RAMB - Setembro 2017

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2017; 63(9):814-823

nificant improvement in 2-year survival rates for both

pembrolizumab regimens versus ipilimumab (55% in

both pembrolizumab arms vs. 43%; HR 0.68; 95CI 0.53-

0.87; p=0.0008 and HR 0.68; 95CI 0.53-0.87; p=0.0008

for 2 week and 3 week schedules compared to ipilimumab,

respectively). The 6-month PFS rate, a co-primary endpoint,

was 47.3; 46.4 and 26.5% respectively, with a HR for disease

progression for pembrolizumab versus ipilimumab of 0.58;

p<0.001 for both 2 and 3-week regimens. ORR were 37, 36

and 13% for the same treatment arms.

38,39

The longest follow-up data of melanoma patients on

treatment with anti-PD1 therapy comes from the phase

1/2 dose escalation expansion cohort of nivolumab in 107

heavily pretreated advanced melanoma patients. The

median overall survival was 17 months, but treated pa-

tients achieved an impressive 5-year survival rate of 34%.

The combined administration of an anti-CTLA-4 and

anti-PD1 antibodies was tested in a randomized phase 2

trial that accrued 142 treatment-naïve patients, with ap-

proximately 75% of BRAF “wild-type” (wt) tumors. Despite

the increased incidence of grade 3 or 4 adverse events (54%

vs. 24%), the combination of nivolumab and ipilimumab

resulted in higher ORR in the BRAFwt population when

compared to ipilimumab monotherapy, which was the

primary endpoint (ORR in BRAFwt patients: 60% vs.

11%).

40,41

The hypothesis that combined immune-check-

point blockade could result in improved outcomes was

further tested in the CheckMate 067 phase 3 trial. In this

study, 945 patients were randomized to receive nivolumab

1 mg/kg plus ipilimumab 3 mg/kg for four doses followed

by nivolumab, nivolumab 3 mg/kg plus placebo or ipili-

mumab 3 mg/kg plus placebo. PFS and overall survival

were the co-primary endpoints of the trial and the results

were updated after a median follow-up of 18 months. The

ORR was 19% for ipilimumab monotherapy compared

with 57.6% for nivolumab plus ipilimumab (p<0.001) and

43.7% for nivolumab alone (p<0.001). The combination

therapy was associated with a 58% relative reduction in

the risk of disease progression when compared to ipilim-

umab alone (HR 0.42; 99.5CI 0.31-0.57; p<0.001); simi-

larly, nivolumab monotherapy resulted in a relative risk

reduction of 45% also compared with ipilimumab alone

(HR 0.55; 99.5CI 0.43-0.76; p<0.001).

Although the study

was not powered for the direct comparison of nivolumab

plus ipilimumab vs. nivolumab, an exploratory analysis

showed that combination therapy reduced the risk for

progression by 24% compared with nivolumab mono-

therapy (HR 0.76; 95CI 0.60-0.92).

41,42

Grade 3 and 4 ad-

verse events for the combination, nivolumab alone, and

ipilimumab alone were 55, 16, and 27%, respectively and

treatment discontinuation due to treatment toxicities

were more frequent in the combination arm.

Longer

follow-up and mature overall survival data are expected.

Due to the high incidence of immune-mediated adverse

events demonstrated in the setting of combined blockade,

alternative treatment regimens are being investigated in

an attempt to enhance the tolerability. As an example, the

phase 1 KEYNOTE-029 trial combined “low dose” ipili-

mumab (1 mg/kg given every 3 weeks for 4 doses) with a

standard dose of pembrolizumab (2 mg/kg given every 3

weeks); ORR in this study was 57%, and grade 3-4 toxici-

ties occurred in 42% of the cases.

While PD-1 blockers, either in monotherapy or in

combination with ipilimumab, became the standard of

care for patients with BRAFwt tumors, the best treatment

to be given upfront remains to be determined for those

with tumors harboring a BRAF mutation, and results of

ongoing studies looking at the best sequence and com-

binations of BRAF/MEK inhibition and immune-check-

point blockade are eagerly awaited, as discussed below.

uture

perspectives

The increasing understanding of the underlying immu-

nologic mechanisms of tumorigenesis and tumor evasion

has prompted the evaluation of additional receptors in-

volved in the T cell response. Studies of agonist antibod-

ies targeting the immune-stimulatory receptors OX40,

CD27, CD137 and GITR are awaited. Similarly, promising

results have been suggested by early-phase clinical trials

investigating molecules targeting the inhibitory co-recep-

tors LAG-3 and TIM-3, as well as indeoleamine 2,3-di-

oxygenase (IDO) inhibition, a tryptophan-metabolizing

enzyme involved in immunosuppressive mechanisms.

Another promising approach already approved for

clinical use in the USA and Europe is talimogene laher-

parepvec (T-VEC), an oncolytic attenuated herpes virus

designed to selectively replicate and lyse tumor cells and

overexpress granulocyte macrophage colony-stimulating

factor (GM-CSF), resulting in induction of tumor-specif-

ic T cell response. In a phase 3 trial with patients with

stage IIIB-IV melanoma, intratumoral injections of T-VEC

produced an improved durable response rate compared

to intratumoral GM-CSF alone (16.3% vs. 2.1%; OR 8.9;

p<0.001), leading to its approval by regulatory agencies.

Phase 1b studies tested combinations of T-VEC with sys-

temic immunotherapies, revealing a safe profile and in-

teresting results. T-VEC in association with ipilimumab

produced an ORR of 50%, with 44% of the patients having

durable responses of at least 6 months; the 18-month

overall survival was 67%.

The combination of TVEC with