every 2 weeks. 18 Histologies tested included melanoma, non–small-cell lung cancer (NSCLC),
renal-cell cancer (RCC), castration-resistant
prostate cancer (CRPC), and colorectal cancer (CRC). Responses were seen in melanoma
and RCC and unusually in NSCLC, including
in both squamous and non-squamous tumors.
Objective responses were noted in 41% of the
107 melanoma patients treated at 3 mg/kg.
Survival was improved, with 1- and 2- year survival rates of 62% and 43% at extended follow
up.50
Subsequently, nivolumab was compared to
chemotherapy in a pair of phase 3 studies
involving both previously untreated (
Checkmate 066) and ipilimumab/BRAF inhibitor–
refractory (CheckMate 037) patients. 19, 20 In both
studies, nivolumab produced durable responses
in 32% to 34% of patients and improved survival over chemotherapy. Compared to ipilimumab, the incidence of irAEs was much lower
with nivolumab. The depth and magnitude of
responses observed led to regulatory approval
for nivolumab in both indications (untreated
and ipilimumab/BRAF inhibitor–treated melanoma) in 2014. Data from both studies are summarized in Table 1.
Pembrolizumab was first evaluated in a phase
1 study of 30 patients with a variety of solid
organ malignancies in which no dose-limiting
toxicities were observed and no defined maxi-
mal tolerated dose was reached.51 Per protocol,
maximal administered dose was 10 mg/kg every
2 weeks. Following startling responses including
2 complete responses of long duration, pembro-
lizumab was evaluated in a large phase 1 study
(KEYNOTE-001) of 1260 patients that evaluated
3 doses ( 10 mg/kg every 2 weeks, 10 mg/kg
every 3 weeks, and 2 mg/kg every 3 weeks) in
separate melanoma and NSCLC substudies. 21
Both ipilimumab-naïve and ipilimumab-treated
patients were enrolled in the melanoma sub-
study. Objective responses were seen in 38% of
patients across all 3 dosing schedules and were
similar in both ipilimumab-naïve and ipilimumab-
treated patients. Similar to nivolumab, most re-
sponders experienced durable remissions.
Pembrolizumab was subsequently compared
to ipilimumab in untreated patients (KEY-
NOTE-006) in which patients were randomly
assigned to receive either ipilimumab or pembrolizumab at 1 of 2 doses: 10 mg/kg every 2
weeks and pembrolizumab 10 mg/kg every
3 weeks. 22 Response rates were greater with
pembrolizumab than ipilimumab, with commensurately greater 1-year survival rates. Rates
of treatment-related adverse events requiring
discontinuation of study drug were much lower
with pembrolizumab than ipilimumab. This
trial was instrumental in proving the superior profile of pembrolizumab over ipilimumab.
The US Food and Drug Administration (FDA)
granted pembrolizumab accelerated approval
for second-line treatment of melanoma in 2014,
and updated this to include a first-line indication in 2015 (Table 1).
EFFICACY OF COMBINED CTLA- 4 AND PD- 1 INHIBITION
Preclinical studies demonstrated that PD- 1
blockade was more effective than CTLA- 4 blockade and combination PD-1/CTLA- 4 blockade
was synergistic, with complete rejection of tumors in approximately half of the treated animals. 14 This hypothesis was evaluated in a phase 1
study that explored both concurrent and sequential combinations of ipilimumab and
nivolumab along with increasing doses of both
agents in PD-1/CTLA- 4–naïve advanced melanoma. 23 Responses were greater in the concurrent arm (40%) than in the sequential arm
(20%) across dose-levels with a small fraction of
patients treated in the concurrent arm experiencing a profound reduction (80%) in tumor
burden.
The superiority of ipilimumab/nivolumab
combination to ipilimumab monotherapy was
demonstrated in a randomized blinded phase 2
study (CheckMate 069). 24 Of the 4 different ipilimumab/nivolumab doses explored in the phase
1 study ( 3 mg/kg and 0.3 mg/kg, 3 mg/kg
