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Healio
October 05, 2011
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Protein Vaccines, Peptide Vaccines, and Non-vaccine Immunotherapies: Clinical Trials Update

Protein-based and peptide-based antigen vaccines are among the most promising forms of cancer vaccine therapy. There are a number of different agents in late-stage clinical trials for the treatment of non–small cell lung cancer (NSCLC) (Table 1). For example, a vaccine based on the protein melanoma-associated antigen-A3 (MAGE-A3) is now in phase 3 trials. Epidermal growth factor (EGF) is expressed in up to 85% of NSCLC tumors, and a vaccine based on this protein is in phase 2/3 clinical trials. The BLP25 peptide vaccine (Stimuvax, Oncothyreon), which is based on the MUC1 tumor antigen, is also being investigated in a phase 3 trial, while several other peptide vaccines are in phase 2, including the telomerase reverse transcriptase (TERT) subunit vaccine, which is expressed in more than 85% of NSCLC tumors.1-5

Table 1. Protein and Peptide Antigen-based Targets in Immunotherapy for NSCLC

*Ongoing trial
† Overexpression of EGFR and its ligands
‡ Mix of carcinoembryonic antigen (CEA), p53, human embryonic growth factor receptor (HER)-2, MAGE-2, and MAGE-3 peptides
Key: EGF — epidermal growth factor; MAGE — melanoma-associated antigen; TERT — telomerase reverse transcriptase; NA — not applicable
Sources: Kakimi K, et al. Lung Cancer. 2009;65:1-8; Sienel W, et al. Eur J Cardiothorac Surg. 2004;25:131-134; Gure AD, et al. Clin Cancer Res. 2005;11:8055-8062; Romero P. Clin Lung Cancer. 2009;9(suppl 1):S28-S36; Ramos TC, et al. Cancer Biol Ther. 2006;5:145-149.

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Protein-based Vaccines

MAGE-A3

MAGE-A3 is almost exclusively a tumor-specific antigen; other than in the testes and the placenta, it is not expressed in normal cells. MAGE-A3 is associated with a poor prognosis.6 MAGE-A3 is associated with increasing expression with increased stage in NSCLC, and data suggest that it is overexpressed more often in squamous cell carcinoma than in adenocarcinoma.3 Importantly, because MAGE-A3 is expressed in only 30% to 50% of NSCLC,2 patients must be tested for tumoral expression of the protein before inclusion in clinical trials, which is not the case for a number of other vaccines. MAGE-A3 can be detected in tumor tissue by the use of reverse transcription polymerase chain reaction (RT-PCR).

In a randomized phase 2 trial of MAGE-A3, 182 patients were randomized 2-to-1 to the vaccine or placebo.7 Treatment consisted of an induction phase of 5 administrations at 3-week intervals followed by a 2-year maintenance phase of 8 administrations every 3 months. The trial was conducted before the introduction of chemotherapy as standard adjuvant therapy for NSCLC, so the population consisted of MAGE-A3-positive patients with completely resected stage IB/II disease without adjuvant chemotherapy. The primary endpoint was disease-free interval; secondary endpoints included safety, disease-free survival, and overall survival.

Although the improvement in disease-free interval of the vaccine was not statistically significant compared to placebo (hazard ratio [HR], 0.73; P = .107), there was a strong signal in favor of the vaccine. Improvement in disease-free survival was also not statistically significant (HR, 0.73; P = .093). A 27% decrease in the relative risk for lung cancer recurrence compared to surgery alone was observed. This result led to a confirmatory phase 3 trial, the MAGE-A3 as Adjuvant, Non–small Cell Lung Cancer Immunotherapy (MAGRIT) study, which is examining the MAGE-A3 vaccine as adjuvant therapy.8 The cohort of patients eligible for the trial has been expanded to include those with resected stage IB to IIIA NSCLC, whose tumors express the MAGE-A3 protein.

The goal of this trial is to recruit more than 2,200 patients in the adjuvant setting. Platinum-based adjuvant chemotherapy is now the standard of care, so patients will receive up to 4 cycles of platinum-based chemotherapy before being randomized 2-to-1 to vaccine or placebo. There is a cohort of patients who are not receiving chemotherapy because of either disease stage or contraindications. This cohort will also be randomized to vaccine or placebo. The primary endpoint of the MAGRIT study is disease-free survival. Secondary endpoints are overall survival; lung cancer-specific survival; 2-, 3-, 4-, and 5-year disease-free survival; anti-MAGE-A3 and anti-protein D seropositivity; and safety profile and serious adverse events.

