|Year : 2022 | Volume
| Issue : 1 | Page : 14-19
Axitinib in management of renal cell carcinoma: Indian perspective
Sagar Bhimrao Bhagat, Amit Y Jadhav, Saiprasad V Patil, Hanmant Venkatrao Barkate
Global Medical Affairs, Glenmark Pharmaceuticals Limited, Mumbai, Maharashtra, India
|Date of Submission||21-Dec-2021|
|Date of Decision||05-Mar-2022|
|Date of Acceptance||14-Mar-2022|
|Date of Web Publication||20-Apr-2022|
Sagar Bhimrao Bhagat
Glenmark Pharmaceuticals Limited, B.D. Sawant Marg, Andheri (East), Mumbai - 400 099, Maharashtra
Source of Support: None, Conflict of Interest: None
Background: Renal cell carcinoma (RCC) is the most common type of kidney cancer. Despite the availability of several tyrosine kinase inhibitors (TKI) and immunotherapies in India, the placing and sequencing of molecules in the management of RCC remains a source of dispute. The purpose of this qualitative survey was to get insight on the positioning of TKIs, specifically Axitinib, in the treatment of RCC. Methodology: This was a cross-sectional, questionnaire-based survey conducted across India among Medical Oncologist involved in the management of metastatic RCC. The questionnaire consists of 15 questions that were validated by a senior oncologist. The responses to the question were compiled in Microsoft Excel version 2018 and analyzed. Results: Total 51 oncologists completed this questionnaire. Majority preferred the International Metastatic RCC Database consortium risk stratification criteria. In favourable risk category sunitinib was preferred while in intermediate/poor risk patient's axitinib plus pembrolizumab was preferred by majority. Pazopanib and axitinib was favoured in patients with advanced age and comorbidities. Axitinib was the choice in patients who had good response to 1st line therapy and who have visceral metastasis. Majority of oncologists endorsed the use of axitinib in elderly with comorbid patients because of its favourable efficacy and tolerability. Conclusion: Axitinib is preferred choice in metastatic RCC patients who have responded well to TKIs in the first line, in elderly patients with associated comorbidities, in patients with renal impairment and in patients with poor performance status. It is a well-tolerated drug with minimal adverse effects which are transient in nature.
Keywords: Axitinib, pembrolizumab, renal cell carcinoma, tyrosine kinase inhibitor
|How to cite this article:|
Bhagat SB, Jadhav AY, Patil SV, Barkate HV. Axitinib in management of renal cell carcinoma: Indian perspective. Oncol J India 2022;6:14-9
|How to cite this URL:|
Bhagat SB, Jadhav AY, Patil SV, Barkate HV. Axitinib in management of renal cell carcinoma: Indian perspective. Oncol J India [serial online] 2022 [cited 2022 May 27];6:14-9. Available from: https://www.ojionline.org/text.asp?2022/6/1/14/343573
| Introduction|| |
Kidney cancer is one of the most common types of cancer in both men and women worldwide. Globally, there were 431,288 new cases of kidney cancer and 179,368 deaths reported by GLOBOCAN 2020. Renal cell carcinoma (RCC) is the most common type of kidney cancer, which accounts for 85% of all kidney malignancies. The incidence of RCC is quite low in Asian countries, as compared to western countries, which could be attributed to a lack of reporting studies. In India, the estimated incidence of RCC is roughly 2/100,000 population for males and around 1/100,000 population for female. Although the incidence of RCC is lower than that of prostate and bladder cancer, the mortality rate is relatively higher.
Traditionally, cytokine inhibitors were used to treat RCC but with low response rates and limited survival. The development of tyrosine kinase inhibitor (TKI) has changed the management algorithm and is now considered as the treatment of choice in the management of RCC. Sunitinib was the first TKI to significantly increase progression-free survival in RCC patients. Given the highly vascular nature of renal cancer, more TKIs targeting vascular endothelial growth factor receptors (VEGFRs) were developed. Amongst all, Axitinib is second generation TKI approved by United State Food and Drug Administration (USFDA) and is positioned by the National Comprehensive Cancer Network (NCCN) 2021 as the category 1 drug in the management of RCC with or without Immunotherapy.
