Adjuvant Setting

The melanoma-associated antigen-A3 (MAGE-A3) protein, encoded by the MAGE-A3 gene, is a tumor-specific antigen not expressed in normal adult tissues except for testis and placenta, which do not present the antigen because of the lack of HLA molecules. The MAGE-A3 vaccine is composed of the MAGE-A3 protein plus an adjuvant. In a phase 2 trial, 182 patients with completely resected MAGE-A3-positive stage IB-II NSCLC were randomized (2:1) to receive MAGE-A3 in combination with the immunostimulant AS02B or placebo. The primary end point was disease-free interval. MAGE-A3 vaccine was administered intramuscularly at 0.5 mL with treatments every 3 weeks for five doses followed by every 3 months for eight doses. The study was conducted between 2002 and 2004, before adjuvant chemotherapy became the standard of care. After a median postresection time of 44 months, 35% of patients in the vaccine group and 43% of patients in the placebo group developed recurrence. There were no significant differences in disease-free interval (hazard ratio [HR], 0.75; 95% confidence interval [CI], 0.46–1.23; P = .2), disease-free survival (DFS; HR, 0.76; 95% CI, 0.48–1.21; P = .248), or overall survival (OS; HR, 0.81; 95% CI, 0.47–1.40; P = .454) between the two arms. Nevertheless, the trend toward positive DFS in the vaccine group and the development of the more potent immunostimulant AS15, led to the initiation of the randomized phase III MAGRIT trial, which screened 13,849 patients with completely resected NSCLC stage IB-III for MAGE-A3. Among the 12,820 patients who had a valid sample, 4210 (33%) had MAGE-A3 positive tumors and 2312 met the eligibility criteria for the study. Patients were randomized 2:1 to the vaccine in combination with the immunostimulant AS15 or placebo. The primary objective was DFS. The vaccine schedule was identical to the phase 2 trial, with 13 doses over a period of 27 months. In the overall population, the median DFS for the vaccine and control groups were 60.5 months and 57.9 months, respectively (HR, 1.02; 95% CI, 0.89–1.18; P = .74). In a subset analysis according to use of adjuvant chemotherapy, MAGE-A3 vaccine was not associated with median DFS improvement in patients who received chemotherapy (HR, 1.10; 95% CI, 0.90–1.34; P = .36) or not (HR, 0.97; 95% CI, 0.80–1.18; P = .76). Based on the MAGRIT results, the development of MAGE-A3 vaccine for NSCLC has been stopped.

Maintenance Therapy

Tecemotide (liposomal BLP-25) is a peptide vaccine targeting MUC1, which is overexpressed and aberrantly glycosylated in NSCLC, making it a target for immunotherapy. In a phase IIB study, 171 patients with advanced NSCLC without disease progression after first-line treatment were randomized to tecemotide plus best supportive care or best supportive care alone. Tecemotide was preceded by one dose of cyclophosphamide, 300 mg/m ² , 3 days before the vaccine. Although the median OS was higher in the vaccine group, it did not reach statistical significance (17.4 vs 13.0 months; HR, 0.745; 95% CI, 0.533–1.042). Nevertheless, when stratified by stage, tecemotide was associated with improved median OS in patients with stage III (median OS not reached vs 13.3 months; HR, 0.52; 95% CI, 0.26–1.05; P = .06) but not for stage IV (15.1 months vs 12.9 months; HR, 0.90; 95% CI, 0.58–0.141; P = .6). To further investigate the role of tecemotide in patients with stage III NSCLC, the larger phase 3 START trial was conducted. A total of 1513 patients were randomly assigned (2:1) to receive tecemotide or placebo, with 1239 patients included in the final analysis. For the total population, tecemotide did not significantly improve OS compared with placebo (median OS, 25.6 months vs 22.3 months; HR, 0.88; 95% CI, 0.75–1.03; P = .123). However, for the 806 patients who previously received concurrent chemoradiotherapy, tecemotide was associated with an increased median OS compared with placebo (30.8 months vs 20.6 months; HR, 0.78; 95% CI, 0.64–0.95; P = .016). However, the subsequent trial START2, which randomized patients to tecemotide or placebo after concurrent chemoradiotherapy, was terminated in September 2014 following the results from the INSPIRE study conducted in Japan, which had a similar design and showed no benefit from tecemotide following chemoradiotherapy in patients with stage III NSCLC.

