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|Ref Type||Journal Article|
|Authors||Arend RC, Davis AM, Chimiczewski P, O'Malley DM, Provencher D, Vergote I, Ghamande S, Birrer MJ|
|Title||EMR 20006-012: A phase II randomized double-blind placebo controlled trial comparing the combination of pimasertib (MEK inhibitor) with SAR245409 (PI3K inhibitor) to pimasertib alone in patients with previously treated unresectable borderline or low grade ovarian cancer.|
|Abstract Text||To compare the combination of a MEK inhibitor (pimasertib) and a PI3K inhibitor (SAR245409) to pimasertib alone in recurrent unresectable borderline/low malignant potential (LMP) or low-grade serous ovarian carcinoma (LGSOC), determining whether combination is superior.Patients with previously treated, recurrent LMP or LGSOC with measurable disease received either combination of pimasertib (60 mg daily) + SAR245409 (SAR) (70 mg daily) or pimasertib alone (60 mg BID) until progression or unacceptable toxicity. Primary endpoint was objective response rate (ORR) by RECIST 1.1, determining whether combination was superior to pimasertib alone. Secondary endpoints included progression free survival (PFS), disease control, and adverse events.Sixty-five patients were randomized between September 2012 and December 2014. ORR was 9.4% (80% CI, 3.5 to 19.7) in the combination arm and 12.1% (80% CI, 5.4 to 22.8) in the pimasertib alone arm. Median PFS was 7.23 months (80% CI, 5.06 to -) and 9.99 (80% CI, 7.39 to 10.35) for pimasertib alone and pimasertib + SAR, respectively. Six-month PFS was 63.5% (80% CI, 47.2% to 75.9%) and 70.8% (80% CI, 56.9% to 80.9%). Eighteen (56.3%) patients in the combination arm and 19 (57.6%) patients in the pimasertib alone arm discontinued the trial. The study was terminated early because of low ORR and high rate of discontinuation.Response to pimasertib alone (ORR 12%) suggests that MEK inhibition could be used as an alternative treatment method to cytotoxic chemotherapy in this population. The MEK inhibitor alone was as effective as the combination, although the trial was limited by small numbers. Additional studies investigating the role of single agent or combination MEK and PI3K inhibition are warranted to further evaluate the utility of these treatments and describe a standard of care for LGSOC.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Therapy Name||Drugs||Efficacy Evidence||Clinical Trials|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|Pimasertib||AS703026|MSC1936369B||MEK inhibitor (Pan) 22 MEK1 Inhibitor 20 MEK2 Inhibitor 18||Pimasertib (MSC1936369B) binds to and inhibits MEK1/2, preventing activation of downstream targets and potentially reducing tumor cell proliferation (PMID: 23587417, PMID: 31870556).|
|Voxtalisib||XL765|XL-765|SAR245409|SAR-245409||mTOR Inhibitor 51 PI3K Inhibitor (Pan) 38||Voxtalisib (XL765) inhibits both PI3K and mTOR kinases and results in inhibition of PI3K pathway signaling, thereby possibly leading to inhibition of cell proliferation, reduced tumor vascularization, and inhibition of tumor growth (PMID: 24634413, PMID: 31870556).|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|Unknown unknown||ovarian cancer||no benefit||Pimasertib + Voxtalisib||Phase II||Actionable||In a Phase II trial, the combination of Pimasertib (MSC1936369B) and XL765 (SAR245409) versus Pimasertib (MSC1936369B) alone resulted in an objective response rate (ORR) of 9.4% and 12.1%, and a median progression-free survival of 9.99 mo and 7.23 mo, respectively, in patients with ovarian carcinoma (n=65), and 18 pts treated with combination and 19 pts treated with single therapy discontinued the study, and thus, the study was terminated due to a low ORR and high rate of discontinuation (PMID: 31870556).||31870556|