First-line Avelumab plus Chemotherapy in Patients with Advanced Solid Tumors: Results from the Phase Ib/II JAVELIN Chemotherapy Medley Study

Abstract

Purpose: Chemotherapy can potentially enhance the activity of immune checkpoint inhibitors by promoting immune priming. The phase Ib/II JAVELIN Chemotherapy Medley trial (NCT03317496) evaluated first-line avelumab + concurrent chemotherapy in patients with advanced urothelial carcinoma or non-small cell lung cancer (NSCLC).

Materials and methods: Avelumab 800 or 1,200 mg was administered continuously every 3 weeks with standard doses of cisplatin + gemcitabine in patients with urothelial carcinoma, or carboplatin + pemetrexed in patients with nonsquamous NSCLC. Dual primary endpoints were dose-limiting toxicity (DLT; phase Ib) and confirmed objective response (phase Ib/II).

Results: In phase Ib, urothelial carcinoma and NSCLC cohorts received avelumab 800 mg (n = 13 and n = 6, respectively) or 1,200 mg (n = 6 each) + chemotherapy. In evaluable patients with urothelial carcinoma treated with avelumab 800 or 1,200 mg + chemotherapy, DLT occurred in 1/12 (8.3%) and 1/6 (16.7%), respectively; no DLT occurred in the NSCLC cohort. In phase II, 35 additional patients with urothelial carcinoma received avelumab 1,200 mg + chemotherapy. Across all treated patients, safety profiles were similar irrespective of avelumab dose. Objective response rates (95% confidence internal) with avelumab 800 or 1,200 mg + chemotherapy, respectively, across phase Ib/II, were 53.8% (25.1-80.8) and 39.0% (24.2-55.5) in urothelial carcinoma, and 50.0% (11.8-88.2) and 33.3% (4.3-77.7) in NSCLC.

Conclusions: Preliminary efficacy and safety findings with avelumab + chemotherapy in urothelial carcinoma and NSCLC were consistent with previous studies of similar combination regimens. Conclusions about clinical activity are limited by small patient numbers.

Significance: This phase Ib/II trial evaluated avelumab (immune checkpoint inhibitor) administered concurrently with standard first-line chemotherapy in patients with advanced urothelial carcinoma or advanced nonsquamous NSCLC without actionable mutations. Efficacy and safety appeared consistent with previous studies of similar combinations, although patient numbers were small.

FIGURE 1

Summary of reductions in tumor size and durations of PFS or response. A, Best percentage change from baseline in target lesions (green bars) and PFS in responding patients (gray bars) in the urothelial carcinoma cohorts.^aB, DOR in responding patients and change in tumor size over time in all patients in the urothelial carcinoma cohorts. C, Best percentage change from baseline in target lesions (green bars) and PFS in responding patients (gray bars) in the NSCLC cohorts. TMB high represents >10 mut/Mb. In urothelial carcinoma cohorts, PD-L1–positive status was defined using an algorithm that combines assessments of PD-L1 staining on tumor and immune cells, which were scored by pathologists (30); in NSCLC cohorts, PD-L1–positive status was defined as PD-L1 expression on ≥1% of tumor cells. PD-L1, programmed death-ligand 1; TMB, tumor mutational burden; FGFR, fibroblast growth factor receptor. ^aTwo patients with no postbaseline tumor assessments who were receiving avelumab 1,200 mg were excluded.

FIGURE 2

Pharmacokinetics of avelumab over time following administration of 800 and 1,200 mg every 3 weeks in the urothelial carcinoma and NSCLC cohorts. A, Serum avelumab C_trough by visit. B, Serum avelumab C_max by visit. C, Serum avelumab concentrations on day 15 visit. Horizontal black line within each box depicts the median, and upper and lower lines depict the third (Q3) and first (Q1) quantiles, respectively. Upper and lower error bars represent Q3 + 1.5 × IQR and Q1 – 1.5 × IQR, respectively. Dashed line represents median, and dotted lines represent 5th and 95th percentiles of historical steady state C_trough (A and C) or C_max (B) from population pharmacokinetic model–based simulations of avelumab 10 mg/kg every 2 weeks in monotherapy (1, 2). IQR, interquartile range.