A case report of acute hepatic and renal failure associated with savolitinib treatment in advanced lung adenocarcinoma

Introduction

Lung cancer has been a predominant cancer in China in recent decades, with the population estimated to reach 1.44 billion in 2020 and continuing to rise, thereby imposing a significant burden on families and society (1). Traditionally, chemotherapy has served as the mainstay treatment for this disease; subsequent advancements have introduced molecular targeted therapies and immune checkpoint inhibitors, which provide more personalized treatment options. For patients harboring specific driver mutations, such as those responsive to EGFR tyrosine kinase inhibitors, oral targeted therapies are recommended by most guidelines and expert consensus due to their efficacy and patient compliance.

Mesenchymal-epithelial transition factor (MET) is a proto-oncogene that encodes the MET receptor tyrosine kinase, which binds to hepatocyte growth factor (HGF) as a ligand and activates downstream signaling pathways that promote cell proliferation, inhibit apoptosis, and facilitate migration. MET alterations include amplification, mutations, gene fusion, with MET exon 14 skipping alteration being the most commonly reported mutation type (2,3). Loss of MET exon 14 leads to the inhibition of ubiquitination and degradation of the MET receptor, which can enhance and sustain activation of MET signaling and ultimately facilitate cancer progression (4,5). MET exon 14 skipping alteration occurs in approximately 3–4% of non-small cell lung cancer (NSCLC) cases (6) and in 13–22% of pulmonary sarcomatoid carcinoma cases (3). Traditional chemotherapy and immune checkpoint inhibitors have demonstrated limited efficacy in these patients. The median overall survival for patients with MET exon 14 skipping alterations in NSCLC treated with chemotherapy is reported to be 6.7 months (7). Similarly unsatisfactory results have been observed with immunotherapy, where the objective response rate (ORR) was 17% [95% confidence interval (CI): 6–36%] and the median progression-free survival (PFS) was 1.9 months (95% CI: 1.7–2.7) (8). In contrast, selective oral MET tyrosine kinase inhibitors, including savolitinib, provide clinically benefits for both treatment-naïve and pretreated NSCLC patients carrying the MET exon 14 skipping alteration (4,5,9). Savolitinib has demonstrated promising therapeutic benefits in these patients, with median PFS reaching 6.8 months and median overall survival reaching 12.5 months (10). Notably, the median time to response was 1.4 months, indicating a rapid onset of action.

Savolitinib has demonstrated a favorable safety profile in clinical studies, primarily characterized by mild to moderate adverse events (AEs) that frequently resolved with dose adjustments or treatment discontinuation (10-14). The most commonly reported treatment-related AEs in NSCLC patients were peripheral edema (54%), nausea (46%), and elevated alanine aminotransferase (ALT) (39%). The incidence of grade 3 or higher AEs was observed in 46% of patients, with elevated aspartate aminotransferase (AST) representing the most common severe AE at 13%. One patient experienced a treatment-related fatal serious AE (SAE) due to tumor lysis syndrome (10); however, no cases of pulmonary interstitial pneumonia or interstitial lung disease were reported. Given the promising efficacy and manageable safety profile of savolitinib, it received approval from the National Medical Products Administration of China in June 2021 for the treatment of surgically unresectable or metastatic NSCLC patients with MET exon 14-skipping alterations who cannot tolerate platinum-based chemotherapy. However, in this report, we describe a case of fatal hepatic and renal failure associated with savolitinib in a patient with NSCLC harboring a primary MET exon 14 mutation. We present this article in accordance with the CARE reporting checklist (15) (available at https://acr.amegroups.com/article/view/10.21037/acr-24-156/rc).

Case presentation

A 62-year-old woman with a body mass index (BMI) of 19.53 kg/m² presented to a local hospital primarily complaining of a cough. She was initially treated with intravenous cefazolin, but her symptoms did not improve, leading to her referral to our hospital in June 2022. A computed tomography (CT) scan revealed significant pleural effusions in the right pleural cavity, necessitating her hospitalization.

She had no history of smoking, hypertension, or diabetes, and her baseline liver function tests, including bilirubin, transaminases, and coagulation tests, showed no abnormal findings (see Table 1 for baseline laboratory data). Pleural drainage alleviated her cough; however, the etiology remained undetermined following analysis of the pleural fluid. An enhanced CT scan was performed following pleural fluid drainage, revealing enlarged mediastinal lymph nodes and a mass in the upper right lobe. Pathological examination of a transbronchial lung biopsy (TBLB) confirmed a diagnosis of lung adenocarcinoma. Subsequently, staging evaluation and tumor genetic testing were conducted, leading to the diagnosis of advanced lung adenocarcinoma (T4N1M1a, IVa stage). Tumor genetic testing (next-generation sequencing) identified mutations in six genes, including MET exon 14 skipping alterations (see Table S1 for a summary of gene mutations), for which savolitinib was the only available targeted therapy option. The patient and her family opted for treatment with savolitinib at a dosage of 600 mg once daily, and she was discharged on July 1st, following an intrapleural injection of recombinant human endostatin.

