JAVELIN Solid Tumor is an international, multicohort, open-label, phase I trial. Key eligibility criteria for this phase Ib expansion cohort were adults with histologically or cytologically confirmed mRCC with a clear-cell component, an Eastern Cooperative Group performance status (ECOG PS) of 0 or 1 and measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Patients were enrolled irrespective of PD-L1 expression status and had received no prior treatment (1 L subgroup) or had disease progression after one prior line of metastatic therapy (2 L subgroup). Key exclusion criteria included prior treatment with a T-cell–targeting antibody/drug; other cancer diagnosis within 5 years prior to study entry; and known autoimmune disease or hypersensitivity to monoclonal antibodies. Full eligibility criteria have been reported [17].

The trial was conducted in accordance with the Declaration of Helsinki and the International Council for Harmonisation Guideline for Good Clinical Practice. The protocol was approved by the institutional review board or independent ethics committee of each centre; all patients provided written informed consent before enrolment.

All patients received avelumab 10 mg/kg by intravenous infusion every 2 weeks until disease progression, unacceptable toxicity, or other criteria for withdrawal were met (reported previously) [17]. Dose reductions were not permitted. Antihistamine premedication was given 30–60 min before each infusion. Grade 2 AEs were managed by treatment delays of up to two subsequent omitted doses; events that did not resolve to grade ≤ 1 or recurred resulted in permanent treatment discontinuation.

Clinical activity and safety were analyzed in all patients who received at least one dose of avelumab. Tumors were assessed every 6 weeks for the first year and every 12 weeks thereafter by investigators according to RECIST v1.1. Safety was assessed at each biweekly visit, and AEs were graded according to the National Cancer Institute’s Common Terminology Criteria for Adverse Events (NCI-CTCAE), v4.0. Immune-related AEs (irAEs) were identified using a prespecified list of Medical Dictionary for Regulatory Activities (MedDRA) preferred terms, followed by comprehensive medical review. Infusion-related reactions (IRRs) were identified using an expanded definition that included both a prespecified list of MedDRA preferred terms (IRR, drug hypersensitivity, or hypersensitivity reaction) that occurred after infusion on the same day or following day, and additional signs/symptoms that occurred on the day of infusion and resolved within 2 days. PD-L1 expression was assessed using a proprietary immunohistochemistry assay (PD-L1 IHC 73–10 assay; Dako, Carpinteria, CA). PD-L1+ status was defined as PD-L1 expression on ≥ 1% of tumor cells.

Prespecified endpoints included confirmed best overall response according to RECIST v1.1 (investigator assessed), duration of response (DOR), progression-free survival (PFS) according to RECIST v1.1, OS, PD-L1 expression, and safety.

Enrolment of the 1 L subgroup began after documentation of two objective responses in the 2 L subgroup. Separate analyses of 1 L and 2 L subgroups were prespecified. The planned sample size of 20 patients in the 2 L subgroup was selected to enable observation of at least two responders with a probability of > 89.8% if the true objective response rate (ORR; proportion of patients with a partial response [PR] or complete response [CR]) was ≥ 18%. The planned sample size of 60 patients in the 1 L subgroup was selected to provide 95% Clopper-Pearson confidence intervals (CIs) for an ORR of 20% (95% CI, 10.8–32.3) in the case of 12 responders and 25% (95% CI, 14.7–37.9) in the case of 15 responders. Time-to-event endpoints were estimated using the Kaplan-Meier method, and CIs for medians were calculated using the Brookmeyer-Crowley method. P values for the association between PD-L1 status and ORR were determined using Fisher exact test.

Between May 11, 2015, and October 13, 2016, 82 patients were enrolled, comprising 62 in the 1 L subgroup and 20 in the 2 L subgroup (Table 1). In the 1 L and 2 L subgroups, respectively, median age was 62 years (range, 36–85) and 69 years (range, 30–80); 43 (69.4%) and 15 (75.0%) patients were male; 25 (40.3%) and 11 (55.0%) had an ECOG PS of 1; and 20 (32.3%) and four (20.0%) had PD-L1+ tumors. At the time of data cutoff (April 27, 2018), median follow-up in the 1 L and 2 L subgroups was 26.2 months (range, 18–29) and 34.1 months (range, 28–35), respectively. Median duration of treatment was 9.6 months (range, 0.9–29.0) in the 1 L subgroup and 5.3 months (range, 0.9–34.5) in the 2 L subgroup. At last follow-up, 12 patients (19.4%) in the 1 L subgroup and two patients (10.0%) in the 2 L subgroup remained on treatment. In both subgroups, the most common reason for discontinuation was disease progression (1 L, n = 40 [64.5%]; 2 L, n = 14 [70.0%]), and other reasons were AE (1 L, n = 4 [6.5%]; 2 L, n = 3 [15%]), withdrawal of consent (1 L, n = 1 [1.6%]), death (1 L, n = 1 [1.6%]; 2 L, n = 1 [5.0%]), and other (1 L, n = 4 [6.5%]; two patients required prohibited concomitant medication, one patient met an exclusion criterion, and one patient decided to undergo surgery).Tab1

