Impact of the Specific Mutation in KRAS Codon 12 Mutated Tumors on Treatment Efficacy in Patients with Metastatic Colorectal Cancer Receiving Cetuximab-Based First-Line Therapy: A Pooled Analysis of Three Trials

Purpose: This study investigated the impact of specific mutations in codon 12 of the Kirsten-ras (KRAS) gene on treatment efficacy in patients with metastatic colorectal cancer (mCRC). Patients: Overall, 119 patients bearing a KRAS mutation in codon 12 were evaluated. All patients received cetuximab-based first-line chemotherapy within the Central European Cooperative Oncology Group (CECOG), AIO KRK-0104 or AIO KRK-0306 trials. Results: Patients with KRAS codon 12 mutant mCRC showed a broad range of outcome when treated with cetuximab-based first-line regimens. Patients with tumors bearing a KRAS p.G12D mutation showed a strong trend to a more favorable outcome compared to other mutations (overall survival 23.3 vs. 14-18 months; hazard ratio 0.66, range 0.43-1.03). An interaction model illustrated that KRAS p.G12C was associated with unfavorable outcome when treated with oxaliplatin plus cetuximab. Conclusion: The present analysis suggests that KRAS codon 12 mutation may not represent a homogeneous entity in mCRC when treated with cetuximab-based first-line therapy. Copyright (C) 2012 S. Karger AG, Base

Radiotherapeutic treatment options for oligotopic malignant liver lesions

Background: Several radiotherapeutic approaches for patients with oligotopic malignant liver lesions unfit for surgical resection exist. The most advanced competitive techniques are high-dose-rate (HDR) brachytherapy, Cyberknife, volume-modulated-arc therapy (VMAT) and Tomotherapy. We evaluated the optimal technique by a planning study for a single ablative dose with different lesion sizes. :Methods We compared dose distributions of HDR-brachytherapy with stereotactic ablative radiotherapy using the Cyberknife, VMAT or Tomotherapy. Tumor-control-probabilities (TCP), normal-tissue-complication-probabilities (NTCP) were determined in a theoretical framework applying a single dose of 20 Gy (demanding 95% coverage) for intrahepatic lesions of 1-5 cm in size. We evaluated therapeutic ratios by TCP (mean dose in the lesion) relative to high-dose (conformality) or low-dose liver exposition in dependency on the lesion size for each technique. In addition, we considered treatment times and accuracy (clinical target volume vs planning target volume). Results: HDR-brachtherapy has the highest therapeutic ratios with respect to high-dose as well as low-dose liver exposition even for extended lesions, and the Cyberknife being suited second best. However, for lesions >= 3 cm diameter the therapeutic ratios of all ablative techniques are increasingly converging, and better tolerance and shorter treatment times of noninvasive external techniques become more important. On the other hand, mean tumor doses of HDR-brachytherapy of near 60 Gy are unattainable by the other techniques gaining only 22-34 Gy, and the conformality of HDR-brachytherapy is still rather good for lesions >= 3 cm diameter. Conclusions: HDR-brachytherapy is by far the most effective technique to treat intrahepatic lesions by a single fraction, but sparing of the surroundings declines with increasing lesion size and approaches the benchmarks of external beam radiosurgery techniques. External beam radiotherapy has the advantage to use suitable fractionation schedules

Clinical relevance and utility of cetuximab-related changes in magnesium and calcium serum levels

Hypomagnesemia and hypocalcemia are common adverse events during cetuximab treatment. The influence of the chemotherapeutic combination on serum levels is unknown and the predictive value is currently under discussion. This analysis investigated 79 patients who had received cetuximab for at least 6 weeks in the day clinic of the Comprehensive Cancer Center, University of Munich. Calcium and magnesium serum levels were analyzed weekly; tumor response and adverse events were followed. Thirty-eight patients had metastatic colorectal cancer (mCRC) and the predictive value of hypomagnesemia was tested in these patients. During therapy, calcium serum levels decreased to about 97% of the baseline levels and were maintained for the duration of treatment. Magnesium levels showed a significant time-dependent decrease. Serum levels of magnesium were lower when cetuximab was combined with a platinum derivative. After a treatment duration of 12 weeks, magnesium levels decreased to 70% in platinum-treated patients, whereas they decreased to only 90% of baseline in patients who did not receive platinum therapy. In patients treated for mCRC, a decrease of serum magnesium below 95% of the baseline levels 14 days after initiating treatment separated patients significantly in terms of survival times. Magnesium levels decrease in a time-dependent manner during cetuximab therapy. As hypomagnesemia was more prominent in patients receiving platinum agents, magnesium measurements may be advised in these patients. In mCRC patients treated with cetuximab, day-14 magnesium serum levels correlated with treatment efficacy