The majority of patients with advanced RCC will require many treatments throughout the course of their disease; thus, clinicians must be familiar with the clinical and molecular aspects of each therapy. Despite the availability of different TKI and immunotherapy in India, the positioning and sequencing of molecules in the management of RCC remain a point of contention. The present qualitative survey was to acquire insight into the positioning of TKIs, particularly Axitinib, in the management of RCC, in patients who are treatment naive and who progress on initial systemic therapy.
| Methodology|| |
This was a cross-sectional, questionnaire-based survey conducted across India from December 2020 to January 2021. Medical Oncologist with minimum 10 years of experience in the management of patients with RCC, working in public and private clinics/hospitals participated in this survey. All oncologist were shared a unique personalized link with questionnaire consisting of 15 questions which were validated by a senior oncologist prior to launch and are primarily focused on patient profiling and positioning toward the use of Axitinib in RCC in both first and second lines of treatment, as well as preference and safety of Axitinib in routine clinical practice.
Based on these parameters these 15 questions are arranged in [Table 1]. First question is based on risk categorization of patients. Next questions 2–4 are based on first line treatment of RCC patients whereas questions 5–12 are based on second line treatment of RCC patients. Question 13 is used for preference use of Axitinib and question 14, and 15 are used for safety profile of Axitinib.
Axitinib in India is available as 1 mg and 5 mg oral tablet with the starting dose of 5 mg once a day and flexible dose titration. Anonymity and confidentiality of the data were preserved. The responses to the question were compiled in Microsoft Excel version 2018 and analyzed.
Categorical data were summarized by number N and percentage (%) in each category, where N represents the total number of participants responding to each question. Data were summarized in frequency tables and graphs.
Since, no patient data was involved in the study, this methodology does not require ethics committee approval.
| Results|| |
Total 51 oncologists across India participated in the survey and their responses were evaluated and analysed. For the risk categorization of patients, 71% oncologists preferred to use International Metastatic RCC Database Consortium (IMDC) while 21% oncologist preferred Memorial Sloan-Kettering Cancer Center (MSKCC) criteria.
In patients with a favourable risk category, 41% oncologists favoured Sunitinib, whereas 29% preferred Axitinib with Pembrolizumab. However, for the intermediate/poor risk category, 73% oncologists favoured Axitinib plus Pembrolizumab, whereas 12% preferred nivolumab + ipilimumab.
Pazopanib was favoured by 51% of oncologists in patients with comorbidities and advanced age, followed by axitinib + pembrolizumab (axi-pembro) (26%), sunitinib (14%), and Axitinib (6%).
Nivolumab (53%) and Axitinib (29%) were the preferred drugs for patients who progressed on first-line sunitinib. Among patients who progressed on first-line TKI + immunotherapy, nearly 45% of oncologists favoured lenvatinib + everolimus, followed by cabozantinib and axitinib in 25% and 16% oncologists respectively.
Nivolumab is favoured by 37% of oncologists in patients who progress within 6 months after receiving first-line therapy, whereas Axitinib is chosen by 41% of oncologists in patients who progress after 6 months of receiving first-line therapy [Table 2].
|Table 2: Percentage oncologist preferring drug for ≤6 months and >6 months duration of 1st line therapy|
Click here to view
According to 27% of oncologists, Nivolumab was the treatment of choice in patients with multiple (>2) metastases, followed by axitinib (26%) and cabozantinib (17%).
Nivolumab, axitinib, and lenvatinib + everolimus were recommended by 25.49%, 23.53%, and 23.53% of oncologists, respectively, in patients with Bulky disease (sum of longest diameter >98 mm).
Cabozantinib was preferred by 29% of oncologists for brain metastasis, whereas Axitinib was favoured by 33% of oncologists for other visceral metastases [Table 3].
