The treatment decisions for NSCLC are primarily dependent on the patient's performance status, extent of disease, and histological subtype. Significant developments in the area of targeted therapies have changed the treatment paradigm for NSCLC.
Despite recent developments in targeted therapies, the overall survival for metastatic NSCLC remains poor. The need for novel therapeutic options has led to the development of various new immunotherapeutic agents including anti-PD-1 and anti-PD-L1 antibodies, which appear to have a promising role in the treatment of the disease. Additionally, other immunotherapy options including CTLA-4 inhibitors and various vaccines are also currently being investigated as potential treatment options.
Lung cancer continues to be the leading cause of cancer related deaths worldwide. Approximately 80% of lung cancers are diagnosed as non-small cell lung cancer (NSCLC), which is further classified into three main histologies: adenocarcinoma, squamous cell carcinoma, and large cell carcinoma. The treatment decisions for NSCLC are primarily dependent on the patient’s performance status, extent of disease, and histological subtype. Significant developments in the area of targeted therapies have changed the treatment paradigm for NSCLC. New drugs targeting EGFR, EML4-ALK, and ROS-1 mutations have provided considerable benefit and new therapeutic options for patients. Despite these advancements, the overall survival (OS) in patients with metastatic disease continues to be poor, and the majority of NSCLC patients are not candidates for these therapies.
There is significant need for novel and alternative therapeutic agents. With this in mind, various immunotherapeutic options have recently garnered significant attention and appear to hold a promising role in the treatment of NSCLC.
The importance of an intact immune system in controlling the growth of cancer cells has been recognized since the beginning of the 20th century.1 Various studies have highlighted the role of the immune system in surveillance for elimination of preclinical cancers and the role of tumor-infiltrating lymphocytes as a prognostic tool.2-4
Immunotherapy has had limited success in the treatment of solid tumors except in the treatment of melanoma and renal cell cancers.5-8 This limitation has been thought to be the result of many factors including secretion of immunosuppressive cytokines and loss of major histocompatibility complex antigen expression.9-11 Recent improvements in our understanding of the functioning of the immune system and its relation to tumor evasion have led to the development of novel agents that have promising results in the treatment of NSCLC. These agents include immune checkpoint inhibitors such as anti-PD-1 antibody, anti-PD-L1 antibody, and CTLA-4 inhibitors, as well as vaccines. This review will discuss these therapeutic options and the emerging data to support their role in the management of patients with lung cancer.
Tumors have various mechanisms by which they evade destruction by the immune system. One of these mechanisms is via the immune checkpoint pathway, which plays a key role in regulating T-cell responses. Under normal circumstances, the immune checkpoints are important in maintenance of self-tolerance by preventing autoimmunity and protecting the tissue from damage when the immune system is activated.12 The expression of immune-checkpoint proteins can be manipulated by the tumor cells to develop resistance mechanisms. The two major inhibitory pathways involve the PD-1/ PD-L1 pathway and the CTLA-4 pathway.
Programmed cell death-1(PD-1) is one of the pathways that inhibits tumor-specific T cells. PD-1 is a member of the B7-CD28 superfamily, and is a cell surface receptor with two known ligands: PD-L1(B7-H1) and PD-L2(B7-DC).13 It is an inhibitory receptor, and mediates immunosuppression.14 PD-1 is expressed on activated CD4+ and CD8+ T cells, natural killer T cells, B cells, activated monocytes, and activated dendritic cells.13,15,16
Binding of the PD-1 receptor with its PD-L1 ligand causes T-cell inhibition and downregulation of T-cell response.17 PD-1 overexpression has been observed in patients with NSCLC,18 and an increase in PD-L1 positive tumor cells have been noted in tumor tissue as compared to normal lung parenchyma.19
Blocking the binding of PD-1 to its PD-L1 ligand can potentially restore the function of chronically exhausted tumor-specific T cells and augment the T-cell response.20
A phase I dose-escalation trial of a fully human IgG4-blocking monoclonal antibody against PD-1, nivolumab, administered once every 2 weeks, evaluated its efficacy in patients with previously treated solid tumors including NSCLC.14 Patients with melanoma, NSCLC, renal cell cancer, castrationresistant prostate cancer, or colorectal cancer were enrolled.
