The addition of the IMA901 vaccine to sunitinib for the first-line treatment of metastatic renal cell carcinoma did not improve overall survival.
The addition of the IMA901 vaccine to sunitinib for the first-line treatment of metastatic renal cell carcinoma (RCC) did not improve overall survival, according to the results of the IMPRINT study, which were published in Lancet Oncology.
Despite encouraging results from a phase II trial that showed an association between overall survival and T-cell response against IMA901, incorporation of the vaccine into a treatment regimen with sunitinib did not improve survival compared with sunitinib alone.
“Exploratory immunomonitoring analyses showed a significantly diminished magnitude of CD8-positive T-cell responses in this study compared with the previous phase II RCC study,” wrote Brian I. Rini, MD, of Cleveland Clinic Taussig Cancer Center, and colleagues.
The IMPRINT study was a phase III trial that randomly assigned 339 patients with treatment-naive metastatic or locally advanced clear-cell RCC to sunitinib plus up to 10 intradermal vaccinations of IMA901 and granulocyte macrophage colony-stimulating factor with one dose of cyclophosphamide (n = 204), or sunitinib alone (n = 135). The primary endpoint was overall survival.
With a median follow-up of 33.27 months, the median overall survival was similar between the two groups (33.17 months for the IMA901 group vs not reached for sunitinib; P = .087). Overall survival was also similar in the subgroup of patients with favorable International Metastatic Renal Cell Carcinoma Database Consortium risk; however, in patients with intermediate risk, the median overall survival was significantly longer for patients assigned sunitinib alone compared with IMA901 (not reached vs 27.85 months).
The researchers analyzed 108 patients in the vaccination group for immune responses to the peptides in IMA901. Compared with data from previous trials, IMA901-specific CD8-positive T-cell responses were reduced threefold.
“The low magnitude of CD8-positive T-cell responses in our study might have resulted from an adverse inhibition of T-cell priming induced by sunitinib or IMA901, or both, as exemplified by a significant reduction of monocytes after the first sunitinib cycle,” the researchers wrote. “Additionally, the timeline of vaccination was longer (up to 17 vaccinations in total) in the phase II trial than in our trial (up to 10 vaccinations), which might have affected the induced immune response.”
Fifty-seven percent of patients in the IMA901 group and 47% of patients in the sunitinib group had grade 3 or worse adverse events. The most common adverse events were hypertension, neutropenia, and anemia in both groups. The most common adverse event in the vaccination group was transient injection-site reaction. Serious adverse events occurred in 2% of patients in the IMA901 group and 6% of patients in the sunitinib group.
The researchers suggested several explanations for the absence of an overall survival benefit for combined therapy in this trial, including the weakened immune response seen in patients assigned to IMA901.
“Although the significant reduction in the magnitude of vaccine-induced immune responses in this trial compared with several previous trials implies that the diminution of immune effect was a result of sunitinib, this speculation is not fully supported by evidence, and other factors (eg, a different patient population compared with previous trials and different vaccine components in the non-RCC trials) might have played a part,” the researchers wrote. “Furthermore, the numerically shorter overall survival in the sunitinib plus IMA901 group might be due to imbalances in baseline characteristics favoring the sunitinib group and prolonged sunitinib exposure in the sunitinib group.”