All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

During outpatient visits on July 28th, the patient reported weakness; however, biochemical tests indicated normal serum potassium and liver function (see Figure 1 for changes in important biochemical tests). On August 8th, she experienced vomiting and decreased oral intake. A week later, she became irritable and restless, prompting her admission to our hospital on August 15th (see figure timeline of the progression of this case). Upon admission, her vital signs were as follows: body temperature 36.5 ℃, heart rate of 130–140 beats/min, respiratory rate of approximately 30 breaths/min, and blood pressure of 110/54 mmHg. She presented in a coma with icteric sclera and skin, rapid and deep breathing, and a negative Babinski sign. Biochemical tests revealed elevated bile pigments, blood ammonia, and transaminase levels, along with azotemia and hyperkalemia. Additionally, prolonged prothrombin time (PT), activated partial thromboplastin time (APTT), and reduced fibrinogen levels were noted. Blood gas analysis indicated severe lactic acidosis and respiratory alkalosis (see Table 2 for biochemical tests from the second admission). Treatment included fasting, mask oxygen inhalation, lactulose via an oro-nasogastric feeding tube, intravenous liver-protective agents, and antibiotics (piperacillin-tazobactam). Artificial liver support was recommended but was rejected by her family. Fresh frozen plasma was administered, and a parenteral nutrition regimen containing branched-chain amino acids was initiated following consultations with gastroenterology and nutrition. Despite continuous intravenous fluids and the administration of noradrenaline, her blood pressure gradually decreased to 85–90/60–50 mmHg. However, her level of consciousness did not recover, and renal function continued to deteriorate, manifesting as anuria and increasing serum creatinine levels. Despite the initiation of continuous renal replacement therapy (CRRT), her condition did not improve, and she succumbed to her illness two days after admission on August 17th.

Figure 1 Changes in important biochemical tests. ALT, alanine aminotransferase; APTT, active partial prothrombin time; AST, aspartate aminotransferase; BUN, blood urea nitrogen; CB, conjugated bilirubin; Cr, creatinine; PT, prothrombin time; UCB, unconjugated bilirubin.

During this admission, essential tests were conducted to aid in the differential diagnosis. Antibodies associated with autoimmune hepatitis and viral hepatitis were negative, and a liver ultrasound revealed a normal-sized liver without gallbladder or pigmented bile duct stones. Renal ultrasound demonstrated enhanced echogenicity in the renal cortex.

Discussion

Savolitinib, a novel agent targeting MET exon 14 skipping alterations, has demonstrated efficacy in clinical trials for NSCLC and renal cell carcinoma (RCC) (10,16). Published studies have generally reported acceptable safety profiles for savolitinib, with most AEs being of grade 1 or 2. Notably, grade ≥3 elevations in aminotransferases (ALT and AST) have been reported; however, severe hepatic failure and renal failure in a patient with advanced lung adenocarcinoma induced by the MET inhibitor savolitinib have not yet been reported. This report highlights a case of acute hepatic failure and renal failure associated with savolitinib, which has been infrequently documented. The patient exhibited typical signs of acute hepatic failure, including reduced appetite, jaundice, elevated transaminases, and prolonged APTT and PT, as well as decreased fibrinogen levels. The onset of unconsciousness and elevated blood ammonia levels suggested hepatic encephalopathy.

In China, the hepatitis B virus is the primary cause of liver disease, followed by drug-induced liver injury, other hepatitis viruses, autoimmune hepatitis, and alcohol consumption (17). However, the patient had no history of hepatitis, did not consume alcohol, and tested negative for hepatitis B surface antigen (HBsAg) as well as autoimmune hepatitis antibodies. Furthermore, liver function tests were normal prior to the initiation of savolitinib treatment, indicating that acute hepatic failure was likely induced by savolitinib. The underlying mechanisms of liver injury may involve the HGF/MET pathway, which is critical not only for cancer cell proliferation but also for normal hepatocyte growth (18).

In addition to acute hepatic failure, the patient developed renal failure, evident from the rapid increase in serum creatinine levels following savolitinib administration, despite normal levels prior to treatment initiation. The association of savolitinib with acute renal failure is plausible.

Compared with the first administration, ALT and AST levels were elevated in the first follow-up after discharge, although they remained within the normal range. In the second follow-up one week later, severe hepatic failure was observed, indicating rapid progression of the dysfunction. Currently, the risk factors for these SAEs remain unclear. Interestingly, lower rates of grade ≥3 AEs were observed with a 400 mg dose compared to a 600 mg dose (12). Given the potential severe consequences, clinicians must remain vigilant regarding possible adverse reactions. It is crucial to monitor liver and kidney function when prescribing savolitinib to facilitate the early diagnosis and treatment of potentially fatal adverse reactions.