The trial has been successful in screening and accruing patients to date. MAGRIT opened in October 2007 at 580 sites globally. As of March 2011, almost 11,000 patients had been screened and nearly 10,000 tumor samples had been tested, of which approximately one-third (3,235) were MAGE-A3-positive. Almost 1,700 patients had been randomized at that time. Expectations are that the trial will complete accrual by the end of 2011, and at that time approximately 12,000 patients in the adjuvant setting will have been screened.

Peptide-based Vaccines

Stimuvax

Stimuvax is a liposomal peptide vaccine that uses as its tumor antigen the peptide backbone of the MUC1 glycoprotein. This vaccine includes the adjuvant monophosphoryl lipid A, which stimulates a non-specific immune response. The liposomal components of the vaccine facilitate immune recognition.

A randomized phase 2 trial of Stimuvax was conducted in patients with advanced NSCLC (stage IIIB/IV) who had undergone chemotherapy or chemoradiation and demonstrated a response or stable disease to their initial therapy.9,10 Those patients were then randomized to receive vaccine or supportive care, with the primary endpoints of survival and safety. The vaccine produced a non-significant increase in overall survival in the intent-to-treat (ITT) population (HR, 0.74; P = .112), although there was a stronger trend toward significance in survival in patients with localized stage IIIB disease (HR, 0.524; P = .069). Many of the latter had chemoradiation as their initial therapy. In this stage IIIB patient subgroup, after nearly 5 years of follow-up, survival in the Stimuvax arm was 30.6 months vs. 13.3 months in the control arm, with a 2-year survival of 49% vs. 27%.

To further investigate the promising results observed in this study with Stimuvax in the stage III setting, the phase 3 START trial was designed to focus on this patient population.11 Eligibility criteria for START include patients with unresectable stage III NSCLC who have undergone chemoradiation and are stable or responding, along with Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. The original study design called for the recruitment of more than 1,300 patients, making this the largest stage III NSCLC trial to date. Patients are randomized 2-to-1 to vaccine or placebo. Treatment consists of 8 cycles of primary treatment followed by maintenance until disease progression. The primary endpoint is survival. Secondary endpoints are time to progression; time to symptom progression; 1-, 2-, and 3-year survival; and safety.

The START trial was interrupted in March 2010 when the FDA placed a clinical hold on Stimuvax. This was the result of a serious adverse reaction in a phase 2 trial of Stimuvax in multiple myeloma. A patient in this study died of encephalitis. This trial was investigating the use of an intensive schedule of low-dose cyclophosphamide administered with the Stimuvax vaccine. The hold was subsequently removed in June 2010, and additional monitoring for serious adverse events was put in place in the START trial.

As a result of the delay, it was felt that patients who were in the middle of their induction phase of the vaccine, or had been within 6 months of starting in the trial, would probably not have developed a sufficient immune response to the vaccine by the time they were placed on hold. Because the delay was 3 months in duration, those patients were replaced when the trial reopened. The accrual goal was therefore increased to 1,476 patients. As of May 2011, 1,822 patients had been screened and 1,444 randomized. Screening has now been completed.

Non-vaccine Immunotherapy

Talactoferrin

Talactoferrin, a dendritic cell activator, is a recombinant form of lactoferrin, the active immune agent in human breast milk and colostrum. Oral talactoferrin is transported by M cells into the Peyer’s patches of the gut-associated lymphoid tissue (GALT) — the largest immune organ in the body — where it induces migration of immature dendritic cells to the GALT and promotes their maturation.

A randomized phase 2 trial of talactoferrin (n = 47) vs. placebo (n = 53) evaluated overall survival in patients with refractory NSCLC.12 Patients had failed either 1 or 2 lines of chemotherapy, at least 1 of which was platinum-based. This trial demonstrated a statistically significant improvement in survival in favor of the talactoferrin arm, both in the ITT population (HR, 0.68; P = .0404) and in the evaluable population (n = 81; HR, 0.59; P = .0171).

A phase 3 trial (FORTIS-M) examining oral talactoferrin as an adjunct in prior nonresponders to treatment is now underway. The study population consists of 720 patients with stage IIIB/IV NSCLC, who have failed 2 or more prior regimens.13 Patients were randomized 2:1 to talactoferrin or placebo. This trial completed its accrual in March 2011.

