Commentary: Organ Preservation and KRASG12C in CRC, October 2022

As always, several provocative publications on colorectal cancer (CRC) have found their way into the medical literature. I will be discussing two of these in my Clinical Edge Journal Scan commentary for the month of October.

The first article, by Kennecke and colleagues, examines the role of neoadjuvant chemotherapy for early rectal cancer. We have been inundated with data showing that organ preservation is achievable in cases of node-positive rectal cancer with neoadjuvant chemoradiotherapy and chemotherapy (total neoadjuvant treatment [TNT] approach). As such, it stands to reason that organ preservation should also be achievable in cases of early, node-negative rectal cancer.

NEO was a single-arm, phase 2 trial examining the role of neoadjuvant chemotherapy only in early rectal cancer. In it, 58 patients with clinical T1-T3ab N0 low-to-mid rectal adenocarcinoma (proficient mismatch repair status) eligible for endoscopic resection were treated with 3 months of mFOLFOX6 (5-fluorouracil, leucovorin, and oxaliplatin) or CAPEOX (capecitabine and oxaliplatin). Those with evidence of tumor regression proceeded to transanal resection.

The primary endpoint was a protocol-specified organ preservation rate, defined as the proportion of patients with tumor downstaging to ypT0/T1 N0/X and who avoided radical surgery. Thirty-three (33) of the 58 patients were successfully downstaged, resulting in a protocol-specified organ preservation rate of 57% (90% CI 45-68). Of note, this treatment had no radiation at all and only used chemotherapy. Of the remaining 23 patients, 13 declined total mesorectal excision (TME) and went into observation. Of the 10 patients who underwent TME, seven had no histopathologic evidence of residual disease. The 1- and 2-year locoregional relapse-free survival rates were 98% (95% CI 86-100) and 90% (95% CI 58-98), respectively, and there were no metastatic recurrences or deaths. Although this is a small study, the results are enormously encouraging, suggesting that organ preservation not only can be achieved in early-stage rectal cancer, but also can be accomplished using only chemotherapy, further reducing morbidity to patients.

The second study I want to discuss was conducted by Ciardiello and colleagues and concerns the KRAS^G12C mutation in colorectal cancer. This mutation is targetable in lung cancer and has led to the approval of sotorasib for the treatment of advanced KRAS^G12C non–small-cell lung cancer . Unfortunately, previous studies of these inhibitors in advanced KRAS^G12C colorectal cancer have yielded disappointing results.

This study looked retrospectively at 6952 cases of metastatic colorectal cancer across Italy. A total of 256 cases (3.7%) demonstrated the KRAS^G12C mutation. Of those, 111 met inclusion criteria and were included in the analysis. Of note, this mutation was associated with a poor response to first-line chemotherapy (38.7%), with a median progression-free survival of 9 months (95% CI 7.5-10.5 months). Median overall survival was 21 months (95% CI 17.4-24.6 months). There was little difference between first-line oxaliplatin-containing regimens compared with those containing irinotecan. Triplet therapy (folinic acid, fluorouracil, oxaliplatin, and irinotecan; FOLFOXIRI) was associated with an objective response rate of 56.3% with a progression-free survival of 13 months and median overall survival of 32 months, suggesting that triplet therapy might be a better approach for these patients when they are identified. This study is important because it corroborates and builds upon data reported in smaller studies demonstrating the general resistance of KRAS^G12C metastatic colorectal cancer to chemotherapeutic treatments.

As always, several provocative publications on colorectal cancer (CRC) have found their way into the medical literature. I will be discussing two of these in my Clinical Edge Journal Scan commentary for the month of October.

The first article, by Kennecke and colleagues, examines the role of neoadjuvant chemotherapy for early rectal cancer. We have been inundated with data showing that organ preservation is achievable in cases of node-positive rectal cancer with neoadjuvant chemoradiotherapy and chemotherapy (total neoadjuvant treatment [TNT] approach). As such, it stands to reason that organ preservation should also be achievable in cases of early, node-negative rectal cancer.

NEO was a single-arm, phase 2 trial examining the role of neoadjuvant chemotherapy only in early rectal cancer. In it, 58 patients with clinical T1-T3ab N0 low-to-mid rectal adenocarcinoma (proficient mismatch repair status) eligible for endoscopic resection were treated with 3 months of mFOLFOX6 (5-fluorouracil, leucovorin, and oxaliplatin) or CAPEOX (capecitabine and oxaliplatin). Those with evidence of tumor regression proceeded to transanal resection.

The primary endpoint was a protocol-specified organ preservation rate, defined as the proportion of patients with tumor downstaging to ypT0/T1 N0/X and who avoided radical surgery. Thirty-three (33) of the 58 patients were successfully downstaged, resulting in a protocol-specified organ preservation rate of 57% (90% CI 45-68). Of note, this treatment had no radiation at all and only used chemotherapy. Of the remaining 23 patients, 13 declined total mesorectal excision (TME) and went into observation. Of the 10 patients who underwent TME, seven had no histopathologic evidence of residual disease. The 1- and 2-year locoregional relapse-free survival rates were 98% (95% CI 86-100) and 90% (95% CI 58-98), respectively, and there were no metastatic recurrences or deaths. Although this is a small study, the results are enormously encouraging, suggesting that organ preservation not only can be achieved in early-stage rectal cancer, but also can be accomplished using only chemotherapy, further reducing morbidity to patients.