Patients with advanced NSCLC who had been previously treated with a platinum-containing regimen were eligible but could not have received more than five prior lines of therapy. Patients with NSCLC were included in the dose-escalation portion of the trial, and were also randomly assigned to receive dosages of 1, 3, or 10 mg/kg. Both squamous and nonsquamous subtypes of NSCLC were included. A maximum tolerated dose (MTD) of the drug was not reached.
A total of 296 patients were enrolled in the study, 122 of whom had NSCLC. Seventy-six (76/122) of the patients were assessable for response. Of the 76 patients, 14 had objective responses per RECIST 1.0. Responses were observed at dosages of 1, 3, and 10 mg/kg with response rates of 6%, 32%, and 18% respectively. Disease response was seen in both squamous and nonsquamous cell histology. Six of 18 (33%) patients with squamous cell histology had a response, whereas 7 of 56 (12%) patients with nonsquamous histology had a response. PD-L1 tumor expression appeared to correlate with a better response to the drug: patients without PD-L1 tumor expression had no response, but 36% of patients with tumor PD-L1 expression had an objective response. Responses were durable with 20 of 31 responses lasting 1 year or more.
The PD-1 antibody appeared to have a favorable side effect profile. The most common adverse events (AE) were fatigue, decreased appetite, diarrhea, nausea, cough, dyspnea, constipation, vomiting, rash, pyrexia, and headache. Grade 3 and 4 treatment-related AEs were observed in 14% of patients.
The most common grade 3 and 4 treatment-related AEs in patients with NSCLC were fatigue, elevated AST, and pneumonitis. Four patients with NSCLC experienced grade 1 or 2 pneumonitis, and 2 patients died of pneumonitis. Early grade pneumonitis was controlled by stopping treatment and/or administering corticosteroids. Ongoing phase II trials with nivolumab are currently under way in NSCLC using the 3 mg/kg dosing.
MK-3475, a humanized monoclonal IgG4 antibody against PD-1, has also demonstrated promising results.21 A presentation at the 15th World Conference on Lung Cancer, held in October 2013, discussed the activity of MK-3475 in NSCLC. The drug was administered at 10 mg/kg every 3 weeks to patients with NSCLC previously treated with 2 systemic regimens.
Thirty-eight patients were enrolled. The most common AEs were fatigue (16%), rash (16%), and pruritus (16%). The incidence of diarrhea was 13%. The overall response rate (ORR) by immune related criteria22 was 24%, whereas the ORR per RECIST was 21%. Ongoing phase II trials will evaluate the efficacy of both the 2 mg/kg and 10 mg/kg dose in patients with NSCLC.
The additional phase II and III studies will help define the role of these promising agents in the treatment of NSCLC.
In a similar manner to the anti-PD-1 antibody, the anti-PD-L1 monoclonal antibody blocks the interaction between the PD-1 receptor and its PD-L1 ligand. In a phase I trial, BMS-936559, a high-affinity, fully human PD-L1-specific, IgG4 monoclonal antibody was administered once every 2 weeks to patients with various solid tumors.23 Patients were required to have documented advanced NSCLC, colorectal cancer, pancreatic cancer, gastric cancer, or breast cancer, and to have progressed after at least one prior line of therapy. A total of 207 patients were enrolled in the study, 75 of whom had NSCLC. Patients with NSCLC were included in the dose escalation phase of the trial and were treated with a 0.3, 1, 3, and 10 mg/kg dose. Of the 75 patients with NSCLC, 49 were evaluable for disease activity. A MTD was not reached. There were 5 objective responses seen: 1 of 13 patients with squamous cell (response rate [RR] of 8%), and 4 of 36 with nonsquamous histology (RR of 11%). An additional 6 patients (12%) had stable disease at 6 months.
