Mutations within the EGFR signaling pathway: Influence on efficacy in FIRE-3—A randomized phase III study of FOLFIRI plus cetuximab or bevacizumab as first-line treatment for wild-type (WT) KRAS (exon 2) metastatic colorectal cancer (mCRC) patients.

2014 ◽  
Vol 32 (3_suppl) ◽  
pp. 445-445 ◽  
Author(s):  
Sebastian Stintzing ◽  
Andreas Jung ◽  
Lisa Rossius ◽  
Dominik Paul Modest ◽  
Ludwig Fischer von Weikersthal ◽  
...  
Keyword(s):  
Pik3ca Mutation ◽  
Braf V600e ◽  
Phase Iii ◽  
Line Treatment ◽  
First Line ◽  
Exon 2 ◽  
Ras Mutations ◽  
Egfr Signaling Pathway ◽  
Kras Exon ◽  
First Line Treatment

445 Background: The FIRE-3 study (AIO KRK-0306) was designed as a randomized multicenter trial to compare the efficacy of FOLFIRI plus cetuximab (cet) to FOLFIRI plus bevacizumab (bev) as first-line treatment in KRAS WT mCRC patients. FOLFIRI plus cet as first-line treatment of KRAS WT mCRC patients resulted in comparable overall response rates (ORR) and progression free survival (PFS) when compared to FOLFIRI plus bev. Overall survival (OS) was significantly longer in the FOLFIRI plus cet arm. Methods: In a preplanned analysis, the effect of mutations within the EGFR dependent pathway were investigated. Next to mutations within KRAS (exon 2, 3, 4), NRAS (exon 2, 3, 4) and BRAF (V600E), mutations within PIK3CA (exon 9 and 20) and Akt were investigated and their impact on ORR, PFS and OS within the FIRE-3 population was evaluated. The analysis of all mutations was carried out employing pyrosequencing. Results: The ITT population consisted of 592 KRAS WT (exon 2) patients. The current analysis includes 488 cases (82.4%) with tumor tissue available. In 407 pts sequencing of all RAS mutations was possible. The ORR within the WT RAS patient group was higher in the FOLFIRI plus cet arm (65.5% vs 59.6%; Fisher´s p: 0.157). HRs (cet; bev) for pts with WT RASwere 0.93 (95% CI, 0.74-1.17; p = 0.54) for PFS and 0.70 (95% CI, 0.53-0.92; p = 0.01) for OS. PIK3CA mutation did not influence PFS nor OS when compared to the RAS wt population. Conclusions: ORR and OS were increased in patients with cet plus FOLFIRI as compared to bev plus FOLFIRI in patients without RAS mutations. Exclusion of patients with RAS mutations identifies a population which is more likely to benefit from cetuximab. Clinical trial information: NCT00433927.

scholarly journals Fluorouracil, Leucovorin, and Irinotecan Plus Cetuximab Treatment and RAS Mutations in Colorectal Cancer

2015 ◽  
Vol 33 (7) ◽  
pp. 692-700 ◽  
Author(s):  
Eric Van Cutsem ◽  
Heinz-Josef Lenz ◽  
Claus-Henning Köhne ◽  
Volker Heinemann ◽  
Sabine Tejpar ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Significant Benefit ◽  
Phase Iii ◽  
Line Treatment ◽  
Wild Type ◽  
First Line ◽  
Exon 2 ◽  
Ras Mutations ◽  
Kras Exon ◽  
First Line Treatment