Patient baseline characteristics

In the 1 L and 2 L subgroups, respectively, the ORR was 16.1% (CR, n = 1 [1.6%]; PR, n = 9 [14.5%]) and 10.0% (PR, n = 2) (Table 2 ; Fig. 1); median DOR was 9.9 months (95% CI, 2.8–not evaluable) and not evaluable (95% CI, 6.9–not evaluable); and 38 (61.3%) and 13 (65.0%) patients had a best overall response of stable disease, resulting in disease control rates of 77.4 and 75.0%. Median PFS was 8.3 months (95% CI, 5.5–9.5) in the 1 L subgroup and 5.6 months (95% CI, 2.3–9.6) in the 2 L subgroup (Fig. 2); 6-month and 12-month PFS rates were 56.7 and 30.9% in the 1 L subgroup, and 47.4 and 15.8% in the 2 L subgroup, respectively. In the 1 L and 2 L subgroups, median OS was not evaluable (95% CI, not evaluable) and 16.9 months (95% CI, 8.3–not evaluable); 6-month and 12-month OS rates were 88.6 and 83.7%, and 90.0 and 65.0%, in the 1 L and 2 L subgroups, respectively.Tab2

Confirmed objective responses

Among evaluable patients in the 1 L subgroup with PD-L1+ (n = 20) or PD-L1− (n = 21) tumors, respectively, the ORR was 10.0% (95% CI, 2.7–24.5) and 14.3% (95% CI, 5.4–29.1), median PFS was 5.8 months (95% CI, 1.9–13.0) and 8.3 months (95% CI, 5.5–15.1), 6-month PFS rates were 48.5% (95% CI, 25.4–68.2) and 66.7% (95% CI, 42.5–82.5), median OS was not evaluable in either group, and 12-month OS rates were 85.0% (95% CI, 60.4–94.9) and 90.5% (95% CI, 67.0–97.5) (Additional file 1). Results from the 2 L subgroup are not reported owing to low patient numbers.

Of patients in the 1 L and 2 L subgroups, 51 (82.3%) and 14 (70.0%) had a treatment-related AE (TRAE) of any grade, including eight (12.9%) and one (5.0%) who had a grade ≥ 3 TRAE, respectively (Table 3; Additional file 2). The only grade ≥ 3 TRAE that occurred in more than one patient was increased lipase (1 L, n = 4 [6.5%]). TRAEs led to discontinuation in three patients (4.8%) in the 1 L subgroup (anaphylactic reaction, aspartate aminotransferase increase, and nephritis) and two patients (10.0%) in the 2 L subgroup (IRR and pneumonitis). IRRs (based on an expanded definition) occurred in 22 patients (35.5%) in the 1 L subgroup and six patients (30.0%) in the 2 L subgroup; all were grade 1 or 2. Of patients in the 1 L and 2 L subgroups, 18 (29.0%) and three (15.0%) had an irAE of any grade, respectively. The most commonly occurring irAEs (≥ 10% in either subgroup) were thyroid disorders (1 L, n = 10 [16.1%]; 2 L, n = 2 [10.0%] and immune-related rash (1 L, n = 9 [14.5%]; 2 L, n = 1 [5.0%]). Two patients (3.2%) in the 1 L subgroup had a grade 3 irAE (rash and colitis, both n = 1); no patients in the 2 L subgroup had a grade 3 irAE. No grade 4 irAEs occurred in either subgroup. In the 1 L and 2 L subgroups, respectively, fourteen patients (22.6%) and seven patients (35.0%) had serious AEs, which were related to treatment in two patients (3.2%) in the 1 L subgroup (grade 3 colitis and grade 2 hyperthermia, both n = 1). Four patients (6.5%) in the 1 L subgroup and two patients (10.0%) in the 2 L subgroup had an AE leading to death (none treatment related).Tab3

Incidence of treatment-related adverse events (TRAEs), infusion-related reactions (IRRs), and immune-related adverse events (irAEs)