Nearly 65% of oncologists believe Axitinib should be used in older patients with comorbidities [Figure 1]. Almost 78.43% of oncologists agreed that Axitinib is well tolerated, with over 80% agreeing that adverse effects with axitinib are transient in nature and do not need drug discontinuation.
|Figure 1: Axitinib preference over other vascular endothelial growth factor receptor inhibitors tyrosine kinase inhibitors|
Click here to view
| Discussion|| |
Last decade has seen approval of seven targeted therapies in the management of advanced RCC. Amongst all, axitinib is an oral multikinase VEGFR inhibitor, which in addition to the VEGFR 1, 2 and 3 also inhibits platelet-derived growth factor α– β and cKIT receptor, with a high potency emphasized by a relatively low inhibitory concentration (IC50) when compared to other TKis such as sunitinib, sorafenib, and lenvatinib. Axitinib was approved in 2014 as a second-line therapy (advanced RCC [Axis] trial) in patients who had progressed on first-line systemic therapy, but in 2020, axitinib, along with Pembrolizumab (Keynote 426 study) and along with Avelumab (JAVELIN Renal 101 study), was approved as a first-line therapy in treatment-naive patients. Initially, the combination was preferred in intermediate and poor-risk patients, but the NCCN 2021 has classified and included the combination in favourable risk patients as well.
Patient risk classification aids in identifying patients and predicting long-term outcomes. MSKCC and IMDC risk categories are commonly utilised in newly diagnosed patients to stratify and assess prognosis. The IMDC criteria capture systemic inflammatory markers, which are key biomarkers for poor prognosis and aid in deciding first-line therapy in newly diagnosed patients. Several studies have found that patients with a high neutrophil-to-lymphocyte ratio had a bad prognosis.,, When compared to the MSKCC method, the major benefit of the IMDC scoring system is its greater accuracy in identifying individuals at high risk.
In India, sunitinib is still regarded as the gold standard drug for the treatment of RCC. Despite the development of immunotherapy medications like Pembrolizumab, Avelumab, and Nivolumab, which are recommended in patients with intermediate/poor-risk, sunitinib is still recommended in patients with favourable-risk. Although the NCCN guidelines recognize active surveillance as useful in certain circumstances, especially in favourable risk category patients, a clear characterization of those circumstances is lacking, also, active surveillance may require regular visits and frequent imaging evaluation. In favourable risk category patients, monotherapy is still preferred because combination therapy is more likely to cause toxicity than monotherapy, and the results of the Keynote-426 trial and the Javelin Renal 101 trial showed no survival benefit with Axi-Pembro/Avelumab over sunitinib in favourable risk category patients. Similar findings were reported in Checkmate 214 trial, which failed to demonstrate a survival advantage of nivolumab and ipilimumab (Nivo-Ipi) versus sunitinib in individuals with favourable risk. For intermediate or poor-risk category patients, Axi-Pembro demonstrated a considerable survival advantage over sunitinib and is hence chosen by many oncologists in India. Though Checkmate 214 trial also highlighted similar findings in intermediate/poor risk category patients, safety associated with Axi-Pembro was better as compared to Nivo-Ipi.
As elderly patients are at a higher risk of toxicity from treatment, they are commonly subjected to dose reduction or stoppage. Elderly patients are typically associated with lower TKI doses and very low immunotherapy doses. This was echoed in the current study, where more than half of oncologists favoured pazopanib monotherapy as a therapeutic option, followed by the Axi-Pembro combination. Currently, the two monotherapy TKIs utilised and available in India for first-line therapy are pazopanib and sunitinib, both of which have been recommended by the NCCN 2021 Guideline. Pazopanib has equal efficacy to sunitinib but has well documented safety benefits. There was a significant patient preference in favour of pazopanib in the PISCES study (70% vs. 22%, P < 0.001), with the most prevalent reasons being less fatigue and improved overall quality of life (QoL) when choosing pazopanib and less diarrhoea when choosing sunitinib. In the COMPARZ phase 3 clinical trial, pazopanib was statistically superior to sunitinib in 11 of the 14 health-related QoL domains.