Purpose The phase III CRYSTAL study demonstrated that addition of cetuximab to fluorouracil, leucovorin, and irinotecan (FOLFIRI) significantly improved overall survival, progression-free survival, and objective response in the first-line treatment of patients with KRAS codon 12/13 (exon 2) wild-type metastatic colorectal cancer (mCRC). Outcome was reassessed in subgroups defined by extended RAS mutation testing. Patients and Methods Existing DNA samples from KRAS exon 2 wild-type tumors from CRYSTAL study patients were reanalyzed for other RAS mutations in four additional KRAS codons (exons 3 and 4) and six NRAS codons (exons 2, 3, and 4) using beads, emulsion, amplification, and magnetics technology. No tissue microdissection was performed. A ≥ 5% mutant allele cutoff was used to call mutations. Results Mutation status was evaluable in 430 (64.6%) of 666 patients with KRAS exon 2 wild-type tumors. Other RAS mutations were detected in 63 (14.7%) of 430 patients. In those with RAS wild-type tumors, a significant benefit across all efficacy end points was associated with the addition of cetuximab to FOLFIRI. In patients with other RAS tumor mutations, no difference in efficacy outcomes between treatment groups was seen. The safety profile in RAS subgroups was similar and in line with expectations. Conclusion In the first-line treatment of mCRC, patients with RAS wild-type tumors derived a significant benefit from the addition of cetuximab to FOLFIRI; patients with RAS tumor mutations did not. Molecular testing of tumors for all activating RAS mutations is essential before considering anti–epidermal growth factor receptor therapy, thereby allowing the further tailoring of cetuximab administration to maximize patient benefit.

PARADIGM study: A multicenter, randomized, phase III study of 5-fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) plus panitumumab or bevacizumab as first-line treatment in patients with RAS (KRAS/NRAS) wild-type metastatic colorectal cancer.

2016 ◽  
Vol 34 (4_suppl) ◽  
pp. TPS776-TPS776 ◽  
Author(s):  
Takayuki Yoshino ◽  
Hiroyuki Uetake ◽  
Katsuya Tsuchihara ◽  
Kohei Shitara ◽  
Kentaro Yamazaki ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Performance Status ◽  
Phase Iii ◽  
Type I ◽  
Line Treatment ◽  
Wild Type ◽  
First Line ◽  
Exon 2 ◽  
First Line Treatment

TPS776 Background: Optimal combination of monoclonal antibody (anti-VEGF vs. anti-EGFR antibody) with standard chemotherapy as first-line treatment in patients (pts) with RAS (KRAS/NRAS) wild-type metastatic colorectal cancer (mCRC) remains controversial. FIRE-3 study demonstrated a significant improvement in overall survival (OS) with anti-EGFR over bevacizumab in pts with KRAS exon 2 wild type mCRC, while CALGB 80405 study did not. PARADIGM study is designed to compare panitumumab vs. bevacizumab combined with mFOLFOX6 in pts with RAS wild-type chemotherapy-naive mCRC. Methods: Eligible pts are aged 20-79 years with ECOG performance status (PS) 0-1 and histologically/cytologically confirmed RAS wild-type mCRC. 800 pts will be randomly assigned in a 1:1 ratio to mFOLFOX6 plus panitumumab or bevacizumab, and stratified according to institution, age (20-64 vs. 65-79 years), and liver metastases (present vs. absent). Each treatment regimen includes oxaliplatin 85 mg/m2, l-leucovorin 200 mg/m2, 5-fluorouracil (5-FU) iv 400 mg/m2 at day 1, 5-FU civ 2400 mg/m2 at day 1-3, and either panitumumab 6 mg/kg or bevacizumab 5 mg/kg at day 1 every two weeks. The primary endpoint is the OS; the study was designed to detect the OS hazard ratio of 0.76, with a one-sided type I error of 0.025 and 80% power. Secondary efficacy endpoints include progression-free survival, response rate, duration of response, and curative resection rate. One interim analysis is planned for the OS when approximately 70% of the targeted 570 events has been observed. Exploratory endpoint is to investigate possible biomarkers including oncogenic mutations using tumor tissue and circulating tumor DNA (Study ID: NCT02394834). As of August 2015, 21 pts have been randomized and recruitment is ongoing. Clinical trial information: NCT02394795.

Liver resectability following S-1+L-OHP with cetuximab as the first-line treatment of unresectable liver limited metastases from KRAS exon 2 wild-colorectal cancer in Japanese patients (KSCC 1002).

