A phase 2 study of temozolomide in pretreated metastatic colorectal cancer with MGMT promoter methylation

Abstract

Background:Presently, few options are available for refractory colorectal cancer (CRC). O6-methyl-guanine-DNA-methyltransferase (MGMT) promoter methylation is a frequent and early event in CRC tumourigenesis. This epigenetic silencing is a predictor of response to the alkylating drug temozolomide in glioblastoma. Preclinical evidences and some case reports showed temozolomide activity in CRC with MGMT silencing, but the available data from clinical trials are inconsistent.Methods:This was a multicentre, phase 2 trial, planned according to a two-stage Simon’s optimal design to investigate activity and safety of temozolomide in refractory CRC harbouring MGMT promoter methylation. The primary end point was overall response rate (ORR). Patients who failed two or more prior treatments received temozolomide at a dose of 150–200 mg m−2 per day on days 1–5 every 28 days.Results:From July 2012 to June 2016, 225 patients were screened, 80 showed MGMT promoter methylation and 41 were enrolled. Overall response rate was 10% and disease control rate was 32%. Median progression-free survival and overall survival were 1.9 and 5.1 months, respectively.Conclusions:Temozolomide showed a modest activity in this heavily pretreated population and the study did not meet its primary end point. The role of temozolomide in CRC remains still controversial and further research is warranted.

Beyond second-line therapy in patients with metastatic colorectal cancer: a systematic review

“…2016 [ 56 ] Phase II, SA/second line in 11% of pts, third line or later in rest 37 CET + S-1 Previous IR, OX and FP, with PD on 5-FU Median PFS: 5.5 mos; 90% CI 4.4–5.7 ORR: 29.7%; 95% CI 15.9–47.0 DCR: 73.0%; CR n =1; PR: n =10; SD: n =16 Median OS: 13.5 mos; 95% CI 8.5–16.5 Median TTF: 4.6 mos; 95% CI 3.2–5.6 Rash: 27.0% Dry skin: 13.5% Anorexia: 10.8% Paronychia: 10.8% Fatigue: 10.8% Diarrhoea: 10.8% Mucositis: 10.8% Neutropaenia: 10.8% Leukopaenia: 2.7% Thrombocytopaenia: 2.7% Anaemia: 5.4% Elevated bilirubin: 8.1% Yoshida et al. 2016 [ 57 ] Phase II, SA/third line and later 31 BE + S-1 >2 previous regimens, including OX and IR DCR: 67.9%; 95% CI 47.6–84.1 CR: 0% PR: 0% SD: 67.9% Median TTF: 3.0 mos; 95% CI 1.8–4.3 Median PFS: 3.7 mos; 95% CI 2.1–5.6 Median OS: 8.6 mos; 95% CI 7.0–11.2 Anorexia: 20% Diarrhoea: 10% Nausea: 7% Fatigue: 7% Mucositis/stomatitis: 3% Rash/desquamation: 3% Decreased Hb: 17% Decreased bilirubin: 7% Neutropaenia: 3% Elevated ALT: 3% Elevated AST: 3% Calegari et al. 2017 [ 58 ] Phase II, SA/third line and later 41 TEM 2 previous, including FP, IR, OX, BE (and anti-EGFR for wt KRAS) ORR: 10% CR: 0% PR: 10% SD: 22% DCR: 32% Median PFS: 1.9 mos (range 1.6–2.35) Median OS: 5.1 mos...…”

“…A number of phase II, single-arm trials evaluated different investigational compounds in unselected patients receiving treatment beyond the second line, but did not indicate any clear survival benefit [ 49 , 50 , 52 , 53 , 56 , 57 ].…”

Biomarker-guided implementation of the old drug temozolomide as a novel treatment option for patients with metastatic colorectal cancer

“…In the initial trial with dacarbazine, responses according to RECIST criteria were observed only in 2 out of 68 patients, although all responders had tumors bearing MGMT promoter methylation [6]. Therefore, even if the trial failed to meet its primary endpoint of overall response rate (ORR), the biological rationale linking MGMT silencing with clinical benefit was considered strong enough to perform the subsequent temozolomide monotherapy trials in patients with mCRC who were molecularly selected for the presence of MGMT methylation [7][8][9][10][11]. In all these trials, methylation-specific PCR (MSP) was adopted as the assay for qualitatively detecting the presence or absence of T MGMT methylation, as previously validated for patients with glioblastoma [12].…”

Immune Checkpoint Inhibitors in pMMR Metastatic Colorectal Cancer: A Tough Challenge

“…Although phase II trials showed that TMZ is an active option in some pretreated patients with mCRC, it is not yet recognized as a standard option in current guidelines due to the lack of a formal comparison, the use of different drug schedules and heterogeneous techniques of detection of MGMT methylation and cut-off levels to define hypermethylation [98][99][100][101][102][103].…”