Dual Targeted Molecular Therapy Fails To Improve Metastatic Pancreatic Cancer OS

Selumetinib plus MK-2206 therapy does not extend overall survival in metastatic pancreatic adenocarcinoma compared with modified FOLFOX chemotherapy

medwireNews: Dual targeting of the MEK and Akt pathways downstream of KRAS has failed to lengthen the overall survival (OS) of patients with metastatic pancreatic adenocarcinoma compared with that achieved by conventional chemotherapy.

The phase II trial assessed the efficacy of selumetinib, a selective adenosine triphosphate uncompetitive inhibitor of MEK 1/2, when used in combination with MK-2206, the first allosteric inhibitor of AKT.

“Because there are currently no drugs that directly target mutant RAS, inhibiting its downstream canonical RAF/MEK/ERK and [PIK3]/AKT signaling pathways was a rational alternate treatment strategy”, explain Vincent Chung, from City of Hope National Medical Center in Duarte, California, USA, and co-investigators.

In all, 58 patients who had failed gemcitabine-based chemotherapy were randomly assigned to receive selumetinib 100 mg/day plus MK-2206 135 mg/week, while 62 patients were treated with the modified FOLFOX regimen.

There was a trend towards shorter median OS in the patients given selumetinib plus MK-2206, at 3.9 months versus 6.7 months with modified FOLFOX, giving a nonsignificant hazard ratio of 1.37, the researchers report in JAMA Oncology.

There was also a trend for poorer progression-free survival with selumetinib plus MK-2206 than modified FOLFOX, at 1.9 versus 2.0 months. And fewer patients given the novel treatment combination achieved a partial response (0 vs 5) or stable disease (12 vs 14), the researchers add.

Furthermore, selumetinib plus MK-2206 was associated with a higher rate of grade 3 or more severe adverse events (39 vs 23 patients) and a higher rate of treatment discontinuation because of side effects (13 vs 7 patients).

“A major contributing factor to the lack of benefit was the frequency of toxicity-related treatment delays and dose reductions in the experimental arm, undermining sustained signaling inhibition”, the authors comment, noting that delays affected 45% versus 10% of those given mFOLFOX.

Discussing the need for better understanding of signalling network pathways in this patient population, the investigators emphasize that "the role of preclinical models of pancreatic cancer and the optimal translation of preclinical successes into trial design must be improved."

“Moreover, clinical testing of targeted agents must include validation of target modulation in treated patients. Obtaining tissue samples before and after treatment is challenging for this population of patients, but the recent advances in liquid biopsies may help to remove the hurdles of serial tissue sampling”, they conclude.

Reference

Chung V, McDonough S, Philip PA, et al. Effect of selumetinib and MK-2206 vs oxaliplatin and fluorouracil in patients with metastatic pancreatic cancer after prior therapy. SWOG S115 study randomized clinical trial. JAMA Oncol; Advance online publication 15 December 2016. doi:10.1001/jamaoncol.2016.5383

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