommended dose

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Hong et al. 2020 (CodeBreaK100) ESMO-MCBS (3)	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 is 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

1. CodeBreaK100: 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 contains dosing details in manuscript PubMed Clinical Trial Registry
   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. 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 contains dosing details in abstract PubMed Clinical Trial Registry