By Dr. Asim Amin
American Cancer Society estimates 65,000 new diagnoses of kidney cancer to be made in 2018, 15,000 will succumb to the disease (Seigel RL et al. Cancer Statistics,2018. CA Cancer J Clin 2018;68:7-30). Globally an estimated 300,000 new cases of kidney cancer are diagnosed annually (GLOBOCAN 2012: http://globocan.iarc.fr/Pages/fact_sheets_population.aspx). The primary management, if cancer is confined to the kidney is surgical resection (nephrectomy); 25-30% of these patients subsequently develop disease recurrence at other sites (metastasis). Almost one third of the patients present with advanced disease that has spread to other organs at the time of initial diagnosis (stage IV). Stage IV disease is deemed to be incurable and historically had a median survival of 12-18 months.
Insights into the biology of the disease over the last 15 years have led to development and approval of a plethora of therapeutic modalities. Traditional chemotherapy has showed no benefit for advanced kidney cancer. Immunotherapy alludes to harnessing the patient’s on immune system to eliminate the cancer on demand has held particular appeal. The first immunotherapy drug to be approved in 1992- interleukin-2 showed durable (potentially curative) responses in a small percentage (7-10%) of patients, however, given the substantial toxicity, this modality was not widely applicable for the overall patient population. Discovery of genetic mutations and critical cell pathways that potentially drive kidney cancer activity led to development of targeted therapy including VEGF-TKIs and mTOR inhibitors starting in 2005. These drugs have clearly had an impact on the natural history of disease, increasing the median survival to 24 months yet they rarely result in durable responses.
T lymphocytes are cells of the immune system that can potentially reject transplants and kill cancer cells. Advances in our knowledge over the last 10 years have led to identification of potential ‘switches’ that control the activity of T lymphocytes. These switches or ‘immune checkpoint’ molecules can both, activate or inhibit T lymphocyte activity. Development of immune checkpoint blockers that can specifically modulate the activity of T lymphocytes and harness the activity of the immune system ‘on demand’ has been named as one of the biggest breakthroughs in oncology by the American Society of clinical oncology (ASCO) and led to the launch of ‘immuno-oncology’ (IO) as the most exciting and rapidly evolving area in cancer therapy. While the proof of concept came from clinical trials in advanced melanoma, IO has now entered the therapeutic arena in several disease sites – kidney cancer being one of them.
Nivolumab (Opdivo), was the first immune checkpoint inhibitor to be approved by the US FDA in November 2015 for those patients with advanced renal cell carcinoma who had previously received treatment and had progression of disease. The combination immunotherapy with Opdivo and Ipilimumab (Yervoy – another immune checkpoint inhibitor) by the US FDA was based on a large phase 3 study called CheckMate 214 that compared the outcomes for patients who had not received any prior therapy to a current standard first line treatment –sunitinib. This study showed a 37% reduction in the risk of death for those patients who received the combination immunotherapy compared to sunitinib. This study also confirmed the overall response rate (decrease in tumor burden ≥ 30% from baseline) for combination immunotherapy to be 40% as had been observed in early phase studies; 9% of the patients had complete resolution of their disease. Almost 65% of the patients who received combination immunotherapy experienced side effects that require intervention compared to 75% who received sunitinib.
This approval adds a frontline immunotherapy that may be applicable to most patients with advanced renal cell carcinoma and is a major addition to the current armamentarium. These improved outcomes can come at the cost of autoimmune side effects that require an experienced team to administer these treatments safely. Levine Cancer Institute has been fortunate to have made the new treatment available to patients in the Carolinas years before this approval in the early phase studies as well as the study that led to the recent approval and thanks all the patients and their families for their participation.
Dr. Asim Amin, director of immuno-therapy at Levine Cancer Institute in Charlotte.