JAVELIN Solid Tumor is an ongoing, international, multicenter, multicohort, open-label, dose-escalation and dose-expansion, phase 1 trial of avelumab in patients with advanced solid tumors (NCT01772004). In this phase 1b, dose-expansion cohort, eligible patients had histologically or cytologically confirmed stage IIIC or IV unresectable melanoma (according to the American Joint Committee on Cancer/Union for International Cancer Control [AJCC/UICC] TNM staging system, 7th edition) [22, 23] and were required to have progressive disease after ≥1 prior standard therapy for metastatic disease. Other eligibility criteria included an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1; age≥18 years; adequate hematologic, hepatic, and renal function; no evidence of brain metastases; and an available fresh or archival tumor specimen. Patients were not selected based on tumor PD-L1 expression. Patients with ocular melanoma were permitted to be enrolled. Patients who received prior therapy with anti–PD-L1/PD-1 antibodies were excluded; however, patients who received prior therapy with anti–CTLA-4 antibodies were eligible. Other exclusion criteria included any previous anticancer treatment or major surgery ≤28 days before the start of study treatment; other cancer diagnosis ≤5 years prior to study entry; rapidly progressive disease; previous stem cell or solid organ transplant; known hypersensitivity to monoclonal antibodies; active or history of autoimmune disease or immunodeficiency; significant acute or chronic infection (e.g., human immunodeficiency virus, hepatitis B virus, hepatitis C virus); persisting toxicity related to prior therapy of grade >1 (except for grade 2 sensory neuropathy); and being pregnant or lactating. Any use of steroids was tapered before study treatment, except for patients with adrenal insufficiency—who could continue treatment at a physiological replacement dose.

This trial was conducted in accordance with the ethics principles of the Declaration of Helsinki and the International Council on Harmonization Guidelines on Good Clinical Practice. The protocol was approved in each center by the institutional review board or independent ethics committee. All patients provided written consent before their enrollment.

Avelumab 10 mg/kg was administered as a 1-h intravenous infusion Q2W until progression, unacceptable toxicity, or occurrence of any other protocol-specified criterion for withdrawal. Dose modifications were not permitted. The following adverse events (AEs) required treatment discontinuation: any grade 4 AE, except single laboratory values out of the normal range that were unrelated to study treatment, without clinical correlate, and resolved in ≤7 days with medical management; any grade ≥3 treatment-related amylase or lipase abnormality that was not associated with symptoms or clinical manifestations of pancreatitis and did not require dose delay; increased ECOG PS ≥3 that did not resolve to ≤2 by cycle day 14 of the following cycle (infusions were not given during the following cycle if the ECOG PS was ≥3 on the day of administration); or any grade 3 AE except for transient (≤6 h) influenza-like symptoms or fever controlled with medical management; fatigue, local infusion-related reaction (IRR), headache, nausea, or emesis that resolved to grade ≤ 1 in ≤24 h; single laboratory values out of the normal range that were unrelated to study treatment and without clinical correlate (excluding grade ≥3 increase in liver enzyme concentrations) that resolved to grade ≤1 in ≤7 days; and tumor flare (local pain, irritation, or localized rash at sites of known or suspected malignant tissue). Grade 2 AEs were managed via reductions in infusion rates and dose delays. AEs that did not resolve to grade ≤1 by the end of the next treatment cycle or that recurred, resulted in permanent withdrawal of avelumab (except for hormone insufficiencies that could be managed by replacement therapy). Premedication with an antihistamine and acetaminophen was administered 30 to 60 min prior to all infusions of avelumab.

Biweekly safety assessments included documentation of AEs and concurrent medications, and ECOG PS; other safety assessments were conducted every 6 weeks and included physical examinations and clinical laboratory tests (hematology and serum chemistry). AEs and laboratory abnormalities were classified and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.0. A serious AE was defined as a life-threatening event that required hospitalization, resulted in disability, was a congenital anomaly, or resulted in death. IRRs (IRR, drug hypersensitivity, or hypersensitivity) occurring on the day of or the day after infusion and IRR symptoms occurring ≤1 day after infusion that resolved ≤2 days after onset were included. Immune-related AEs (irAEs) were identified using a prespecified list of AE terms and concomitant medication (eg, corticosteroids and hormone replacement) and relationship to study treatment was based on investigator assessment.

