- 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).
- Since 2015 three new regimens have received FDA approval:
Regimen Indication Nivolumab (a programmed death 1 (PD-1) immune checkpoint inhibitor monoclonal antibody) Monotherapy for advanced RCC after treatment with a VEGF-targeting agent Nivolumab + ipilimumab (a CTLA-4 inhibitor) Intermediate- and poor-risk, previously untreated patients with aRCC Pembrolizumab (anti-PD-1) or avelumab (anti-PD-ligand (L) 1) with axitinib (a VEGF receptor tyrosine kinase inhibitor) aRCC Nivolumab + ipilimumab Treatment-naïve advanced clear cell renal carcinoma (accRCC)
- Other regimens under investigation include:
Regimen Indication Nivolumab First-line treatment of patients with aRCC Atezolizumab (anti-PD-L1) monotherapy or in combination with bevacizumab (anti-VEGF antibody) vs. sunitinib Phase I – Treatment-naïve accRCC Pembrolizumab Treatment-naïve accRCC
- RCC histologies other than clear cell, collectively known as non-clear cell renal cell carcinomas (nccRCC), account for 15–25% of primary kidney malignancies.
- nccRCC comprises a diverse group of tumors including papillary, chromophobe, collecting duct, translocation, medullary, and unclassified subtypes with pathologic and molecular features as well as clinical phenotypes distinct from ccRCC.
- As a new standard in the field, every patient should receive an anti-PD-1-based therapy as initial treatment unless there is a specific contraindication to this approach.
- This is especially 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.
Immunotherapy for Advanced RCC
First-Line Treatment of accRCC
- Initiate systemic therapy first rather than cytoreductive nephrectomy in patients presenting with metastatic RCC with:
- IMDC poor risk categorization (80%)
- brain metastases (67%)
- a large tumor burden outside primary kidney lesion (60%).
Note: Cytoreductive nephrectomy is still considered a preferable option for patients with the majority of their tumor burden confined to their primary and no other IMDC (International Metastatic RCC Database Consortium) risk factors besides presenting with stage IV disease.
- Of the possible combination therapies including a VEGF inhibitor combined with an immune checkpoint inhibitor, the preferred combination for patients with aRCC is pembrolizumab plus axitinib. (94%)
- Recommended treatments for treatment-naïve, ECOG 0 ccRCC patients determined to need systemic therapy and having no contraindication to receiving either an IO or an anti-VEGF therapy:
- with "favorable" risk per IMDC:
- axitinib/pembrolizumab (50%)
- nivolumab/ipilimumab (28%)
- TKI monotherapy (11%)
- either axitinib/avelumab or HD IL-2 (6%).
- with "intermediate/poor" risk per IMDC:
- nivolumab/ipilimumab (78%)
- axitinib/pembrolizumab (17%)
- ICI monotherapy (6%).
- with "favorable" risk per IMDC:
- For treatment-naïve patients, IO monotherapy is preferred over IO-based doublet therapy for:
- patients with a history of autoimmune disease that is not potentially life threatening and is not currently on immunosuppressive agents (56%)
- elderly patients (e.g. 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%)
- patients with liver metastases with mildly increased LFTs (6%).
Note: 17% of panel members do NOT favor IO monotherapy over IO-based doublet therapy.
- All patients without a contraindication to immunotherapy should receive an IO-based regimen in the first line.
Notes: 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 potential contraindication, although the activity of IO-based doublets in this setting is unknown.
- For a previously treated, ECOG 0, clear cell mRCC patient with “favorable” risk whose tumors progressed on front-line therapy with sunitinib, treat with a checkpoint immunotherapy (100%):
- nivolumab monotherapy (37%)
- ipilimumab plus nivolumab combination immunotherapy if the patient can tolerate. (63%)
Note: As standard of care shifts to immunotherapy regimens in the first line setting, this situation will be unlikely 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 receive a checkpoint inhibitor-based treatment regimen.
- Treat patients with disease progression after nivolumab/ipilimumab combination therapy with:
- cabozantinib (72%)
- axitinib (22%)
- HD IL-2 (6%).
- Treat patients with disease progression after IO/VEGFR TKI combination therapy (either axitinib/pembrolizumab or axitinib/avelumab) with:
- cabozantinib (83%)
- nivolumab/ipilimumab (11%)
- lenvantinib/everolimus (6%).
Note: Specifically, the subcommittee also acknowledged that no data existed for the use of nivolumab/ipilimumab in patients with disease progression on an IO/TKI combination or for the use of an IO/TKI combination in patients with disease progression on front-line nivolumab/ipilimumab, and suggested that clinical trials to obtain such data would be useful.
