Adagrasib Treatment After Sotorasib-Related Hepatotoxicity in Patients With KRAS^G12C-Mutated Non–Small Cell Lung Cancer: A Case Series and Literature Review

Abstract

PURPOSE

KRAS is the most commonly mutated driver oncogene in non–small cell lung cancer (NSCLC). Sotorasib and adagrasib, KRAS^G12C inhibitors, have been granted accelerated US approval; however, hepatotoxicity is a common side effect with higher rates in patients treated with sotorasib proximal to checkpoint inhibitor (CPI) therapy. The aim of this study was to assess the feasibility and safety of adagrasib after discontinuation of sotorasib because of treatment-related grade 3 hepatotoxicity through real-world and clinical cases.

METHODS

Medical records from five patients treated in real-world settings were retrospectively reviewed. Patients had locally advanced or metastatic KRAS^G12C-mutated NSCLC and received adagrasib after sotorasib in the absence of extracranial disease progression. Additional data were collected for 12 patients with KRAS^G12C-mutated NSCLC enrolled in a phase Ib cohort of the KRYSTAL-1 study and previously treated with sotorasib. The end points associated with both drugs included timing and severity of hepatotoxicity, best overall response, and duration of therapy.

RESULTS

All patients were treated with CPIs followed by sotorasib (initiated 0-64 days after CPI). All five real-world patients experienced hepatotoxicity with sotorasib that led to treatment discontinuation, whereas none experienced treatment-related hepatotoxicity with subsequent adagrasib treatment. Three patients from KRYSTAL-1 transitioned from sotorasib to adagrasib because of hepatotoxicity; one experienced grade 3 ALT elevation on adagrasib that resolved with therapy interruption and dose reduction.

CONCLUSION

Adagrasib may have a distinct hepatotoxicity profile from sotorasib and is more easily combined with CPIs either sequentially or concurrently. These differences may be used to inform clinical decisions regarding an initial KRAS^G12C inhibitor for patients who recently discontinued a CPI or experience hepatotoxicity on sotorasib.

INTRODUCTION

After decades of iterative scientific progress, the US Food and Drug Administration (FDA) granted accelerated approval of targeted KRAS inhibitors, the most commonly mutated oncogenic driver in non–small cell lung cancer (NSCLC).^1-6 These orally available small-molecule inhibitors, sotorasib and adagrasib, target KRAS^G12C, the most frequent mutant variant occurring in 14% of lung adenocarcinomas.^5-9

CONTEXT

• Key Objective

• Severe hepatotoxicity has been reported in patients with KRAS^G12C-mutated non–small cell lung cancer receiving sotorasib (a KRAS^G12C inhibitor), particularly when administered proximal to checkpoint inhibitor (CPI) therapy. The objective of this study was to use real-world and clinical trial data to discern the safety of adagrasib (another KRAS^G12C inhibitor) after sotorasib discontinuation because of hepatotoxicity.

• Knowledge Generated

• Treatment history, doses, safety, and responses from eight real-world and clinical trial cases were summarized. Overall, seven of eight patients received sotorasib within 60 days of pembrolizumab; all patients discontinued sotorasib because of hepatotoxicity. No real-world patients experienced hepatotoxicity with adagrasib; one clinical trial patient experienced grade 3 hepatotoxicity, which resolved after therapy interruption and dose reduction.

• Relevance

• These data suggest that adagrasib has a distinct hepatotoxicity profile compared with sotorasib. This study could be used to inform clinical decisions, particularly for patients who have recently discontinued CPI therapy or have previously experienced hepatotoxicity with sotorasib.

Sotorasib was granted accelerated approval in the United States in May 2021 for treatment of adult patients with KRAS^G12C-mutated locally advanced or metastatic NSCLC who have received at least one prior systemic therapy.^2,3 In a post hoc analysis of the phase III CodeBreaK 200 study of sotorasib (960 mg once daily) versus docetaxel (75 mg/m² once every 3 weeks), the incidence of grade ≥3 hepatotoxic treatment-related adverse events (TRAEs) with sotorasib increased with a shorter interval between prior checkpoint inhibitor (CPI) therapy.¹⁰

