High dose aldesleukin (HD IL-2), a T-cell growth factor, is an effective immunotherapy for metastatic melanoma (mM) and metastatic renal cell carcinoma (mRCC), yielding a 14–25% objective response rate (ORR) (complete and partial responses) with prolonged response duration, often decades, for complete responders [1–8]. Extensive clinical experience and detailed management guidelines over the last 30 years of HD IL-2 use has ensured predictable short term toxicity and minimal to no lasting residual toxicity [1–9]. As the studies which led to approval for HD IL-2 are decades old, we developed the PROCLAIM^SM database, a multi-institutional clinical registry of patients treated with HD IL-2, implemented in 2011, with retrospective data collected back to 2006 and prospective data entered to the present. Seventy-five percent of subjects have been entered prospectively. This is the largest database of real-world outcomes of contemporary IL-2 treatment. Multiple reports have been generated from this database [2, 3, 6–8, 10].

Survival of patients with mRCC is heterogeneous, but may be projected by several prognostic scoring systems based on clinically available risk factors [11–14]. Studies utilizing cytokine therapy identified the following factors as significant for poor survival: elevated lactate dehydrogenase, elevated calcium, anemia with hemoglobin below lower limit of normal (LLN), the renal tumor remaining in place during treatment for metastatic disease, and impaired performance status [11–15]. The International Metastatic Renal Cell Cancer Database Consortium (IMDC) risk criteria have evolved from prior systems [11, 12, 15], and have been successfully applied to assess survival outcomes among patients treated with either anti-vascular endothelial growth factor (VEGF) targeted therapy or immunotherapy [16, 17].

Prognostic scoring systems do not necessarily predict treatment outcome and therefore it is important to assess the efficacy of each new therapy in the different prognostic groups. A recently reported randomized trial evaluated the outcome for patients with mRCC treated with the combination of anti-programmed death − 1 (anti-PD1) and anti-cytotoxic T-lymphocyte-associated antigen-4 (anti-CTLA-4) checkpoint inhibitors (CPI) compared to those treated with sunitinib [18]. Surprisingly, favorable risk patients treated with CPI immunotherapy had a lower 18-month overall survival (OS) compared to favorable risk patients treated with sunitinib, but for patients with intermediate and poor risk, the reverse was observed [18]. In this trial’s analysis, PD-ligand1 (PD-L1) expression was not entirely predictive of CPI benefit, leaving the observed outcome not easily explained. The results of this trial led to FDA approval of the combination of ipilimumab and nivolumab for intermediate and poor risk mRCC patients, but not for those with favorable risk.

In view of the above outcome of more efficacious results with sunitinib compared to CPI immunotherapy in favorable risk mRCC patients, and because patients selected for HD IL-2 treatment meet physiologic parameters allowing them to tolerate treatment and are not selected by IMDC risk criteria specifically [2, 3, 5–10], we have interrogated the PROCLAIM^SM HD IL-2 treatment database for survival outcome by IMDC clinical risk criteria of patients with mRCC treated with HD IL-2 [10, 19]. This report represents the first analysis of survival of mRCC patients entered into this database utilizing the IMDC risk factors and risk categories and evaluating their impact on survival.

All data in the PROCLAIM database was collected under an ethics committee-approved clinical protocol approved at all contributing clinical sites [19]. Review of patient characteristics finds the registry patients to be consistent with prior reports of HD IL-2 treated patients, with 75% of patients male, median age 57 years, 95% having had nephrectomy, and with 94% specified as having a clear cell component on histology.

The IMDC risk factors for poor survival are the following: a) impaired performance status, b) less than 1 year interval from diagnosis to systemic treatment, c) hemoglobin less than LLN, d) corrected serum calcium above upper LN (ULN), e) neutrophil count above ULN, f) platelet count above ULN. The favorable risk patient group has none of these risk factors; the intermediate risk group has 1–2 risk factors, and the poor risk group has 3 or more risk factors [16, 17].

Among 939 mRCC patients in the database, 810 patients had data for all 6 IMDC criteria. Among the 810 patients, 365 patients had no prior therapy; 414 had therapy following IL-2, 89 had therapy prior to IL-2, and 356 had IL-2 alone, with no prior or subsequent therapy. Some subjects were in more than one group, ie some with no therapy prior, may have had therapy post-IL-2 or IL-2 alone. For 721 patients (89%), HD IL-2 was initial therapy for advanced mRCC.

