Study shows immunotherapy extends disease-free survival in post-surgery kidney cancer patients

Results from a new randomized clinical trial suggest pembrolizumab (KEYTRUDA) given to patients after nephrectomy could help prevent the recurrence of renal cell carcinoma. The researchers called the results “clinically meaningful,” as they suggest pembrolizumab reduces the risk of disease recurrence or death by 32% compared to placebo. The results support pembrolizumab “as a potential new standard of care for patients at high risk of disease recurrence following surgery,” said Dr. Toni Choueiri, lead author of the study and director of the Lank Center for Genitourinary Oncology at the Dana-Farber Cancer Institute in Boston. Intravenous delivery of pembrolizumab every three weeks was associated with significantly longer survival without disease compared to patients who were given placebo. After two years, 77.3% of patients in the pembrolizumab group and 68.1% in the placebo group had no recurrence of renal cell carcinoma. “The KEYNOTE-564 results have potentially practice-changing implications for patients with post nephrectomy with a high risk of disease recurrence,” Dr. Choueiri wrote to the Medical Post. The trial, called KEYNOTE-564, included 992 patients who were disease free but at high risk for recurrence of renal cell carcinoma after nephrectomy. Patients were randomized equally to get 200 mg pembrolizumab or placebo, given intravenously once every three weeks for one year. Patients had a partial or radical nephrectomy at least 12 weeks before starting the trial. The median follow-up was 24 months. A third of the patients in the pembrolizumab group experienced adverse events of grade 3 or higher, compared to 17% in the placebo group. A total of 38.9% of patients in the pembrolizumab group and 26.6% of patients in the placebo group stopped the therapy (or placebo), either due to adverse events (20.7% in the pembrolizumab group; 2% in the placebo group) or a recurrence of kidney cancer. The most common adverse event was fatigue, diarrhea, pruritus and arthralgia; similar to what had been seen in previous trials involving pembrolizumab. “Assessment of irreversible toxic effects will be important in the risk–benefit determination of adjuvant therapy with pembrolizumab,” wrote Dr. Rana McKay from the University of California in San Diego, La Jolla. Dr. McKay wrote an editorial that accompanied the publication of the results in a recent issue of the New England Journal of Medicine. Read: Key clinical guidelines and statements—May to June 2021 Between 50% to 80% of people with renal cell carcinoma who have a nephrectomy have their disease re-appear following surgery. Over the years, various adjuvant therapies to prevent recurrence have been studied. This included vascular endothelial growth factor (VEGF)-targeted therapy, such as axitinib (Inlyta), pazopanib (Votrient), sorafenib (Nexavar) and sunitinib (Sutent). Of the trials that tested agents for adjuvant therapy, only S-TRAC (Sunitinib Treatment of Renal Adjuvant Cancer) and KEYNOTE-564 reached the primary endpoint of improved disease-free survival, Dr. McKay wrote. Yet, S-TRAC did not show sunitinib improved overall survival compared to placebo, where KEYNOTE4-564 suggests that pembrolizumab could potentially have an overall survival benefit. Eighteen patients in the pembrolizumab group died compared to 33 patients in the placebo group. “Longer follow-up will be critical for the assessment of the effect of pembrolizumab therapy on overall survival,” Dr. McKay wrote. Pembrolizumab is an anti-programmed death 1 (PD-1) monoclonal antibody. It targets PD-1 on T cells and the ligand it binds to, PD-L1 on cancer cells. In general terms, PD-1 and PD-L1 suppress T cells from attacking other cells, including cancer cells. When pembrolizumab binds to the PD-1 receptor, it blocks PD-L1 on the cancer cell and the T cell response is restored. Pembrolizumab was first approved in Canada in 2015 and is now approved for numerous indications, including treating bladder cancer, melanoma and head and neck squamous cell carcinoma. It is currently approved for first-line treatment of adult patients with advanced or metastatic renal cell carcinoma in combination with axitinib, with no prior systemic therapy for metastatic renal cell carcinoma. “Based on results from the first prespecified interim analysis of KEYNOTE-564, pembrolizumab may become a common adjuvant treatment for patients with high risk of disease recurrence post nephrectomy,” Dr. Choueiri said. “It is not yet clear whether the use of pembrolizumab in the adjuvant setting will impact subsequent treatment decisions in the advanced setting and additional analyses are needed to inform on this question.” Dr. McKay noted that there were more patients with tumours positive for the programmed death ligand 1 (PD-L1) in the pembrolizumab group (25% of patients) compared to the placebo group (22.7% of patients), although the benefits of pembrolizumab on disease-free survival were found to be independent of PD-L1 status. “One of the important questions that will be relevant to the clinical application of pembrolizumab will be to define which patient groups are likely to derive benefit from therapy,” she wrote. The researchers plan a longer-term follow-up. “A clinically beneficial adjuvant therapy has been much anticipated for patients with renal-cell carcinoma. The results of this trial herald the dawn of a new era in the treatment of renal-cell carcinoma,” Dr. McKay wrote. The results were also announced in late June at the American Society of Clinical Oncology (ASCO) annual meeting. They were published in the NEJM in August. Read: Halifax cancer researcher studies effects of radon gas and arsenic exposure

Study shows immunotherapy extends disease-free survival in post-surgery kidney cancer patients

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