Polyradiculitis as a Neurological Complication Associated with Adagrasib: A Case Report

Adagrasib is a novel KRAS G12C inhibitor that has demonstrated clinical activity in patients with non-small-cell lung cancer and colorectal cancer harboring this mutation [1, 2]. It is currently being evaluated in the KRYSTAL-1 study, a phase 1–2 multiple expansion cohort trial (NCT03785249). Adagrasib is generally well-tolerated. Neurological adverse events reported so far were uncommon and non-specific [1‒4]. This case report describes to our best knowledge the first patient with polyradiculitis as a neurological complication of adagrasib, which appeared to be dose-related and resolved after treatment with prednisone and dose reduction of adagrasib.

A 70-year-old woman attended our hospital with a 4-day history of severe radiating lower back pain with nausea and vomiting, without headache. She had a diagnosis of pulmonary adenocarcinoma with a solitary brain metastasis 2 years prior to the current presentation, for which she previously underwent pulmonary lobectomy, brain stereotactic radiotherapy, and chemo-immunotherapy. The biopsy from her previous pulmonary lobectomy showed a KRAS G12C mutation. Five weeks before presentation she started treatment with adagrasib in the KRYSTAL-1 study (NCT03785249). Her starting dose was 600 mg twice daily, which was reduced 2 weeks after start to 400 mg twice daily because of grade 1 blood creatinine increase (an increase from 124 μmol/L to 173 μmol/L, with recovery after dose adjustment).

The pain was located in the thoracolumbar region radiating toward the ventrolateral side of both legs. On neurological examination hypesthesia of left upper leg and bilateral reduced distal vibratory sensation were found. Deep tendon reflexes were reduced in the upper extremities and absent in lower extremities with a normal plantar reflex. Muscle strength of ankle extensors was slightly reduced on both sides, otherwise muscle strength was intact. Vital signs were normal. There were no signs of urinary or fecal incontinence.

Laboratory testing showed elevated liver enzymes (alanine aminotransferase 102 U/L, aspartate aminotransferase 102 U/L, γ-glutamyltransferase 95 U/L, alkaline phosphatase 240 U/L), infection parameters were low. MRI neuraxis showed contrast-enhancement of cauda equina (shown in Fig. 1), suspected for either inflammation or leptomeningeal metastases. There was no indication of contrast enhancement at the cervical level (shown in online suppl. Fig. 1; for all online suppl. material, see https://doi.org/10.1159/000541988). Cerebrospinal fluid analysis was performed twice with both times showing a mild pleocytosis (15 and 7 cells/μL), elevated total protein (783 and 816 mg/L) and normal glucose. Infectious causes including Varicella Zoster, Borrelia and Lues were ruled out. Cerebrospinal fluid cytology showed no atypical cells indicating metastasis.

Differential diagnosis at this point consisted of leptomeningeal metastasis or neurotoxicity of adagrasib. Adagrasib was withheld and prednisone was started at 60 mg per day and the patient was discharged. Follow-up 3 weeks later showed gradual clinical improvement and reduced contrast-enhancement of cauda equina on MRI (shown in Fig. 2), advocating for an inflammatory reaction and against leptomeningeal metastasis. Adagrasib was resumed at a lower dose (200 mg twice daily), and prednisone was tapered over a total period of 2 months.

At the 200 mg twice daily dose, the observed trough and peak plasma concentrations were 1,078 and 1,377 ng/mL, respectively, corresponding with an estimated AUC of 8,291 ng*h/mL, translating to an extrapolated AUC of 24.873 ng*h/L in the approved dose of 600 mg twice daily. As reference, the geometric mean of the AUC at the approved dose as reported by the license holder is very similar at 31.600 ng*h/L, showing that the observed exposure to adagrasib was normal and as expected for the 200 mg twice daily dose [5]. It is known that the systemic exposure required in preclinical models for adequate KRAS inhibition should be approximately 750 ng/mL to 1,750 ng/mL [5]. The observed plasma concentrations at the 200 mg dose were in this range.

At 2- and 5-month follow-up, patient showed ongoing effective tumor response and further improvement of her neurological symptoms at the 200 mg twice daily adagrasib dose. The adagrasib area under the plasma concentration time curve during a dosing interval was estimated at the 200 mg dose, by sampling a trough and peak concentration and subsequent Bayesian estimation of the AUC using the population pharmacokinetic model as reported in the FDA multidiscipline review [6].

To the best of our knowledge, this is the first case of a patient with polyradiculitis as a result of neurotoxicity of adagrasib. In previous studies, hepatotoxicity and gastrointestinal toxicity were the most common reported adverse events of adagrasib and neurological complications were uncommon and not very specific. In a phase 2 cohort of 116 patients with non-small-cell lung cancer, dizziness (20.7%), back pain (19.8%), headache (14.7%), muscular weakness (11.2%), mental status change (4.3%), delirium (3.4%), and seizure (2.6%) were reported [1]. Similar reports of neurological complications were made in cohorts with colorectal cancer or other solid tumors [2‒4]. Polyradiculitis has also not been previously reported in cohorts of other KRAS G12C inhibitors such as sotorasib and garsorasib [7‒9].

The exact pathophysiological mechanism resulting in neurotoxicity attributed to adagrasib is uncertain, and our patient’s analysis did not reveal a specific explanation. We have assumed the relationship between the polyradiculitis and adagrasib based on the timing of symptom onset in relation to the initiation of therapy and the improvement of neurological symptoms following dose adjustment, along with the exclusion of other causes. Adagrasib is recognized for its capacity to penetrate the central nervous system [4], which may be linked to the development of neurotoxicity. Although the CSF analysis did not offer specific insights into the underlying mechanism, it did show a mild pleocytosis and elevated protein levels, suggesting a mild inflammatory response.

Currently, there is practical guidance available for management of adverse events in adagrasib, specifically for the most common problems such as diarrhea, nausea, fatigue, liver enzyme or blood creatinine changes and electrocardiogram abnormalities [10]. Generally, it is advised to interrupt treatment and, if permitted, continue at a lower dose due to its dose-dependent pharmacokinetics. In our case, we additionally treated with prednisone because of a presumed auto-inflammatory underlying process.

This case report demonstrates that polyradiculitis is a potential complication of adagrasib and that symptoms may resolve after temporary treatment interruption with reintroduction at a lower dose. After the dose reduction, our patient still had an effective tumor response. In future cases with a similar presentation, we recommend to consider the same treatment strategy. Through this case report, we aim to bring attention to the possibility of this side effect, as we believe it is important to be aware of it for future patients undergoing treatment with adagrasib. The CARE checklist has been completed by the authors for this case report, attached as online supplementary material.

Written informed consent for publication of this case report and any accompanying images was obtained from the patient. Ethical approval is not required for this study in accordance with local or national guidelines.

The authors have no conflicts of interest to disclose.

No funding was received.

K.E.L. was involved in patient care, reviewed the literature, collected patient data, and prepared the manuscript. R.H. was involved in interpretation of results and prepared and revised the manuscript. J.M.M.G. was involved in patient care and revised the manuscript. M.M.H. initiated the project, was involved in patient care and revised the manuscript. All authors read and approved the final manuscript.

All data generated or analyzed during this study are included in this article and its online supplementary material files. Further inquiries can be directed to the corresponding author.