Jan 19 2016
By Shreeya Nanda, Senior medwireNews Reporter
Addition of the TG4010 vaccine to first-line chemotherapy improves outcomes in patients with advanced non-small-cell lung cancer (NSCLC), show the results of a placebo controlled trial.
The TIME trial also supports the use of baseline values of CD16, CD56, CD69 triple-positive activated lymphocytes – the so-called TrPAL biomarker – to select patients most likely to benefit from TG4010.
The investigators explain that TG4010 is a suspension of modified vaccinia virus encoding the MUC1 tumour-associated antigen and interleukin 2, where the former provides the antigenic stimulus and the latter optimises antigen presentation to T cells.
The phase IIb section of the trial included 222 patients with stage IV NSCLC without a known activating epidermal growth factor receptor mutation and with MUC1 positivity in at least 50% of tumour cells. Study participants were randomly assigned to receive chemotherapy, as selected by the investigator, together with either TG4010 at a dose of 108 plaque forming units or placebo, administered once a week for 6 weeks and then every 3 weeks.
After a median follow-up of 18.2 months, median progression-free survival (PFS) was 5.9 months for the 111 patients in the TG4010 treatment arm. This was significantly longer than the 5.1 months for the 111 patients given placebo, and equated to a hazard ratio (HR) of 0.74.
Moreover, a significantly higher proportion of TG4010- than placebo-treated patients achieved a complete or partial response (40 vs 29%) and the duration of response was also longer with TG4010 (median 30.1 vs 18.7 weeks).
When patients were stratified by baseline TrPAL values, addition of TG4010 resulted in a significantly extended PFS relative to placebo among those with levels equal to or below the cutoff based on the third quartile of TrPAL distribution among screened participants (median 5.8 vs 5.0 months, HR=0.66). However, patients with TrPAL values above the threshold derived no such benefit from the vaccine.
The finding that only patients with low TrPAL values, which indicate the presence of activated natural killer cells, benefit from TG4010 immunotherapy is consistent with the dual role of natural killer cells in the regulation of an adaptive immune response, say the researchers. Beyond a certain level of activation, natural killer cells switch from positive regulation to immune-suppressive behaviour, they explain.
Researcher Elisabeth Quoix (Hôpitaux Universitaires de Strasbourg, France) and co-authors report in The Lancet Oncology that the safety profile of TG4010 was “favourable”.
The most frequent adverse events associated with the vaccine were injection-site reactions of grade 1 or 2, occurring in 33% versus 4% of patients in the placebo group.
Neutropenia (38%), anaemia (11%) and fatigue (11%) were the most common grade 3 or 4 toxicities in the TG4010 treatment arm, but the researchers attributed these to chemotherapy or underlying disease, adding that there were no grade 3 or 4 toxicities related specifically to TG4010 administration.
Writing in an accompanying comment, Charles Butts (University of Alberta, Edmonton, Canada) and Randeep Sangha (Cross Cancer Institute, Edmonton, Alberta, Canada), observe that thus far, the results of the TIME trial are “encouraging”.
They believe that this vaccine strategy has potential to lead to successful stimulation of T cells but caution: “Whether this strategy alone is enough to succeed without specifically addressing tumour-induced immunosupression needs confirmation in the phase 3 trial.”
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