If the ADAPT study replicates the results of the previous phase II study of AGS-003 plus sunitinib, this regimen will have the distinct advantage of being one of the most well-tolerated combinatorial regimens in the first-line setting for metastatic clear cell variant renal cell carcinoma.— Neeraj Agarwal, MD
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As reviewed in this issue of The ASCO Post, Brian Rini, MD, and colleagues recently reported results from the phase III IMPRINT trial,1 which randomized HLA-A*02–positive patients with treatment-naive metastatic clear cell variant renal cell carcinoma, in favorable- and intermediate- risk categories, to receive sunitinib (Sutent) plus IMA901 (n = 204) vs sunitinib alone (n = 135). The primary endpoint was overall survival.
IMA901, an “off-the-shelf” peptide vaccine, is composed of nine different human leukocyte antigen (HLA) class I (ie, HLA-A*02)-binding tumor-associated peptides and one HLA class II-binding tumor-associated peptide. Patients in the experimental arm also received granulocyte macrophage colony-stimulating factor (GM-CSF) plus priming with cyclophosphamide prior to the first dose of IMA901.
The IMPRINT study was developed based on encouraging results from two earlier studies with IMA901 in the metastatic renal cell carcinoma population: (1) a phase I study showing the safety of combination IMA901 and GM-CSF, as well as a correlation between immune response against tumor-associated peptides and clinical outcome,2 and (2) a subsequent phase II randomized study in which patients were treated with IMA901 and GM-CSF with or without a priming dose of cyclophosphamide, again showing a significant association between overall survival benefit and T-cell response against tumor peptides as well as reduction of immunosuppressive regulatory T cells with cyclophosphamide priming.3
However, despite these encouraging preliminary results, the IMPRINT study did not meet its primary endpoint. There was no difference in median overall survival between the two treatment arms: 33.17 months (95% confidence interval [CI] = 27.81–41.36 months) in the sunitinib/IMA901 group vs not reached (95% CI = 33.67 to not reached) in the sunitinib group (hazard ratio [HR] = 1.34, P = .087). Furthermore, there was no improvement in progression-free survival or objective responses in the experimental arm. Notably, this phase III study was unable to replicate the correlation between immune response and clinical outcome seen in the earlier studies.
Why Did the IMPRINT Trial Fail?
Why did the IMPRINT study fail despite promising data from earlier studies? The differences in patient and disease characteristics between the current study and earlier trials may have played a role. One other reason may be a difference in study design, with the addition of sunitinib to IMA091 in the IMPRINT study. Sunitinib was likely chosen for its inhibitory effects on immunosuppressive myeloderived suppressive cells and regulatory T cells.
Furthermore, sunitinib has now been shown to attenuate expression of immune checkpoints such as cytotoxic T-lymphocyte–associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) on tumor-infiltrating T cells.4 Given its multitude of immune-stimulatory effects, sunitinib was expected to complement the antitumor effects of immunotherapy. However, the results of the IMPRINT study suggest a more complex, yet unknown, interplay may have occurred between sunitinib and IMA901.
Failure of Past Vaccine Strategies
So far, the approach of vaccine therapy in the setting of metastatic clear cell variant renal cell carcinoma has not been successful. In addition to the IMA901 vaccine, two other vaccine strategies have failed to improve outcomes. TG-4010, a recombinant modified vaccinia virus expressing interleukin-2 plus MUC1 antigen in combination with cytokines, was tested in a phase II trial of 37 patients with treatment-naive metastatic renal cell carcinoma.5 MUC1 overexpression has previously been shown to be associated with a poor prognosis in metastatic renal cell carcinoma. However, given the modest efficacy of TG-4010 in this study, further development was not pursued.
Another vaccine was MVA-5T4, a modified vaccinia Ankara encoding the oncofetal tumor antigen 5T4. In a phase III study of 732 patients with treatment-naive metastatic clear cell variant renal cell carcinoma who had undergone nephrectomy, patients were randomized to receive the standard of care plus MVA-5T4 vs standard of care alone.6 Standard of care included interleukin-2, interferon-alpha or sunitinib. Disappointingly, there was no improvement in overall survival, the primary endpoint, with MVA-5T4.
Promising Phase II Data
Despite a history of negative vaccine trials in metastatic clear cell variant renal cell carcinoma, AGS-003, a “personalized” immunotherapy, has shown promise in a phase II study and is currently being evaluated in the phase III ADAPT study, with the results eagerly awaited. AGS-003 is manufactured ex vivo from the patient’s own mature monocyte-derived dendritic cells harvested by leukopheresis, which are subsequently electroporated with the patient’s amplified tumor RNA and synthetic CD40L RNA.7 When AGS-003 is administered intradermally, the tumor RNA–loaded mature dendritic cells present unique patient-specific tumor antigens via major histocompatibility complex (MHC) class I presentation to T cells in draining lymph nodes. Furthermore, CD40 ligation promotes CD8-positive T-cell recruitment through regional production of interleukin-12.