Patients who progressed on first-line sunitinib were preferred the immunotherapy drug Nivolumab, followed by axitinib, whereas those who progressed on first-line TKIs plus immunotherapy were preferred the combination of lenvatinib + everolimus, followed by Cabozantinib and Axitinib. Until recently, sequential therapies of TKIs followed by TKIs were considered the treatment of choice, but with the introduction of immunotherapy, the algorithm and hence clinical practices have changed dramatically. Nivolumab, cabozantinib, axitinib, and lenvatinib + everolimus are all second-line category 1 drugs mentioned in the NCCN guideline 2021. Axitinib was the established therapy among patients who progressed on first line systemic therapy, mainly sunitinib, and had shown progression free survival (PFS) advantage in the AXIS trial. Whereas Nivolumab when compared to everolimus in the CheckMate 025 trial showed survival advantage without the PFS advantage. To emphasize the survival advantage, the European Society for Medical Oncology- European Association of Urology (ESMO-EUA) guideline classified Nivolumab as category 1-A and recommended it as a preferred choice., TKIs, such as Lenvatinib, Axitinib, and Cabozantinib, were preferred medications for patients who were prescribed a combination of TKI plus immunotherapy mainly checkpoint inhibitor in the first line therapy. Since, axitinib is the preferred TKI to combine with an Immunotherapy drug, Lenvatinib is the preferred TKI in India. Wiele et al. also provided data highlighting the overall survival benefit in a retrospective study of 40 patients with lenvatinib + everolimus who progressed on TKI + immunotherapy.
Not only does the type of therapy used in the first line determine the therapy administered in the second line, but the response to the first line therapy is also important. In the present study, immunotherapy, particularly Nivolumab, was favoured in patients who progressed before 6 months of first-line therapy, whereas Axitinib was recommended in patients who progressed after 6 months of first-line therapy. Ishihara et al. found that patients who have a long-term response to first-line TKI therapy may have a better prognosis with second-line molecular targeted therapy. Similar findings were reported by Li et al. who demonstrated that patients who responded to first-line sunitinib achieved satisfactory disease control with second-line axitinib. The sunitinib-axitinib sequence was safe and efficacious, according to an Italian multicenter real-world SAX research that found that the response to preceding sunitinib associated strongly with the increased PFS of Axitinib. For those patients who progress early in the course of the first line treatment, immunotherapy will help in the aggressive treatment in the second line. Aside from intrinsic resistance, early progression in RCC can be caused by acquired or adaptive resistance to targeted therapy, which may be characterized by gene mutations other than (or in addition to) Von Hippel-Lindau (VHL) (e.g., SETD2 and BAP1 with poor prognosis and aggressive illness in nonmetastatic individuals). A systemic review comparing the FDA approved second line therapy and the pivotal trial highlighted Nivolumab should be considered in patients who do not tolerate the first line VEGF-TKI well, hypothesizing, whether shifting the mechanism of action toward PD-1 inhibition might restore or improve sensitivity to subsequent VEGFR inhibition for treatment sequencing.
We also sought to determine treatment choices in patients with disease burden. Nivolumab, axitinib and cabozantinib were the preferred drugs for those with multiple metastases (≥2). Nivolumab, axitinib, and lenvatinib + everolimus were the preferred drugs for those with bulky disease (>98 mm). Patients with bulky disease and/or multiple metastases have a poor prognosis and an aggressive disease profile; thus, Nivolumab was chosen to be the treatment of choice for such an aggressive disease profile, considering the relative nature of resistance. Prognostic factor analysis from the AXIS trial revealed that patients with IMDC poor-risk category who had bulky disease, liver and/or bone metastasis benefited from axitinib more than sorafenib Hazard ratio (HR = 0.38, P = 0.009). Axitinib was preferable in patients with visceral metastasis, while Cabozantinib was favoured in patients with brain metastasis, followed by axitinib. Axitinib demonstrated good results and enhanced PFS as a second line therapy in patients with lung and liver and/or bone metastases in both IMDC and MSKCC poor-risk category patients, according to a subgroup analysis of multiple trials. Among the approved TKIs, Cabozantinib has been demonstrated to effectively cross the blood-brain barrier and to have action in patients with brain metastases.
