Does Adding IMA901 Vaccine to Sunitinib Improve Survival in Advanced Renal Cell Carcinoma?
In the phase III IMPRINT trial reported in The Lancet Oncology, Rini et al 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. IMA901 contains 10 tumor-associated peptides. A phase II study had shown an association between overall survival and T-cell responses to the vaccine.
Study Details
In this open-label trial, 339 HLA-A*02-positive patients from 124 sites in Germany, France, Italy, the Netherlands, Norway, United Kingdom, 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, 1 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/IMA901and sunitinib groups, median age was 62 and 60 years; 70% and 65% were male; 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 undergone nephrectomy; and the proportion of patients with more than three affected organs was 48% and 41% on radiologist assessment and 46% and 33% on investigator assessment.
Survival
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 vsnot reached (95% CI = 33.67 to not reached) in the sunitinib group (hazard ratio [HR] = 1.34, P = .087). Hazard ratios were 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).
Immune Responses
Assessment of immune responses to the IMA901 peptides in 108 patients in the sunitinib/IMA901group showed that magnitude of IMA901-specific CD8-positive T-cell responses were threefold lower than those 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.
Adverse Events
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 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 sunitnib/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.”
The study was funded by Immatics Biotechnologies.
Brian I. Rini, MD, of the Cleveland Clinic Taussig Cancer Institute, is the corresponding author of The Lancet Oncology article.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