The phase II study of AGS-003 enrolled patients with an intermediate or poor prognostic risk category metastatic clear cell variant renal cell carcinoma.7 Patients were treated with 1 cycle of sunitinib (4 weeks on, followed by 2 weeks off), followed by concomitant AGS-003 immunotherapy every 3 weeks for 5 doses and then every 12 weeks until disease progression or the end of the study. Median progression-free survival and overall survival were 11.2 months and 30.2 months, respectively. Of 21 patients, 13 (62%) achieved a clinical benefit (9 with partial response and 4 with stable disease). Treatment with AGS-003 was well tolerated, with injection-site reactions as the primary adverse event. Remarkably, overall survival was more than 5 years in 5 patients (24%), with 2 patients achieving durable responses for more than 5 years.7
The phase III ADAPT study has already completed accrual of 450 patients with de novo metastatic clear cell variant renal cell carcinoma. These patients were randomized to sunitinib plus AGS-003 vs sunitinib alone, with a primary endpoint of overall survival, after cytoreductive nephrectomy.
Dramatic Shifts in Treatment Paradigm Expected
Although the treatment paradigm of metastatic clear cell variant renal cell carcinoma in the first-line therapy setting has not changed for the past 5 years or so—ie, since the approval of pazopanib (Votrient) in April 2012—it is expected to undergo dramatic shifts in the very near future. Cabozantinib (Cabometyx), a multityrosine kinase inhibitor with activity against vascular endothelial growth factor (VEGF), MET, and AXL, has recently shown significantly improved progression-free survival and objective response over sunitinib.8 Additionally, multiple registration trials are ongoing in this setting, including combinations of anti-VEGF and anti–PD-1 therapies (bevacizumab [Avastin] plus atezolizumab [Tecentriq] vs bevacizumab, axitinib [Inlyta] plus avelumab vs sunitinib) or combinations of two immune checkpoint inhibitors (ipilimumab [Yervoy] plus nivolumab [Opdivo] vs sunitinib). All these combinations are very promising.
However, if the ADAPT study replicates the results of the previous phase II study of AGS-003 plus sunitinib, this regimen will have the distinct advantage of being one of the most well-tolerated combinatorial regimens in the first-line setting for metastatic clear cell variant renal cell carcinoma. Despite the setbacks in the recent past, the vaccine therapy approach in metastatic clear cell variant renal cell carcinoma remains promising. ■
Disclosure: Dr. Agarwal is a consultant for Pfizer, Exelixis, Argos Therapeutics, Cerulean Pharma, Medivation, Eisai, and Novartis.
Dr. Agarwal is Director of Genitourinary Oncology Program and Associate Director of Clinical Trials, Huntsman Cancer Institute, University of Utah, Salt Lake City.
1. Rini BI, Stenzl A, Zdrojowy R, et al: IMA901, a multipeptide cancer vaccine, plus sunitinib versus sunitinib alone, as first-line therapy for advanced or metastatic renal cell carcinoma (IMPRINT): A multicentre, open-label, randomised, controlled, phase 3 trial. Lancet Oncol 17:1599-1611, 2016.
2. Kirner A, Mayer-Mokler A, Reinhardt C: IMA901: A multi-peptide cancer vaccine for treatment of renal cell cancer. Hum Vaccin Immunother 10:3179-3189, 2014.
3. Walter S, Weinschenk T, Stenzl A, et al: Multipeptide immune response to cancer vaccine IMA901 after single-dose cyclophosphamide associates with longer patient survival. Nat Med 18:1254-1261, 2012.
4. Hooren LV, Georganaki M, Huang H, et al: Sunitinib enhances the antitumor responses of agonistic CD40-antibody by reducing MDSCs and synergistically improving endothelial activation and T-cell recruitment. Oncotarget. July 1, 2016 (early release online).
5. Oudard S, Rixe O, Beuselinck B, et al: A phase II study of the cancer vaccine TG4010 alone and in combination with cytokines in patients with metastatic renal clear-cell carcinoma: Clinical and immunological findings. Cancer Immunol Immunother 60:261-271, 2011.
6. Amato RJ, Hawkins RE, Kaufman HL, et al: Vaccination of metastatic renal cancer patients with MVA-5T4: A randomized, double-blind, placebo-controlled phase III study. Clin Cancer Res 16:5539-5547, 2010.
7. Amin A, Dudek AZ, Logan TF, et al: Survival with AGS-003, an autologous dendritic cell-based immunotherapy, in combination with sunitinib in unfavorable risk patients with advanced renal cell carcinoma: Phase II study results. J Immunother Cancer 3:14, 2015.
