Page 1072 - Clinical Immunology_ Principles and Practice ( PDFDrive )

ChaPTEr 77 Immunotherapy of Cancer 1037

Antibodies against another immune checkpoint inhibitor, KEY CONCEPTS
PD-1 (nivolumab), have also been explored for the treatment
of patients with metastatic melanoma. A phase III study in patients US Food and Drug Administration-Approved
with advanced melanoma who progressed after ipilimumab Checkpoint Inhibitors in Melanoma
therapy demonstrated an objective response rate (ORR) of 31.7% • Ipilimumab: metastatic melanoma, used in the adjuvant setting
in patients treated with nivolumab compared with an ORR of • Nivolumab: first-line treatment for metastatic melanoma; treatment
10.6% in patients treated with chemotherapy alone. 19 of refractory unresectable or metastatic melanoma
Another randomized clinical trial in patients with previously • Pembrolizumab: first-line treatment for metastatic melanoma
untreated metastatic melanoma without BRAF mutation showed • Ipilimumab plus nivolumab: first-line treatment for patients with previ-
an improved OS in patients treated with nivolumab (72.9%) ously untreated, unresectable, or metastatic melanoma
compared with patients treated with dacarbazine chemotherapy
(42.1%) at 1 year. Subgroup analysis demonstrated that the
nivolumab-treated patients had improved OS regardless of chemotherapy. OS and PFS were significantly better with
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expression of the ligand for PD-1 (PD-L1) on tumor cells. nivolumab compared with docetaxel, regardless of PD-L1 expres-
Based on these two phase III trials, nivolumab was FDA approved sion on tumor cells. This led to FDA approval of nivolumab for
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for the treatment of patients with refractory unresectable or the treatment of patients with squamous NSCLC. This approval
metastatic melanoma and also for the first-line treatment of was subsequently expanded to all subtypes of NSCLC, based on
patients with metastatic melanoma. another phase III study that demonstrated a median OS of 12.2
Another anti-PD-1 mAs, pembrolizumab, was investigated months for patients with nonsquamous NSCLC who received
in a phase II study that randomized patients with metastatic nivolumab treatment compared with 9.4 months for patients
melanoma who were previously treated with ipilimumab and a who received docetaxel. 26
BRAF inhibitor. Patients received either pembrolizumab 2 mg/ Similarly, another phase III study evaluated pembrolizumab
kg every 3 weeks, pembrolizumab 10 mg/kg every 3 weeks, or versus docetaxel for the treatment of patients with previously
chemotherapy. The 6-month progression-free survival (PFS) was treated advanced NSCLC (both squamous and nonsquamous).
significantly higher in patients treated with pembrolizumab Patients enrolled in this trial were selected to have at least 1%
compared with patients treated with chemotherapy (34% in of tumor cells positive for the expression of PD-L1. The median
2 mg/kg cohort, 38% in 10 mg/kg cohort, and 16% in chemo- OS observed with pembrolizumab was 10.4 months with the
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therapy cohort). The FDA approved pembrolizumab at a dose 2 mg/kg dose and 12.7 months with the 10 mg/kg dose versus
of 2 mg/kg intravenous every 3 weeks for the treatment of 8.5 months with docetaxel. In patients with at least 50% of tumor
refractory melanoma. Pembrolizumab versus ipilimumab was cells expressing PD-L1, the OS was 14.9 months with pembro-
then investigated in another phase III trial, where patients were lizumab 2 mg/kg and 17.3 months with pembrolizumab 10 mg/
randomized to two pembrolizumab regimens (10 mg/kg dose kg versus 8.2 months after treatment with docetaxel. Based on
every 2 weeks or every 3 weeks) and an ipilimumab regimen these findings, the FDA approved pembrolizumab as single-agent,
(3 mg/kg dose every 3 weeks for 4 cycles), with PFS and OS as second-line therapy for patients with NSCLC whose tumors
the primary endpoints. The 6-month PFS was 47.3% with express PD-L1. 27
pembrolizumab treatment every 2 weeks compared with 46.4% Another phase III trial investigated pembrolizumab versus
with pembrolizumab treatment every 3 weeks, and 26.5% with chemotherapy in previously untreated patients with advanced
ipilimumab treatment. One-year estimates of survival were 74.1% NSCLC, with PD-L1 expression on at least 50% of tumor cells
for patients receiving pembrolizumab every 2 weeks, 68.4% for and without epidermal growth factor receptor (EGFR) or
those receiving pembrolizumab every 3 weeks, and 58.2% for anaplastic lymphoma kinase (ALK) mutations. The study
those receiving ipilimumab, leading to the FDA approval of demonstrated statistically significant improvements in OS for
pembrolizumab as a first-line treatment for patients with meta- patients randomized to pembrolizumab compared with chemo-
static melanoma. 22 therapy; the study also showed a significant improvement in
Another phase III trial compared ipilimumab, nivolumab, median PFS of 10.3 months in the pembrolizumab group versus
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and the combination in patients with untreated, unresectable, 6.0 months in the chemotherapy group. This study led to the
or metastatic melanoma with PFS and OS as coprimary endpoints. approval of pembrolizumab as first-line therapy for the treatment
Treatment with combination therapy was statistically superior, of patients with metastatic NSCLC whose tumors express PD-L1.
leading to a median PFS of 11.5 months versus 6.9 months for Several other PD-1/PD-L1 checkpoint inhibitors are in late-
nivolumab alone versus 2.8 months for ipilimumab alone. stage clinical testing for patients with lung cancer.
However, the data on the OS were not sufficiently mature to
present. Based on these findings, the FDA approved combination
therapy with ipilimumab plus nivolumab as first-line treatment
for patients with previously untreated, unresectable, or metastatic KEY CONCEPTS
melanoma, regardless of PD-L1 expression on tumor cells. 23 FDA-Approved Checkpoint Inhibitors in Non–
Lung Cancer Small-Cell Lung Cancer
Similar to melanoma, NSCLC is also characterized by high • Nivolumab: treatment of all subtypes of non–small-cell lung cancer
24
mutational load, and immune checkpoint therapy has led to (NSCLC)
durable antitumor response in NSCLC. • Pembrolizumab: single-agent, second-line therapy for NSCLC expressing
In a phase III study, patients with advanced squamous NSCLC PD-L1
who progressed during or after first-line chemotherapy were • Pembrolizumab first-line therapy for metastatic NSCLC expressing
PD-L1
randomly assigned to receive nivolumab versus docetaxel