The society for immunotherapy of cancer consensus statement on immunotherapy for the treatment of advanced renal cell carcinoma (RCC)

Abstract
The approval of immunotherapeutic agents and immunotherapy-based combination strategies in recent years has revolutionized the treatment of patients with advanced renal cell carcinoma (aRCC). Nivolumab, a programmed death 1 (PD-1) immune checkpoint inhibitor monoclonal antibody, was approved as monotherapy in 2015 for aRCC after treatment with a VEGF-targeting agent. In April 2018, the combination of nivolumab and ipilimumab, a CTLA-4 inhibitor, was approved for intermediate- and poor-risk, previously untreated patients with aRCC. Then, in 2019, combinations therapies consisting of pembrolizumab (anti-PD-1) or avelumab (anti-PD-ligand (L) 1) with axitinib (a VEGF receptor tyrosine kinase inhibitor) were also approved to treat aRCC and are likely to produce dramatic shifts in the therapeutic landscape. To address the rapid advances in immunotherapy options for patients with aRCC, the Society for Immunotherapy of Cancer (SITC) reconvened its Cancer Immunotherapy Guidelines (CIG) Renal Cell Carcinoma Subcommittee and tasked it with generating updated consensus recommendations for the treatment of patients with this disease.

Introduction
The development of novel immuno-oncology (IO) thera- peutics has transformed the treatment paradigm for patients with advanced renal cell carcinoma (aRCC) and altered the role of previous approaches involving antian- giogenic agents targeting the vascular endothelial growth factor (VEGF) pathway. On November 23, 2015, the U.S. Food and Drug Administration (FDA) approved the anti-PD-1 monoclonal antibody nivolumab (Bristol Myers Squibb) for treatment of patients with aRCC after prior anti-angiogenic therapy [1]. On April 16, 2018 the FDA approved combination immunotherapy nivolumab (anti-PD-1) and ipilimumab (Bristol Myers Squibb; anti- cytotoxic T-lymphocyte-associated protein-4 [CTLA-4])for the treatment of patients with intermediate or poor risk, previously untreated aRCC. Then, on April 19, 2019 and on May 14th, 2019, FDA approved pembroli- zumab (Merck, Inc.; anti-PD-1) in combination with axi- tinib (Pfizer, Inc.; a VEGF receptor tyrosine kinase inhibitor; TKI) as well as avelumab (EMD Serono/Pfizer inc.; anti-PD-L1) in combination with axitinib, respect- ively, for the first-line treatment of patients with aRCC. Such approvals of first-line combination regimens will further expand and complicate RCC treatment options.The advances in IO therapy over the past decade prompted the need to apply this knowledge to improve the management of patients with aRCC, including the emergence of IO in combination with TKIs, appropriate patient selection considerations, therapy sequencing, re-the original Renal Cell Carcinoma clinical guidelines in November 2016 to provide evidence-based recommen- dations on how best to incorporate immunotherapies into practice for the treatment of patients with aRCC [2]. Recent advances in IO combinations have substan- tially added to the treatment approaches for patients with aRCC.

To address these advances, the SITC Cancer Immunotherapy Guidelines – Advanced Renal Cell Carcinoma Subcommittee determined that the field would benefit from the production of an updated con- sensus recommendation. This panel – including expert physicians, nurses, scientists, and a patient advocate – regularly communicated via email, teleconference, and in-person between September 2018 and June 2019 to review existing new data and determine how to incorpor- ate these results into an updated aRCC-specific consensus management guidelines. These resulting recommenda- tions are meant to provide guidance to clinicians with the most up-to-date data and recommendations on how to best integrate immunotherapy into the treatment para- digm for patients with advanced RCC.The National Academy of Medicine’s (NAM, formerly the Institute of Medicine) Standards for Developing Trustworthy Clinical Practice Guidelines reported in March 2011 were used as a model to generate this con- sensus statement [3]. In addition, methods applied previ- ously to SITC consensus guidelines were used in order to develop and organize this manuscript [4]. As outlined by NAM, consensus guideline standards should include a transparent process for guideline development, funding sources, and the reporting and management of conflicts of interest accomplished by a multidisciplinary and bal- anced committee. The committee, nominated to estab- lish an evidence-based foundation for recommendations and rating system to assess the strength of the evidence, reports the results through a peer-reviewed publication and publicly available website, and updates the statement as required by changes in the field. A draft of this consensus statement was made publicly available for comment between 8/12/2019 and 9/15/2019. The sub- committee should base its recommendations on evi- dence in the literature with a rating system to evaluate the strength of supporting peer-reviewed publications and results from reported clinical trials.This consensus statement is intended to provide guid- ance and is not a substitute for the professional judg- ment of each individual treating physician and for each individual patient. Full consensus recommendations, for this disease as well as others, can be found on the SITC website [5]. Due to differences in drug approval, avail- ability and regulations in some countries, this panelfocused solely on United States FDA-approved drugs and regimens for the treatment of aRCC patients.The Cancer Immunotherapy Guideline – Renal Cell Car- cinoma subcommittee consisted of nineteen participants, including thirteen medical oncologists, three urologists, one nurse, one nurse practitioner, and one patient advo- cate (Additional file 1). 100% of clinical subcommittee members reported previous experience/knowledge about the use IO therapy for the treatment of patients with aRCC.

The subcommittee convened in February 2019 in accordance with the National Academy of Medicine and SITC processes to review guideline development pro- gress as well as discuss the results from a previously distributed questionnaire collecting information on the participants’ role in the care of patients with aRCC and their current approach to various aspects of patient management. The clinical questionnaire addressed topics related to the role of the subcommittee members including primary clinical focus, experience with FDA- approved agents used for immunotherapy treatments, and current practices in the use or recommendation for use of such agents. The final consensus statement was made available to the entire SITC membership for open comment.Similar to the National Comprehensive Cancer Network (NCCN), SITC Cancer Immunotherapy Guidelines use categories of evidence. All recommendations are consid- ered category 2A unless otherwise noted [6]. Consensus was defined as ≥75% agreement among SITC’s Cancer Immunotherapy Guidelines committee members.In accordance with previous SITC practices used in development of consensus guidelines, nominated multi- disciplinary subcommittee members were both SITC members and nonmembers who were expected to be affected by the development of clinical guideline recom- mendations including clinicians, patient representatives, nurses, and others. All subcommittee members were re- quired to disclose any conflicts of interest using a SITC- specific disclosure form, mandating disclosure of full financial details and relationships with commercial en- tities that could be expected to have direct regulatory or commercial impact resulting from the publication of this statement. No commercial funding was provided to sup- port the consensus subcommittee, literature review, or the preparation of this manuscript.The MEDLINE database was used to search the scien- tific literature for current therapies related to renal cell carcinoma and immunotherapy in humans and encom- passed articles published from 2012 to 2019, including clinical trials, meta-analyses, practice guidelines, and re- search in humans. The search terms included “renal cell carcinoma OR RCC” and “ipilimumab”, “nivolumab”, “ipilimumab AND nivolumab”, “PD-1,” “PD-L1,” “CTLA- 4”, “immunotherapy”, “immune checkpoint inhibitor”, “PD-1/PD-L1”, “combination therapy AND immunother- apy”, “immunotherapy AND biomarkers”, “adverse event”, “immunotherapy AND non-clear cell”, “pembrolizumab”, “ipilimumab”, and “toxicity”.

