The MODUL study: biomarker-driven maintenance therapy following first-line standard induction treatment of metastatic colorectal cancer
In MODUL, patients with measurable, unresectable, previously untreated metastatic colorectal cancer (mCRC) received up to eight cycles of induction treatment (FOLFOX + bevacizumab) followed by randomisation to control or experimental maintenance treatment in one of four biomarker-driven cohorts. Exploratory biomarker findings revealed that selective pressure of the treatment arm leads to acquired mutations that reactivate and converge in the MAPK pathway as drivers of resistance to cetuximab plus vemurafenib.
MODUL is an adaptable, phase II, signal-seeking trial testing novel agents as first-line therapy for predefined subgroups of patients with unresectable, previously untreated metastatic colorectal cancer (mCRC). Previously reported findings from Cohort 2 of MODUL demonstrated that, despite activity in other, immune-responsive tumour types, there was no improvement in progression-free survival (PFS) or overall survival (OS) with the addition of atezolizumab to fluoropyrimidine (FP)/bevacizumab as first-line maintenance treatment in patients with BRAF wild-type mCRC. At WCGIC 2021, efficacy, safety and exploratory biomarker findings from a cohort of patients with BRAF-mutant mCRC were reported.
MODUL study design
In MODUL, patients with measurable, unresectable, previously untreated mCRC received up to eight cycles of induction treatment (FOLFOX plus bevacizumab), followed by randomisation to control or experimental maintenance treatment in one out of four biomarker-driven cohorts. Control treatment consistent of fluoropyrimidine (FP) with 1600–2400 mg/m2 fluorouracil (5-FU) 46 hours intravenous (IV) infusion on day 1 every two weeks (Q2W) plus leucovorin (LV) 400 mg/m2 two hour infusion on day 1 Q2W or 1000 mg/m2 twice daily (BID) capecitabine orally on days 1–14 Q3W. Bevacizumab was added to the control regimen at a dose of 5 mg/kg 15–30-min IV infusion on day 1 Q2W. In patients with BRAF-mutated mCRC (Cohort 1), experimental treatment was 5-FU/LV (1600–2400 mg/m2 5-FU 46-h IV infusion on day 1 Q2W) and LV (400 mg/m2 two hour infusion on day 1 Q2W) plus cetuximab (500 mg/m2 IV infusion on day 1 Q2W) plus vemurafenib (960 mg BID orally). An exploratory genomic analysis was performed on archival tissue and plasma samples collected at cycle 1, day 1 of the induction phase and on plasma samples collected at progressive disease or at the end of treatment. Tissue samples were processed using FoundationOne and plasma samples were processed on FoundationOneLiquid, respectively, to uncover mutations that drive acquired resistance to cetuximab plus vemurafenib.
Efficacy, safety and exploratory biomarker findings
In total, 60 patients were randomised into the maintenance treatment in Cohort 1 (N= 40 in the 5-FU/LV + cetuximab + vemurafenib arm and N= 20 in the FP + bevacizumab arm). After a median follow-up of 16.4 months, median PFS was 10.0 months in the 5-FU/LV plus cetuximab plus vemurafenib arm, as compared to 11.6 months in the control arm (HR[95%CI]: 0.95[0.50-1.82], p= 0.87). Overall survival was slightly more in favour of the experimental arm (median OS 24.0 vs. 21.3 months, HR[95%CI]: 0.69[0.34-1.38], p= 0.29), although this difference was not statistically significant. Safety was similar to that observed in previous trials of vemurafenib-based regimens, with no new safety concerns. Of note, due to events unrelated to Cohort 1, the MODUL study was closed to enrolment prematurely and results from the Cohort 1 efficacy analysis should therefore be considered as descriptive only.
The exploratory genomic analysis included 49 patients (N=15 in the control arm and N= 34 in the experimental arm). MAPK pathway genes, KRAS, NRAS, BRAF, NF1 and MAP2K1 mutations in the presence of BRAFV600E were detected as drivers of acquired resistance at time of disease progression in a patient with stable disease during experimental treatment. Acquired alterations in MAPK pathway genes were higher in 5-FU/LV plus cetuximab plus vemurafenib-treated patients than in FP/bevacizumab-treated patients. These data emphasise that patients previously treated with anti-EGFR therapy and/or vemurafenib must be re-assessed for their genomic landscape at the time of enrolment.
MODUL is the largest randomised umbrella maintenance study in the first-line mCRC setting and the largest chemo-immunotherapy study in this setting reported to date. While median PFS appeared to be longer in the control arm, median OS and ORR appeared to be longer in the experimental arm. Exploratory biomarker findings revealed that selective pressure of the treatment arm leads to acquired mutations that reactivate and converge in the MAPK pathway as drivers of resistance to cetuximab and vemurafenib.
Ducreux M, et al. 5-FU/LV + cetuximab + vemurafenib as maintenance therapy for BRAF-mutant (BRAFmut) metastatic colorectal cancer (mCRC): Efficacy, safety, and exploratory biomarker findings from Cohort 1 of the MODUL trial. Presented at 2021 ESMO World Congress on Gastrointestinal Cancer; Abstract O-9.