Data from one real-world study found that of 19 patients who initiated sotorasib within 30 days of prior CPI (40% of all patients in this cohort), 11 (58%) patients experienced grade ≥3 hepatotoxicity on sotorasib.¹¹ A second real-world study reported that 15 of 53 (28%) patients with CPI exposure within 12 weeks of initiation of sotorasib experienced grade ≥3 TRAEs; of them, 13 of 15 had grade ≥3 hepatotoxicity, with five patients requiring systemic steroids.¹² Of the 33 patients with their last exposure to CPI therapy ≥12 weeks before initiation of sotorasib, none experienced grade ≥3 TRAEs.¹² Different doses of sotorasib in combination with pembrolizumab were evaluated in the CodeBreaK 100/101 study. Initial presentation of data from 19 patients treated concurrently with pembrolizumab and sotorasib across all doses found 47% experienced grade ≥3 hepatotoxicity.¹³ In patients receiving pembrolizumab and sotorasib (960 mg once daily), three of four (75%) had grade ≥3 hepatotoxicity, suggesting that concurrent use of sotorasib and CPIs may not be well tolerated by all patients.¹³ Notably, it is the combination of sotorasib with pemetrexed plus carboplatin, not pembrolizumab, that has been taken forward to phase III development in the treatment-naïve setting.¹⁴

Adagrasib is currently the other FDA-approved inhibitor of KRAS^G12C.³ Among 116 patients treated with adagrasib (600 mg twice daily) in the phase I/II KRYSTAL-1 (ClinicalTrials.gov identifier: NCT03785249) study, the most common any-grade TRAEs were diarrhea, nausea, and vomiting.¹⁵ The most common grade ≥3 TRAEs were increased lipase (6%) and anemia (5%).¹⁵ The most common TRAEs leading to dose interruption or reduction were nausea (16%; 13%), fatigue (12%; 10%), increased ALT (10%; 10%), and increased AST (9%; 6%).¹⁵ In an exploratory analysis of KRYSTAL-1, grade ≥3 hepatotoxicity was not reported in any of the 12 patients who initiated adagrasib within 30 days of CPI therapy.¹⁶ Additionally, the phase II KRYSTAL-7 study (N = 148) evaluating adagrasib in combination with pembrolizumab as first-line treatment reported 24 patients (16%) with a grade ≥3 treatment-related AST/ALT increase.¹⁷

Given that hepatotoxicity is a common, significant side effect of these drugs and available data suggest possible differences in the rates of hepatotoxicity between adagrasib and sotorasib, the current case series aimed to evaluate the feasibility and safety of adagrasib treatment after discontinuation of sotorasib because of treatment-related grade 3 hepatotoxicity.

METHODS

Data Source and Study Population

Medical records from five patients with KRAS^G12C-mutated NSCLC treated in real-world settings were retrospectively reviewed by the treating physicians. Patients eligible for selection had confirmed locally advanced or metastatic KRAS^G12C-mutated NSCLC and received adagrasib after sotorasib during their course of treatment in the absence of extracranial disease progression.

Additional data were collected on 12 patients with KRAS^G12C-mutated NSCLC enrolled in a phase Ib cohort of the KRYSTAL-1 study of adagrasib who had previously received sotorasib. Full eligibility criteria have been published.¹⁵

End Points and Assessments

Timing and severity of treatment-related hepatotoxicity, best overall response (BOR), duration of therapy (DOT), and line of therapy were recorded for both drugs. In the patient cases provided from real-world clinical practice, toxicities were observed by the treating physician and recorded in medical notes. Clinical response was assessed by the investigator using magnetic resonance imaging (MRI) or computed tomography (CT) scans. In patient cases from KRYSTAL-1, AEs were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (version 5.0).¹⁵ All patients in KRYSTAL-1 underwent baseline brain, chest, abdomen and pelvis, and bone lesion imaging using MRI, CT, positron emission tomography (PET), or PET-CT. Disease evaluation was every 6 weeks for 1 year and every 12 weeks thereafter; scans were assessed by blinded independent review according to RECIST version 1.1.¹⁵

Consent

Permission to report real-world case studies was received from patients or their families. KRYSTAL-1 was approved by an institutional review board or independent ethics committee at each participating site and conducted in accordance with Good Clinical Practice guidelines, defined by the International Conference on Harmonisation. All patients provided written informed consent to participate on the basis of the principles of the Declaration of Helsinki.