All dose levels were well tolerated, and the most common treatment-related AEs were fatigue, infusion reactions, arthralgia, rash, nausea, pruritus, headache, and diarrhea. Grade 3 or 4 AEs were noted in 19 of 207 patients (9%). Potential immune-related AEs were observed in 81 of 207 patients (39%) and included rash, hypothyroidism, hepatitis, and single cases of sarcoidosis, endophthalmitis, diabetes mellitus, and myasthenia gravis. Side effects were generally managed with treatment discontinuation and/or use of glucocorticoids with symptomatic relief.
Other anti-PD-L1 antibodies such as MPDL3280A are also showing promising activity in NSCLC.24 At the American Society of Clinical Oncology (ASCO) 2013 Annual Meeting, Spigel et al reported an ORR of 24% in patients with NSCLC treated with MPDL3280A.24 The drug was administered every 3 weeks to patients with both squamous and nonsquamous histology at dosages of 1, 15, or 20 mg/kg. Several cases of rapid tumor shrinkage were observed, as well as a few cases of delayed response after an initial presumed radiographic progression. There appeared to be a correlation between PD-L1 protein expression and drug efficacy: patients who were PD-L1 tumor status-positive showed an ORR of 100% (4/4), whereas patients who were PD-L1 tumor status negative showed an ORR of 15% (4/26). The drug was well tolerated with an incidence of 34% of grade 3 or 4 AEs including pericardial effusion (6%), dehydration (4%), dyspnea (4%), and fatigue (4%).
No grade 3-5 pneumonitis or diarrhea was observed. Final analysis of the data is still pending, but preliminary data are indicating promising activity of this agent in the treatment of NSCLC. This agent is currently being evaluated at 1200 mg IV every 3 weeks in various phase II studies. These ongoing phase II and III clinical trials should elucidate the role of anti-PD-L1 antibody in the NSCLC treatment armamentarium.
The CTLA-4 pathway is another inhibitory pathway involved in immune checkpoint inhibition. It is important in early T-cell activation.25,26 Blocking the inhibitory signal from CTLA- 4 potentiates T-cell activation, proliferation, and infiltration into tumors.27 Ipilimumab, a fully human monoclonal antibody, specifically blocks the binding of CTLA-4 to its ligands (CD80/CD86). This drug has shown significant improvement in OS in patients with previously treated and untreated metastatic melanoma,8,28 and has received US Food and Drug Administration(FDA) approval for its use.
Ipilimumab’s potential role in NSCLC was studied in a randomized, double-blind phase II trial in patients with stage IIIB/IV NSCLC.29 Patients were randomized 1:1:1 to receive carboplatin and paclitaxel with ipilimumab at 10 mg/kg or placebo in different combinations. In order to assess the best order of therapy, 2 dosing schedules were used: Ipilimumab concurrently with carboplatin and placlitaxel for 4 doses followed by placebo, or phased sequence dosing, with 2 doses of placebo followed by 4 doses of ipilimumab. After 6 cycles of the combination, patients received either placebo or ipilimumab every 12 weeks for maintenance therapy. Patient received maintenance therapy until evidence of disease progression. Tumor response was assessed via modified World Health Organization (mWHO) criteria and an immune-related response criteria (irRC) to account for immune-related changes on scans.
Two hundred and four patients with chemotherapy naïve NSCLC were randomized, and 203 were treated. Results showed improvement in the immune related-progression free survival (PFS) in the phased schedule (hazard ratio [HR], 0.72; P = .05) with median immune-related (ir)-PFS of 5.7 months. The concurrent ipilimumab regimen did not improve ir-PFS with a hazard ratio of 0.81 (P = .13) with median ir- PFS of 5.5 months. The results using the mWHO criteria were similar: there was a benefit seen with the phased ipilimumab (HR, 0.69; P = .02) but not for concurrent ipilimumab (HR, 0.88; P = .25). The median mWHO-PFS was 5.1 months for the phased ipilimumab group and 4.1 months for the concurrent ipilimumab group.
