You are viewing a javascript disabled version of the site. Please enable Javascript for this site to function properly.
Go to headerGo to navigationGo to searchGo to contentsGo to footer
In content section. Select this link to jump to navigation

Double Immune Checkpoint Blockade in Renal Cell Carcinoma

Abstract

 Long considered an immunogenic tumour, immunotherapy has been the cornerstone of systemic treatment in renal cell carcinoma (RCC) for decades, since the introduction of interleukin 2 and interferon-alfa in the 1980s to the more recently approved immune checkpoint inhibitors. Moreover, on the basis that anti-CTLA-4 and anti-PD-1/PD-L1 intrinsic mechanisms are different, double checkpoint inhibition was proposed to further improve anti-tumor immune response. The first trial to assess double checkpoint inhibition was Checkmate 016 (nivolumab and ipilimumab). It showed acceptable safety and promising antitumor activity that led to the first phase III trial with combination immunotherapy in RCC, Checkmate 214. This trial showed superior overall survival and response rate of the combination immunotherapy (nivolumab and ipilimumab) versus sunitinib in intermediate- and poor-risk advanced RCC, leading to its approval in this setting. Despite these advances, there is still room for improvement. In this context, cytokines and T-cell costimulatory molecules are currently under investigation. This review summarizes the principles of immunotherapy and its role in RCC, provides an update on double checkpoint blockade and discusses the major challenges with double checkpoint blockade.

RATIONALE FOR IMMUNOTHERAPY

Three steps need to be achieved in order to yield antitumor immunity: 1) immunization, which implies antigen presentation and dendritic cell maturation; 2) T-cell response, which requires interaction between stimulatory and inhibitory molecules and surface proteins; and 3) immunosuppression, which implicates tumor microenvironment strategies that alter T cell effects through suppressive ligands (such as PD-L1,PD-L2) or molecules (indoleamine 2,3-dyoxygenase-IDO) among others [1, 2].

T-cell response regulation has revolutionized cancer therapeutics. By removing known inhibitory pathways, T-cell response is allowed to act freely. One of the effectors of this carefully delineated balance are the cytotoxic T-cells surface proteins that allow for restraint of immune response, known as checkpoint proteins [3]. In nature, checkpoint proteins display a wide variety, but two have been well described in literature. Cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) and Programmed cell death protein (PD-1) are surface proteins that undergo upregulation after T-cells are activated [4, 5]. These inhibitory checkpoint proteins exemplify different mechanisms and pathways but ultimately have the same objective: to improve antitumor immune response [6, 7].

T-cell activation requires interaction between CD28 on the T-cell surface and B7 on the antigen-presenting cell surface. CTLA-4 displaces CD28 from B7, which ensures T-cell suppression and at the same time enhances T regulatory cells activation and suppresses helper T-cells [4, 8]. Mellman et al. suggest that tumor-protective T-cells would then become activated after CTLA-4 blockade [1]. In contrast, PD-1 and its ligands (PD-L1 and PD-L2), members of the B7 gene family, operate through a different inhibitory pathway [9]. These transmembrane proteins, found in T- and B-cells, are responsible for activation of T regulatory cells through de novo conversion of CD4+ T-cells and inhibition of interferon-γ, tumor necrosis factor-α and IL-2 production, allowing for immunosuppressive function. Furthermore, if PD-1 is expressed persistently on T-cells an exhaustive phenotype emerges depicting diminished immune function [10]. PD-1 ligands (PD-L1 and PD-L2) are not only expressed by antigen presenting cells but many non-immune cells and even tumor cells [5, 11]. Thus, they present a diversity of ligands that differ in nature, function and implications fortherapy.

The well-balanced immune structure can also be hijacked by the tumor microenvironment so cancer can develop, progress and prevail in the organism. This understanding introduced the concepts of immunoevasion and tumor-promoting inflammation among cancer hallmarks [12, 13]. Immune checkpoint blockade with an anti-CTLA-4 and anti-PD-1/PD-L1 represent part of these advances in several immunogenic cancer types such as melanoma, non-small-cell lung cancer (NSCLC) and renal cell carcinoma (RCC), among others [14].

