Immunotherapy for Non-small Cell Lung Cancer: Current Agents and Potential Molecular Targets

Cytokine Immunotherapy

Interleukin-1α (IL-1α). Interleukin 1α (IL-1α) is a proinflammatory cytokine that potentially drives tumor growth through various mechanisms. Notably, IL-1α mediates the early phases of sterile inflammation and recruitment of neutrophils and monocytes in response to tissue injury by functioning as an “alarmin”; subsequent release of various factors drives the physiological process of wound healing (8, 9). In malignancies, the induction of tumor-associated macrophages (TAM) by IL-1α produces several growth factors and cytokines that support cancer cell proliferation, angiogenesis, and suppression of adaptive immune response (10).

MABP1 is a human monoclonal antibody that targets IL-1α. In a phase I study, 16 patients with NSCLC who were refractory to the standard chemotherapy were given MABP1 in a dose escalating manner. The median overall survival (OS) was 7.6 months, and the median progression-free survival (PFS) was 57 days. Interestingly, there was a correlation between the patients with anti-epidermal growth factor receptor (EGFR) pretreatment and a better treatment outcome. Median OS in the anti-EGFR pretreated patients was 9.4 months, versus non-pretreated patients with a median OS of 4.8 months. Median PFS was also higher in the anti-EGFR pretreated group than non-pretreated group (97 days and 78 days, respectively) (11). The sample size was small, and the study was underpowered to be conclusive. Nevertheless, given the relative success in the anti-EGFR pretreatment group, the relationship of EGFR, IL-1α, and NSCLC should be an area of continued study, especially considering the encouraging results from MABp1 in the treatment of colorectal cancer (12). No follow-up study of MABp1 treatment for NSCLC has been initiated to date.

Interleukin-2 (IL-2). Interleukin 2 (IL-2) was originally found as a T-cell activator, but it was later discovered that its effects occur in a dose-dependent manner. It has been shown that IL-2 could promote the activity of CD8+ T cells and natural killer cells at high doses. At lower doses, it could preferentially increase T regulatory cell population (13). In vitro, tumor-induced immunosuppressive phenomena were found to be reversible with the addition of exogenous IL-2 (14).

The efficacy of IL-2 treatment in patients with NSCLC remains questionable. In a phase III study, 239 patients with stage IIIb or IV NSCLC were randomly assigned to receive either gemcitabine + cisplatin (chemotherapy only), or gemcitabine + cisplatin + IL-2 (chemotherapy + IL-2). The median OS and median PFS was 10.5 and 6.6 months respectively in the chemotherapy + IL-2 arm; 12 and 6.9 months respectively in the chemotherapy only arm. The statistical differences of these two groups were nonsignificant in both OS and PFS (15). Yet, in a separate phase I/II trial, 45 patients with stage III NSCLC were studied. Thirteen patients received gemcitabine, cisplatin, and recombinant IL-2 (rIL-2), followed by surgery (chemotherapy + IL-2 + surgery). The remaining 32 patients received gemcitabine, cisplatin, and surgery (chemotherapy + surgery). The 5-year OS in the chemotherapy + IL-2 + surgery group was 59% compared to the group without rIL-2 therapy at 32% (16). A striking 66% reduction in the hazard of death was observed in patients receiving rIL-2 immunotherapy. Despite this, no significant difference was found between the two groups in OS and event-free survival (EFS). Overall, further research is warranted to determine the efficacy of IL-2 immunotherapy treatment in patients with NSCLC (Table I).

Checkpoint Inhibitors

T-cell mediated immunity is a highly regulated, multistep process. Each step consists of both co-stimulatory and co-inhibitory cues that prime T-cells to either proceed or terminate their activation. Cytotoxic T-lymphocyte associated antigen 4 (CTLA 4) and programmed cell death protein 1 (PD1) are two of the most widely studied immune-checkpoint receptors for cancer therapy. Both are negative regulators of T-cell activation, and ligands that bind to these receptors are expressed in many cell types to prevent a reaction against self-antigens under normal physiological conditions (17, 18). To evade immune-surveillance, many tumor cells take advantage of this mechanism by expressing ligands that may bind to these two receptors, thereby inhibiting T-cell activation (17, 18). Immune checkpoint inhibitors counter this strategy by inhibiting these inhibitory pathways, allowing for T-cell mediated immunity against tumor cells to carry on as a result (19).

