High-dose Interleukin-2 Can Produce a High Rate of Response and Durable Remissions in Appropriately Selected Patients With Metastatic Renal Cancer

Purpose High-dose aldesleukin (HD IL-2) received FDA approval for the treatment of mRCC in 1992, producing a 14% objective response rate (ORR) and durable remissions. Retrospective studies suggested that clinical and pathologic features could predict for benefit. The Cytokine Working Group conducted this prospective trial to validate proposed predictive markers of response to HD IL-2. Experimental Design Standard HD IL-2 was administered to prospectively evaluate whether the ORR of mRCC patients with “good” predictive pathologic features based on an “integrated selection” model (ISM) (e.g. clear-cell histology sub-classification and carbonic anhydrase-9 (CA-9) IHC staining) was significantly higher than the ORR of a historical, unselected population. Archived tumor was collected for pathologic analysis including tumor programmed death-ligand 1 (PD-L1) expression. Results 120 eligible patients enrolled between 11/06 and 7/09; 70% were MSKCC intermediate risk, 96% had clear cell RCC and 99% had prior nephrectomy. The independently assessed ORR was 25% (30/120, 95% CI = 17.5%–33.7%, p=0.0014) (3 CR, 27 PR) and was higher than a historical ORR. Thirteen patients (11%) remained progression-free at 3 years and the median OS was 42.8 months. ORR was not statistically different by ISM classification (“good-risk” 23% vs. “poor-risk” 30%, (p=0.39)). ORR was positively associated with tumor PD-L1 expression (p=0.01) by IHC. Conclusions In this prospective, biomarker validation study, HD IL-2 produced durable remissions and prolonged survival in both “good” and “poor-risk” patients. The proposed ISM was unable to improve the selection criteria. Novel markers (e.g. tumor PD-L1expression) appeared useful, but require independent validation.

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“…Application of this model was reported to produce an impressive ORR (52%) in a small, prospective study. (13)…”

Section: Introductionmentioning

confidence: 99%

The High-Dose Aldesleukin “Select” Trial: A Trial to Prospectively Validate Predictive Models of Response to Treatment in Patients with Metastatic Renal Cell Carcinoma

McDermott

Cheng

Signoretti

et al. 2015

Clinical Cancer Research

136

118

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“…7,8,[54][55][56] Immunotherapy also has the capacity to induce prolonged SD, although that has not been as carefully quantified. The potential benefits of immunotherapy seem to be restricted to the clear cell phenotype.…”

Section: Immunotherapymentioning

confidence: 99%

“…Interleukin-2 is also associated with a percentage of durable complete responses among patients with mRCC, and these patients have now been followed for decades without recurrence of their disease. 7,8,[54][55][56] More judicious patient selection has further enriched the responder population. 7,8,54 The utilization of these treatments has been limited by the complexity and intensity of treatment, requiring specialized centers to administer this therapy.…”

Section: Immunotherapymentioning

confidence: 99%

“…7,8,[54][55][56] More judicious patient selection has further enriched the responder population. 7,8,54 The utilization of these treatments has been limited by the complexity and intensity of treatment, requiring specialized centers to administer this therapy. Nevertheless, with an outcome which includes decades of response, Interleukin-2 remains in the armamentarium for mRCC.…”

Section: Immunotherapymentioning

confidence: 99%

“…5,6 The distinction between clear cell and nonclear cell types of renal cancer defined the observation that clear cell renal cancer is more likely to be responsive to immunotherapy and nonclear cell is not. 7,8 This is the most definitive distinction with an impact on treatment choices currently.…”

mentioning

confidence: 98%

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State-of-the-Art Management of Renal Cell Carcinoma

Mourad¹,

Dutcher²,

Ennis³

2014

American Journal of Clinical Oncology

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In the United States, renal cell cancer (RCC) is the third most common genitourinary tumor and the seventh most common cancer. Standard treatment of the primary tumor in RCC is complete resection by either a radical or partial nephrectomy which can be done as an open procedure or laparoscopically. Given the increasing incidence in the diagnosis of early-stage RCC and the toxicity and invasiveness associated with surgery, less invasive options (eg, radiofrequency ablation) have been used recently as an alternative. Although conventional radiotherapy plays a role in the palliative setting, its role is otherwise limited. This is partly because of the in vitro and clinical data showing that RCC is relatively radioresistant to radiotherapy. The advances in immobilization and image guidance have led several investigators to consider stereotactic techniques to overcome this resistance with impressive results in the metastatic setting. Recent retrospective and prospective phase II trials of RCC stereotactic body radiotherapy have shown excellent local controls up to 90% to 98%. Given these results and the noninvasive nature of stereotactic body radiotherapy this modality should be further evaluated as a treatment of choice for the primary RCC tumor. Although RCC is also resistant of conventional chemotherapy agents, exciting recent advances have emerged in the treatment of systemic disease with the development of targeted agents in addition to immunotherapy-based treatments. In the current critical review we discuss these emerging trends in localized and systemic treatment as well as possible interesting combinations of the 2 modalities.

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