Congress Alerts

Clinical Spotlight from the 2011 Lung Cancer Conference in Amsterdam

Emerging Immunotherapies in Lung Cancer

July 8, 2011—Despite recent advances in the management of lung cancer, it is still the leading cause of cancer-related mortality worldwide. Immunotherapeutic strategies represent a new treatment option in clinical practice for several cancers, and have been very successful in improving patient outcomes in these malignancies. Although there are currently no approved immunotherapies for lung cancer, several options are being examined in clinical trials. Updates from these trials at major congresses in 2011 have shown promising results.

Talactoferrin alfa
Talactoferrin alfa is an oral, recombinant form of human lactoferrin, an immunomodulatory protein found in human milk and colostrum that plays a role in establishing immune function in the gut-associated lymphoid tissues (GALT) of infants. Talactoferrin is postulated to promote antitumor immune activity by causing the recruitment and activation of dendritic cells in the GALT. Recently, talactoferrin has shown antitumor activity in two phase II trials in advanced non-small cell lung cancer (NSCLC).

In a phase II, placebo-controlled trial, LF-0206,¹ patients with newly diagnosed, advanced-stage NSCLC were randomized to receive either 1.5 g talactoferrin BID or placebo BID on a 6-week cycle (5 weeks on/1 week off) for a maximum of three cycles. Patients in both arms received carboplatin (AUC 5) and paclitaxel (175 mg/mg²) q 3 weeks for 6 cycles (C/P). The primary endpoint was confirmed response rate in the evaluable patient population. Key results (N = 110) include:

Addition of oral talactoferrin to C/P resulted in a higher response rate than treatment with placebo plus C/P in the evaluable population (primary endpoint).
- Talactoferrin vs placebo: 47% vs 29% (P =.05)
There was a trend toward longer overall survival (OS) and progression-free survival (PFS) in patients receiving talactoferrin in the intent to treat (ITT) population
- Median PFS: 7.0 months vs 4.2 months (HR = .85; P = .24)
- Median OS: 10.4 months vs 8.5 months (HR = .87; P =.26)
Patients receiving talactoferrin with chemotherapy had fewer adverse events than those receiving chemotherapy alone

In a second phase II, placebo-controlled trial, LF-0201,² patients with advanced-stage NSCLC for whom one or more previous lines of therapy had failed were randomized to receive either 1.5 g talactoferrin BID or placebo BID on a 12 weeks on, two weeks off schedule, for a maximum of 3 cycles. The primary endpoint was OS. Overall survival was assessed across a variety of prognostic subgroups. Key findings (N = 100) are as follows:

There was a 65% improvement in median OS for patients receiving talactoferrin (6.1 months vs 3.7 months; HR = .68; P = .04) in the ITT population
Survival favored talactoferrin independent of any prognostic factor examined
- Prognostic factors analyzed include sex, age, performance status, histology, disease stage, and line of treatment
Patients receiving talactoferrin experienced statistically fewer adverse events than patients receiving placebo (P <.01)

These studies suggest that talactoferrin has immunostimulatory properties and is active against lung cancer tumors. To further examine the safety and efficacy of talactoferrin in NSCLC, two phase III trials are currently underway. FORTIS-C and FORTIS-M will examine talactoferrin in first-line and third-line NSCLC, respectively.

Talactoferrin’s immunomodulatory effects extend beyond NSCLC. In a study of talactoferrin in patients with severe sepsis,³ patients receiving 1.5 g talactoferrin in addition to standard care (q 8 hours, beginning within 24 hours of onset of sepsis) had reduced 28-day mortality versus patients receiving placebo and standard care (talactoferrin vs placebo: 14.4% vs 26.6%; P = .052). The mortality reduction associated with talactoferrin was consistent across different sites and types of infections.

Ipilimumab
Ipilimumab is a fully human monoclonal antibody that potentiates immune response by selective inhibition of cytotoxic T lymphocyte antigen 4 (CTLA-4). Ipilimumab has demonstrated success in enhancing OS in patients with metastatic melanoma, and has shown promising results in a phase II trial of ipilimumab plus paclitaxel and carboplatin in first-line treatment of patients with advanced NSCLC⁴. In this trial, patients were randomized to receive either concurrent ipilimumab + P/C, phased ipilimumab + P/C, or placebo + P/C. Doses (10 mg/kg ipilimumab, 175 mg/m² paclitaxel, AUC6 carboplatin) were administered intravenously every 3 weeks for a maximum of 6 cycles. Following chemotherapy, ipilimumab was continued every 12 weeks until toxicity or disease progression. The primary endpoint of this study was immune-related (ir) PFS, with PFS and OS being key secondary endpoints. Results in 204 patients are as follows:

Both schedules of ipilimumab improved median irPFS
- Concurrent vs placebo: 5.52 months vs 4.63 months (HR = .775; P =.094)
- Phased vs placebo: 5.68 months vs 4.63 months (HR = 0.686; P = .026)
There were no statistically significant improvements in OS in the total population
In patients with squamous tumors, there was a trend toward improved PFS and OS for patients receiving ipilimumab on a phased schedule
Ipilimumab was associated with low rates of grade 3/4 adverse events

Based on this trial, there appears to be a trend toward improved irPFS and OS in patients with squamous histology receiving ipilimumab on a phased schedule. A larger phase III trial is needed to fully elucidate the benefit of ipilimumab in NSCLC.

MAGE-A3 ASCI
Melanoma-associated antigen A3 (MAGE-A3) is a tumor-specific antigen commonly expressed in several tumor types, including lung. MAGE-A3 ASCI (antigen-specific cancer immunotherapeutic), a vaccine composed of recombinant MAGE-A3 protein and two immunostimulants, has been compared to placebo in a phase II trial for NSCLC. At a median of 28 months follow-up, MAGE-A3 ASCI showed a trend toward superior disease-free survival compared to placebo (HR = .73; P = .093). MAGE-A3 ASCI therapy was tolerable, with primarily grade 1 and 2 adverse events. (J Clin Oncol. 2007;25(18S): Abstract 7554.)

Based on these results, MAGE-A3 ASCI is being examined in the global phase III MAGRIT (MAGE-A3 as Adjuvant Non-Small Cell Lung Cancer Immunotherapy) trial. MAGRIT compares MAGE-A3 ASCI to placebo in patients with MAGE-A3+, stage IB-IIIA NSCLC. Following resection, patients will be randomized 2:1 to receive either placebo or MAGE-A3 ASCI. Up to four cycles of platinum-based adjuvant chemotherapy are allowed prior to randomization; adjuvant radiotherapy is not allowed. The primary endpoint is disease-free survival in the overall population and in the population that did not receive adjuvant chemotherapy. As of January 2011, 1579 patients of the target 2270 had been randomized. Screening data⁵ from 8470 resected tumors has shown an overall MAGE-A3 expression rate of 33.4%. MAGE-A3 expression is more common in squamous tumors (47.5%) compared to nonsquamous tumors (25.7%). Further data from the MAGRIT trial are forthcoming.

Digurmarti R, et al. J Thorac Oncol. 2011;6(6):1098-1103.

Parikh PM, et al. J Clin Oncol. 2011;29(suppl): Abstract 7569.

Crawford J, et al. J Clin Oncol. 2011;29(suppl): Abstract 9024.

Lynch TJ, et al. Presented at: 14th World Conference on Lung Cancer; 3-7 July 2011: Amsterdam, the Netherlands. Abstract MO21.06.

Kim JH, et al. Presented at: 14th World Conference on Lung Cancer; 3-7 July 2011: Amsterdam, the Netherlands. Abstract MO21.08.