Articles which were screened by subcommittee members to include only papers with clinically accurate and relevant information and to remove duplicates articles from independent searches, resulting in a final citation list catalogued using EndNote X7. The citation list was supplemented with additional articles identified by the panel, as appropriate and necessary for a comprehensive literature review.Consistent with current FDA-approved immunother- apies, the Cancer Immunotherapy Guideline – Renal Cell Carcinoma subcommittee generated the following consensus recommendations for management of aRCC.Traditional oncology clinical trials are generally de- signed to investigate one novel therapeutic agent or combination in comparison to a standard of care ther- apy. Cross-trial comparisons of two or more novel thera- peutic strategies is hazardous, even with a common control arm, given the multiple potential variables in trial conduct including eligibility criteria, endpoints, pa- tient management, timeframe, participating countries and institutions and availability of salvage therapies. This lack of statistical evidence comparing one specific ap- proach to another in relation to their benefit beyond the standard of care poses an obvious limitation to the con- clusions made by the subcommittee and to the develop- ment of the consensus recommendations provided.The integration of immunotherapeutic monoclonal anti- bodies directed against CTLA-4, PD-1, and PD-L1 – also known as IO agents – is now an essential part of the overall treatment strategy for patients with aRCC [7].Table 1 describes major phase 3 trials investigating first- line IO-based therapies in patients with aRCC.Formerly, patients with aRCC primarily received se- quential monotherapy with TKIs and possibly mTOR- targeted therapy [1]. A subset of patients with mRCC were also able to receive treatment with high dose IL-2 which produced durable responses (CRs and some PRs) in a small subset of patients; however the majority of pa- tients were not able to receive this treatment due to its potential toxicity, complexity and thus limited availabil- ity [15]. In 2015, single-agent nivolumab became avail- able in the second-line treatment of aRCC and paved the way for future immunotherapy regimens.

Based on the results of CheckMate 214, Keynote-426 and other phase III combination therapy trials, IO and IO/TKI strategies have changed the treatment paradigm for pa- tients with aRCC [Fig. 1. Treatment Algorithm] [9, 16].Regarding whether IMDC categories are still relevant for treatment decision making in light of the develop- ment of the IO-based combination therapy regimens in determining whether or not to recommend anti-PD-1 combination therapy, 59% of subcommittee members felt they were not relevant, while 41% felt that they still provided information that might influence treatment choice. Distinctly, in determining whether or not to rec- ommend anti-PD-1/TKI combination therapy, 76% of subcommittee members felt they were not relevant, while 24% felt that they still provided information that might influence treatment choice. Regardless of their clinical decision making utility, most subcommittee members thought the categories were still useful in assessing prognosis and for stratifying patients in clinical trials. Feedback from the patient advocacy community suggested that going forward, when using IMDC risk cri- teria in decision making with patients, the words “poor” risk and “favorable” risk should either be replaced with high risk and low risk or the community should move toward IMDC groups 1, 2, and 3., The majority of the subcommittee (74%) routinely order laboratory and other tests to determine IMDC risk group stratificationprior to treatment of patients with newly diagnosed accRCC.In addressing preliminary issues surrounding front- line management of RCC, the subcommittee recom- mends initiating systemic therapy first rather than cytoreductive nephrectomy in patients presenting with metastatic RCC with: IMDC poor risk categorization (80% of committee members), brain metastases (67%) or a large tumor burden outside primary kidney le- sion (60%) [17]. Cytoreductive nephrectomy is still considered a preferable option for patients with the majority of of their tumor burden confined to their primary and no other IMDC risk factors besides pre- senting with stage IV disease.Very little data exists regarding nivolumab monotherapy for first-line treatment of patients with aRCC [18].

How- ever, the randomized phase 3 CheckMate 214 trial ex- amined nivolumab plus ipilimumab combination therapy followed by nivolumab monotherapy, compared to suni- tinib monotherapy in previously untreated patients with accRCC [9, 10]. Patients received either nivolumab (3 mg/kg) plus ipilimumab (1 mg/kg) intravenously every three weeks for up to four doses, followed by nivolumab (3 mg/kg) every two weeks, or sunitinib (50 mg) orally once per day for four weeks, during a 6-week cycle (Su- nitinib 50 mg 4/2). This dosing schedule was derived from the previous CheckMate016 study finding that thisdosing was better tolerated than ipilimumab 3 mg/kg plus nivolumab 1 mg/kg with equal efficacy in patients with previous VEGF pathway therapy [5]. Outcomes were stratified according to the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC), a validated model which categorizes the prognosis of pa- tients with aRCC according to favorable-, intermediate-, or poor-risk disease depending on the presence of well- characterized clinical and laboratory risk factors [19, 20]. Primary endpoints included OS, ORR and PFS [9] in IMDC intermediate or poor-risk patients (I/P; n = 847) although the trial included subjects in all risk categories [20]. The trial demonstrated statistically significant im- provements in OS and ORR for patients receiving the combination compared with those receiving sunitinib that persisted at the 30-month follow-up (Table 2). Among the responders, 52% of patients receiving the im- munotherapy combination experienced a response dur- ation ≥18 months compared with 28% of patients treated with sunitinib. Of note, reported ORR, CR rate and re- sponse durability data from the 30-month follow-up in favorable risk patients treated with nivolumab/ipilimu- mab, detailed in Table 3, suggest that exclusion of favor- able risk patients from the potential long term benefits of IO therapy may not be justified.

That is, the subset of patients with durable CR or significant PR may justify consideration of ipilimumab plus nivolumab although the hazard ratios for OS, PFS and the ORR numerically, but no longer significantly, favor sunitinib for the entire favorable risk cohort. Importantly, patients reported bet- ter health-related quality of life (as measured by the FKSI-19) with nivolumab plus ipilimumab compared to those treated with sunitinib [9].More recently, combinations of antiangiogenic agentswith immunotherapeutic strategies have been evaluated. The biologic rationale for these combinations stems from preclinical studies in models which involved either non-clear cell tumors (e.g. RENCA) or other types of cancer altogether but which suggested that anti-VEGFagents could enhance antitumor immunity by increasing antigen presenting cell function, enhancing immune cell tumor infiltration, and decreasing effect of myeloid de- rived suppressor cells and macrophages in the tumor microenvironment [21].IMmotion150 (NCT01984242), a randomized phase 2 study of atezolizumab (anti-PD-L1) monotherapy or in com- bination with bevacizumab (anti-VEGF antibody) versus su- nitinib was investigated in 305 patients with treatment-naive cRCC. After progression on atezolizumab or sunitinib, crossover to atezolizumab/bevacizumab was allowed. Re- ported PFS hazard ratios for ITT patient population treated with atezolizumab/bevacizumab or atezolizumab monother- apy versus sunitinib were 1.0 (95% confidence interval (CI), 0.69–1.45) and 1.19 (95% CI, 0.82–1.71), respectively. After first-line treatment, 78% of patients treated with sunitinib and 60% of patients treated with atezolizumab who pro- gressed later received atezolizumab/bevacizumab and achieved ORRs of 28 and 24%, respectively. Subsequently, the IMmotion151 (NCT02420821) phase 3 trial investigated the combination of atezolizumab with bevacizumab, com- pared to sunitinib [14].

Atezolizumab was administered at 1200 mg + bevacizumab at 15 mg/kg IV every 3 weeks or su- nitinib at 50 mg 4/2. Primary endpoints included PFS in PD-L1+ patients (Table 3; ≥1% tumor-infiltrating immune cells [IC]) and OS in intent-to-treat (ITT) patients. Median survival follow-up was 15 months. PFS benefit was improved in the combination arm compared to sunitinib; however, no OS benefit was observed (Tables 1 and 3) [14].An open-label, phase Ib, single-arm clinical trial inves- tigated the combination of axitinib, a small molecule tyrosine kinase inhibitor TKI, and pembrolizumab in 52 treatment-naïve patients with aRCC. Median PFS was20.9 months (95% CI, 15.4 to not evaluable) and an ORR of 73.1% was reported, including CRs in 7.7%, suggestive of substantial antitumor activity [22].The phase 3 KEYNOTE-426 (NCT02853331) clinical trial further examined the combination of pembrolizumab with axitinib compared to sunitinib in patients with previouslyAtezolizumab vs. placebo as adjuvant therapy for 1 year in patients with RCC at high risk of disease recurrence following nephrectomyPembrolizumab vs. placebo (saline solution) as adjuvant therapy given after nephrectomy on 3-week cycles for up to 17 cycles in patients with resected intermedi- ate or high risk ccRCCBlinded Independent Central Review (BICR)-assessed disease-free survival (DFS)Independent review facility (IRF)- assessed DFS.Safety and efficacy and investigator- assessed DFS.Perioperative nivolumab vs. nephrectomy alone in treating patients with high-risk RCC Recurrence-free survival (RFS).Durvalumab monotherapy vs. durvalumab + tremelimumab vs. no intervention (active monitoring) as adjuvant therapy for 1 year in patients with resected primary RCC at high or intermediate risk of relapseDFS and OS.untreated accRCC. 861 patients were randomly assigned to receive pembrolizumab at a dose of 200 mg intravenously every three weeks for up to 35 doses plus axitinib 5 mg or- ally twice daily, or sunitinib (50 mg 4/2). At 12.8-month me- dian follow-up, 59.0% of patients in the pembrolizumab/ axitinib arm and 43.1% in the sunitinib arm remained on treatment.

