Sotorasib offers a paradigm shift in the treatment of KRAS G12C-mutated NSCLC

Kirsten rat sarcoma viral oncogene (KRAS) mutations are common in non-small cell lung cancer (NSCLC) and are associated with poor prognosis, likely due to poor responses to most systemic therapies and lack of targeted therapies. At a recent webinar organized by Amgen, Associate Professor Daniel Tan from the National Cancer Centre, Singapore, gave an overview of the biomarker testing landscape in NSCLC. Associate Professor Thomas John from the Peter MacCallum Hospital, Australia, addressed the optimal treatment strategy for KRAS-mutant NSCLC and the role of sotorasib, a first-in-class RAS GTPase family inhibitor approved in Singapore for the treatment of adults with KRAS^G12C-mutated locally advanced or metastatic NSCLC who have received at least one prior systemic therapy.

Biomarker testing landscape in NSCLC
Currently, over 60 percent of advanced NSCLC patients have druggable mutations in various genes, including KRAS, epidermal growth factor receptor (EGFR), v-Raf murine sarcoma oncogene homolog B1 (BRAF), MET, human epidermal growth factor receptor (HER2), anaplastic lymphoma kinase (ALK), and c-ros oncogene 1 (ROS1). [Int J Mol Sci 2021;22:612]

“There is an increasing number of targetable genetic alterations, and each molecular subset has individual treatment strategies and resistance trajectories. These have contributed to the increased importance of biomarker testing in the frontline and resistant settings,” said Tan.

However, not all alterations are actionable, he cautioned. “The actionability of discovered alterations is contingent on the appropriate clinical and genomic context.”

Roles of molecular profiling
Comprehensive genomic profiling has shed light on various mutations and co-occurrence of genomic alterations in NSCLC at diagnosis and their impact on clinical outcomes. For example, EGFR co-alterations potentially impair the efficacy of tyrosine kinase inhibitors (TKIs) and are associated with secondary resistance mechanisms, resulting in poorer patient outcomes. [Nat Med 2012;18:521-528; Clin Cancer Res 2013;19:2240-2247; Nat Genet 2017;49:1693-1704] “This information is still in the process of being incorporated into risk-stratification models,” commented Tan.

Besides risk stratification and biomarker taxonomy, molecular profiling can track disease adaptation over time. One study investigated acquired resistance to KRAS^G12C inhibition in patients with KRAS^G12C-mutant cancers treated with adagrasib. Diverse genomic and histologic mechanisms impart resistance to covalent KRAS^G12C inhibitors, and new therapeutic strategies are required to delay and overcome this drug resistance. [N Engl J Med 2021;384:2382-2393]

In addition, multiparametric molecular biomarkers can be used to dissect outpatient segments and stratify them to precise immunotherapy strategies or targeted strategies. Co-mutations may further delineate therapeutically relevant subsets, for example, co-mutations in STK11-KEAP1 were associated with poor response to immune checkpoint blockade. [ESMO Open 2020;5(2):e000706]

KRAS mutation demographics
KRAS mutations occur in about 25–30 percent of patients with non-squamous cell NSCLC, representing the most prevalent genomic driver event in NSCLC. [N Engl J Med 2021;384:2371-2381] KRAS^G12C mutations are more common in Western than in Asian populations (approximately 13 percent vs 5 percent of NSCLC cases) and are more common in current or former smokers with non-squamous histology. [J Clin Oncol 2022;40:611-625]

In the ATORG-005 study, a real-world observational multicentre study of advanced KRAS-mutant NSCLC patients in Asia, KRAS^G12D was the most common subtype (25.5 percent), followed by ^G12C (24.5 percent) and ^G12V (19.4 percent). [JTO Clin Res Rep 2021;3:100261] “This study revealed unique demographics of KRAS mutations in Asian NSCLC,” said Tan. “The proportion of never-smokers in this cohort was considerably higher at 34.3 percent than from Western countries, which ranged from 6.4 to 7.1 percent. The non-^G12C subgroup had a higher proportion of never-smokers than the ^G12C subgroup, at 41.1 percent and 13.2 percent, respectively.”

