Preoperative Chemoradiotherapy With CApecitabine and Temozolomide in MGMT Silenced, MSS, Locally Advanced RecTal Cancer

Overview

In patients with locally advanced rectal cancer (LARC), preoperative chemo-radiotherapy (CTRT) is considered the standard of care. Preoperative CTRT approach often results in a significant tumor downstaging and local control, with evidence of complete pathological response (pCR) rate of about 15% in high volume institutions. In high-risk LARC a new strategy called total neoadjuvant therapy (TNT) has emerged, in which systemic chemotherapy with fluorouracil and oxaliplatin (RAPIDO trial) or with the triplet FOLFIRINOX (as was used in the PRODIGE 23 study) is incorporated before or after the administration of short-course RT or neoadjuvant CTRT and prior to surgery. However, given the fact that TNT may represent an overtreatment for a subset of patients, additional therapeutic strategies are warranted to improve the outcomes also in patients with lower risk that are not good candidate for a TNT. In the era of personalized medicine, tumor molecular profiling may lead to the identification of therapeutic targets for pharmacological intervention potentially useful to enhance treatment outcomes. O(6)-methylguanine-DNA-methyltransferase (MGMT) repairs DNA damage induced by alkylating agents and MGMT inactivation due to promoter methylation confers enhanced sensitivity to alkylating agents such as temozolomide (TMZ). TMZ has modest activity in patients with MGMT-methylated pretreated metastatic colorectal cancer and responses are restricted to tumors with complete MGMT loss by immunohistochemistry (IHC) and microsatellite stable (MSS) status. Both capecitabine and temozolomide induces deoxythymidine triphosphate thymidine pool depletion might induce deoxyribonucleic acid (DNA)-double strand breaks and eventually apoptosis in rapidly dividing cells. On the basis of such evidences, there is a strong biological and clinical rationale for testing the addition of TMZ to capecitabine-based CTRT in patients with MGMT silenced and MSS technically resectable LARC. The aim of this trial is investigating whether the addition of TMZ to standard concurrent capecitabine-based long-course chemoradiation may increase pCR rate as compared to historical control in patients with locally advanced rectal cancer not candidate to TNT and molecularly selected for the presence of MGMT silencing and microsatellite stable status.