Immunotherapy has been used in kidney cancer for decades [15, 16]. RCC has been considered as an immunogenic tumor because of the increased infiltration of immune cells including T-cells, dendritic cells, natural killer T-cells, macrophages and memory cells, and also increased cytokine secretion. In the 1980s and 1990s, RCC immunotherapy was based on high-dose interleukin-2 (IL-2) and interferon-alfa (IFNa), which elicited a high burden of toxicities and yielded low efficacy. More recently, Nivolumab, an anti-PD-1 monocloncal antibody, was the first immune checkpoint inhibitor approved by the FDA in 2015 based on results of the CheckMate 025 study [16–18]. This was later followed by subsequent otherapprovals.

In addition, based on the core concept that anti-CTLA-4 and anti-PD-1/PD-L1 intrinsic mechanisms are different, double checkpoint inhibition was proposed to further improve anti-tumor immune response. Anti-CTLA-4 acts in lymphoid organs in the early steps of immune response. In contrast, anti-PD-1/PD-L1 acts in the tumor microenvironment later in the response. In this review we will summarize the current evidence of double immune checkpoint blockade in RCC.

Double immune checkpoint blockade

Simultaneous pathway blockade and sequential blockade are the backbone of combination therapy in RCC. The association of both immune checkpoint inhibitors in a preclinical setting is more effective disrupting the tumor microenvironment [19]. In RCC, the concept has been proven to be clinically effective within the Checkmate-016 and Checkmate-214 trials.

IPILIMUMAB-NIVOLUMAB COMBINATION IN ADVANCED RENAL CELL CARCINOMA

Checkmate-016

The first study to assess the combination of immune checkpoint inhibitors (ICI) in mRCC was the Checkmate-016 study (NCT01472081) [20]. This phase I trial was based on previous results on patients with melanoma and lung cancer where double immune checkpoint blockade was more effective than monotherapy and also on efficacy evidence of anti-CTLA-4 antibodies in mRCC [14, 21]. Its primary endpoint was the overall safety and tolerability of nivolumab plus ipilimumab. Eligible patients were divided in 3 groups that received nivolumab 3mg/kg plus ipilimumab 1mg/kg (N3I1), nivolumab 1mg/kg plus ipilimumab 3mg/kg (N1I3) or nivolumab 3mg/kg plus ipilimumab 3mg/kg (N3I3) every 3 weeks for four cycles and then only nivolumab 3mg/kg every 2 weeks until progression or toxicity. Accrual on N3I3 group was discontinued due to the observed high-grade 3 or 4 adverse effects (AEs) (83.3%). On the other hand, high-grade AEs in N3I1 and N1I3 treatment groups were 38.3% and 61.7%, respectively. N3I1 treatment group had also lower treatment-related AEs, lower treatment discontinuation rates and less patients requiring immune modulating medications (61.7% vs 83.0%). After a median follow-up of 22.3 months, the objective response rate (ORR) for both treatment-naive arms was 40% and the progressive disease (PD) rate as best response was 17%. Complete response (CR) and partial response (PR) rates in N3I1 treated patients were 10.6% and 29.8%, respectively. In comparison, there were no CR in N1I3 treated patients and the PR rate was 40.4%. Safety profile favoured N3I1 treatment group, therefore it was selected for further development in a phase III trial.

