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PATIENTS WITH KRAS-MUTATED NSCLC MAY FACE RAPID PROGRESSION AND NEED ALTERNATIVE TREATMENT OPTIONS1-3

For over 40 years, KRAS had been challenging to target due to the protein’s smooth surface providing few binding pockets for small molecules, and high binding affinity for GTP.4,5

See 3 reasons why KRAS G12C may require a treatment that can challenge its relentlessness in advanced NSCLC. 

GTP=guanosine triphosphate; KRAS=Kirsten rat sarcoma viral oncogene homologue; NSCLC=non-small cell lung cancer.

Reason 1

KRAS G12C IS A COMMON DRIVER MUTATION WITH A POOR PROGNOSIS1-3,6,7

In NSCLC, the KRAS G12C mutation is almost as prevalent as EGFR mutations

In patients with advanced NSCLC treated with chemotherapy, the presence of a KRAS G12C mutation may be correlated with a poorer prognosis compared to patients with KRAS wild type.3,7

ALK=anaplastic lymphoma kinase; BRAF=B-Raf proto-oncogene; EGFR=epidermal growth factor receptor; HER2=human epidermal growth factor receptor 2; MET=mesenchymal epithelial transition; NTRK1=neurotrophic tyrosine receptor kinase; PIK3CA=phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha; RET=rearranged during transfection; ROS1=proto-oncogene C-Ros1, receptor tyrosine kinase.

Prevalence of specific driver mutations in lung adenocarcinoma1,6

Mutation prevalence in NSCLC, chart
Reason 2

HIGH RISK FOR CNS METASTASES9

In a retrospective study, 40% of patients with KRAS G12C-mutated advanced NSCLC developed brain metastases

  • In a prospective, single-center study, ~50% of patients with NSCLC and brain metastases were asymptomatic10†

When your patients progress, consider prompt 2L treatment
Human body

*Based on retrospective analysis of patients with KRAS G12C–mutated advanced nonsquamous NSCLC (n=65) from a large tertiary referral center.9
†In a single-center, prospective, observational study of treatment-naïve patients with NSCLC (N=496); brain metastases were detected in 104 (21%); 53 (51%) were asymptomatic.10

Reason 3

CONTINUOUS REGENERATION MAY REQUIRE CONTINUOUS INHIBITION11-13

  • KRAS G12C mutations produce abnormal KRAS proteins that lead to aberrant signaling and uncontrolled cellular proliferation14-16
  • KRAS G12C may need to be continuously inhibited to suppress tumorigenesis11-13
KRAS proteins, including G12C, regenerate every 24-48 hours
Lungs reacting to KRAS G12C

References:

  1. Pakkala S, Ramalingam SS. Personalized therapy for lung cancer: striking a moving target. JCI Insight. 2018;3(15):e120858.
  2. Acker F, Stratmann J, Aspacher L, et al. KRAS mutations in squamous cell carcinomas of the lung. Front Oncol. 2021;11:788084.
  3. Hames ML, Chen H, Iams W, Aston J, Lovly CM, Horn L. Correlation between KRAS mutation status and response to chemotherapy in patients with advanced non-small cell lung cancer. Lung Cancer. 2016;92:29-34.
  4. Ghimessy A, Radeczky P, Laszlo V, et al. Current therapy of KRAS-mutant lung cancer. Cancer Metastasis Rev. 2020;39(4):1159-1177.
  5. Lu S, Jang H, Muratcioglu S, et al. Ras conformational ensembles, allostery, and signaling. Chem Rev. 2016;116(11):6607-6665.
  6. Nassar AH, Adib E, Kwiatkowski DJ. Distribution of KRASG12C somatic mutations across race, sex, and cancer type. N Engl J Med. 2021;384(2):185-187.
  7. Svaton M, Fiala O, Pesek M, et al. The prognostic role of KRAS mutation in patients with advanced NSCLC treated with second- or third-line chemotherapy. Anticancer Res. 2016;36(3):1077-1082.
  8. Mok TSK, Yao W, Duruisseaux M, et al. KRYSTAL-12: phase 3 study of adagrasib versus docetaxel in patients with previously treated locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring a KRASG12C mutation. Oral presentation at ASCO 2024. Abstract LBA8509.
  9. Cui W, Franchini F, Alexander M, et al. Real world outcomes in KRAS G12C mutation positive non-small cell lung cancer. Lung Cancer. 2020;146:310-317.
  10. Naresh G, Malik PS, Khurana S, et al. Assessment of brain metastasis at diagnosis in non–small cell lung cancer: a prospective observational study from north India. JCO Glob Oncol. 2021;7:593-601.
  11. Stites EC, Shaw AS. Quantitative systems pharmacology analysis of KRAS G12C covalent inhibitors. CPT Pharmacometrics Syst Pharmacol. 2018;7(5):342-351.
  12. Shukla S, Allam US, Ahsan A, et al. KRAS protein stability is regulated through SMURF2: UBCH5 complex-mediated β-TrCP1 degradation. Neoplasia. 2014;16(2):115-128.
  13. Bergo MO, Gavino BJ, Hong C, et al. Inactivation of Icmt inhibits transformation by oncogenic K-Ras and B-Raf. J Clin Invest. 2004;113(4):539-550.
  14. Fernández-Medarde A, Santos E. Ras in cancer and developmental diseases. Genes Cancer. 2011;2(3):344-358.
  15. Cox AD, Fesik SW, Kimmelman AC, Luo J, Der CJ. Drugging the undruggable RAS: mission possible? Nat Rev Drug Discov. 2014;13(11):828-851. 
  16. Waters AM, Der CJ. KRAS: the critical driver and therapeutic target for pancreatic cancer. Cold Spring Harb Perspect Med. 2018;8(9):a031435.
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IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS

Gastrointestinal Adverse Reactions

 

  • KRAZATI can cause severe gastrointestinal adverse reactions

  • Monitor and manage patients using supportive care, including antidiarrheals, antiemetics, or fluid replacement, as indicated. Withhold, reduce the dose, or permanently discontinue KRAZATI based on severity

QTc Interval Prolongation

 

  • KRAZATI can cause QTc interval prolongation, which can increase the risk for ventricular tachyarrhythmias (eg, torsades de pointes) or sudden death

  • Avoid concomitant use of KRAZATI with other products with a known potential to prolong the QTc interval. Avoid use of KRAZATI in patients with congenital long QT syndrome and in patients with concurrent QTc prolongation

  • Monitor ECGs and electrolytes, particularly potassium and magnesium, prior to starting KRAZATI, during concomitant use, and as clinically indicated in patients with congestive heart failure, bradyarrhythmias, electrolyte abnormalities, and in patients who are unable to avoid concomitant medications that are known to prolong the QT interval. Correct electrolyte abnormalities. Withhold, reduce the dose, or permanently discontinue KRAZATI, depending on severity

Hepatotoxicity

 

  • KRAZATI can cause hepatotoxicity, which may lead to drug-induced liver injury and hepatitis

  • Monitor liver laboratory tests (AST, ALT, alkaline phosphatase, and total bilirubin) prior to the start of KRAZATI, and monthly for 3 months or as clinically indicated, with more frequent testing in patients who develop transaminase elevations. Reduce the dose, withhold, or permanently discontinue KRAZATI based on severity

Interstitial Lung Disease/Pneumonitis

 

  • KRAZATI can cause interstitial lung disease (ILD)/pneumonitis, which can be fatal

  • Monitor patients for new or worsening respiratory symptoms indicative of ILD/pneumonitis (eg, dyspnea, cough, fever) during treatment with KRAZATI. Withhold KRAZATI in patients with suspected ILD/pneumonitis and permanently discontinue KRAZATI if no other potential causes of ILD/pneumonitis are identified

ADVERSE REACTIONS

 

  • Serious adverse reactions occurred in 57% of 116 patients who received adagrasib in NSCLC patients. The most common adverse reactions in NSCLC patients (≥20%) were diarrhea, nausea, fatigue, vomiting, musculoskeletal pain, hepatotoxicity, renal impairment, dyspnea, edema, decreased appetite, cough, pneumonia, dizziness, constipation, abdominal pain, and QTc interval prolongation

DRUG INTERACTIONS

 

  • Strong CYP3A4 Inducers: Avoid concomitant use.

  • Strong CYP3A4 Inhibitors: Avoid concomitant use until adagrasib concentrations have reached steady state (after ~8 days).

  • Sensitive CYP3A4 Substrates: Avoid concomitant use with sensitive CYP3A4 substrates.

  • Sensitive CYP2C9 or CYP2D6 Substrates or P-gp Substrates: Avoid concomitant use with sensitive CYP2C9 or CYP2D6 substrates or P-gp substrates where minimal concentration changes may lead to serious adverse reactions.

  • Drugs That Prolong QT Interval: Avoid concomitant use with KRAZATI.

Please see Drug Interactions Section of the Full Prescribing Information for additional information.

USE IN SPECIFIC POPULATIONS

Females and Males of Reproductive Potential

 
  • Infertility: Based on findings from animal studies, KRAZATI may impair fertility in females and males of reproductive potential

Lactation

 
  • Advise not to breastfeed

Please see Full Prescribing Information.

 

1914-US-2500139   01/26

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1914-US-2500138   01/26

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