The therapeutic landscape for advanced clear cell renal cell carcinoma (ccRCC) is rapidly evolving with improved knowledge of the biology of disease leading to the incorporation of a variety of antiangiogenic agents and immunotherapies.... more
The therapeutic landscape for advanced clear cell renal cell carcinoma (ccRCC) is rapidly evolving with improved knowledge of the biology of disease leading to the incorporation of a variety of antiangiogenic agents and immunotherapies. In this review, we discuss historical, current, and emerging first line treatment options for patients with advanced ccRCC. These include data with single agent vascular endothelial growth factor receptor tyrosine kinase inhibitors (TKIs): sunitinib, pazopanib and cabozantinib as well as the recently reported results for the combination of lenvatinib and everolimus (mTOR inhibitor). We also discuss results of the nivolumab antiprogrammed cell death (PD-1)/ipilimumab (anti-cytotoxic T lymphocyte-associated antigen 4) combination as well as emerging front-line data with nivolumab and pembrolizumab (anti-PD-1) monotherapy. Finally, we review data supporting recent approvals of TKI and anti-PD-1 or anti-PD-Ligand 1 (PD-L1) combinations (e.g., axitinib/pembrolizumab, axitinib/avelumab and cabozantinib/nivolumab) and initial outcomes of lenvatinib (multi-kinase inhibitor) and pembrolizumab. With many individual and combination treatment options and the lack of head-to-head comparisons, treatment selection will depend on the goals of therapy (endpoints) and the identification and validation of clinical and tumor-based predictive biomarkers that are linked to the desired treatment endpoints.
Background The phase III study CheckMate 238 demonstrated improved relapse-free survival (RFS) with NIVO 3 mg/kg vs IPI 10 mg/kg in patients (pts) with resected stage III/IV melanoma. Sustained efficacy benefit at 24 mo of follow-up with... more
Background The phase III study CheckMate 238 demonstrated improved relapse-free survival (RFS) with NIVO 3 mg/kg vs IPI 10 mg/kg in patients (pts) with resected stage III/IV melanoma. Sustained efficacy benefit at 24 mo of follow-up with NIVO vs IPI was previously reported. Here we present a 36mo analysis of efficacy and biomarker data from this study. Methods Pts aged ≥ 15 y with completely resected stage IIIB/C or IV melanoma were randomized 1:1 to receive NIVO (3 mg/kg Q2W; N = 453) or IPI (10 mg/kg Q3W for 4 doses; Q12W thereafter; N = 453) for ≤ 1 y or until disease recurrence/unacceptable toxicity. RFS was the primary endpoint; exploratory endpoints included distant metastases-free survival (DMFS) in pts with stage III disease and potential biomarkers of efficacy. Results With 36 mo of follow-up, NIVO continued to demonstrate superior RFS vs IPI (HR, 0.68; P
Immune checkpoint inhibitors (ICIs) are the key drugs used in patients with non-small cell lung cancer (NSCLC). However, anti-PD-1 therapy might worsen chronic infection by reactivating the immune response to infectious diseases. Here, we... more
Immune checkpoint inhibitors (ICIs) are the key drugs used in patients with non-small cell lung cancer (NSCLC). However, anti-PD-1 therapy might worsen chronic infection by reactivating the immune response to infectious diseases. Here, we describe a case of successful treatment with nivolumab in a patient with NSCLC complicated by pulmonary aspergilloma, which was safely treated by surgical resection before administration of nivolumab. In conclusion, to safely treat patients with locally limited chronic pulmonary aspergillosis (CPA), surgical resection should be considered before ICI therapy.
Bempegaldesleukin (BEMPEG: NKTR-214) is an immunostimulatory IL-2 cytokine prodrug engineered to deliver a controlled, sustained and preferential IL-2 pathway signal. Nivolumab (NIVO), a PD-L1 inhibitor, has been shown to prolong survival... more
Bempegaldesleukin (BEMPEG: NKTR-214) is an immunostimulatory IL-2 cytokine prodrug engineered to deliver a controlled, sustained and preferential IL-2 pathway signal. Nivolumab (NIVO), a PD-L1 inhibitor, has been shown to prolong survival in patients with advanced melanoma and recurrence-free survival in the adjuvant setting. PIVOT-02 showed that BEMPEG plus NIVO was well-tolerated and demonstrated clinical activity as first-line therapy in metastatic melanoma. PIVOT-12 is a randomized, Phase III, global, multicenter, open-label study comparing adjuvant therapy with BEMPEG plus NIVO versus NIVO alone in adult and adolescent patients with completely resected cutaneous stage III/IV melanoma at high risk of recurrence. The primary objective is to compare the efficacy, as measured by recurrence-free survival, of BEMPEG plus NIVO versus NIVO.
PURPOSE In extensive-disease small-cell lung cancer (ED-SCLC), response rates to first-line platinum-based chemotherapy are robust, but responses lack durability. CheckMate 451, a double-blind phase III trial, evaluated nivolumab plus... more
PURPOSE In extensive-disease small-cell lung cancer (ED-SCLC), response rates to first-line platinum-based chemotherapy are robust, but responses lack durability. CheckMate 451, a double-blind phase III trial, evaluated nivolumab plus ipilimumab and nivolumab monotherapy as maintenance therapy following first-line chemotherapy for ED-SCLC. METHODS Patients with ED-SCLC, Eastern Cooperative Oncology Group performance status 0-1, and no progression after ≤ 4 cycles of first-line chemotherapy were randomly assigned (1:1:1) to nivolumab 1 mg/kg plus ipilimumab 3 mg/kg once every 3 weeks for 12 weeks followed by nivolumab 240 mg once every 2 weeks, nivolumab 240 mg once every 2 weeks, or placebo for ≤ 2 years or until progression or unacceptable toxicity. Primary end point was overall survival (OS) with nivolumab plus ipilimumab versus placebo. Secondary end points were hierarchically tested. RESULTS Overall, 834 patients were randomly assigned. The minimum follow-up was 8.9 months. OS w...
Purpose of Review Therapeutic alternatives to treat metastatic renal cell carcinoma (mRCC) are increasing, and combination therapies, including antiangiogenic agents and tyrosine kinase/mTOR/immune checkpoint inhibitors, are identified as... more
Purpose of Review Therapeutic alternatives to treat metastatic renal cell carcinoma (mRCC) are increasing, and combination therapies, including antiangiogenic agents and tyrosine kinase/mTOR/immune checkpoint inhibitors, are identified as the gold standard driven by the results of recent clinical studies. Nevertheless, the real-world RCC population is very heterogeneous, with categories of patients not represented in the enrolled trial population who may not benefit more from these treatments. The purpose of this expert review is to assess the rationale on which tyrosine kinase alone may still be a viable first-line treatment option for some subgroups of patients with mRCC. Recent Findings The first-line treatment with tyrosine kinase inhibitor monotherapy can still be considered an effective tool for addressing selected mRCCs, as highlighted by the successful outcome in a range of subjects such as favorable-risk patients, the ones suffering from autoimmune diseases, those with panc...
Aim: To investigate how previous systemic therapy such as anti-angiogenesis can influence cancer immunotherapy for non-small cell lung cancer (NSCLC). Methods: A total of 134 patients with advanced NSCLC who were treated with nivolumab... more
Aim: To investigate how previous systemic therapy such as anti-angiogenesis can influence cancer immunotherapy for non-small cell lung cancer (NSCLC). Methods: A total of 134 patients with advanced NSCLC who were treated with nivolumab were retrospectively reviewed. Correlation between status of prior anti-angiogenesis treatment and clinical characteristics were determined. Impact of prior anti-angiogenesis on therapeutic outcome of nivolumab was investigated for tumor efficacy such as progression-free survival (PFS). Results: Sixteen patients were treated with at least one anti-angiogenesis agent prior to nivolumab. The prior use of anti-angiogenesis agent was associated with stage IV disease, non-squamous histology, and two or more lines of systemic therapy. Median PFS was significantly shorter in the prior anti-angiogenesis group than in no prior anti-angiogenesis group (8.3 vs. 11.3 weeks, log-rank P = 0.006). Multivariate analyses demonstrated that only prior anti-angiogenesis ...
Purpose Mucosal melanoma is an aggressive malignancy with a poor response to conventional therapies. The efficacy and safety of nivolumab (a programmed death-1 checkpoint inhibitor), alone or combined with ipilimumab (a cytotoxic... more
Purpose Mucosal melanoma is an aggressive malignancy with a poor response to conventional therapies. The efficacy and safety of nivolumab (a programmed death-1 checkpoint inhibitor), alone or combined with ipilimumab (a cytotoxic T-lymphocyte antigen-4 checkpoint inhibitor), have not been reported in this rare melanoma subtype. Patients and Methods Data were pooled from 889 patients who received nivolumab monotherapy in clinical studies, including phase III trials; 86 (10%) had mucosal melanoma and 665 (75%) had cutaneous melanoma. Data were also pooled for patients who received nivolumab combined with ipilimumab (n = 35, mucosal melanoma; n = 326, cutaneous melanoma). Results Among patients who received nivolumab monotherapy, median progression-free survival was 3.0 months (95% CI, 2.2 to 5.4 months) and 6.2 months (95% CI, 5.1 to 7.5 months) for mucosal and cutaneous melanoma, with objective response rates of 23.3% (95% CI, 14.8% to 33.6%) and 40.9% (95% CI, 37.1% to 44.7%), respe...
Recent findings from studies [KEYNOTE 10, 24, 189, 407 (pembrolizumab); Check Mate-17,57,227 (nivolumab); IM power 131,150,OAK (atezolizumab)] using checkpoint inhibitors as a monotherapy as well as in combination of chemotherapy has... more
Recent findings from studies [KEYNOTE 10, 24, 189, 407 (pembrolizumab); Check Mate-17,57,227 (nivolumab); IM power 131,150,OAK (atezolizumab)] using checkpoint inhibitors as a monotherapy as well as in combination of chemotherapy has demonstrated improved outcome in patients with advanced NSCLC without actionable mutation driver and also showed a tolerable toxicity profile and durable response. Based on analysis of studies performed in the first line management of advanced NSCLC, pembrolizumab is preferred for patients without actionable driver mutation. Pembrolizumab should be used as a monotherapy in patients with PD-L1 expression ≥ 50%. In others, it should be added to chemotherapy. For patients with actionable driver mutation, osimertinib for sensitizing EGFR mutation is preferred over afatinib, gefitinib, erlotinib as a first line therapy. For patients with ALK rearrangement alectinib is preferred over crizotinib restricting use of crizotinib as first line therapy to patients with ROS1 rearrangement. Dabrafenib + trametinib have been found effective in patients with BRAFV600E mutations.