Intracranial Efficacy of Adagrasib in Patients From the KRYSTAL-1 Trial With KRAS^G12C-Mutated Non–Small-Cell Lung Cancer Who Have Untreated CNS Metastases

Abstract

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.

Patients with Kirsten rat sarcoma viral oncogene homolog (KRAS)–mutated non–small-cell lung cancer (NSCLC) and untreated CNS metastases have a worse prognosis than similar patients without KRAS mutations. Adagrasib has previously demonstrated CNS penetration preclinically and cerebral spinal fluid penetration clinically. We evaluated adagrasib in patients with KRAS^G12C-mutated NSCLC and untreated CNS metastases from the KRYSTAL-1 trial (ClinicalTrials.gov identifier: NCT03785249; phase Ib cohort), in which adagrasib 600 mg was administered orally, twice daily. Study outcomes included the safety and clinical activity (intracranial [IC] and systemic) by blinded independent central review. Twenty-five patients with KRAS^G12C-mutated NSCLC and untreated CNS metastases were enrolled and evaluated (median follow-up, 13.7 months); 19 patients were radiographically evaluable for IC activity. Safety was consistent with previous reports of adagrasib, with grade 3 treatment-related adverse events (TRAEs) in 10 patients (40%) and one grade 4 (4%) and no grade 5 TRAEs. The most common CNS-specific TRAEs included dysgeusia (24%) and dizziness (20%). Adagrasib demonstrated an IC objective response rate of 42%, disease control rate of 90%, progression-free survival of 5.4 months, and median overall survival of 11.4 months. Adagrasib is the first KRAS^G12C inhibitor to prospectively demonstrate IC activity in patients with KRAS^G12C-mutated NSCLC and untreated CNS metastases, supporting further investigation in this population.

INTRODUCTION

The Kirsten rat sarcoma viral oncogene homolog (KRAS) is mutated in approximately 25% of non–small-cell lung cancer (NSCLC) cases,^1-3 with the glycine-to-cysteine mutation at codon 12 (KRAS^G12C) occurring in approximately 14% of adenocarcinomas.⁴ CNS metastases are observed at diagnosis in 27%-42% of patients with KRAS^G12C-mutated NSCLC.^5-8 Patients with KRAS-mutated NSCLC and CNS metastases have a worse prognosis and higher rates of CNS failure compared with patients without KRAS mutations.^9-11

Adagrasib (MRTX849), a KRAS^G12C inhibitor that selectively and irreversibly binds the switch II pocket of KRAS^G12C,¹² has demonstrated CNS penetration, intracranial (IC) tumor regression, and increased survival in multiple preclinical models.¹³ Preliminary clinical data have similarly shown cerebral spinal fluid penetration and regression of CNS lesions by imaging.¹³

KRYSTAL-1 (ClinicalTrials.gov identifier: NCT03785249) is an ongoing trial of adagrasib in patients with advanced KRAS^G12C-mutated solid tumors.¹⁴ Here, we report data from a phase Ib cohort evaluating adagrasib monotherapy in patients with NSCLC and untreated CNS metastases.

METHODS

Patients with KRAS^G12C-mutated NSCLC with untreated CNS metastases received adagrasib monotherapy at the recommended phase II dose (600 mg twice a day administered orally [capsule, fasted state]). Study oversight and methodology are described in the Data Supplement ([Appendix 1.1 and 1.2], online only).

Patients

All patients had KRAS^G12C-mutated NSCLC; neurologically stable, asymptomatic, untreated CNS metastases; and Eastern Cooperative Oncology Group performance status of 0 or 1. Full eligibility criteria are provided in the Data Supplement (Appendix 1.3).

Objectives and End Points

Primary objectives were to characterize the safety and IC clinical activity of adagrasib. Safety assessments included documentation of adverse events (AEs), laboratory abnormalities, dose interruptions, and treatment discontinuations. CNS efficacy was evaluated by blinded independent central review (BICR) using modified CNS RECIST v1.1¹⁵ and modified Response Assessment in Neuro-Oncology Brain Metastases (mRANO-BM)¹⁶ criteria; with both criteria, measurable lesions had a size ≥5 mm. Systemic clinical activity was evaluated according to RECIST v1.1 per BICR. Overall survival (OS) and 1-year survival rate were evaluated. Full details are provided in the Data Supplement (Appendix 1.4).