Adjuvant Therapy And Related Failures Within An IO-Related Treatment Paradigm For Patients With accRCC
- Recommend nivolumab/ipilimumab to a patient with aRCC who received prior adjuvant IO therapy within the last 6 months. (67%)
- Recommend IO/TKI therapy to a patient with advanced RCC who had previously received either adjuvant IO or adjuvant sunitinib therapy within the last 6 months. (67%)
- Treat patients whose disease has progressed at or beyond 6 months following adjuvant anti-PD-1/PD-L1 monotherapy with an IO/IO or IO/TKI regimen following adjuvant immunotherapy:
- nivolumab/ipilimumab (47%)
- axitinib/pembrolizumab (47%)
- Treat patients whose disease has progressed >6 months following completion of adjuvant sunitinib with nivolumab/ipilimumab combination therapy. (93%)
Immune-Related Adverse Events Recognized And Managed In Patients With accRCC
- Hold PD-1 based monotherapy (including during the maintenance component of the nivolumab/ipilimumab regimen) due to irAEs:
- if it is a grade 3 toxicity (50%)
- with some worrisome grade 2 toxicities (diarrhea, arthritis, dyspnea, hepatitis, etc). (50%)
Note: Another reason to hold PD-1 monotherapy includes occurrence of multiple grade 2 toxicities.
- For clinically-significant grade 3 irAEs in patients with accRCC receiving PD-1 based monotherapy (excluding endocrinopathies stable on replacement), hold therapy and start oral high dose (HD) steroids, tapering over 4-6 weeks once symptoms resolve. (72%)
- For a patient with stable disease or better on scans who has stopped induction therapy with nivolumab/ipilimumab due to a grade 3 or higher irAE:
- 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 (50%)
- observe the patient while off all therapy until progression. (50%)
ote: No member supported the concept of resuming therapy while the patient was still on steroid therapy >10 mg of prednisone equivalent per day.
- For any grade irAE from nivolumab/ipilimumab combination therapy:
- hold nivolumab/ipilimumab for grade 2 toxicities, treat with immunosuppressive drugs if they do not resolve, and resume with nivolumab monotherapy when/if the toxicities resolve (67%)
- hold treatment for grade 1 or 2 toxicities (diarrhea, arthritis, LFT abnormalities) to see if they worsen before resuming. (27%)
- For grade 3 toxicity (e.g. diarrhea, LFT abnormalities) from IO/TKI combination therapy that could be from either drug:
- 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%)
- give steroids and hold the IO component but continue axitinib (6%).
- For any grade irAE from IO/TKI combination therapy:
- hold axitinib treatment for grade 1 or 2 toxicities (diarrhea, arthritis, LFT abnormalities) to see if they worsen before resuming (60%)
- Do NOT hold treatment unless the patient is experiencing a Grade 3 toxicity (33%).
- The best way to educate patients on potential risks and side effects of immunotherapy is by meeting with the patient plus the patient’s family in office visits and giving the patient literature/guidelines to read.
- Patients should be provided with literature in the doctor’s office (or online resources) to learn more fully about how immunotherapy works, what kinds of treatments and trials are available, and what their experience of treatment 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.
Evaluate, Monitor and Manage Treatment Response To Immunotherapy In Patients With accRCC
- Although evaluation of patient response to immunotherapy still relies on Response Evaluation Criteria in Solid Tumors (RECIST) criteria for reporting endpoints, immune-related response criteria (irRC) are being recognized as better able to address the unique treatment-related responses which occur under immunotherapy.
- Patients tolerating immunotherapy with asymptomatic disease progression and/or mixed response should typically be treated based on irRC with continued treatment until progression is confirmed with a repeat scan.
- If progression is not confirmed then patient should continue on therapy.
- As to which endpoint is believed to be the most important 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 effectiveness.
- The 3-year landmark OS from VEGFR TKI/IO to IO/IO based combination therapies is the most relevant endpoint. (74%)
- Recommended standardized testing for routine monitoring of patients should include LFTs (100%), TFTs (T4/TSH; 100%), CBC (94%), and LBC-glucose. (83%)
- Other items recommended for routine monitoring include CPK/Troponin (33%), urinalysis (28%) and serum cortisol (22%).
- CPK/troponin testing is recommended due to the low risk but serious consequences of myocarditis and myositis.
- Cortisol testing is recommended due to the potential impact of delayed detection of adrenalitis/hypophysitis.
- 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), repeat scans in 4-12 weeks and continue nivolumab if the patient is clinically well until additional progression is documented. (75%)
- For patients with a CR or near CR after ipilimumab plus nivolumab induction and 6-9 months of maintenance nivolumab therapy:
- stop therapy at this point and monitor the patient (50%)
- treat the patient for a given number of cycles after best response before stopping (50%).
Note: No members supported the notion of continuing therapy indefinitely.