Clinical activity was assessed every 6 weeks by the investigators according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 [24]. Radiographic tumor assessments were performed at baseline and then every 6 weeks thereafter for the first 12 months, then every 12 weeks. For patients who had a partial response or complete response, a confirmatory computed tomography or magnetic resonance imaging scan was performed no sooner than 28 days later and preferably at the scheduled 6-week interval visit.

PD-L1 expression was assessed using a proprietary immunohistochemistry assay (Dako PD-L1 immunohistochemistry 73-10 pharmDx; Dako, Carpinteria, CA) [18–21]. In this study, PD-L1–positive status was defined prospectively using a cutoff of ≥1% of tumor cell membrane staining of any intensity; other PD-L1 cutoffs were also evaluated.

The primary objectives of the JAVELIN Solid Tumor trial were to assess dose-limiting toxicities within the first 3 weeks of treatment in the dose-escalation part of the study and confirmed best overall response as adjudicated by an independent review committee in specified expansion cohorts (not including melanoma) [13]. Prespecified endpoints in the melanoma cohort included investigator-assessed confirmed best overall response per RECIST v1.1, progression-free survival (PFS) per RECIST v1.1, overall survival (OS), tumor PD-L1 expression, and safety. All subgroup analyses of patients with ocular/non-ocular melanoma and those who received prior ipilimumab therapy were exploratory. Changes in the sum of target lesion diameters from baseline were evaluated in patients with baseline tumor assessments and ≥1 postbaseline assessment.

A sample size of 50 patients was planned to provide point estimates and 95% Clopper-Pearson CIs for an objective response rate (ORR) of 10% (95% CI, 3.3–21.8%) in the case of 5 responders, and of 20% (95% CI, 10.0–33.7%) in the case of 10 responders. Time-to-event endpoints were estimated with the Kaplan-Meier method, and CIs for the medians were calculated using the Brookmeyer-Crowley method. P values for association between categorical variables were determined using the Fisher exact test. Safety and clinical activity were analyzed in all patients who received ≥1 dose of avelumab.

As of December 31, 2016, 51 patients had received avelumab monotherapy (Table 1). Most patients had cutaneous melanoma (n = 28 [54.9%]), and 16 patients (31.4%) had ocular melanoma. Among all patients, 17 (33.3%) and 9 (17.7%) received 2 or ≥3 prior lines of therapy for metastatic or locally advanced disease, respectively; patients had received a median of 2 prior treatments (range, 0–4 treatments). Most patients (n = 26 [51.0%]) had received prior therapy with ipilimumab (anti–CTLA-4).Tab1

Patient demographics and baseline characteristics

At the time of data cutoff, the median duration of treatment with avelumab was 3.2 months (range, 0.5–27.2 months), and the median follow-up time was 24.2 months (range, 16.1–31.5 months). Patients had received a median of 7 doses of avelumab (range, 1–56 doses). At the time of analysis, treatment was ongoing in 6 patients (11.8%). Reasons for treatment discontinuation included progressive disease (n = 30 [58.8%]), AE (n = 8 [15.7%]), consent withdrawal (n = 3 [5.9%]), and death (n = 2 [3.9%]).

Of all 51 patients, the confirmed ORR per RECIST v1.1 was 21.6% (95% CI, 11.3–35.3) (Table 2), with complete response in 4 patients (7.8%), partial response in 7 patients (13.7%), stable disease in 16 patients (31.4%), and progressive disease in 18 patients (35.3%); disease control was achieved in 52.9% of patients. Six patients (11.8%) were not evaluable for best overall response due to lack of available postbaseline assessments (n = 4), postbaseline assessments with an overall response that was non-evaluable (n = 1), or stable disease of insufficient duration (n = 1). Most responses occurred rapidly: of the 11 responses, 4 occurred by first postbaseline assessment (1 complete response and 3 partial responses), and 4 additional patients achieved a partial response by the second postbaseline assessment (Fig. 1a). Responses were ongoing in 8 of 11 responding patients (72.7%) at the cutoff date. The median duration of response (DOR) was not estimable (range, 2.6 months-not estimable). Based on Kaplan-Meier estimates, 80.0% (95% CI, 40.9–94.6) and 68.6% (95% CI, 30.5–88.7) of responding patients had DOR of 6 and 12 months, respectively. Of 45 patients with baseline and postbaseline assessments, 15 (33.3%) experienced tumor shrinkage of ≥30% (Fig. 1b).Tab2

