Safety and Intracranial Activity of Adagrasib in Patients With KRAS^G12C-Mutated Non–Small-Cell Lung Cancer and Untreated CNS Metastases in the KRYSTAL-1 Trial: A Case Series

Introduction

CNS metastases occur in 27%-42% of patients with non–small-cell lung cancer (NSCLC) that harbor KRAS^G12C mutations at diagnosis.^1-4 Prognosis is worse and the incidence of CNS failure is higher in patients with KRAS-mutated NSCLC and CNS metastases, compared with patients without KRAS mutations.^5-8

Adagrasib, a KRAS^G12C inhibitor, was granted accelerated approval by the US Food and Drug Administration in December 2022 for the treatment of adult patients with KRAS^G12C-mutated locally advanced or metastatic NSCLC who have received at least one previous systemic therapy.⁹ Adagrasib has demonstrated cerebral spinal fluid penetration in patients (mean K_p,uu 0.47).^10,11 In a prospective analysis from the KRYSTAL-1 phase Ib cohort enrolling patients with NSCLC with untreated CNS metastases at baseline (KRYSTAL-1 CNS metastases cohort), adagrasib demonstrated an intracranial (IC) objective response rate of 42% and an IC disease control rate of 90% (n = 19) per blinded independent central review (BICR) using modified CNS RECIST v1.1.¹² The median IC duration of response (DOR) was 12.7 months, the median IC progression-free survival (PFS) was 5.4 months, and the median overall survival (OS) was 11.4 months.¹² To our knowledge, this is first prospective analysis of a KRAS^G12C inhibitor in patients with untreated CNS metastases. This analysis provides strong proof-of-concept that adagrasib penetrates the CNS supporting further clinical evaluation in this patient population.

We report clinical details and IC efficacy outcomes of five patient cases with NSCLC and untreated CNS metastases from the KRYSTAL-1 CNS metastasis cohort,¹² selected to illustrate scenarios relevant to the use of adagrasib in routine clinical practice (focal leptomeningeal disease [LMD]; concurrent stereotactic radiosurgery [SRS]; IC efficacy of adagrasib as first-line therapy; dose reduction; and presence of common comutations).

Methods

The five patients with KRAS^G12C-mutated NSCLC from the KRYSTAL-1 CNS metastases cohort presented in this case series received adagrasib 600 mg twice a day (capsule, fasted state). Evaluation of known or suspected CNS metastases was performed at baseline using magnetic resonance imaging with/without gadolinium or computed tomography. Scans were performed at baseline and every 6 weeks until week 49, followed by a scan every 12 weeks. CNS lesions were evaluated by BICR per modified CNS RECIST v1.1; measurable lesions had a size of ≥5 mm.

Further study details are described elsewhere.^10,12 The protocol was approved by the relevant institutional review boards or ethics committees. This study was conducted in accordance with the principles of the Declaration of Helsinki and International Council for Harmonisation guidelines for Good Clinical Practice.^13,14 All patients provided written informed consent to enter the study and for publication of their anonymized study data.

Results

Baseline characteristics and efficacy data for all five patient cases are provided in Tables 1 and 2, respectively; patient treatment journeys are detailed in Figure 1. For the purposes of comparison, IC response data for all other patients in the KRYSTAL-1 CNS metastases cohort in the categories represented by the five cases described below are presented in Table 3.

TABLE 1.

Baseline Characteristics, Previous Systemic Therapy, and Radiotherapy for Each Patient Case

Patient	Age, Years	ECOG PS	Metastatic Sites	Comutations	Previous Systemic Therapya	Previous Radiotherapy
1	75	1	Brain (including focal LMD), chest, and lymph node	TP53, FGF3, FGF4 amplification	Pembrolizumab plus carboplatin/pemetrexed (DOT, 1.4 months; BOR, PD)	Gamma knife SRS to the left frontal area of the brain
2	70	0	Brain, lymph node, and spleen	STK11, KEAP1, BRCA2	Carboplatin/pemetrexed (DOT, 2.9 months; BOR, PD)	Three rounds of palliative SRS to CNS lesions over 18 months before adagrasib treatment
3	58	0	Brain, bone, chest, lymph node, and pleural	None detected	None	NA
4	61	0	Brain, bone, and lymph node	TP53, HGF S5101, and CDK4 amplification	Carboplatin/paclitaxel (DOT, 1.2 months; BOR, PD)	Palliative radiotherapy (gamma knife SRS) for four CNS metastases
5	63	1	Brain, bone, liver, and adrenal	TP53, STK11, CDKN2A loss	Pembrolizumab plus carboplatin/pemetrexed (DOT, 3.7 months; BOR, SD)	NA

Abbreviations: BOR, best overall response; DOT, duration of treatment; ECOG PS, Eastern Cooperative Oncology Group Performance Status; LMD, leptomeningeal disease; NA, not applicable; PD, progressive disease; SD, stable disease; SRS, stereotactic radiosurgery.