Checkmate-214

Ipilimumab plus nivolumab combination has not been compared with either nivolumab or ipilimumab alone in mRCC. However, results from Checkmate-016 led to the conduct of a phase III trial with the combination. In the Checkmate 214, 1096 patients with previously untreated mRCC were randomized 1:1 to receive nivolumab 3mg/kg plus ipilimumab 1mg/kg every 3 weeks for four doses, then only nivolumab 3 mg/kg every 2 weeks or sunitinib 50 mg, orally, daily, for 4 weeks on followed by 2 weeks off. Primary endpoints were overall survival (OS), ORR and progression-free survival (PFS) in the intermediate and poor IMDC risk-groups. After a median of 25.2 months, there was a significant improvement in 18-month OS (75% with the combination versus 60% with sunitinib) and ORR (42% vs 27%, respectively, P < 0.001), favouring nivolumab plus ipilimumab combination [22]. The median OS was not reached (NR) and 26 months for immunotherapy combination and sunitinib, respectively. Of note, the CR rate was 9% and 1%, respectively, and the median PFS was 11.6 and 8.4 months, respectively (HR 0.82, p = 0.03). Similar benefit was seen when evaluating the whole cohort including all IMDC risk-groups (favorable, intermediate and poor) (secondary endpoint). The safety profile showed any-grade and high-grade AEs of 93% and 46%, respectively, in the immunotherapy combination arm, and 97% and 63%, respectively, in the sunitinib arm. Interestingly, although the AE-related treatment discontinuation rate was superior in the ICI combination arm (22%) versus the sunitinib arm (12%), patients who discontinued in the experimental arm due to drug-related AEs experienced long-term benefit, with durable responses after the last dose of treatment. Moreover, the recently reported PROs (patient reported outcomes) as an exploratory endpoint, showed an improvement of health-related quality of life (HRQOL) across all instruments (Assessment of Cancer Therapy Kidney Sympton Index-19, Functional Assessment of Cancer Therapy-General, and EuroQol five dimensional three level) for the immunotherapy combination arm in patients with intermediate or poor risk mRCC [23]. Efficacy in the favorable IMDC risk-group only was evaluated as an exploratory outcome. In this favorable-risk group, sunitinib treated patients had higher 18-month OS, ORR and PF. However, it should be mentioned that the CR rate in favorable-risk patients treated was higher with the immunotherapy combination (11% versus 5%). Also as an exploratory analysis, among intermediate and high risk patients who had quantifiable PD-L1 expression (<or ≥1%) the combination immunotherapy arm showed superiority in both OS and ORR irrespective of PD-L1 expression versus the control arm. However, mPFS among patients with < 1% PD-L1 expression was similar in both arms of treatment (HR 1.00; 95% CI, 0.80 to 1.26), whereas among patients with ≥1% PD-L1 expression mPFS was superior with the immunotherapy combination (HR 0.46; 95% CI, 0.31–0.67) [22]. On April 16, 2018, the FDA approved the double immune checkpoint blockade, nivolumab plus ipilimumab, for the treatment of intermediate or poor risk, previously untreated advanced RCC patients.

OTHER COMBINATIONS

Despite the remarkable progress that has been achieved with ipilimumab and nivolumab combination, there is still room for improvement in efficacy and safety profile. It remains unclear whether the enhanced efficacy of combined anti PD-1 and anti-CTLA4 therapy is mediated by additive engagement or through independent mechanisms from each drug [24]. T-cell costimulatory molecules represent a vast number of proteins under investigation such as LAG3, TIM3 or TIGIT, VISTA from the immunoglobulin superfamily (IgSF) or OX40, GITR, 4-1BB, CD40 from the tumor necrosis factor receptor superfamily (TNFRSF) and others. Better understanding of each specific protein and its stimulatory role are required for an enhanced development of novel immune checkpoint blockade combinations [25]. Table 3 shows selected combinations in early clinical development phase.

Table 1

Efficacy outcomes in the Checkmate-016 and the Checkmate-214

EfficacyCheckmate 016 (N3I1)Checkmate 214
ORR40% (95% CI 26.4 to 55.7)42% (95% CI, 37 to 47)
Overall Survivalnot reached (95% CI, 26.7 months to not reached)not reached (95% CI, 28.2 months to not estimable)
12 -month OS81%80% (95CI, 76 to 84)
PFS7 months (95% CI, 3.7 to 14.3 months)11.6 months (95% CI, 8.7 to 15.5)
Table 2

Safety outcomes in the Checkmate-016 and the Checkmate-214 studies

Treatment related adverse effects.Checkmate 016Checkmate 214
N47547
Median Age (range)54(26–68)62(26–85)
MSKCC/ IMDC intermediate-poor risk55.30%77.70%
Treatment ArmNivo 3mg/kg+Ipi 1mg/kgNivo 3mg/kg+Ipi 1mg/kg
Any grade92%93%
Grade 3-4 toxicity38.30%46%
Discontinuation rate for toxicity10.60%22%
Table 3