CTLA-4 inhibitors: Ipilimumab. CTLA-4 (or CD152) is expressed on T lymphocytes, it competes with CD28, which is a co-stimulatory receptor on T lymphocytes, by binding with B7 (CD80 or CD86) on antigen presenting cells (APCs) with higher affinity and avidity. An inhibitory signal is generated when CTLA-4 binds with B7 (20).

Ipilimumab is one such immune checkpoint inhibitor that targets against CTLA-4 inhibitory receptor, and it has shown promising results in treating patients with melanoma (21). In a phase II study, Ipilimumab plus chemotherapy (paclitaxel and carboplatin) was trialed in 204 patients with NSCLC. Three regimens were assigned randomly to patients, which included a concurrent regimen consisting of four doses of ipilimumab with chemotherapy followed by two doses of a placebo with chemotherapy; a phased regimen consisting of two doses of placebo with chemotherapy followed by four doses of ipilimumab with chemotherapy; and a control regimen consisted of up to six doses of placebo with chemotherapy. Median immune-related PFS (irPFS) was longer with phased regimen (5.7 months) than concurrent regimen (5.5 months) and control regimen (4.6 months). After assessed by the mWHO criteria, the PFS was statistically improved in the phased regimen (mWHO-PFS of 5.1 months) compared to the control regimen (mWHO-PFS of 4.2 months), but no improvement was seen with the concurrent regimen (mWHO-PFS of 4.1 months) (22).

A subsequent phase III study of 956 patients with NSCLC showed a rather disappointing result. The difference in median OS between the ipilimumab + chemotherapy (Paclitaxel and Carboplatin) regimen (13.4 months) and placebo + chemotherapy regimen (12.4 months) was statistically insignificant. Median PFS also did not show any significant difference between the two groups (5.6 months in ipilimumab + chemotherapy vs. 5.6 months in placebo + chemotherapy) (23).

Programmed cell death protein (PD-1/PD-L1) inhibitors: Nivolumab. Like CTL-4, PD-1 is also expressed on T-cells as an inhibitory receptor. It binds to PD-1 ligand (PD-L1 or PD-L2) which is expressed on antigen presenting cells. The interaction of PD-1/PD-L provides an inhibitory signal to T-cells by promoting the conversion of a naïve T-cell to a Treg cell. High levels of Treg cells as a result suppress the action of anti-tumor T-cells (24). There are two classes of drugs currently under development targeting the interaction of PD/PD-1, anti-PD-1 and anti-PD-L1 drugs.

Nivolumab is an IgG4 fully human monoclonal antibody directed against PD-1. It disrupts PD-1 binding with PD-L1 and the subsequent downstream signaling events that result in the inhibition of antitumor T-cells. Two phase III trials (Checkmate 017 & Checkmate 057) with nivolumab were conducted in patients with NSCLC that had progressed during or after platinum-based doublet chemotherapy.

In Checkmate 017, 272 patients with squamous NSCLC were randomly assigned to receive nivolumab every two weeks, or chemotherapy (docetaxel) every three weeks. Docetaxel is an FDA-approved medication for NSCLC and is the gold standard treatment for previously treated advanced NSCLC. As such, it is an appropriate indicator of the efficacy of Nivolumab (25, 26). Treatment in the Nivolumab arm resulted in a significantly longer median OS (9.2 months) compared with the docetaxel arm (6.0 months). Median PFS was also longer in the nivolumab arm (3.5 months) compared with the docetaxel arm (2.8 months), the difference was statistically significant (38% lower risk of progression) (25).

In Checkmate 057, a similar trial was conducted, this time with patients with non-squamous NSCLC that had progressed during or after platinum-based doublet chemotherapy. Again, 582 patients were assigned randomly to receive either nivolumab every two weeks, or docetaxel every three weeks. This study also found favorable results with nivolumab. The median OS was 12.2 months in the nivolumab arm compared with 9.4 months in the docetaxel arm. Even though median PFS was lower in nivolumab (2.3 months) than docetaxel (4.2 months; statistically nonsignificant difference) median duration of response (DOR) was impressively longer with nivolumab (17.3 months) than docetaxel (5.6 months) (26).

Shortly after the release of Checkmate 017 and Checkmate 057, the U.S. Food and Drug Administration (FDA) officially approved nivolumab (OPDIVO®) in October 2015 for the treatment of patients with metastatic NSCLC with progression on or after platinum-based chemotherapy. The recommended dose and schedule of nivolumab is 3 mg/kg intravenously every two weeks (27).

