The promising role of nivolumab in renal cell cancers

ABSTRACT

The therapeutic efficacy of checkpoint inhibitors across numerous tumor types has resulted in approval for neoplasms such as melanoma and lung cancer. Nivolumab is a fully humanized IgG4 antibody that inhibits immune checkpoint between programmed death 1 (PD-1) on T cells and PD-1 ligand 1 (PD-L1) and ligand 2 (PD-L2) on immune and cancer cells. Motzer and Colleagues published the findings of Nivolumab versus everolimus in advanced kidney cancer in the November issue of the New England Journal of Medicine. This trial showed that nivolumab resulted in better median overall survival of 25 months compared to everolimus at 19.6 months, with a hazard ratio for death at 0.73, meeting pre-specified criterion for superiority in favor of nivolumab. These findings mark the defining beneficial role of immune checkpoint inhibitor therapy in metastatic kidney cancer.

Kidney cancers occur in over 60,000 of patients in the United States with 14,000 deaths predicted in 2015 alone.¹ While early stage kidney cancers are cured often with surgery alone, metastatic or advanced kidney cancers are often challenging to treat despite recently available drug therapies. These treatments often involve the use of vascular endothelial growth factor (VEGF) pathway inhibitors and mammalian target of rapamycin (mTOR) inhibitors. Everolimus is currently approved by the US Food and Drug Administration for the 2^nd line treatment of metastatic kidney cancer post-failure of VEGF inhibitors. While the use of immunotherapy with high-dose IL-2 has historically brought about the only potential durable responses or complete regression,² it has also been wrought with potential toxicity which has somewhat dampened the enthusiasm for widespread adoption of its use in the community.

Previous studies have shown that programmed death ligand-1 (PD-L1) expression is associated with poor prognosis in renal-cell carcinoma.³ Nivolumab is a fully human IgG4 antibody that inhibits immune checkpoint between programmed death 1 (PD-1) on T cells and PD-1 ligand 1 (PD-L1) and ligand 2 (PD-L2) on immune and cancer cells, thus improving immunosurveillance to cancers. To this end, Motzer et al. published the results of a phase III randomized clinical trial, CheckMate 025, that included patients diagnosed with advanced renal cell carcinoma who had previously undergone standard anti-angiogenic treatment.⁴ The trial enrolled a total of 821 patients across 146 sites in 24 countries and were randomized to nivolumab (n = 410) or everolimus (n = 411). Patients had a median age of 62 years, were predominantly male (75%) and white (88%), had lung metastases as the most common site (67%), followed by liver, and bone, and majority had undergone a previous nephrectomy (88%), and were treated with prior first-line sunitinib (59%). Patients were administered either nivolumab (3mg/kg intravenous dose) every 2 weeks) or everolimus (10 mg once a day orally). The primary end point was overall survival whereas the secondary end points comprised of objective response rates, safety, progression-free survival, as well as the correlative association between survival and tumor expression of PD-L1.

Results showed that nivolumab yielded a longer median overall survival at 25.0 months as compared to everolimus group at 19.6 months. Death rate was also lower in the nivolumab group (45% vs 52%, hazard ratio [HR] 0.73). The benefit was preserved across various subgroups and risks, including those based on region, MSKCC prognostic score, and number of previous regimens of antiangiogenic therapy. The objective response rate was better with nivolumab than everolimus (25% vs 5%, p < 0.001). However, the median time of response and median duration of response were similar between the two groups. A delayed benefit in progression free survival was also noted as depicted by the late separation of survival curves after 6 months, after which the median progression-free survival for the nivolumab group was longer at 4.6 months compared to those who were administered everolimus at 4.4 months (HR = 0.88, p = 0.11). Durability of response was also noted for a larger proportion of patients who responded to treatment and had an on-going response at 12 months in the nivolumab group (32 vs 6 patients, 31% vs 27%). Interestingly, nivolumab showed improvement in overall survival despite lack of PD-L1 expression. Patients were treated for 5.5 months with nivolumab, with half requiring dose delays. In the everolimus group, patients were treated for 3.7 months, with 66% of patients requiring dose delays and 32% requiring dose reductions. Dose reductions were not allowed in the nivolumab group.

Adverse events were less common in the nivolumab group (79% vs 88%). The most common adverse events for nivolumab were fatigue (33%), nausea (14%), and pruritus (14%). The most common adverse events seen with everolimus use were fatigue (34%), stomatitis (29%), and anemia (24%). Grade 3 or 4 events were also less common in the nivolumab group (19% vs 37%). There were no deaths attributed to nivolumab, while there were 2 deaths attributed to everolimus, which were due to septic shock and acute bowel ischemia. Additional self-reported patient outcomes showed improvement in their quality of life from baseline with nivolumab, while no change was experienced with everolimus.

In conclusion, nivolumab use in advanced metastatic kidney cancer met the primary endpoint of significantly improved overall survival compared to everolimus. The improved on-going response to treatment suggests that nivolumab, as with other immunotherapies, may have a beneficial delayed treatment effect. Despite demonstrable clinical benefits of immune checkpoint inhibitors, limited biomarker data exists to guide therapeutic response to immune checkpoint inhibitors in metastatic kidney cancers. While the known mechanism of nivolumab is PD-L1 inhibition, higher PD-L1 expression should theoretically have improved survival. However, there was no statistically significant survival difference regardless of the PD-L1 levels, which raises the question of whether another underlying mechanism is operative for nivolumab response or whether a refinement of the biomarker assay for prediction of response to nivolumab is needed. Therefore, the use of these PD-1 or PD-L1 inhibitors probably should not be limited only to patients with companion diagnostic tests that are positive for the biomarker. Moreover, the side-effects of nivolumab were relatively manageable. Grade 3 and 4 events occurred almost 50% less frequently with nivolumab than with everolimus. Questions do remain regarding the utility of single agent nivolumab vs. combination with other drugs such as another checkpoint inhibitor Ipilimumab or other tyrosine kinase inhibitors. The encouraging results of nivolumab certainly herald the emergence and potential addition of a new armamentarium against metastatic kidney cancers, which overall still has poor survival especially in those who are refractory to conventional treatment.

Disclosure of potential conflicts of interest

Dr. Aragon-Ching serves on the Speakers' Bureau of Bristol-Myers Squibb (BMS), all other authors have no conflict of interest.