Preoperative CTRT (long-course radiotherapy with a recommended dose of 45-50 Gy in 25-28 fractions plus a boost with a further 5.4 Gy in 3 fractions, and concomitant administration of oral capecitabine or continuous intravenous infusions of 5-fluorouracil) is considered the standard of care in the management of LARC, based on the significantly better down-staging and local control obtained by preoperative CTRT compared with radiotherapy (RT) alone, with a consequent reduction of local recurrence rate, and given its superior tolerability profile compared with postoperative treatment. Preoperative CTRT approach often results in a significant tumor downstaging and local control, with evidence of complete pathological response (pCR) rate of about 15% in high volume institutions. In high-risk LARC a new strategy called total neoadjuvant therapy (TNT) has emerged, in which systemic chemotherapy with fluorouracil and oxaliplatin (RAPIDO trial) or with the triplet FOLFIRINOX (as was used in the PRODIGE 23 study) is incorporated before or after the administration of short-course RT or neoadjuvant CTRT and prior to surgery. However, given the fact that TNT may represent an overtreatment for a subset of patients, additional therapeutic strategies are warranted to improve the outcomes also in patients with lower risk that are not good candidate for a TNT. In the era of personalized medicine, tumor molecular profiling may lead to the identification of therapeutic targets for pharmacological intervention potentially useful to enhance treatment outcomes. About 30-40% of colorectal carcinomas (CRCs) are characterized by the promoter methylation of the O(6)-methylguanine-DNA-methyltransferase (MGMT) gene, encoding a repair enzyme involved in the elimination of alkyl groups from the O6-position of guanine, usually caused by alkylating agents. MGMT defect, due to epigenetic silencing of the MGMT gene, may be involved in early steps of colorectal tumor genesis leading to an increase of G-to-A transitions and may be associated with enhanced chemosensitivity to alkylating agents including dacarbazine and its oral analogue temozolomide (TMZ) - as shown for melanoma and glioblastoma. Previous phase II studies showed that TMZ can induce an objective response by RECIST criteria in about 10% of heavily pre-treated patients with advanced CRC carrying MGMT promoter methylated, as determined by the qualitative assay methylation-specific polymerase chain reaction (MSP). To refine patient selection for TMZ therapy, we recently showed how digital PCR quantification of MGMT methylation may further refine patient selection, with benefit restricted to those with highly hyper-methylated tumors. Moreover, we showed that MGMT negative/low expression by immunohistochemistry (IHC) is found in about one third of MSP-methylated samples and is associated with increased response rate, since patients with retained MGMT expression in their tumors do not benefit from TMZ therapy. Therefore, ongoing trials (MAYA \[NCT03832621\], ARETHUSA \[NCT03519412\], FLIRT-bev \[NCT04689347\], ERASE-TMZ \[EUDRACT:2020-005437-32\]) select patients based on lack of MGMT expression assessed by means of IHC and presence of MGMT methylation by pyrosequencing or methylBEAMing. Finally, patients with microsatellite instability-high (MSI-high) metastatic colorectal cancer (mCRC) are intrinsically resistant to TMZ and therefore should be excluded by clinical trials on TMZ-based therapies. Based on these data, an assessment of MGMT promoter methylation coupled with absent protein expression and of the microsatellite instability status could optimize the prediction of response. Finally, previous reports indicate that acquired resistance to TMZ may emerge through the induction of a MSI-like phenotype with emergence of MMR gene mutations and elevated tumor mutational burden characterized by G\>A transitions (signature 8 according to Alexandrov et al, Nature 2013). The recently completed MAYA trial (NCT03832621) investigated the combination of TMZ with nivolumab and ipilimumab in patients with metastatic and chemorefractory disease; however, no data are available on potential synergy between RT and TMZ in inducing potential sensitization to immunotherapy of "cold" tumors and translational data are required. Both capecitabine and temozolomide induces deoxythymidine triphosphate. Thymidine pool depletion might induce deoxyribonucleic acid (DNA)-double strand breaks and eventually apoptosis in rapidly dividing cells. On the basis of such evidences, there is a strong biological and clinical rationale for testing the addition of TMZ to capecitabine-based CTRT in patients with MGMT silenced and MSS technically resectable LARC. Concurrent treatment with TMZ during RT followed by adjuvant TMZ is the standard of care for the treatment of malignant glioblastomas, showing a survival benefit compared to radiation alone, at the cost of a limited additional toxicity. When used together to radiotherapy, TMZ stabilize RT-induced double-strand breaks by producing 12-base adducts in DNA, including the cytotoxic lesions O6-methylguanine and 3-methyladenine. Therefore, the synergy between RT and TMZ could be of particular value in patients with MGMT silenced, MSS rectal cancers candidates for preoperative CTRT. Therefore, there is a strong rationale to investigate capecitabine plus temozolomide (CAPTEM)-based CTRT in this molecular subgroup. In a phase 1 study, Jeong and colleagues evaluated the dose limiting toxicity (DLT) and the recommended dose (RD) of temozolomide when combined with capecitabine as preoperative CTRT in patients with molecularly unselected LARC, showing that this treatment strategy is feasible and safe. No dose limiting toxicities were observed in patients treated with the highest temozolomide dose level tested in the study of 75 mg/m2/day, nor National Cancer Institute Common Terminology Criteria for Adverse Event (NCI-CTCAE) grade IV adverse events (AEs) were observed. Overall, the most frequent AE reported was nausea, occurring in 77.2% of the 22 patients treated. The MGMT promoter hypermethylation was detected in the 72.7% of patient enrolled. Tumor downstaging of the primary tumor and lymph nodes was observed in 81.8% and 72.7% of patients, respectively, the R0 resection rate was 90.9% and a pCR of the primary tumor (ypT0) was achieved in 31.8% of patients. As expected, the pCR rates were higher in the hypermethylated than in the unmethylated MGMT group (37.5% vs 16.7%), although this difference did not reach the statistical significance (odds ratio= 0.33; 95% Confidence Interval \[CI\], 0.03-3.58; p=0.616). The aim of this trial is investigating whether the addition of TMZ to standard concurrent capecitabine-based long-course chemoradiation may increase pCR rate as compared to historical control in patients with locally advanced rectal cancer not candidate to TNT and molecularly selected for the presence of MGMT silencing and microsatellite stable status.