In terms of axitinib's role in the overall management of RCC, the majority of oncologists felt it is good medicine to utilise in elderly patients with comorbidities and renal impairment. One-third of those polled thought it could be useful in patients with poor performance status and hepatic impairment. In terms of axitinib's safety, the majority believe that the side effects are mild and transient, and that the treatment is highly well tolerated in clinical practice, with the Axis trial reporting discontinuation rate of 9%. In clinical practice, axitinib is one of those drugs where up-titration is possible based on the effect of clinical effect of the drug after 2 weeks of treatment because it is well tolerated drug with fewer side effects. In AXIS trial, gastrointestinal side effects were common, particularly nausea and anorexia, in addition to the antiangiogenic side effect of hypertension. Axitinib's long-term safety analysis (≥2 years) revealed that the majority of adverse events (AEs) occurred during the first 6 months of treatment, with rates remaining stable or decreasing over time. The same was true with common Grade 3 AE rates, which reduced or plateaued over time. No dose adjustment is required according to age, gender, weight and renal function. It is also reported to have minimal drug-drug interaction with other drugs. A two-fold increase in axitinib level has been reported in patients with moderate hepatic impairment; therefore, dose adjustment is required in such patients; however, in patients with severe hepatic impairment, given the lack of clinical trial evidence, it is recommended to avoid in severe hepatic impairment. The fact that axitinib is the most potent VEGFR inhibitor with very low off-target action contributes to its safety.
| Conclusion|| |
The current qualitative study identifies patient risk categorization as the most crucial stage in initiating treatment in newly diagnosed metastatic RCC patients. Sunitinib in the favourable risk category, and Axitinib plus Pembrolizumab in the intermediate and poor-risk categories were regarded as the preferred choice therapy. The treatment options in the second line are determined by the duration of the response and the type of therapy employed in the first line. Immunotherapy is favoured in patients who do not tolerate first-line therapy well, whereas TKis are preferred in those who tolerate first-line therapy well. Axitinib is preferred in patients who have responded well to TKIs in the first line, in elderly patients with associated comorbidities, in patients with renal impairment, and in patients with poor performance status. Axitinib is a well-tolerated drug with minimal adverse effects which are transient in nature.
The authors gratefully acknowledge and thank the 51 oncologists across India who participated in this survey.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Abraham GP, Cherian T, Mahadevan P, Avinash TS, George D, Manuel E. Detailed study of survival of patients with renal cell carcinoma in India. Indian J Cancer 2016;53:572-4.
] [Full text]
Motzer RJ, Escudier B, Gannon A, Figlin RA. Sunitinib: Ten years of successful clinical use and study in advanced renal cell carcinoma. Oncologist 2017;22:41-52.
Bellesoeur A, Carton E, Alexandre J, Goldwasser F, Huillard O. Axitinib in the treatment of renal cell carcinoma: Design, development, and place in therapy. Drug Des Devel Ther 2017;11:2801-11.
Rini BI, Escudier B, Tomczak P, Kaprin A, Szczylik C, Hutson TE, et al.
Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): A randomised phase 3 trial. Lancet 2011;378:1931-9.
Rini BI, Plimack ER, Stus V, Gafanov R, Hawkins R, Nosov D, et al.
Pembrolizumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma. N Engl J Med 2019;380:1116-27.
Motzer RJ, Penkov K, Haanen J, Rini B, Albiges L, Campbell MT, et al.
Avelumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma. N Engl J Med 2019;380:1103-15.
Tanaka N, Mizuno R, Ito K, Shirotake S, Yasumizu Y, Masunaga A, et al.
External validation of the MSKCC and IMDC risk models in patients treated with targeted therapy as a first-line and subsequent second-line treatment: A Japanese multi-institutional study. Eur Urol Focus 2016;2:303-9.
Shinohara N, Abe T. Prognostic factors and risk classifications for patients with metastatic renal cell carcinoma. Int J Urol 2015;22:888-97.
Shinohara N, Obara W, Tatsugami K, Naito S, Kamba T, Takahashi M, et al.
Prognosis of Japanese patients with previously untreated metastatic renal cell carcinoma in the era of molecular-targeted therapy. Cancer Sci 2015;106:618-26.
Goebell PJ, Ivanyi P, Bedke J, Bergmann L, Berthold D, Boegemann M, et al
. Consensus paper: Current state of first- and second-line therapy in advanced clear-cell renal cell carcinoma. Future Oncol 2020;16:2307-28.
