In a dose-finding, dose-expansion phase Ib trial (JAVELIN Renal 100) reported in The Lancet Oncology, Toni K. Choueiri, MD, of Dana-Farber Cancer Institute and Brigham and Women’s Hospital, and colleagues determined the maximum tolerated dose of the immune checkpoint inhibitor avelumab (Bavencio) in combination with the vascular endothelial growth factor (VEGF) inhibitor axitinib (Inlyta) and found high activity of the combination in the first-line treatment of resected advanced clear cell renal cell carcinoma.¹

Study Details

In the ongoing study, between October 2015 and September 2016, 6 patients were enrolled into a dose-finding phase and 49, into a dose-expansion phase at 14 sites in the United States, UK, and Japan. Patients in the dose-finding phase received 5 mg of axitinib orally twice daily for 7 days followed by combination therapy with 10 mg/kg of avelumab intravenously every 2 weeks and 5 mg off axitinib twice daily. In the dose-expansion phase, 10 patients received this regimen, with the remainder starting treatment with the combination without axitinib lead-in. The primary endpoint of the study was dose-limiting toxicity within the first 4 weeks (2 cycles) of treatment with the combination regimen. Confirmed objective response on Response Evaluation Criteria in Solid Tumors (v1.1) was a secondary endpoint.

Among all 55 patients, the median age was 60 years (31% ≥ 65 years); 76% were male; 80% were white and 11% Asian; all had an Eastern Cooperative Oncology Group performance status of 0 or 1; Memorial Sloan Kettering Cancer Center risk category was favorable in 51% and intermediate in 46%; and the number of target tumor sites was 1 for 46%, 2 for 42%, and 3 for 13%.

Dose-Finding Phase

Patients in the dose-finding cohort received a median of 32.5 avelumab infusions during a median follow-up of 69.7 weeks, with median durations of treatment being 66.6 weeks with axitinib and 66.0 weeks with avelumab. One patient had a dose-limiting toxicity (grade 3 proteinuria) that led to axitinib dose reduction and resolved without sequelae; the patient continued treatment with avelumab at 10 mg/kg and axitinib at 3 mg twice daily. Among the six patients, four (67%) had grade 3 or 4 treatment-related adverse events, consisting of grade 3 hypertension, palmar-plantar erythrodysesthesia, proteinuria, and mucosal inflammation and a grade 4 increase in lipase concentration. At the end of the dose-finding phase, the maximum tolerated dose established for the combination was avelumab at 10 mg/kg every 2 weeks and axitinib at 5 mg twice daily.

Response Rates

At data cutoff in April 2017, median follow-up for all 55 patients was 52.1 weeks. A total of 54 patients received avelumab and axitinib, with 1 patient receiving axitinib alone due to an adverse event occurring before the start of avelumab (grade 3 increase in blood creatine phosphokinase). At the time of cutoff, combination treatment was ongoing in 29 patients (53%), 2 (4%) were receiving axitinib alone, and 1 (2%) was receiving avelumab alone. Patients received avelumab for a median of 37.0 weeks and axitinib for a median of 36.0 weeks.

The safety profile of the combination of avelumab plus axitinib in treatment-naive patients with advanced renal cell carcinoma seemed to be manageable with promising anti-tumor activity, justifying the ongoing phase 3 trial of the combination vs sunitinib.

— Toni K. Choueiri, MD

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At data cutoff, 32 of all 55 patients (58%) had an objective response, including all 6 patients in the dose-finding phase and 26 of 49 patients (53%) in the dose-expansion phase. A complete response was observed in three patients (6%). The disease control rate was 78%. At data cutoff, 24 patients had ongoing responses; the median duration of response was not reached. The median time to achieve an objective response was 6.8 weeks. Tumor shrinkage was observed in 45 of 54 patients (83%) assessed after baseline.

Among 52 patients with data on programmed cell death ligand 1 (PD-L1) expression on tumor cells, response was observed in 27 of 41 (66%) with expression ≥ 1% and in 4 of 11 (36%) with expression < 1%. Response was observed in 19 of 28 patients (68%) with expression ≥ 5% and in 12 of 24 patients (50%) with expression < 5%.

Adverse Events

Among all patients, 58% had grade ≥ 3 treatment-related adverse events, with the most common being hypertension (29%); increased concentrations of alanine transaminase (ALT), amylase, and lipase; and palmar-plantar erythrodysesthesia syndrome (7% each). Overall, 36% of patients had serious adverse events, which were considered related to treatment in 22%. Immune-related adverse events of any grade occurred in 23 patients (42%), with the most common being hypothyroidism in 13 (24%), rash in 7 (13%), hepatitis in 3 (6%), and hyperthyroidism in 3 (6%). Grade ≥ 3 immune-related adverse events occurred in 5 patients (9%), with the most common being rash and hepatitis (2 patients, 4% each). Adverse events led to discontinuation of treatment in 10

patients (18%), including avelumab in 7 patients (13%) and axitinib in 4 patients (7%). Only increased ALT level (three patients, 6%) resulted in treatment discontinuation in more than one patient. A treatment-related adverse event, autoimmune myocarditis, resulted in death in one patient.

The investigators concluded: “The safety profile of the combination of avelumab plus axitinib in treatment-naive patients with advanced renal cell carcinoma seemed to be manageable and consistent with that of each drug alone, and the preliminary data on antitumour activity are encouraging. A phase 3 trial is assessing avelumab and axitinib compared with sunitinib monotherapy.” ■

DISCLOSURE: For full disclosures of the authors, visit www.thelancet.com.

REFERENCE

1. Choueiri TK, Larkin J, Oya M, et al: Preliminary results for avelumab plus axitinib as first-line therapy in patients with advanced clear-cell renal-cell carcinoma (JAVELIN Renal 100): An open-label, dose-finding and dose-expansion, phase 1b trial. Lancet Oncol 19:451-460, 2018.