IMA901 did not improve overall survival when added to sunitinib as first-line treatment in patients with metastatic renal cell carcinoma.— Brian I. Rini, MD, and colleagues
In the phase III IMPRINT trial reported in The Lancet Oncology, Brian I. Rini, MD, of the Cleveland Clinic Taussig Cancer Institute, and colleagues found no overall survival benefit of adding the multipeptide cancer vaccine IMA901 to sunitinib (Sutent) in the first-line treatment of locally advanced or metastatic renal cell carcinoma.1 IMA901 contains 10 tumor-associated peptides. A phase II study had shown an association between overall survival and T-cell responses to the vaccine.
In this open-label trial, 339 HLA-A*02-positive patients from 124 sites in Germany, France, Italy, the Netherlands, Norway, UK, Hungary, Poland, Russia, Romania, and the United States were randomized 3:2 between December 2010 and December 2012 to receive sunitinib plus IMA901 (n = 204) or sunitinib monotherapy (n = 135). Sunitinib was given as 50 mg orally once daily for 4 weeks on and 2 weeks off treatment until disease progression, death, or withdrawal of consent. Evidence suggested that 4 weeks of sunitinib results in a reduction in myeloid-derived suppressor cells and regulatory T cells. Thus, a 5-week time point was selected for vaccination to achieve a favorable immunomodulatory effect and optimal antitumor T-cell response.
In the vaccination group, one dose of cyclophosphamide at 300 mg/m2 was given 3 days before the first vaccination. Patents then received 10 intradermal doses of IMA901 at 4.13 mg and granulocyte-macrophage colony-stimulating factor at 75 μg, given as 6 doses over the first 3 weeks (days 1, 2, 3, 8, 15, and 22) and 4 doses at 3-week intervals thereafter (days 43, 64, 85, and 106). The primary endpoint was overall survival on intent-to-treat analysis.
For the sunitinib/IMA901 and sunitinib groups, median age was 62 and 60 years; 70% and 65% were male; region was Central/Eastern Europe for 63% and 65%; 46% and 51% had a Karnofsky performance status of 100; International Metastatic Database Consortium (IMDC) risk group was intermediate for 71% in both and favorable for 27% and 26%; 90% and 91% had received nephrectomy; and the proportion of patients with at least three affected organs was 48% and 41% on radiologist assessment and 46% and 33% on investigator assessment.
Median follow-up was 33.27 months. Median overall survival was 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). The hazard ratio was 0.82 (P = .59) among patients with a favorable risk and 1.52 (P = .028) among those with an intermediate risk. Median progression-free survival was 15.22 months vs 15.12 months (P = .74) on independent central review and 15.12 vs 17.92 months on investigator assessment (P = .27).
Assessment of immune responses to the IMA901 peptides in 108 patients in the sunitinib/ IMA901 group showed that the magnitude of IMA901-specific CD8-positive T-cell responses was threefold lower than that indicated by data from phase I and II trials in metastatic renal cell carcinoma and other solid tumors. No clear association of T-cell responses with clinical outcome was observed. A significant reduction (P < .0001) in monocytes was observed after the first sunitinib treatment cycle.
Grade ≥ 3 adverse events occurred in 57% of the sunitinib/IMA901 group and 47% of the sunitinib group, with the most common being hypertension (12% vs 5%), neutropenia (8% vs 5%), and anemia (6% vs 5%) in both groups. Mild-to-moderate transient injection-site reactions (eg, erythema [10%] and pruritus) were the most frequent adverse events of any grade related to IMA901. There were no significant differences between the groups in terms of the frequency of adverse events of any grade that occurred in > 5% of patients. Sunitinib was discontinued due to adverse events in 13% of the sunitinib/IMA901 group and 17% of the sunitinib group. Serious adverse events leading to death occurred in four patients (2%) in the sunitinib/IMA901 group and eight patients (6%) in the sunitinib group; three in the sunitinib/IMA901 group (respiratory failure and circulatory collapse, esophageal varices hemorrhage, and cardiac arrest) were considered possibly related to sunitinib and one in the sunitinib group (cerebrovascular accident) was considered possibly related to treatment.
The investigators concluded: “IMA901 did not improve overall survival when added to sunitinib as first-line treatment in patients with metastatic renal cell carcinoma. The magnitude of immune responses needs to be improved before further development of IMA901 in this disease is indicated.” ■
Disclosure: The study was funded by Immatics Biotechnologies. For full disclosures of the study authors, visit www.thelancet.com.
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.
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...!-->!-->