OS, PFS, and ORR benefits were observed with the combination across all risk groups and PD-L1 expres- sion levels (Table 4) [11]. Results of this study mark the first time that a treatment improved endpoints of OS, PFS and ORR as frontline therapy in aRCC across all risk groups.Parallel with previously reported phase 1 pembrolizu- mab/axitinib data, phase 1 data for the Javelin Renal 100 (NCT02493751) study demonstrated a manageable safetyprofile with encouraging antitumor activity [23]. Succes- sively, the JAVELIN Renal 101 (NCT02684006) phase 3 study investigated the combination of avelumab (anti-PD- L1) with axitinib in 886 previously untreated patients with aRCC. Avelumab was administered at 10 mg/kg IV every two weeks in combination with axitinib, 5 mg orally twice daily. Sunitinib was given at 50 mg 4/2. Median PFS was improved in the combination arm compared to the suniti- nib arm in the overall population, irrespective of risk fac- tor and PD-L1 status (Tables 1, and 2) [12]. However, no overall survival benefit has been demonstrated for this combination. Specifically, at a median follow-up for over- all survival of 11.6 months and 10.7 months, among the patients with PD-L1–positive tumors, deaths from anySH Sarcomatoid HistologyCell population used: τ = tumor cells, ¥ = immune cells, β = both tumor and immune cellsAntibody used: a = Rabbit 28–8 (Dako), b = Mouse 22C3 (pharmDx), c = Rabbit SP263 (Ventana), d = Rabbit SP142 (Ventana)cause were observed in 37 patients (13.7%) who received avelumab plus axitinib and in 44 patients (15.2%) who re- ceived sunitinib (HR, 0.82; 95% CI, 0.53 to 1.28; p = 0.38). The median follow-up was 11.6 months and 10.7 months, respectively. In the overall population, HR for death for the two groups was 0.78 (95% CI, 0.554, 1.084; p = 0.14).Of the possible combination therapies including a VEGF inhibitor combined with an immune checkpoint inhibitor, 94% of the subcommittee recommended pem- brolizumab plus axitinib as the preferred combination for patients with aRCC.For a treatment naïve, ECOG 0 ccRCC patient with “favorable” risk per IMDC, who is determined to need systemic therapy and has no contraindication to receiv- ing either an IO or an anti-VEGF therapy, 50% of the subcommittee recommend treatment with axitinib/pem- brolizumab, 28% recommend treatment with nivolumab/ ipilimumab, 11% recommend TKI monotherapy, and 6% recommend treatment with either axitinib/avelumab or HDIL-2.

For a treatment naïve, ECOG 0 ccRCC patient with “intermediate/poor” risk per IMDC, who is determined to need systemic therapy and has no contraindication to re- ceiving either an IO or an anti-VEGF therapy, 78% recom- mend treatment with nivolumab/ipilimumab, 17% of the subcommittee recommend treatment with axitinib/pem- brolizumab, and 6% recommend ICI monotherapy.Anti-PD-1 monotherapy has also been tested as first-line therapy in patients with accRCC. Results from cohort A of the phase 2 KEYNOTE-427 trial (NCT02853344) investigating pembrolizumab (anti- PD-1) monotherapy as first-line therapy for the treat- ment of patients with accRCC were presented at the 2018 American Society of Clinical Oncology (ASCO) Congress [24]. Pembrolizumab was administered at a dose of 200 mg intravenously every three weeks for two years or until confirmed progressive disease (PD), unacceptable toxicity, or patient withdrawal. Median follow-up was 7.2 (0.9–11.7) months at the data cutoff (October 6, 2017). Of 107 patients, 37.3, 47.3, and 15.5% had IMDC risk categories of favorable, inter- mediate, and poor, respectively. Confirmed ORR was 38.2% (n = 42; 95% CI, 29.1–47.9) with 3 CR (2.7%)and 39 (35.5%) PRs in the overall patient population. ORR for patients with favorable, intermediate/poor risk IMDC was 31.7 and 42%, respectively. Median duration of response (DOR) was not reached (range, 1.4+ to 8.2+) [24]. Checkpoint inhibitor monotherapy, however, has not yet been approved by regulatory au- thorities or tested in a randomized study, and thus the precise role requires further investigation.In determining when to give a treatment-naïve patient IO monotherapy over an IO-based doublet therapy, the subcommittee recommend IO monotherapy for patientswith a history of autoimmune disease that is not poten- tially life threatening and is not currently on immuno- suppressive agents (56%), elderly patients over 80 years of age (50%), patients with a history of vascular disease such as stroke, recent ischemic cardiac disease without CABG (39%), patients with poor performance status (28%), patients with IMDC favorable risk (6%), and pa- tients with liver metastases with mildly increased LFTs (6%). 17% of subcommittee members would never rec- ommend IO monotherapy over an IO-based doublet therapy.

Given the current data, the subcommittee felt that all patients without a contraindication to immunotherapy should receive an IO-based regimen in the first line. Contraindications to anti-PD1 therapy include active or a history of life threatening autoimmune conditions and the requirement for corticosteroids (> 10 mg prednisone equivalent) for treatment of cancer-related conditions. Additionally, disease progression within 6 months of an adjuvant immunotherapy regimen was felt to be a poten- tial contraindication, although the activity of IO-based doublets in this setting are unknown.In 2015, backed by the results of the CheckMate 025 trial (NCT01668784), nivolumab gained FDA approval for the treatment of patients with aRCC who have re- ceived prior antiangiogenic therapy [1]. While this second-line therapy approval changed the treatment landscape for patients with aRCC previously treated with VEGFR TKIs, there exists considerable uncertainty and limited data as to how to treat patients with aRCC who have progressed on more recently approved first-line IO-based combination therapies.Literature review and second-line consensus recommendationsCategory 1 evidence is provided in data from CheckMate 025 for use of single agent anti-PD-1 immunotherapy for patients with accRCC who were previously treated with a VEGFR TKI.The randomized phase 3 CheckMate 025 study com- pared nivolumab to everolimus as therapy in previously treated patients with RCC. In this study, patients re- ceived either 3 mg/kg of nivolumab intravenously every two weeks or 10 mg everolimus orally once per day. Me- dian overall survival (OS) for nivolumab compared to everolimus was 25.0 months (95% confidence interval [CI], 21.8 to not estimable [NE]) and 19.6 months (95% CI, 17.6 to 23.1), respectively. The hazard ratio (HR) for death was 0.73 (98.5% CI, 0.57 to 0.93; P = 0.002). Theobjective response rate (ORR) was greater in patientstreated with nivolumab compared to everolimus (25% vs. 5%; odds ratio, 5.98 [95% CI, 3.68 to 9.72]; P < 0.001).Median progression-free survival (PFS) for nivolumab versus everolimus was 4.6 months (95% CI, 3.7 to 5.4)and 4.4 months (95% CI, 3.7 to 5.5; HR = 0.88, 95% CI,0.75 to 1.03; P = 0.11), respectively [16]. The role of nivolumab monotherapy is evolving given that nivolu- mab plus ipilimumab is now a front-line standard, the approval of other PD-1 pathway based combinations (see above), and thus fewer patients will be receiving nivolumab monotherapy.Nivolumab was initially investigated in combination with CTLA-4 antibodies in patients with mRCC, ap- proximately half of whom had received prior therapy, as part of the CheckMate 016 study. Confirmed ORR was seen in 36.2 and 40.4% of patients, respectively with ei- ther nivolumab 3 mg/kg + ipilimumab 1 mg/kg (N3I1 arm) or nivolumab 1 mg/kg + ipilimumab 3 mg/kg (N1I3 arm) regimen [5, 10]. Median PFS was 7.0 and 9.4 months for each regimen, respectively. Follow-up data suggested that over 50% of patients were alive and free from subsequent therapy at 3 years [25].