2015 ◽  
Vol 33 (3_suppl) ◽  
pp. 755-755
Author(s):  
Yuji Miyamoto ◽  
Yasunori Emi ◽  
Shoji Tokunaga ◽  
Toru Beppu ◽  
Yoshihiro Kakeji ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Liver Resection ◽  
Line Treatment ◽  
Phase Ii Trials ◽  
First Line ◽  
Eligibility Criteria ◽  
Exon 2 ◽  
Ecog Ps ◽  
Kras Exon ◽  
First Line Treatment

755 Background: There is no data concerning liver resectability following S-1+L-OHP (C-SOX) with cetuximab (Cmab) as the first-line treatment of unresectable liver limited metastases from KRAS exon 2 wild-colorectal cancer by prospective, multi-center study in Japan. The Kyushu Study group of Clinical Cancer (KSCC) conducted phase II trials in this setting. Methods: Eligibility criteria included unresectable liver limited metastases from histologically confirmed advanced colorectal cancer, ECOG PS 0-1 and adequate general condition. Patients (pts) received 4-6 cycles of C-SOX (oxaliplatin 130 mg/m2, day 1 followed by S-1 80 mg/m2 po [days 1-14] every 3 weeks) with weekly durable intravenous (DIV) Cmab administration at 400 mg/m2 (day 1) and 250 mg/m2/week (except day 1), followed by evaluating the liver resectability. Results: Of the 33 pts enrolled from March 2010 to July 2013; M/F, 20/13; median age, 64 years (range 48-83); ECOG PS 0/1, 27/6; primary lesion -/+, 18/15; number of liver metastasis 1-4/5 or more, 10/23; uni-/bi-lobular liver meta. 5/28; synchronous/metachronous 30/3. The number of FAS and SAS cases was 33. Response without confirmation for CR, PR, SD, PD and NE were 1 (3.0%), 20 (60.6%), 6 (18.2%), 3 (9.1%) and 3 (9.1%), respectively. An overall response rate was 63.6% (95% CI: 46.3–81.0%). The liver resectability for all time treatment was 16/33 (48.5%). The number of R0 cases was 13 pts (39.4%). Median progression free survival (liver resection was not censored and not event, events = relapse, progression, secondary cancer, and death) for 16 liver resection cases and 17 not-resection cases were 25.0 months (8.1-not reached), 4.5 months (3.0-10.8), respectively. Median overall survival (mOS) for all 33cases was 31.6 months (14.8, not reached). Median OS for 17 not-resection cases was 14.0 (6.4-not reached), and mOS for 16 liver resection cases was not reached and 3-year survival rate was 51.4%. Conclusions: C-SOX + Cmab regimen is safe and effective for unresectable liver limited metastases from KRAS exon 2 wild-colorectal cancer, and might be to lead the high liver resectability. Clinical trial information: UMIN000004331.

Influence of adjuvant pretreatment on outcome of FIRE-3 (AIO KRK-0306): A randomized phase III study of FOLFIRI plus cetuximab or bevacizumab as first-line treatment for wild-type (WT) KRAS (exon 2) metastatic colorectal cancer (mCRC) patients.

2015 ◽  
Vol 33 (3_suppl) ◽  
pp. 515-515 ◽  
Author(s):  
Sebastian Stintzing ◽  
Dominik Paul Modest ◽  
Ludwig Fischer von Weikersthal ◽  
Thomas Decker ◽  
Alexander Kiani ◽  
...  
Keyword(s):  
Adjuvant Chemotherapy ◽  
Survival Data ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Rank Test ◽  
Line Treatment ◽  
Wild Type ◽  
First Line ◽  
Exon 2 ◽  
First Line Treatment

515 Background: The FIRE-3 study (AIO KRK-0306) was designed to compare the efficacy of FOLFIRI + cetuximab (cet) to FOLFIRI + bevacizumab (bev) as first-line treatment in KRAS WT mCRC patients. FOLFIRI plus cet resulted in comparable overall response rates (ORR) and progression free survival (PFS) when compared to FOLFIRI + bev. Overall survival (OS) was significantly longer in the FOLFIRI + cet arm. Methods: In an exploratory subgroup analysis, patients pretreated with adjuvant chemotherapy were analyzed by Fisher's exact and log rank-test according to tumor response (ORR) and survival data. Patients of the ITT (n=592) and the final RAS wild-type population (n=400) were investigated. Results: See table. Conclusions: Results in patients treated with any adjuvant chemotherapy mirrored those in the whole study population. In adjuvant pretreated RASwt patients a significantly higher ORR was reached in the cet arm when compared to the bev arm (p=0.01). The role of adjuvant treatment on efficacy of first-line therapy remains to be further evaluated. Clinical trial information: NCT00433927. [Table: see text] [Table: see text]

scholarly journals SABCS 2020: update on triple-negative and metastatic HER2-positive breast cancer

