Combination immunotherapy may raise response rate in mRCC

April 17, 2017

“The data from our study show that combination therapy [for metastatic renal cell carcinoma] may offer a much higher response rate with manageable side effects,” says study author Jianjun Gao, MD, PhD.

Combination treatment built on immune checkpoint inhibitor therapy showed promising clinical and immunologic activity in patients with metastatic renal cell carcinoma (mRCC) in an early phase I clinical trial, reported investigators from the University of Texas MD Anderson Cancer Center, Houston at the American Association of Cancer Research annual meeting in Washington.

The open-label pilot study randomized 60 patients who were eligible for cytoreductive nephrectomy, metastectomy, or post-treatment biopsy 1:2:1 to nivolumab (Opdivo) as monotherapy or combined with bevacizumab (Avastin) or ipilimumab (Yervoy). About 10 weeks after starting therapy, patients underwent their planned surgical procedure and then continued on nivolumab monotherapy for up to 2 years. Blood and tumor samples obtained pretreatment and at the surgical procedure were analyzed for correlations between clinical responses and changes in immune cell infiltration and gene expression.

At the data cut-off, median duration of treatment was 17 weeks and 44 patients were evaluable for post-procedure clinical responses. There was a single complete response in a patient receiving nivolumab + bevacizumab. Objective response rates (complete + partial) in the nivolumab, nivolumab + bevacizumab, and nivolumab + ipilimumab groups were 42%, 53%, and 38%, respectively, and rates of disease progression in the three arms were 25%, 16%, and 38%, respectively.

Laboratory investigations showed increased T cell infiltration in samples taken from responders compared to nonresponders as well as differences in gene expression.

The incidence of grade 3 or higher toxicities was 19% for nivolumab monotherapy, 27% in the nivolumab + ipilimumab group, and 41% among patients receiving nivolumab + bevacizumab. However, 17% of grade 3 or higher toxicities in the latter patients were hypertension related to bevacizumab that was well controlled medically.

Next: "The data from our study show that combination therapy may offer a much higher response rate with manageable side effects."

 

“Immune checkpoint inhibitors have revolutionized cancer therapy, but the clinical response rate is still quite low, about 20%, when these agents are used as monotherapy. The data from our study show that combination therapy may offer a much higher response rate with manageable side effects. Thus, it may benefit an even higher proportion of patients with mRCC,” said first author Jianjun Gao, MD, PhD.

“Longer follow-up in a larger study is needed to determine if the combinations may also improve the durability of responses compared with nivolumab monotherapy,” added Dr. Gao.

Senior author Padmanee Sharma, MD, PhD, commented on the importance of the studies characterizing the immune and molecular markers. She told Urology Times, “Detailed laboratory studies of tumor samples from patients are needed to understand the molecular and immunologic mechanisms of response and resistance to therapy. This information will be important for guiding our next steps in developing future combination treatment strategies.”

At the time of data cutoff, the number of available tumor samples was too small to have sufficient power for finding any statistically significant differences in gene expression between treatment arms.

Nivolumab is approved for treatment of advanced RCC; bevacizumab used with interferon alfa is approved for treatment of mRCC. The rationale for combining ipilimumab with nivolumab is that the two checkpoint inhibitors act on different T cell signaling pathways, the CTLA-4 inhibitory pathway and PD-1 inhibitory pathway, respectively.

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“We were also interested in testing this combination because it is approved for treatment of metastatic melanoma based on demonstration of improved anti-tumor T cell responses and clinical responses,” said Dr. Gao.

“Bevacizumab is an anti-VEGF agent that affects angiogenesis and potentially immune responses, and so we hypothesized that its combination with nivolumab may also lead to enhanced anti-tumor T cell responses.”

The two nivolumab-based combination regimens are the subject of further investigation. Expansion of the phase I trial with the addition of 45 more patients is planned.

“We expect the data that are generated will enable development of a larger study investigating nivolumab plus bevacizumab,” said Dr. Sharma.

Ipilimumab + nivolumab is being compared with sunitinib (Sutent) in a phase III trial of patients with previously untreated advanced RCC or mRCC. Patient accrual is complete in this study sponsored by Bristol-Myers Squibb.

Dr. Sharma is an unpaid consultant to Bristol-Myers Squibb. The study was funded by the National Institutes of Health and Bristol-Myers Squibb.

More on Targeted Therapy:

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