Conclusions

This case underscores the necessity of monitoring hepatic and renal function in patients treated with savolitinib, enabling the early detection and intervention of potentially fatal adverse effects.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://acr.amegroups.com/article/view/10.21037/acr-24-156/rc

Peer Review File: Available at https://acr.amegroups.com/article/view/10.21037/acr-24-156/prf

Funding: This work was supported by the Science Pre-research Foundation of the Second Affiliated Hospital of Soochow University (grant number SDFEYJC2329).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://acr.amegroups.com/article/view/10.21037/acr-24-156/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Gao S, Li N, Wang S, et al. Lung Cancer in People’s Republic of China. J Thorac Oncol 2020;15:1567-76. [Crossref] [PubMed]
2. Davies KD, Lomboy A, Lawrence CA, et al. DNA-Based versus RNA-Based Detection of MET Exon 14 Skipping Events in Lung Cancer. J Thorac Oncol 2019;14:737-41. [Crossref] [PubMed]
3. Liu X, Jia Y, Stoopler MB, et al. Next-Generation Sequencing of Pulmonary Sarcomatoid Carcinoma Reveals High Frequency of Actionable MET Gene Mutations. J Clin Oncol 2016;34:794-802. [Crossref] [PubMed]
4. Makimoto G. Diagnosis and treatment of non-small cell lung cancer (NSCLC) harboring MET Ex14 skipping: have we met the desired drug? Transl Lung Cancer Res 2024;13:1438-43. [Crossref] [PubMed]
5. Dempke WCM, Reuther S, Hamid Z, et al. Oncogene alterations in non-small cell lung cancer-have we MET a new target? Transl Lung Cancer Res 2022;11:1977-81. [Crossref] [PubMed]
6. Guo R, Luo J, Chang J, et al. MET-dependent solid tumours - molecular diagnosis and targeted therapy. Nat Rev Clin Oncol 2020;17:569-87. [Crossref] [PubMed]
7. Gow CH, Hsieh MS, Wu SG, et al. A comprehensive analysis of clinical outcomes in lung cancer patients harboring a MET exon 14 skipping mutation compared to other driver mutations in an East Asian population. Lung Cancer 2017;103:82-9. [Crossref] [PubMed]
8. Sabari JK, Leonardi GC, Shu CA, et al. PD-L1 expression, tumor mutational burden, and response to immunotherapy in patients with MET exon 14 altered lung cancers. Ann Oncol 2018;29:2085-91. [Crossref] [PubMed]
9. Jørgensen JT, Urbanska EM, Mollerup J. MET targeted therapy in non-small cell lung cancer patients with MET exon 14-skipping mutations. Transl Lung Cancer Res 2024;13:940-6. [Crossref] [PubMed]
10. Lu S, Fang J, Li X, et al. Once-daily savolitinib in Chinese patients with pulmonary sarcomatoid carcinomas and other non-small-cell lung cancers harbouring MET exon 14 skipping alterations: a multicentre, single-arm, open-label, phase 2 study. Lancet Respir Med 2021;9:1154-64. [Crossref] [PubMed]
11. Yang JJ, Fang J, Shu YQ, et al. A phase Ib study of the highly selective MET-TKI savolitinib plus gefitinib in patients with EGFR-mutated, MET-amplified advanced non-small-cell lung cancer. Invest New Drugs 2021;39:477-87. [Crossref] [PubMed]
12. Yoh K, Hirashima T, Saka H, et al. Savolitinib ± Osimertinib in Japanese Patients with Advanced Solid Malignancies or EGFRm NSCLC: Ph1b TATTON Part C. Target Oncol 2021;16:339-55. [Crossref] [PubMed]
13. Gan HK, Millward M, Hua Y, et al. First-in-Human Phase I Study of the Selective MET Inhibitor, Savolitinib, in Patients with Advanced Solid Tumors: Safety, Pharmacokinetics, and Antitumor Activity. Clin Cancer Res 2019;25:4924-32. [Crossref] [PubMed]
14. Choueiri TK, Plimack E, Arkenau HT, et al. Biomarker-Based Phase II Trial of Savolitinib in Patients With Advanced Papillary Renal Cell Cancer. J Clin Oncol 2017;35:2993-3001. [Crossref] [PubMed]
15. Riley DS, Barber MS, Kienle GS, et al. CARE guidelines for case reports: explanation and elaboration document. J Clin Epidemiol 2017;89:218-35. [Crossref] [PubMed]
16. Choueiri TK, Heng DYC, Lee JL, et al. Efficacy of Savolitinib vs Sunitinib in Patients With MET-Driven Papillary Renal Cell Carcinoma: The SAVOIR Phase 3 Randomized Clinical Trial. JAMA Oncol 2020;6:1247-55. Erratum in: JAMA Oncol 20201;6:1473. [Crossref] [PubMed]
17. Liver Failure and Artificial Liver Group, Chinese Society of Infectious Diseases, Chinese Medical Association. Severe Liver Disease and Artificial Liver Group, Chinese Society of Hepatology, Chinese Medical Association. Zhonghua Gan Zang Bing Za Zhi 2019;27:18-26.
18. Matsumoto K, Funakoshi H, Takahashi H, et al. HGF-Met Pathway in Regeneration and Drug Discovery. Biomedicines 2014;2:275-300. [Crossref] [PubMed]