Belagenpumatucel-L (Lucanix) is a tumor vaccine consisting of four allogeneic NSCLC cell lines modified with transforming growth factor-β ₂ -antisense plasmid. In a phase III trial, 532 patients with stage III or IV NSCLC without progression after platinum-based chemotherapy were randomly assigned to maintenance belagenpumatucel-L or placebo. The vaccine was well tolerated with injection site reactions and fatigue being the most common adverse events. Nevertheless, it was not associated with a significant improvement in the median progression-free survival (PFS; 4.3 months vs 4.0 months; HR, 0.99; 95% CI, 0.82–1.20; P = .947) or median OS (20.3 months vs 17.8 months; HR, 0.94; 95% CI, 0.73–1.20; P = .594).

Racotumomab-alum is a tumor vaccine targeting the NeuGGM3 tumor-associated ganglioside. In a phase 2 study, 176 patients with advanced NSCLC who received front-line chemotherapy and achieved at least stable disease (SD) were randomly assigned to racotumomab-alum or placebo. Patients in the racotumomab-alum group had better median PFS (5.3 months vs 3.9 months; HR, 0.73; 95% CI, 0.53–0.99; P = .039) and OS (8.2 months vs 6.8 months; HR, 0.63; 95% CI, 0.46–0.87; P = .004) compared with placebo.

Vx-001 is an HLA-A*0201-restricted vaccine targeting the human telomerase reverse transcriptase tumor antigen. In a phase 2 study, 46 HLA-A*0201-positive patients with advanced NSCLC and residual or progressive disease after first-line treatment were treated with six doses of Vx-001. The overall response rate (ORR) and SD rate were 7% and 28%, respectively, with median PFS of 3.8 months and median OS of 19 months. Patients who mounted immune responses (defined as the number of interferon-γ-spots-forming-cells from blood mononuclear cells significantly increased after vaccination compared with the background) had a significantly prolonged median OS compared with those who did not (40.0 months vs 9.2 months; P = .02). Vaccination was well tolerated. Common adverse events were mild and included injection-site reaction, anemia, fatigue, and nausea.

First-line Therapy

TG4010 is a vaccine composed of the modified vaccinia virus Ankara containing the sequence for interleukin 2 and MUC-1, which is a tumor-specific antigen overexpressed in many epithelial tumors including lung cancer. The TIME is a phase 2b/3 trial examining the addition of TG4010 immunotherapy to chemotherapy in patients with previously untreated advanced NSCLC and MUC1 expression in greater than or equal to 50% of the TCs. In the phase 2b part, 222 patients were randomly assigned to receive TG4010 versus placebo in addition to chemotherapy with a platinum-based doublet. The primary end point was PFS. For the total population, the median PFS for the TG4010 and the placebo arms were 5.9 months and 5.1 months, respectively (HR, 0.74; 95% CI, 0.55–0.98; P = .019). The median OS, however, despite numerically superior in patients treated with TG4010, did not reach statistical significance (12.7 months vs 10.6 months; HR, 0.78; 95% CI, 0.57–1.06; P = .055). The most common adverse event with TG4010 was grade 1 or 2 injection-site reactions. There were no grade 3 or 4 adverse events associated with TG4010 only. The phase 3 part of the TIME study is ongoing.

Previously Treated Patients

A phase 2 study evaluated a tumor vaccine composed of a granulocyte-macrophage colony-stimulating factor–producing and CD40L-expressing bystander cell line and allogeneic TCs. Twenty-four patients were enrolled with a median of four previous lines of systemic treatment. No objective responses were observed. Median PFS and OS were 1.7 and 7.9 months, respectively. Common adverse events included headache and injection site reaction.

GVAX is a tumor vaccine consisting of autologous TCs mixed with an allogeneic cell line secreting granulocyte-macrophage colony-stimulating factor. In a phase 1/2 trial, 86 patients with advanced NSCLC had tumor harvested for vaccine preparation, and 49 patients eventually received the vaccine treatment. A total of 76% of patients had received at least one line of chemotherapy before the vaccination. No objective responses were observed but SD for greater than or equal to 12 weeks was observed in 14% of patients. Median PFS and OS were 4.4 and 7.0 months, respectively. The most common adverse events were injection site reactions, fatigue, dyspnea, nausea, and fever.

