Vaccines for the Treatment of Non–Small Cell Lung Cancer (NSCLC)

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Although vaccines are not yet a standard procedure in the therapeutic management of patients with NSCLC, they may play an important role in the future

Therapeutic cancer vaccines are classified as either whole-cell vaccines (such as the belagenpumatucel-L vaccine, developed from 4 different NSCLC cell lines) or vaccines that target specific antigens (such as the mucin-1 protein that is targeted by the tecemotide and TG4010 vaccines).^1-3 A number of lung cancer vaccine candidates have been evaluated in clinical studies (Table 1).



Several of these vaccines have demonstrated prolonged survival time in phase 2 and 3 studies; however, some of the trials were terminated without reaching their primary end point, and many studies involving cancer vaccination with defined tumor antigens have shown that this strategy works only in a subset of patients (Table 2).⁴



Melanoma-Associated Antigen-A3 (MAGE-A3)

The MAGE-A3 protein is normally expressed only on cancer cells and not on normal cells (except in germline and placental cells); it is expressed in approximately one-third of tumors in patients diagnosed with stage IB/IIIA disease, and it may be associated with a poor prognosis.^5,6

Results from a double-blind, randomized, placebo-controlled phase 2 study in 182 patients with completely resected MAGE-A3–positive stage IB to II NSCLC showed that at a median follow-up of 44 months, the tumor recurrence rate was 35% in the group of patients treated with the vaccine versus 43% in the group that received placebo.⁷ Disease-free interval (the primary end point of the study), disease-free survival (DFS), and overall survival (OS) were not significantly different between the groups. However, based on the favorable recurrence rate seen in this study, a phase 3 study (MAGRIT) was initiated 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 first coprimary end point of the study was DFS versus placebo in the overall MAGE-A3–positive population, the second coprimary end point was DFS versus placebo in the subset of MAGE-A3–positive patients who did not receive chemotherapy, and the third coprimary end point was DFS in a gene signature–positive subpopulation, which was designed to identify a subset of MAGE-A3–positive patients who may benefit from the treatment.

Results from the MAGRIT study did not meet either its first or second coprimary end point. In April 2014, the MAGRIT study was terminated after establishing that it will not be possible to identify a subpopulation of gene signature–positive patients with NSCLC who may benefit from the treatment (third coprimary end point) due to an insufficient treatment effect.⁸

PRAME

A randomized, double-blind, placebo-controlled phase 2 study (PEARL; NCT01853878) is under way to evaluate the effect of PRAME (PReferentially Expressed Antigen of MElanoma) immunotherapy in patients with NSCLC after resection of their tumor. The primary end point of this study is DFS approximately 60 months after randomization. Secondary end points include OS approximately 60 months after randomization and DFS at 2, 3, 4, and 5 years after randomization. The estimated study completion date is September 2016.

Tecemotide (L-BLP25)

Tecemotide is a peptide vaccine that targets the mucin-1 protein (MUC1), a cell membrane glycoprotein that is overexpressed and abnormally glycosylated in NSCLC and other cancers.^9,10 MUC1 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.¹¹ MUC1 is also associated with oncogenesis and resistance to chemotherapy,¹² and it is overexpressed in about 60% of patients with lung cancer.¹¹

An international, randomized, double-blind, placebo-controlled phase 3 study (START; NCT00409188) was conducted to determine whether the tecemotide vaccine improves survival in patients with stage III unresectable NSCLC when given as maintenance therapy after chemoradiation.^13,14 A total of 1513 patients were randomly assigned (1006 to tecemotide and 507 to placebo); however, 274 patients were excluded from the primary analysis population as a result of a clinical hold, resulting in a modified intention-to-treat population consisting of 829 patients in the tecemotide group and 410 in the placebo group. The primary end point of the START study was OS.

