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Society for Immunotherapy of Cancer 2016
The 31st annual SITC meeting hosted 2,700 medical professionals November 9–13 in National Harbor, Maryland. The record-setting attendance was reflective of the intense current interest in immunotherapies. We review below two key sessions on the checkpoint inhibitor nivolumab (Opdivo, Bristol-Myers Squibb) in antitumor combinations for the treatment of solid malignancies.
Urelumab Is Safe and Active as Monotherapy And in Combination With Nivolumab in Hematologic and Solid Malignancies
Preclinical models of combined urelumab and nivolumab have demonstrated robust antitumor activity with increased interferon gamma (IFNγ) production versus monotherapy. Because each enhances immune cell activity through distinctly different mechanisms, their activity in patients with advanced cancers may be synergistic, Dr. Massarelli said. Urelumab is a fully human IgG4 monoclonal antibody that binds to and activates CD137-expressing cytotoxic T cells.
A monotherapy study evaluated urelumab in patients with advanced malignancies (0.1 or 0.3 mg/kg every three weeks) or advanced non-Hodgkin’s lymphoma (8 mg every three or six weeks). The combination study evaluated urelumab (3 mg or 8 mg every four weeks) plus nivolumab (3 mg/kg or 240 mg every two weeks) in patients with advanced solid tumors or B-cell lymphoma or patients with diffuse large B-cell lymphoma (DLBCL), melanoma, non–small-cell lung cancer (NSCLC), or squamous cell carcinoma of the head and neck (SCCHN; cohort expansion). Mean age was approximately 65 years. In the combination study, 28% of patients had no prior treatment, and 70% had one or more prior lines of therapy. In the monotherapy study, all patients had been treated previously.
With the urelumab plus nivolumab combination, increases in IFNγ-induced peripheral cytokine expression (CXCL9/CXCL10) following treatment were larger than those that occurred with urelumab monotherapy. In a small sample of melanoma tumors, greater numbers of CD8-positive T cells and increased CXCL9 gene expression (and a trend toward increased IFNγ gene expression) were observed.
In the monotherapy trial, drug-induced liver injury in one patient led to discontinuation of the 0.3-mg/kg dose of urelumab. No treatment-related deaths were reported, and only three of 70 patients withdrew due to treatment-related adverse events.
The monotherapy overall response rate (ORR) was 10% (5% complete and 5% partial remission), with all responses occurring in those with B-cell non-Hodgkin’s lymphoma (B-NHL). The confirmed disease control rates (DCR) for B-NHL, colorectal cancer (CRC), SCCHN, and other solid tumors were 28%, 18%, 20%, and 39%, respectively.
Among the 128 combination-therapy patients receiving flat-dose urelumab (8 mg every four weeks) and nivolumab (240 mg every two weeks), adverse events led to discontinuation in 10% of patients (seven of 128 patients any grade; six of 128 patients grades 3–4). Fatigue was the most commonly reported adverse event (31% any grade; 0% grades 3–4). “This indicates that these two agents can be safely administered together,” Dr. Massarelli said.
The ORR (confirmed and unconfirmed) was 50% among 46 melanoma anti-programmed cell death-1 (PD-1)/programmed death ligand-1 (PD-L1) naïve patients and the DCR rate (confirmed and unconfirmed) was 70%. DCRs were 21% for DLBCL, 21% for NSCLC (anti-PD-1/PD-L1) progressors, 35% for NSCLC (anti-PD-1/PD-L1 naïve), 23% for SCCHN, and 33% for other solid tumors.
PD-L1 status (1% or greater or less than 1%) had no effect on ORR in melanoma patients receiving the urelumab plus nivolumab combination who were anti-PD-1/PD-L1 naïve, with rates of 50% (1% or greater) and 47% (less than 1%).
Among patients receiving combination therapy with urelumab and nivolumab, safety was manageable at all evaluated doses. Dr. Massarelli concluded that in the urelumab monotherapy trial, the 0.1-mg/kg and 8-mg doses demonstrated manageable safety profiles and peripheral pharmacodynamic activity. Promising antitumor activity was observed in melanoma patients.
