Abstract only
3570
Background: O
6
-methylguanine-DNA-methyltransferase (MGMT) is a DNA repair protein that removes mutagenic and cytotoxic adducts from O
6
-guanine in DNA. Roughly 40% of colorectal ...cancers (CRCs) display MGMT deficiency due to promoter hypermethylation leading to silencing of the gene. Alkylating agents exert their antitumor activity by DNA methylation at the O
6
–guanine site, inducing base pair mismatch; therefore, activity of these compounds may be enhanced in CRCs lacking MGMT (Esteller, 2004; Pegg, 1990). Despite anecdotal reports about activity of dacarbazine in CRC (Shacham-Shmueli, 2011) no clinical trials assessed monotherapy with dacarbazine for metastatic CRC. Methods: We conducted a phase II study of dacarbazine in CRCs who had failed standard therapies (oxaliplatin, irinotecan, fluoropyrimidines and cetuximab or panitumumab if KRAS WT), PS=0-1, with adequate organ function, and measurable disease as per RECIST criteria assessed by CT scans at baseline and every 8 weeks. All patients had tumor tissue assessed for MGMT as promoter hypermethylation. Patients received dacarbazine 250 mg/m
2
i.v. d1-4, q21 until PD or untolerable toxicity (with a maximum of 6 cycles in case of SD). We employed a Simon, two-stage design to determinate if the ORR of dacarbazine treatment would be ≥ 10%. Secondary endpoints were association of response/resistance with loss of expression of MGMT, PFS and disease control rate. Results: In the first stage, from June 2011 to November 2011 we enrolled 40 pts (male 68%, median age 67 y range 29-81, PS=0 50%, KRAS mut 55%). Pts received a median of 3 cycles range 1-11. Toxicities included (All Grades/Grade 3-4 %): fatigue (58/5), constipation (38/0), nausea/vomiting (35/0), anemia (20/2.5), platelet count decrease (10/5). 36 pts were evaluable for objective response. Overall, 2 pts (5%) achieved PR and 5 pts (12.5%) had SD. All pts with PR had tumors with MGMT promoter hypermethylation. Conclusions: Having exceeded the boundaries of futility (at least 2 objective responses in the first stage), the trial proceeds to the second stage, enrolling 28 more patients. Analysis of MGMT promoter hypermethylation and association with sensitivity/resistance is performed at the end of the second stage.
The introduction into clinical practice of
KRAS
mutational status for selection of patients has dramatically improved the results from use of anti-EGFR monoclonal antibodies cetuximab or panitumumab ...for metastatic colorectal cancer. More refined selection of patients by means of other molecular alterations, for example
BRAF
,
PIK3CA
, and
NRAS
has enabled further increases in responses to first-line and other therapy for metastatic disease. Elucidation of differences among specific subtypes of
KRAS
mutations affecting sensitivity, and identification of other mechanisms by which tumor cell resistance is acquired, revealing “druggable” molecular targets to overcome resistance, are clearly a priority of clinical research. Recent data have revealed potentially different activity of the G13D
KRAS
mutation in conferring resistance to cetuximab. This review examines the most recent evidence available on codon 13 mutation in metastatic colorectal cancer, including both preclinical and available clinical data, indicating differences between codon 13 and other
KRAS
mutations and analyzing its prognostic and predictive use in EGFR-targeted therapy.
ROS1 tyrosine kinase inhibitors (TKIs) were found to provide a substantial clinical benefit for patients with advanced ROS1-positive (ROS1+) NSCLC. Nevertheless, TKI resistance inevitably develops ...with different mechanisms, preventing prolonged responses. For this reason, next-generation compounds are under clinical development. ROS1 F2004 substitutions have been previously detected on circulating tumor DNA of patients progressing to entrectinib. Hereby, we report the case of a patient with ROS1+ NSCLC in which F2004V-acquired mutation was detected on a site of disease progression, after entrectinib and crizotinib failure. A subsequent treatment with next-generation TKI repotrectinib led to disease response, providing the first clinical evidence of activity of repotrectinib against F2004V resistance mutation.
ROS1 tyrosine kinase inhibitors (TKIs) have demonstrated significant clinical benefit for patients with advanced ROS1+ non-small cell lung cancer (NSCLC). However, TKI resistance inevitably develops ...with different mechanisms, preventing prolonged responses. For this reason, next-generation compounds are under clinical development. ROS1 F2004 substitutions have been previously detected on circulating tumor DNA of patients progressing to Entrectinib. Hereby, we report the case of patient with ROS1+ NSCLC in which F2004V acquired mutation was detected on a site of disease progression, after Entrectinib and Crizotinib failure. A subsequent treatment with next generation TKI Repotrectinib lead to disease response, providing the first clinical evidence of activity of Repotrectinib against F2004V resistance mutation.