Summary of Selected Studies of Double Immune checkpoint blockade

PhaseTrialYearTreatment ongoingTitle
Phase IIIb/IVNCT02982954 Checkmate 920January 2023Nivolumab plus IpilimumabSafety Trial of Nivolumab Combined With Ipilimumab in Subjects With Previously Untreated, Advanced or Metastatic RCC
Phase IIINCT03138512 Checkmate 914July 2023Nivolumab plus IpilimumabA Phase 3 Randomized Study Comparing Nivolumab and Ipilimumab Combination vs Placebo in Participants with Localized Renal Cell Carcinoma Who Underwent Radical or Partial Nephrectomy and Who Are at High Risk of Relapse
NCT03288532 RAMPARTDecember 2037Active Monitoring or Durvalumab or Durvalumab plus TremelimumabAn International Investigator-led Phase III Multi Arm Multi Stage Multi-centre Randomised Controlled Platform Trial of Adjuvant Therapy in Patients With Resected Primary Renal Cell Carcinoma (RCC) at High or Intermediate Risk of Relapse
Phase IINCT03203473 OMNIVORE StudyNovember 2014Nivolumab or Nivolumab plus IpilimumabPhase II Study of Optimized Management of Nivolumab Based on REsponse in Patients With Advanced Renal Cell Carcinoma
Phase I/IINCT02335918January 2020Nivolumab plus VarlilumabA Phase l/ll Dose Escalation and Cohort Expansion Study of the Safety, Tolerability and Efficacy of Anti-CD27 Antibody (Varlilumab) Administered in Combination With Anti-PD-1 (Nivolumab) in Advanced Refractory Solid Tumors
NCT02089685 KEYNOTE-029June 2020Pembrolizumab plus Pegylated Interferon alfa-2b or Pembrolizumab plus IpilimumabPembrolizumab Plus Pegylated Interferon alfa- 2b or Ipilimumab for Advanced Melanoma or Renal Cell Carcinoma: Dose-Finding Results from the Phase Ib Study
NCT02983045 PIVOT-02June 2021Phase I: NKTR-214 + nivolumab Phase II: NKTR- 214 + nivolumab+ipilimu mabA Dose Escalation and Cohort Expansion Study of CD122-Biased Cytokine (NKTR-214) in Combination With Anti-PD-1 Antibody (Nivolumab) or in Combination With Nivolumab and Anti-CTLA4 Antibody (Ipilimumab) in Patients With Select Advanced or Metastatic Solid Tumors
Phase INCT02496208September 2019Cabozantinib plus Nivolumab or Cabozantinib plus Nivolumab plus IpilimumabA Phase 1 Study of Cabozantinib Plus Nivolumab (CaboNivo) Alone or in Combination With Ipilimumab (CaboNivoIpi) in Patients With Advanced/Metastatic Urothelial Carcinoma and Other Genitourinary Tumors
NCT01975831December 2019Durvalumab plus TremelimumabPhase 1 study to evaluate the safety and tolerability of MEDI4736 (durvalumab, DUR)+tremelimumab (TRE) in patients with advanced solid tumors.
NCT02210117November 2020Arm A: Nivolumab or Arm B: Nivolumab plus Bevacizumab or Arm C: Nivolumab plus IpilimumabA Pilot Randomized Tissue-Based Study Evaluating Anti-PD1 Antibody or Anti-PD1 + Bevacizumab or Anti-PD1 + Anti-CTLA-4 in Patients With Metastatic Renal Cell Carcinoma Who Are Eligible for Cytoreductive Nephrectomy, Metastasectomy or Post-Treatment Biopsy
NCT02614456December 2021Nivolumab plus Interferon-gammaCombination Immunotherapy With Interferon- gamma and Nivolumab for Patients With Advanced Solid Tumors: A Phase 1 Study

Cytokines were the main treatment for mRCC during preceding decades; however the rate of response was low. A novel C122-biased cytokine (NTRK-214) is currently under development in combination with nivolumab and ipilimumab in the phase I/II PIVOT-02 trial. It is expected that NKTR-214 may unleash T cell proliferation and disrupt the tumor microenvironment. The combination of NKTR-214 and nivolumab assures a potentially non-overlapping effective synergistic mechanism. This study was conceived as a 4 part study (NCT02983045). Study part 1 determined doses and scheduling according to safety and efficacy profile of the combination. The selected dose and schedule was NKTR-214 0.006 mg/kg and nivolumab 360 mg every 3 weeks per intravenous infusion. In study Part 2, the combination was given to patients with metastatic melanoma, RCC, urothelial carcinoma, non-small cell lung cancer or triple negative breast cancer. The RCC cohort enrolled 48 patients of which PD-L1 status was unknown for 4 patients, negative for 30 patients, and positive for 14 patients. Preliminary results showed in previously untreated RCC patients an overall ORR of 46%. The median time on study was 5.6 months. The PD-L1 negative patients ORR was 53% (9/17), while it was 29% (2/7) for PD-L1 positive patients [26]. In part 3 of the study, a triple combination will be attempted in order to assess safety, tolerability and efficacy (ORR): NKTR-214 0.006 mg/kg plus nivolumab 360 mg every 3 weeks, and ipilimumab 1mg/kg every 6 weeks. Study part 4 will plan to enrol more patients to further evaluate the tripletcombination.

