Practice Update | Onology

COLON & RECTUM 24

First-line chemotherapy combined with cetuximab or bevacizumab for KRAS wild-type advanced or metastatic colorectal cancer JAMA: The Journal of the American Medical Association Take-home message • This study evaluated the addition of cetuximab versus bevacizumab to FOLFOX6 or FOLFIRI in 1137 patients with previously untreated advanced or metastatic KRAS wild-type colorectal cancer. Median OS was 30.0 months in the cetuximab-chemotherapy group and 29.0 months in the bevacizumab-chemotherapy group (HR, 0.88; P = 0.08). Median PFS was 10.5 months in the cetuximab-chemotherapy group and 10.6 months in the bevacizumab-chemotherapy (HR, 0.95; P = 0.45). Response rates were not significantly different for cetuximab and bevacizumab (59.6% vs 55.2%, respectively; difference, 4.4%; P = 0.13). • There is no significant difference between the addition of cetuximab or bevacizumab to chemotherapy with regard to OS or PFS in patients with untreated advanced or metastatic KRAS wild-type colorectal cancer. Abstract IMPORTANCE Combining biologic monoclonal antibodies with chemotherapeutic cytotoxic drugs provides clinical benefit to patients with advanced or metastatic colorectal can- cer, but the optimal choice of the initial biologic therapy in previously untreated patients is unknown. OBJECTIVE To determine if the addition of cetuximab vs bevacizumab to the combination of leucovorin, fluorouracil, and oxaliplatin (mFOLFOX6) regimen or the combination of leucovorin, fluorouracil, and irinotecan (FOLFIRI) regimen is superior as first-line therapy in advanced or metastatic KRAS wild-type (wt) colorectal cancer. DESIGN, SETTING, AND PARTICIPANTS Patients (≥18 years) enrolled at community and academic centers throughout the National Clinical Trials Network in the United States and Canada (November 2005–March 2012) with previously untreated advanced or metastatic colorectal cancer whose tumors were KRAS wt chose to take either the mFOLFOX6 regimen or the FOLFIRI regimen as chemotherapy and were randomized to receive either cetuximab (n=578) or bevacizumab (n=559). The last date of follow-up was December 15, 2015. INTERVENTIONS Cetuximab vs bevacizumab combined with either mFOLFOX6 or FOLFIRI chemotherapy regimen chosen by the treating physician and patient. MAIN OUTCOMES AND MEASURES The primary end point was overall survival. Secondary objectives included progression-free survival and overall response rate, site-reported confirmed or unconfirmed complete or partial response. RESULTS Among 1137 patients (median age, 59 years; 440 [39%] women), 1074 (94%) of patients met eligibility criteria. As of December 15, 2015, median follow-up for 263 surviv- ing patients was 47.4 months (range, 0–110.7 months), and 82% of patients (938 of 1137) experienced disease progression. The median overall survival was 30.0 months in the cetuximab-chemotherapy group and 29.0 months in the bevacizumab-chemotherapy group with a stratified hazard ratio (HR) of 0.88 (95% CI, 0.77–1.01; P=0.08). The median progression-free survival was 10.5 months in the cetuximab-chemotherapy group and 10.6 months in the bevacizumab-chemotherapy group with a stratified HR of 0.95 (95% CI, 0.84–1.08; P=0.45). Response rates were not significantly different, 59.6% vs 55.2% for cetuximab and bevacizumab, respectively (difference, 4.4%, 95% CI, 1.0–9.0%, P=0.13). CONCLUSIONS AND RELEVANCE Among patients with KRAS wt untreated advanced or met- astatic colorectal cancer, there was no significant difference in overall survival between the addition of cetuximab vs bevacizumab to chemotherapy as initial biologic treatment. Effect of first-line chemotherapy combined with cetuximab or bevacizumab on over- all survival in patients with KRAS wild-type advanced or metastatic colorectal cancer: a randomized clinical trial. JAMA 2017 Jun 20;317(23)2392-2401, AP Venook, D Nied- zwiecki, HJ Lenz, et al.

Clinical implications of monitoring circulating tumor DNA in patients with colorectal cancer Clinical Cancer Research Take-home message • This longitudinal cohort study was designed to evaluate the predictive value of circu- lating tumor DNA (ctDNA) for recurrence in 45 patients who underwent resection for colorectal cancer. A total of 371 plasma samples were analyzed. Samples from 27 patients were positive for ctDNA postop- eratively in the 14 who had relapsed but in none of the non-relapsing patients. Relapse was detected at a lead time of 9.4 months compared with detection using CT imaging. The ctDNA levels appeared to correlate with changes in tumor volume. • The authors concluded that ctDNA serves as a reliable marker of residual disease and identifies patients at very high risk of relapse. Abstract PURPOSE We investigated if detection of circulating tumor DNA (ctDNA) after resection of colorectal cancer (CRC) identifies the patients with the highest risk of relapse, and furthermore, whether longitudinal ctDNA analysis allows early detection of relapse and informs about response to intervention. EXPERIMENTAL DESIGN In this longitudinal cohort study we used massively parallel sequencing to identify somatic mutations and used these as ctDNA markers to detect minimal residual disease and to monitor changes in tumor burden during a three year follow-up period. RESULTS A total of 45 patients and 371 plasma samples were included. Longitudinal samples from 27 patients revealed ctDNA post-operatively in all relapsing patients (n=14), but not in any of the non-relapsing patients. ctDNA detected relapse with an average lead-time of 9.4 months compared to CT imaging. Of 21 patients treated for local- ized disease, six had ctDNA detected within 3 months post-surgery. All six later relapsed compared to four of the remaining patients (Hazard ratio (HR), 37.7, 95% con- fidence interval (CI), 4.2–335.5; P<0.001). The ability of a 3 month ctDNA analysis to predict relapse was confirmed in 23 liver metastasis patients (HR 4.9; 95% CI, 1.5–15.7; P=0.007). Changes in ctDNA levels induced by relapse intervention (n=19) showed good agreement with changes in tumor volume (Kappa=0.41, Spearman’s rho=0.4). CONCLUSIONS Postoperative ctDNA detection provides evidence of residual disease and identifies patients at very high risk of relapse. Longitudinal surveillance enables early detection of relapse and informs about response to intervention. These observations have implications for the post-operative management of CRC patients. Clinical implications of monitoring circulating tumor DNA in patients with colorectal cancer. Clin Cancer Res 2017 Jun 09;[EPub Ahead of Print], LV Schøler, T Reinert, MW Ørntoft, et al.

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