Greater Benefit for Nivolumab 1 mg/Ipilimumab 3 mg in Previously Treated Metastatic Urothelial Cancer
In previously treated patients with metastatic urothelial carcinoma (mUC), chemotherapy efficacy is poor and associated with significant toxicity, Dr. Sharma said. Monotherapy trials (phase 1/2 and 2) of nivolumab have shown notable antitumor activity in patients previously treated for mUC, with overall response rates (ORR) of 19.6% and median overall survival (OS) of 8.7 months. Both preclinical and clinical data with the combination of nivolumab, a programmed cell death-1 blockade, and ipilimumab (Yervoy, Bristol-Myers Squibb), a cytotoxic T-lymphocyte–associated antigen-4 blockade, have shown improved antitumor activity in advanced melanoma, non–small-cell lung cancer, and metastatic renal cell carcinoma.
Dr. Sharma presented first results from Checkmate 032, the first trial of combination immunotherapy in mUC. The phase 1/2 study compared two dosing strategies of nivolumab combined with ipilimumab in patients with previously treated metastatic disease. Twenty-eight patients received nivolumab 1 mg/kg plus ipilimumab 3 mg/kg (intravenously [IV] every three weeks for four cycles) and 104 patients received nivolumab 3 mg/kg plus ipilimumab 1 mg/kg (IV every three weeks for four cycles), with all receiving maintenance with nivolumab 3 mg/kg IV every two weeks. The primary endpoint was investigator-assessed confirmed ORR.
Median age was greater in patients in the nivolumab 1-mg/ipilimumab 3-mg group (50.0% versus 45.2% were 65 years of age or older). Both groups had approximately 60% of patients treated with two or more prior regimens. Programmed death ligand-1 expression was higher than 1% in more patients in the nivolumab 1-mg/ipilimumab 3-mg group (38.5% versus 28.8%).
More patients are continuing treatment in the nivolumab 1-mg/ipilimumab 3-mg group (46.2% versus 14.4%). Also in that group, discontinuation for disease progression was lower (38.5% versus 64.4%). Elevation of alanine aminotransferase and aspartate aminotransferase levels was greater with the higher nivolumab dose (17.3%/11.5% versus 0%/0%, respectively). Treatment discontinuation rates were 7.7% for nivolumab 1 mg/ipilimumab 3 mg and 13.5% for nivolumab 3 mg/ipilimumab 1 mg.
Dr. Sharma said, “Grade 3–4 adverse event rates were around 30% and very similar for both groups.”
“It’s very important to note the overall response rate compared to the 19% with nivolumab monotherapy reported in Lancet Oncology and the 15% rate previously reported for atezolizumab,” Dr. Sharma said, stating that confirmed ORR was 38.5% in the nivolumab 1-mg/ipilimumab 3-mg group (95% confidence interval [CI], 20.2–59.4) and 26.0% in the nivolumab 3-mg/ipilimumab 1-mg group (95% CI, 17.9–35.5). Historical controls, she added, are 10% or less.
Complete response (3.8% versus 2.9%) and partial response rates (34.6% versus 23.1%) were higher with the higher ipilimumab dose regimen. The progressive disease rate, however, was higher with the lower ipilimumab dose regimen (26.9% versus 41.3%). Median tumor change from baseline in the target lesion was –27.8% in the nivolumab 1-mg/ipilimumab 3-mg group and 0% in the nivolumab 3-mg/ipilimumab 1-mg group. While median time to response was similar for both groups (1.4 months), ongoing response rates were higher for the higher ipilimumab dose group (80% versus 70%), as were the median progression-free survival (4.3 months versus 2.6 months) and median OS rates (10.2 versus 7.3 months).
“Efficacy with nivolumab 3 mg plus ipilimumab 1 mg did not appear to differentiate from that with nivolumab monotherapy,” Dr. Sharma observed. Nivolumab monotherapy findings had been reported previously.
While the cohort size is small, she said the findings are “very promising.” Dr. Sharma noted that the nivolumab 1-mg/ipilimumab 3-mg cohort is being expanded to 92 patients.
Commenting on a question raised after her presentation regarding the possibility of using ipilimumab at 10 mg/kg, Dr. Sharma responded, “With ipilimumab 3 mg/kg you get the same T-cell activation as with ipilimumab 10 mg/kg. Our monitoring showed, however, that ipilimumab 1 mg/kg does not give you the same level of T-cell activation as with 3 mg/kg—which would not give you the same level of antitumor response.”