A study was conducted to further investigate the efficacy of nivolumab in the treatment of NSCLC with various clinical factors. They concluded that patients with performance status (PS) of 2, or symptomatic brain metastases were not suitable for nivolumab treatment for NSCLC. The median PFS of NSCLC patients with PS 2 (1.1 months) was significantly lower than patients with PS <2 (6.6 months); median OS of NSCLC patients with symptomatic brain metastases (3.1 months) was also significantly lower than patients without brain metastases (11.2 months) (28).

PD-1 inhibitors: Pembrolizumab. Pembrolizumab is an IgG4 humanized antibody, and like Nivolumab, it is directed against PD-1. Two studies were of particular importance in the advancement of pembrolizumab as a primary treatment of care for NSCLC: KEYNOTE-010 & KEYNOTE-024.

In KEYNOTE-010, a phase II/III trial, 1034 NSCLC patients with at least 1% of tumor cells positive for PD-L1, who experienced disease progression after at least two cycles of platinum-doublet chemotherapy, were randomly assigned into three arms of treatment: pembrolizumab 2 mg/kg intravenously over 30 min every 3 weeks, pembrolizumab 10 mg/kg intravenously over 30 min every 3 weeks, or docetaxel 75 mg/m² intravenously over 1 h every 3 weeks. Overall, the median OS was significantly longer with pembrolizumab 2 mg/kg (10.4 months) and pembrolizumab 10 mg/kg (12.7 months) than docetaxel (8.5 months). Median OS of patients with at least 50% tumor cells expressing PD-L1 was also significantly longer with pembrolizumab 2 mg/kg (14.9 months) and pembrolizumab 10 mg/kg (17.3 months) than docetaxel (8.2 months). In the total population, median PFS showed no significant difference between 2 mg/kg or 10 mg/kg pembrolizumab and docetaxel (3.9 months vs. 4.0 months vs. 4.0 months, respectively). However, the median PFS of patients with at least 50% tumors cell expressing PD-L1 was significantly longer with pembrolizumab 2 mg/kg (5.0 months) and pembrolizumab 10 mg/kg (5.2 months) than docetaxel (4.1 months) (29).

In KEYNOTE-024, a phase III trial, 305 patients with NSCLC, who had PD-L1 expression on at least 50 % tumor cells and no sensitizing mutation of the EGFR gene or translocation of the anaplastic lymphoma kinase (ALK) gene, were randomly assigned with either pembrolizumab, or platinum-based chemotherapy of the investigator’s choice (carboplatin + pemetrexed, cisplatin + pemetrexed, carboplatin + gemcitabine, cisplatin + gemcitabine, or carboplatin + paclitaxel). The median PFS was significantly longer in the pembrolizumab group (10.3 months) than in the chemotherapy group (6 months). Median OS was not reached in either group, the estimated rate of 6-month OS was significantly higher in the pembrolizumab group (80.2%) than in the chemotherapy group (72.4%), with a hazard ratio for death of 0.60 (30).

Based on the desirable results from KEYNOTE-010 and KEYNOTE-024, pembrolizumab (KEYTRUDA®) was approved by the U.S. FDA in October 2016 for the first-line treatment of patients with metastatic NSCLC with 50% or more tumor cells with PD-L1 expression (as determined by an FDA-approved test), no EGFR or ALK genomic tumor aberrations, and no prior systemic chemotherapy treatment. The recommended dose and schedule for pembrolizumab is 200 mg intravenously every three weeks. Pembrolizumab is the first checkpoint inhibitor for first-line treatment of lung cancer approved by the U.S. FDA (31). Pembrolizumab was previously granted accelerated approval by the U.S. FDA in October 2015 for second-line treatment of patients with NSCLC whose tumors express PD-L1 (as determined by an FDA-approved test) with disease progression on or after platinum containing chemotherapy (32). This approval was based on a phase I KEYNOTE-001 trial, which demonstrated that higher objective response rates (ORR) and longer PFS were observed in NSCLC patients with PD-L1 expression in at least 50% of tumor cells (33).