This data sup- port the combination of nivolumab/ipilimumab as sal- vage therapy after prior VEGFR therapy (see below for data related to second-line therapy).A small-scale retrospective analysis of patients treated with HD IL-2 following disease progression after PD-1 or PD-L1 inhibitor treatment showed that prior check- point inhibitor therapy may not be detrimental to subse- quent treatment with HD IL-2 in patients with RCC. Of 17 patients with mRCC who previously received PD-1 or PD-L1 inhibitors, there were 4 responses (2 complete, 2 partial) to HD-IL-2 therapy and the toxicity profile was similar to that seen in patients receiving front-line HD IL-2 [26].For a previously treated, ECOG 0, clear cell mRCC pa- tient with “favorable” risk whose tumors progressed on front-line therapy with sunitinib, 100% of the subcom- mittee recommend treating with a checkpoint immuno- therapy but were split in 37/63% by nivolumab monotherapy versus ipilimumab plus nivolumab com- bination immunotherapy if the patient can tolerate. Of note, as standard of care shifts to immunotherapy regi- mens in the first line setting, this situation will be un- likely to occur in the future and the use of VEGFR TKI monotherapy as first-line therapy will be limited to those patients who are perceived to be unable to be receive a checkpoint inhibitor based treatment regimen.In treating patients with disease progression after nivo- lumab/ipilimumab combination therapy, 72% of the sub- committee recommend treatment with cabozantinib, 22% recommend axitinib and 6% recommend HD IL-2.In treating patients with disease progression after IO/ VEGFR TKI combination therapy (either axitinib/pembrolizumab or axitinib/avelumab), the subcommittee consensus was to recommend treatment with cabozanti- nib (83%), while 11% recommended nivolumab/ipilimu- mab and 6% recommended lenvantinib/everolimus.Specifically, the subcommittee also acknowledged that no data existed for the use of nivolumab/ipilimumab in patients with disease progression on an IO/TKI combin- ation or for the use of a IO/TKI combination in patients with disease progression on front-line nivolumab/ipili- mumab, and suggested that clinical trials to obtain such data would be useful.With sunitinib approved in the adjuvant setting based on data from the S-TRAC trial and the widespread use of IO therapy in ongoing adjuvant and neoadjuvant tri- als, questions regarding management strategies arise [27].

Issues include the risk of potentially permanent side effects (diabetes, immune related arthritis, etc.) as- sociated with IO, especially important after potentially curative surgery, the duration of treatment, and the choice of therapy in patients who have received various prior adjuvant treatments.Literature review and consensus recommendations Several phase III adjuvant therapy trials are ongoing in the treatment of RCC (Table 2).In determining which factors would influence their rec- ommendation against treating patients with advanced RCC with combination IO, 67% of the subcommittee would recommend nivolumab/ipilimumab to a patient with aRCC who received prior adjuvant IO therapy within the last 6 months (33% of the subcommittee would choose not to recommend nivolumab/ipilimumab in this setting). Similarly 67% of the subcommittee would recommend IO/TKI therapy to a patient with ad- vanced RCC who had previously received either adjuvant IO or adjuvant sunitinib therapy within the last 6 months (33% of the subcommittee would choose not to recommend IO/TKI therapy in this setting).In patients whose disease has progressed at or beyond 6 months following adjuvant anti-PD-1/PD-L1 mono- therapy, the subcommittee was split (47%/47%) as to their recommendation of an IO/IO or IO/TKI regimen following adjuvant immunotherapy, specifically nivolu- mab/ipilimumab vs. axitinib/pembrolizumab.In patients whose disease has progressed > 6 months following completion of adjuvant sunitinib, the majorityof the subcommittee (93%) recommends treatment with nivolumab/ipilimumab combination therapy.

Patients treated with immunotherapy have demon- strated specific side effects known as immune-related adverse events (irAEs). Overall, monoclonal antibodies targeting checkpoint proteins have a different and less predictable toxicity profile than VEGFR TKIs [28–34]. Although 30–40% of patients can have severe toxicities from nivolumab/ipilimumab requiring a course of corti- costeroids and/or other immunosuppressive agents, many patients have minimal side effects from IO ther- apy. However, irAEs are consistently reported and can affect any organ system, including but not limited to manifestations such as colitis, pneumonitis, endocrino- pathies, or hepatitis [28, 29, 31, 35, 36]. Additional man- agement considerations in patients with aRCC may include the occurrence of nephritis in patients with a single kidney. While complete management recommen- dations are outside the context of this manuscript, the subcommittee discussed general irAE management strat- egies in patients with aRCC.All studies discussed below (Table 2.) were graded ac- cording to the National Cancer Institute Common Ter- minology Criteria for Adverse Events (CTCAE), version 4.0.The subcommittee discussed when to change clinical management of patients treated with IO therapies based on irAEs. The subcommittee felt that kidney cancer management of irAEs is aligned with the management of these toxicities in other solid tumor and provided rec- ommendations concerning when, at which grade of tox- icity, and for which adverse events to hold therapy. For further detail into toxicity management strategies please refer to ASCO’s Management of Immune-Related Ad- verse Events in Patients Treated with Immune Check- point Inhibitor Therapy: American Society of Clinical Oncology Clinical Practice Guideline.The subcommittee was split in deciding when to hold PD-1 based monotherapy (including during the mainten- ance component of the nivo/ipi regimen) due to irAEs.

Fifty percent recommended not holding treatment un- less it is a grade 3 toxicity, while 50% supported holding of therapy for patients with some worrisome grade 2 toxicities (diarrhea, arthritis, dyspnea, hepatitis, etc).Another reason to hold PD-1 monotherapy included oc- currence of multiple grade 2 toxicities.Regarding how to best manage clinically-significant grade 3 irAEs in patients with accRCC receiving PD-1 based monotherapy (excluding endocrinopathies stable on replacement), the majority of the subcommittee (72%) advised holding therapy and starting oral high dose (HD) steroids and tapering over 4–6 weeks once symptoms resolve.For a patient with stable disease or better on scans who has stopped induction therapy with nivolumab/ipili- mumab due to a grade 3 or higher irAE, the subcommit- tee is split 50/50% in their recommendation to either wait until toxicity is ≤ grade 1 and the patient is taking prednisone at a dose of 10 mg/d or less and then begin anti-PD-1 monotherapy maintenance versus observing the patient while off all therapy until progression. No member supported the concept of resuming therapy while the patient was still on steroid therapy > 10 mg of prednisone equivalent per day.Regarding when to hold nivolumab/ipilimumab com- bination therapy due to any grade irAEs, the majority of the subcommittee (67%) recommends to hold nivolu- mab/ipilimumab for grade 2 toxicities, treat with im- munosuppressive drugs if they do not resolve, and resume with nivolumab monotherapy when/if the toxic- ities resolve, while a substantial minority of the subcom- mittee (27%) recommends to hold treatment for grade 1 or 2 toxicities (diarrhea, arthritis, LFT abnormalities) to see if they worsen before resuming.Regarding when to hold IO/TKI combination therapy due to grade 3 toxicity (e.g. diarrhea, LFT abnormalities) that could be from either drug, the subcommittee rec- ommends to hold axitinib for 2–3 days to see if toxicity improves (56%), hold both drugs and give steroids (22%), hold both drugs to see if toxicity improves (17%) or give steroids and hold the IO component, but continue axi- tinib (6%).Regarding when to hold IO/TKI combination therapy due to any grade irAEs, the subcommittee was split in their recommendation of either holding axitinib treat- ment for grade 1 or 2 toxicities (diarrhea, arthritis, LFT abnormalities) to see if they worsen before resuming (60%) or to recommend not to hold treatment unless the patient is experiencing a Grade 3 toxicity (33%).

