Avelumab monotherapy as first-line or second-line treatment in patients with metastatic renal cell carcinoma: phase Ib results from the JAVELIN Solid Tumor trial

Background Antibodies targeting programmed death-1 (PD-1) or programmed death-ligand 1 (PD-L1) have shown clinical activity in the treatment of metastatic renal cell carcinoma (mRCC). This phase Ib cohort of the JAVELIN Solid Tumor trial assessed the efficacy and safety of avelumab (anti–PD-L1) monotherapy in patients with mRCC as either first-line (1 L) or second-line (2 L) treatment. Methods Patients with mRCC with a clear-cell component who were treatment naive (1 L subgroup) or had disease progression after one prior line of therapy (2 L subgroup) received avelumab 10 mg/kg intravenous infusion every 2 weeks. Endpoints included confirmed best overall response, duration of response (DOR), progression-free survival (PFS), overall survival (OS), PD-L1 expression, and safety. Results A total of 62 patients were enrolled in the 1 L subgroup, and 20 patients were enrolled in the 2 L subgroup. In the 1 L and 2 L subgroups, confirmed objective response rates were 16.1 and 10.0%, median DOR was 9.9 months (95% confidence interval [CI], 2.8–not evaluable) and not evaluable (95% CI, 6.9–not evaluable), median PFS was 8.3 months (95% CI, 5.5–9.5) and 5.6 months (95% CI, 2.3–9.6), and median OS was not evaluable (95% CI, not evaluable) and 16.9 months (95% CI, 8.3–not evaluable), respectively. Treatment-related adverse events (TRAEs) of any grade occurred in 51 patients in the 1 L subgroup (82.3%) and 14 patients in the 2 L subgroup (70.0%). Grade ≥ 3 TRAEs occurred in eight patients in the 1 L subgroup (12.9%) and one patient in the 2 L subgroup (5.0%). No treatment-related deaths occurred. Conclusion Avelumab showed clinical activity and a manageable safety profile in both the 1 L and 2 L treatment setting in patients with mRCC. These data support the use of avelumab in combination with other agents in mRCC. Trial registration ClinicalTrials.gov: NCT01772004; registered 21 January, 2013.


Background
Renal cell carcinoma (RCC) is the most common type of kidney cancer, with clear-cell RCC being the most common subtype [1]. Historically, metastatic RCC (mRCC) has had a poor prognosis, with an average 5-year survival rate of ≈11% [2]. Also, mRCC is highly resistant to chemotherapy and radiation treatment [3,4]. In recent years, progress has been made in the treatment of advanced or metastatic RCC and multiple targeted therapies have been approved, including tyrosine kinase inhibitors (TKIs), mammalian target of rapamycin inhibitors), and the antivascular endothelial growth factor antibody bevacizumab in combination with interferon alpha [5]. These targeted therapies have shown clinical activity and prolonged survival in patients with mRCC [6]; however, responses are generally short-lived, development of treatment resistance is common [5,7], and different classes of targeted therapy are associated with characteristic toxicity profiles that have implications for patient treatment selection [5].
In recent years, immune checkpoint inhibitors (ICIs) have become an established therapeutic class, with clinical activity seen in various tumor types [8,9]. In RCC, the immune checkpoint protein programmed death-1 (PD-1) and its ligand (PD-L1) are widely expressed on immune cells that infiltrate the tumor microenvironment and tumor cells, respectively [10][11][12]. Moreover, increased PD-1/L1 expression in RCC is associated with aggressive pathological features and a worse prognosis [10][11][12]. In patients with mRCC, anti-PD-1 and anti-PD-L1 antibodies have shown promising responses and improved overall survival (OS), both as monotherapy and in combination with other classes of agents. Nivolumab (anti-PD-1) was the first agent in this class to be approved by regulatory authorities, based on findings from the randomized phase III CheckMate 025 trial, which compared nivolumab monotherapy with everolimus in patients with advanced RCC who had received prior antiangiogenic therapy [13]. More recently, nivolumab in combination with ipilimumab (anti-cytotoxic T-lymphocyte protein 4) was approved for patients with previously untreated, intermediate-or poor-risk, advanced RCC, based on OS data from the phase III CheckMate 214 trial of nivolumab plus ipilimumab compared with sunitinib [14].
Avelumab is a human IgG1 monoclonal antibody that binds PD-L1, inhibiting the interaction with PD-1 and restoring antitumor immune responses [15]. Avelumab has been approved in various countries for the treatment of metastatic Merkel cell carcinoma and advanced urothelial carcinoma that has progressed following platinum-containing therapy [16]. The large, phase I, multicohort JAVELIN Solid Tumor trial (> 1700 patients; NCT01772004) assessed avelumab monotherapy in various tumors [17][18][19][20][21][22][23]. Here we report the efficacy and safety data from the phase Ib cohort of patients with mRCC, including subgroups who received either firstline (1 L) or second-line (2 L) avelumab monotherapy. When this study was initiated, phase III data for an ICI (nivolumab) as a 2 L treatment for advanced RCC had been reported [13]; however, no data for 1 L ICI treatment had been reported, providing the rationale to investigate the clinical activity of avelumab in both the 1 L and 2 L treatment settings. Subsequently, studies of anti-PD-1/PD-L1 antibodies in combination with targeted therapies as 1 L treatment for advanced or metastatic RCC were reported [14,[24][25][26][27]; this includes trials of avelumab combined with axitinib, particularly the recently reported phase III JAVELIN Renal 101 study, which showed superior efficacy with this regimen compared with sunitinib, and led to the recent FDA approval of avelumab and axitinib in combination for the treatment of advanced RCC [16,25,26]. Pembrolizumab (anti-PD-1) in combination with axitinib has also been approved by the FDA [24]. By evaluating the activity of avelumab monotherapy, the current study provides context for the improved efficacy seen with avelumab plus axitinib.

