Prolonged Cancer Control With Adagrasib in Patients With Metastatic, KRAS^G12C-Mutated NSCLC After Sotorasib-Induced Hepatotoxicity: A Case Report

Abstract

Both sotorasib and adagrasib are approved for use in metastatic KRAS^G12C-mutated NSCLC after cancer progression on chemotherapy and immunotherapy. Hepatoxicity is a commonly encountered adverse effect of both agents, and little data exists about the safety of sequential use of these agents when hepatotoxicity is encountered. In this case report, we describe a patient who developed recurrent hepatotoxicity with sotorasib and was able to switch to adagrasib without hepatotoxicity and subsequently experienced a prolonged cancer response. We also describe a previously unreported adagrasib adverse effect of photoinduced skin hyperpigmentation.

Introduction

KRAS is known to be the most frequently mutated RAS protooncogene isoform, with up to 30% of all human cancers carrying gain-of-function mutations.¹ The specific KRAS^G12C mutation is found in about 13% of NSCLC and 3% of colorectal cancers, and is associated with worse clinical outcomes.^2,3 Existing KRAS^G12C inhibitors lock KRAS into its inactive guanosine diphosphate–bound confirmation.^4,5 The KRAS^G12C inhibitors sotorasib and adagrasib were both recently approved by the U.S. Food and Drug Administration to target KRAS^G12C-mutated metastatic NSCLC after progression on chemoimmunotherapy. The approval was on the basis of data from phase 2 data exhibiting response rates between 37% to 43% and duration of response between 8.5 months and 11.1 months.^6,7 Hepatotoxicity is relatively common with these agents, with treatment-related elevations in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) occurring in up to 15% of patients and dose modification or discontinuation because of adverse events in up to 7% of patients.^6,7 Emerging data revealed high rates of hepatotoxicity with concurrent KRAS^G12C therapy (particularly sotorasib) and immune checkpoint inhibitors (ICI).⁸ Regarding sequential ICI and KRAS^G12C inhibitor use, limited retrospective data suggest the highest risk of hepatotoxicity from sotorasib is within the first 90 days of ICI discontinuation.^9,10 For patients who develop severe hepatotoxicity on one KRAS^G12C inhibitor, it is currently unclear whether the other KRAS^G12C inhibitor can safely be used. If safe, this strategy could afford patients prolonged cancer control.

Case Presentation

The patient is a 52-year-old woman who initially presented to her primary care provider with a cough and night sweats. At presentation, she had a 28-pack-year tobacco smoking history. She had recently quit smoking. She had no known significant radon exposure. Her father had died of lung cancer and had a history of tobacco use. A computed tomography (CT) scan was obtained, which revealed right upper lobe nodules, right-sided mediastinal, cervical, and axillary lymph node enlargement, and a contralateral nodule in the left lower lobe. A cervical lymph node biopsy was performed and the patient was diagnosed with lung adenocarcinoma; subsequent positron emission tomography–CT confirmed the previously listed sites of disease. Brain magnetic resonance imaging (MRI) did not reveal any brain metastases at diagnosis. At diagnosis, her stage was T3N3M1c (stage IVB). Testing of the lymph node sample revealed a programmed death-ligand 1 tumor proportion score of 0% and a KRAS^G12C mutation. She was subsequently started on chemoimmunotherapy with carboplatin, pemetrexed, and pembrolizumab obtaining a partial response, and she proceeded to maintenance pemetrexed and pembrolizumab.

A year later, CT revealed two new right lung nodules and an increase in bilateral axillary nodes. The patient was started on sotorasib 960 mg orally daily approximately six weeks after her last cycle of chemoimmunotherapy. However, 6 weeks after starting sotorasib, her AST and ALT increased to 356 U/L and 518 U/L. The hepatitis virus panel was negative and imaging did not reveal any evidence of liver metastases or biliary obstruction. Thus, the transaminitis was attributed to sotorasib, and the drug was withheld for the next 2 months. Steroids were not administered during this time. Her liver function tests (LFTs) subsequently normalized (Fig. 1). Trials of sotorasib 480 mg and 240 mg were initiated, but LFTs increased each time, and sotorasib was ultimately discontinued. Notably, the patient’s CT revealed improvement in disease throughout the sotorasib trials.

Figure 1.

ALT (U/L) and AST (U/L) trend of patient from initial sotorasib treatment to present. Significant elevation in LFTs were exhibited after sotorasib treatment was trialed at 960 mg, 480 mg, and 240 mg at multiple time points, including after prolonged break. LFTs returned to normal after sotorasib was discontinued with subsequent tolerance of adagrasib as illustrated by the lack of LFT elevation. ALT, alanine aminotransferase; AST, aspartate aminotransferase; BID, twice daily; LFT, liver function test.