Among the patients in the modified intention-to-treat population, median OS was 25.6 months (95% CI, 22.5-29.2) in the group treated with tecemotide versus 22.3 months (95% CI, 19.6-25.5) in the group that received placebo (adjusted hazard ratio [HR], 0.88; 95% CI, 0.75-1.03; P = .123). Although the results showed no significant survival benefit between the tecemotide and placebo treatment groups in the overall patient population, subgroup analyses showed a difference in tecemotide activity following sequential versus concurrent chemoradiotherapy (Figure 1): patients receiving concurrent chemoradiotherapy followed by tecemotide showed a notable OS benefit. In the patients who received previous concurrent chemoradiotherapy, median OS for the 538 (65%) of 829 patients assigned to tecemotide was 30.8 months (95% CI, 25.6-36.8) compared with 20.6 months (95% CI, 17.4-23.9) for the 268 (65%) of 410 patients assigned to placebo (adjusted HR, 0.78; 95% CI, 0.64-0.95; P = .016). Among the patients who received previous sequential chemoradiotherapy, OS did not differ between the 291 (35%) patients in the tecemotide group and the 142 (35%) patients in the placebo group (19.4 months [95% CI, 17.6-23.1] vs 24.6 months [95% CI, 18.8-33.0], respectively; adjusted HR, 1.12; 95% CI, 0.87-1.44; P = .38). The biologic rationale for such a difference in the response to tecemotide of NSCLC patients who previously received concurrent as opposed to sequential chemoradiotherapy remains unclear.¹⁵



An updated analysis after approximately 20 months of additional median follow-up time confirmed the results of the primary analysis.¹⁶ In the overall patient population, median OS was 25.8 months with tecemotide versus 22.4 months with placebo (HR, 0.89; 95% CI, 0.77-1.03; P = .111); in the subgroup previously treated with concurrent chemoradiotherapy, median OS was 29.4 months with tecemotide versus 20.8 months with placebo (HR, 0.81; 95% CI, 0.68-0.98; P = .026). As in the primary analysis, no improvement in OS was seen with sequential chemoradiotherapy.

A press release at the end of 2012 stated that the phase 3 START study did not meet its primary end point of demonstrating a statistically significant improvement in OS, but notable treatment effects were seen in certain subgroups.¹⁷

Another multicenter, randomized, double-blind, placebo-controlled phase 3 study (INSPIRE; NCT01015443) is being conducted in patients of East Asian ethnicity with unresectable, stage IIIA or IIIB NSCLC who have had a response or stable disease after at least 2 cycles of platinum-based chemoradiotherapy. East Asian ethnicity is an independent favorable prognostic factor for survival in NSCLC. It has been suggested that the favorable prognosis is most likely due to a higher incidence of epidermal growth factor receptor (EGFR) mutations among this patient population.¹⁸ The design of the INSPIRE study is almost identical to that of the START study. INSPIRE enrolled approximately 420 unresectable, stage III NSCLC patients across China, Hong Kong, South Korea, Singapore, and Taiwan.

TG4010 (MVA-MUC1-IL2)

TG4010 is another antigenic vaccine targeting MUC1. TG4010 is a bivalent cancer vaccine comprised of a modified vaccinia virus Ankara (MVA) strain expressing the coding sequences of the MUC1 antigen and the cytokine interleukin-2.^19,20

The TG4010 vaccine has been studied in an open-label, phase 2b study (NCT00415818) in combination with first-line cisplatin-gemcitabine chemotherapy versus cisplatin-gemcitabine chemotherapy alone in patients with advanced (stage IIIB or IV) NSCLC expressing MUC1 by immunohistochemistry.¹⁹ A total of 148 patients were enrolled; 74 patients were allocated to the combination therapy group, and the other 74 patients received the same chemotherapy alone. The primary end point, 6-month progression-free survival (PFS), was achieved in 32 (43.2%) of 74 patients (95% CI, 33.4-53.5) in the combination group, and in 26 (35.1%) of 74 patients (95% CI, 25.9-45.3) in the group that received chemotherapy alone, suggesting that TG4010 enhances the effect of chemotherapy in advanced NSCLC. Median OS did not differ significantly between groups.

In this study, a subset of patients was identified that appeared to respond particularly well to treatment with TG4010 and chemotherapy versus chemotherapy alone. This subset consisted of patients with normal levels of triple-positive activated lymphocyte (TrPAL) cells (CD16+, CD56+, and CD69+) at baseline. Within this subpopulation, a retrospective analysis showed an improved clinical outcome for patients with a 6-month increase in median OS (P = .062).¹⁹ Response rate, time to progression, and PFS data also indicated that normal levels of TrPAL cells at baseline could be an appropriate predictive biomarker associated with positive clinical outcomes for patients with NSCLC treated with TG4010 in combination with chemotherapy.

