Ilixadencel, a Cell-based Immune Primer, plus Sunitinib Versus Sunitinib Alone in Metastatic Renal Cell Carcinoma: A Randomized Phase 2 Study

Abstract

Background: The prognosis of patients with synchronous metastatic renal cell carcinoma (mRCC) is poor. Whereas single-agent tyrosine kinase inhibition (TKI) is clearly insufficient, the effects can be enhanced by combinations with immune checkpoint inhibitors. Innovative treatment options combining TKI and other immune-stimulating agents could prove beneficial.

Objective: To evaluate the clinical effects on metastatic disease when two doses of allogeneic monocyte-derived dendritic cells (ilixadencel) are administrated intratumorally followed by nephrectomy and treatment with sunitinib compared with nephrectomy and sunitinib monotherapy, in patients with synchronous mRCC.

Design setting and participants: A randomized (2:1) phase 2 multicenter trial enrolled 88 patients with newly diagnosed mRCC to treatment with the combination ilixadencel/sunitinib (ILIXA/SUN; 58 patients) or sunitinib alone (SUN; 30 patients).

Outcome measurements and statistical analysis: The primary endpoints were 18-mo survival rate and overall survival (OS). A secondary endpoint was objective response rate (ORR) assessed up to 18 mo after enrollment. Statistic evaluations included Kaplan-Meier estimates, log-rank tests, Cox regression, and stratified Cochran-Mantel-Haenszel tests.

Results and limitations: The median OS was 35.6 mo in the ILIXA/SUN arm versus 25.3 mo in the SUN arm (hazard ratio 0.73, 95% confidence interval 0.42-1.27; p = 0.25), while the 18-mo OS rates were 63% and 66% in the ILIXA/SUN and SUN arms, respectively. The confirmed ORR in the ILIXA/SUN arm were 42.2% (19/45), including three patients with complete response, versus 24.0% (six/25) in the SUN arm (p = 0.13) without complete responses. The study was not adequately powered to detect modest differences in survival.

Conclusions: The study failed to meet its primary endpoints. However, ilixadencel in combination with sunitinib was associated with a numerically higher, nonsignificant, confirmed response rate, including complete responses, compared with sunitinib monotherapy.

Patient summary: We studied the effects of intratumoral vaccination with ilixadencel followed by sunitinib versus sunitinib only in a randomized phase 2 study. The combination treatment showed numerically higher numbers of confirmed responses, suggesting an immunologic effect.

Keywords: Allogeneic dendritic cells; Ilixadencel; Intratumoral administration; Metastatic renal cell carcinoma; Off the shelf; Phase 2 trial; Randomized; Sunitinib.

Fig. 1

Overall trial profile. During enrollment, 111 patients were assessed for eligibility; 29 patients were screening failures and 88 were randomized. Patients were stratified according to the Heng criteria (high and intermediate risk). Fifty-eight patients (17 high-risk and 41 intermediate-risk patients) were allocated to receive ilixadencel (ILIXA) before nephrectomy and sunitinib (SUN) after nephrectomy (defined as the ILIXA/SUN group), whereas 30 patients (eight high-risk and 22 intermediate-risk patients) were allocated to sunitinib (SUN) alone after nephrectomy (defined as the SUN group).

Fig. 2

Kaplan-Meier estimate of survival for all patients. Survival probability (all patients) is displayed graphically using Kaplan-Meier, including summaries of the number of events (marked as a black star) and censored observations (marked as black circles). The red line represents ilixadencel and sunitinib strata (high and intermediate risk), and the blue line represents sunitinib strata (high and intermediate risk). The patients at risk for each stratum are indicated below the figure. CR = complete response.