PD-L1 inhibitors: Atezolizumab. PD-L1 inhibitors target the same pathway and act in a similar fashion as PD-1 inhibitors. However, PD-L1 inhibitors target against the ligands, which are expressed on tumor cells. Atezolizumab is a human IgG1 monoclonal antibody that targets the protein PD-L1. Studies have shown encouraging results with Atezolizumab therapy. In POPLAR, a phase II trial, 287 patients with NSCLC with disease progression on or after platinum-containing chemotherapy were randomly assigned to receive atezolizumab or docetaxel once every three weeks. In addition, PD-L1 expression level was assessed by immunohistochemistry (IHC) in tumor cells (TCs) and tumor-infiltrating immune cells (ICs). Median OS was significantly longer in the atezolizumab group (12.6 months) than in the docetaxel group (9.7 months). Increasing OS was also associated with increasing PD-L1 expression in TCs, or ICs, or both. There was no significant OS difference between the atezolizumab and docetaxel group in patients without PD-L1 expression (34).

In OAK, a phase III trial, 850 patients with NSCLC who had previously received 1-2 cytotoxic chemotherapy regimens (more than one platinum-based combination therapy) were randomly assigned to receive either atezolizumab or docetaxel every 3 weeks. Patients with a history of autoimmune disease, previous treatments with docetaxel, CD137 agonists, anti-CTLA4, or PD-L/PD-L1 pathway immunotherapies were excluded. In the intent to treat (ITT) population, median OS was significantly longer in the atezolizumab group (13.8 months) than in the docetaxel group (9.6 months). In the populations with PD-L1 expression in ≥1% of TCs and ICs (TC 1/2/3 or IC 1/2/3), median OS was again significantly longer with atezolizumab (15.7 months) than with docetaxel (10.3 months). Unlike the POPLAR trial, the OAK trial showed an improvement in OS regardless of PD-L1 expression, which meant that patients in the TC 0 or IC 0 population also had statistically longer OS with atezolizumab treatment compared to docetaxel. However, similar to POPLAR, the OAK trial showed that patients with higher PD-L1 expression gained greater benefit from atezolizumab than from docetaxel, with TC3 or IC3 having median OS of 20.5 months in the atezolizumab group vs. 8.9 in the docetaxel group (35).

Based on the success of POPLAR and OAK trials, the U.S. FDA granted atezolizumab (TECENTRIQ®) approval in October 2016 for the treatment of patients with NSCLC, whose disease progressed on or after platinum-based chemotherapy. The recommended dose and schedule for atezolizumab is 1200 mg intravenously every three weeks (36).

There have been continuous efforts exploring atezolizumab as a first-line treatment for NSCLC. In the phase II BIRCH trial, 667 patients with NSCLC and PD-L1 expression of 5% or more on TCs or ICs were separated into three groups: first-line atezolizumab treatment (no prior chemotherapy for NSCLC), second-line atezolizumab treatment (disease progression on or after no more than one prior platinum-containing chemotherapy for NSCLC), and third-line treatment (disease progression on or after at least two prior platinum-containing chemotherapy for NSCLC). ORR was higher in the first-line treatment group than the second and third-line treatment group (22%, 19%, and 18%, respectively). Higher PD-L1 expression was associated with higher ORR. In the TC3/IC3 subgroup, ORR was 31%, 26%, and 27% in the first-line, second-line, and third-line treatment group respectively. Median OS was significantly longer in the first-line treatment group (20.1 months) than the second-line treatment group (15.5 months) and third-line treatment group (13.2 months) (37).

In the phase III IMpower150 study, 1202 patients with non-squamous NSCLC were randomly assigned to receive atezolizumab + carboplatin + paclitaxel (ACP), bevacizumab + carboplatin + paclitaxel (BCP), or atezolizumab + BCP (ABCP) every 3 weeks. As previously described, carboplatin + paclitaxel chemotherapy is a standard first-line treatment of care for patients with NSCLC. Bevacizumab is known for its anti-vascular endothelial growth factor (VEFG) activity and it was approved for the treatment of NSCLC as a combined therapy with chemotherapy. Therefore, it was studied whether bevacizumab may improve the efficacy of atezolizumab for NSCLC treatment, via the inhibition of VEGF-mediated immunosuppression. Indeed, the immunotherapeutic effects of atezolizumab + bevacizumab were shown to be synergistic. Median PFS was significantly longer in the ABCP group (8.3 months) than in the BCP group (6.8 months). Median OS was also significantly longer in the ABCP group (19.2 months) than the BCP group (14.7 months). Additionally, the benefits of ABCP over BCP were seen in patients with non-squamous NSCLC, regardless of PD-L1 expression or EGFR/ALK genetic alteration status (38).

