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Table of Contents
ORIGINAL ARTICLE-REAL WORLD DATA
Year : 2021  |  Volume : 4  |  Issue : 1  |  Page : 55-60

Real-world data of second-line immunotherapy in metastatic clear cell renal cell carcinoma: A retrospective study


Department of Medical Oncology, Max Institute of Cancer Care; Department of Medical Oncology, Max Super Speciality Hospital, Delhi, India

Date of Submission06-Oct-2020
Date of Decision24-Nov-2020
Date of Acceptance04-Mar-2021
Date of Web Publication26-Mar-2021

Correspondence Address:
Waseem Abbas
Max Institute of Cancer Care, Shalimar Bagh, Delhi; Max Super Speciality Hospital, Shalimar Bagh, FC-50, C and D Block, Shalimar Bagh, Delhi - 110 088
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/CRST.CRST_247_20

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  Abstract 


Background: Targeted therapies have prolonged the survival of patients with metastatic renal cell carcinomas (RCC). However, the majority of patients with metastatic RCC develop treatment resistance and disease progression. The programmed cell death protein 1 inhibitors offer a new ray of hope for such patients.
Objectives: The primary objective of this study was to evaluate the overall survival (OS) of patients with relapsed metastatic RCC treated with immunotherapy in the second-line setting. The secondary objectives were to assess the safety profile and objective response rate (ORR) for nivolumab.
Materials and Methods: This retrospective study was conducted in the Department of Medical Oncology at the Max Institute of Cancer Care, a tertiary care center in Delhi, India. Patients with histologically proven stage IV RCC who had progressed on first-line tyrosine kinase inhibitors (TKIs) and treated with at least four cycles of nivolumab at our center between December 2015 and January 2019 were enrolled in the study. The OS, progression-free survival (PFS), immune-mediated adverse events (irAEs), and ORR were determined.
Results: Out of 50 patients with metastatic RCC who progressed on first-line TKIs, 19 received immunotherapy with nivolumab. The median age of the patients was 62 years (range, 31–71 years); the male-to-female ratio was 2:1. The median follow-up time and duration of treatment were 11 months (range, 2–23) and 4.5 months (95% confidence interval [CI], 3.52–5.96), respectively, and 8 (42.1%) patients were alive at the time of analysis. The median OS was 13 months (95% CI, 10.4–15.5) from the start of nivolumab therapy, and the median PFS was 8 months (95% CI, not evaluable). The best response was progressive disease in 47.3%; the ORR was 26.3%. Grade 1/2 and grade 3/4 adverse events were observed in 68.4% and 10.5% of the patients, respectively. Adverse events of any grade were reported in 13 (68.6%) patients. Fatigue and hypothyroidism were the most frequently observed irAEs associated with nivolumab and occurred in 4 (21%) and 11 (57.8%) patients, respectively. Four (15.7%) patients developed grade 1 pruritus. No fatal toxicities were recorded.
Conclusion: Nivolumab is efficacious and safe as a second-line treatment option for metastatic RCC in Indian patients.

Keywords: Checkpoint inhibitors, clear cell carcinoma, immunotherapy, nivolumab, renal cell carcinoma


How to cite this article:
Abbas W, Aggarwal A, Pankaj P, Jain R. Real-world data of second-line immunotherapy in metastatic clear cell renal cell carcinoma: A retrospective study. Cancer Res Stat Treat 2021;4:55-60

How to cite this URL:
Abbas W, Aggarwal A, Pankaj P, Jain R. Real-world data of second-line immunotherapy in metastatic clear cell renal cell carcinoma: A retrospective study. Cancer Res Stat Treat [serial online] 2021 [cited 2021 Apr 22];4:55-60. Available from: https://www.crstonline.com/text.asp?2021/4/1/55/312072




