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| REVIEW ARTICLE |
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| Year : 2022 | Volume
: 5
| Issue : 1 | Page : 35-38 |
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Role of axitinib and other tyrosine kinase inhibitors in the management of metastatic renal cell carcinoma
Sagar Bhagat, Nishtha Khatri, Saiprasad Patil, Hanmant V Barkate
Global Medical Affairs, Glenmark Pharmaceuticals Ltd, Mumbai, Maharashtra, India
| Date of Submission | 26-May-2022 |
| Date of Decision | 29-Jun-2022 |
| Date of Acceptance | 11-Jul-2022 |
| Date of Web Publication | 02-Sep-2022 |
Correspondence Address:
Dr. Nishtha Khatri
Global Medical Affairs, Glenmark Pharmaceuticals Ltd, Mumbai, Maharashtra
India
 Source of Support: None, Conflict of Interest: None
DOI: 10.4103/jco.jco_5_22
The selection of chemotherapeutic agents in the management of metastatic renal cell carcinoma is a challenge as it has to strike a delicate balance between adverse effects and patient affordability based on the individual risk stratification. In this narrative review, authors have discussed about the various tyrosine kinase inhibitors available and the preference for axitinib as the first-line drug when used as a single agent or in combination with immunotherapeutic agents. This review article has been written based on a literature search of relevant articles conducted from September 2020 to December 2020 across PubMed and Google Scholar. Keywords: Axitinib, metastatic renal cell carcinoma, tyrosine kinase inhibitors
How to cite this article:
Bhagat S, Khatri N, Patil S, Barkate HV. Role of axitinib and other tyrosine kinase inhibitors in the management of metastatic renal cell carcinoma. J Curr Oncol 2022;5:35-8 |
| Background | |  |
Renal cell carcinoma (RCC) accounts for 3% of all tumors worldwide, and its incidence is increasing progressively.[1] Almost one-third of the RCC cases are diagnosed at a later stage when the tumor has already metastasized.[2] The treatment of metastatic RCC is a challenge because its management has to have an intricate balance ensuring disease control along with a good quality of life, reduced frequency of drug-related adverse events, and a reduced financial burden to the patient. The age of the patient, presence of comorbidities, extent of disease spread, and performance status of the patient are important considerations while deciding the line of treatment to be adopted. Risk stratification of the patient is the crucial step to be undertaken before deciding the therapy. The International Metastatic Renal-Cell Carcinoma Database Consortium (IMDC) is frequently used over Memorial Sloan–Kettering Cancer Center (MSKCC) because of its ease-of-use to perform risk stratification as well as for deciding the first- and second-line therapy. Risk stratification is the key step prior to the initiation of proper treatment.[3] The initial period is extremely crucial for cancer patients and needs to be monitored adequately to conclude on a clinical decision. In a country like India, financial status of the patients can play an important role in deciding the therapy administered to the patient.[4]
The volume of the disease and performance status of the patient could help in deciding the best regimen for mRCC in different patient populations. For symptomatic patients with metastatic disease (significant bleeding), nephrectomy may be done. Over the years, cytoreductive nephrectomy has remained as a cornerstone in the management of RCC with metastasis in patients with a good prognosis. Cytoreductive nephrectomy may be beneficial in favorable patients on tyrosine kinase inhibitors (TKI), whereas postoperative TKI or immunotherapy (IO) has shown an improved survival among patients.[5],[6]
The various systemic therapy options available for mRCC include inhibitors of TKI, vascular endothelial growth factor (VEGF), cytokines, mammalian target of rapamycin (mTOR), and IO.[7] The selection of monotherapy or combination therapy is dependent on the patient profile, and the choice of the chemotherapeutic agent depends on risk stratification. Single-agent TKI or a combination of TKI and IO are the preferred systemic treatment options for favorable, intermediate, and poor risk category patients with advanced RCC. Yet, there is no distinguishable mention about the use of specific TKIs as a part of individualized treatment of patients. Although axitinib is a commonly used TKI as a monotherapy as well as in combination with IO, there is no literature focusing on the well-defined positioning of axitinib. Hence, the authors of the current article decided to discuss about the various TKIs available with a special emphasis on the use of axitinib as the first-line drug when used as a single agent or in combination with immunotherapeutic agents.
