Adjuvant immunotherapy with MAGE-A3 does not prolong disease free survival in patients with NSCLC

Results from the largest therapeutic trial ever done in lung cancer failed to show an advantage in disease free survival (DFS) of adjuvant therapy with the recMAGE-A3 + AS15 cancer immunotherapeutic compared to placebo in patients who underwent surgery for their lung cancer. Only about 40% of lung cancer patients are cured after surgery. In 2004, the large IALT study introduced adjuvant chemotherapy (ACT) in standard practice resulting in an improvement of the cure rate. However, the 5-year disease-free survival (DFS) remains poor (35-50%) and about half of patients will not receive ACT for various reasons. The presented phase III trial investigated whether the recMAGE-A3 + AS15 cancer immunotherapeutic (MAGE-A3 CI) given as adjuvant therapy improved DFS in patients with resected NSCLC.

MAGRIT was a randomised, double-blind, placebo-controlled trial in patients with completely resected MAGE-A3-positive NSCLC Stages IB, II, and IIIA who did or did not receive ACT. Patients were randomly assigned (2:1) to receive 13 intramuscular injections of MAGE-A3 CI or placebo over a 27-month treatment period. The three co-primary endpoints were DFS in the overall and in the no-ACT population and DFS in patients with a potentially predictive gene signature.

Out of 13,849 patients screened, 4,210 patients had a MAGE-A3 positive tumor sample and 2,272 patients were randomised and treated. Overall, 52% of the patients received ACT; 47%, 36% and 17% were Stage IB, II and IIIA, respectively. The median follow-up at the time of the final analysis was 39 months. At that time, the median DFS was 60.5 months with MAGE-A3 CI compared to 57.9 months with placebo (HR[95%CI]: 1.024 [0.891-1.177]; p = 0.73). In patients who did not receive ACT, the median DFS was 58.0 and 56.9 months for MAGE-A3 CI and placebo respectively (HR[95%CI]: 0.970 [0.797-1.179]; p = 0.7572). The rate of grade ≥ 3 adverse events (16%) did not differ between treatment groups.

In summary, treatment of NSCLC patients with MAGE-A3 CI did not increase DFS compared to placebo in either the overall population or in patients who did not receive ACT. Nevertheless, despite the negative outcome of the study some important messages can be derived from this trial. Given the modern thoracic surgery and the modern adjuvant chemotherapy used in the trial, this study sets a benchmark for future work, with an expected 5-year survival of more than 50%. Furthermore, the MAGE-A3 therapy was very well tolerated with mild side effects and no increase in immune-mediated disorders. This confirms that cancer vaccination is a gentle treatment modality. In order to improve the outcomes currently seen with cancer vaccination, researchers should go back to the bench to obtain a better understanding of the mechanism of action of this treatment modality. One very promising option in this respect consists of the combination of ‘checkpoint inhibitors’ with cancer vaccination.

Reference

Vansteenkiste J, Cho B, Vanakesa T, et al. MAGRIT, a double-blind, randomized, placebo-controlled Phase III study to assess the efficacy of the recMAGE-A3 + AS15 cancer immunotherapeutic as adjuvant therapy in patients with resected MAGE-A3-positive non-small cell lung cancer (NSCLC). Presented at ESMO 2014; Abstract 1173O.