Vascular Targeted Agent Addition to Chemotherapy Fails To Improve Mesothelioma Survival

Combining chemotherapy with a drug that modifies the tumour microenvironment does not extend overall survival for patients with progressing malignant pleural mesothelioma

medwireNews: A phase III trial has failed to demonstrate an overall survival (OS) benefit for patients with malignant pleural mesothelioma whose chemotherapy is supplemented with NGR-hTNF, an agent designed to boost intratumoural drug uptake and allow T-cell infiltration.

But participants with particularly aggressive disease resulting in a short treatment-free interval may have derived some clinical benefit from the combination strategy, the investigators say.

As reported in The Lancet Oncology, the NGR015 study included patients with any histological subtype of malignant pleural mesothelioma, who had progressed during or after first-line chemotherapy. 

After a median of 18.7 months, the primary endpoint of OS was a median of 8.5 months for the 200 patients who were assigned to receive an investigator’s choice of gemcitabine, vinorelbine or doxorubicin chemotherapy plus NGR-hTNF 0.8 µg/m2 given as a 1-hour infusion once a week.

This did not significantly differ from the median OS of 8.0 months for the 200 patients who were given chemotherapy plus a placebo infusion, report Vanesa Gregorc, from Ospedale San Raffaele in Milan, Italy, and colleagues.

Further analysis, however, identified significant heterogeneity in OS when patients were grouped by the length of interval between completion of first-line treatment and initiation of second-line therapy.

Among the 198 patients with a treatment-free duration of less than 4.8 months, receipt of NGR-hTNF was associated with significantly improved OS versus placebo, with a hazard ratio (HR) for death of 0.68. By contrast, there was no significant difference in OS between the treatment arms among the 200 patients who had a longer treatment-free duration, the authors say.

Patients with short treatment-free durations also had significantly better median progression-free survival (PFS) with NGR-hTNF than placebo (3.4 vs 1.9 months, HR=0.67), and were more likely to achieve (61 vs 47%) and maintain disease control (median 5.7 vs 4.5 months).

The near identical HRs for OS and PFS in patients with a short treatment-free interval given NGR-hTNF versus placebo suggests that “the delay in tumour progression did not just extend time on treatment but translated into a proportional survival gain”, comment Vanesa Gregorc et al.

The researchers believe that the survival benefit with NGR-hTNF in the short treatment-free interval groups “might plausibly be due to a hypervascular tumour microenvironment”. This is characterised by high levels of serum lactate dehydrogenase which in turn has previously been linked to poor prognosis but improved sensitivity to anti-angiogenic agents, they observe.

Grade 3 or more severe study-emergent adverse events were common in both the NGR-hTNF and placebo treatment arms (70 vs 61%), including neutropenia (18 vs 19%), pain (6 vs 8%), dyspnoea (5 vs 4%) and chills (5 vs 0%). Serious treatment-related adverse events occurred in 9% and 10% of patients, respectively, and there were no treatment-related deaths.

Taking into consideration this “favourable safety profile”, the researchers conclude the “hypothesis-generating findings of improved outcomes with NGR-hTNF in the short treatment-free interval subgroup deserve a confirmatory randomised trial in patients with malignant pleural mesothelioma that rapidly progresses less than 6 months after front-line therapy, using [OS] as the primary endpoint and [PFS] and time to symptomatic deterioration as secondary endpoints.”

 

Reference

Gregorc V, Gaafar RM, Favaretto A, et al. NGR-hTNF in combination with best investigator choice in previously treated malignant pleural mesothelioma (NGR015): a randomised, double-blind, placebo-controlled phase 3 trial . Lancet Oncol; Advance online publication 9 May 2018.
DOI: https://doi.org/10.1016/S1470-2045(18)30193-1

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