ASCO Reading Room | KRAS Inhibitors and Hepatotoxicity in Lung Cancer: “Not All Effects Are Class Effects”

Two KRAS inhibitors granted accelerated FDA approval for KRAS-mutated non-small cell lung cancer (NSCLC): sotorasib (Lumakras) and adagrasib (Krazati). Both drugs have proven value in their respective trials, as have CodeBreaK 200 and KRYSTAL-1. However, hepatotoxicity is a common side effect for both, with higher rates in patients treated with sotorasib in close proximity to a checkpoint inhibitor (PCI), noted Hatim Husain, MD, of the Moores Cancer Center at UC San Diego Health in La Jolla, Calif., and colleagues.

As they explained in their study in JCO Precision OncologyThe team assessed the feasibility and safety of adagrasib after discontinuation of sotorasib due to treatment-related grade 3 hepatotoxicity, using clinical and real-world case reports. Highlights of the medical records-based research include:

• All patients were treated with CPIs followed by sotorasib, which was started 0 to 64 days after CPI.

• Among 5 real-life patients, sotorasib-induced hepatotoxicity occurred systemically and led to treatment discontinuation

• None of these patients experienced hepatotoxicity related to subsequent adagrasib treatment.

• Three patients with KRYSTAL-1 switched from sotorasib to adagrasib due to hepatotoxicity, and one experienced a grade 3 alanine transaminase (ALT) elevation on adagrasib, which subsequently resolved with treatment interruption and dose reduction.

The take-home message, Husain and co-authors said, was that “the reported differences in treatment-related hepatotoxicity between adagrasib and sotorasib underscore that, even if drugs within a class modulate the same target, not all effects are class effects and that the spectrum of off-target events may differ between agents.”

Possible reasons for these differences, according to the team, may be related to the different pharmacokinetic (PK) and chemical properties of adagrasib and sotorasib – adagrasib showed low peak-to-trough PK variability, thus avoiding a high maximum concentration (C_max), which could limit any off-target activity.

In contrast, “sotorasib…has a high C content_max “Short time after administration, potentially contributing to off-target activity, as well as non-dose-dependent PK that may limit the effectiveness of measures to reduce off-target cysteine ​​reactivity using lower doses,” Husain and colleagues noted.

Although the case series had a very small number of patients, the authors argued that the differences observed in their trial between the two agents “may be used to inform clinical decisions when choosing the initial KRAS G12C inhibitor if the patient has recently stopped a CPI or if the patient has intolerable hepatotoxicity on sotorasib.”

In related research, Yuankai Shi, MD, PhD, of the Chinese Academy of Medical Sciences in Beijing, is a co-investigator in a single-arm phase II study of the investigational agent glecirasib in participants with locally advanced or metastatic disease. KRAS G12C Mutated CPNPC.

Patients participating in the 43-site trial in China, which has an estimated study completion date of December 2025, must have received prior platinum-based therapy and ICI as well as appropriate targeted agents for any actionable mutation “according to local standards,” Shi and colleagues said.

Here are some of Shi’s remarks on the trial during a plenary session at ASCO 2024, along with a commentary on the findings from Julia Rotow, MD, of Dana-Farber Cancer Center in Boston.

What was the motivation for this trial of glecirasib?

Shi: KRAS G12C The mutation occurs in approximately 13% of patients with NSCLC in the United States and 4% in China. Glecirasib is a highly selective, orally bioavailable covalent inhibitor of the KRAS G12C gene. This pivotal trial of glecirasib monotherapy at a RP2D (recommended phase II dose) of 800 milligrams QD enrolled a total of 119 patients with a median age of 62 years. Most patients were male with an ECOG performance status (PS) of 1; 95% of patients had stage 4 adenocarcinoma at the time of initial treatment, and 94.1% had received prior immunotherapy and platinum-based chemotherapy.

Rotow: This drug is similar to our current FDA-approved KRAS inhibitors, adagrasib and sotorasib.

What are the conclusions of the study?

Shi: The study met its primary endpoint. Of 119 patients, 4 had no evaluable disease by the independent review committee (IRC). A total of 117 evaluable patients were included in the efficacy analysis; 3.4% achieved a confirmed complete response, 44.4% achieved a confirmed partial response, and 38.5% maintained stable disease.

Glecirasib resulted in a confirmed overall response rate of 47.9%, and the disease control rate was 86.3%. The median follow-up was 10.4 months; 74.2% of patients were still on treatment at data cutoff. The median time to response was 1.4 months. Most patients with a partial response were still on treatment at data cutoff. The median duration of response was not reached. The median overall survival (OS) was 13.6 months, and the 6-month and 12-month response rates were 83% and 54.6%, respectively.

What about adverse effects, including hepatotoxicity?

Shi: More than 5% of grade 3-4 treatment-related adverse events (TRAEs) that occurred were related to liver toxicity, such as increased ALT and AST (aspartate aminotransferase), increased blood bilirubin, and increased gamma-glutamyl transferase (GGT).

Rotow: Glecirasib has a distinct side effect profile, different from sotorasib and adagrasib. Side effects of glecirasib were seen in at least 10% of patients. The most common was anemia, but the rate of hepatotoxicity was particularly notable. For example, 35% to 48% had grade 3 LFT (liver function test) abnormalities and about 6% to 11% had grade 3 or greater abnormalities of either AST or ALT. This is something to watch for if we treat a patient with this agent.

What is the main message to take away?

Rotow: In the CodeBreaK 100 study, the response rate to sotorasib in previously treated patients was 37.1% and the median progression-free survival (PFS) was 6.8 months. The phase I/II KRYSTAL-1 study showed a response rate to adagrasib in previously treated lung cancer patients of 42.9% with a similar PFS of 6.5 months. There is no comparative study here; this is a comparison between trials.

You see what appears to be a trend toward better response rate and better progression-free survival for glecirasib. So 47.9% versus 28 to 43%, depending on which other trial you look at. And progression-free survival of 8.2 months versus 5.6 to 6.8 months in the previous studies that are available. So the efficacy appears to be moving in the right direction, but it is modest and may be in the range of variation across trials, so continued confirmation will be needed.

Read the study by Husain and colleagues here.