The majority of the subcommittee agreed the best way to educate patients on potential risks and side ef- fects of immunotherapy was by meeting with the pa- tient plus the patient’s family in office visits and giving the patient literature/guidelines to read. The subcommittee recommends that patients should be provided with literature in the doctor’s office (or on- line resources) to learn more fully about how im- munotherapy works, what kinds of treatments andtrials are available, and what their experience of treat- ment might be like, including toxicities. Given the less predictable toxicity profile of IO therapy, patients should have clear guidance and instructions on when to contact their provider to report symptoms to help protect against development of grade 3 AEs.With the many new IO treatment regimens available comes the need to better understand patient monitoring and management strategies, including testing prior to immunotherapy administration, when to hold or delay treatment in the event of an irAE, for how long to con- tinue treatment, and when to treat beyond progression.Response kinetics following treatment with IO differs from those with molecularly targeted or cytotoxic agents. Treating physicians should be aware that non- linear response patterns may occur during and post- treatment with immunotherapy. For instance, pseudo- progression, defined as an initial flare of tumor size (sug- gestive of tumor progression) followed by a reduction in tumor mass is considered an uncommon, but possible, event in solid tumors [37, 38]. However, it should be noted that most progression is real and requires a change in therapy regimen.As such, new methods of disease evaluation and sur- veillance have been developed, including IO-based re- sponse metrics, such as the immune-related response criteria (irRC) and immune-related Response Evaluation Criteria in Solid Tumors (iRECIST) [38, 39]. Based on these considerations, subcommittee members discussed optimal metrics with which to evaluate the clinical bene- fit of immunotherapy, how best to use radiographic re- sponse criteria such as RECIST, and time intervals for imaging evaluation of IO efficacy in order to prevent premature withdrawal of a potentially effective therapy for patients with aRCC.

All studies demonstrating efficacy of anti-PD-1 and anti- CTLA-4 have used RECIST v1.1 and this version con- tinues to be used in most current immunotherapy clin- ical trials [40].Traditional response evaluation by RECIST considers a significant (≥20%) increase in the size of tumor lesions and/or the development of new lesions to be explicit evi- dence of disease progression. However, tumors treated with immunotherapy do not follow the same response patterns as those treated with chemotherapy and targeted treatments and immunotherapy-based response patterns such as tumor flare would be viewed as diseaseprogression and may lead to premature discontinuation of treatment. Therefore, as some patients may benefit from continued immunotherapy beyond RECIST-defined first progression.One study analyzed immune-modified response evalu- ation criteria in solid tumors (imRECIST) to assess its added value in capturing cancer immunotherapy re- sponses. The study examined atezolizumab data from clinical trials and analyzed modifications made in devel- oping imRECIST from RECIST v1.1. Such modifications included allowance for best overall response after PD as well as changes in PD definitions as new lesions and non-target lesions arise. RECIST v1.1 was modified so that PFS by imRECIST did not count initial PD as an event if subsequent scans showed disease control. OS was evaluated using conditional landmarks in patients whose PFS differed by imRECIST versus RECIST v1.1 Overall, immune-based response criteria appear more suitable for evaluation of immunotherapy [39, 41–43].Although evaluation of patient response to immuno- therapy still relies on RECIST criteria for reporting end- points, immune-related response criteria (irRC) are being recognized as better able address the unique treatment-related responses which occur under im- munotherapy. Patients tolerating immunotherapy with asymptomatic disease progression and/or mixed re- sponse should typically be treated based on irRC with continued treatment until progression is confirmed with a repeat scan. If progression is not confirmed then pa- tient should continue on therapy.As to which endpoint is believed to be the most im- portant in evaluating an IO treatment for patients with aRCC, the subcommittee ranked the given endpoints in order from most to least importance: landmark OS, CR rate, median PFS, treatment free survival (TFS), OR rate, disease control rate (DCR), quality of life and cost effect- iveness.

Furthermore, when comparing VEGFR TKI/IO to IO/IO based combination therapies, the subcommit- tee agreed (74%) that 3-year landmark OS was the most relevant endpoint.Regarding routine monitoring of patients, the majority of the subcommittee recommended standardized testing of LFTs (100%), TFTs (T4/TSH; 100%), CBC (94%) andLBC-glucose (83%). Other items recommended for rou- tine monitoring included CPK/Troponin (33%), urinaly- sis (28%) and serum cortisol (22%). CPK/troponin testing is due to low risk, but serious consequences of myocarditis and myositis and the cortisol testing was recommended due to the potential impact of delayed de- tection of adrenalitis/ hypophysitis.A subgroup analysis of a randomized phase 2 trial (NCT01354431) in patients with mRCC investigated the safety and efficacy of treatment with nivolumab beyond investigator-assessed first progression. Of 168patients randomized to nivolumab, 154 experienced progression. Of those who progressed, 36 were treated beyond first progression, 26 were treated beyond first progression for ≤6 weeks, and 92 were not treated be- yond first progression. Following initial progression, 69% of patients treated beyond progression experi- enced subsequent tumor reduction or stabilization in target lesion size with a low incidence of TRAEs. Re- sults of this analysis demonstrated that a proportion of patients who continued treatment beyond RECIST- defined first progression experienced sustained reduc- tions in tumor burden or stable disease, with an ac- ceptable safety profile, noting this is a small and highly-selected subgroup of patients [44].In CheckMate 025, 78% of patients treated with nivo- lumab progressed after initial treatment and 48% of these patients continued to be treated for ≥4 weeks after first progression. Nivolumab therapy was permitted after RECIST v1.1 defined progression if clinical benefit was observed [45]. 13% of patients who continued nivolumab treatment post-progression experienced ≥30% tumor burden reduction from the baseline assessment of first progression [45].

For an aRCC patient on anti-PD-1 monotherapy (e.g. nivolumab) who experiences RECIST-defined PD (e.g. in maintenance phase of ipilimumab/nivolumab or on nivolumab monotherapy) the majority of the subcommittee (75%) recommend to repeat scans in 4–12 weeks and to continue nivolumab if the patient is clinically well, until additional progression is documented.Regarding how long to continue therapy in a patient with a CR or near CR after ipilimumab plus nivolumab induction and 6–9 months of maintenance nivolumab therapy, the subcommittee was split between recom- mending to stop at this point and monitor the patient versus treating the patient for a given number of cycles after best response before stopping. No members sup- ported the notion of continuing therapy indefinitely.*Note: in Keynote-426, pembrolizumab was adminis- tered for a maximum of 35 cycles (2 years) [11].Patient receives axitinib/IO combination therapy. At month 9 they have a CR/near CR/ over 80% response. In the absence of limiting toxicity, 94% of the sub- committee would be comfortable with stopping the IO component at 35 doses (2 year, however the sub- committee was split regarding whether they would be comfortable with stopping axitinib at any time: 56% would NOT recommend to stop axitinib maintenance therapy while 44% of the subcommittee would recom- mend stopping axitinib at some point.In the absence of toxicity, the subcommittee recom- mended stopping IO therapy when patients demonstrate complete response (94%), confirmed or symptomaticprogression (69%), and have received two years of ther- apy without PD (56%).The majority of patients with aRCC will have disease progression on novel regimens, highlighting the import- ance of developing predictive biomarkers to better deter- mine who will benefit from treatment with checkpoint blockade and/or an anti-PD1 in combination with VEGF inhibition and who might need an additional treatment approach.Tumor expression of PD-L1 is utilized clinically as a bio- marker of predicted response to ICIs in several solid tu- mors; however, the complexity of patient selection using PD-L1 IHC limits utility, and improved biomarkers and approaches are needed . Not only are there various assays and antibodies currently in use for measurement of PD-L1 expression, but there are also discrepancies as to how to define PD-L1 positivity ranging from positive PD-L1 ex- pression of 1 to 50%.