In CITYSCAPE, a phase II trial, patients with chemotherapy-naive, PD-L1-positive recurrent or metastatic NSCLC were randomly assigned tiragolumab (600 mg) plus atezolizumab (1200 mg) or placebo plus atezolizumab intravenously once every 3 weeks. The median PFS was 5.4 months in the tiragolumab plus atezolizumab group versus 3.6 months in the placebo plus atezolizumab group. This trial showed that tiragolumab plus atezolizumab improved the objective response rate and PFS compared to atezolizumab alone. With a safety profile roughly the same to atezolizumab alone, the combination of these two immunotherapies is a promising treatment for locally advanced unresectable or metastatic NSCLC (39).

Regardless of being used as a monotherapy or in combination with other immunotherapies such as bevacizumab or tiragolumab, atezolizumab as a first-line treatment will continue to be an area of growing interest in patients with NSCLC, while further investigation is warranted.

PD-L1 inhibitors: Durvalumab. Durvalumab is a fully human IgG1 monoclonal antibody that binds PD-L1 on tumor cells. In the ATLANTIC phase II study, 444 patients with NSCLC who had received at least two prior rounds of chemotherapy were treated with durvalumab every two weeks. Patients with advanced NSCLC without EGFR or ALK genetic aberrations (EGFR-/ALK-), with ≥25% or ≥90% of tumor cells expressing PD-L1 achieved an ORR of 16.4% and 30.9%, respectively. Although there was no significant median PFS difference between the wildtype patients with PD-L1 ≥25% and ≥90% (3.3 months vs. 2.5 months respectively), median OS was longer in patients with ≥90% PD-L1 than in patients with ≥25% PD-L1 (not reached vs. 10.9 months respectively). Again, like the previously introduced checkpoint inhibitors, greater response with durvalumab was observed in NSCLC patients with higher PD-L1 expression in tumor cells (40).

In the phase III PACIFIC trial, 713 patients with stage III NSCLC who had no disease progression after receiving two or more cycles of platinum-containing chemotherapy were randomly assigned to receive durvalumab or placebo in a 2:1 ratio every two weeks. The median PFS was significantly longer in the durvalumab group (16.8 months) than in the placebo group (5.6 months), this PFS benefit with durvalumab was seen in patients regardless of their PD-L1 expression level. ORR was also higher with durvalumab than with placebo (28.4% vs. 16.0% respectively), while OS was not assessed in this study (41).

Based on results from the PACIFIC trial, the U.S. FDA approved durvalumab (IMFINZI®) in February 2018 for the treatment of patients with unresectable stage III NSCLC, whose disease has not progressed following platinum-containing chemotherapy and radiation therapy. The recommended dose and schedule for durvalumab is 10 mg/kg intravenously every two weeks (42).

PD-L1 inhibitors: Avelumab. Avelumab is yet another fully human IgG1 monoclonal antibody that targets PD-L1. Avelumab is unique in its antibody-dependent cell-mediated cytotoxicity (ADCC) property, which is absent in other PD-L1 inhibitors. As such, avelumab can lyse target cells in the presence of peripheral blood mononuclear cells (PMBC) and natural killer (NK) cells, in addition to its anti PD-L1 action (43).

In the phase 1b JAVELIN trial, 184 patients with stage IIIB or IV progressive or platinum-resistant NSCLC were initiated treatment with avelumab every 2 weeks. Overall, 92 patients (50%) achieved disease control, which had confirmed response or stable disease as their best overall response (44).

In the subsequent phase III JAVELIN Lung 200 study, 792 patients who had stage IIIB or IV or recurrent NSCLC and disease progression after treatment with platinum-based chemotherapy were randomly assigned to receive avelumab every 2 weeks or docetaxel every 3 weeks. Among the 792 patients, 264 participants in the avelumab group and 265 participants in the docetaxel group had PD-L1 positive tumors. In patients with PD-L1 positive tumors, the difference in the median OS was statistically non-significant between the avelumab (11.4 months) and docetaxel (10.3 months) groups. However, patients in the avelumab group had shown a better safety profile. Treatment-related adverse events occurred in 251 of 393 avelumab-treated patients (64%), and 313 of 365 in docetaxel-treated patients (86%). Enrollment for this study is closed, but the trial is ongoing (45) (Table II).

Immune Checkpoint Inhibitor Combined Therapies

In theory, combining two different types of checkpoint inhibitors may create additive or synergistic effects by further enhancing the blockade of immune cells inhibition. Ongoing studies are being conducted to investigate the combination of PD-L1/PD-1 pathway and CTLA-4 pathway targeting agents as possible treatment for patients with NSCLC.

