Surgery For Stage IV RCC

• Nephrectomy remains an important component of management of patients with mRCC. (A for IFN and IL-2 and C for VEGF-targeted agents and resection of oligometastases)

Role of Systemic Therapy For Resected Stage II/III RCC

• The current standard of care in the adjuvant setting is either observation or enrollment in a clinical trial. (A for lack of efficacy of multiple therapies in phase III trials)
  • The panel was supportive of initiating studies utilizing programmed death (PD-1) pathway blocking agents in the neoadjuvant and/or adjuvant setting. Such trials are in development (Table 1).

High Dose (HD) IL-2 in the Treatment of MRCC

• Selected patients with mRCC who have undergone nephrectomy should be referred to a center of excellence for further discussion, as appropriate. (A/B/C)
  • All such patients should have a discussion regarding IL-2. (67%)
  • Patients should be selected for this discussion. (33%)

Criteria for Considering IL-2 Therapy

• Only patients with clear cell histology should be considered for HD IL-2. (B/C)
  • Patients with tumors having sarcomatoid features should receive IL-2, depending upon the proportion of sarcomatoid features noted and the biologic behavior of the disease (rapid or indolent). (60%)
  • Patients with extensive granular features or Fuhrman grade 4 histology should not receive IL-2. (13%)
  • Clinical and physiologic criteria should also be evaluated prior to recommending HD IL-2. (A)
    • The following are established criteria for patients to undergo HD IL-2 treatment:
      • Adequate heart and lung function
      • ECOG performance status (PS) 0–1, preferably 0
      • Age (physiologic versus chronologic), but the upper limit for both is usually in the upper 70s
      • Absence of central nervous system (CNS) metastases (or treated metastases with no residual edema)

Immunotherapy in MRCC Patients With CNS Metastases

• Evidence regarding management of CNS metastases is inconclusive. Therefore, proceeding with HD IL-2 in this setting should be individualized, based on clinical judgment. (A/C)
  • Use a VEGFR TKI after local treatment of CNS disease. (47%)
  • Treat CNS lesion(s) with either surgery or stereotactic RT first, then consider proceeding with HD IL-2 if other criteria are met. (40%)

Evaluation of Risk Factor Categories in Deciding Whether to Use IL-2

• Prognostic categories developed to predict survival in patients with mRCC are used to guide treatment decisions.
  • High risk patients with expected poor survival are not considered initial candidates for HD IL-2. (B/C) Alternative treatments include:
    • Anti-VEGFR TKI (53%)
    • Temsirolimus (20%)
    • Clinical trials, if available (27%)

Duration of Treatment With HD IL-2 and When to Change Therapy (C)

• Give a second two-week course of therapy to those patients with responding or stable disease (SD) 12 weeks following HD IL-2. (80%)
• Continue to observe, especially in patients with SD, until progression is documented, and then start another treatment. (13%)
  • There are anecdotal cases of patients who have achieved a durable complete response (CR) with one course of HD IL-2.
    Note: It has not been prospectively evaluated whether patients who have SD as their best response to the first course of HD IL-2 can achieve either a better response or delayed progression with additional courses of therapy. However, if no contraindication exists, the majority of the Task Force would proceed with a second course before changing treatment.

Progression Following HD IL-2

• Even if response to HD IL-2 lasts at least 6 months:
  • proceed to another therapy (73%)
  • recommend another course of HD IL-2. (13%)
  • resect residual disease if complete removal is feasible. (13%)
  • Patients who respond well to two courses of IL-2 but have residual oligometastatic disease should:
    • Undergo surgical resection of the residual tumor (73%)
    • Receive another course of HD IL-2 (20%)
    • Switch to TKI (7%).
      Note: All data were considered anecdotal; patients should be treated according to clinical judgment.

Low Does IL-2 or Low Dose IL-2 Combined With IFN

• There is limited to no role for low dose IL-2 as a single agent, with the possible exception of patients with impaired organ function. (B based on a prospective, uncontrolled trial)
• Efficacy data favor HD IL-2 compared to low dose IL-2. (A)
  Note: Investigation of low dose regimens in conjunction with new immunotherapies is a research consideration, given that checkpoint inhibitors are being studied at much lower doses in combination than those used in the original single agent trials. Alternative schedules should also be explored in the context of combination immunotherapy or immunotherapy with targeted agents.(B)

HD IL-2 as Second-Line Therapy (A)

After Anti-VEGF TKI

• Following initial anti-VEGF TKI, anti-PD-1 agents are the preferred second-line immunotherapy. (67%)
  Note: This is based on the logistics of outpatient anti-PD-1 therapy and the less stringent eligibility criteria, rather than being a comparison with other immunotherapy agents.
• If anti-PD-1 agents are not available, HD IL-2 should be considered as second-line therapy after a washout period, in appropriate patients (C).
  Note: Patients should be evaluated carefully with a cardiac echo and show adequate cardiac function prior to initiation of IL-2 therapy.

After anti-PD-1 Therapy (C)

• HD IL-2 could be used after anti-PD-1 therapy based on the lower risk of persistent immune-related adverse events with anti-PD-1 agents compared with other checkpoint inhibitors (e.g., anti-CTLA-4 agents). (73%)
  Note: The scientific rationale for this therapeutic sequence is based on the different, potentially synergstic, mechanisms of action of HD IL-2 and anti-PD-1 therapy.

Summary of HD IL-2 Recommendation

• Eligible patients (clear cell histology with adequate organ reserve after nephrectomy, with few adverse risk features) should be considered for IL-2 therapy at centers with adequate experience.

IFN in the Treatment of RCC

• Do NOT use IFN, even in combination with bevacizumab and even at lower IFN doses. (60%)
• Use IFN as a single agent. (13%)
  Note: The efficacy recommendation for IFN as a single agent is level A, based on the fact that anti-VEGF receptor and mTOR inhibitor targeted therapies have superior PFS compared to single agent IFN.

Role of PD-1 Blockade (either with Anti- PD-1 or Anti- PD-L1)

These recommendations are based only on the phase I and II data that were available at the time.

• Preferred treatment for patients who progress on anti-VEGF TKI therapy but have good ECOG PS (≤1):
  • Anti-PD-1 agents in clinical trials or as a commercial agent, if available (67%)
  • IL-2 in appropriate patients after TKIs (13%)
  • Either axitinib or everolimus (6.7%)
    Note: Due to their more favorable toxicity profiles, many patients and physicians would prefer anti-PD-1 immunotherapy to HD IL-2.

Metastatic Non Clear Cell RCC

• HD IL-2 should be reserved for patients with clear cell RCC. (A/B)
  Note: There was lack of consensus on the initial treatment for patients with metastatic non-clear cell RCC. Clinical trials are likely to be the best initial treatment option for such patients, provided there is a strong scientific rationale for the treatment. In the absence of a clinical trial, a VEGFR TKI is preferred.

Table 1. Select Immunotherapy Agents and Ongoing Immunotherapy Clinical Trials in RCC

Table 2. Ongoing Phase III Studies in Front-Line Advanced/Metastatic RCC

Stage IV RCC Immunotherapy Treatment Algorithm