For some agents, the benefit appears to be enriched in PD-L1+ patients; however, because only 20–30% of RCC tumors express PD-L1 and tumor re- sponses can be seen in patients with PD-L1- tumors, the number of responders with PD-L1- tumors can exceed those with PD-L1+ tumors. Therefore PD-L1 expression may be useful for patient stratification on clinical trials, but is not currently useful for treatment decisions and should not be routinely tested for. Biomarker data for CheckMate 025, CheckMate 214, Javelin Renal 101, and IMmotion150–151 are detailed in Table 4.In CheckMate 025, tumor PD-L1 expression was ana- lyzed (28–8 Dako assay) as either ≥1% or ≥ 5% of tumor cells. PD-L1 expression in this setting with nivolumab monotherapy was prognostic of poor outcome but not predictive of an overall survival effect, meaning nivolu- mab benefit was identified irrespective of PD-L1 expres- sion [16, 47, 48].Checkmate 214 analyzed the entire population as well as patients stratified by tumor PD-L1 expression. Longer PFS with the combination therapy relative to sunitinib was observed among patients whose tumors displayed≥1% PD-L1 expression but not among those with < 1% PD-L1 expression. Longer OS and a greater ORR, on the other hand, were observed with nivolumab plus ipilimu- mab across all tumor PD-L1 expression levels, although the benefit was enhanced in the population with ≥1% PD-L1 expression (Table 4). Furthermore, CR rate was 16 and 7% in patients with > 1% PD-L1 and < 1% PD-L1expression, respectively [9]. Similar to results of Check- Mate 025, these results suggest that factors other than PD-L1 expression may be contributing to response and OS benefit from the combination therapy [16, 49]. Con- versely, results of Keynote-426 demonstrated OS, PFS, and ORR benefits with the combination across all risk groups and regardless of tumor-based PD-L1 expression level (Table 4) [11].In IMmotion150, patients were initially stratified by PD-L1 status, positivity being PD-L1 expression ≥1% (Ventana SP142 IHC assay) on tumor infiltrating im- mune cells. In patients with PD-L1+ tumors, PFS hazard ratios were 0.64 (95% CI, 0.38–1.08) and 1.03 (95% CI,0.63–1.67), respectively [46, 50].Subsequently, IMmotion151 met its primary endpoint of improved PFS in PD-L1-positive patients (≥ 1% tumor- infiltrating immune cells [IC]) treated with atezolizumab plus bevacizumab across all MSKCC risk groups com- pared to sunitinib [51].

For patients with PDL1+ tumors, PFS benefit was demonstrated in the atezolizumab- bevacizumab combination arm compared to sunitinib (mPFS: 11.2 vs. 7.7 mo; HR, 0.74; 95% CI, 0.57–0.96). Inthe same group, ORR was 43% and DOR was not reached for the combination arm vs 35% and 12.9 months for sunitinib-treated patients, respectively (Table 4).In KEYNOTE-427, which examined pembrolizumab monotherapy in patients with accRCC, the response rate was higher in those with tumor-based expression of PD- L1 of ≥1% versus those with PD-L1 expression < 1% [24]. PD-L1 status was assessed using a combined positive score (CPS) method in which the number of PD-L1 stain- ing cells of all types was divided by the total viable tumor cells and multiplied by 100 [52]. Specifically, in 46 patients with a CPS of at ≥1, confirmed ORR was 50.0%, and in 53 patients with a CPS < 1, it was 26% [24].Eighty-nine percent of the subcommittee does not order any biomarker testing prior to treatment of pa- tients with newly diagnosed ccRCC with immunother- apy. Two subcommittee members (11%) reported that they typically order tumor PD-L1 expression testing.In addition to analysis by PD-L1 tumor expression (Table 4), IMmotion150, IMmotion151 and JAVELIN Renal 101 trials conducted exploratory biomarker ana- lyses to investigate the role of angiogenesis and T- effector gene expression signatures (GEs) in therapeutic outcomes. While the analysis from IMmotion150 sug- gested that tumor mutation and neoantigen burden were not associated with PFS, angiogenesis, T-effector/IFN-γ response, and myeloid inflammatory gene expression signatures were strongly associated with PFS within and across treatment groups, with a demonstrated improve- ment in PFS in T-effector high/Myeloid high tumors inthe combination arm compared to atezolizumab mono- therapy but not in the T-effect high Myeloid low arm. On the other hand sunitinib performed better in the an- giogenic high than in the angiogenesis low population [46, 51, 53]. Such results are hypothesis-generating, al- though not yet impacting clinical practice.In CheckMate 025, many patients with poor risk features and/or sarcomatoid components demonstrated the greatest benefit with nivolumab [16, 47, 48].An exploratory analysis of CheckMate 214 retrospect- ively evaluated the efficacy and safety of nivolumab plus ipilimumab vs sunitinib in patients with treatment-naive, advanced or metastatic clear cell RCC, with sarcomatoid features.

Among patients with available tissue, tumor PD-L1 expression of at least 1% was observed in 50% of those with sarcomatoid RCC vs 27.5% of those without sarcomatoid features. Among patients with sarcomatoid RCC, ORR was 56.7% (95% CI, 43.2–69.4%) with nivolu-mab plus ipilimumab vs 19.2% (95% CI, 9.6–32.5%) with sunitinib (P < .0001). Significantly, the rate of CR was 18.3% with nivolumab plus ipilimumab vs 0% with suni- tinib [54].Patients with sarcomatoid histology with a good per- formance status were also included in the IMmotion151 study (Table 4). Interestingly, PD-L1 prevalence was higher in sarcomatoid tumors, compared to non- sarcomatoid tumors and angiogenesis gene expression was lower in sarcomatoid compared to non-sarcomatoid tumors (p = 4.73e-16) [51]. Particular benefit was ob- served in patients whose tumors demonstrated a sarco- matoid histology component.As for first-line treatment for patients with sarcoma- toid RCC irrespective of IMDC risk factors, 83% of the subcommittee recommend nivolumab plus ipilimumab combination immunotherapy while 11% recommend treatment with axitinib/pembrolizumab and 6% would recommend axitinib/avelumab.RCC histologies other than clear cell, collectively known as non-clear cell renal cell carcinomas (nccRCC), account for 15–25% of primary kidney malignancies [55]. nccRCC comprises a diverse group of tumors in- cluding papillary, chromophobe, collecting duct, trans- location, medullary and unclassified subtypes with pathologic and molecular features as well as clinical phe- notypes distinct from ccRCC [56, 57]. Very few studies have sought to investigate whether immunotherapy is safe and effective in treating patients with advanced non-clear cell renal cell carcinoma (anccRCC).While category 1 evidence does not exist regarding im- munotherapy for patients with anccRCC, checkpoint blockade has demonstrated encouraging anti-tumor ac- tivity in this population, suggesting these patients should not be excluded from clinical trials or consideration for treatment with immunotherapy agents.First-line pembrolizumab monotherapy was evalu- ated in a cohort of patients with anccRCC from KEYNOTE-427 (Cohort B). 165 treatment naïve pa- tients with nccRCC, received pembrolizumab at 200 mg IV Q3W for 35 cycles, lasting about two years or until PD, unacceptable toxicity, or withdrawal. Con- firmed histologies included: papillary 72% (n = 118), chromophobe 13% (n = 21), unclassified 16% (n = 26). 68% of patients were determined to be intermediate/ poor IMDC risk, and 62% were PD-L1+ (combined positive score [CPS] ≥1 for PD-L1+).