RESULTS

Cases From Real-World Practice

Characteristics, treatment history, and historical outcomes for five real-world cases are provided in Table 1. Patient treatment journeys, dosages, and responses are summarized in Figure 1; individual patient narratives are captured below.

TABLE 1.

Characteristics and Outcomes for Patients With KRAS^G12C-Mutated NSCLC Who Received Sotorasib Before Adagrasib

Case	No. of Regimens Before Adagrasib	Interval Between Prior CPI and Sotorasib, Days	Duration of Sotorasib, Days	BOR to Sotorasib	Interval Between Sotorasib and Adagrasib, Days	Duration of Adagrasib, Days	BOR to Adagrasib	Hepatotoxicity on Adagrasib (maximum grade reported)		Patient Status at Data Cutoff
1	6	27a	Second line: 71; fifth line: 6	PRb	65	172 (ongoing)	PR	None	Alive
2	2	28	46	SD	15	97 (ongoing)	SD	None	Alive
3	3	63	70	SD	36	138 (ongoing)	SD	None	Alive
4	2	18	160	SD	23	110 (ongoing)	SD	None	Alive
5	4	0	57	PR	175	133	PR	None	Dead
6	2	22	51	PD	21	95	SD	Grade 3 ALT elevation Grade 3 AST elevation	Dead
7	2	0	59	NEc	85	177	SD	Grade 1 ALT elevation Grade 1 AST elevation Grade 1 ALP elevation	Alive
8	2	30	29	NEc	63	133	SD	None	Dead

Abbreviations: ALP, alkaline phosphatase; BOR, best overall response; CPI, checkpoint inhibitor; NE, not evaluable; NSCLC, non–small cell lung cancer; PD, progressive disease; PR, partial response; SD, stable disease; TRAE, treatment-related adverse event.

^a Interval between prior CPI and second-line sotorasib; interval between prior CPI and fifth-line sotorasib was 28 days.

^b BOR on second-line sotorasib; BOR to fifth-line sotorasib was SD.

^c Participant discontinued because of hepatotoxicity and was therefore NE.

FIG 1.

Patient treatment journeys and responses with sotorasib and adagrasib treatment.^a (A) Patient 1 received adagrasib 66 days after sotorasib discontinuation. The total duration of treatment was 77 days with sotorasib (second line 71 days; fifth line 6 days) and 172 days with adagrasib. (B) Patient 2 received adagrasib 16 days after sotorasib discontinuation. The total duration of treatment was 46 days and 97 days with sotorasib and adagrasib, respectively. (C) Patient 3 received adagrasib 37 days after sotorasib discontinuation. The total duration of treatment was 70 days and 138 days with sotorasib and adagrasib, respectively. (D) Patient 4 received adagrasib 24 days after sotorasib discontinuation. The total duration of treatment was 160 days and 110 days with sotorasib and adagrasib, respectively. (E) Patient 5 received adagrasib 176 days after sotorasib discontinuation. The total duration of treatment was 57 days and 133 days with sotorasib and adagrasib, respectively. Where grade of AST and ALT elevations differed, the maximum grade is reported. ^aDay 0 represents the baseline between treatment history and initiation of adagrasib treatment and is also day 1 of adagrasib treatment. The timeline numbers in blue represent the start date of each regimen relative to day 0/day 1, apart from last day of the final treatment, which represents the last day of therapy or the date of data cutoff, whichever came first. ^bALT elevation only. ^cGrade 1 ALT, G2 AST elevation. ^dAST/ALT/ALP elevation. ALP, alkaline phosphatase; BID, twice daily; G, grade; NE, not evaluable; PD, progressive disease; PR, partial response; QD, once daily; SD, stable disease.