Early Phase Clinical Studies with Immune Checkpoint Inhibitors

Nivolumab is a fully humanized IgG4 antibody against PD-1. In a small phase 1 study, 39 patients with advanced refractory solid tumors were treated with nivolumab, which was well tolerated with no maximum tolerated dose reached. There were six patients with NSCLC among the total of 39 patients. Nivolumab was well tolerated at all dose levels. One out of six patients with NSCLC had a mixed response. In a larger phase 1 trial, the CheckMate 003, a total of 296 patients with melanoma, NSCLC, prostate cancer, renal cancer, or colorectal cancer were treated with nivolumab at the doses of 1, 3, or 10 mg/kg every 2 weeks for up to 96 weeks. The updated report included 129 patients with previously treated NSCLC, of which 54% had received three or more prior systemic therapy regimens. The treatment was well tolerated, with the maximum tolerated dose not reached at the highest planned dose of 10 mg/kg. The most common adverse events were fatigue (24%), decreased appetite (12%), and diarrhea (10%). Four patients (3%) developed grade 3 or higher treatment-related pneumonitis resulting in three deaths. The ORR for the dose levels of 1, 3, 10 mg/kg were 3.0%, 24.3%, and 20.3%, respectively. The median PFS for all patients was 2.3 months. The 3-year OS survivals for the cohorts of 1, 3, and 10 mg/kg were 15%, 27%, and 14%, respectively. There were no significant differences in ORR, PFS, or OS according to histology subtypes. The dose of 3 mg/kg every 2 weeks was selected for phase 3 studies.

Pembrolizumab is a fully humanized IgG4 antibody against PD-1. The Keynote 001 trial was a phase 1 study examining the safety profile of pembrolizumab in advanced NSCLC. A total of 495 patients receiving pembrolizumab were assigned to a training or validation groups. Pembrolizumab was given at 2 mg/kg or 10 mg/kg every 3 weeks, or 10 mg/kg every 2 weeks. Fatigue, pruritus, and decreased appetite were the most common side effects. Severe pneumonitis occurred in 1.8% of patients, including one death. The ORR for all patients, previously untreated, and previously treated patients was 19.4%, 24.8%, and 18.0%, respectively, without differences according to dose, regimen, or histology. The median PFS for all patients, treatment-naive and previously treated, was 3.7 months, 6.0 months, and 3.0 months, respectively. The median OS for all patients, previously untreated, and previously treated patients was 12.0, 16.2, and 9.3 months, respectively. Using a training group of 182 patients, a proportion score (PS), defined as the percentage of TCs positive for membranous PD-L1 expression of at least 50%, was selected as the cutoff level and subsequently tested in the validation group. In patients with a PS of greater than or equal to 50%, the ORR for all patients, those previously treated, and those who were treatment-naive were 45.2%, 43.9%, and 50.0%, respectively. In this group, the median PFS for all patients, previously treated, and previously untreated patients was 6.3, 6.1, and 12.5 months, respectively, with median OS not reached in any of the groups. The median PFS and OS in patients with a PS of greater than or equal to 50% were longer compared with those with a PS of 1% to 49% or less than 1%.

Atezolizumab (MPDL3280A) is a fully humanized monoclonal antibody against PD-L1. In a phase 1 study, 277 patients with advanced cancer were treated with atezolizumab given intravenously every 3 weeks. In patients with NSCLC, the ORR and 24-week PFS were 21% and 45%, respectively. The response to atezolizumab was associated with PD-L1 expressions on tumor-infiltrating ICs ( P = .015) but not on the TCs ( P = .920). Treatment was well tolerated up to the maximum dose of 20 mg/kg. The most common toxicities included fatigue (24.2%), decreased appetite (11.9%), nausea (11.6%), and pyrexia (11.6%). Severe adverse events occurred in 12.6% of patients, with fatigue being the most frequent (1.8%). One percent of patients had immune-associated severe adverse events.

Randomized Clinical Trials with Immune Checkpoint Inhibitors

The encouraging results from the early studies led to further examination of these checkpoint inhibitors in comparison with the standard of care chemotherapy docetaxel in randomized controlled trials ( Table 2 ).

Table 2

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