NcXHF

BEX, LARKIN, AND VOSS
limited expression levels can still benefıt from treatment. 13,16
The limitations of using immunohistochemistry as a biomarker
chiefly lie in the dynamic nature of PD-L1 expression
and in differences in tissue processing, among other differences.
Recent data in melanoma revealed that neoantigen signatures,
which are the results of acquired somatic mutations,
can correlate with treatment effectiveness of CTLA-4 inhibition.
17 These data suggest that genomic profıling of the tumor
tissue may prove useful as a predictive biomarker for
checkpoint inhibitors.
Checkpoint Inhibitor Combinations
Concurrent blockade of PD-1 and CTLA4 is hypothesized to
be complementary in regulating adaptive immunity. For
RCC, this notion is supported by data from a phase I study
combining nivolumab with the CTLA4-directed fully humanized
monoclonal antibody ipilimumab in a heterogeneous
group of 44 patients (80% pretreated). 18 A 45% ORR,
with 80% of the responses ongoing at the time of report,
prompted the sponsor to move straight into a phase III study
(NCT02231749), which is presently ongoing. This trial is recruiting
untreated patients with metastatic disease, who are
randomly assigned 1:1 to receive the combination of nivolumab
plus ipilimumab versus sunitinib on the comparator
arm. With PFS and OS as the coprimary endpoints, the trial is
designed to challenge the current treatment paradigm of a
VEGF kinase inhibitor as the widely accepted standard of
care in fırst-line settings. Note that the combination’s unique
toxicity profıle frequently requires the use of systemic corticosteroids
and other immunosuppressants for the treatment
of immune-mediated adverse events. This challenge raises
the question of whether the combination, if proven successful
in this pivotal trial, could enter practice as a new standard
in lieu of a VEGF kinase inhibitor.
Other checkpoint inhibitor combinations, including
CTLA4-directed tremelimumab plus the PD-1 inhibitor
Medi4736 (NCT02261220) or the anti-KIR–directed antibody
lirilumab plus nivolumab (NCT01714739), are much
earlier in their development for RCC. Potential synergism
with cytokine therapy is being explored in an RCC expansion
cohort of a phase I study combining nivolumab with recombinant
IL-21 (NCT01629758).
Combining Checkpoint Inhibitors with Approved
Targeted Agents
Beyond its principal role as a regulator of angiogenesis,
VEGF has various immunomodulatory effects. Accordingly,
VEGF tyrosine kinase inhibitors (TKIs) as well as the VEGF-A directed
monoclonal antibody bevacizumab have demonstrated
immune stimulatory effects across various tumor
models (reviewed by Vanneman et al 19 ), lending support to
combining checkpoint inhibitors with approved targeted
therapies. High response rates for combinations of VEGF
TKI therapy with CTLA4 inhibition 20 as well as with PD-1
blockade 21 suggest that such synergism in fact exists. At the
same time, these trials reported a notable increase in
treatment-induced organ dysfunction. The combination of
nivolumab and standard-dose sunitinib, for instance, demonstrated
encouraging antitumor activity, with an ORR of
52% across 33 patients, but grade 3 to 4 treatment-related
adverse events were recorded in greater than 70% of patients.
21 Such fındings make this combination hardly appear
suitable for further development on a larger scale. With the
suggestion of synergism, however, and in consideration of
the notion that immunotherapy may extend the duration of
disease control, the fıeld should not prematurely abandon
combinations of TKI and checkpoint inhibition. For further
development, however, we may need to explore alternate
treatment schedules, such as lower dosing levels, sequenced
introduction of agents, or alternating dosing schedules.
Safety data from other TKI/PD-1 combination trials is
awaited, including the two combination trials pairing the
PD-1–directed monoclonal antibody pembrolizumab plus
pazopanib (NCT02014636) or axitinib (NCT02133742).
Similar to prior experiences combining VEGF-targeted
therapy with other agents, bevacizumab seems to pair with
checkpoint inhibition without notable increases in toxicity.
Data from a phase I study combining bevacizumab and the
monoclonal PD-L1–directed antibody MPDL3280 suggested
a favorable safety profıle, with less than 5% grade 3 to
4 adverse events and four of 10 patients achieving a partial
response; nine of 10 patients remained on study at the time of
the report. 22 This result prompted a large, randomized, phase
II study (NCT01984242) that is presently enrolling untreated
patients with 1:1:1 random assignment among standarddose
sunitinib, MPDL3280 monotherapy, and the combination
of MPDL3280 plus bevacizumab. Thus, its favorable
tolerance when used as a partner with other agents may
bring attention to bevacizumab, an agent previously approved
in the fırst-line setting but currently underutilized
in that setting.
Vaccine Studies
A number of vaccination strategies, including autologous,
multipeptide, and antigen-directed vaccines, are being tested
in metastatic RCC. 23 Although it is unlikely that these could
replace the current standard of targeted therapy in treatmentnaive
patients, immunomodulatory effects argue in favor of
pairing vaccines with approved targeted therapies. In the
phase III ADAPT trial (NCT1582672) patients undergoing
cytoreductive nephrectomy were randomly assigned to standard
targeted therapy plus autologous vaccination with AGS-
003 or to standard therapy alone. This trial is based on
encouraging data from a previous open-label, phase II study
of sunitinib plus AGS-003 that reported a median PFS of 11.2
months and a median OS of 30.2 months. 23 Another phase III
study (NCT01265901) is comparing standard sunitinib to
vaccination with sunitinib plus IMA901, a multipeptide vaccine
of nine tumor-associated peptides administered after a
single dose of cyclophosphamide. Both studies have OS as a
primary endpoint, because successful vaccination should
have a longer-lasting immunomodulatory anticancer effect.
The substantial efforts to bring checkpoint inhibitors into
routine practice now raise questions for the further develop-
e242
2015 ASCO EDUCATIONAL BOOK | asco.org/edbook