Adagrasib safe and clinically active in non-small cell lung cancer

In the phase 2 KRYSTAL-1 study, adagrasib showed encouraging clinical activity and a manageable safety profile in patients with previously treated non-small cell lung cancer (NSCLC) bearing a KRAS-G12C mutation. The results of this trial have initiated the accelerated approval process of this drug in the USA. The confirmatory phase 3 KRYSTAL-12 trial is currently running to compare adagrasib with docetaxel in this population.

Adagrasib is a covalent inhibitor of KRAS-G12C that has demonstrated clinical activity in a variety of KRAS-G12C-mutated solid tumours [1,2]. In one cohort of the phase 2 KRYSTAL-1 study (NCT03785249), Dr Alexander Spira (Virginia Cancer Specialists Research Institute, VA, USA) and colleagues tested adagrasib monotherapy (600 mg, oral, twice daily) in patients with previously treated KRAS-G12C mutated NSCLC (n=116) [3]. The primary endpoint was the objective response rate (ORR) by blinded independent central review. Results were published in The New England Journal of Medicine in June 2022 [4].

An objective response was confirmed in 43% of the participants with measurable disease at baseline (n=112), with 1% of the participants displaying a complete response and 42% of the participants showing a partial response. The disease control rate was 80%. The ORR was 51% if only evaluable participants were included in the calculation. Most of the responses were deep, with 75% of the responders reaching a tumour reduction >50%. The median time to response was 1.4 months and the median duration of response was 8.5 months. After 6 months, 52% of the participants were progression-free. This percentage dropped to 29% at 12 months. The corresponding overall survival rates were 71% at 6 months and 51% at 12 months. Notably, the intracranial response ORR was 33% in participants (n=33) with previously treated, stable CNS metastases, with 15% showing a complete response and 18% showing a partial response. The disease control rate for this subgroup of participants was 85%.

Dr Spira mentioned that the safety profile of adagrasib was manageable in the study cohort. Predominantly grade 3 but also grade 4 adverse events were observed in 43% of the patients. Nausea (4%), fatigue (4%), increased alanine aminotransferase (4%) and aspartate aminotransferase (3%) levels, and decreased appetite (3%) were the most frequently noticed grade 3 or 4 adverse events. Dose reductions or dose interruptions due to treatment-related adverse events occurred in 52% and 61% of the participants. Only 7% of the participants discontinued the study drug after a treatment-related adverse event.

Adagrasib is being reviewed by the FDA for accelerated approval as a treatment for patients with KRAS-G12C mutated NSCLC who received at least one prior systemic therapy. Also, the confirmatory phase 3 KRYSTAL-12 trial (NCT04685135) is currently running to compare adagrasib with docetaxel in this population.

1. Weiss J, et al. Ann Oncol. 2021;32(suppl_5):S1294.
2. Bekaii-Saab TS, et al. J Clin Oncol. 2022;40(4_suppl):519–519.
3. Spira A, et al. KRYSTAL-1: Activity and safety of adagrasib (MRTX849) in patients with advanced/metastatic non–small cell lung cancer (NSCLC) harboring a KRASG12C mutation. Abstract 9002, ASCO 2022 Annual Meeting, 3–7 June, Chicago, IL, USA.
4. Jänne PA, et al. N Engl J Med. Jun 3, 2022. DOI: 10.1056/NEJMoa2204619.

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Posted on 5 August 202215 February 2024