Intracranial efficacy of adagrasib in patients with KRAS G12C mutated non-small cell lung cancer (NSCLC): are results KRYSTAL clear?

Lung cancer is one of the most common types of cancer and to date remains the leading cause of cancer mortality for both men and women worldwide (1). The treatment landscape of lung cancer—particularly non-small cell lung cancer (NSCLC) has been changing rapidly with the advent of targeted therapy and immunotherapy (2). Therapeutic agents have been developed against multiple activating mutations in driver oncogenes over the past two decades except against Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations which remain notoriously ‘undruggable’ until the recent approval of mutant-specific KRAS G12C inhibitors sotorasib and adagrasib. KRAS mutations constitute the most common activating alterations in NSCLC in the Western hemisphere with an incidence of approximately 30%. KRAS G12C is the predominant mutation variant in NSCLC, constituting approximately 40% of all KRAS mutations in NSCLC, thus comprising between 11–13% of all mutations found in NSCLC in non-Asian population (3). Moreover, in a single-institute retrospective analysis of treatment outcomes using whole brain radiation among NSCLC patients with demonstrable brain metastases prior to initiating systemic therapy, patients with KRAS mutant NSCLC had the worst response rate and intracranial progression-free survival (PFS) (20% and 6 months, respectively) as compared to those with epidermal growth factor receptor (EGFR) (64.5% and 18.2 months), anaplastic lymphoma kinase (ALK) (54.5% and 18.4 months) mutations and even to those without any driver mutations (35.4% and 8.7 months), thus emphasizing the need to find other avenues of treatment (4). In NSCLC patients with KRAS G12C mutation, central nervous system (CNS) metastases are observed at diagnosis in 27–42% of patients (5). A Swedish registry notes the incidence of CNS metastasis in KRAS G12C mutated NSCLC to be 27.5% versus 18.5% in other KRAS variants (6). These findings are in contrast with a different single US institution survey, showing no significant difference observed in terms of mutation variants among stage IV NSCLC patients with brain metastases (KRAS G12C 37.2% versus other KRAS variants 33.5%) (7).

In Dec 2022, the Food and Drug Administration (FDA) granted accelerated approval to adagrasib, only the second drug after sotorasib, which was initially approved under the same mechanism in May 2021, for previously treated advanced-stage KRAS G12C mutant NSCLC (8). Preclinical studies with adagrasib demonstrated cerebrospinal fluid (CSF) penetration of the drug to clinically relevant levels resulting in tumor regression. It was also shown to demonstrate P-glycoprotein multi-drug resistance (MDR) pump inhibition, suggesting a possible mechanism of its CNS penetration. A predictor for blood-brain barrier (BBB) permeability—the unbound brain-to-plasma partition coefficient was found to be comparable to that of osimertinib which is established to have intracranial activity (9). Confirming these findings clinically, the CSF concentration of adagrasib was found to be more than the target half maximal inhibitory concentration (IC₅₀) in the KRYSTAL-1 trial cohort of KRAS G12C mutated NSCLC patients with known baseline untreated brain metastases who were enrolled (9). Adagrasib monotherapy in this cohort of NSCLC patients with untreated CNS metastases demonstrated an intracranial (IC) objective response rate (ORR) of 42% (95% CI: 20.3% to 66.5%). The IC disease control rate (DCR) was 90% while the median IC (PFS) was 5.4 months (12-month PFS, 33.9%) The median time to response was 2.1 months with the median IC duration of response (DOR) being 12.7 months (10).

Similarly, in the phase II KRYSTAL-1 study, adagrasib demonstrated an IC ORR of 33% and DCR of 85% in KRAS G12C mutated NSCLC patients with treated, stable brain metastasis at the time of study enrollment (11). The IC-DOR and IC PFS were 11.2 months (95% CI: 2.99 to not evaluable) and 5.4 months (95% CI: 3.3 to 11.6), respectively. That the CNS outcomes with adagrasib are not clearly superior among those who had stable pre-treated brain metastases versus those who had untreated brain metastases can be interpreted in two ways. One is that in carefully selected patients, radiotherapy before initiation of adagrasib may not necessarily prolong the duration of disease control in the brain. Secondly, the lack of enhancement of CNS outcomes with local therapies administered to the brain alludes to the lack of durability (e.g., emergence of acquired resistance) with adagrasib in the control of extracranial disease that ultimately serves as the source for development of new brain metastases. So how do these results compare to what is known with outcomes of patients treated with sotorasib?

Data from the prospective evaluation of sotorasib in KRAS G12C mutated cancer with untreated brain metastases in the NSCLC arm are not yet publicly reported (NCT04185883). Patients with active untreated brain metastases were excluded in the Code-BreaK100 trial. However, out of the 16 patients with brain metastases evaluable using central RANO-BM criteria, 12 patients showed stable disease and 2 showed complete response to sotorasib demonstrating an intracranial disease control rate of 88% (12).