Response and outcomes in all patients and select patient subgroups

Median PFS was 3.1 months (95% CI, 1.4–6.3) (Table 2), and 14 patients (27.5%) were event-free at the cutoff date. The 6- and 12-month rates of PFS were 39.2 and 17.4%, respectively. The PFS curve demonstrated a stable plateau following the 12-month time point (Fig. 2a).Fig2Fig. 2

PFS (a) and OS (b) in all patients

Of 35 patients with cutaneous or mucosal melanoma, melanoma of the canthus, or unknown primary (collectively referred to as patients with non-ocular melanoma), the ORR was 31.4% (95% CI, 16.9–49.3) (Table 2), which included the previously described 11 patients with an objective response. ORRs according to tumor site subgroups are shown in Additional file 1: Table S1.

In patients with non-ocular melanoma, median PFS was 3.9 months (95% CI, 2.0–9.0), and 6- and 12-month PFS rates were 47.1 and 25.9%, respectively. Median OS was 17.2 months (95% CI, 9.3-not estimable), and 12- and 24-month OS rates were 64.9% and 44.8%, respectively. No objective responses were observed in the 16 patients with ocular melanoma, although 7 of 16 patients (43.8%) had transient stable disease. Median PFS was 1.7 months (95% CI, 1.4–4.1), with 6- and 12-month rates of PFS of 23.4 and 0%, respectively. Median OS was not yet reached (95% CI, 3.6 months-not estimable); the 12-month OS rate was 50.0% and the 24-month OS rate was not estimable (Table 2 , Fig. 3 , and Additional file 2: Figure S1).Fig3Fig. 3

PFS (a) and OS (b) in patients with non-ocular and ocular melanoma

Overall, 50 patients (98.0%) had an AE (Additional file 6: Table S3), 39 (76.5%) of whom had a treatment-related AE (TRAE) of any grade (Table 3). The most common TRAEs (occurring in >10% of patients) were IRR (n= 15 [29.4%]), fatigue (n= 9 [17.6%]), and chills (n= 6 [11.8%]). Grade 3 TRAEs occurred in 4 patients (7.8%): nausea, gamma-glutamyltransferase increased, hypokalemia, and lipase increased (n = 1 [2.0%] each). A TRAE led to permanent discontinuation in 5 patients (9.8%)—most commonly IRR (n = 3 [5.9%]), nausea (n = 1 [2.0%]), and sarcoidosis (n = 1 [2.0%]). Serious TRAEs occurred in 3 patients (5.9%): IRR (resolved with concomitant medication), pyrexia (resolved with concomitant medication), and sarcoidosis (led to treatment discontinuation). All serious AEs of any causality are shown in Additional file 7: Table S4. No grade 4 TRAEs and no treatment-related deaths were reported.Tab3

Incidence of treatment-related adverse events

IRRs occurred at the first infusion in 8 patients (15.7%), at the second infusion in 3 patients (5.9%), at the third infusion in 1 patient (2.0%), and at the fourth or later infusion in 3 patients (5.9%). IRRs led to treatment discontinuation in 3 patients (5.9%). Five patients (9.8%) experienced irAEs related to treatment, and all were grade 1/2: hypothyroidism and pneumonitis (n = 2 [3.9%] each) and hyperthyroidism, sarcoidosis, and vitiligo (n = 1 [2.0%] each) (Table 3). An irAE led to treatment discontinuation in 1 patient (2.0%) due to sarcoidosis (previously mentioned serious, treatment-related event).