| Materials and Methods | | |
This is a narrative review that evaluated the literature related to TKIs and axitinib in advanced RCC. A literature search was conducted from September 2020 to December 2020 across PubMed and Google Scholar to include all the relevant articles published pertaining to the topic of this article until December 2020.
| Treatment Options in Advanced RCC | | |
Single-agent TKI
An important question that arises is which drug should be the most preferred TKI. Although we know that sunitinib has been the gold standard in the treatment of advanced RCC, axitinib has demonstrated good response rates and has a good safety profile. One major side effect of axitinib as reported in phase III AXIS trial is the development of hypertension.[8] The dose of axitinib can be titrated based on blood pressure and is usually well-tolerated. Sorafenib can be considered for patients with financial constraints and affordability issues. Pazopanib is an easier drug to be utilized with respect to acute toxicity and numerically higher response rates when compared with sunitinib.[9] Moreover, the tolerability and quality of life with pazopanib are better than sunitinib. Cabozantinib is a TKI with well-demonstrated response rates and with a relatively tolerable safety profile compared with the other TKIs.[10] Yet, the role of axitinib cannot be undermined as axitinib can be used with no requirement for dose correction in patients with renal dysfunction and in those with high serum creatinine levels.[11]
Combination therapy with TKI
Factors such as patient profile, affordability, and drug toxicity have to be borne in mind when a combination therapy is being planned for a patient. A combination of pembrolizumab and axitinib is a good option in high-risk patients as it has a higher progression-free survival (PFS),[12] whereas a combination of nivolumab and ipilimumab can be preferred over pembrolizumab plus axitinib if the patient has less adverse prognostic factors.[13],[14] For clear-cell histology, pembrolizumab plus axitinib or a single-agent TKI can be used.[12]
In cases where there is any effusion or ascites, bevacizumab could be considered.[15] If a patient is symptomatic or has sarcomatoid histology, a combination of two IO can be advised or a combination of a TKI and an IO can be used.[16] In cases of hyperprogression or in cases where the patient does not respond quickly enough with two IOs, IO-TKI combination is preferred. In clinical practice, decisions must be taken on the basis of providing patients a good response rate, PFS, and an affordable treatment cost.
When a combination therapy is planned for an advanced RCC of clear-cell histology, it should consist of two different classes of drugs such as TKI + IO. Although nivolumab and ipilimumab are IO drugs, their mechanism of action is different (one is an anti-programmed death-ligand-1 drug and the other is a cytotoxic T-lymphocyte–associated antigen 4 inhibitor). For post-TKI therapy, lenvatinib–everolimus combination is used frequently in the second line when compared with everolimus alone.
| Important Recommendations for the Selection of the Next-Line Treatment | | |
Treatment can be started with pazopanib or sunitinib, and depending on the duration of response, a second VEGF inhibitor can be considered.
If disease control > 1 year for the first-line single agent: Continue using VEGF inhibition with sequential single agents such as axitinib or cabozantinib.
Brief response to the first-line single-agent VEGF inhibition: Consider a VEGF IO combination axitinib + pembrolizumab.
No response to the first-line VEGF inhibition: Drop VEGF and switch to IO ipilimumab + nivolumab or nivolumab.
No response to the first-line combination VEGF + IO: Switch to the second-line VEGF such as cabozantinib or axitinib or lenvatinib + everolimus.