This report focuses on those who received HD IL-2 alone to assess outcome by risk factor category (Table 1). We provide survival data for those with sequential therapies in Additional file 1: Table S1. Herein we also report response to HD IL-2 and response duration for all patients by risk categories (Table 2).Tab1

Survival by risk groups of 356 patients treated with HD IL-2 alone

Outcome is calculated using product-limit survival estimates by Kaplan-Meier analysis, producing response duration and survival curves. We evaluated the survival outcome of mRCC patients treated with HD IL-2 by IMDC risk category, and by treatment sequence, with OS calculated from initiation of IL-2 treatment in all groups. Figure 1 presents data for those treated with IL-2 alone by risk group. Additional file 1: Figure S1 presents data for all 810 patients and Additional file 1: Figure S2 presents survival for those who received therapy post IL-2. Additional file 1: Figures S3–S5 demonstrate complete and partial response and stable disease duration for all responders by risk category. Additional file 1: Figure S6 presents OS for the small group with therapy prior to IL-2, calculated from the start of the initial therapy for mRCC.Fig1Fig. 1

Overall survival by RCC risk: IL-2 alone

Among the 810 patients, approximately 25% were entered retrospectively, and 75% were entered prospectively. The median follow-up is 23.4 months (range 0.2–124+ months). Overall, 721 patients (89%) in this registry cohort were treatment-naїve prior to receiving IL-2 and were in the intermediate risk category (59%).

In this analysis of mRCC patients in the PROCLAIM^SM HD IL-2 registry, all IMDC risk groups have median and 2-year survivals following HD IL-2 that are consistent with recent reports of CPI immunotherapy or anti-VEGF targeted therapy for mRCC. All risk categories have improved survival compared with historical cytokine data [11–15] and are consistent with data from a recent prospective study, IL-2 “Select” [5] and other contemporary reports [2–4, 6–8].

In the high dose IL-2 alone patient group, favorable and intermediate risk patients demonstrate prolonged OS, and many experience years of treatment-free survival following IL-2 therapy. Further, the prolonged OS and 74% 2-year survival for the favorable risk group treated with IL-2 alone is in contrast to the outcome from the randomized trial of combined checkpoint inhibition, in which the favorable risk group had a better 18-mo OS with sunitinib compared with CPI [18]. This contrast demonstrates the nuances and differences between different categories of immunotherapy in the treatment of mRCC that are yet to be sorted out.

Eligibility for HD IL-2 treatment includes physiologic evaluation which may enrich for favorable risk patients, although the percentage of intermediate risk patients is similar to other mRCC treatment reports. Nevertheless, these eligibility criteria might inadvertently select an even better subset of each IMDC risk group for outcome when treated with IL-2 alone or with IL-2 followed by subsequent therapy, yielding durable response and survival. In support of this concept, even poor risk patients meeting IL-2 therapy criteria demonstrated clinical benefit with best clinical responses of CR, PR and SD reported, and 2 year OS of 40–50%.

Among responders in all treatment sequences, median response duration (CR and PR) following HD IL-2 was greater than or equal to 5 years regardless of risk category. However, durable stable disease was observed primarily in favorable risk (median > 5 years) and intermediate risk (median > 3 years) groups, with 10% durable SD among the poor risk group.

The CR rate of 5.4% is consistent with prior reports of IL-2 alone, but less than that of the combination ipilimumab/nivolumab arm of Checkpoint 214 in first line patients [18]. However, it is of note that the CR rate for single agent nivolumab in mRCC in both a large clinical trial experience and a large registry experience is 1 and 1.2%, respectively [20, 21]. Additionally, the CR plus PR rate for HD IL-2 alone is 25%, again consistent with prior reports of IL-2 and possibly allowing for resection of residual disease in PR patients, yielding “surgical CRs”, often with long-term disease-free intervals. The CR + PR rate for nivolumab alone was reported as 25 and 20% [20, 21].

HD IL-2 treatment yields durable responses among mRCC patients of all risk categories eligible for HD IL-2 therapy, and prolonged survival among mRCC patients, particularly in the favorable and intermediate risk groups. This therapy has the advantage of yielding prolonged treatment-free survival among responders. Additionally, data supporting feasibility of concurrent administration of IL-2 with CPIs is accumulating, potentially enhancing response rates. HD IL-2 remains an important treatment option for mRCC patients meeting eligibility criteria, both as first line and subsequent therapy. Combination studies are ongoing.