  Introduction Top


Renal cell carcinomas (RCC) account for 2.4% of all adult malignancies.[1] The estimated number of new cases of RCC diagnosed annually is 338,000, and about 30% of the patients present with metastatic disease.[2],[3],[4],[5] In 2018, a total of 119,992 cases of RCC were diagnosed in India, comprising 1.3% of all malignancies. RCC leads to 9911 deaths per year and has a 5-year prevalence of 31,577.[3] The standard of care for patients with metastatic RCC a decade ago was immunotherapy with interleukins and interferon-alpha.[6],[7] Thereafter, the advent of targeted therapies such as the tyrosine kinase inhibitors (TKIs) and mammalian target of rapamycin (mTOR) pathway inhibitors successfully increased the survival of patients with favorable, intermediate, and poor-risk disease to 43, 22, and 7.3 months, respectively, despite the fact that the majority of patients with metastatic RCC eventually develop resistance to treatment and disease progression.[8],[9] Multiple newer strategies are available in the second-line setting for the treatment of metastatic RCC; everolimus in combination with lenvatinib or cabozantinib has been shown to confer a significant survival advantage as second-line therapy.[10],[11] The emergence of the programmed cell death protein 1 (PD-1) inhibitors has rekindled the interest in immunotherapy.

Nivolumab, a human monoclonal antibody that functions as an immune checkpoint inhibitor, acts via the disruption of the interaction between the PD-1 receptor and its ligands, the programmed death-ligand 1 (PD-L1) and PD-L2.[12] The Food and Drug Administration approved nivolumab for patients with metastatic RCC based on a phase III randomized study from 2015.[13] The CheckMate 025 trial showed that nivolumab led to better overall survival (OS) and progression-free survival (PFS) than everolimus in patients with previously treated RCC [Table 1].[13],[14] Therefore, we aimed to assess the safety and efficacy of nivolumab in Indian patients with metastatic RCC who had progressed on first-line TKIs.
Table 1: Results of CheckMate 025 study depicting the comparison of overall survival and progression-free survival in the patients with advanced clear cell renal cell carcinoma who had relapsed after one or two lines of prior antiangiogenic therapy and who received either nivolumab or everolimus

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  Materials and Methods Top


General study details

This retrospective study was conducted in the Department of Medical Oncology at the Max Institute of Cancer Care, Shalimar Bagh, a tertiary care center in Delhi, India, between December 2015 and January 2019. The study was approved by the Institutional Ethics Committee [Study protocol included as Supplementary appendix 1]. Given the retrospective nature of the study, the need for obtaining a written informed consent was waived. The study was not registered with a public clinical trials registry as it was a retrospective analysis. The study was conducted in accordance with the various ethical principles established by the Declaration of Helsinki and the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use's Guideline for Good Clinical Practice and the Indian Council of Medical Research guidelines.

Participants

Patients with histologically proven stage IV clear cell RCC who had progressed on first-line TKIs, had an Eastern Cooperative Oncology Group performance score of 0–2, and had received at least 4 cycles of nivolumab were enrolled in the study. Patients were eligible if they had received only one prior line of therapy (sunitinib or pazopanib). Patients who had a history of autoimmune disease, were on systemic immunosuppressive therapy, or were previously treated with T-cell co-stimulators or immune checkpoint inhibitors were excluded.

Variables

The primary endpoint was OS. The secondary endpoints were PFS, the rate of immune-mediated adverse events (irAEs), and the objective response rate (ORR).

Study methodology

Eligible patients were screened from the hospital database. All the data were obtained from the electronic medical records. The treatment to be given to the patients was decided in a multidisciplinary tumor board based on the prior lines of treatment, medical history, comorbidities, economic background as well as the patients' affordability and medical insurance coverage. Toxicity assessment was performed based on the clinical examination and routine laboratory testing, including the complete blood count, liver and renal function tests, and thyroid profile. The adverse events were reported as per the Common Terminology Criteria for Adverse Events, version 5.0 (U.S. Department of Health And Human Services,Washington D.C, USA). The response was assessed using computed tomography (CT) scans performed once every 2 months and was evaluated as per the Response Evaluation Criteria in Solid Tumors criteria, version 1.1. Hyperprogression was defined as a 50% increase in the tumor size as seen on a scan for disease progression.[15] PFS was defined as the period from the start of nivolumab till the date of disease progression or death due to any cause. OS was defined as the time from the date of start of nivolumab to the date of death or the date of last follow-up in the surviving patients. We performed an exploratory analysis to calculate the median OS from the date of diagnosis to the date of death or the date of last follow-up in the surviving patients.