The median OS was 12.2 months for the phased schedule, 9.7 months for the concurrent schedule, and 8.3 months for the chemotherapy only group. Additional analysis indicated a greater benefit to patients with squamous cell histology (HR, 0.55) than in patients with nonsquamous histology (HR, 0.81) in the group who received the phased schedule only, indicating possible benefit of immunotherapy in this histology.
The overall incidence of grade 3 and 4 AEs was 20% for the concurrent ipilimumab arm, 15% for the phased ipilimumab arm, and 6% for the control (chemotherapy only) arm.
Fatigue, alopecia, nausea, vomiting, and peripheral neuropathy were seen in all groups. Rash, pruritus, and diarrhea had a higher incidence in patients receiving ipilimumab. Grade 3 rash and diarrhea were the most common significant grade 3 or 4 immune-related toxicities observed. One death was attributed to septic shock from epidermal necrolysis.
Data are pointing to ipilimumab as an additional potential immunotherapeutic agent that may have efficacy in NSCLC. The potential benefit of this drug in squamous cell histology has led to additional trials that are currently ongoing to help define the importance of histology in helping to select immunotherapeutic agents in the treatment of NSCLC. Additionally, data from melanoma are pointing toward synergistic activity between ipilimumab and other immunotherapy agents.30
These results have led to the development of current clinical trials looking at the combination of CTLA-4 inhibitors with anti-PD-1 or PD-L1 antibodies as having a potential role in the treatment of NSCLC.
An alternative approach to immunotherapy in the treatment of NSCLC is the use of vaccines to help modulate the immune system to attack tumor cells. Cancer vaccines typically incorporate a source of tumor antigen combined with a type of “adjuvant,” components that potentiate immune response to an antigen and/or modulate it toward the desired immune response.11,31
Tumor-associated antigens include whole autologous or allogeneic tumor cells, lysates of tumor cells, defined proteins, specific peptide epitopes, or mRNA/DNA encoding for relevant antigens.31
The two types of vaccines being studied in NSCLC are antigen- based vaccines and tumor cell vaccines. Antigen-based vaccines expose the host’s immune system to a specific antigen expressed on the tumor cell. Alternatively, the tumor cell vaccines are made from either autologous or allogeneic tumor cells and have the advantage of exposing the host’s immune system to a greater variety of tumor antigens. There have been a number of trials using these various approaches with a few showing potential benefit.
Melanoma-associated antigen-A3 (MAGE-A3)
The MAGE-A3 protein is normally expressed only on cancer cells and not normal cells. However, it may be expressed in testicular germ cells and placental trophoblasts. It is typically expressed in 30% to 50% of lung cancers depending on the stage and histologic subtype, and it may be associated with a poor prognosis.32 A recently published phase II trial evaluated the possible role of the vaccine in patients with MAGEA3 positive stage IB or II NSCLC.33 Patients were randomly assigned to adjuvant MAGE-A3 or placebo in 2:1 randomization with 5 administrations at 3 week intervals followed by 8 administrations every 3 months. The primary endpoint of the study was disease-free interval. One hundred eighty two patients were randomized to placebo (n = 60) or the vaccine (n = 122). Grade 3 and 4 AEs were recorded in 14% of patients receiving MAGE-A3 and in 13% of patients receiving placebo. Only 3 AEs were considered to be related to the MAGE-A3 vaccine: administration site reaction, exacerbation of chronic obstructive pulmonary disease, and pain in the leg where the injection was given. At a median follow-up of 44 months, the tumor recurrence rate was 35% in the cohort who received the vaccine versus 43% in the placebo-treated group.33 Disease free interval, disease-free survival, and OS were not significantly different between the two groups.
The MAGE-A3 as Adjuvant Non-Small-Cell Lung Cancer Immunotherapy (MAGRIT) trial is designed to test the benefits of MAGE-A3 in patients with resected stage IB through IIIA MAGE-A3 positive NSCLC after administration of adjuvant chemotherapy. The study has completed accrual, but outcome data are still pending.
