Phase I/II trial of pimasertib plus gemcitabine in patients with metastatic pancreatic cancer

Abstract

The selective MEK1/2 inhibitor pimasertib has shown anti-tumour activity in a pancreatic tumour model. This phase I/II, two-part trial was conducted in patients with metastatic pancreatic adenocarcinoma (mPaCa) (NCT01016483). In the phase I part, oral pimasertib was given once daily discontinuously (5 days on/2 days off treatment) or twice daily continuously (n = 53) combined with weekly gemcitabine (1,000 mg/m ) in 28-day cycles to identify the recommended phase II dose (RP2D) of pimasertib. In the phase II part, patients were randomised to pimasertib (RP2D) or placebo plus weekly gemcitabine (n = 88) to investigate progression-free survival (PFS), overall survival (OS) and safety. The RP2D was determined to be 60 mg BID. PFS and OS outcomes did not indicate any treatment benefit for pimasertib over placebo in combination with gemcitabine (median PFS 3.7 and 2.8 months, respectively, HR = 0.91, 95% CI: 0.58-1.42: median OS 7.3 vs. 7.6 months, respectively). KRAS status did not influence PFS or OS. The incidence of grade ≥3 adverse events was 91.1% and 85.7% for pimasertib/gemcitabine and placebo/gemcitabine respectively, but there was a higher incidence of ocular events with pimasertib/gemcitabine (28.9% vs. 4.8% for placebo/gemcitabine). In conclusion, no clinical benefit was observed with first-line pimasertib plus gemcitabine compared with gemcitabine alone in patients with mPaCa.

Gemcitabine‐induced epithelial‐mesenchymal transition‐like changes sustain chemoresistance of pancreatic cancer cells of mesenchymal‐like phenotype

“…34 A phase I/II randomized trial of the combination MEK inhibitor pimasertib/gemcitabine versus gemcitabine did not supported further development of this combination in a first-line treatment of metastatic pancreatic cancer. 35 Interestingly, our data…”

“…Actually, a phase II randomized clinical trial in patients with metastatic PC showed that the combination of the MEK inhibitor trametinib with gemcitabine did not improve overall survival, disease‐free survival, overall response rate or duration of response in comparison to gemcitabine alone . A phase I/II randomized trial of the combination MEK inhibitor pimasertib/gemcitabine versus gemcitabine did not supported further development of this combination in a first‐line treatment of metastatic pancreatic cancer . Interestingly, our data show that MEK inhibition could be of potential interest only after progression on gemcitabine and in the subtype of mesenchymal pancreatic tumor cells.…”

TPL2 enforces RAS-induced inflammatory signaling and is activated by point mutations

“…Induction of MAPK activity is a well-established mechanism that allows cancer cells to endure genotoxic stress (48). However, MEK inhibitors fail to potentiate chemotherapy in pancreatic cancer (49,50), suggesting that targeting MAPK alone is insufficient, or that compensatory escape mechanisms such as enhanced NF-κB activity should be cotargeted. Similarly, in a prostate cancer model, addition of an NF-κB pathway inhibitor significantly potentiates the antitumor effect of MEK inhibitors (51).…”

MALAT1 plays important role in MEK inhibitor, RG7420, on the proliferation and migration of endometrial cancer cell through sponging miR-129-5p/ TAK1

“…Colorectal Cancer [14] , pancreatic cancer [15] . Since now there are a few reports about MEK inhibitor (arm A, D) or irinotecan (arm B, C) [16] .…”