To confirm the results from this study, a phase 2b/3 randomized, placebo-controlled study (TIME; NCT01383148) evaluating TG4010 in combination with chemotherapy in patients with stage IV MUC1-positive NSCLC was initiated.²¹ The primary objective of the phase 2b part of the study, to validate the baseline TrPAL level as a predictive biomarker for efficacy, was achieved in patients with normal TrPAL before treatment. Among the 221 patients in the study, 170 (77%) had normal TrPAL levels. In patients with normal TrPAL, the observed HR for PFS was 0.74 (95% CI, 0.53-1.02), which corresponds to a 98.6% Bayesian probability that the true HR is <1, passing the threshold of 95% needed to consider the end point met in this subgroup of patients. In the subgroup with high TrPAL levels, the required number of events for analysis was not yet reached. Analysis in patients with the lowest baseline level of TrPAL (3 lowest quartiles, n = 152) shows an HR for PFS of 0.66 (95% CI, 0.46-0.96; P = .014), consistent with the observation made in the previous study.²²

Among the 221 patients in the study, 195 (88%) had nonsquamous histology, and 131 of these patients had both nonsquamous carcinoma and low TrPAL levels. Subgroup analyses showed that TG4010 improves PFS with statistical significance in nonsquamous carcinoma, both in the overall population and in patients with low TrPAL. First results on OS trend in favor of TG4010.

These data support the concept that baseline TrPAL level is a potential biomarker to identify patients more likely to benefit from TG4010 treatment. They also confirm TG4010 efficacy and safety profiles in patients with stage IV NSCLC and warrant the continuation of the phase 3 part of the TIME study, with OS as a primary end point. Based on these results, the phase 3 part of the TIME study will enroll only patients with nonsquamous disease.

Recombinant Human Epidermal Growth Factor (EGF)-Based Vaccine

The EGFR signaling pathway mediated by EGF ligands is associated with the occurrence of cell proliferation, apoptosis, angiogenesis, and metastasis. EGF overexpression can be observed in many solid tumors and is typically associated with more aggressive disease progression and unfavorable prognosis.²³

A therapeutic anticancer vaccine was developed in Cuba that consists of a yeast-derived recombinant human EGF protein and an Escherichia coli–derived P64K Neisseria meningitides protein, which is coupled with a Montanide ISA 51 immunoadjuvant.^24-26 The EGF-based vaccine is approved in Cuba, Peru, and Venezuela for the treatment of patients with stage IIIB/IV NSCLC after first-line chemotherapy.²⁷

The EGF-based cancer vaccine was investigated in a randomized phase 2 study in 80 patients with stage IIIB/IV NSCLC who had completed a first-line chemotherapy regimen at least 4 weeks before entering the trial.²⁸ Patients were randomized 1:1 to receive the EGF vaccine or best supportive care.

Vaccination with EGF was immunogenic. Anti-EGF antibodies were evaluated in 69 patients. A total of 51.4% of vaccinated patients met the criteria of “good anti-EGF antibody response,” whereas no patients in the control group did. Vaccination reduced the EGF concentration; a major decrease was seen in 64.3% of vaccinated patients. Mean EGF concentration in nonvac­cinated patients was significantly higher than in vaccinated patients. A significant inverse correlation was observed between the anti-EGF antibody titers and the EGF concentration in the vaccinated patients but not in the control patients.

A strong correlation was seen between the decrease in EGF concentration and survival. Vaccinated patients with minimal EGF concentration (below a threshold of 168 pg/mL; n = 17) survived a median of 13 months; patients who did not reach such a reduction in EGF concentration (n = 17) survived a median of 5.6 months (P = .0024).

The group of patients treated with the vaccine achieved a median OS of 6.47 months, whereas the median OS in the control arm was 5.33 months. Thus, a trend toward a survival advantage for the vaccine group was seen; however, it was not statistically significant at this small sample size. This trend toward a survival advantage became significant when patients were stratified by age. Vaccinated patients who were 60 years of age or younger survived significantly longer (median, 11.57 months) than those in the control group (median, 5.33 months; P = .0124). In the subset of patients older than 60 years of age, no significant differences in survival were seen between the 2 groups.

A multicenter, open-label, randomized phase 3 study (NCT02187367) will be conducted in patients with inoperable, stage IV NSCLC who are positive for the selective EGF biomarker and wild-type EGFR. This study is not yet open for participant recruitment.

Belagenpumatucel-L

Belagenpumatucel-L is a nonviral, genetically modified, allogenic vaccine that is made from 4 irradiated NSCLC tumor cell lines (2 adenocarcinoma, 1 squamous cell carcinoma, and 1 large cell carcinoma) modified with transforming growth factor ?2 (TGF-?2) antisense plasmid.²⁹ Elevated levels of TGF-?2 are known to be linked to immunosuppression in cancer patients, and TGF-?2 levels are inversely correlated with prognosis in patients with NSCLC.²⁹ By using the TGF-?2 antisense plasmid as part of the vaccine, TGF-?2 expression is downregulated, and the immune response is heightened.^29,30

Belagenpumatucel-L was investigated in an international, multicenter, randomized, double-blind, placebo-controlled phase 3 study (STOP; NCT00676507) as maintenance therapy in 532 patients with advanced NSCLC (42 with stage IIIA and 490 with stage IIIB/IV) that did not progress following front-line chemotherapy.³¹ Patients were randomized 1:1 to either belagenpumatucel-L (n = 270) or placebo (n = 262). The primary end point was OS.