Talactoferrin is also being investigated as first-line therapy in combination with chemotherapy.14 A phase 2 trial randomized 110 patients 1:1 to carboplatin/paclitaxel plus either talactoferrin or placebo. The primary endpoint in this trial was confirmed response rate by CT scan using Response Evaluation Criteria In Solid Tumors (RECIST). The trial met its primary endpoint; in the evaluable patient group, there was a significant benefit with treatment, with response rates of 47% vs. 29%, respectively (P = .05). Response rate in the ITT patients (n = 110) showed a trend towards improvement in the talactoferrin arm compared to placebo, at 42% vs. 27%, respectively (P = .08). Patients treated with talactoferrin also had improved median progression-free survival and overall survival rates (Table 2). Patients with a partial response experienced significantly improved survival rates vs. those who did not respond to treatment (P < .01). Talactoferrin appeared to be well-tolerated, with no drug-related serious adverse events.

Table 2. Progression-free Survival and Overall Survival with Talactoferrin as First-line Chemotherapy

* Prospectively defined as patients who received at least 1 dose of study drug as well as 1 dose of C/P, and who had at least 1 CT scan after start of treatment (excludes patients who died [5] or dropped out [5] prior to the first post-treatment CT).
† Duration of response was measured from date of first occurrence of a confirmed response to date of tumor progression or death. N = 38, with 23 and 15 patients in the TLF and placebo arm, respectively.
Key: C — carboplatin; P — paclitaxel; OS — overall survival; PFS — progression-free survival; TLF — talactoferrin
Source: Wang Y, et al. J Clin Oncol. 2006;24(18S):7095.

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To further evaluate talactoferrin in this setting, FORTIS-C, another large phase 3 trial, is currently recruiting. This will be a randomized, double-blind, placebo-controlled study of oral talactoferrin in combination with carboplatin and paclitaxel as first-line therapy in patients with locally advanced or metastatic NSCLC. The study will include 1,100 patients with previously untreated stage IIIB/IV NSCLC.

T-cell Activation/Inhibition

The vaccines that have been discussed function primarily by increasing the T-cell response to antigens. However, the interface between T cells and other cells, such as dendritic cells, is complex. In addition to molecules that promote activation when presented to the T-cell receptors, there are a number of other molecules that have an inhibitory effect on T cells (Figure). One of these molecules is cytotoxic T lymphocyte-associated antigen 4 (CTLA4). In the normal activation of T cells, the antigen is presented to the T-cell receptors by antigen-presenting cells via the major histocompatibility complex present on their surface. This process also requires co-stimulation with B7 presenting to CD28 to activate the T cells. Normally, when the T cells are activated, CTLA4 becomes expressed on the surface, and because it binds with greater affinity to B7 than does CD28, it decreases the co-stimulation and inhibits the T-cell activation, acting as a negative feedback mechanism to prevent a hyperactive immune response.

Figure. T Cell Activation/Inhibition

There are a variety of molecules that regulate T-cell function, rendering them attractive targets for immunotherapy.
Key: CTLA4 — cytotoxic T lymphocyte-associated antigen; ICOS — inducible T-cell co-stimulator; TCR — T-cell receptor; TNF-R — tumor necrosis factor receptor
Sources: Walunas TL, et al. J Exp Med. 1996;183(6):2541-2550; Carter L, et al. Eur J Immunol. 2002;32(3):634-643.

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Ipilimumab

The anti-CTLA4 monoclonal antibody ipilimumab binds CTLA4 so it can no longer interact with B7, allowing B7 to continue to bind to CD28, thus preventing T-cell inactivation. Ipilimumab is recognized as a major advance in the treatment of malignant melanoma. A randomized phase 3 trial of ipilimumab with or without a vaccine in patients with advanced disease showed a significant improvement in survival, including durable responses in patients to 5 years, with no evidence of disease.15 Immune-related adverse events related to skin, gastrointestinal tract, liver, and endocrine system were observed in 60% of patients.

Ipilimumab has also shown activity against NSCLC. A randomized phase 2 trial with 3 arms compared 2 different ipilimumab regimens: ipilimumab given concurrently with carboplatin/paclitaxel chemotherapy, and a phased approach in which patients received 2 cycles of chemotherapy alone first, after which ipilimumab was added to the chemotherapy.16 The control arm consisted of chemotherapy alone. In the 2 ipilimumab arms, patients were permitted to continue on maintenance ipilimumab afterwards. The primary endpoint for the trial was immune-related progression-free survival. Both schedules showed an improvement in progression-free survival with ipilimumab; results for the phased schedule were statistically significant (HR, 0.686; P = .026), although the magnitude of the effect was small until about 3 months.

