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Non-small cell lung cancer (NSCLC) is the most common type of lung cancer in the United States, accounting for about 80-85% of all cases. Historically, NSCLC had a high mortality rate, but this has declined in recent years.

Over the past few decades, we have identified many driver mutations in oncogenes, which are genes involved in the development of cancer. These mutations can be targeted with drugs, which has led to improved outcomes for patients with NSCLC. One of the most frequently mutated oncogenes in NSCLC is KRAS. Activating KRAS mutations are found in up to 30% of patients with nonsquamous NSCLC. The most common type of KRAS mutation is KRAS G12C, which is seen in up to 40% of cases with KRAS-mutant lung cancer.

Sotorasib is a targeted cancer therapy that binds directly to the KRAS G12C protein in its inactive form, blocking its interaction with downstream signaling pathways. The FDA granted accelerated approval to sotorasib in 2021 based on a multicenter, single-arm, phase II study that showed a 37% objective response rate (RR), a median progression-free survival (PFS) of 6.8 months, and a median overall survival (OS) of 12.5 months in patients with advanced KRAS G12C-mutant NSCLC who had progressed on systemic therapy.

Other G12C-directed agents are currently under development, including adagrasib, which recently received accelerated approval from the FDA.

Most patients with NSCLC have co-occurring genomic alterations leading to significant heterogeneity in disease biology and response to systemic therapy. This may lead to a shorter response, resistance, or increased toxicity to targeted therapies. For example, concurrent inactivating mutations in STK11 and KEAP1 have been associated with worse outcomes to anti-PD-(L)1 therapy, and concurrent KEAP1 mutations have been associated with shorter responses to both platinum-based chemotherapy and anti-PD-(L)1 therapy.

While our understanding of the factors that determine response or resistance to sotorasib is still limited, clinical trials have shown that responses to sotorasib and adagrasib occur across all STK11/KEAP1 mutation statuses. The impact of comutation status on durability of response or overall survival is unknown.

A recent of 105 patients with advanced KRAS G12C-mutant NSCLC who started sotorasib outside of clinical trials between June 2021 and August 2022 aimed to identify clinical and genomic features associated with outcomes, toxicity rates, and the association of pretreatment clinical characteristics with toxicity development. Of the 105 patients, 13 were treatment-naive and 92 had received at least one prior line of systemic therapy for advanced disease.

The study showed that the median real-world PFS (rwPFS) was 5.3 months, the median time on drug was 7.2 months, and the median OS was 12.6 months. Among the 102 of 105 patients evaluable for response assessment, the real-world response rate (rwRR) was 28% and the real-world disease control rate was 74%.

Notably, among the 13 patients who were treatment-naive in the advanced setting, the median rwPFS was 11.0 months and the median OS was not reached with a median follow-up of 14.1 months.

Patients with concurrent mutations in KEAP1 had shorter median PFS (2 months) and OS (5.2 months) with sotorasib, while there were no significant associations between concurrent TP53 or STK11 mutations and activity. However, no significant association of TP53, STK11, or KEAP1 mutations with rwRR was observed. Similarly, there were no significant differences in OS or rwRR between PD-L1-negative and PD-L1-positive tumors.

The most common treatment-related adverse events (TRAEs) of grade 3 or higher were elevated liver function tests (LFTs). The most common reasons for TRAE-related discontinuation of therapy were elevated LFTs (86%) and diarrhea (21%). Additionally, high-grade toxicities, particularly hepatotoxicity, were almost exclusively associated with recent anti-PD-(L)1 therapy exposure in the 12 weeks before starting sotorasib.

Although this real-world study is limited by its retrospective design and small sample size, it reflects outcomes from multiple institutions and can help clinicians make better decisions about when and how to sequence anti-PD-(L)1 therapies and sotorasib, as well as develop appropriate monitoring plans. This is especially important for patients who start sotorasib within 12 weeks of receiving anti-PD-(L)1 therapies because of disease progression.

More research is needed to find the best ways to reduce toxicity and improve targeted therapies for patients with advanced NSCLC harboring KRAS G12C mutations.

Arun Kumar, MD, is a hematology and oncology fellow at Medstar Georgetown University Hospital in Washington, D.C.; Omer Bajwa, MD, is chief internal medicine resident at Luminis Health Anne Arundel Medical Center in Annapolis, Maryland.

Read the study here and a Q&A related to it here.