^a Most recent previous systemic therapy.

TABLE 2.

Efficacy and Treatment Outcomes for Each Patient Case

Patient	IC BORa	IC DOR,a Months	IC PFS,a Months	Systemic BORb	OS, Months	Site(s) of Disease Progression
1	PR	4.1	5.6	SD	20.4 (censored)	CNS/week 24
2	PR	3.9	5.4	PR	8.4 (censored)	CNS/week 23 Extracranial New adrenal LN/week 36 New mediastinal LN/week 36
3	CR	7.0c (censored)	9.7c (censored)	PR	10.4 (censored/ongoing)	No progression (ongoing)
4	PR	12.7	15.4	SD	15.4	No progression
5	PR	5.6 (censored)	7.0 (censored)	PR	8.3 (censored)	Extracranial New axillary LN/week 30 Progression of adrenal lesion/week 30

Abbreviations: BICR, blinded independent central review; BOR, best overall response; CR, complete response; DOR, duration of response; ECOG PS, Eastern Cooperative Oncology Group Performance Status; IC, intracranial; LN, lymph node; OS, overall survival; PFS, progression-free survival; PR, partial response; SD, stable disease.

^a Assessed by CNS RECIST.

^b Assessed by BICR using RECIST.

^c Ongoing response to treatment.

FIG 1.

Patient treatment journeys and responses. ^aFor entry into the cohort, patients had to have untreated CNS metastases before initiation of adagrasib. ^bTreatment was held for 3 days because of radiotherapy and restarted at 600 mg twice a day, which was administered until treatment discontinuation. ^cPatient 3 received 600 mg twice a day for 6.4 months before adagrasib dose was reduced to 400 mg twice a day because of grade 2 treatment-related nausea (ongoing). ^dPatient 4 received 600 mg twice a day for 0.7 months before adagrasib dose was reduced to 400 mg twice a day for 5 days, because of grade 1 ALT and AST increase, to 200 mg twice a day for 0.4 months, because of grade 2 blood creatinine increase, and then re-escalated to 400 mg twice a day until treatment discontinuation. ^ePatient 5 received 600 mg twice a day for 0.7 months before adagrasib dose was reduced to 400 mg twice a day until treatment discontinuation. BOR, best overall response; CR, complete response; IC, intracranial; PD, progressive disease; PR, partial response; SD, stable disease; SRS, stereotactic radiosurgery.

TABLE 3.

Overview of IC Efficacy in All Evaluable Patients With the Selected Clinical Scenario

Clinical Characteristic	Patient, No.	IC Response,a No. (%)	IC BOR,a No. (%)
			CR	PR	SD	PD	NE
Patients with focal LMD	4	1 (25.0)	0 (0)	1 (25.0)	2 (50.0)	0 (0)	1 (25.0)
Patients undergoing concurrent SRS with adagrasib	3	2 (66.7)	0 (0)	2 (66.7)	0 (0)	1 (33.3)	0 (0)
Patients with no previous systemic therapy	4	2 (50.0)	2 (50.0)	0 (0)	1 (25.0)	0 (0)	1 (25.0)
Patients with a dose reductionb	7c	4 (57.1)	1 (14.3)	3 (42.9)	2 (28.6)	1 (14.3)	0 (0)
Patients with comutations at baseline	13	5 (38.5)	1 (7.7)	4 (30.8)	7 (53.8)	0 (0)	1 (7.7)

Abbreviations: BOR, best overall response; CR, complete response; IC, intracranial; LMD, leptomeningeal disease; NE, not evaluable; PD, progressive disease; PR, partial response; SD, stable disease; SRS, stereotactic radiosurgery.

^a Assessed by CNS RECIST.

^b Includes patients who received 400 mg twice a day for the majority of their treatment (n = 5); patients who received 200 mg twice a day for most of their treatment (n = 1); and patients with multiple dose reductions throughout their treatment (n = 1).

^c All patients who were radiographically evaluable.

Patient 1: Focal LMD

A patient with a history of smoking was diagnosed by radiologic assessment per central review with focal LMD secondary to KRAS^G12C-mutated NSCLC and metastases in the chest and lymph node (Fig 1A). Per BICR, the patient had three untreated IC target lesions and five IC nontarget lesions at baseline. IC best overall response (BOR) was partial response (PR), which was noted in the first on-study scan. In the CNS, the DOR was 4.1 months and the PFS was 5.6 months. The duration of treatment (DOT) was 5.6 months, systemic BOR was stable disease (SD), and the patient remained alive at data cutoff (OS, 20.4 months, censored). The patient discontinued adagrasib treatment because of objective IC progressive disease (PD), identified by scan at week 24, without evidence of systemic PD.

