Sequential Sotorasib After Anti–PD-L1 Therapy in Patients with NSCLC Associated with Liver Toxicity

Improvements in the treatment of advanced non–small-cell lung cancer (NSCLC) have reduced mortality rates for this patient population, and targeted therapies for patients with specific mutations and the use of checkpoint inhibitors with or without chemotherapy have driven this improvement.¹ For patients with advanced NSCLC who need to receive second-line or beyond treatment, the standard of care after use of checkpoint inhibitors or platinum-based chemotherapy is single-agent pemetrexed or chemotherapy with docetaxel with or without antiangiogenic therapy.¹ The response to this therapy is poor and patients generally progress in a matter of months.¹ The Kirsten rat sarcoma (KRAS) viral oncogene is the most prevalent driver of NSCLC and is found in 25% to 30% of patients.¹ The KRAS G12C subtype is found in 13% of patients with NSCLC.¹ This mutation activates KRAS, leading to activation of downstream oncogenic pathways and uncontrolled growth of cells.¹ This made treatment difficult until KRAS inhibitors were developed.¹ Among the KRAS inhibitors is sotorasib, which targets KRAS G12C to permanently inactivate it.¹

In a presentation at the 2022 European Lung Cancer Congress in Prague, Czech Republic, Dr Ali Chour presented the results of a study of 102 patients with KRAS G12C–mutation NSCLC treated at 16 French cancer centers with anti–PD-L1 followed by sotorasib. Sotorasib-induced liver and non-liver toxicity were the primary focus of this study. Anti–PD-L1 was the last treatment before starting sotorasib for 45.1% of patients (IO-sequence cohort), whereas 83.3% of the remaining 54 patients received anti–PD-L1 at a later time (non-IO sequence group). In the IO-sequence cohort, the median time to last anti–PD-L1 infusion and sotorasib start was 1.2 months, whereas the median time for the non-IO sequence cohort was 7.4 months.

Both groups experienced similar grade 1 and 2 sotorasib-related adverse events (SRAEs), but when grade 3 or more SRAEs were examined, 23.5% of the IO-sequence cohort and 6.86% of the non-IO sequence cohort had ≥1 grade ≥3 SRAEs. Evaluation of each group’s SRAEs found that the IO-sequence cohort had 45 grade ≥3 SRAEs, including 31 that were specific to the liver. Gamma-glutamyl transferase (GGT) elevation was found in 8.8% of these patients, alanine aminotransferase (ALT) elevation in 7.8%, aspartate aminotransferase (AST) elevation in 6.9%, alkaline phosphatase in 3.9%, and total bilirubinemia in 2.94%. For the non-IO sequence group, 12 grade ≥3 SRAEs were experienced, including 7 specific to the liver. This included GGT elevation in 2.9% of these patients, ALT elevation in 1.96%, and AST elevation in 1.96%. In the IO-sequence group, 2 grade 5 SRAEs occurred: hepatitis and toxic epidermal necrolysis.

The researchers concluded that the use of sotorasib sequentially after anti–PD-L1 therapy in patients with NSCLC may be associated with liver toxicity.

Reference:

1. Skoulidis F, Li BT, Dy GK, et al. Sotorasib for lung cancers with KRAS p.G12C mutation. N Engl J Med. 2021;384(25):2371-2381.

Source: Chour A, Denis J, Lafitte C, et al. Sotorasib-induced liver and non-liver toxicity associated with sequential sotorasib following anti-PD(L)1 in KRASG12C mutant lung cancer. Ann Oncol. 2022;33(2):S490S50.