Multiple case reports have been published describing potential activity of sotorasib in the setting of untreated brain metastases, with IC PFS ranging from 1.2 to 17 months (13-15). Notably, in an exploratory analysis of CNS outcomes among patients with known treated stable brain metastases at the time of enrollment into the phase 3 CODEBREAK200 trial comparing sotorasib (n=40) versus docetaxel (n=29) as 2^nd/3^rd line therapy for KRAS-G12C mutant NSCLC, median IC PFS was 9.6 months with sotorasib versus 5.4 months with docetaxel [hazard ratio (HR) 0.53, P=0.03] (16). Among those with measurable CNS metastases for RANO-BM evaluation, response rate of 33.3% was noted for sotorasib (n=18) versus 15.4% for docetaxel (n=13). In comparison, the results of the phase 3 KRYSTAL-12 trial comparing adagrasib and docetaxel in previously treated advanced NSCLC were released at ASCO 2024. Patients with active brain metastases were excluded however, 17% patients in the adagrasib arm vs. 18% patients in the docetaxel arm had stable brain metastases at baseline. The median PFS in patients with known treated brain metastases at baseline in the adagrasib arm was 4.1 vs. 4.2 months in the docetaxel arm, while median PFS in patients without brain metastases at baseline in the adagrasib arm was 5.8 vs. 3.6 months in the docetaxel arm. The safety profiles of both adagrasib and docetaxel were found to be consistent with previous reports (17). The results of both sotorasib and adagrasib in this patient population appear to be similar. However, caution should be applied in superficially comparing the results across trials at face value given small sample sizes. While IC PFS with sotorasib may appear to be numerically superior to IC PFS reported for adagrasib, the caveat is that concerns had been raised regarding the reliability of the PFS data in CODEBREAK200 due to investigator bias favoring sotorasib, aside from other trial conduct concerns (13,18,19).

Like other targeted therapies for NSCLC, the development of resistance to KRAS G12C-targeted treatment is nearly unavoidable. Additionally, the efficacy of such therapies can be influenced by the presence of concurrent mutations. For example, co-mutation with STK11 is associated with lower overall survival and resistance to immune checkpoint inhibitors while co-mutation with KEAP1 is associated with lower sensitivity to platinum-based chemotherapy adversely affecting survival outcomes (7,20). A multicenter retrospective study analyzing real-world data revealed that KEAP1 mutations were associated with shorter PFS and OS when treated with KRAS G12C targeted treatments while no such associations were found with co-mutated STK11 and TP53 (21). Although KRAS mutations are generally mutually exclusive with other actionable driver mutations, activation of bypass signaling through other oncogenic drivers have been documented with KRAS G12C inhibitors (22-24). Mechanisms of drug resistance appear to be similar between the 1^st generation KRAS G12C inhibitors adagrasib and sotorasib (22,23).

Comparing the toxicity profiles of adagrasib and sotorasib, both drugs exhibit similar adverse events (AEs), including gastrointestinal symptoms (such as diarrhea and nausea), fatigue, and elevated liver enzymes but at different grades and frequencies, such that dose reductions overall are required in more than half of patients receiving adagrasib (11) at the recommended phase II dose versus only in 15% for sotorasib (25). Dose-dependent QTc prolongation has also been documented among patients treated with adagrasib but not with sotorasib, with 6% of patients in a pooled safety analysis of adagrasib showing QTc >501 ms and 11% of patients with an increase from baseline QTc of >60 msec (26). However, another key AE of interest is hepatoxicity, based on observations of increased incidence of severe hepatotoxicity two to threefold higher among patients who received immune checkpoint inhibitors (ICIs) within 90 days before initiation of sotorasib at 960 mg daily dose as compared to those who had longer washout period (25). CODEBREAK 101 evaluating the combination of sotorasib with ICIs also showed prohibitively high rates of grade 3 or higher hepatotoxicity (40–100%) with the combination even with reduced dosage of sotorasib (27). In contrast, among those who received the combination of adagrasib 400 mg BID with pembrolizumab 200 mg q3 weeks as 1^st line therapy for patients with KRAS G12C mutated NSCLC (KRYSTAL-7) and with a median follow-up duration of 10.1 months, grade 3 or higher levels of alanine aminotransferase (ALT) or Aspartate aminotransferase (AST) increase were reported at much lower rates of 9% or 13% respectively (28). Table 1 summarizes key comparisons between the two agents.

In conclusion, the main strength of the study reported by Negrao et al rests with the specific enrollment of patients with untreated brain metastases to confirm preclinical findings of potential CNS efficacy noted in murine models (8), i.e., it remains the only prospective study to date of a KRAS G12Ci with efficacy reported in NSCLC patients with untreated CNS metastases at baseline. Its main limitation derives from the underlying drug itself, as the first-generation KRAS G12Ci’s overall have lower response rate and PFS of both intracranial and extracranial disease compared to next-generation targeted therapies against other oncogenic drivers, such as TKIs against EGFR, ALK, ROS1, MET. Regardless, adagrasib is another option in the treatment of KRAS-G12C mutant NSCLC, with distinct toxicity profile from sotorasib.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, AME Clinical Trials Review. The article has undergone external peer review.

Peer Review File: Available at https://actr.amegroups.com/article/view/10.21037/actr-24-17/prf

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-24-17/coif). G.K.D. has received consulting fees from Amgen, Astra Zeneca, Bayer, Eli Lilly, Janssen, Mirati, Novartis, Regeneron, and was on the Data Safety Monitoring Board of WCG Clinical. The other author has no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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