Statistical Considerations

The safety population was defined as all patients who received ≥1 dose of the study drug. The clinical activity evaluable population included all patients who received ≥1 dose and had disease assessments at baseline and on-study. Statistical analyses and study assessments are described in the Data Supplement (Appendix 1.5 and 1.6).

RESULTS

Patients

As of August 1, 2022, 25 patients with NSCLC were enrolled, and 19 were evaluable for IC activity by CNS RECIST v1.1, of whom 14 had target lesions and five patients had nontarget lesions only (Data Supplement [Appendix Fig 1]). One additional patient did not have measurable/evaluable CNS metastases at baseline using CNS RECIST v1.1 but was evaluable for systemic activity and IC activity using mRANO-BM criteria. The median follow-up was 13.7 months (95% CI, 8.5 to not evaluable). The median age was 66 years, and the median number of previous systemic therapies was 1 (Table 1).

TABLE 1.

Patient Demographics and Clinical Characteristics

Safety

Treatment-related AEs (TRAEs) of any grade occurred in 25 patients (100%); 10 patients (40%) experienced a grade 3 TRAE (Table 2). The most common TRAEs were nausea, diarrhea, vomiting, increased alanine aminotransferase, increased aspartate aminotransferase, and fatigue. One patient experienced a grade 4 TRAE (neutropenia); no grade 5 TRAEs were reported. TRAEs led to dose modifications in 15 patients (60%; dose reduction in eight patients [32%], dose interruption in 14 patients [56%]); two patients (8%) discontinued treatment (grade 3 acute pancreatitis and grade 2 fatigue).

TABLE 2.

Summary of TRAEs (N = 25)

CNS-specific TRAEs, categorized as nervous system disorders, included dysgeusia (24%), dizziness (20%), ataxia (8%), and aphasia, confused state, encephalopathy, headache, and insomnia (each 4%). The majority of CNS-specific TRAEs were grade 1-2; four patients experienced grade 3 CNS-specific TRAEs (dizziness, n = 3; encephalopathy, n = 1), and there were no grade ≥4 CNS-related events (Table 2). Treatment-emergent AEs are summarized in the Data Supplement (Appendix Table 1).

Clinical Outcomes

The confirmed IC objective response rate (ORR) per RECIST v1.1 criteria was 42% (95% CI, 20.3 to 66.5; three patients had complete IC response and five patients partial IC response; Data Supplement [Appendix Table 2]; Fig 1A). IC responses by comutational status are shown in the Data Supplement (Appendix Table 3). The IC disease control rate (DCR) was 90%. The median IC progression-free survival (PFS) was 5.4 months (12-month PFS, 33.9%; Fig 1B). The median time to response was 2.1 months; the median IC duration of response (DOR) was 12.7 months, with treatment ongoing for >10 months in two patients still in response (Fig 1C). Of eight patients with confirmed IC response, four (50%) recorded their first response at the second on-study scan. All patients with an IC response had a dose modification during treatment. The CNS failure rate was 37% (7 of 19); two patients experienced CNS progression only. Among 20 patients evaluable for IC activity per mRANO-BM, the confirmed IC ORR was 35% and IC DCR was 85%. Additional IC efficacy outcomes per mRANO-BM are shown in the Data Supplement (Appendix Table 2).

FIG 1.

Efficacy outcomes for evaluable patients per CNS RECIST v1.1 (n = 19). (A) Waterfall plot of maximum percent tumor change from baseline (only patients with target lesions are shown). (B) Kaplan-Meier graphical representation of intracranial PFS. (C) Swimmer plot showing individual duration of treatment, time to first dose modification, response, clinical outcome, and most commonly administered dose at data cutoff. (D) Kaplan-Meier graphical representation of OS for the full analysis set (N = 25). ^aTime to first dose modification due to any cause, including missed dose, AE, or others. For patients who had a dose modification (reduction or interruption) after initiation of treatment because of an AE, adagrasib could be restarted at the 600 mg twice a day dose following resolution of AEs if deemed appropriate. AE, adverse event; NE, not evaluable; OS, overall survival; PFS, progression-free survival.