Owing to the patient’s recurrent sotorasib-induced hepatitis, her treatment was changed to docetaxel and ramucirumab from which a partial response was achieved. The patient received 18 cycles before developing severe fatigue, generalized edema, and diarrhea approximately 14 months later. Her positron emission tomography–CT at that time revealed a new 2.8 cm hypermetabolic right upper lobe nodule along with new, hypermetabolic right cervical and left pelvic lymph nodes. Given the cancer progression, docetaxel and ramucirumab were discontinued. At that time, sotorasib was trialed again at half dosing, 480 mg daily. However, hours after starting sotorasib, the patient developed diffuse abdominal pain distension and jaundice. LFTs performed within 48 hours of initiating sotorasib exhibited grade 3 hepatotoxicity with AST 157 U/L, ALT 199 U/L, and total bilirubin 3.7 mg/dL; thus, sotorasib was permanently discontinued. Brain MRI was then obtained a month later and revealed small cortical metastases.

Given the patient’s known KRAS^G12C mutation, the oncology team initiated adagrasib at a reduced dose of 600 mg daily. The patient tolerated the initial dose without LFT elevation, and so it was increased to 400 mg twice daily. Subsequent brain MRI revealed total resolution of the previous posterior left parietal lobe lesion and decreasing ring enhancement in the previous right medial parietal cortex. Although the intracranial response was exhibited at the 400 mg twice-daily dosing of adagrasib, given the persistent disease in the right medial parietal cortex, the adagrasib dose was escalated to the full dose of 600 mg twice daily. A month later, new CT imaging revealed stable bilateral pulmonary nodules and a decreased inguinal node. After 9 months of adagrasib initiation, her brain metastases further decreased, and the extracranial disease remains controlled.

Notably, after approximately 6 weeks of full dose adagrasib, the patient experienced diffuse hyperpigmentation of the skin on sun exposure. The hyperpigmentation involved all body surfaces, thus, qualifying as grade 2, but she had no pain or psychosocial impact. Mild improvement in the hyperpigmentation was noted with reduced sun exposure, but her skin pigmentation remains darker than baseline. There were no other medication changes that occurred around the development of the hyperpigmentation and cortisol and adrenocorticotropic hormone levels were normal. Therefore, the hyperpigmentation was attributed to adagrasib. The patient declined dermatology evaluation. She has experienced grade 1 nausea and diarrhea that is well controlled with antiemetics and antidiarrheals. She has not experienced other adverse effects during treatment.

Discussion

Treatment for KRAS^G12C-mutated NSCLC now includes the irreversible KRAS^G12C inhibitors sotorasib and adagrasib. These agents have reasonable activity and adverse effect profiles, particularly in comparison to chemotherapeutic agents like docetaxel.¹¹ However, grade 3 or higher adverse events, including nausea and LFT elevation are encountered with existing KRAS^G12C inhibitors, occasionally resulting in dose reduction or drug discontinuation. There is little data on the safety of switching between KRAS^G12C inhibitors when intolerable toxicities are encountered.

The successful treatment of our patient with adagrasib after toxicity-related discontinuation of sotorasib highlights the potential to reap the benefits of treatment while avoiding recurrent toxicity by sequencing KRAS^G12C inhibitors. However, as this is a single case report, this strategy cannot be generalized as universally safe and effective. Previous reports suggest the timing of sotorasib after ICI impacts the risk of hepatotoxicity.^9,10 However, our patient experienced hepatotoxicity after both short and long intervals between ICI and sotorasib exposure, perhaps signifying that once severe sotorasib hepatotoxicity develops, the risk of recurrent hepatotoxicity is high regardless of duration of dose interruption. Existing hepatotoxicity data have led some to postulate that adagrasib is the safer and preferred option to treat KRAS^G12C-mutated NSCLC. However, sotorasib and adagrasib had nearly identical rates of grade 3 AST/ALT elevation in their registrational phase 2 trials, and it is not proven that there is an appreciably higher risk of severe hepatotoxicity in patients who receive sequential immunotherapy and sotorasib in comparison with adagrasib. Both sotorasib and adagrasib are recommended by the National Comprehensive Cancer Network as second-line therapies for metastatic KRAS^G12C-mutated NSCLC.¹² Therefore, it is likely that sotorasib will continue to be used in clinical practice, and this case report can help inform clinical decision-making when sotorasib-induced hepatotoxicity is encountered.

Adagrasib has previously exhibited intracranial control in patients with previously treated brain metastases, and this case further signify the intracranial activity of adagrasib, allowing the patient to defer brain radiation.¹³ In addition, diffuse hyperpigmentation on sun exposure has not previously been reported as an adverse effect of adagrasib, though it was evident in this patient, and is pertinent to consider for those patients who may be averse to this potential. The hyperpigmentation was partially reversible by reducing sun exposure; however, the patient’s skin pigmentation did not return to baseline while receiving adagrasib.

Conclusions

As illustrated in this case report, the use of adagrasib after severe sotorasib-induced hepatotoxicity was both safe and effective, resulting in prolonged intra-and extracranial cancer control in a patient with metastatic KRAS^G12C-mutated NSCLC. Adagrasib also induced previously unreported skin hyperpigmentation on sun exposure. Sequencing KRAS^G12C inhibitors when significant toxicity is encountered may be a feasible strategy that warrants further exploration.

CRediT Authorship Contribution Statement

Natalie Stratton: Data Curation, Writing -Original Draft, Writing – Reviewing and Editing.

Jonathan Thompson: Conceptualization, Writing – Reviewing and Editing, Supervision.

Disclosure

The authors declare no conflict of interest.