Dynamics in treatment response and disease progression of metastatic colorectal cancer (mCRC) patients with focus on BRAF status and primary tumor location: analysis of untreated RAS-wild-type mCRC patients receiving FOLFOXIRI either with or without panitumumab in the VOLFI trial (AIO KRK0109)

Purpose: In mCRC, disease dynamics may play a critical role in the understanding of long-term outcome. We evaluated depth of response (DpR), time to DpR, and post-DpR survival as relevant endpoints. Methods: We analyzed DpR by central review of computer tomography images (change from baseline to smallest tumor diameter), early tumor shrinkage (≥ 20% reduction in tumor diameter at first reassessment), time to DpR (study randomization to DpR-image), post-DpR progression-free survival (pPFS = DpR-image to tumor progression or death), and post-DpR overall survival (pOS = DpR-image to death) with special focus on BRAF status in 66 patients and primary tumor site in 86 patients treated within the VOLFI-trial, respectively. Results: BRAF wild-type (BRAF-WT) compared to BRAF mutant (BRAF-MT) patients had greater DpR (− 57.6% vs. − 40.8%, p = 0.013) with a comparable time to DpR [4.0 (95% CI 3.1–4.4) vs. 3.9 (95% CI 2.5–5.5) months; p = 0.8852]. pPFS was 6.5 (95% CI 4.9–8.0) versus 2.6 (95% CI 1.2–4.0) months in favor of BRAF-WT patients (HR 0.24 (95% CI 0.11–0.53); p < 0.001). This transferred into a significant difference in pOS [33.6 (95% CI 26.0–41.3) vs. 5.4 (95% CI 5.0–5.9) months; HR 0.27 (95% CI 0.13–0.55); p < 0.001]. Similar observations were made for patients stratified for primary tumor site. Conclusions: BRAF-MT patients derive a less profound treatment response compared to BRAF-WT patients. The difference in outcome according to BRAF status is evident after achievement of DpR with BRAF-MT patients hardly deriving any further disease control beyond DpR. Our observations hint towards an aggressive tumor evolution in BRAF-MT tumors, which may already be molecularly detectable at the time of DpR

Study protocol of the FIRE-8 (AIO-KRK/YMO-0519) trial: a prospective, randomized, open-label, multicenter phase II trial investigating the efficacy of trifluridine/tipiracil plus panitumumab versus trifluridine/tipiracil plus bevacizumab as first-line treatment in patients with metastatic colorectal cancer

Background: Initial systemic therapy for patients with metastatic colorectal cancer (mCRC) is usually based on two- or three-drug chemotherapy regimens with fluoropyrimidine (5-fluorouracil (5-FU) or capecitabine), oxaliplatin and/or irinotecan, combined with either anti-VEGF (bevacizumab) or, for RAS wild-type (WT) tumors, anti-EGFR antibodies (panitumumab or cetuximab). Recommendations for patients who are not eligible for intensive combination therapies are limited and include fluoropyrimidine plus bevacizumab or single agent anti-EGFR antibody treatment. The use of a monochemotherapy concept of trifluridine/ tipiracil in combination with monoclonal antibodies is not approved for first-line therapy, yet. Results from the phase II TASCO trial evaluating trifluridine/tipiracil plus bevacicumab in first-line treatment of mCRC patients and from the phase I/II APOLLON trial investigating trifluridine/tipiracil plus panitumumab in pre-treated mCRC patients suggest favourable activity and tolerability of these new therapeutic approaches. Methods: FIRE-8 (NCT05007132) is a prospective, randomized, open-label, multicenter phase II study which aims to evaluate the efficacy of first-line treatment with trifluridine/tipiracil (35 mg/m(2) body surface area (BSA), orally twice daily on days 1-5 and 8-12, q28 days) plus either the anti-EGFR antibody panitumumab (6 mg/kg body weight, intravenously on day 1 and 15, q28 days) [arm A] or (as control arm) the anti-VEGF antibody bevacizumab (5 mg/kg body weight, intravenously on day 1 and 15, q28 days) [arm B] in RAS WT mCRC patients. The primary objective is to demonstrate an improved objective response rate (ORR) according to RECIST 1.1 from 30% (control arm) to 55% with panitumumab. With a power of 80% and a two-sided significance level of 0.05, 138 evaluable patients are needed. Given an estimated drop-out rate of 10%, 153 patients will be enrolled. Discussion: To the best of our knowledge, this is the first phase II trial to evaluate the efficacy of trifluridine/tipiracil plus panitumumab in first-line treatment of RAS WT mCRC patients. The administration of anti-EGFR antibodies rather than anti-VEGF antibodies in combination with trifluridine/tipiracil may result in an increased initial efficacy