Statistics

A formal sample size calculation was not done for this study. All patients fulfilling the eligibility criteria were enrolled in the study. The Statistical Package for Social Sciences (IBM Corp. Released 2012. IBM SPSS Statistics for Windows, version 21.0. Armonk, NY, USA: IBM Corp.) was used for statistical analysis. The OS and PFS were determined using the Kaplan–Meier survival analysis, and the follow-up was calculated using the reverse Kaplan–Meier method.[16] The cutoff date for survival analysis was May 2020.


  Results Top


Demographics

Of the 50 patients with metastatic RCC who had relapsed, 19 patients were treated with nivolumab [Figure 1]. The median age of the patients was 62 years (range, 31–71). The male-to-female ratio was 2:1. In 13 (68.4%) patients, the cost of therapy was covered by medical insurance. The remaining 6 (31.6%) patients paid for the medications out of their own pocket. Patients with financial constraints opted for the alternative non-cross-resistant vascular endothelial growth factor receptor TKIs/mTOR inhibitors as per the general clinical practice. Patients were categorized based on the International Metastatic RCC Database Consortium scores for low, intermediate, and high risk [Table 2].[1] PD-L1 testing was not performed for any patient.
Figure 1: Patient recruitment flowchart for the study evaluating the efficacy and safety of nivolumab in Indian patients with metastatic relapsed renal cell carcinoma (ACRONYM: ECOG-Eastern Cooperative Oncology Group)

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Table 2: Demographic variables of patients with metastatic renal cell carcinoma who received nivolumab in the relapsed setting

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Treatment details

Nivolumab 240 mg was administered intravenously every 14 days. The median number of nivolumab cycles administered was 9 (interquartile range, 6–12). Two patients discontinued treatment with nivolumab due to grade 3 pneumonitis and hyperprogression. No patient was treated beyond progression.

Response rates

All the patients had measurable disease at the start of treatment and underwent at least one restaging CT scan. Most of the patients (47.3%) had progressive disease as the best response to nivolumab. The ORR was 26.3%; 5 (26.3%) patients had partial response, and 5 (26.3%) had stable disease.

Survival

A total of 8 (42.1%) patients were alive at the median follow-up of 11 months (range, 2–23). Disease progression occurred in 9 patients, and 11 patients have died. The most common reason for the cessation of the therapy was disease progression. The median PFS was 8 months (95% confidence interval [CI], Not reached [NR]-NR), and the median OS was 13 months (95% CI, 10.4–15.5). The median OS from the date of diagnosis was 33 months (95% CI, 29.5–36.4) [Figure 2]a & [Figure 2]b.
Figure 2: (a) The overall survival of patients with metastatic relapsed renal cell carcinoma treated with nivolumab at a median follow-up of 11 months. (b) The progression-free survival of patients with metastatic relapsed renal cell carcinoma treated with nivolumab at a median follow-up of 11 months

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Adverse events

Adverse events of any grade were reported in 13 (68.6%) patients. Fatigue and hypothyroidism were the most frequently observed irAEs associated with nivolumab and occurred in 4 (21%) and 11 (57.8%) patients, respectively. Four (15.7%) patients developed grade 1 pruritus. Two (10.5%) patients developed grade 3/4 adverse events; pneumonitis and hyperprogression were observed in 1 (5.2%) patient each. The patient with hyperprogression subsequently died of disease progression. No fatal toxicities were recorded. Other adverse events of grade 1/2 severity observed were nausea (10.5%), vomiting (5.2%), diarrhea (5.2%), stomatitis 5.2%, rash (10.5%), alopecia (5.2%), and pneumonitis (5.2%) [Table 3].
Table 3: Adverse events in patients with metastatic renal cell carcinoma who received nivolumab in the relapsed setting

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  Discussion Top


In our study, we found that the median OS, PFS, and ORR of the patients with relapsed metastatic RCC receiving nivolumab in the second line were 13 months (95% CI, 10.4–15.5), 8 months (95% CI, NR–NR), and 26.3%, respectively. Although the median OS in the CheckMate 025 study was higher at 25.8 months (95% CI, 22.2–29.8) as compared to 13 months achieved in our study, the median PFS and ORR reported with nivolumab in our study were roughly comparable (8 months and 26.3% in our study versus 4.2 months and 25% in the CheckMate 025 study). In addition, in the CheckMate 025 study, 78% of the patients progressed on nivolumab, while in our study, 47.3% of the patients progressed after initial treatment, showing an overall benefit in the time to disease progression.[17],[18] The reason for the shorter OS but relatively similar PFS and ORR observed in our study could be the lack of treatment options post relapse because of the reduced access and affordability.