BLP25 Liposome vaccine
Mucin-1 (MUC-1) is a highly glycosylated type 1 transmembrane protein with a molecular weight of 200 kD that is expressed on the cell surface of various cancers including breast, lung, pancreatic, ovarian, gastric, and colon cancers.34 MUC-1 has been shown to be involved in cell-cell interactions between malignant and endothelial cells, and thus has been targeted to prevent metastatic spread of tumor cells along with providing antitumor activity.35 MUC-1 is also associated with oncogenesis and resistance to chemotherapy,36 and it is overexpressed in about 60% of patients with lung cancer.35 Liposomal BLP25 (L-BLP25) is a peptide-based vaccine targeting the exposed core peptide of MUC-1. It is comprised of BLP25 lipopeptide, immunoadjuvant monophosphoryl lipid A, and three lipids (cholesterol, dimyristoyl phosphatidylglycerol, and dipalmitoyl phosphatidylcholine) to form a liposomal product.37 A phase IIB, open-label, randomized trial evaluated L-BLP25 in patients with stage IIIB or IV NSCLC who had responded to or were stable after first-line chemotherapy.37 The primary objectives were safety and OS.
One hundred seventy one patients were randomly assigned to best supportive care according to provider’s discretion (n = 83) or vaccine with cyclophosphamide (n = 88). One dose of cyclophosphamide was given 3 days prior to the vaccine administration. Eight weekly vaccines were delivered subcutaneously followed by maintenance injections once every 6 weeks until disease progression. The updated results38 showed the median OS for patients in the L-BLP25 arm was 17.2 months versus 13 months for patients in the best supportive care arm with an HR of 0.745 (95% CI, 0.533-1.0420).
The survival rate of patients who received the vaccine was 31% at 3 years as compared with 17% to those who received best supportive care. The OS and 3 year survival appeared to favor patients with stage IIIB loco-regional disease with median survival of 30.6 months versus 13.3 months, respectively (HR, 0.548, 95% CI 0.301-0.999). Three year survival was 49% in patients receiving L-BLP25 plus best supportive care and 27% in those receiving best supportive care in this subgroup (P = .070). No significant toxicities were reported. The results of the phase III START: Stimulating Targeted Antigenic Responses to NSCLC Trial were presented at the 2013 ASCO Annual Meeting.39 One thousand five hundred thirteen patients with unresectable stage III NSCLC who did not progress after treatment with chemotherapy and radiation were randomized 2:1 to L-BLP25 or placebo. Sixty five percent of the patients had concurrent chemoradiation, whereas 35% had sequential chemotherapy and radiation. Median OS was 25.6 months with L-BLP25 versus 22.3 months with placebo. Although the trial failed to meet its primary endpoint of OS, the results were encouraging in patients receiving initial concurrent chemoradiotherapy. Patients with concurrent chemoradiotherapy(n = 806) had a median OS of 30.8 months (L-BLP25) versus 20.6 months with placebo, while the median OS with sequential chemoradiotherapy was 19.4 months with L-BLP25 versus 24.6 months with placebo.
The START2 trial is a phase III, multicenter, randomized, double-blind, placebo controlled clinical trial that will assess the efficacy, safety, and tolerability of L-BLP25 in patients with unresectable, locally advanced (stage IIIA or IIIB) NSCLC who have had a response or stable disease after at least 2 cycles of platinum-based concurrent chemoradiotherapy.
Recombinant human epidermal growth factor
Epidermal growth factor receptor (EGFR) is expressed in approximately 40% to 80% of patients with NSCLC.11,40 The recombinant human epidermal growth factor (rHU-EGF) vaccine uses recombinant EGF fused to a carrier protein P64K with an adjuvant.
