Two KRAS inhibitors have earned accelerated approval from the FDA for KRAS-mutated non-small cell lung most cancers (NSCLC): sotorasib (Lumakras) and adagrasib (Krazati). Each have confirmed their worth of their respective trials, corresponding to CodeBreaK 200 and KRYSTAL-1. Hepatotoxicity, nonetheless, is a standard aspect impact for each, with larger charges in sufferers handled with sotorasib proximal to checkpoint inhibitor (CPI) remedy, famous Hatim Husain, MD, of Moores Most cancers Heart at UC San Diego Well being in La Jolla, California, and colleagues.
As they defined of their examine in JCO Precision Oncology, the workforce evaluated the feasibility and security of adagrasib after discontinuation of sotorasib because of treatment-related grade 3 hepatotoxicity by “real-world” and scientific circumstances. Highlights from the medical records-based analysis have been as follows:
- All sufferers have been handled with CPIs adopted by sotorasib, which was began 0-64 days after CPI
- Amongst 5 real-world sufferers, sotorasib-driven hepatotoxicity occurred throughout the board and led to therapy discontinuation
- None of these sufferers had treatment-related hepatotoxicity with subsequent adagrasib therapy
- Three KRYSTAL-1 sufferers transitioned from sotorasib to adagrasib because of hepatotoxicity, and one in every of them skilled grade 3 alanine transaminase (ALT) elevation on adagrasib, which then resolved with remedy interruption and dose discount.
The take-home message, Husain and co-authors mentioned, was that the “reported variations in treatment-related hepatotoxicity between adagrasib and sotorasib spotlight that, whereas medication inside a category modulate the identical goal, not all results are class results, and that the spectrum of off-target occasions could differ between brokers.”
Potential causes for the variations, the workforce mentioned, could relate to the various pharmacokinetics (PK) and chemical properties of adagrasib and sotorasib — adagrasib has proven low peak-to-trough PK variability, thus avoiding a excessive peak focus (Cmax), which may restrict any off-target exercise.
In distinction, “sotorasib … demonstrates a excessive Cmax shortly after administration, doubtlessly contributing to off-target exercise, together with non–dose-dependent PK which will restrict the effectiveness of measures to scale back off-target cysteine reactivity by use of decrease doses,” Husain and colleagues famous.
Whereas the case sequence had a really small variety of sufferers, the authors argued that the variations seen of their trial between the 2 brokers “could also be used to tell scientific selections when selecting the preliminary KRAS G12C inhibitor if the affected person has just lately discontinued a CPI or if the affected person experiences insupportable hepatotoxicity on sotorasib.”
In associated analysis, Yuankai Shi, MD, PhD, of the Chinese language Academy of Medical Sciences in Beijing, is a co-investigator on a single-arm, part II examine of the investigational agent glecirasib in contributors with regionally superior or metastatic KRAS G12C mutated-NSCLC.
Sufferers within the 43-site, China-based trial, which has an estimated examine completion date of December 2025, should have obtained prior platinum-based remedy and an ICI in addition to acceptable focused brokers for any actionable mutations “per native requirements,” Shi and colleagues acknowledged.
The next are some remarks from Shi concerning the trial at a 2024 ASCO Plenary Session, in addition to a commentary on the findings from Julia Rotow, MD, of Dana-Farber Most cancers Heart in Boston.
What was the impetus for this glecirasib trial?
Shi: KRAS G12C mutation happens in roughly 13% of NSCLC sufferers within the U.S. and 4% in China. Glecirasib is a covalent extremely 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 complete of 119 sufferers, median age of 62. Most sufferers have been male with an ECOG PS [performance status] of 1; 95% of sufferers had adenocarcinoma underneath stage 4 on the time of preliminary therapy, and 94.1% had obtained prior immunotherapy and platinum-based chemotherapy.
Rotow: This drug is just like our present FDA-approved KRAS inhibitors, adagrasib and sotorasib.
What have been a number of the examine findings?
Shi: The examine has met its main endpoint. Out of 119 sufferers, 4 didn’t have evaluable illness for the IRC [independent review committee]. A complete of 117 evaluable sufferers have been included within the efficacy evaluation; 3.4% achieved a confirmed full response, 44.4% achieved a confirmed partial response, and 38.5% maintained steady illness.
Glecirasib resulted in a confirmed total response price of 47.9%, and the illness management price was 86.3%. Median follow-up was 10.4 months; 74.2% of sufferers are nonetheless ongoing with therapy on the time of knowledge cutoff. The median time to response was 1.4 months. Most partial-response sufferers are ongoing on the time of knowledge cutoff. The median length of response has not been reached. Median OS [overall survival] was 13.6 months, 6-month and 12-month response charges have been 83% and 54.6%, respectively.
What about antagonistic occasions, particularly hepatotoxicity?
Shi: Greater than 5% of the occurring grade 3-4 TRAEs [treatment-related adverse events] have been associated to liver toxicity, corresponding to ALT and AST [aspartate aminotransferase] elevated, blood bilirubin elevated, and the GGT [gamma-glutamyl transferase] elevated.
Rotow: Glecirasib does have a definite aspect impact profile, which is totally different from that of sotorasib and adagrasib. The glecirasib TRAEs have been seen in a minimum of 10% of sufferers. The commonest of those was anemia, however notably notable is the speed 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 larger abnormalities from each AST or ALT. It is one thing to look at for if we have been treating a affected person with this agent.
What’s the primary take-home message?
Rotow: Within the CodeBreaK 100 examine, there was a response price on sotorasib in beforehand handled sufferers of 37.1% and a median progression-free survival [PFS] of 6.8 months within the KRYSTAL-1 part I/II examine confirmed a response price with adagrasib in beforehand handled lung most cancers of 42.9% with the same PFS of 6.5 months. There is no head-to-head examine right here; this can be a cross-trial comparability.
You do see what seems to be a development in direction of a greater response price and higher PFS of glecirasib. So 47.9% in contrast with 28-43%, relying on the opposite trial you take a look at. And PFS of 8.2 months in contrast with 5.6-6.8 months on the prior obtainable research. So efficacy seems to be trending in the precise route, however that is modest and might be inside the vary of cross-trial variation, so ongoing affirmation will probably be wanted.
Learn the examine by Husain and colleagues right here.
The examine by Husain’s group was supported by Mirati Therapeutics.
Husain and co-authors disclosed relationships with, and/or assist from, a number of entities together with Mirati Therapeutics.
The examine by Shi’s group is supported by Jacobio Prescribed drugs.