Nivolumab has been shown to be efficacious with low toxicity in patients who have received prior lines of treatment for advanced RCC. Improved outcomes have been observed with newer immunological agents that hinder tumor-induced immunosuppression.[19] In the Checkmate 025 study, 116 (28%) patients had received two prior lines of treatment with TKIs before nivolumab, whereas in our study, patients who received only one prior line of therapy with TKIs were included.[13] This could be the reason for the marginally better PFS observed in our study.

Adverse events of any grade were observed in 44.8% of the patients in the CheckMate 025 study, whereas in our study, these events were observed in 68.4% of the patients.[13] The most common treatment-related adverse events of any grade were fatigue and pruritus that were observed in 34.7% and 15.5% of the patients, respectively, in the CheckMate 025 study compared to 21% each in our study. Other adverse reactions such as nausea, rash, and diarrhea were observed in 28%, 28%, and 25% of the patients, respectively, in the CheckMate 025 study and 10.5%, 10.5%, and 5.2% of the patients, respectively, in our study.

Rauthan et al. presented the results from their retrospective study on 15 Indian patients with metastatic RCC who received nivolumab in the relapsed setting at the American Society of Clinical Oncology 2018 meeting.[20] The authors reported that 33% of the patients in their study achieved an objective response (20% showed complete responses), which is similar to the ORR of 26.3% observed in our study. In addition, in their study, progressive disease was observed in 46.6% of the patients, which is also similar to what we have reported (47.4%). Moreover, the median PFS of the patients in Rauthan et al.'s study was 5 months, which was lower than that reported in our study (8 months). This could be attributed to the fact that 15.6% of the patients in Rauthan et al.'s study had received more than one line of therapy before nivolumab.[20]

Given the high cost and only modest efficacy of nivolumab, it is essential to identify the subgroup of patients that might respond to nivolumab. In the CheckMate 025 study, longer survival was observed with nivolumab as compared to everolimus, in patients with a high Memorial Sloan-Kettering Cancer Center (MSKCC) prognostic score, in those aged less than 75 years, and in those who had received only one previous line of therapy with antiangiogenic agents.[17] Sarfaty et al. assessed the cost-effectiveness of nivolumab as second-line treatment for advanced RCC in patients from the United States of America and found that nivolumab was more cost-effective than everolimus.[21] Data on subsequent lines of treatment after progression on nivolumab are currently lacking. In our study, the most common TKI used after nivolumab was axitinib.

Our study was limited by its retrospective design and small sample size. Other limitations include the absence of a control group and the lack of data related to the quality of life of the patients. In addition, we excluded patients who received less than four doses of nivolumab in an attempt to remove the potential bias resulting from financial constraints in view of the high cost of the drug. All the five patients who were excluded from the study because they had received less than four doses of nivolumab had financial constraints and could not afford to continue on nivolumab.


  Conclusion Top


Our study shows that nivolumab is efficacious and well tolerated in Indian patients with metastatic relapsed RCC. However, definitive conclusions will require testing its efficacy and toxicity in larger prospective studies.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.


  Supplementary Appendix 1: Study Protocol Top







  Introduction Top


Renal cell carcinoma (RCC) accounts for 2.4% of the adult malignancies.[1]. The estimated number of new cases of RCC annually is 338,000; 30% present with metastatic disease.[2],[3],[4],[5] In India, in the year 2018, there were 119,992 cases of RCC diagnosed, contributing to 1.3% of all malignancies leading to 9911 deaths per year, with a 5-year prevalence of 31,577.[3] The standard of care for patients with metastatic RCC a decade ago was immunotherapy with interleukins and interferon-alpha.[6],[7]The advent of subsequent targeted therapies, the tyrosine kinase inhibitors (TKIs), and mammalian target of rapamycin-mediated pathway inhibitors successfully increased the survival in patients with favorable (43 months), intermediate (22 months), and poor-risk (7.3 months) disease, despite the fact that the majority of patients with metastatic RCC developed resistance to treatment and disease progression.[8],[9] Multiple newer strategies are available in the second-line setting for the treatment of metastatic RCC; everolimus in combination with lenvatinib and cabozantinib have both been shown to confer a significant survival advantage as second-line therapy.[10],[11] The advent of the programmed death-ligand 1 (PDL-1) inhibitors has rejuvenated interest in immunotherapy.

