May 2015, Vol. 2, No. 3

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Immuno-Oncology Combination Approaches for Lung Cancer


With the advent of new immunotherapeutic agents, including checkpoint inhibitors that target the programmed death-1 (PD-1) pathway and the cytotoxic T-lymphocyte antigen 4 (CTLA-4) pathway, investigations are being conducted to elucidate the potential combination of various therapies and their possible synergistic activity with chemotherapy

Immune checkpoint blockade with monoclonal antibodies directed at the inhibitory immune receptors PD-1 (or one of its ligands, PD-L1) or CTLA-4 are showing some promise in clinical trials as monotherapy; however, there is evidence suggesting that these agents may be more effective as part of a combination regimen.1

In addition to CTLA-4 and PD-1/PD-L1, numerous other immunomodulatory targets have been identified preclinically, many with corresponding therapeutic antibodies that are being investigated in clinical trials.2 The majority of these targets are T-cell surface receptors, but targets in other immunologic cell populations are being investigated. For example, natural killer (NK) cells express killer immunoglobulin-like receptors (KIRs), which bind human leukocyte antigen class I molecules on target cells, thereby delivering an inhibitory signal preventing NK cell–mediated cytotoxicity. Anti-KIR antibodies may release these inhibitory KIR-mediated signals, thereby enabling tumor cytotoxicity and immune clearance.2 Another checkpoint protein target is lymphocyte activation gene 3 (LAG-3), a CD4-related inhibitory receptor coexpressed with PD-1.2 In animal models, inhibition of LAG-3 by a monoclonal antibody slowed the growth of established tumors, and it caused synergistic tumor regression when combined with an anti–PD-1 antibody.3 Dual checkpoint blockade strategies, such as those combining anti–CTLA-4, anti–PD-L1, anti–LAG-3, or anti-KIR, are being tested to increase the proportion and durability of tumor responses.

Dual Checkpoint Blockade

Some of the current clinical studies exploring the dual T-cell checkpoint blockade with anti–CTLA-4 and anti–PD-1/PD-L1 are listed in Table 1.

Lirilumab, a fully human monoclonal antibody to KIR, in combination with nivolumab, has demonstrated an early efficacy signal in preclinical models.2 A trial of nivolumab with lirilumab in human solid tumors is under way, including 32 patients with non–small cell lung cancer (NSCLC).4 A similar trial is testing the combination of lirilumab with ipilimumab, accruing up to 20 patients with NSCLC in a dose-expansion cohort.5 Ongoing NSCLC clinical studies exploring the dual T-cell checkpoint blockade with anti–CTLA-4 or anti–PD-L1 combined with anti-KIR or anti–LAG-3 are listed in Table 2.

Checkpoint Blockade plus Targeted Therapy

In a study of 125 patients with NSCLC, including 56 (44.8%) whose tumors had epidermal growth factor receptor (EGFR) mutations, 29 (23.2%) with KRAS-mutated tumors, 10 (8.0%) with ALK translocations, and 30 (24.0%) whose tumors were EGFR/KRAS/ALK wild type (triple negative); PD-1/PD-L1 expression was assessed by immunohistochemistry.6 PD-1 positivity (+) was significantly associated with current smoking status (P = .02) and with the presence of KRAS mutations (P = .006), whereas PD-L1+ was significantly associated with adenocarcinoma histology (P = .005) and with the presence of EGFR mutations (P = .001). Among the 95 patients treated with gefitinib or erlotinib (both EGFR tyrosine kinase inhibitors [TKIs]), 49 patients (51.6%) were positive for PD-L1 expression. They achieved a significantly higher response rate (61.2% vs 34.8%; P = .01), a significantly longer time to progression (11.7 vs 5.7 months; P <.0001), and longer overall survival (OS; 21.9 vs 12.5 months; P = .09) compared with PD-L1–negative patients. In the subset of 55 patients with EGFR-mutated tumors treated with EGFR TKIs, those who were PD-L1 positive (70.9%) showed a longer time to progression (13.0 vs 8.5 months; P = .011). The OS was 29.5 months in PD-L1–positive patients compared with 21.0 months in PD-L1–negative patients. However, no differences were identified in PD-1–positive versus PD-1–negative patients. These results suggest that PD-L1 expression is correlated with EGFR mutation and support a rationale for checkpoint inhibitors combined with EGFR TKIs in patients with EGFR-mutant NSCLC. Studies investigating this and other combinations of checkpoint inhibitors and targeted therapies are listed in Table 3.