Prevalence and influence on outcome of HER2/neu, HER3 and NRG1 expression in patients with metastatic colorectal cancer

Our aim was to explore the impact of the HER2/neu, HER3 receptor as well as their ligands' neuregulin (NRG1) expression on the outcome of patients with metastatic colorectal cancer (mCRC). NRG1, HER2/neu and HER3 expression was evaluated in 208 patients with mCRC receiving 5-FU/LV plus irinotecan or irinotecan plus oxaliplatin as the first-line treatment. Biomarker expression was correlated with the outcome of patients. NRG1 (low: 192 vs. high: 16), HER2/neu (low: 201 vs. high: 7) and HER3 (low: 69 vs. high: 139) expressions were assessed in 208 patients. High versus low NRG1 expression significantly affected progression-free survival (PFS) 4.7 vs. 8.2 months, hazard ratio (HR): 2.45; 95{\%} confidence interval (CI): 1.45-4.13; P=0.001, but not overall survival (OS) (15.5 vs. 20.7 months, HR: 1.33; 95{\%} CI: 0.76-2.35; P=0.32). High versus low HER3 expression (PFS: 7.1 vs. 8.8 months, HR: 1.11; 95{\%} CI: 0.82-1.50; P=0.50; OS: 19.8 vs. 21.1 months, HR: 0.95; 95{\%} CI: 0.70-1.30; P=0.75) and high compared with low HER2/neu expression (PFS: 7.7 vs. 8.0 months, HR: 1.07; 95{\%} CI: 0.71-1.60; P=0.75; OS: 16.6 vs. 21.1 months, HR: 1.13; 95{\%} CI: 0.75-1.71; P=0.57) did not influence outcome. High NRG1 expression was associated with inferior PFS in the FIRE-1 trial. We did not detect a prognostic impact of HER2/neu and HER3 overexpression in mCRC. The frequency of overexpression was comparable with other studies

Outcome according to KRAS-, NRAS- and BRAF-mutation as well as KRAS mutation variants: pooled analysis of five randomized trials in metastatic colorectal cancer by the AIO colorectal cancer study group

BACKGROUND: To explore the impact of KRAS, NRAS and BRAF mutations as well as KRAS mutation variants in patients with metastatic colorectal cancer (mCRC) receiving first-line therapy. PATIENTS AND METHODS: A total of 1239 patients from five randomized trials (FIRE-1, FIRE-3, AIOKRK0207, AIOKRK0604, RO91) were included into the analysis. Outcome was evaluated by the Kaplan-Meier method, log-rank tests and Cox models. RESULTS: In 664 tumors, no mutation was detected, 462 tumors were diagnosed with KRAS-, 39 patients with NRAS- and 74 patients with BRAF-mutation. Mutations in KRAS were associated with inferior progression-free survival (PFS) and overall survival (OS) [multivariate hazard ratio (HR) for PFS: 1.20 (1.02-1.42), P = 0.03; multivariate HR for OS: 1.41 (1.17-1.70), P < 0.001]. BRAF mutation was also associated with inferior PFS [multivariate HR: 2.19 (1.59-3.02), P < 0.001] and OS [multivariate HR: 2.99 (2.10-4.25), P < 0.001]. Among specific KRAS mutation variants, the KRAS G12C-variant (n = 28) correlated with inferior OS compared with unmutated tumors [multivariate HR 2.26 (1.25-4.1), P = 0.001]. A similar trend for OS was seen in the KRAS G13D-variant [n = 71, multivariate HR 1.46 (0.96-2.22), P = 0.10]. More frequent KRAS exon 2 variants like G12D [n = 152, multivariate HR 1.17 (0.86-1.6), P = 0.81] and G12V [n = 92, multivariate HR 1.27 (0.87-1.86), P = 0.57] did not have significant impact on OS. CONCLUSION: Mutations in KRAS and BRAF were associated with inferior PFS and OS of mCRC patients compared with patients with non-mutated tumors. KRAS exon 2 mutation variants were associated with heterogeneous outcome compared with unmutated tumors with KRAS G12C and G13D (trend) being associated with rather poor survival