Study design and patients
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.

Treatment
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.

Assessments
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.
TRAEs led to discontinuation in three patients (4.8%) in the 1 L subgroup (anaphylactic reaction, aspartate aminotransferase increase, and nephritis) and two patients

Discussion
In this phase Ib study, avelumab monotherapy showed clinical activity as a 1 L or 2 L treatment for patients with mRCC. Responses were durable (median DOR was 9.9 months [1 L] and not evaluable [2 L]), and disease control rates were high in both subgroups (1 L, 77.4%; 2  includes AEs categorized as infusion-related reaction, drug hypersensitivity, or hypersensitivity reaction that occurred on the day of infusion or day after infusion, in addition to signs/symptoms of infusion-related reaction (based on a prespecified list of MedDRA preferred terms) that occurred on the same day of infusion and resolved within 2 days d Includes AEs classified by investigators as related or unrelated to treatment 1 L first-line subgroup, 2 L second-line subgroup, AE adverse event, MedDRA Medical Dictionary for Regulatory Activities, TRAE treatment-related adverse events, TSH thyroid-stimulating hormone L, 75.0%). Median PFS was 8.3 months in the 1 L subgroup and 5.6 months in the 2 L subgroup, and 12month OS rates were 83.7% (1 L; median, not evaluable) and 65.0% (2 L; median, 16.9 months). Responses to avelumab occurred irrespective of PD-L1 status, and no significant survival difference was seen between PD-L1+ and PD-L1− populations. Avelumab showed an acceptable safety profile, including a low rate of grade 3/4 TRAEs (12.9 and 5.0% in the 1 L and 2 L subgroups, respectively). These results are comparable with those reported with TKI monotherapy [7]. Results of this study were generally consistent with those in previous studies of anti-PD-1/PD-L1 monotherapy administered as either 1 L or 2 L treatment for mRCC. In the nivolumab monotherapy arm of the phase III CheckMate 025 study (patients with previously treated advanced clear-cell RCC [n = 410]), median PFS was 4.6 months (95% CI, 3.7-5.4), median OS was 25 months (95% CI, 21.8-not evaluable), the ORR was 25%, and 19% of patients had a grade 3/4 TRAE [13]. In the atezolizumab monotherapy arm of the randomized, phase II IMmotion150 study of patients with treatmentnaive mRCC (n = 103), median PFS was 6.1 months (95% CI, 5.4-13.6), OS was not reported, the ORR was 25% (CR, 11%; PR, 14%), and 17% of patients had a grade 3/4 TRAE [28]. Finally, in cohort A of the phase II KEYNOTE-427 study, which enrolled patients with advanced clear-cell RCC (n = 110), 1 L pembrolizumab monotherapy resulted in a median PFS of 6.9 months (95% CI, 5.1-not evaluable), 6-month OS rate of 92.4% (median, not reached), and ORR of 33.6% (95% CI, 24.8-43.4), and 18.2% of patients had a grade 3-5 TRAE [29].

Conclusion
In conclusion, results from this study show the efficacy and safety of avelumab in patients with mRCC, supporting the foundational role of ICIs within combination treatment regimens for this disease.

Supplementary information
Supplementary information accompanies this paper at https://doi.org/10. 1186/s40425-019-0746-2. has a co-research, co-development or co-marketing/co-promotion agreement or where the product has been out-licensed, it is recognized that the responsibility for disclosure may be dependent on the agreement between parties. Under these circumstances, Merck KGaA will endeavor to gain agreement to share data in response to requests.

Ethics approval and consent to participate
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, and all patients provided written informed consent before enrolment.

Consent for publication
Not applicable.