There was also a treatment benefit for the secondary endpoint of overall survival. In the phased ipilimumab arm, the median survival was 12 months vs.
8 months in the control group. A phase 3 trial is planned to further explore the potential of ipilimumab in the treatment of NSCLC. This trial will recruit 800 patients with advanced or recurrent squamous NSCLC, comparing carboplatin/paclitaxel alone with carboplatin/paclitaxel plus ipilimumab in the phased approach.17

PD-1

Like CTLA4, the PD-1 receptor inhibits T-cell activity through interaction with B7 ligands, in this case PD-Ll and PD-L2. PD-1 ligands are expressed on dendritic cells, and also on some human epithelial tumor cells. Antibodies that have been developed to block PD-1 prevent the inhibitory signal from being delivered to the T cell. One such molecule under investigation is BMS-936558, an IgG4 monoclonal antibody with no antibody-dependent or cell-dependent cytotoxicity (ADCC/CDCC) and a high affinity for PD-1. BMS-936558 blocks binding to both PD-L1 and PD-L2. BMS-936558 is in early development, but data from a phase 1 study were encouraging.18 Responses, which appeared to be durable, were detected in patients with melanoma, renal, and colorectal cancer. A mixed response was observed in a patient with NSCLC. Receptor occupancy lasted approximately 3 months at all tested doses. The serum half-life was 12 days to 20 days. Importantly, BMS-936558 was well-tolerated, unlike the CTLA4 blockers, including ipilimumab, which cause numerous significant immune-related adverse events. Common adverse events associated with BMS-936558 included rash, fatigue, lymphopenia, and arthralgia/myalgia.

A second phase 1 trial, again including patients with NSCLC, confirmed the durability and tolerability of this agent.19 Multiple doses (1, 3, and 10 mg/kg) administered at a schedule of once every 2 weeks were examined. In this trial, the maximum tolerated dose was not reached. Activity at the multiple dose levels was detected. The adverse event profile was consistent with an immunomodulatory mechanism of action. Responses again appeared to be durable. One patient with NSCLC showed a partial response, and has survived for more than 14 months at the 3 mg/kg dose in this study. Overall, 5 of 10 patients had durable stable disease at the higher doses. Some of those with stable disease had reduction in tumor burden, although they did not meet the criteria for partial response. The stable disease in a number of these patients was very durable.

Pseudoprogression

There is a phenomenon known as pseudoprogression, or flare, which seems to be unique to immunotherapies, particularly with the CTLA4 blockers. Pseudoprogression was initially reported with ipilimumab, but was subsequently observed with other agents. In a number of studies, some patients experienced either significant increase in size of the target lesions, or development of new lesions, but eventually responded, some in a durable manner. Evidence of this was seen in response patterns in patients with melanoma treated with ipilimumab.20 Some patients responded well initially, while others experienced an initial small increase in tumor, followed by a response. In another group, the target lesions increased to the point where they met RECIST criteria for progression, but subsequently showed significant improvement with time. There were also patients who developed new lesions that subsequently shrank with no further intervention.

A case of new lesions that resolved spontaneously was also observed in a phase 3 trial of belagenpumatucel-L (Bazhenova L, personal communication). A 47-year-old woman who had a complete response to initial chemotherapy with cisplatin/pemetrexed plus bevacizumab was randomized in the trial. A new lesion was detected at the first CT scan. This was a new lymph node in the para-aortic space that met the criteria for progression. A biopsy showed lymphocytes only, no malignancy. A repeat biopsy was planned, but the lesion resolved before this could be performed.

Because of the possibility of pseudoprogression, a longer time than expected may be required before an immune response is observed. Discontinuation of immunotherapy after apparent “early” disease progression may not be appropriate unless confirmed. For patients undergoing immunotherapy, it is recommended that suspected progression should be confirmed by further imaging or biopsy after 4 weeks in individuals who are not showing clinical deterioration.

Conclusions

Randomized phase 2 trials of a number of protein, peptide, and non-vaccine immunotherapies suggest that there is potential to improve survival. Furthermore, the initiation of some large randomized phase 3 trials —particularly START and MAGRIT — suggest that phase 3 clinical trials of immunotherapies on a global scale are feasible, and are supported by the oncology community. The MAGRIT trial will be the largest adjuvant trial ever to have been completed, and START is the largest trial in stage III disease. These are significant achievements and demonstrate the interest that these agents have generated in patients and in the oncology community. Ultimately, data from the phase 3 trials over the next 1 to 2 years will determine whether these agents will enter the armamentarium of treatment for patients with NSCLC.

References

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