Nivolumab was the first human immune checkpoint inhibitor antibody. Its mechanism of action is via the inhibition of the immune response by disruption of the PD-1 receptor with its ligands PD-L1 and PD-L2.[12] The Food and Drug Administration approval of nivolumab in patients with metastatic RCC was based on a phase III randomized study in 2015.[13] The trial, CheckMate 025, showed that nivolumab led to better overall survival (OS) and progression-free survival (PFS) as compared to everolimus in patients with previously treated RCC. The aim of our retrospective study was to assess the safety and efficacy of nivolumab in our Indian patients with relapsed RCC.

Aim and objectives

Aim

The primary objective is to measure OS of patients with relapsed metastatic RCC treated with immunotherapy in the second-line setting and to assess the safety profile and response rate of nivolumab.

Rationale

There are a limited number of studies on nivolumab in second-line treatment to metastatic RCC patients and survival status in Indian subjects. Hence, our study will add to the available OS data and will be the first study on Indian patients.

Objectives

Primary objective

  • The primary objective is to measure OS of patients with relapsed metastatic RCC treated with immunotherapy in the second-line setting.


Secondary objective

  • The secondary objectives are to assess the safety profile and response rate of nivolumab.


Primary and secondary endpoints

  • The primary endpoint of our study is OS
  • The secondary endpoints are PFS, the immune-mediated adverse events, and the objective response rate.



  Materials and Methods Top


General study details

This retrospective study will be conducted in the Department of Medical Oncology at the Max Institute of Cancer Care, Shalimar Bagh, a tertiary care center in Delhi, India. All the subjects fulfilling the eligibility criteria will be included in this retrospective study from December 2015 to January 2019 [Supplementary Figure 1].



Data collection methodology

The eligible patients will be screened from the hospital database of all patients with metastatic relapsed RCC between December 2015 and January 2019. All the data will be obtained from the online software archived in the institution. The database is maintained by the site staff, archived, and stored by the medical record department. The treatment of the patients is decided in the multidisciplinary tumor board, and the treatment decision is based on the prior lines of treatment, medical history, comorbidities, economic background and the patient decision to opt for the treatment on the basis of the ability to pay, and medical insurance coverage. The toxicity assessment will be performed on the basis of the clinical examination and on routine laboratory testing including the complete blood count, liver and renal function tests, and thyroid profile. The adverse events will be reported as per the Common Terminology Criteria for Adverse Events, version 5.0 (U.S. Department Of Health And Human Services,Washington D.C, US). The response will be assessed by computed tomography scans done once every 2 months and calculated as per the Response Evaluation Criteria in Solid Tumors (RECIST) criteria, version 1.1(Elsevier Ltd,North York , Ontario, Canada). We will be doing an exploratory analysis to calculate the median survival from the date of diagnosis.

Hyperprogression is defined as a 50% increase in the tumor size as compared to the prior scans of disease progression.[14]

Study area

This study will be conducted retrospectively on the available data of patients retrieved from the tertiary care hospital – Max Super Speciality Hospital, Shalimar Bagh, New Delhi.

Study population

The primary eligibility criteria for inclusion in our study were as follows:

Inclusion criteria

  • Histologically proven clear cell RCC
  • Patients with stage IV disease who had progressed on first-line TKIs
  • Patients who had an Eastern Cooperative Oncology Group score of 2 and below
  • Patients who have received at least four cycles of nivolumab. Patients will be eligible if they have received only one prior therapy (sunitinib or pazopanib).


Exclusion criteria

  • Patients who had a history of autoimmune diseases, those who were on systemic immunosuppressive therapy, and those previously treated with T-cell co-stimulator or checkpoint-targeted agents will be excluded.


Statistical Methods

There will be no formal sample size calculation. All patients eligible during the study period will be included in the study. The Statistical Package for Social Sciences (SPSS), version 21.0 (IBM Corp. Released 2012. IBM SPSS Statistics for Windows, version 21.0. Armonk, NY, USA: IBM Corp.) will be the software used for the statistical analysis. The survival analysis will be performed using the Kaplan–Meier methodology, and the follow-up will be calculated using the reverse Kaplan–Meir method.[15] The cutoff date for survival analysis will be May–June 2020.