- If at month 9 of axitinib/IO combination therapy a patient has a CR/near CR/ over 80% response in the absence of limiting toxicity or disease progression, stop the IO component at 35 doses (2 years). (94%)
- Do NOT stop axitinib at any time. (56%)
- Stop axitinib at some point. (44%)
Biomarker Testing In Patients With aRCC
- It is not necessary to order any biomarker testing prior to treatment of patients with newly diagnosed ccRCC with immunotherapy. (89%)
Note: Tumor PD-L1 expression testing is optional. (11%)
Angiogenesis and T-effector gene expression signatures (GEs):
- Not yet impacting clinical practice
- Recommend first-line treatment for patients with sarcomatoid RCC irrespective of IMDC risk factors:
- Nivolumab plus ipilimumab combination immunotherapy (83%)
- axitinib/pembrolizumab (11%)
- axitinib/avelumab. (6%)
Patients With accRCC Who Should Not Receive Immunotherapy
- The most influential general factors to consider when determining NOT to give nivolumab/ipilimumab combination therapy in patients with aRCC:
- history of potentially life-threatening autoimmune condition and/or need for immunosuppressive therapy (94%)
- poor performance status (50%)
- advanced patient age and IMDC risk stratification (39%).
- The most influential general factors to consider when determining NOT to give IO/TKI combination therapy in patients with aRCC:
- history of potentially life-threatening autoimmune condition and/or need for immunosuppressive therapy (72%)
- recent history of cardiovascular co-morbidities (39%)
Note: Other factors felt to be important were advanced patient age (33%) and poor performance status (33%).
- Currently active autoimmune disease requiring medication would be considered a reason NOT to provide combination immunotherapy to an intermediate/poor risk patient with mRCC. (94%)
- Do NOT treat patients receiving >10 mg per day prednisone or equivalent steroid dosing (for any reason). (75%)
- Do NOT exclude patients from treatment due to significant burden/pace of disease requiring rapid tumor burden reduction. (56%)
- Specific to checkpoint inhibitor monotherapy, do NOT treat patients with aRCC who currently have active autoimmune disease requiring immunosuppressive medication (93%) or who require corticosteroid use 10 mg/d prednisone equivalent (67%).
- Consider using checkpoint inhibitor-based therapy in patients with advanced RCC who currently have controlled HIV and/or a history of hepatitis C or B infection. (89%)
- Do NOT use VEGFR TKI/checkpoint inhibitor combination therapy to treat patients with aRCC who:
- currently have active autoimmune disease requiring immunosuppressive medication (87%)
- require corticosteroid use >10 mg/d prednisone equivalent (53%)
- have poor performance status (20%).
Quality of Life
- Patients in the sunitinib-therapy group reported a clinically meaningful deterioration from baseline and bothersome symptoms, while more patients treated with nivolumab, nivolumab plus ipilimumab, or atezolizumab plus bevacizumab reported more symptom stability or an improvement in health-related quality of life.
Advanced RCC Immunotherapy Treatment AlgorithmFigure 1. Immunotherapy treatment algorithm for advanced 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 defined as: i. Patients without active autoimmune conditions requiring immunosuppressive therapy or a history of potential life threatening autoimmune conditions; and ii. Patients without the need for corticosteroids to treat other conditions (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.
Notes: A) Clinical Trials are always an option for any patient, in any category.
B) This recommendation may change as data matures.
RCC Risk Calculatorhttps://www.guidelinecentral.com/calculators/rcc-risk
AbbreviationsaccRCC, advanced clear cell RCC; AI, autoimmune; aRCC, advanced RCC; anccRCC, advanced non-clear cell RCC; cc, clear cell; CR, complete response; ECOG, Eastern Cooperative Oncology Group; FDA, U.S. Food and Drug Administration; IMDC, International Metastatic RCC Database Consortium; irAEs, immune-related adverse events; irRC, immune-related response criteria; ITT, intent-to-treat; LBC, lamellar body count; nccRCC, non-clear cell RCC; OS, overall survival; PD, progressive disease; PD-1, programmed cell death 1; PD-L1, programmed cell death ligand 1; PFS, progression-free survival; RCC, renal cell carcinoma; RECIST, Response Evaluation Criteria in Solid Tumors; HD IL-2, high dose interleukin-2; TKI, tyrosine kinase inhibitors; VEGF, vascular endothelial growth factor
Rini, B.I., Battle, D., Figlin, R.A. et al. The society for immunotherapy of cancer consensus statement on immunotherapy for the treatment of advanced renal cell carcinoma (RCC). J ImmunoTherapy Cancer 7, 354 (2019) doi:10.1186/s40425-019-0813-8
This pocket guide attempts to define principles of practice that should produce high-quality patient care. It is applicable to specialists, primary care providers and ancillary healthcare providers. This pocket guide should not be considered exclusive of other methods of care reasonably directed at obtaining the same results. The ultimate judgment concerning the propriety of any course of conduct must be made by the clinician after consideration of each individual patient situation.
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