A randomized, phase II trial in patients with stage IIIB or IV NSCLC evaluated the efficacy of an EGFR vaccine with primary endpoint being OS.41 Eighty patients with stage IIIB or IV NSCLC were randomly assigned 1:1 to receive the EGF vaccine or supportive care. All patients had finished first-line chemotherapy regimens at least 4 weeks prior to enrollment. Cyclophosphamide was given 3 days prior to the first dose of the vaccine. The vaccine was then administered intramuscularly weekly for 4 doses followed by monthly injections until disease progression. The mean survival of the vaccinated group was 12.73 months (median 6.47 months), whereas the mean survival of the control arm was 8.52 months (median 5.33 months).
There was a trend toward a survival advantage for the vaccine group that was not significant with the sample size being taken into consideration. Age appeared to make a difference: vaccinated patients under the age of 60 years survived longer than controls (mean 18.53 months; median 11.57 months vs mean, 7.55 months, median 5.33 months). A median OS of 11.7 months was seen in patients who developed an antibody response to the vaccine compared with an OS of 3.6 months in patients with a poor antibody response. Treatment was well tolerated with no grade 3 or 4 AEs observed. As with other the other vaccines, an ongoing phase III trial is further evaluating the role of anti-EGFR vaccine as a therapeutic option in NSCLC.
Tumor Cell Vaccines
Belagenpumatucel-L (Lucanix) is a nonviral, gene-modified allogeneic vaccine with potential immunostimulatory and antineoplastic activities. It is made with 4 irradiated NSCLC cell lines (H460, H520, SKLU-1, and RH2) modified with transforming growth factor β2(TGF-β2) antisense plasmid.42 Increased TGF-β levels have been associated with a poor prognosis in NSCLC.43,44 By using the TGF-β2 antisense plasmid as part of the vaccine, TGF-β2 expression is downregulated and the immune response is heightened.42,11
A phase II trial evaluated the efficacy of belagenpumatcel- L in 75 patients with NSCLC with stage II-IV disease.42 Patients were randomly assigned to 3 different dosages of the vaccine given once a month or every other month for a maximum of 16 doses. The response rate of the vaccine was 15%. The median OS for all patients was 441 days. For patients with advanced-stage disease (61 patients with stage IIIB to IV disease), the high-dose cohorts had improved OS of 581 days versus the low-dose cohort which had a median OS of 252 days (P = .0186). The vaccine was well tolerated with 1 patient developing grade 3 arm swelling at the injection site, and another patient developing chronic myelocytic leukemia possibly related to the vaccine treatment.
Belagenpumatucel-L is now being studied in a phase III trial in patients with stage IIIA, IIIB, and IV NSCLC whose disease is stable or responding to first-line platinum-based chemotherapy or concomitant radiation. The primary endpoint will be OS.
With the advent of new immunotherapeutic agents, new options are available to patients with NSCLC. Even though these agents are still under investigation, they appear to have promising results. The optimal timing, possible combination of various therapies, and potential synergistic activity with chemotherapy is yet to be determined. Multiple clinical trials in various stages of development are studying these immunotherapy options in NSCLC (Table). These immunotherapy agents open up new avenues for treatment, and may provide long term benefits to patients with NSCLC.
CTLA-4 and PD-1
CTLA-4 and PD-L1
ABOUT THE AUTHORS
Affiliation: Ani Balmanoukian, MD, is associate director of Thoracic Oncology and Therapeutics, and Omid Hamid, MD, is chief of Translational Research and Immunotherapy at The Angeles Clinic and Research Institute in Los Angeles, CA.
Disclosure: Dr. Balmanoukian reports no conflicts of interest to disclose. Dr. Hamid has served as a consultant or on a paid advisory board for Merck & Co., Inc., Genentech, Inc., and Bristol-Myers Squibb, has received lecture fees from Genentech, Inc., and Bristol- Myers Squibb, and has received research support for clinical trials in this subject matter from The Angeles Clinic and Research Institute.
Address correspondence to: Ani Balmanoukian MD, The Angeles Clinic and Research Institute, 11818 Wilshire Blvd Suite 200, Los Angeles, CA 90024; phone: (310)231-2102; email: abalmanoukian@ theangelesclinic.org.