Adagrasib Shows Potential For Advanced NSCLC With KRAS G12C Mutations

Author: By Lynda Williams, Senior medwireNews Reporter 

medwireNews: Initial results from the KRYSTAL-1 trial suggest that the adagrasib is well tolerated and may have activity against non-small-cell lung cancer (NSCLC) harbouring KRASG12C mutations. 

The findings for the selective inhibitor of the mutated KRASG12C protein, found in around 14% of NSCLC adenocarcinoma patients, were presented at the European Lung Cancer Virtual Congress 2021 by Gregory Riely, from Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College in New York, USA. 

He explained the study is recruiting patients with unresectable or metastatic NSCLC with the KRASG12C mutation who have progressed despite chemotherapy and PD-L1 inhibitor treatment. 

The current presentation focused on 79 patients who received adagrasib 600 mg twice daily in the phase I/Ib (n=18) or phase II (n=61) section of the trial and were followed up for a pooled median of 3.6 months.  

The patients were aged a median 65 years, 57% were female and 85% were White, with most (78%) having a ECOG performance status of 1. The majority (95%) were current or former smokers and 96% had nonsquamous histology, the presenter said. 

Treatment-related adverse events (TRAEs) were assessed in 110 patients given adagrasib 600 mg twice daily, including 31 patients from other cohorts.  

The majority (85%) had any-grade TRAEs, most commonly nausea (54%), diarrhoea (51%), vomiting (35%), fatigue (32%) and increased levels of alanine transaminase (20%) and aspartate transaminase (17%). Grade 3–4 TRAEs occurred in 30%, including fatigue (6%), increased levels of both liver enzymes (5% each) and QT prolongation (3%). There were two grade 5 events, one case of pneumonitis in a patient previously affected by the AE and one cardiac failure. 

In all, 4.5% of patients discontinued adagrasib because of TRAEs, the investigator noted. 

Biomarker analysis of biopsy samples taken from three patients at day 8 of treatment provided “clear evidence” of inhibition of KRAS signalling and other pathways, such as MYC, the presenter commented. 

Moreover, 45% of the 51 clinically evaluable patients in the phase I–II sections of the trial achieved an objective response, all of which were partial, and 51% had stable disease, giving a disease control rate of 96%. 

Analysis of the 14 patients in phase I–Ib gave a median treatment duration of 8.2 months and this group were followed up for a median 9.6 months, with four of the six responding patients continuing treatment after more than 11 months, said the presenter. 

Gregory Riely also reported preliminary exploratory findings for the impact of co-mutations on adagrasib efficacy.  

The objective response rate rose to 64% for the 14 patients who had an STK11 mutation alongside their KRASG12C mutation versus 33% for the 30 patients who did not, whereas the presence of KEAP1 and TP53 co-mutations did not seem to affect response, he said. 

Further analysis of three patients with STK11 co-mutations indicated these tumours were “immune cold” at baseline but two of the tumours showed an increase in immune response transcripts after adagrasib therapy, prompting the presenter to hypothesize that “[a]dagrasib treatment recruits T cells into the tumor and may reverse STK11-mediated immune suppression”. 

The KRYSTAL-1 trial is ongoing with a new cohort of patients with KRASG12C and STK11 co-mutations, he concluded. 

Reference 

Riely G, Ou SI, Rybkin I, et al. KRYSTAL-1: Activity and preliminary pharmacodynamic (PD) analysis of adagrasib (MRTX849) in patients (Pts) with advanced non-small-cell lung cancer (NSCLC) harboring KRASG12C mutation. J Thorac Oncol 2021;16(suppl_4): S748–S802.