Despite overall survival results from second-line treatment with the therapeutic tumour cell vaccine, belagenpumatucel-L, did not meet predefined end point in the entire population of patients with late stage non-small cell lung cancer (NSCLC), the phase III STOP trial identified subgroups of patients who derived notable clinical benefit. Significantly prolonged overall survival with belagenpumatucel-L were demonstrated in stage IIIB/IV patients who began belagenpumatucel-L within 12 weeks of the completion of front-line chemotherapy. A significant, clinically meaningful prolongation of overall survival was also observed in the non-adenocarcinoma subset.
Previously unreported findings were presented by Dr. Giuseppe Giaccone of the Medical Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, USA, on 28 September, during the Presidential Session I: Best and Late Breaking Abstracts (Abstract E17-7081) at the 17th ECCO – 38th ESMO – 32nd ESTRO European Cancer Congress. This congress convened in Amsterdam, The Netherlands from the 27th of September through the 1st of October, 2013 and was one of a series of congresses organised in joint partnership with ESSO, EACR, EONS and SIOPE to offer multidisciplinary and multi-professional educational opportunities in oncology.
This phase III study evaluated vaccination with belagenpumatucel-L as maintenance therapy for patients with stages T3N2-IIIA, IIIB, and IV NSCLC who did not progress after front-line chemotherapy.
What is belagenpumatucel-L?
Belagenpumatucel-L(Lucanix®) uses genetically modified whole tumour cells to stimulate the patient's own immune system to attack the tumour. It is comprised of 4 transforming growth factor (TGF)-ß2 antisense gene-modified, irradiated, allogeneic NSCLC cell lines.
The design of belagenpumatucel-L is based on the concept that higher levels of TGF-β2 often associate with immunosuppression which negates natural killer (NK) cell activity and suppresses dendritic cells, two crucial elements in preventing oncogenesis. Data have shown that immunosuppression and elevated TGF-β2 inversely correlate with poorer prognosis in NSCLC. Belagenpumatucel-L may be immunostimulatory and have antineoplastic activity by eliciting a specific T cell response against the patient’s NSCLC cells. The immunogenicity of the vaccine may be potentiated by suppression of tumour production of TGF-β2 due to the antisense RNA expressed by the plasmid TGF-β2 transgene element of the vaccine, thus initiating strong immune responses that may induce a long-term clinical benefit.
Prior phase II study withbelagenpumatucel-L
A phase II clinical trial evaluating belagenpumatucel-L in 75 patients with NSCLC stages II-IV showed a dose-related survival improvement in patients who received a minimum of 2.5 x 107 cells per injection over a course of up to a maximum of 16 injections. In the 61 stage IIIB and IV patients who were assessable, a 15% partial response rate was demonstrated plus an increase in cytokine production (interferon gamma, IL-6, IL-4) was observed among clinical responders, who also showed an elevated antibody response to vaccine HLA antigens. Treatments showed a favourable safety profile with no severe side effects.
The results of phase III trial withbelagenpumatucel-L
Based on data from the phase II study, a placebo-controlled, randomised, multinational phase III clinical trial (STOP) enrolled patients with stage III/IV NSCLC who did not progress following front-line chemotherapy to evaluate the utility of belagenpumatucel-L as second-line maintenance therapy in improving overall survival (OS) versus placebo (primary endpoint).
Of 532 patients enrolled in the STOP trial, 42 patients had stage IIIA and 490 patients had stage IIIB/IV disease. All patients were undergoing front-line therapy and were eligible for randomisation between 4 and 17.4 weeks from the end of this treatment. The patients were randomised 1:1 to receive either belagenpumatucel-L (n=270) or placebo (n=262) until disease progression or withdrawal. Belagenpumatucel-L was given by one monthly and two quarterly intradermal injections. Patient characteristics of age, disease stage and type were well balanced between the two arms. Overall, patient median age was 61 years; 57% of patients had adenocarcinoma, 27% squamous and 6% of patients had large cell carcinoma.
STOP did not meet its predefined primary end point in the entire patient population; median OS was 20.3 months with the vaccine compared to 17.8 months with placebo (hazard ratio [HR] 0.94; p = 0.594).
However, prognostic factors for improved outcome were identified by predefined Cox regression that showed a significant, clinically meaningful greater OS with belagenpumatucel-L over placebo; outcome was shown to be significantly impacted by the time interval between randomisation and the end of frontline chemotherapy (p = 0.002). The OS was improved by 7.3 months with belagenpumatucel-L in 305 stage IIIB/IV patients who were randomised within 12 weeks of chemotherapy completion. In this cohort the median OS was 20.7 months with belagenpumatucel-L compared to 13.4 months with placebo (HR 0.75; p = 0.083).
Other factors prognostic of better outcome were disease stage, whether prior radiation was received and histology. The patients with confirmed pretreatment radiation showed optimally improved median OS of 29.8 months difference between the treatments; patients receiving belagenpumatucel-L following radiation showed median OS of 40.1 months compared to 10.3 months with placebo (HR 0.45; p = 0.014).
Analysis of overall survival by disease subtype showed that 99 patients with stage IIIB/IV non-adenocarcinoma who were randomised within 12 weeks of the completion of chemotherapy experienced median OS of 19.9 months with belagenpumatucel-L versus 12.3 month with placebo, a difference of 7.6 months (HR 0.55; p = 0.036).
Belagenpumatucel-L was well tolerated; one serious adverse event, grade 2 allergic rash, was reported.
Although the overall survival was not improved, this analysis identified specific subgroups of patients who achieved marked improvement in survival, leading to an investigators meeting with USA Federal Drug Administration (FDA) that confirmed interest in continuing study in the specific subsets of patients identified by this analysis. The investigators concluded that these data, along with a strong safety profile, support the continued development of belagenpumatucel-L for this indication.
The study was sponsored by NovaRx Corporation.