O-025
A randomized, multicenter, phase 2 trial comparing CAPTEM versus FOLFIRI as second-line treatment for MGMT-methylated, RAS-mutated metastatic colorectal cancer patients
Introduction
Non-randomized studies showed an overall response rate (ORR) to temozolomide (TMZ) of about 10% in refractory metastatic colorectal cancer (mCRC) patients with MGMT methylation assessed by qualitative assays, i.e. methylation-specific PCR (MSP). The activity of irinotecan/FOLFIRI was modest in second-line trials (4-16%). The efficacy of TMZ may be improved by its combinatorial use in earlier treatment lines, and by refining the molecular selection beyond MSP. We showed that lack of MGMT expression by immunohistochemistry (IHC) and/or elevated MGMT % methylation by MethylBEAMing are prognostic for higher ORR and PFS in TMZ-treated patients.
Non-randomized studies showed an overall response rate (ORR) to temozolomide (TMZ) of about 10% in refractory metastatic colorectal cancer (mCRC) patients with MGMT methylation assessed by qualitative assays, i.e. methylation-specific PCR (MSP). The activity of irinotecan/FOLFIRI was modest in second-line trials (4-16%). The efficacy of TMZ may be improved by its combinatorial use in earlier treatment lines, and by refining the molecular selection beyond MSP. We showed that lack of MGMT expression by immunohistochemistry (IHC) and/or elevated MGMT % methylation by MethylBEAMing are prognostic for higher ORR and PFS in TMZ-treated patients.
Methods
This multicenter, randomized, open-label phase 2 trial investigated PFS superiority of second-line CAPTEM (Arm A) over FOLFIRI (arm B) in RAS-mutated mCRC patients with MGMT methylation centrally confirmed by MSP. Eligible patients had ECOG PS 0-1, measurable disease, and failed first-line oxaliplatin-based therapy (or had relapse within 6 months from completion of oxaliplatin-based adjuvant treatment). Randomization to arm A (capecitabine 750 mg/sqm b.i.d. days 1-14 plus TMZ 75 mg/sqm b.i.d. days 10-14 q28 days) or arm B was performed on 1:1 basis and stratified according to time elapsed from the start of oxaliplatin-containing chemotherapy and PD (< vs. ≥9 months); prior bevacizumab (yes vs. no). Treatment was continued for up to 6 cycles in Arm A or 12 cycles in Arm B, or PD, unacceptable toxicity or consent withdrawal. A one-sided log rank test with an overall sample size of 82 subjects (41 per arm) achieved a 90% power at a 5% significance level to detect an increase of median PFS (mPFS) from 2 to 4 months. Secondary endpoints: safety, QoL, overall survival, ORR, response duration. Exploratory endpoints: validation of the predictive value of MGMT IHC and methylBEAMing.
This multicenter, randomized, open-label phase 2 trial investigated PFS superiority of second-line CAPTEM (Arm A) over FOLFIRI (arm B) in RAS-mutated mCRC patients with MGMT methylation centrally confirmed by MSP. Eligible patients had ECOG PS 0-1, measurable disease, and failed first-line oxaliplatin-based therapy (or had relapse within 6 months from completion of oxaliplatin-based adjuvant treatment). Randomization to arm A (capecitabine 750 mg/sqm b.i.d. days 1-14 plus TMZ 75 mg/sqm b.i.d. days 10-14 q28 days) or arm B was performed on 1:1 basis and stratified according to time elapsed from the start of oxaliplatin-containing chemotherapy and PD (< vs. ≥9 months); prior bevacizumab (yes vs. no). Treatment was continued for up to 6 cycles in Arm A or 12 cycles in Arm B, or PD, unacceptable toxicity or consent withdrawal. A one-sided log rank test with an overall sample size of 82 subjects (41 per arm) achieved a 90% power at a 5% significance level to detect an increase of median PFS (mPFS) from 2 to 4 months. Secondary endpoints: safety, QoL, overall survival, ORR, response duration. Exploratory endpoints: validation of the predictive value of MGMT IHC and methylBEAMing.