KEY POINTS AND CHALLENGES WITH DOUBLE IMMUNE CHECKPOINT BLOCKADE

Why double and not single-agent?

Double immune checkpoint blockade has been shown to be more powerful than single-agent immunotherapy across different tumour types, but also more toxic [27]. However, the superiority of immunotherapy doublets versus single agents has not yet been demonstrated for mRCC. It is known that nivolumab alone benefits previously treated metastatic renal cell carcinoma patients [22, 28], but the magnitude of the benefit with the addition of ipilimumab was just recently clarified. Recent data with pembrolizumab monotherapy in untreated mRCC patients has shown encouraging activity [29], with a confirmed ORR of 38.2% (n = 42; 95% CI 29.1–47.9) with 3 complete responses (2.7%) and 39 (35.5%) partial responses. The durable clinical response rate was 59.1% with a favourable safety profile. It seems clear that the addition of ipilimumab is more toxic and some patients may not need the combinations [14]. Further research to better understand which patients do really benefit the combination is required to avoid toxicities (financial and non-financial). Clinical trials with adaptive design such as TITAN (NCT02917772) or OMNIVORE (NCT03203473) will help to understand this issue.

What is the optimal duration of treatment?

There is evidence showing that patients who respond to immunotherapy and combination immunotherapy achieve durable responses and long-term survival [30]. Although immune checkpoint blockade is already a standard of care across different tumour types, there is no clear evidence about the duration of treatment on responders. In recent data from the Keynote-006 4-year survival and outcomes after cessation of pembrolizumab showed that 86% of the patients who completed pembrolizumab 2 years remained progression-free 20 months after the last dose of treatment [31]. Also, it has been shown that nearly 70% of the melanoma patients who obtained a complete or partial response and discontinued single-agent nivolumab due to toxicity maintained their responses despite the discontinuation of treatment [30, 32]. Moreover, this may be even more complex when it comes to patients who achieve a complete response. The clinical trial Keynote-001 showed that a high proportion of patients who achieved a complete response are able to maintain the response for a long time after the end of treatment, with an estimated 24 month disease-free survival of 89% [31]. Altogether, these results suggest stopping immune checkpoint blockade after a certain period of time on treatment could be a reasonable approach. However, further research on this topic is warranted.

How should we assess atypical responses?

Although there is lack of evidence, we are now familiar with the so known “pseudoprogression” which usually appears as a radiological progression with target lesion increase but without clinical deterioration. There are data suggesting that treatment beyond progression may be an option for some patients [33, 34]. However, there is also evidence supporting that some patients may have hyperprogressive disease, but little is known about the mechanisms involved [35]. It has been speculated to be a result of immunotherapy but it has also been suggested to be the consequence of aggressive natural tumour behaviour. Nonetheless, knowledge on this field is scarce and further studies are needed to better understand and define which patients are more likely to rapidly progress and which ones will instead experience pseudoprogression and therefore benefit of treatment beyond radiological progression [36].

CONCLUSIONS

Several trials will be conducted in the next years to elucidate the impact of novel combinations on RCC therapy. In the near future, the patient’s tumor biology should be matched with the best corresponding first line option among a handful of options: either monotherapy or combinations. Double immune checkpoint blockade has shown favourable results, but adverse effects should be taken into consideration. The most definitive evidence of double checkpoint inhibitor therapy on intermediate-poor risk patients with previously untreated advanced RCC are the results from Checkmate trial 214 with a remarkable 9% complete response rate.

Although we are now familiar with immune checkpoint blockade therapies, there are still some open questions. Optimal duration of treatment or unexpected radiological responses, including primary refractory disease, require further study.

REFERENCES

[1] 

Mellman I , Coukos G , Dranoff G . Cancer immunotherapy comes of age. Nature. 2011 Dec;480(7378):480–9.