PFS will be determined from the start of immunotherapy till the date of disease progression or death due to any cause. RECIST criteria will be used to determine progression. OS is defined as the time from the date of start of nivolumab to the date of death or the date of last follow-up in surviving patients.

Ethical consideration

The study will be conducted in accordance with the various ethical principles established by the Declaration of Helsinki and the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use's Guideline for Good Clinical Practice and the Indian Council of Medical Research guidelines.

Informed consent form

Informed consent forms will not be taken and waiver application will be applied as it is a retrospective study.

Participant's confidentiality

Any data, forms, reports, and other records that leave the site will be identified only by a participant identification number (patient ID) to maintain confidentiality. All records will be kept in a locked file cabinet. All computer entry and networking programs will be done using patient IDs only.

Publications of research findings

After the completion of the study, under the discretion of the guide, we intend to immediately publish the results in international and national journals.

  1. Mazza C, Escudier B, Albiges L. Nivolumab in renal cell carcinoma: Latest evidence and clinical potential. Ther Adv Med Oncol 2017;9:171-81.
  2. Fisher R, Gore M, Larkin J. Current and future systemic treatments for renal cell carcinoma. Semin Cancer Biol 2013;23:38-45.
  3. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018;68:394-424.
  4. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Kidney Cancer. Ver. 3. Fort Washington, PA: National Comprehensive Cancer Network; 2015. Available from: https: https://www.nccn.org/professionals/physician_gls/default.asp. [Last accessed on 2020 Oct 01].
  5. Afinitor (Everolimus) Prescribing Information. East Hanover, NJ: Novartis Pharmaceuticals; 2015. Available from: https://www.novartis.us/sites/www.novartis.us/files/afinitor.pdf?irmasrc=ONCWB0043&source=01030. [Last accessed on 2020 Oct 01].
  6. Dabney R, Devine R, Sein N, George B. New agents in renal cell carcinoma. Target Oncol 2014;9:183-93.
  7. Raman R, Vaena D. Immunotherapy in metastatic renal cell carcinoma: A comprehensive review. Biomed Res Int 2015;2015:367354.
  8. Motzer RJ, Rini BI, David F, Bruce G, Timothy M, Michael R, et al. Nivolumab for metastatic renal cell carcinoma: Results of a randomized phase II trial. J Clin Oncol 2015;33:1430-7.
  9. Heng DY, Xie W, Regan MM, Harshman LC, Bjarnason GA, Vaishampayan UN, et al. External validation and comparison with other models of the International Metastatic Renal-Cell Carcinoma Database Consortium prognostic model: A population-based study. Lancet Oncol 2013;14:141-8.
  10. Choueiri TK, Escudier B, Powles T, Tannir NM, Mainwaring PN, Rini BI, et al. Cabozantinib versus everolimus in advanced renal cell carcinoma (METEOR): Final results from a randomised, open-label, phase 3 trial. Lancet Oncol 2016;17:917-27.
  11. Motzer RJ, Hutson TE, Glen H, Michaelson MD, Molina A, Eisen T, et al. Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: A randomised, phase 2, open-label, multicentre trial. Lancet Oncol 2015;16:1473-82.
  12. Guo L, Zhang H, Chen B. Nivolumab as Programmed Death-1 (PD-1) inhibitor for targeted immunotherapy in tumor. J Cancer 2017;8:410-6.
  13. Kazandjian D, Suzman DL, Blumenthal G, Mushti S, He K, Libeg M, et al. FDA approval summary: Nivolumab for the treatment of metastatic non-small cell lung cancer with progression on or after platinum-based chemotherapy. Oncologist 2016;21:634-42.
  14. Abbas W, Rao RR, Popli S. Hyperprogression after immunotherapy. South Asian J Cancer 2019;8:244-6.
  15. Chakraborty S. A step-wise guide to performing survival analysis. Cancer Res Stat Treat 2018;1:41-5.




 
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Fisher R, Gore M, Larkin J. Current and future systemic treatments for renal cell carcinoma. Semin Cancer Biol 2013;23:38-45.  Back to cited text no. 2
    
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