At a median follow-up of 11.1 months, 56% of patients discontin- ued anti-PD-1 therapy due to PD or clinical progres- sion. ORR was 24.8% (95% CI, 18.5–32.2), with 8[4.8%] CRs and 33 [20%] PRs. ORR (95% CI) was25.4% (17.9–34.3) in patients with papillary histology tumors, 9.5% (1.2–30.4) in those with chromophobe tumors, and 34.6% (17.2–55.7) in those with unclassi- fied nccRCC. ORR (95% CI) was 28.3% (16.8–42.3) for patients with favorable and 23.2% (15.8–32.1) with intermediate/poor IMDC risk and 33.3% (24.3–43.4) and 10.3% (3.9–21.2) for patients with tumor CPS ≥ 1 and CPS < 1 expression, respectively. Grade 3–5 TRAEs occurred in 11% of patients, while 6% discon- tinued due to TRAEs. Two patients died from TRAEs including pneumonia and cardiac arrest. Overall, pem- brolizumab monotherapy in patients with anccRCC demonstrated promising antitumor activity, particu- larly in those patients with papillary or unclassified histology [58].In a retrospective study, patients from six centers in theUS who received at least one dose of nivolumab for non- clear cell mRCC (nccmRCC) were analyzed by patient char- acteristics and ORR according to RECIST v1.1 and TRAEs [59]. Of the 41 patients identified, tumor histologies in- cluded 16 papillary, 14 unclassified, 5 chromophobe, 4 col- lecting duct, 1 Xp11 translocation and 1 MTSCC (mucinous tubular and spindle cell carcinoma). Of the 35 patients evaluable for best response, 7 (20%) had PR and 10 (29%) had SD. The remaining 18 patients (51%) had PD (14 patients with radiographic PD and 4 patients with clinical PD) as best response. Observed PRs were in unclassified, papillary and collecting duct subtypes and 3 of the 4 pa- tients with chromophobe histology had SD without ob- served response. Among patients who experienced an objective response to treatment, the tumor decreased in size by a mean percentage of 38%. Over the entire cohort,median follow-up was 8.5 months and median treatment duration was 3.0 months.

Median PFS was 3.5 months and median OS was not reached., Median time to best response was 5.1 months, and median DOR was not reached (2/7 re- sponders had PD during follow-up). TRAEs of any grade were noted in 37% of patients, with fatigue (12%), fever (10%) and rash (10%) being the most common. ICI treat- ment was suspended in 34% and discontinued in 15% of pa- tients due to intolerance [59].The subcommittee recommend IO-based therapy for first-line treatment of patients with papillary and unclas- sified RCC, specifically single-agent anti-PD-1 for either subtype with the additional treatment possibilities of ipi- limumab/nivolumab combination therapy for the latter. The subcommittee was undecided between treatments with an IO-based monotherapy versus a TKI for first- line treatment of patients with chromophobe RCC. For patients with nccRCC whose disease has progressed on frontline VEGFR TKI, the subcommittee recommended anti-PD-1 monotherapy (nivolumab; 56%), or treatment with a TKI, specifically cabozantinib (22%).Limited data exist on the safety and efficacy of check- point inhibitors in patients reliant on steroids or with underlying immune dysfunction. Current FDA approvals for combination therapy nivolumab plus ipilimumab and nivolumab monotherapy for patients with aRCC do not specify any eligibility restrictions such as underlying autoimmunity or other contraindications. Since both CTLA-4 and PD-1/PD-L1 pathways play vital roles in the systemic balance of the immune system, concerns arise in considering the possible toxicities linked with blocking associated signals and releasing the immune system in a patient whose immune system is already reacting to autologous organs/tissues. Additionally, con- cerns remain as to whether immunosuppressive therap- ies used to control a patient’s underlying symptoms would hinder any therapeutic benefit of checkpoint in- hibition. The subcommittee discussed whether specific groups of aRCC patients would not be good candidates for IO treatment.

Literature review and consensus recommendations General patient inclusion and exclusion criteria for clinical trials investigating checkpoint blockade in aRCC were similar in first- and second-line immunotherapy-based clinical trials in other solid tumor settings. Relevant trial exclusion criteria included history of autoimmune disease (except controlled and treated hypothyroidism or type Idiabetes mellitus), history of idiopathic pulmonary fibrosis, or pneumonitis, positive human immunodeficiency virus (HIV) test, active or chronic hepatitis B or C, prior allo- geneic stem cell or solid organ transplantation, or current therapy with systemic corticosteroids (> 10 mg daily pred- nisone equivalent) or other immunosuppressive medications.Of the general factors to consider when determining NOT to give nivolumab/ipilimumab combination ther- apy in patients with aRCC, the subcommittee felt that history of potentially life threatening AI condition and/ or need for immunosuppressive therapy (94%), poor per- formance status (50%), and advanced patient age and IMDC risk stratification (39%) were the most influential. Of the general factors to consider when determining NOT to give IO/TKI combination therapy in patients with aRCC, the subcommittee agreed that history of po- tentially life threatening AI condition and/or need for immunosuppressive therapy (72%) and recent history of cardiovascular co-morbidities (39%) were the most influ- ential. Other factors felt to be important were advancedpatient age (33%) and poor performance status (33%). While very little data exists investigating the use of im-mune checkpoint blockade in patients with aRCC with preexisting autoimmune disorders, there have been some studies done in patients with melanoma examining treat- ment with ipilimumab or anti-PD-1 in this patient popu- lation. A retrospective review analyzed 30 patients with advanced melanoma and preexisting autoimmune disor- ders who received ipilimumab (mostly low-dose prednis- one or hydroxychloroquine). In this study, the objective response rate was still 20%, including 1 CR – consistent with response rates reported in other populations.

Add- itionally, 50% of patients experienced neither a flare of their autoimmune disease or grade 3 or higher irAE (27 and 33% of patients experienced each, respectively) [60]. Other studies reporting the use of ipilimumab therapy in patients with rheumatoid arthritis and multiple sclerosis (MS) demonstrated clinical activity with either no or only a mild increase in arthritic symptoms [61–63].Retrospective reviews were also conducted in studies examining anti-PD-1 therapy in patients with advanced melanoma and either preexisting autoimmune disease and/or a history of irAEs during prior treatment with ipilimumab were treated with anti–PD-1 therapy. ORR was 33%, mirroring response rates seen in other popula- tions. Although 30% of patients developed additional irAEs, the majority were easily managed [64].94% of the subcommittee agreed that currently ac- tive autoimmune disease requiring medication would be considered a reason not to provide combination immunotherapy to an intermediate/poor risk patient with mRCC and 75% of the subcommittee recom- mend against treating patients receiving steroiddosing (for any reason) > 10 mg per day prednisone or equivalent. Fifty-six percent of the subcommittee, however, do not recommend excluding patients from treatment due to significant burden/pace of disease requiring rapid tumor burden reduction.While IO therapies have become SOC for multiple malignancies patients such as those who present with a poor ECOG performance status or chronic viral infec- tions [human immunodeficiency virus (HIV), hepatitis B (HBV) and hepatitis C (HCV)] were underrepresented in early clinical trials. A retrospective analysis investigated underrepresented patients treated with ICI-based mono- therapy and combination therapies from January 2011 to April 2018, including patients with HIV, HBV/HCV, or a pre-treatment ECOG PS ≥2. Among patients with HIV, any grade and grade ≥ 3 irAEs were 24 and 10% with an ORR of 29%. In the HBV/HCV cohort, grade and grade ≥ 3 irAEs were 50 and 26% with an ORR of 21%. No viral reactivation was noted during ICI treat- ment. For patients with ECOG PS ≥2, the ORR was 14%. Any grade and grade ≥ 3 irAEs in this cohort were 20 and 4%. This data suggests that ICI therapy was not as- sociated with significant safety concerns or lack of effi- cacy in the discussed populations [cite: ASCO abstract #2587, Neil J. Shah].Specific to checkpoint inhibitor monotherapy, the sub-committee recommends NOT treating patients with aRCC who currently have active autoimmune disease re- quiring immunosuppressive medication (93%), or who require corticosteroid use > 10 mg/d prednisone equiva- lent (67%).In regards to patients with advanced RCC who cur- rently have controlled HIV and/or a history of hepatitis C or B infection, 89% of the subcommittee would NOT recommend AGAINST using checkpoint inhibitor-based therapy.Specific to VEGFR TKI/checkpoint inhibitor combin- ation therapy, the subcommittee recommends NOT treating patients with aRCC who currently have active autoimmune disease requiring immunosuppressive medication (87%), require corticosteroid use > 10 mg/d prednisone equivalent (53%), or who have poor perform- ance status (20%).