One study is combining the anti–PD-L1 antibody MEDI4736 with the EGFR TKI gefitinib; another study is evaluating MPDL3280A (an anti–PD-L1 monoclonal antibody) in combination with erlotinib (an EGFR TKI). Still another study will investigate nivolumab, an anti–PD-L1 antibody, with EGF816, a third-generation EGFR TKI that is active against T790 mutations. In addition, separately, the study will investigate nivolumab in combination with INC280, a selective inhibitor of c-MET receptor tyrosine kinase.

Ipilimumab, a fully human monoclonal antibody that specifically blocks the binding of CTLA-4 to its ligands (CD80/CD86), was approved by the FDA for the treatment of unresectable or metastatic melanoma in 2011.7 Ipilimumab is being investigated in combination with the EGFR TKI erlotinib or the small molecule ALK inhibitor crizotinib.

The anti–CTLA-4 antibody tremelimumab is being studied in combination with the EGFR TKI gefitinib in an open-label phase 1 study. The biologic rationale for such a study is that even though the disease is progressing, it is likely that EGFR-sensitive clones, although diminished under the pressure from the EGFR TKI, are still present. Therefore, withdrawing the inhibitory pressure of the EGFR TKI can potentially allow regrowth of the EGFR-sensitive cells. On the other hand, the proliferation of EGFR-resistant clones needs to be suppressed by another therapeutic approach. Therefore, the combination of gefitinib with immune checkpoint blockade is very attractive and may result in clinical benefit in NSCLC with mutated EGFR. Examples of ongoing clinical studies combining anti–CTLA-4 antibodies with EGFR TKI–targeted therapy are listed in Table 4.

Additional Studies of Checkpoint Blockade plus Targeted Therapy

Numerous other studies are under way investigating various combinations of checkpoint inhibitors and targeted therapies (Table 5). Among these is a study combining the recently approved anti–PD-L1 molecular antibody nivolumab with varlilumab, a fully human monoclonal antibody that targets CD27, a critical molecule in the activation pathway of lymphocytes.

Checkpoint Blockade plus Targeted Therapy plus Chemotherapy

Some studies are investigating more complex interventions that involve not only checkpoint blockade and targeted therapy, but also chemotherapy (Table 6).

Immunotherapy plus Chemotherapy

The rationale for the use of immunotherapy in associa­tion with chemotherapy is based on the assumption that tumor-specific antigen released during chemotherapy-
induced tumor necrosis may increase tumor-specific immunity and therefore enhance the immunotherapeutic efficacy.8 This hypothesis may explain the trend in favor of the sequential association of ipilimumab and chemotherapy in comparison with the concurrent association as highlighted in the phase 2 ipilimumab study reported below.

Ipilimumab plus Chemotherapy

Ipilimumab was investigated in a randomized, double-blind, phase 2 study that assessed the monoclonal antibody in combination with first-line chemotherapy in patients with advanced NSCLC (stage IIIB/IV) or extensive-stage small cell lung cancer (SCLC). Patients were randomized 1:1:1 to receive paclitaxel/carboplatin with either placebo or ipilimumab in 1 of 2 alternative regimens, concurrent ipilimumab (ipilimumab plus pac­litaxel/carboplatin followed by placebo plus paclitaxel/carboplatin) or phased ipilimumab (placebo plus pac­litaxel/carboplatin followed by ipilimumab plus pac­litaxel/carboplatin). Treatment was administered intravenously every 3 weeks for 18 weeks. Eligible patients continued ipilimumab or placebo every 12 weeks as maintenance therapy. Tumor response was assessed via modified World Health Organization (mWHO) criteria and an immune-related response criteria to account for immune-related changes on scans. The primary end point was immune-related progression-free survival (irPFS). Other end points were progression-free survival (PFS), best overall response rate (BORR), immune-related BORR (irBORR), OS, and safety. The results for NSCLC and SCLC were reported separately.9,10

Results for the 204 patients with chemother­apy-naive NSCLC showed that the study met its primary end point of improved irPFS for phased ipilimumab versus the control (hazard ratio [HR], 0.72; P = .05), but not for concurrent ipilimumab (HR, 0.81; P = .13).9 Phased ipilimumab also improved PFS according to mWHO criteria (HR, 0.69; P = .02). Phased ipilimumab, concurrent ipilimumab, and control treatments were associated with a median irPFS of 5.7, 5.5, and 4.6 months, respectively, a median PFS of 5.1, 4.1, and 4.2 months, respectively, an irBORR of 32%, 21%, and 18%, respectively, a BORR of 32%, 21%, and 14%, respectively, and a median OS of 12.2, 9.7, and 8.3 months (Figure 1A). Results from a subgroup analysis indicated a greater benefit to patients with squamous cell histology (HR, 0.55) than in patients with nonsquamous histology (HR, 0.82) in the group who received the phased schedule; however, in the group that received the concurrent schedule, differences in irPFS versus that in the control arm were similar between squamous and nonsquamous subsets (HRs, 0.85 and 0.77, respectively). Overall rates of grade 3/4 immune-related adverse events (AEs) were 15%, 20%, and 6% for phased ipilimumab, concurrent ipilimumab, and control, respectively. Two patients (concurrent, 1 patient; control, 1 patient) died of treatment-related toxicity.