The second study I want to discuss was conducted by Ciardiello and colleagues and concerns the KRAS^G12C mutation in colorectal cancer. This mutation is targetable in lung cancer and has led to the approval of sotorasib for the treatment of advanced KRAS^G12C non–small-cell lung cancer . Unfortunately, previous studies of these inhibitors in advanced KRAS^G12C colorectal cancer have yielded disappointing results.

This study looked retrospectively at 6952 cases of metastatic colorectal cancer across Italy. A total of 256 cases (3.7%) demonstrated the KRAS^G12C mutation. Of those, 111 met inclusion criteria and were included in the analysis. Of note, this mutation was associated with a poor response to first-line chemotherapy (38.7%), with a median progression-free survival of 9 months (95% CI 7.5-10.5 months). Median overall survival was 21 months (95% CI 17.4-24.6 months). There was little difference between first-line oxaliplatin-containing regimens compared with those containing irinotecan. Triplet therapy (folinic acid, fluorouracil, oxaliplatin, and irinotecan; FOLFOXIRI) was associated with an objective response rate of 56.3% with a progression-free survival of 13 months and median overall survival of 32 months, suggesting that triplet therapy might be a better approach for these patients when they are identified. This study is important because it corroborates and builds upon data reported in smaller studies demonstrating the general resistance of KRAS^G12C metastatic colorectal cancer to chemotherapeutic treatments.

As always, several provocative publications on colorectal cancer (CRC) have found their way into the medical literature. I will be discussing two of these in my Clinical Edge Journal Scan commentary for the month of October.

The first article, by Kennecke and colleagues, examines the role of neoadjuvant chemotherapy for early rectal cancer. We have been inundated with data showing that organ preservation is achievable in cases of node-positive rectal cancer with neoadjuvant chemoradiotherapy and chemotherapy (total neoadjuvant treatment [TNT] approach). As such, it stands to reason that organ preservation should also be achievable in cases of early, node-negative rectal cancer.

NEO was a single-arm, phase 2 trial examining the role of neoadjuvant chemotherapy only in early rectal cancer. In it, 58 patients with clinical T1-T3ab N0 low-to-mid rectal adenocarcinoma (proficient mismatch repair status) eligible for endoscopic resection were treated with 3 months of mFOLFOX6 (5-fluorouracil, leucovorin, and oxaliplatin) or CAPEOX (capecitabine and oxaliplatin). Those with evidence of tumor regression proceeded to transanal resection.

The primary endpoint was a protocol-specified organ preservation rate, defined as the proportion of patients with tumor downstaging to ypT0/T1 N0/X and who avoided radical surgery. Thirty-three (33) of the 58 patients were successfully downstaged, resulting in a protocol-specified organ preservation rate of 57% (90% CI 45-68). Of note, this treatment had no radiation at all and only used chemotherapy. Of the remaining 23 patients, 13 declined total mesorectal excision (TME) and went into observation. Of the 10 patients who underwent TME, seven had no histopathologic evidence of residual disease. The 1- and 2-year locoregional relapse-free survival rates were 98% (95% CI 86-100) and 90% (95% CI 58-98), respectively, and there were no metastatic recurrences or deaths. Although this is a small study, the results are enormously encouraging, suggesting that organ preservation not only can be achieved in early-stage rectal cancer, but also can be accomplished using only chemotherapy, further reducing morbidity to patients.

The second study I want to discuss was conducted by Ciardiello and colleagues and concerns the KRAS^G12C mutation in colorectal cancer. This mutation is targetable in lung cancer and has led to the approval of sotorasib for the treatment of advanced KRAS^G12C non–small-cell lung cancer . Unfortunately, previous studies of these inhibitors in advanced KRAS^G12C colorectal cancer have yielded disappointing results.

This study looked retrospectively at 6952 cases of metastatic colorectal cancer across Italy. A total of 256 cases (3.7%) demonstrated the KRAS^G12C mutation. Of those, 111 met inclusion criteria and were included in the analysis. Of note, this mutation was associated with a poor response to first-line chemotherapy (38.7%), with a median progression-free survival of 9 months (95% CI 7.5-10.5 months). Median overall survival was 21 months (95% CI 17.4-24.6 months). There was little difference between first-line oxaliplatin-containing regimens compared with those containing irinotecan. Triplet therapy (folinic acid, fluorouracil, oxaliplatin, and irinotecan; FOLFOXIRI) was associated with an objective response rate of 56.3% with a progression-free survival of 13 months and median overall survival of 32 months, suggesting that triplet therapy might be a better approach for these patients when they are identified. This study is important because it corroborates and builds upon data reported in smaller studies demonstrating the general resistance of KRAS^G12C metastatic colorectal cancer to chemotherapeutic treatments.