[2] 

Chen DS , Mellman I . Elements of cancer immunity and the cancer–immune set point. Nature. 2017 Jan;541(7637):321–30.

[3] 

Chikuma S , Kanamori M , Mise-Omata S , Yoshimura A . SOCS: Potential immune checkpoint molecules for cancer immunotherapy. Cancer Sci. 2017.

[4] 

Azuma M , Ito D , Yagita H , Okumura K , Phillips JH , Lanier LL , et al. B70 antigen is a second ligand for CTLA-4 and CD28. Nature. 1993;366(6450):76–9.

[5] 

Butte MJ , Peña-Cruz V , Kim M-J , Freeman GJ , Sharpe AH . Interaction of human PD-L1 and B7-1. Molecular Immunology. 2008;45(13):3567–72.

[6] 

Sharma P , Allison JP . The future of immune checkpoint therapy. Science. 2015 Apr 3;348(6230):56–61.

[7] 

Page DB , Postow MA , Callahan MK , Allison JP , Wolchok JD . Immune modulation in cancer with antibodies. Annual Review of Medicine. 2014;65(1):185–202.

[8] 

Snyder A , Makarov V , Merghoub T , Yuan J , Zaretsky JM , Desrichard A , et al. Genetic basis for clinical response to CTLA-4 blockade in melanoma. N Engl J Med. 2014;371(23):2189–99.

[9] 

Ohaegbulam KC , Assal A , Lazar-Molnar E , Yao Y , Zang X . Human cancer immunotherapy with antibodies to the PD-1 and PD-L1 pathway. Trends in Molecular Medicine. 2015;21(1):24–33.

[10] 

Keir ME , Butte MJ , Freeman GJ , Sharpe AH . PD-1 and its ligands in tolerance and immunity. Annual Review of Immunology. 2008;26(1):677–704.

[11] 

Buchbinder EI , Desai A . CTLA-4 and PD-1 pathways: Similarities, differences, and implications of their inhibition. American Journal of Clinical Oncology. 2016;39(1):98–106.

[12] 

Hanahan D , Weinberg RA . Hallmarks of cancer: The next generation. Cell. 2011;144(5):646–74.

[13] 

Hanahan D , Weinberg RA . The hallmarks of cancer. Cell. 2000;100(1):57–70.

[14] 

Larkin J , Chiarion-Sileni V , Gonzalez R , Grob JJ , Cowey CL , Lao CD , et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. New England Journal of Medicine. 2015;373(1):23–34.

[15] 

Adler A , Gillon G , Lurie H , Shaham J , Loven D , Shachter Y , et al. Active specific immunotherapy of renal cell carcinoma patients: A prospective randomized study of hormono-immuno-versus hormonotherapy. Preliminary report of immunological and clinical aspects. J Biol Response Mod. 1987;6(6):610–24.

[16] 

Fyfe G , Fisher RI , Rosenberg SA , Sznol M , Parkinson DR , Louie AC . Results of treatment of 255 patients with metastatic renal cell carcinoma who received high-dose recombinant interleukin-2 therapy. J Clin Oncol. 1995;13(3):688–96.

[17] 

McDermott DF , Regan MM , Clark JI , Flaherty LE , Weiss GR , Logan TF , et al. Randomized phase III trial of high-dose interleukin-2 versus subcutaneous interleukin-2 and interferon in patients with metastatic renal cell carcinoma. J Clin Oncol. 2005;23(1):133–41.

[18] 

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(19):1803–13.

[19] 

Curran MA , Montalvo W , Yagita H , Allison JP . PD-1 and CTLA-4 combination blockade expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumors. Proceedings of the National Academy of Sciences. 2010;107(9):4275–80.

[20] 

Hammers HJ , Plimack ER , Infante JR , Rini BI , McDermott DF , Lewis LD , et al. Safety and efficacy of nivolumab in combination with ipilimumab in metastatic renal cell carcinoma: The checkMate 016 study. Journal of Clinical Oncology. 2017;35(34):3851–8.

[21] 

Callahan MK , Kluger H , Postow MA , Segal NH , Lesokhin A , Atkins MB , et al. Nivolumab plus ipilimumab in patients with advanced melanoma: Updated survival, response, and safety data in a phase I dose-escalation study. J Clin Oncol. 2018;36(4):391–8.

[22] 

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(14):1277–90.