Results for the 130 patients with chemotherapy-naive extensive-disease SCLC showed that phased ipilimu­mab, but not concurrent ipilimumab, improved irPFS versus control (HR, 0.64; P = .030).10 No improvement was seen in PFS (HR, 0.93; P = .37) or OS (HR, 0.75; P = .13). Phased ipilimumab, concurrent ipilimumab, and control, respectively, were associated with median irPFS of 6.4, 5.7, and 5.3 months; median PFS of 5.2, 3.9, and 5.2 months; median OS of 12.9, 9.1, and 9.9 months (Figure 1B). Overall rates of grade 3/4 immune-related AEs were 17%, 21%, and 9% for phased ipilimumab, concurrent ipilimumab, and control, respectively.

Ongoing clinical studies of ipilimumab in combination with chemotherapy are listed in Table 7.

Pembrolizumab plus Chemotherapy
Ongoing clinical studies of pembrolizumab in combination with chemotherapy are listed in Table 8.

Nivolumab plus Chemotherapy
A phase 2 trial of nivolumab given after “epigenetic priming” with the chemotherapy drugs azacitidine and entinostat in patients with recurrent metastatic NSCLC and a phase 1 safety study of nivolumab plus nab-paclitaxel/carboplatin chemotherapy are under way (Table 9).

MPDL3280A plus Chemotherapy

The anti–PD-L1 molecular antibody MPDL3280A is being investigated in combination with chemotherapy in both squamous and nonsquamous NSCLC (Table 10). In one study, the MPDL3280A/chemotherapy combination is being studied both with and without the vascular endothelial growth factor–targeted antibody bevacizumab.

Concluding Remarks
With the advent of new immunotherapeutic agents, new options are available to patients with NSCLC. Although these agents are still under investigation, they appear to have promising results—albeit in a minority of patients. Combinatorial strategies, including with novel immune checkpoint inhibitors, targeted agents, and chemotherapy, are undergoing investigation, and toxicity and efficacy results from these studies will help define the optimal role for immune-based therapeutics in NSCLC.


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  2. Creelan BC. Update on immune checkpoint inhibitors in lung cancer. Cancer Control. 2014;21:80-89.
  3. Woo SR, Turnis ME, Goldberg MV, et al. Immune inhibitory molecules LAG-3 and PD-1 synergistically regulate T-cell function to promote tumoral immune escape. Cancer Res. 2012;72:917-927.
  4. Sanborn R, Sharfman WH, Segal NH, et al. A phase I dose-escalation and cohort expansion study of lirilumab (anti-KIR; BMS-986015) administered in combination with nivolumab (anti-PD-1; BMS-936558; ONO-4538) in patients (Pts) with advanced refractory solid tumors. J Clin Oncol. 2013;31(suppl). Abstract TPS3110.
  5. Rizvi NA, Infante JR, Gibney GT, et al. A phase I study of lirilumab (BMS-986015), an anti-KIR monoclonal antibody, administered in combination with
    ipilimumab, an anti-CTLA4 monoclonal antibody, in patients (Pts) with select advanced solid tumors. J Clin Oncol. 2013;31(suppl). Abstract TPS3106.
  6. D’Incecco A, Andreozzi M, Ludovini V, et al. PD-1 and PD-L1 expression in molecularly selected non-small-cell lung cancer patients. Br J Cancer. 2015;112:95-102.
  7. Yervoy [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2015.
  8. Tomasini P, Khobta N, Greillier L, et al. Ipilimumab: its potential in non-small cell lung cancer. Ther Adv Med Oncol. 2012;4:43-50.
  9. Lynch TJ, Bondarenko I, Luft A, et al. Ipilimumab in combination with paclitaxel and carboplatin as first-line treatment in stage IIIB/IV non-small-cell lung cancer: results from a randomized, double-blind, multicenter phase II study. J Clin Oncol. 2012;30:2046-2054.
  10. Reck M, Bondarenko I, Luft A, et al. Ipilimumab in combination with paclitaxel and carboplatin as first-line therapy in extensive-disease-small-cell lung cancer:
    results from a randomized, double-blind, multicenter phase 2 trial. Ann Oncol. 2013;24:75-83.
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