Reference Detail

Ref Type

Journal Article

PMID

(31870556)

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.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Gynecologic oncology	156	2	2020 02	301-307	Gynecol Oncol

URL

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.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
Pimasertib	Pimasertib	4	3
Voxtalisib	Voxtalisib	5	2

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
Pimasertib		AS703026\|MSC1936369B	MEK inhibitor (Pan) 24 MEK1 Inhibitor 26 MEK2 Inhibitor 24	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) 40	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