While the use of corticosteroids for treatment of immune-related adverse events do not seem to affect therapeutic efficacy, the potential impact of baseline use of corticosteroids at the time of treatment initiation has had only limited study. In one study involving IO-naïve patients with NSCLC treated in two independent co- horts, ninety (14%) of 640 patients treated with anti-PD- (L)1 monotherapy were receiving the equivalent of ≥10 mg of prednisone daily at the start of checkpoint block- ade. In both independent cohorts, baseline corticoste- roids were associated with decreased ORR, PFS, and OSwith PD-(L)1 blockade. Moreover, in a multivariable analysis of both cohorts, baseline corticosteroid use remained significantly associated with decreased PFS (hazard ratio, 1.3; P = .03), and OS (hazard ratio, 1.7; P < .001) [65].Many studies indicate significant quality of life im- provements in cancer patients being treated with im- munotherapies compared to TKIs. Quality of life issues include diarrhea, nausea, anxiety, and functionality to take part in a normal, everyday life. As patients with aRCC encounter many of these issues, the subcommittee discussed potential quality of life concerns pertaining to treatment with immunotherapies.Literature review and consensus recommendations Category 1 evidence from aRCC trials demonstrated that while patients in the standard-therapy group reported a clinically meaningful deterioration from baseline and bothersome symptoms, more patients treated with nivo- lumab, nivolumab plus ipilimumab or atezolizumab plus bevacizumab reported more symptom stability or an im- provement in health related quality of life.In a secondary analysis of CheckMate 025 which com- pared health-related quality of life (HRQoL) between treatment arms and in relation to OS, 706 patients re- ported that treatment with nivolumab was associated with improvement in QoL, whereas those patients treated with everolimus experienced a deterioration in QoL. Assessments were made before any clinical activ- ities and at the first two follow-up visits [66]. As assessed by the Functional Assessment of Cancer Therapy–Kid- ney Symptom Index–Disease Related Symptoms (FKSI- DRS; a disease-specific questionnaire), 55% of patients treated with nivolumab experienced clinically meaning- ful HRQoL improvement versus 37% in the everolimus arm (p < 0·001). Likewise, patients treated with nivolu- mab experienced an improvement from baseline in HRQoL beginning at week 20 (mean [SD], 0.6 [3.8], p = 0·031) through week 104 (3.5 [4.1], p = 0.001). Those treated with everolimus experienced a meaningful de- terioration (p < 0.04) from baseline in HRQoL, starting at week 4 (− 1.5 [4.5], p < 0.001) through week 32 (− 1.1[4.7], p = 0.019) and again from week 60 (− 1.6 [4.4], p =0.016) through week 64 (− 1.5 [4.8], p = 0.040).

In CheckMate 214, statistically significant differences in the mean change from baseline were observed using FKSI- 19, the revised FKSI questionnaire, total scores favoring nivolumab plus ipilimumab at all but two post-baseline time points through two years of follow-up (P < 0.05). Des- pite the prevalence of side effects and greater percentage of patients stopping treatment in CheckMate 214, patientswho received the immunotherapy combination reported higher quality of life throughout the study. Specifically, des- pite the need for 29% of patients on the combination im- munotherapy arm to receive immunomodulatory agents (high-dose glucocorticoids [≥40 mg of prednisone per day or equivalent]) to manage select treatment-related adverse events, the quality of life for patients on this treatment was superior to that for patients receiving sunitinib [9, 10].In IMmotion151, PROs evaluated as exploratory end- points found that patients on atezolizumab and/or ate- zolizumab plus bevacizumab maintained daily function with minimal symptom interference versus sunitinib, in- dicating improved quality of life on with ICI therapy ver- sus TKIs [67]. Specifically, patients completed the MD Anderson Symptom Inventory (MDASI) and FKSI-19 questionnaires on days 1 and 22 of each 6 week treat- ment cycle, at the end of treatment, and during survival follow-up. Clinical survey topics included symptom bur- den (MDASI symptom severity and symptom interfer- ence with daily living) and bother from treatment side effects (FKSI-19 GP5 item). Patients receiving the com- bination therapy reported milder and more stable symp- tom severity, less interference, and better HRQoL compared to patients receiving sunitinib, who reported worsened interference on a more frequent basis. TTD in interference was also delayed in the combination arm versus sunitinib (median for atezolizumab plus bevacizu- mab was 11.3 months vs 4.3 months for sunitinib [HR 0.56; 95% CI 0.46, 0.68]). Finally, a greater proportion of atezolizumab plus bevacizumab-treated patients reported none or little bother due to treatment side effects vs sunitinib-treated patients [68].

Conclusions
Immunotherapy has emerged as a new pillar of cancer treatment for patients with aRCC. With FDA approved immunotherapies for aRCC now in the frontline, the field is currently focused on which treatments to offer to which patients. Trials comparing front line options head to head linked to predictive biomarkers and using IO endpoints such as 3 year landmark OS and treatment free survival are needed to help rationally select between existing options for specific patient populations. Further, information is lacking on how best to manage patients on TKI/IO combination regimens and how to treat such patients if and when they exhibit disease progression. Similarly, advancement of other immunotherapies and strategies will be vital for continued progress in treating patients with this disease, as will overcoming challenges such as tumor immune resistance, immune escape and immune-related adverse events [69]. As a new standard in the field, every patient should re- ceive an anti-PD-1-based therapy as initial treatment un- less there is a specific contraindication to this approach. This is particularly true for patients with sarcomatoid histology, where the benefit of immunotherapy relative to VEGF TKI appears to be particularly strong. Recent data also supports treating patients with papillary and unclassified RCC with IO-based therapy in the first line setting. However, there remains a need for biomarkers to better predict patient response and to help decide the best treatment approach for each patient. Additionally, it remains to be determined whether new IO combinations including VEGFR TKIs will elicit properties of IO ther- apy, enabling the patient the ability to stop treatment with persistent benefit.

Further studies need to address the question of who should receive combinations of IO with VEGFR TKI relative to who should receive nivolu- mab/ipilimumab combination therapy, how to best man- age toxicity, and not only when to stop treatment but also what is the appropriate management for patients who have stopped therapy. Figure 1 Immunotherapy treatment algorithm for ad- vanced RCC based on current FDA approvals for first-line therapy. All treatment options shown may be appropriate. The final selection of therapy should be individualized based on patient eligibility and therapy availability based on the treating physician’s discretion. The goal of these algorithms are to provide advice as the consensus recommendations of the Subcommittee. 1) Baseline imaging considerations: CNS imaging is recommended for all patients; bone imaging should be considered for symptomatic patients. 2) “Need for systemic therapy” is defined as: not having low volume, slow growing disease. 3) “Candidate for immunotherapy” is de- fined as: i. Patients without active autoimmune conditions requiring immunosuppressive therapy or a history of poten- tial life threatening autoimmune conditions; and ii. Patients without the need for corticosteroids Axitinib to treat other condi- tions (e.g. brain metastases or spinal cord, compression, lymphangitic spread of tumor). 4) Refractory is defined as: disease progression by RECIST and/or irRECIST or clinical disease progression