Results
From November 2014 to February 2019, 155 patients were screened and 82 (arm A/B: 41/41) were enrolled in 18 Italian sites. Baseline characteristics (arm A/B): males 44%/56%, median age 70/67, ECOG PS 0 54%/51%, right-sidedness 37%/39%, single metastatic site 44%/34%, previous bevacizumab 68%/66%, median 1st-line PFS 9.4/10.2 months. At a median follow up of 26.6 months, 70 PFS and 46 OS events were collected. The study did not meet its primary endpoint, but median PFS was 3.6 in Arm A vs 4.1 months in Arm B (HR 1.26; 95% CI, 0.78-2.02; P = .34) and median OS was 9.1 vs 14.2 (HR 1.08; 95% CI, 0.60-1.94; P = .79). ORR and DCR (arm A/B): 12%/10% and 51/51%. Grade 3-4 adverse events: 15%/44% (diarrhea 0%/12.2%, stomatitis 0%/7.3%, hand-foot syndrome 0%/2.4%, anemia 2.4%/9.8%, neutropenia 2.4%/22.0%, thrombocytopenia 7.3%/0%, fatigue 2.4%/4.9%). Neither MGMT IHC nor MethylBEAMing status were prognostic. MGMT IHC positive subgroup, arm A vs arm B: median PFS, 2.0 vs 4.1 months (HR 2.06; 95% CI, 0.96-4.45; P = .06), median OS, 6.4 vs 10.6 months (P = .78), ORR (0% vs 14%) and DCR (25% vs 55%; Odds Ratio 0.28; 95%CI, 0.06-1.31; P = .11). In MGMT IHC negative subgroup, no differences between the two arms were noted in all the endpoints. Interaction IHC x arm: P = .171 for PFS, P = .917 for OS, P = .06 for DCR. Similar accuracy was achieved by MethylBEAMing. QoL data will be presented.
From November 2014 to February 2019, 155 patients were screened and 82 (arm A/B: 41/41) were enrolled in 18 Italian sites. Baseline characteristics (arm A/B): males 44%/56%, median age 70/67, ECOG PS 0 54%/51%, right-sidedness 37%/39%, single metastatic site 44%/34%, previous bevacizumab 68%/66%, median 1st-line PFS 9.4/10.2 months. At a median follow up of 26.6 months, 70 PFS and 46 OS events were collected. The study did not meet its primary endpoint, but median PFS was 3.6 in Arm A vs 4.1 months in Arm B (HR 1.26; 95% CI, 0.78-2.02; P = .34) and median OS was 9.1 vs 14.2 (HR 1.08; 95% CI, 0.60-1.94; P = .79). ORR and DCR (arm A/B): 12%/10% and 51/51%. Grade 3-4 adverse events: 15%/44% (diarrhea 0%/12.2%, stomatitis 0%/7.3%, hand-foot syndrome 0%/2.4%, anemia 2.4%/9.8%, neutropenia 2.4%/22.0%, thrombocytopenia 7.3%/0%, fatigue 2.4%/4.9%). Neither MGMT IHC nor MethylBEAMing status were prognostic. MGMT IHC positive subgroup, arm A vs arm B: median PFS, 2.0 vs 4.1 months (HR 2.06; 95% CI, 0.96-4.45; P = .06), median OS, 6.4 vs 10.6 months (P = .78), ORR (0% vs 14%) and DCR (25% vs 55%; Odds Ratio 0.28; 95%CI, 0.06-1.31; P = .11). In MGMT IHC negative subgroup, no differences between the two arms were noted in all the endpoints. Interaction IHC x arm: P = .171 for PFS, P = .917 for OS, P = .06 for DCR. Similar accuracy was achieved by MethylBEAMing. QoL data will be presented.
Conclusion
TMZ is an old drug with activity in MGMT-methylated mCRC and its use should be explored by phase 3 trials restricting the molecular selection to MGMT-negative +/-MGMT % hyper-methylated tumors.
TMZ is an old drug with activity in MGMT-methylated mCRC and its use should be explored by phase 3 trials restricting the molecular selection to MGMT-negative +/-MGMT % hyper-methylated tumors.
Publisher
Oxford University Press
Source Journal
Annals of Oncology