The systemic ORR was 30%, with a median DOR of 5.6 months and a median PFS of 5.3 months (Data Supplement [Appendix Table 2 and Fig 2]). The concordance rate between systemic and IC (per CNS RECIST v1.1) disease control was 79% (Data Supplement [Appendix Table 4]). The median OS was 11.4 months (12-month OS, 41.1%; Fig 1D).

DISCUSSION

Patients with KRAS-mutated NSCLC and untreated CNS metastases have limited treatment options and poor clinical outcomes.^9-11 Radiation therapy has been the historical standard of care, but recent interest has focused on targeted drugs with CNS penetration (eg, epidermal growth factor receptor or anaplastic lymphoma kinase inhibitors).^17,18 This approach avoids adverse effects of radiation such as necrosis and cognitive impairment.^19,20

The results presented here are the first prospective data for a KRAS^G12C inhibitor in patients with NSCLC and untreated CNS metastases. Adagrasib 600 mg twice a day achieved promising IC clinical activity, a high concordance rate between IC and systemic activity (79%), and a low rate of CNS failure (37%). These results provide proof-of-concept for adagrasib's ability to penetrate the CNS and provide CNS activity. The safety and tolerability profile seen in this cohort, with the most common CNS-specific TRAEs reported being dysgeusia and dizziness, was broadly consistent with previous reports from the KRYSTAL-1 trial.^14,21

No other KRAS^G12C inhibitor has previously demonstrated IC activity in a prospective clinical trial, although case studies^22-24 and post hoc analyses from registrational data sets^13,25 have demonstrated IC responses with sotorasib and adagrasib. However, the post hoc analyses from both sotorasib and adagrasib required adequately treated CNS metastases including radiation before enrollment, leading to an inability to fully interpret the IC activity of the KRAS^G12C inhibitor.^13,25

Limitations of this study include its exploratory nature, limited follow-up period, small evaluable patient population, and exclusion of patients with poor performance status. Additionally, a full analysis of subsequent treatment was unavailable. Therefore, further analyses are required to elucidate the optimal timing and sequencing of adagrasib in relation to radiotherapy. Additional data generation efforts are ongoing in the KRYSTAL program across different lines of therapy in patients with NSCLC, including those with untreated CNS metastases.

In conclusion, adagrasib is the first KRAS^G12C inhibitor to prospectively demonstrate IC activity, including ongoing responses, in patients with KRAS^G12C-mutated NSCLC and untreated CNS metastases. Adagrasib had a manageable safety profile with few CNS-specific TRAEs. These findings support continued clinical development of adagrasib for patients with KRAS^G12C-mutated NSCLC.

DATA SHARING STATEMENT

At Mirati Therapeutics, we are committed to patient care, advancing scientific understanding, and enabling the scientific community to learn from and build on the research we have undertaken. To that end, we will honor legitimate requests for our clinical trial data from qualified researchers and investigators for conducting methodologically sound research. We will share study-level clinical trial data, clinical study reports, study protocols, and statistical analysis plans from clinical trials for which results have been posted on ClinicalTrials.gov for products and indications approved by regulators in the United States and/or European Union. Sharing is subject to protection of patient privacy and respect for the patient's informed consent. In general, data will be made available for specific requests approximately 24 months after clinical trial completion from our in-scope interventional trials. For additional information on proposals with regard to data sharing collaborations with Mirati, please email us at medinfo@mirati.com.

AUTHOR CONTRIBUTIONS

Conception and design: Marcelo V. Negrao, Alexander I. Spira, Jose M. Pacheco, Hirak Der-Torossian, James G. Christensen, Joshua K. Sabari

Provision of study materials or patients: Marcelo V. Negrao, Alexander I. Spira, Rebecca S. Heist, Pasi A. Jänne, Jose M. Pacheco, Jared Weiss, Shirish M. Gadgeel, Karen Velastegui, Joshua K. Sabari

Collection and assembly of data: All authors

Data analysis and interpretation: All authors

Manuscript writing: All authors

Final approval of manuscript: All authors

Accountable for all aspects of the work: All authors

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Intracranial Efficacy of Adagrasib in Patients From the KRYSTAL-1 Trial With KRAS^G12C–Mutated Non–Small-Cell Lung Cancer Who Have Untreated CNS Metastases

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/authors/author-center.

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