2021 ◽  
Author(s):  
Rupert Bartsch
Keyword(s):  
Breast Cancer ◽  
Triple Negative ◽  
Phase Iii ◽  
Line Treatment ◽  
First Line ◽  
Her2 Positive ◽  
Her2 Positive Breast Cancer ◽  
Pretreated Patients ◽  
First Line Treatment ◽  
Positive Breast Cancer

SummaryOne year into the severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) pandemic, the 2020 San Antonio Breast Cancer Symposium (SABCS) was another large congress held in a virtual format. Despite these circumstances, clinically relevant data were presented, and this short review focuses on developments in the fields of triple-negative breast cancer (TNBC) and metastatic HER2-positive breast cancer. A quality-of-life (QoL) analysis from IMPassion031 showed that adding atezolizumab to neoadjuvant chemotherapy was not associated with a detrimental effect on QoL, while the burden of treatment-induced side effects increased with each cycle of neoadjuvant therapy in both treatment arms. KEYNOTE-355 evaluated the addition of pembrolizumab to chemotherapy as first-line treatment in metastatic TNBC (mTNBC); a significant improvement of progression-free survival (PFS) was reported in the pembrolizumab arm. At the 2020 SABCS, results with respect to different chemotherapy backbones were reported and the benefit of pembrolizumab was maintained irrespective of the type of taxane. Disappointingly, the phase III IPATunity130 study could not confirm a PFS improvement with the AKT inhibitor ipatasertib when added to paclitaxel as first-line treatment in mTNBC. A biomarker analysis from the phase III ASCENT study showed that the antibody–drug conjugate sacituzumab govitecan was superior to chemotherapy by investigator’s choice independent of Trop‑2 expression and BRCA mutation status. In HER2-positive breast cancer, the PRECIOUS trial suggested a small albeit significant benefit with reinduction of pertuzumab in later treatment lines in patients progressing on prior dual HER2-blockade in the first- or second-line setting. The HER2-specific tyrosine kinase inhibitor tucatinib when added to trastuzumab and capecitabine was shown to improve PFS and overall survival (OS) over trastuzumab and capecitabine alone in pretreated patients in the randomized HER2CLIMB trial; this benefit was apparently independent of hormone-receptor expression. An update from the DESTINY-Breast01 trial reported a median PFS of 19.4 months with trastuzumab deruxtecan in heavily pretreated patients. Finally, an analysis from the PERTAIN trial with > 6 years median follow-up showed excellent OS in patients with luminal B/HER2-positive receiving first-line trastuzumab/pertuzumab in combination with endocrine therapy suggesting that chemotherapy-free treatment is an option in highly selected patients.

The cost-effectiveness of atezolizumab in first-line for metastatic triple negative breast cancer is heavily linked to PD-L1 level

2021 ◽  
pp. 107815522110194
Author(s):  
Jacopo Giuliani ◽  
Beatrice Mantoan ◽  
Andrea Bonetti
Keyword(s):  
Breast Cancer ◽  
Triple Negative ◽  
Controlled Trial ◽  
Metastatic Breast ◽  
Cost Effective ◽  
Phase Iii ◽  
Line Treatment ◽  
First Line ◽  
Pivotal Phase ◽  
First Line Treatment

The present analysis was conducted to assess the pharmacological costs of atezolizumab as first-line treatment in triple negative metastatic breast cancer (mBC). Pivotal phase III randomized controlled trial (RCT) was considered. Nine hundred and two patients were included. Differences in costs between the 2 arms (atezolizumab plus nabpaclitaxel versus placebo plus nab-paclitaxel) was 17 398 €, with a cost of 7564 €per month of OS-gain in the overall population and 2485 €per month of OS-gain in PD-L1-positive (≥1) population. Combining pharmacological costs of drugs with the measure of efficacy represented by the OS, atezolizumab could be considered cost-effective in first-line treatment for triple-negative mBC only in PD-L1-positive population, but a reduction of costs is mandatory.

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