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. 2023 Oct 13;29(20):4068-4075.
doi: 10.1158/1078-0432.CCR-23-0621.

Molecular Results and Potential Biomarkers Identified from the Phase 3 MILO/ENGOT-ov11 Study of Binimetinib versus Physician Choice of Chemotherapy in Recurrent Low-Grade Serous Ovarian Cancer

Rachel N Grisham #  1 , Ignace Vergote #  2 , Susana Banerjee  3 , Esther Drill  1 , Elsa Kalbacher  4 , Mansoor Raza Mirza  5 , Ignacio Romero  6 , Peter Vuylsteke  7   8 , Robert L Coleman  9 , Felix Hilpert  10 , Amit M Oza  11 , Anneke Westermann  12 , Martin K Oehler  13 , Sandro Pignata  14 , Carol Aghajanian  1 , Nicoletta Colombo  15   16 , David Cibula  17 , Kathleen N Moore  18 , Josep M Del Campo  19 , Regina Berger  20 , Christian Marth  21 , Jalid Sehouli  22 , David M O'Malley  23 , Cristina Churruca  24 , Gunnar Kristensen  25 , Andrew Clamp  26 , John Farley  27 , Gopa Iyer  1 , Isabelle Ray-Coquard  28 , Bradley J Monk  29
Affiliations

Molecular Results and Potential Biomarkers Identified from the Phase 3 MILO/ENGOT-ov11 Study of Binimetinib versus Physician Choice of Chemotherapy in Recurrent Low-Grade Serous Ovarian Cancer

Rachel N Grisham et al. Clin Cancer Res. .

Abstract

Purpose: We present the results of a post hoc tumor tissue analysis from the phase 3 MILO/ENGOT-ov11 study (NCT01849874).

Patients and methods: Mutation/copy-number analysis was performed on tissue obtained pre-randomization. The Kaplan-Meier method was used to estimate progression-free survival (PFS). Unbiased univariate analysis, Cox regression, and binary logistic regression were used to test associations between mutation status and outcomes, including PFS and binary response by local RECIST 1.1.

Results: MILO/ENGOT-ov11 enrolled 341 patients, ranging in age from 22 to 79, from June, 2013 to April, 2016. Patients were randomized 2:1 to binimetinib or physician's choice of chemotherapy (PCC). The most commonly altered gene was KRAS (33%). In 135 patients treated with binimetinib with response rate (RR) data, other detected MAPK pathway alterations included: NRAS (n = 11, 8.1%), BRAF V600E (n = 8, 5.9%), RAF1 (n = 2, 1.5%), and NF1 (n = 7, 5.2%). In those with and without MAPK pathway alterations, the RRs with binimetinib were 41% and 13%, respectively. PFS was significantly longer in patients with, compared with those without, MAPK pathway alterations treated with binimetinib [HR, 0.5; 95% confidence interval (CI) 0.31-0.79]. There was a nonsignificant trend toward PFS improvement in PCC-treated patients with MAPK pathway alterations compared with those without (HR, 0.82; 95% CI, 0.43-1.59).

Conclusions: Although this hypothesis-generating analysis is limited by multiple testing, higher RRs and longer PFS were seen in patients with low-grade serous ovarian cancer (LGSOC) treated with binimetinib, and to a lesser extent in those treated with PCC, who harbored MAPK pathway alterations. Somatic tumor testing should be routinely considered in patients with LGSOC and used as a future stratification factor.

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Figures

Figure 1. Flow diagram representing numbers of patients with next-generation sequencing data available from archival tissue collected at the time of study entry, and associated outcomes data.
Figure 1.
Flow diagram representing numbers of patients with next-generation sequencing data available from archival tissue collected at the time of study entry, and associated outcomes data.
Figure 2. A, Binimetinib and physician's choice of chemotherapy treatment groups (n = 215), Kaplan–Meier plot of progression-free survival by treatment arm and KRAS mutation status (Mut vs. WT). B, Binimetinib and physician's choice of chemotherapy treatment groups (n = 215), Kaplan–Meier plot of progression-free survival by treatment arm and MAPK alteration status. (MEK162, binimetinib; Mut, mutant; WT, wild-type; ALT, alteration). The x-axis is percentage of patient's progression-free survival; the y-axis is time in months.
Figure 2.
A, Binimetinib and physician's choice of chemotherapy treatment groups (n = 215), Kaplan–Meier plot of progression-free survival by treatment arm and KRAS mutation status (Mut vs. WT). B, Binimetinib and physician's choice of chemotherapy treatment groups (n = 215), Kaplan–Meier plot of progression-free survival by treatment arm and MAPK alteration status. (MEK162, binimetinib; Mut, mutant; WT, wild-type; ALT, alteration). The x-axis is percentage of patient's progression-free survival; the y-axis is time in months.
Figure 3. Swimmer plot representing the duration of treatment for patients treated with binimetinib (n = 144). Best response by RECIST v1.1 criteria, reason for treatment discontinuation, and MAPK pathway alteration status are detailed in the legend.
Figure 3.
Swimmer plot representing the duration of treatment for patients treated with binimetinib (n = 144). Best response by RECIST v1.1 criteria, reason for treatment discontinuation, and MAPK pathway alteration status are detailed in the legend.
Figure 4. CT scan images from a patient with a KRAS G12D mutation and a sustained complete response while on treatment with binimetinib. A, CT scan at study enrollment in 2015. B, CT scan in 2020 displaying sustained complete response with resolution of perihepatic adenopathy.
Figure 4.
CT scan images from a patient with a KRAS G12D mutation and a sustained complete response while on treatment with binimetinib. A, CT scan at study enrollment in 2015. B, CT scan in 2020 displaying sustained complete response with resolution of perihepatic adenopathy.
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