Adagrasib for previously treated KRAS G12C mutation-positive advanced non-small-cell lung cancer [ID6339]

Lung cancer is the third most common cancer and the most common cause of cancer death in the UK accounting for 10% of all new cancer cases and 20% of all cancer deaths in 2020.(1) Most lung cancers are diagnosed at an advanced stage when the cancer has spread to lymph nodes and other organs in the chest (locally advanced disease; stage 3) or to other parts of the body (metastatic disease; stage 4).

In 2022 92% (around 33000) of people diagnosed with lung cancer in England had NSCLC.(2)KRAS is a protein that controls a signalling pathway crucial for cell growth differentiation and survival.

KRAS is the most frequently mutated oncogene in cancer including lung cancer with KRAS G12C mutation occurring in about 11% of NSCLC.(3) It is more common in non-squamous NSCLC and relatively rare in squamous NSCLC.(4)For untreated metastatic non-squamous NSCLC people may be offered pembrolizumab with pemetrexed and platinum chemotherapy (TA683) or pemetrexed and platinum chemotherapy irrespective of PD-L1 expression.

If the non-squamous NSCLC expressed PD-L1 on less than 50% of tumour cells people may be offered atezolizumab plus bevacizumab carboplatin and paclitaxel (TA584) or pemetrexed with platinum doublet chemotherapy.

If the non-squamous NSCLC expressed PD-L1 on over 50% of tumour cells they may be offered pembrolizumab (TA531) or atezolizumab (TA705) monotherapy.

For untreated squamous NSCLC people may be offered pembrolizumab with carboplatin and paclitaxel (TA770) if the NSCLC expresses PD-L1 on less than 50% of cells or on over 50% of cells if there is a need for urgent clinical intervention.

If the squamous NSCLC expresses PD-L1 on more than 50% of its tumour cells people may be offered pembrolizumab (TA531) or atezolizumab (TA705) monotherapy.For KRAS G12C positive NSCLC that has been previously treated sotorasib is recommended within the cancer drugs fund (TA781).

Docetaxel or docetaxel with nintedanib (TA347) may be offered as a second line treatment irrespective of first-line treatment.

If chemotherapy without immunotherapy was used as a first-line treatment then people may be offered an immunotherapy monotherapy consisting of either nivolumab (TA655 & TA713) atezolizumab (TA520) or pembrolizumab (for PD-L1 positive disease TA428).

If an immunotherapy monotherapy was used at first line then people may be offered platinum-based chemotherapy as a second-line treatment.References:1. NHS England. Cancer Registration Statistics England 2020. Accessed March 20242. Royal College of Surgeons of England (2024). National Lung Cancer Audit: State of the Nation Report 2024.

Accessed May 20243. Reita D Pabst L Pencreach E et al (2022) . Direct Targeting KRAS Mutation in Non-Small Cell Lung Cancer: Focus on Resistance. Cancers (Basel). Mar 4;14(5):13214.

Martin P Leighl NB Tsao MS and Shepherd FA (2013) KRAS mutations as prognostic and predictive markers in non–small cell lung cancer. Journal of Thoracic Oncology 8(5):530-542.