Patient 1

Patient 1 had CNS metastases at diagnosis and received six regimens before adagrasib (Fig 1A). Sotorasib was associated with a BOR of partial response (PR) with second-line treatment. Second-line treatment with sotorasib (960 mg once daily) was interrupted for 35 days because of grade 3 AST/ALT elevations of 15 days duration and restarted at a lower dosage (240 mg once daily). The 240 mg dose of sotorasib was administered for 7 days then discontinued because of grade 2 AST/ALT elevations. Fifth-line treatment with sotorasib was at a dosage of 480 mg once daily for 6 days before discontinuation because of grade 1 AST/ALT elevations. The patient initiated seventh-line adagrasib (600 mg twice daily), which was ongoing at the time of data collection. The duration between discontinuation of sotorasib treatment and initiation of adagrasib treatment was 65 days. BOR at 172 days of treatment with adagrasib was PR. The patient experienced two grade 1 TRAEs with adagrasib (diarrhea and dyspnea) and a grade 2 TRAE of nausea/vomiting, all occurring on the first day of adagrasib treatment. TRAEs were resolved with prochlorperazine (nausea and vomiting) and loperamide (diarrhea). At data cutoff, the patient was alive and stable, with normal levels of AST/ALT that were maintained throughout adagrasib treatment.

Patient 2

Patient 2 had asymptomatic, stable CNS metastases at diagnosis and received two regimens before adagrasib (Fig 1B). Total DOT with sotorasib was 46 days with a BOR of stable disease (SD). Treatment with sotorasib (initiated at 960 mg once daily) was interrupted twice because of treatment-related grade 3 AST/ALT elevations; this was resolved by sotorasib interruption for 8 days, followed by dose reduction to 480 mg once daily, with a subsequent interruption for 15 days and dose reduction to 240 mg once daily. The patient also experienced grade 2 fatigue (ongoing despite dose reduction to 240 mg once daily) and ongoing grade 1 diarrhea. All three events were considered treatment related, and the patient ultimately discontinued sotorasib because of grade 3 AST/ALT elevation. Sixteen days after discontinuation of sotorasib, the patient began adagrasib treatment (600 mg twice daily, permanently reduced to 400 mg twice daily after 83 days), which is ongoing. While on adagrasib, the patient experienced treatment-related grade 2 diarrhea after 16 days, which was managed with loperamide and reduced to grade 1 after 7 days. The patient also experienced treatment-related grade 1 creatinine increase after 42 days, which remained unresolved despite aggressive fluid hydration. The adagrasib dose was reduced to 400 mg twice daily after 83 days, but both diarrhea and increased creatinine levels remain ongoing with supportive care at the time of data cutoff. BOR at 98 days of treatment with adagrasib was SD. At the time of data collection, the patient was alive and stable.

Patient 3

Patient 3 had recurrent metastatic lung adenocarcinoma and had received three prior systemic regimens, before initiating fourth-line treatment with adagrasib (Fig 1C). The total DOT with sotorasib was 70 days with a BOR of SD. The patient experienced treatment-related grade 3 AST/ALT increase with 960 mg once daily sotorasib, which led to treatment interruption followed by sequential dose reductions (to 480 mg once daily and 240 mg once daily). Sotorasib was interrupted for 36 days because of grade 3 AST/ALT elevation and subsequent diarrhea (with a possible contribution of palliative radiotherapy to the sacrum for growing bone metastasis while sotorasib was interrupted) which necessitated emergency room treatment with loperamide. The patient experienced severe constipation because of loperamide overuse and had a subsequent emergency room visit. Rechallenge with sotorasib at 240 mg once daily immediately led to AST/ALT elevations (grade 2), and the drug was discontinued. One cycle of docetaxel was administered as third-line therapy, but the patient experienced immediate progression of subcutaneous metastases. The patient then initiated adagrasib (37 days after sotorasib) as fourth-line treatment (600 mg twice daily). The dose of adagrasib was reduced to 400 mg twice daily after 43 days because of diarrhea and constipation (after progression to grade 3 22 days after adagrasib initiation). The patient experienced one additional episode of treatment-related diarrhea that progressed to grade 3, which quickly resolved with loperamide. Of note, the AST/ALT elevations did not recur on adagrasib. The total DOT was 138 days and BOR was SD. At the time of data collection, the patient was alive and stable.