| Immunotherapy | | |
IO has emerged as one of the cornerstones in the management of mRCC. IO-based combinations showed higher response rates and immunomodulation with sustained overall survival (OS) in some combinations.[17] Ideal candidates for IO include patients without active autoimmune conditions requiring immunosuppressive therapy or those with a history of potential life-threatening autoimmune conditions, patients without the need for corticosteroids to treat other conditions (e.g., brain metastases or spinal cord, compression, lymphangitic spread of tumor), and patients belonging to intermediate/poor-risk group patients who can afford it. IO–IO combination is ideal for obtaining complete response (CR). The most widely used frontline IO therapy includes ipilimumab/nivolumab and pembrolizumab/axitinib, both having OS benefit.[18]
Other combinations that are under study include avelumab/axitinib vs sunitinib (PFS benefit, FDA approval),[19] atezolizumab/bevacizumab vs sunitinib (PFS benefit, not approved),[20] pembrolizumab/lenvatinib vs sunitinib (completed),[21] and nivolumab/cabozantinib vs sunitinib (completed).[22]
A combination of dual immunotherapeutic agents such as nivolumab plus ipilimumab against axitinib–pembrolizumab combination is preferred by many oncologists for the treatment of poor-risk patients without affordability issues, who have no autoimmune disease or no contraindications to IO. Axitinib plus pembrolizumab is used in IMDC-favorable, intermediate-risk patients and in cases of immune-related adverse events associated with dual IO therapy. If axitinib–pembrolizumab combination fails, then lenvatinib or cabozantinib can be used.
Axitinib could be used if TKI followed by TKI is preferred, as a single agent with >1 year of good tolerance and PFS. For failed IO and TKI, the best response rate is given by lenvatinib and pembrolizumab. A combination of lenvatinib + everolimus for the second-line treatment is more preferred by the oncologists because of superior response rates and median OS for 25 months.[23] With high doses of interleukin-2, CR has been observed in patients with advanced disease. Patients who have been given IO-TKI combinations have shown a good response with no further disease progression. Everolimus–lenvatinib is a potent regime for patients who progressed on IO-TKI. Sorafenib and everolimus must be avoided as single agents.[24]
| Second-Line Therapy | | |
Drugs such as axitinib (proven data compared with sorafenib), nivolumab alone (data compared with everolimus), everolimus plus lenvatinib, and cabozantinib are the four main therapeutic agents that can be used as second-line agents for the management of mRCC.
In case of the second-line management, the choice of drugs between axitinib, sorafenib, and everolimus will depend on how the patient responded to the first-line therapy. If the patient responded very well to a VEGF-TKI first line, another VEGF-TKI can be considered down the line. If the patient responded poorly to a VEGF-TKI, an mTOR inhibitor can be considered. A comparison of the two active VEGF-targeted agents in patients of mRCC in the AXIS trial demonstrated a good PFS with axitinib when compared with sorafenib in previously treated patients.[25],[26] A network meta-analysis by Leung et al. demonstrated that axitinib is a better second-line targeted therapy option to prolong PFS after the first-line treatment failure and is associated with the least likelihood of withdrawal due to adverse effects.[27] Moreover, the analysis also demonstrated that sunitinib is better compared with sorafenib. In terms of toxicity, axitinib is better than both sorafenib and everolimus.
| Role of Axitinib | | |
Axitinib should be used appropriately especially when combined with other agents. The dose of axitinib is 5 mg twice daily, which can be increased to 10 mg twice a day. Continuous monitoring of blood pressure is extremely crucial, and the dose needs to be titrated according to blood pressure readings. The class effect of VEGF TKIs especially skin rash (scrotal rash) and oral ulcers can be taken care of by preventive therapy. Axitinib is the easiest to handle, accessible, versatile, and a cost-effective TKI drug for the treatment of mRCC. It is very well tolerated (vs sorafenib and everolimus). Axitinib can be used along with pembrolizumab as a first-line therapy and as a second-line therapy in patients who have failed other TKIs. As a second-line agent, it can be used as a standard when sunitinib or pazopanib or combination of TKI and IOs is used as first-line agents. Axitinib is a vital choice of the treatment armamentarium considering affordability issues in our country for IO postprogression on a TKI.[28],[29],[30]
Acknowledgements
We would like to acknowledge the clinical inputs shared by Dr. Shyam Aggarwal, Dr. T. P. Sahoo, Dr. Tejinder Singh, and Dr. Ghanshyam Biswas.
Financial support and sponsorship
This study was funded by Glenmark Pharmaceuticals.
Conflicts of interest
SB, NK, SP, and HVB are employees of Glenmark Pharmaceuticals.
Authors’ contributions
All authors have contributed equally for the conception, design, drafting, review, and final approval of the article.
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