Patient 2: Concurrent SRS After CNS Progression

A patient with a history of smoking was diagnosed with oligometastatic KRAS^G12C-mutated NSCLC to the brain, lymph node metastasis, and recent recurrent metastatic disease to the spleen (Fig 1B). Per BICR, the patient had three untreated IC target lesions and two IC nontarget lesions at baseline. IC BOR was PR and was observed in the first on-study scan. The IC DOR was 3.9 months, and the IC PFS was 5.4 months. The DOT was 8.3 months, systemic BOR was PR, and the patient remained alive at data cutoff (OS, 8.4 months, censored). IC PD was identified by scan at week 23, and the patient underwent treatment with SRS while continuing adagrasib. After SRS, the patient remained on treatment with adagrasib until subsequent systemic progression (new adrenal lesions and mediastinal lymph node involvement) at week 36; there was no additional CNS PD at this time.

Patient 3: No Previous Systemic Therapy

A patient with a history of smoking was diagnosed with brain, bone, chest, lymph node, and pleural metastases secondary to KRAS^G12C-mutated NSCLC. No systemic treatment was received before enrollment (Fig 1C; Table 2). Per BICR, the patient had one untreated IC nontarget lesion at baseline. CNS BOR was complete response (CR); first response was observed in the second on-study scan. The IC DOR was 7.0 months (censored/ongoing), and the IC PFS was 9.7 months (censored/ongoing). The DOT was 10.6 months, systemic BOR was PR, and the patient remained alive at data cutoff (OS, 10.4 months, censored/ongoing). Adagrasib dose was reduced to 400 mg twice a day after 6.4 months because of persistent grade 2 treatment-related nausea. After dose reduction, the IC CR and systemic response were maintained with treatment ongoing at data cutoff.

Patient 4: Adagrasib Dose Reduction for a Majority of Treatment

A patient with a history of smoking was diagnosed with brain, bone, and lymph node metastases secondary to KRAS^G12C-mutated NSCLC (Fig 1D). Per BICR, the patient had one untreated IC target lesion and one IC nontarget lesion at baseline. IC BOR of PR was observed in the first on-study scan. The IC DOR was 12.7 months, and the IC PFS was 15.4 months. The DOT was 14.2 months, systemic BOR was SD, and the OS was 15.4 months. Adagrasib dosage was reduced after 3 weeks to 400 mg twice a day because of grade 2 ALT and AST increase and to 200 mg twice a day at week 9 because of grade 2 blood creatinine increase. Treatment with adagrasib was re-escalated at week 12 to 400 mg twice a day and remained at this level until the patient discontinued the study. No systemic or CNS PD occurred up to week 60; treatment discontinuation occurred at week 62 because of altered mental status.

Patient 5: Tumor Comutations at Baseline

A patient with a history of smoking was diagnosed with KRAS^G12C-mutated NSCLC and brain, bone, liver, and adrenal metastases (Fig 1E). Per BICR, the patient had one untreated IC target lesion at baseline. IC BOR of PR was observed in the first on-study scan. The IC DOR was 5.6 months (censored), and the IC PFS was 7.0 months (censored). The DOT was 7.2 months, systemic BOR was PR, and the patient remained alive at data cutoff (OS, 8.3 months, censored). Adagrasib dose was reduced to 400 mg twice a day at week 3 because of grade 2 vomiting and nausea, which resolved after dose modification. No CNS progression occurred while on study; however, new extracranial lesions in axillary lymph nodes and progression of the adrenal target lesion were observed at week 30. The patient discontinued adagrasib treatment at week 32.

Discussion

A prospective analysis of the KRYSTAL-1 CNS metastases cohort, from which these patient cases originated, demonstrated that adagrasib 600 mg twice a day achieved promising CNS activity.¹² These cases provide additional details of the CNS activity of adagrasib, suggesting that adagrasib might have IC clinical activity, regardless of baseline characteristics (Table 3). CNS responses to adagrasib were durable as first-line treatment and in the presence of radiotherapy, commonly occurring comutations at baseline, focal LMD, or dose reduction before first radiographic response.

To date, adagrasib is the only KRAS^G12C inhibitor with prospective data demonstrating CNS activity in patients with untreated CNS metastases.^8,12 Most patients in this case series did not discontinue adagrasib because of CNS progression, which is consistent with the overall KRYSTAL-1 CNS metastases cohort¹² and indicates that adagrasib may delay development of additional CNS metastases.

Definitive conclusions about the CNS activity of adagrasib in these scenarios of interest cannot be drawn from these cases because of limited patient numbers and follow-up.¹² However, these cases deepen our clinical understanding of adagrasib and represent proof of concept for adagrasib use in patients with NSCLC and untreated CNS metastases across multiple clinical scenarios.

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 upon 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 US and/or EU. 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: Ezra Bernstein, Joshua K. Sabari

Administrative support: Pasi A. Jänne

Provision of study materials or patients: All authors

Collection and assembly of data: Ezra Bernstein, Kaiwen Wang, Marcelo V. Negrao, Joshua K. Sabari

Data analysis and interpretation: Ezra Bernstein, Jia Luo, Pasi A. Jänne, Joshua K. Sabari

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

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