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Two KRAS inhibitors have earned accelerated approval from the FDA for KRAS-mutated non-small cell lung cancer (NSCLC): sotorasib (Lumakras) and adagrasib (Krazati). Both have proven their value in their respective trials, such as and . Hepatotoxicity, however, is a common side effect for both, with higher rates in patients treated with sotorasib proximal to checkpoint inhibitor (CPI) therapy, noted Hatim Husain, MD, of Moores Cancer Center at UC San Diego Health in La Jolla, California, and colleagues.

As they explained in their study in, the team evaluated the feasibility and safety of adagrasib after discontinuation of sotorasib due to treatment-related grade 3 hepatotoxicity through "real-world" and clinical cases. Highlights from the medical records-based research were as follows:

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

• Among 5 real-world patients, sotorasib-driven hepatotoxicity occurred across the board and led to treatment discontinuation

• None of those patients had treatment-related hepatotoxicity with subsequent adagrasib treatment

• Three KRYSTAL-1 patients transitioned from sotorasib to adagrasib due to hepatotoxicity, and one of them experienced grade 3 alanine transaminase (ALT) elevation on adagrasib, which then resolved with therapy 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 highlight that, while 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 the differences, the team said, may relate to the varying pharmacokinetics (PK) and chemical properties of adagrasib and sotorasib -- adagrasib has shown low peak-to-trough PK variability, thus avoiding a high peak concentration (C_max), which could limit any off-target activity.

In contrast, "sotorasib ... demonstrates a high C_max shortly after administration, potentially contributing to off-target activity, along with non–dose-dependent PK that may limit the effectiveness of measures to reduce off-target cysteine reactivity by use of lower doses," Husain and colleagues noted.

While the case series had a very small number of patients, the authors argued that the differences seen 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 discontinued a CPI or if the patient experiences intolerable hepatotoxicity on sotorasib."

In related research, Yuankai Shi, MD, PhD, of the Chinese Academy of Medical Sciences in Beijing, is a co-investigator on a of the investigational agent glecirasib in participants with locally advanced or metastatic KRAS G12C mutated-NSCLC.

Patients in the 43-site, China-based trial, which has an estimated study completion date of December 2025, must have received prior platinum-based therapy and an ICI as well as appropriate targeted agents for any actionable mutations "per local standards," Shi and colleagues stated.

The following are some remarks from Shi about the trial at a 2024 , as well as a commentary on the findings from Julia Rotow, MD, of Dana-Farber Cancer Center in Boston.

What was the impetus for this glecirasib trial?

Shi: KRAS G12C mutation occurs in approximately 13% of NSCLC patients in the U.S. and 4% in China. Glecirasib is a covalent highly selective and orally bioavailable KRAS G12C inhibitor. This pivotal trial of glecirasib monotherapy at an RP2D [recommended Phase II dose] of 800 milligram QD enrolled a total of 119 patients, median age of 62. Most patients were male with an ECOG PS [performance status] of 1; 95% of patients had adenocarcinoma under stage 4 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 were some of the study findings?

Shi: The study has met its primary endpoint. Out of 119 patients, 4 did not have evaluable disease for the IRC [independent review committee]. 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%. Median follow-up was 10.4 months; 74.2% of patients are still ongoing with treatment at the time of data cutoff. The median time to response was 1.4 months. Most partial-response patients are ongoing at the time of data cutoff. The median duration of response has not been reached. Median OS [overall survival] was 13.6 months, 6-month and 12-month response rates were 83% and 54.6%, respectively.

What about adverse events, especially hepatotoxicity?

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

Rotow: Glecirasib does have a distinct side effect profile, which is different from that of sotorasib and adagrasib. The glecirasib TRAEs were seen in at least 10% of patients. The most common of these was anemia, but particularly notable is the rate of hepatotoxicity. So 35-48% of some grade of abnormalities of the LFTs [liver function tests], and 6-11% or so hitting grade 3 or higher abnormalities from both AST or ALT. It's something to watch for if we were treating a patient with this agent.

What is the main take-home message?

Rotow: In the study, there was a response rate on sotorasib in previously treated patients of 37.1% and a median progression-free survival [PFS] of 6.8 months in the KRYSTAL-1 phase I/II study showed a response rate with adagrasib in previously treated lung cancer of 42.9% with a similar PFS of 6.5 months. There's no head-to-head study here; this is a cross-trial comparison.

You do see what appears to be a trend towards a better response rate and better PFS of glecirasib. So 47.9% compared with 28-43%, depending on the other trial you look at. And PFS of 8.2 months compared with 5.6-6.8 months on the prior available studies. So efficacy appears to be trending in the right direction, but this is modest and could be within the range of cross-trial variation, so ongoing confirmation will be needed.

Read the study by Husain and colleagues here.