Nivolumab and Ipilimumab Monotherapy Trials
Nivolumab is a monoclonal antibody that selectively blocks the programmed death-1 (PD-1) transmembrane protein on T cells, B cells and NK cells, which activates the immune system and promotes apoptosis.8 In the Phase 1 study of nivolumab, CheckMate 003, 34 pretreated patients (≥ 1 systemic therapy) with metastatic clear cell renal cell carcinoma (mccRCC) were included.9 The overall response rates (ORR) ranged from 24% in patients receiving 1 mg/kg to 31% in those receiving 10mg/kg. Importantly, 5 patients sustained a response for greater than a year. Fourteen percent of patients experienced grade 3 or higher treatment related adverse events (TRAE); most commonly diarrhea, rash, and pruritis. Only 5% of patients discontinued therapy because of intolerability. The updated analysis of the phase 1 data demonstrated that at a minimum follow up of 63.9 months, 29% of patients had a response.10 Median duration of response was 12.9 months (95% CI 8.4-not estimable). Median OS was 22.4 months (95% CI 12.5–48.6 months) with survival curves plateauing around 3 years.
Given the efficacy and safety established in CheckMate 003, the Phase 2 Checkmate 010 trial investigated nivolumab at 0.3 mg/kg, 2 mg/kg, 10 mg/kg in patients with mccRCC, who were previously treated with VEGF directed therapy.11 In the 268 patients randomized, nivolumab was active across all cohorts (ORR 20%, 22%, and 20%, respectively) and no dose-response relationship was detected by median progression-free survival (PFS, 2.7 months, 4.0 months, and 4.2 months, respectively, p=0.9). McDermott et al presented the 3 year follow up for CheckMate 010, noting the ORR remained at 21% and the 3 year OS rate was 41%.12
Based on these data, the Phase III CheckMate 025 trial randomized patients with mccRCC previously treated with anti-angiogenic therapy to receive nivolumab 3 mg/kg IV every 2 weeks versus everolimus 10 mg oral daily (Table 1).13 Of the 821 patients who were randomized, patients who received nivolumab had a better ORR (25% vs 5%, p< 0.001) and longer median OS (25 months vs 19.6 months, HR 0.73; 95% CI 0.57–0.93; p=0.002) but no clear difference in PFS (p=0.11). Nivolumab was better tolerated than everolimus with fewer grade 3 or higher TRAE (19% vs 37%). In a subgroup analysis, OS favored nivolumab both in patients who were PD-L1 positive (≥1% expression) with a median OS of 21.8 months vs 18.8 months (HR 0.79; 95% CI 0.53–1.17) and those who were PD-L1 negative (<1% expression) with a median OS of 27.4 months vs 21.2 months (HR 0.77; 95% CI 0.60–0.97). Final analysis of CheckMate 025 showed that at a minimum follow up of 64 months, patients treated with nivolumab continued to show a better response (23% vs 4%) as well as improved survival benefit (25.8 months vs 19.7 months, HR 0.73; 95% CI 0.62–0.85).14
Recently, two trials explored the efficacy and tolerability of nivolumab in a “real world” population. The Nivolumab Expanded Access Program looked specifically at patients older than 70 years (subgroup 1) and older than 75 years (subgroup 2). Similar response rates (27% vs 28%), 18 month survival rates (23.2% vs 22.8%) and safety profiles (27% vs 40%) were noted across all ages.15 There were no increased rates of discontinuation in older patients compared to younger patients. Similarly, the NIVOREN GETUG AFU trial evaluated the response to nivolumab in tyrosine kinase (TKI) refractory patients.16 Their inclusion criteria was broad, including patients with ECOG >1 (15%) and poor risk disease (25.5%) with variable prior treatments (85% prior nephrectomy, 22% ≥ 2 prior treatments, 21% prior mTOR therapy). At a median follow up of 20.9 months, the ORR was 21% with a 12 month OS rate of 69%. Both these studies showed similar efficacy and safety when compared to CheckMate 025.
Overall, nivolumab has proven sustainable antitumor activity regardless of PD-L1 status and good tolerability across all ages. It has also demonstrated improved efficacy compared to everolimus in refractory mRCC patients. As a result, in November 2015 the FDA approved the use of nivolumab in mRCC patients who received prior anti-angiogenic therapy.
Ipilimumab is a monoclonal antibody that targets the cytotoxic T- lymphocyte- associated protein 4 (CTLA-4) expressed on the surface of T regulatory cells and activated T cells; which causes T effector cell activation and proliferation as well as reducing regulatory T cell suppression.8 Yang et al conducted a study looking at the efficacy of ipilimumab monotherapy in previously treated mccRCC using either low dose (LD; 3 mg/kg once followed by 1 mg/kg every 3 weeks) or high dose (HD; 3 mg/kg every 3 weeks).17 The arms were not compared because of uneven ratios of those who had received prior IL-2 therapy in each cohort. Partial response (PR) was noted in 5% in the LD arm and 13% in the HD arm, respectively. However, of those who benefited from ipilimumab (n=6) across both arms, 4 patients were able to sustain a response for greater than a year.
Thirty-three percent of patients had grade 3 or higher TRAE, notably autoimmune-related enteritis, dermatitis, and endocrine deficiencies. There was an association between TRAE and response rates with 30% of patients who had a grade 3 or higher TRAE achieving a response to treatment compared to 0% of patients without a TRAE had a response. However, given the concurrent emerging benefit of nivolumab and ipilimumab combination therapy (as noted in the section below), subsequent investigation of ipilimumab monotherapy was not pursued.
Nivolumab and Ipilimumab Combination Trials
Given the individual clinical efficacy in mRCC and efficacy in combination in melanoma,18,19 the combination of ipilimumab and nivolumab was subsequently investigated. In the Phase I CheckMate 016 trial, patients with mccRCC were randomized to three arms: N3I1 (nivolumab 3 mg/kg + ipilimumab 1 mg/kg), N1I3 (nivolumab 1 mg/kg + ipilimumab 3 mg/kg), and N3I3 (nivolumab 3 mg/kg + ipilimumab 3 mg/kg), followed by nivolumab 3 mg/kg every 2 weeks until progression or toxicity.20 Of note, the analysis matched patients between the N3I1 and N1I3 arms only due to dose limiting toxicity or progression in the N3I3 arm. These patients included treatment-naïve patients, patients who had prior cytokine therapy, and patients who received prior neoadjuvant or adjuvant therapy for localized disease. At a median follow up of 22.3 months, ORR was equivalent in both arms (40%) and 1 year OS was comparable (67.3% vs 69.6%). However, complete responses (CR) were only seen in the N3I1 arm (11% vs 0%). Higher doses of ipilimumab were also associated with higher toxicity (38.3% vs 61.7%, respectively). The most common grade 3 or higher TRAE in the N3I1 arm were increased liver function tests and diarrhea. In the N1I3 arm, the most common TRAE were liver dysfunction, colitis, lymphopenia, and fatigue. Treatment discontinuation secondary to TRAE in the N3I1 and N1I3 arms were 10.6% versus 27.7%, respectively. Updated results continued to show a continued benefit in the N3I1 arm compared to the N1I3 arms in both tolerability (grade 3 TRAE 43% vs 64%) and durability (105 weeks vs 79.4 weeks).21 Thus, due to better tolerability and complete response rates, the combination of N3I1 was the recommended dose for subsequent clinical trials.
The randomized phase III CheckMate 214 trial explored investigated the combination of nivolumab 3mg/kg and ipilimumab 1mg/kg every 3 weeks for four doses followed by nivolumab 3mg/kg every 2 weeks versus sunitinib in treatment-naïve patients.22 (Table 1) Although all International Metastatic RCC Database Consortium (IMDC) risk groups were included, the primary endpoint was in the IMDC intermediate and poor risk groups. At a median follow up of 25.2 months, the patients receiving ipilimumab and nivolumab had improved response rates (42%, 9% CR vs 27%, 1% CR; p<0.001), median PFS (11.6 mo vs 8.4 mo, HR 0.82, p=0.03) and OS (NR vs 26.6 mo; HR 0.66; 95% CI 0.54–0.80; p<0.0001) compared to sunitinib. TRAE rates were similar in both arms (93% vs 97%), however there were increased rates of discontinuation because of TRAE in the sunitinib arm (12% vs 22%). The most common TRAE in the ipilimumab and nivolumab arm were fatigue, pruritis, diarrhea, rash, and nausea. Of the 436 patients treated with ipilimumab and nivolumab that had an immune mediated TRAE, 35% of patients required high dose steroids (≥ 40 mg prednisone daily). Exploratory analyses showed improved ORR (p<0.001) and median PFS (HR 0.46, 95% CI 0.31–0.67). Cella et al looked at the health-related quality of life benefit of the combination of ipilimumab with nivolumab versus sunitinib using the Functional Assessment of Cancer Therapy Kidney Symptom Index-19 (FKSI-19), Functional Assessment of Cancer Therapy-General (FACT-G), and EuroQol five dimensional three level (EQ-5D-3L) assessment tools.23 There was a reduction in the risk of deterioration across all patient recorded outcome assessment tools (HR0.54; 95% CI 0.46–0.63 to HR 0.75, 95% CI 0.63–0.89).
Long term follow up of Checkmate 214, continues to show improved median PFS (HR0.76, 95% CI 0.63–0.91; p<0.01) and median OS (HR 0.66; 95% CI 0.55–0.80; p<0.0001) compared to those treated with sunitinib.24 When comparing durability of response to ipilimumab and nivolumab versus sunitinib (ORR 42% vs 26%; p<0.0001), 68% vs 52% of patients continued to sustain a response at 42 months of follow up. Of those who achieved a complete response on ipilimumab with nivolumab, the median treatment free interval was 34.6 months (0.5–49.7 months). Thus, the combination of nivolumab with ipilimumab has become a standard of care for front-line treatment of patients with intermediate and poor risk mccRCC.
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