[23] 

Cella D , Grünwald V , Escudier B , Hammers HJ , George S , Nathan P , et al. Patient-reported outcomes of patients with advanced renal cell carcinoma treated with nivolumab plus ipilimumab versus sunitinib (CheckMate 214): A randomised, phase 3 trial. The Lancet Oncology. 2019;20(2):297–310.

[24] 

Wei SC , Duffy CR , Allison JP . Fundamental mechanisms of immune checkpoint blockade therapy. Cancer Discovery. 2018;8(9):1069–86.

[25] 

Marin-Acevedo JA , Dholaria B , Soyano AE , Knutson KL , Chumsri S , Lou Y . Next generation of immune checkpoint therapy in cancer: New developments and challenges. Journal of Hematology & Oncology [Internet]. 2018 Dec [cited 2019 Jan 15];11(1). Available from: https://jhoonline.biomedcentral.com/articles/10.1186/s13045-018-0582-8.

[26] 

Diab A . Pivot-02: Preliminary safety, efficacy and biomarker results from dose escalation of the Phase 1/2 study of CD-122-biased agonist NKTR-214 plus nivolumab in patients with locally advanced/metastatic melanoma, renal cell carcinoma and non-small cell lung cancer. In National Harbor, MD; 2017.

[27] 

Errico A . Melanoma: CheckMate 067—frontline nivolumab improves PFS alone or in combination with ipilimumab. Nature Reviews Clinical Oncology. 2015;12(8):435–5.

[28] 

Escudier B , Sharma P , McDermott DF , George S , Hammers HJ , Srinivas S , et al. CheckMate 025 randomized phase 3 study: Outcomes by key baseline factors and prior therapy for nivolumab versus everolimus in advanced renal cell carcinoma. European Urology. 2017;72(6):962–71.

[29] 

Meeting Library | Pembrolizumab monotherapy as first-line therapy in advanced clear cell renal cell carcinoma (accRCC): Results from cohort A of KEYNOTE-427. [Internet]. [cited 2018 Jun 4]. Available from: https://meetinglibrary.asco.org/record/160560/abstract.

[30] 

Hodi FS , Chiarion-Sileni V , Gonzalez R , Grob J-J , Rutkowski P , Cowey CL , et al. Nivolumab plus ipilimumab or nivolumab alone versus ipilimumab alone in advanced melanoma (CheckMate 067): 4-year outcomes of a multicentre, randomised, phase 3 trial. The Lancet Oncology. 2018;19(11):1480–92.

[31] 

Robert C , Long GV , Schachter J , Arance A , Grob JJ , Mortier L , et al. Long-term outcomes in patients (pts) with ipilimumab (ipi)-naive advanced melanoma in the phase 3 KEYNOTE-006 study who completed pembrolizumab (pembro) treatment. Journal of Clinical Oncology. 2017;35(15_suppl):9504–4.

[32] 

Wolchok JD , Chiarion-Sileni V , Gonzalez R , Rutkowski P , Grob J-J , Cowey CL , et al. Overall survival with combined nivolumab and ipilimumab in advanced melanoma. New England Journal of Medicine. 2017;377(14):1345–56.

[33] 

Cortesi E, Cappuzzo F., Galli L., Bearz A., Pignata S.. 892P - Treatment beyond progression in patients with advanced RCC participating in the Expanded Access Programme (EAP) Annals of Oncology (2017) 28 (suppl 5): v295–v329. 2017.

[34] 

Escudier B , Motzer RJ , Sharma P , Wagstaff J , Plimack ER , Hammers HJ , et al. Treatment beyond progression in patients with advanced renal cell carcinoma treated with nivolumab in checkMate 025. European Urology. 2017;72(3):368–76.

[35] 

Hyperprogressive disease (HPD) is a newpattern of progression in cancer patients treated by anti-PD-1/PD-L1 | Clinical Cancer Research [Internet]. [cited 2019 Jan 15]. Available from: http://clincancerres.aacrjournals.org/content/early/2016/11/08/1078-0432.CCR-16-1741

[36] 

De Velasco G , Krajewski KM , Albiges L , Awad MM , Bellmunt J , Hodi FS , et al. The heterogeneity of radiologic response with anti-PD-1/PD-L1 therapy in metastatic Renal Cell Carcinoma (mRCC). Cancer Immunol Res. 2015.