Patient 4

Patient 4 had received two prior regimens before starting third-line treatment with adagrasib (Fig 1D). The total DOT with sotorasib was 160 days with a BOR of SD. After 91 days at 960 mg once daily, the sotorasib dosage was reduced to 480 mg once daily because of treatment-related grade 3 AST/ALT elevation. The patient also experienced grade 2 diarrhea and grade 2 myalgia. Treatment and management strategies for TRAEs included a hepatology referral and testing for hepatitis, alcohol avoidance, and medication reconciliation. Sotorasib was subsequently discontinued because of hepatotoxicity. The patient then initiated adagrasib (600 mg twice daily) when liver function tests returned to grade 1 (24 days after discontinuation of sotorasib). On adagrasib, the patient experienced treatment-related grade 1 diarrhea (treated with diet and loperamide) and treatment-related grade 2 fatigue; both events were ongoing at the time of data collection. The patient also experienced grade 2 decreased appetite which improved to grade 1 after 2 months. All TRAEs were first reported 21 days after treatment with adagrasib began; none required dose reduction. BOR at 110 days of treatment with adagrasib was SD. At the time of data collection, the patient was alive and stable.

Patient 5

Patient 5 had received four regimens before initiating fifth-line adagrasib (Fig 1E). The total DOT with second-line sotorasib was 57 days with a BOR of PR. After 49 days of treatment with sotorasib (960 mg once daily), the dosage was held for 30 days because of treatment-related grade 3 AST/ALT/alkaline phosphatase (ALP) elevations then restarted at a reduced dose of 480 mg once daily after complete resolution of elevated AST/ALT, and ALP elevation was reduced to grade 1. Sotorasib at the 480 mg dose was administered for 8 days before treatment was permanently discontinued because of recurrent hepatotoxicity. The patient initiated adagrasib (600 mg twice daily) 176 days after sotorasib. No hepatotoxicity-related TRAEs were experienced by the patient while on adagrasib; however, adagrasib was eventually discontinued because of progressive disease (PD). The DOT with adagrasib was 133 days with a BOR of PR. At the time of data collection, the patient had died.

Patients From KRYSTAL-1

Twelve patients from a phase Ib cohort of the KRYSTAL-1 study were identified as having received sotorasib before adagrasib, three of whom transitioned because of hepatotoxicity. Data for these patients are presented in Table 1 (patients 6-8). Patient treatment journeys, dosages, and responses are summarized in Figure 2; individual patient narratives are captured below.

FIG 2.

Patient treatment journeys and responses with sotorasib and adagrasib treatment in patients from the KRYSTAL-1 study.^a (A) Patient 6 received adagrasib 23 days after sotorasib discontinuation. The total duration of treatment was 51 days and 95 days with sotorasib and adagrasib, respectively. (B) Patient 7 received adagrasib 86 days after sotorasib discontinuation. The total duration of treatment was 59 days and 177 days with sotorasib and adagrasib, respectively. (C) Patient 8 received adagrasib 64 days after sotorasib discontinuation. The total duration of treatment was 29 days and 133 days with sotorasib and adagrasib, respectively. Where grade of AST and ALT elevations differed, the maximum grade is reported. ^aDay 0 represents the baseline between treatment history and initiation of adagrasib treatment and is also day 1 of adagrasib treatment. The timeline numbers in blue represent the start date of each regimen relative to day 0/day 1, apart from last day of the final treatment, which represents the last day of therapy or the date of data cutoff, whichever came first. ^bALT elevation. ^cEvent ongoing. BID, twice daily; G, grade; NE, not evaluable; PD, progressive disease; PR, partial response; QD, once daily; SD, stable disease.

Patient 6

Patient 6 had received two regimens before initiating treatment with adagrasib (Fig 2A). Second-line treatment with sotorasib (960 mg once daily) was associated with a BOR of PD and was interrupted and dose reduced twice (480 mg once daily, 240 mg once daily) and eventually discontinued because of repeat episodes of grade 3 AST/ALT elevation. The interval between discontinuation of sotorasib treatment and initiation of adagrasib treatment was 21 days. The patient began treatment with adagrasib (600 mg twice daily) which continued for 95 days before disease progression after a BOR of SD. During adagrasib treatment, the patient experienced AST/ALT elevations and blood creatine phosphokinase elevation that peaked at grade 3; all of these TRAEs resolved after dose interruption and reduction to 600 mg once daily after 27 days. At the time of data collection, the patient had died.