Results showed that the primary end point of improving OS was not met: the median OS was 20.3 months in the group treated with belagenpumatucel-L and 17.8 months in the group that received placebo (HR, 0.94; P = .594; Figure 2).



However, subgroup analyses showed that the time elapsed between the end of frontline chemotherapy and randomization in the study had a significant impact on survival outcomes. Other prognostic factors were stage, pretreatment radiation, and histology. In the subgroup of patients (n = 305) with stage IIIB/IV NSCLC who enrolled within 12 weeks of completion of frontline chemotherapy, a median OS of 20.7 months was observed for those treated with belagenpumatucel-L compared with 13.4 months for those who received placebo, a difference of 7.3 months (HR, 0.75; P = .083).

Patients with stage IIIB/IV nonadenocarcinoma randomized within 12 weeks of the completion of chemotherapy (n = 99) had a median OS of 19.9 months in the group treated with belagenpumatucel-L versus 12.3 months in those who received placebo, a difference of 7.6 months (HR, 0.55; P = .036).

In the subgroup of patients who received radiation therapy prior to enrollment, a median OS of 40.1 months was observed for those who received belagenpumatucel-L compared with 10.3 months for those in the control group, a difference of 29.8 months (HR, 0.45; P = .014).

Thus, while the overall trial did not meet its predefined end point, a considerable increase in OS was observed in stage IIIB/IV patients who began belagenpumatucel-L treatment within 12 weeks of the completion of frontline chemotherapy. A significant, clinically meaningful prolongation of OS was also observed in the subset of patients with nonadenocarcinoma.

Racotumomab-Alum Vaccine

Gangliosides are a broad family of glycolipids that contain neuraminic acid (Neu; also called sialic acid) in their structure and are present in the outer layer of the plasma membrane. These gangliosides are virtually undetectable in normal human cells, but they are highly expressed in certain human cancer cells, including NSCLC, making them an attractive target for anticancer therapeutics.^32,33

Racotumomab-alum is an anti-idiotype vaccine, composed of the monoclonal antibody racotumomab and the adjuvant aluminum hydroxide, targeting the NeuGcGM3 tumor-associated ganglioside.³²

The racotumomab-alum vaccine was evaluated in a randomized, multicenter, placebo-controlled phase 2/3 study as switch maintenance therapy in patients with stage IIIB/IV NSCLC who had at least stable disease after first-line chemotherapy.³⁴ A total of 176 patients were randomized to receive either racotumomab-alum (n = 87) or placebo (n = 89). The vaccination schedule consisted of 5 doses of either racotumomab-alum or a placebo administered at 14-day intervals (induction period), followed by monthly booster doses (maintenance period). Median OS was 8.23 months in the group treated with the vaccine and 6.80 months in the group that received placebo (HR, 0.63; 95% CI, 0.46-0.87; P = .004; Figure 3). Median PFS in vaccinated patients was 5.33 months versus 3.90 months in those who received placebo (HR, 0.73; 95% CI, 0.53-0.99; P = .039). The subgroup of patients who developed anti-NeuGcGM3 antibodies capable of binding and killing NeuGcGM3-expressing tumor cells showed significantly longer median survival times.



A prospective, randomized, open-label, parallel-group, multicenter phase 3 study (NCT01460472) is under way in Argentina, Brazil, Cuba, Indonesia, Philippines, Singapore, and Thailand to evaluate racotumomab-alum plus best supportive care versus best supportive care alone in patients with stage IIIA (nonresectable), IIIB, or IV NSCLC who have achieved a partial or complete response or stable disease with standard first-line treatment. The primary end point of the study is OS.

Concluding Remarks

A number of therapeutic vaccines have been investigated in clinical trials for the treatment of patients with NSCLC. Although some of the studies ended unsuccessfully, some of the results are promising. In particular, exceptional benefits of employing vaccines can be achieved in selected patient subgroups, and studies suggest that predictive biomarkers can be used to identify the patients for whom vaccine immunotherapy may be most advantageous.

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