Motzer RJ, Tannir NM, McDermott DF, Arén Frontera O, Melichar B, Choueiri TK, et al.
Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N Engl J Med 2018;378:1277-90.
Hermansen CK, Donskov F. Outcomes based on age in patients with metastatic renal cell carcinoma treated with first line targeted therapy or checkpoint immunotherapy: Older patients more prone to toxicity. J Geriatr Oncol 2021;12:827-33.
Escudier B, Porta C, Bono P, Powles T, Eisen T, Sternberg CN, et al
. Randomized, controlled, double-blind, cross-over trial assessing treatment preference for pazopanib versus sunitinib in patients with metastatic renal cell carcinoma: PISCES Study. J Clin Oncol 2014;32:1412-8.
Motzer RJ, Hutson TE, Cella D, Reeves J, Hawkins R, Guo J, et al.
Pazopanib versus sunitinib in metastatic renal-cell carcinoma. N Engl J Med 2013;369:722-31.
Motzer RJ, Escudier B, McDermott DF, George S, Hammers HJ, Srinivas S, et al.
Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med 2015;373:1803-13.
Escudier B, Porta C, Schmidinger M, Rioux-Leclercq N, Bex A, Khoo V, et al.
Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2019;30:706-20.
de Joode K, van der Veldt AA. Re: Laurence Albiges, Tom Powles, Michael Staehler, et al.
Updated European Association of Urology Guidelines on Renal Cell Carcinoma: Immune checkpoint inhibition is the new backbone in first-line treatment of metastatic clear-cell renal cell carcinoma. Eur Urol 2019;76:151-6: Active Surveillance in Metastatic Renal Cell Cancer: Missing a Chance for Cure? Eur Urol 2020;77:e76-7.
Wiele AJ, Ross J, Chahoud J, Lim Z, Xiao L, Campbell MT, et al
. 964PLenvatinib (Len) alone or in combination with Everolimus (Eve) in heavily Pretreated Patients (pts) with Metastatic Renal Cell Carcinoma (mRCC) after Immune Checkpoint Inhibitors (ICI) and VEGFR-targeted therapies: A single-institution experience. Ann Oncol 2019;30: V356-402.
Ishihara H, Kondo T, Yoshida K, Omae K, Takagi T, Iizuka J, et al.
Time to progression after first-line tyrosine kinase inhibitor predicts survival in patients with metastatic renal cell carcinoma receiving second-line molecular-targeted therapy. Urol Oncol 2017;35:542.e1-9.
Li JR, Yang CK, Wang SS, Chen CS, Chiu KY, Cheng CL, et al.
First-line treatment result influence second-line regimen selection in targeted therapy for metastatic renal cell carcinoma. Anticancer Res 2014;34:5643-7.
Facchini G, Rossetti S, Berretta M, Cavaliere C, Scagliarini S, Vitale MG, et al.
Second line therapy with axitinib after only prior sunitinib in metastatic renal cell cancer: Italian multicenter real world SAX study final results. J Transl Med 2019;17:296.
Porta C, Paglino C, Grünwald V. Sunitinib re-challenge in advanced renal-cell carcinoma. Br J Cancer 2014;111:1047-53.
Tannir NM, Pal SK, Atkins MB. Second-line treatment landscape for renal cell carcinoma: A comprehensive review. Oncologist 2018;23:540-55.
Bracarda S, Bamias A, Casper J, Negrier S, Sella A, Staehler M, et al
. Is axitinib still a valid option for mRCC in the second-line setting? Prognostic factor analyses from the AXIS trial. Clin Genitourin Cancer 2019;17:e689-703.
Ueda K, Suekane S, Hirano T, Ogasawara N, Chikui K, Uemura K, et al
. Efficacy of axitinib as second-line treatment in locally advanced and metastatic renal cell carcinoma. Anticancer Res 2018;38:5387-92.
Abdelaziz A, Vaishampayan U. Cabozantinib for renal cell carcinoma: Current and future paradigms. Curr Treat Options Oncol 2017;18:18.
[Table 1], [Table 2], [Table 3]