Patient 7

Patient 7 had CNS metastases at diagnosis and had received two regimens before initiating treatment with adagrasib (Fig 2B). The BOR to second-line sotorasib was not evaluable (NE) owing to the patient discontinuing treatment because of grade 3 AST/ALT elevations. The interval between discontinuation of sotorasib treatment and initiation of adagrasib treatment was 85 days. The patient began treatment with adagrasib (600 mg twice daily) with a treatment duration of 177 days and a BOR of SD. On adagrasib, the patient experienced grade 1 TRAEs of AST/ALT and ALP elevations. The TRAEs of AST/ALT elevations resolved spontaneously after one abnormal value; however, grade 1 ALP increase persisted during treatment. At the time of data collection, the patient was alive.

Patient 8

Patient 8 had received two regimens before initiating treatment with adagrasib (Fig 2C). The BOR to second-line sotorasib was NE owing to the patient discontinuing treatment because of grade 3 AST/ALT elevations. Dose interruption was sufficient to resolve the grade 3 AST/ALT elevations; however, the patient entered the KRYSTAL-1 study instead of resuming sotorasib. The interval between discontinuation of sotorasib and initiation of adagrasib treatment was 63 days. The patient began treatment with adagrasib (600 mg twice daily) with a treatment duration of 133 days and a BOR of SD. The patient experienced no hepatic toxicity or grade 3 TRAEs with adagrasib with only grade 1 maculopapular rash and grade 1 fatigue observed. At the time of data collection, the patient had died.

DISCUSSION

All five patients from real-world clinical practice reported here experienced severe hepatotoxicity with sotorasib (initiated 19-64 days after CPI) that led to treatment discontinuation; none experienced treatment-related hepatotoxicity with subsequent adagrasib. Additionally, 12 patients from KRYSTAL-1 had prior sotorasib, with three experiencing severe sotorasib-related hepatotoxicity; all three had initiated sotorasib within 31 days of CPI. Of these three, two had hepatotoxicity with adagrasib; neither required steroid treatment for event resolution. One patient experienced transient elevations of AST/ALT (maximum severity grade 3), which resolved with therapy interruption and dose reduction. The second patient experienced transient elevations of AST/ALT and ALP; all events were grade 1 with only ALP elevation ongoing at the time of data collection. Most (n = 7/8) of the patients reported here received sotorasib within 60 days of pembrolizumab. A recent retrospective review of 31 patients reported a greater risk of hepatotoxicity among those who received sotorasib within 90 days of CPI (75% within 30 days [n = 3/4]; and 64% within 90 days [n = 7/11]) versus patients who received sotorasib >90 days after a CPI (n = 0/13); thus, it is possible that sotorasib might be safely administered after a CPI if the interval between treatments is sufficiently long.¹⁸ Patients in this study received prior pembrolizumab, per treatment guidelines¹⁹; therefore, it is not possible to ascertain whether hepatotoxicity with sotorasib is an anti–PD-1/PD-L1 class effect or specific to pembrolizumab. In a phase Ib study (CodeBreaK 100/101), somewhat lower rates of grade 3-4 hepatotoxicity were observed in patients treated with sotorasib concurrently with atezolizumab compared with patients receiving concurrent pembrolizumab (60% v 79%, n = 6/10 and n = 15/19, respectively).¹³ However, this study had a small number of participants and insufficient statistical power to draw conclusions.¹³ Studies are ongoing to investigate adagrasib in combination with other CPIs including nivolumab and durvalumab (ClinicalTrials.gov identifier: NCT05472623 and NCT05848843).

