Renal Cell Carcinoma Vaccine Fails to Improve Outcomes

Brian Rini, MD

The IMA901 multipeptide vaccine added to sunitinib failed to improve outcomes versus sunitinib alone as first-line therapy for advanced/metastatic renal cell carcinoma (RCC). These disappointing results, presented at the 2015 European Cancer Congress, point out the difficulties in developing therapeutic vaccine and illuminate areas where refinements are needed if a vaccine is to be effective in RCC.

“There was no improvement in overall survival when adding IMA901 to first-line sunitinib in patients with advanced renal cell cancer. Survival was comparable in both arms in favorable risk patients. Longer overall survival was observed in intermediate-risk patients with sunitinib alone. Methods to improve immune responses would need to be identified before further development of IMA901 in metastatic renal cell carcinoma is indicated,” said lead author Brian Rini, MD, associate professor of Medicine, the Cleveland Clinic Lerner College of Medicine at Case Western Reserve University.

The open-label phase III trial compared the multipeptide vaccine in combination with sunitinib with sunitinib alone, which is standard first-line therapy and is thought to have immune-boosting properties.

“Favorable reductions in regulatory T cells suggest that sunitinib modulates the tumor microenvironment and assists in the immune response,” he said.

Phase II results with the vaccine alone plus or minus cyclophosphamide showed an association between magnitude of T-cell responses and survival, Rini explained. Patients given cyclophosphamide had a better immune response.

The phase III open-label trial enrolled 339 patients with metastatic RCC who were HLA-A*02 positive and had favorable or intermediate risk status. Following 1 cycle of sunitinib, patients were randomized 3:2 to up to 10 intradermal vaccinations of IMA901 plus 75 μg GM-CSF plus sunitinib (50 mg; standard 4 weeks on/2 weeks off) versus sunitinib alone. Patients in the vaccine arm were given a single infusion of cyclophosphamide 3 days before the first vaccination to reduce regulatory T cells.

For the primary endpoint of overall survival (OS), 204 patients in the vaccine arm and 135 in the sunitinib arm were evaluable.

“There was no overall survival advantage to the investigational arm of the vaccine. In fact, the hazard ratio favored the control arm of the trial,” Rini stated.

Median OS was 33.1 months in the vaccine arm versus not reached in the control arm, which was not statistically significant.

When analyzed according to risk status, the survival curves for the two arms overlapped in favorable-risk patients and favored the control arm for intermediate risk patients (27. 8 weeks for the vaccine versus not reached for the control arm, P <.05).

Progression-free survival (PFS) was longer than expected in both arms and not significantly different—about 15 months according to central review. By contrast, investigator analysis showed longer PFS in intermediate-risk patients treated with sunitinib alone: 15.1 months in the vaccine arm versus 17.9 months in the control arm, which led to higher exposure to sunitinib in the control arm.

The vaccine had a favorable safety profile, with similar rates of adverse events in both arms. Transient injection-site reactions were the most frequent vaccine-related adverse events.

Immune data showed that sunitinib led to a significant decrease in monocytes after the first injection. There was no clear or significant association between T-cell responses and clinical outcome, including survival.

“The effect of sunitinib could have negatively affected the vaccine response, but this is a hypothesis. The magnitude of response to IMA901 in this trial is less compared with other studies of the vaccine in different tumor types,” said Rini.

“With tumor vaccines, there is a huge difference between our goals and what actually happens. Many trials of tumor vaccines fail. Many steps are involved in developing therapeutic vaccines,” said Ignacio Melero, MD, who discussed this trial at the meeting.

He commended the investigators of the study and said that the vaccine was “smartly developed.”

“The phase II results were enticing, showing a survival difference in renal cell carcinoma in patients premedicated with cyclophosphamide who developed immune responses. The phase III trial is well conducted, but the trial is basically negative with no difference in survival. In my opinion, this is may be related to prolonged exposure to sunitinib,” he continued.

“The data from phase II were not replicated. Those patients who mounted an immune response did not do better,” he emphasized.

Melero, professor of immunology at the University of Navarra, Pamplona, Spain, suggested the following possible ways to improve vaccine development for RCC: longer peptides; neoantigens; no sunitinib; combination with checkpoint inhibitors; rethink the biology of immune response induction.

Rini B, Stenzl A, Zdrojowy R, et al. Results from an open-label, randomized, controlled phase 3 study investigating IMA901 multipeptide cancer vaccine in patients receiving sunitinib as first-line therapy for advanced/metastatic RCC. Presented at: 2015 European Cancer Congress; September 25-29; Vienna, Austria. Abstract LBA 17.