“KRAS^G12C mutations have a higher predominance of females to males in Black and White populations, but significantly more males than females in the Asian population. [N Engl J Med 2021;384:185-187] This could reflect a higher degree of smoking in males vs females in Asia,” postulated John.

A first-in-class oral therapy for KRAS^G12C-mutated NSCLC
“The advent of sotorasib, the first-in-class KRAS^G12C inhibitor, demonstrates that KRAS is no longer undruggable,” said John. “Sotorasib efficacy in the CodeBreak 100 trial has led to an accelerated US FDA approval in adults with KRAS^G12C-mutated NSCLC who have received at least one prior systemic therapy.”

CodeBreak 100 is a single-arm, pooled phase I/II trial of 174 patients with locally advanced or metastatic KRAS^G12C-mutated NSCLC previously treated with standard therapies. It included patients with stable brain metastases at baseline. All received sotorasib 960 mg orally once daily until disease progression. Radiographic scans were done every 6 weeks up to week 48, and once every 12 weeks thereafter.

“In the phase I portion of the trial (n=48), sotorasib was fairly well tolerated, with diarrhoea and fatigue as the most common adverse events (AEs) reported. There were no dose-limiting toxicities or treatment-related fatal AEs reported. Grade 3 or 4 treatment-related AEs occurred in about 11.6 percent of patients, and the frequency of discontinuations due to treatment-emergent AEs was low at 7 percent,” said John. “In terms of pharmacokinetic profile, sotorasib irreversibly binds to the mutated KRAS^G12C protein, enabling a once-daily dosing.”

In the phase II part of the trial (n=126), the objective response rate (ORR) was 37.1 percent and the median duration of response (DOR) was 11.1 months. Median progression-free survival (PFS) was 6.8 months, while median overall survival (OS) was 12.5 months. [N Engl J Med 2021;384:2371-2381] “Notably, the majority of patients (81 percent) had previously received both platinum-based chemotherapy and PD-1 or PD-L1 therapy,” pointed out John.

At the 2-year follow-up, sotorasib demonstrated meaningful and durable efficacy, with a median OS of 12.5 months (95 percent confidence interval [CI], 10–17.8) and a 2-year OS rate of 32.5 percent in patients with pre-treated KRAS^G12C-mutated NSCLC. (Table 1)

A PFS benefit of at least 12 months was experienced by 46.2 percent of patients with STK11-mutant/KEAP1 wild-type disease (n=13), 45.5 percent of those with STK11 wild-type/KEAP1 wild-type disease (n=33), 16.7 percent of patients with STK11-mutant/KEAP1-mutant disease (n=12), and 14.3 percent of those with STK11 wild-type/KEAP1-mutant disease (n=7). “Patients with KEAP1 co-mutations appeared to have worse outcomes, whereas improved efficacy with sotorasib was seen in patients with STK11-mutant and concurrent wild-type KEAP1,” observed John.

Fresh from ESMO 2022: CodeBreak 200
On the heels of the sotorasib launch in Singapore, the primary analysis of the confirmatory phase III CodeBreak 200 trial was presented at the ESMO Congress 2022 showing that sotorasib, given once daily, led to a significantly superior PFS and a significantly higher ORR than standard of care intravenous docetaxel in heavily pre-treated patients with KRAS^G12C-mutated NSCLC. [ESMO 2022, abstract LBA 10]

One-year PFS rates were 24.8 percent for sotorasib vs 10.1 percent for docetaxel. The PFS benefit was consistent across subgroups, even in those with a history of brain metastases. The ORR was also significantly higher for sotorasib at 28.1 percent vs 13.2 percent for docetaxel (p<0.001). Disease control rate was 82.5 percent vs 60.3 percent. OS did not differ between groups, although the study was not powered for OS. Sotorasib also had a more favourable safety profile than docetaxel.

Key takeaways
The approval of sotorasib in major markets, including Singapore, represents a significant advance in the treatment of pre-treated patients with KRAS^G12C-mutated NSCLC, who previously had very limited therapeutic options. Broad panel molecular testing, ideally with next-generation sequencing at diagnosis, is critical to optimize treatment strategies for patients with advanced or metastatic NSCLC.