Available data suggest that adagrasib has a distinct hepatotoxicity profile from that of sotorasib and that adagrasib is more easily combined with CPIs either sequentially or concurrently. In cohort A of KRYSTAL-1 (N = 116), 4.3% and 3.4% of patients experienced treatment-related grade ≥3 increased ALT or AST, respectively; rates of treatment-related grade 1/2 increases were 23.3% for ALT and 21.6% for AST. Elevations of AST and ALT resolved quickly, with a median time to resolution of 1.7 weeks (range, 0.3-15.1)¹⁵; only two patients required steroids for event resolution.¹⁸ One patient, who had treatment-related AST/ALT elevations, discontinued because of hepatotoxicity.¹⁵ In a post hoc exploratory analysis of 12 patients who initiated adagrasib within 30 days of CPI, none had treatment-related grade ≥3 hepatotoxicity.¹⁶ Preliminary data (8.7 months follow-up) from the phase II KRYSTAL-7 study (N = 148) showed that concurrent administration of a lower dose of adagrasib (400 mg twice daily) plus pembrolizumab (200 mg intravenous once every 3 weeks) in treatment-naïve patients with KRAS^G12C-mutated NSCLC had a manageable safety profile, consistent with either agent as monotherapy and a low rate of TRAEs leading to discontinuation.¹⁷ Liver-related TRAEs were predominantly low grade and occurred early in treatment, with elevations of ALT and AST occurring in 38% and 32% of patients, respectively.¹⁷ Twenty-four (16%) patients had grade ≥3 treatment-related AST/ALT increases with 10 receiving concomitant steroids. Most patients resumed the combination; four resumed adagrasib only, and none resumed pembrolizumab only. Three patients had recurrence of any grade treatment-related AST/ALT increase after resuming therapy. No patients discontinued both drugs because of AST/ALT increases or hepatic-related TRAEs.¹⁷ The ongoing KRYSTAL-7 (phase III) and KRYSTAL-17 (phase II) trials of adagrasib (400 mg twice daily) plus pembrolizumab-based therapy in the first-line setting across various PD-L1 expression levels will provide further data on rates, timing, and management of hepatotoxicity events with concurrent CPIs and adagrasib therapy.

Reported differences in treatment-related hepatotoxicity between adagrasib and sotorasib highlight that, while drugs within a class modulate the same target, not all effects are class effects; the spectrum of off-target events may differ between agents. Pharmacokinetics (PK) and chemical properties of adagrasib and sotorasib may partially explain the differentiated toxicity profiles observed. Adagrasib was chosen for clinical development partly because it has optimized binding affinity for KRAS^G12C within the switch-II pocket, which could limit binding to non-KRAS^G12C cysteines.²⁰ Furthermore, adagrasib PK demonstrate low peak-to-trough variability, avoiding a high peak concentration (C_max) and thereby potentially limiting any off-target activity.^20,21 By contrast, sotorasib exhibits high off-target cysteine reactivity and numerous off-target binding sites.²² High cysteine reactivity may also lead to the production of immunogenic non-specific cysteine adducts,²³ resulting in T-cell–mediated autoimmune responses in target organs such as the liver. Sotorasib also demonstrates a high C_max shortly after administration, potentially contributing to off-target activity, along with non–dose-dependent PK that may limit the effectiveness of measures to reduce off-target cysteine reactivity by use of lower doses.^1,24

This current case series is limited by the small number of patients for whom data were available. Additionally, the use of real-world evidence may be associated with confounding factors unaccounted for and/or recall bias. Three patients in this study received therapies between sotorasib and adagrasib and thus had a longer interval from prior CPI. Evaluation of the safety and tolerability of sequential adagrasib in real-world and clinical trial patients who experienced hepatotoxicity with sotorasib suggests that off-target effects of these two KRAS^G12C inhibitors may be differentiated and not a class effect. These differences may be used to inform clinical decisions when choosing the initial KRAS^G12C inhibitor if the patient has recently discontinued a CPI or if the patient experiences intolerable hepatotoxicity on sotorasib. In the present case series, most patients who discontinued sotorasib because of hepatotoxicity did not have hepatotoxicity with adagrasib. This, together with more general reports of hepatotoxicity from CodeBreaK 200 and KRYSTAL-1, plus preliminary findings from KRYSTAL-7, indicates that adagrasib is a feasible option where hepatotoxicity is a concern.

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 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 regards to data sharing collaborations with Mirati, please email us at medinfo@mirati.com.

AUTHOR CONTRIBUTIONS

Conception and design: Jia Luo, Narjust Florez, Yanyan Lou, Patrick C. Ma, Alexander I. Spira, Debra Ryan, Hatim Husain

Provision of study materials or patients: Jia Luo, Yanyan Lou, Patrick C. Ma, Alexander I. Spira, Hatim Husain, Narjust Florez

Collection and assembly of data: Jia Luo, Narjust Florez, Yanyan Lou, Kevin Lu, Patrick C. Ma, Alexander I. Spira, Debra Ryan, Hatim Husain

Data analysis and interpretation: Jia Luo, Narjust Florez, Anjali Donnelly, Yanyan Lou, Patrick C. Ma, Alexander I. Spira, Debra Ryan, Hatim Husain

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

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/po/author-center.

Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments).