Page 1073 - Clinical Immunology_ Principles and Practice ( PDFDrive )

1038 ParT EighT Immunology of Neoplasia

chemotherapy. The approval was based on data from a nonran-
Renal Cell Carcinoma domized trial in patients with HNSCC who failed to respond
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Antiangiogenic therapies have been the established treatment to platinum-based chemotherapy. Following treatment, pem-
for patients with metastatic RCC. However, patients eventually brolizumab demonstrated an ORR of 16%. The median OS
develop innate or adaptive resistance to antiangiogenic therapy, observed with pembrolizumab was 9.6 months, compared with
which could be attributed partly to changes in the immune the historical median OS of only 6 months. In this trial, responses
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microenvironment, proving a strong rationale to investigate were seen in patients with human papillomavirus (HPV)-positive
the clinical effects of immune checkpoint therapy in RCC patients. tumors (24%) as well as in patients with HPV-negative tumors
A phase III study in patients with advanced or metastatic (16%), respectively.
RCC, who had received at least one prior treatment, demonstrated Another phase III trial investigated nivolumab versus standard
improved OS of 25 months after treatment with nivolumab single-agent systemic therapy (methotrexate, docetaxel, or cetux-
compared with OS of 19.6 months in patients treated with imab) in patients with recurrent or metastatic HNSCC after
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everolimus. Based on this trial, the FDA approved nivolumab platinum-based chemotherapy. This study demonstrated that
as second-line therapy for patients with metastatic RCC. New treatment with nivolumab resulted in longer OS of 7.5 months
immune-based treatment strategies for treating RCC patients compared with an OS of 5.1 months with standard single-agent
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are in development. therapy. These findings led to the FDA approval of nivolumab
in the treatment of platinum-refractory recurrent HNSCC.
Bladder Cancer
Platinum-based chemotherapy has been the established first-line Hodgkin Lymphoma
treatment for patients with metastatic bladder cancer; no new A phase I study of nivolumab in previously treated patients
therapies have been established in the past 30 years, including with relapsed or refractory Hodgkin lymphoma demonstrated
no standardized second-line treatment because of the dismal an objective response of 87%, including 17% of patients with a
objective response rates of 10% or less with tested chemotherapies. complete response and 70% of patients with a partial response;
However, preclinical studies have demonstrated clinical benefits the remaining 13% had stable disease. The Reed-Sternberg cells
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with immune checkpoint therapy in bladder tumors. A single- that define Hodgkin lymphoma have frequent amplification of
arm phase II study investigated the role of an anti-PD-L1 antibody chromosome 9p24.1, which leads to expression of PD-1 ligand in
(atezolizumab), to block one of the ligands that interacts with Reed-Sternberg cells and provides strong rationale for immune
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PD-1, in patients with locally advanced or metastatic urothelial checkpoint therapy that blocks the PD-1/PD-L1 axis. Findings
bladder cancer whose disease had progressed after previous from this study led to FDA approval of nivolumab for patients
treatment with platinum-based chemotherapy. Compared with with previously treated relapsed or refractory Hodgkin lymphoma.
the historical control ORR of 10%, treatment with atezolizumab
resulted in a significantly improved ORR of 15% for all treated
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patients, regardless of PD-L1 expression. This study led to FDA EARLY AND LATE-PHASE TRIALS WITH
approval of atezolizumab in patients with locally advanced or CHECKPOINT THERAPY IN OTHER TUMORS
metastatic urothelial bladder cancer whose cancers had progressed
during or after treatment with platinum-based chemotherapy. Pancreatic Cancer
A phase I/II study investigated nivolumab in patients with Pancreatic cancer has a poor prognosis with limited treatment
locally advanced or metastatic urothelial cancer whose disease options. A poor understanding of the immune microenvironment
had progressed after previous treatment with platinum-based in pancreatic cancer has been a roadblock in developing effective
chemotherapy. This study demonstrated that nivolumab mono- treatment strategies. We have generated preliminary data to
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therapy led to an ORR of 24.4%. Another, larger phase II study indicate that pancreatic tumors have immune infiltrates and
assessed the clinical activity and safety of nivolumab in 270 differentially express inhibitory immune checkpoints compared
patients with metastatic bladder cancer who had progressive with tumors that respond to checkpoint therapy, such as mela-
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disease despite first-line platinum-based chemotherapy. This noma and bladder cancer. Therefore treatment of pancreatic
study reported an ORR of 19.6% with nivolumab therapy. 34 cancer with combination strategies that include immune
Additionally, in another phase I/II study that treated patients checkpoint therapy is being explored.
with metastatic bladder cancer who progressed after platinum- Early-phase trials with ipilimumab have demonstrated delayed
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based chemotherapy, patients who received combination treatment responses in patients with advanced pancreatic cancer. Immune
with ipilimumab 3 mg/kg plus nivolumab 1 mg/kg had an ORR checkpoint therapies that are under development for treating
of 38.5% versus an ORR of 26% for patients who received ipili- pancreatic cancer include pembrolizumab, nivolumab with or
mumab at 1 mg/kg plus nivolumab at 3 mg/kg; patients without ipilimumab, and durvalumab with or without treme-
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who received nivolumab alone had an ORR of 24.4%. These limumab (ClinicalTrials.gov).
early findings with higher-dose ipilimumab provide evidence
for improved responses with combination immune checkpoint Prostate Cancer
therapy. Despite advances in the treatment of metastatic castration-
resistant prostate cancer (mCRPC), novel immune-based strategies
Head and Neck Cancer that can provide durable and long-term responses in patients
Head and neck cancer is one of the cancer types for which new are still needed. Sipuleucel-T (autologous cellular immunotherapy)
immune-based cancer treatments are currently in development. is the only approved immunotherapy for patients with prostate
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In 2016, pembrolizumab was FDA approved for the treatment cancer. However, the exact mechanism of action of sipuleucel-T
of patients with recurrent or metastatic head and neck squamous- remains to be elucidated, and clinical metrics and/or biomarkers
cell carcinoma (HNSCC) that continued to progress despite to evaluate responses with sipuleucel-T are currently lacking.