Durvalumab plus tremelimumab. One such therapy is the combination of durvalumab and tremelimumab. Like ipilimumab, tremelimumab is a CTLA-4 checkpoint inhibitor, but presently, tremelimumab is rarely being studied as a monotherapy agent for NSCLC. In a phase Ib trial, 102 patients with immunotherapy-naïve, confirmed locally/metastatic NSCLC were given durvalumab and tremelimumab in a doseescalating manner. It was determined that durvalumab 20 mg/kg plus tremelimumab 1 mg/kg every 4 weeks was the best combination for the expansion phase, based on safety and clinical activity (46).

In another recent phase II trial, 78 patients were randomly assigned to either receive durvalumab plus tremelimumab alone or in combination with low-dose or hypofractionated radiotherapy. The treatment-related serious adverse events occurred in only 4% of patients receiving durvalumab plus tremelimumab alone; however, these adverse events occurred in 19% of patients receiving additional low-dose radiotherapy and 15% in patients receiving hypofractionated radiotherapy. It was concluded that radiotherapy did not increase positive responses when combined with PD-L1 plus CTLA-4 inhibition in patients with NSCLC resistant to PD-1and PD-L1 therapy (47).

In the subsequent phase III ARCTIC study, patients with NSCLC with wildtype EGFR and ALK, who had received at least two systemic regimens (including one platinum-containing chemotherapy) were separated into two sub-study groups. In Sub-study A, patients with PD-L1 expression on at least 25% of tumor cells were randomly assigned to receive either durvalumab or chemotherapy (erlotinib, gemcitabine, or vinorelbine). The results for study A showed that the median OS was 11.7 (durvalumab) versus 6.8 (chemotherapy) months, and the median PFS was 3.8 (durvalumab) versus 2.2 (chemotherapy) months. In Sub-study B, patients with wildtype PD-L1 were randomly assigned to receive durvalumab + tremelimumab, or chemotherapy (erlotinib, gemcitabine, or vinorelbine). The results for study B showed that the median OS was 11.5 (durvalumab + tremelimumab) versus 8.7 (chemotherapy) months and the median PFS 3.5 (durvalumab + tremelimumab) versus 2.2 (chemotherapy) months. In this trial durvalumab alone and with a combination of tremelimumab was shown to be clinically successful in improving OS and PFS (48).

Nivolumab plus ipilimumab. Nivolumab plus ipilimumab is another combination that is currently being explored as possible first-line therapy for NSCLC. In a sub-cohort of the phase I CheckMate 012 study, 78 patients with NSCLC were randomly assigned to receive 1 mg/kg of nivolumab every two weeks + 1 mg/kg of ipilimumab every six weeks, 3 mg/kg of nivolumab every two weeks + 1 mg/kg of ipilimumab every twelve weeks, or 3 mg/kg of nivolumab every two weeks + 1 mg/kg of ipilimumab every six weeks, only data from the latter two groups were available in this trial. ORRs were 47% in the every-12-week cohort and 38% in the every-6-week cohort. The median PFS was longer in the every-12-week cohort (8.1 months) than in the every-6-week cohort (3.9 months). Like other immune checkpoint inhibitors, there was an increase in treatment benefits correlated with PD-L1 expression. ORR was 57% in patients with ≥1% tumor cells PD-L1 expression, and up to 92% in patients with ≥50% tumor cells PD-L1 expression. Another notable statistic is the difference in PFS between patients with nivolumab + ipilimumab combined therapy and nivolumab monotherapy in another cohort of the same trial. In patients with ≥1% PD-L1 expression, median PFS was longer with nivolumab + ipilimumab (8.1 months in the every-12 week cohort, 10.6 months in the every-6-week cohort) than that with nivolumab monotherapy (3.5 months) (49).

A current study is being conducted over 422 chemotherapy-naïve patients, randomly assigned in a 1 to 1 ratio to receive platinum containing chemotherapy and either pembrolizumab or nivolumab plus ipilimumab. The primary endpoint for this trial will be overall survival (OS), but the results will be examined for their association with therapeutic effects and adverse events. If this trial is successful, then nivolumab plus ipilimumab in combination with platinum-containing chemotherapy could be established as a more effective standard treatment for advanced NSCLC (50).

The combination of two immune checkpoint inhibitors as treatments for NSCLC has shown positive results thus far. Other combinations of immune checkpoint inhibitors may also be further studied as treatment for NSCLC in future trials (Table III).