Dataset Information

Patients with RAS wild-type right-sided unresectable liver-confined mCRC also benefit from cetuximab plus chemotherapy in first-line treatment.

ABSTRACT: Growing evidence indicates that primary tumor location of metastatic colorectal cancer (mCRC) can affect response to specific therapy. This study aimed to assess the impact of primary tumor location on efficacy of cetuximab in Chinese patients with mCRC. We included patients with RAS wild-type liver-limited mCRC treated with first-line cetuximab plus chemotherapy or chemotherapy alone between June 2008 and December 2016. All patients were categorized as having left-sided tumors or right-sided tumors. Progression free survival (PFS), overall survival (OS), objective response rate (ORR) and conversion rate of surgery for liver metastases was analyzed according to tumor location and treatment. Right-sided tumors were characterized with larger primary tumor, poorer differentiation, more lymph node metastases and larger and more liver metastases. For patients with left-sided tumors (N=233), addition of cetuximab to chemotherapy significantly improved ORR (68.9% vs. 30.6%, OR=5.01, P < 0.001), conversion rate of liver surgery (33.5% vs. 10.8%, OR=4.18, P < 0.001), PFS (12.1 months vs. 6.1 months, HR=0.42, P < 0.001), and OS (not evaluable vs. 23.1 months, HR=0.31, P < 0.001). Among patients with right-sided tumors (N=85), cetuximab plus chemotherapy, compared with chemotherapy alone, also significantly improved ORR (56.8% vs. 29.3%, OR=3.18, P=0.010), PFS (9.3 months vs. 5.1 months, OR=0.57, P=0.012) and OS (25.3 months vs. 16.8 months, HR=0.56, P=0.032) but conversion rate of liver surgery (20.5% vs. 9.8%, HR=2.38, P=0.171). Our results demonstrated differential effect of cetuximab on efficacy outcomes based on tumor sidedness. Also, we found that patients with right-sided tumors also benefit from cetuximab plus chemotherapy but not as great as left-sided tumors and in general, did worse. In conclusion, findings of previous studies about differential effect of anti-EGFR therapy based on tumor sidedness are applicable to an Asian population.

SUBMITTER: Zheng P

PROVIDER: S-EPMC6291650 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Patients with RAS wild-type right-sided unresectable liver-confined mCRC also benefit from cetuximab plus chemotherapy in first-line treatment.

Zheng Peng P Ren Li L Feng Qingyang Q Zhu Dexiang D Chang Wenju W He Guodong G Ji Meiling M Jian Mi M Lin Qi Q Yi Tuo T Wei Ye Y Xu Jianmin J

American journal of cancer research 20181101 11

Growing evidence indicates that primary tumor location of metastatic colorectal cancer (mCRC) can affect response to specific therapy. This study aimed to assess the impact of primary tumor location on efficacy of cetuximab in Chinese patients with mCRC. We included patients with RAS wild-type liver-limited mCRC treated with first-line cetuximab plus chemotherapy or chemotherapy alone between June 2008 and December 2016. All patients were categorized as having left-sided tumors or right-sided tu ...[more]

PMID: 30555748

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Project description:IntroductionImmunotherapy has limited efficacy in metastatic colorectal cancer (mCRC). Understanding mechanisms mediating immune resistance in microsatellite stable (MSS) colorectal tumors remains an ongoing challenge. Novel combination immunotherapy-based approaches have been developed under the rationale of overcoming immune resistance and developing effective immune response against colorectal tumor cells. Preclinical studies have demonstrated that cetuximab may modulate immune response to cancer cells. In this scenario, the inhibition of PD-L1 with IgG1 MAb avelumab in combination with anti-EGFR IgG1 monoclonal antibody cetuximab could be a strategy for potentiating antitumor activity. The CAVE phase II single-arm clinical trial provided the first evidence of clinical activity of combining cetuximab plus avelumab in 77 patients with RAS wild-type (WT) mCRC. This combination had a good toxicity profile, with a low rate of common grade 3 adverse events.Patients and methodsBased on results obtained with the CAVE clinical trial, here we describe the design and rationale for the phase II, randomized CAVE 2 clinical study of the combination of avelumab plus cetuximab as a rechallenge strategy in pre-treated RAS, BRAF WT mCRC patients treated in first line with chemotherapy in combination with cetuximab and who have had a clinical benefit (complete or partial response) from treatment. A total of 173 patients will be randomized (2:1) to cetuximab + avelumab (115) or cetuximab as a single agent (58). The primary endpoint is overall survival. Key secondary endpoints include overall response rate, progression-free survival, and safety. For each patient, before treatment, a blood sample will be obtained and analyzed for circulating free tumor DNA according to NGS (Foundation/Roche), to identify RAS/BRAF WT patients to be enrolled. The same procedure will be performed at the progression of the disease. Additional blood/plasma, tumor, and fecal samples will be collected and centrally stored for additional translational studies.DiscussionThis study will provide the rationale to test immunotherapy-based combinations in the clinical setting, offering new opportunities for RAS WT mCRC patients.Clinical trial registration[https://clinicaltrials.gov/ct2/show/NCT05291156], identifier [NCT05291156].

Project description:BackgroundThe OPUS study demonstrated that addition of cetuximab to 5-fluorouracil, folinic acid and oxaliplatin (FOLFOX4) significantly improved objective response and progression-free survival (PFS) in the first-line treatment of patients with KRAS exon 2 wild-type metastatic colorectal cancer (mCRC). In patients with KRAS exon 2 mutations, a detrimental effect was seen upon addition of cetuximab to FOLFOX4. The current study reports outcomes in subgroups defined by extended RAS testing.Patients and methodsSamples from OPUS study KRAS exon 2 wild-type tumours were reanalysed for other RAS mutations in four additional KRAS codons (exons 3-4) and six NRAS codons (exons 2-4) using BEAMing. A cutoff of ⩾5% mutant/wild-type sequences was selected to define RAS status; we also report an analysis using a cutoff based on the technical lower limit for mutation identification (0.1%).ResultsOther RAS mutations were detected in 31/118 (26%) evaluable patients. In the extended analysis of RAS wild-type tumours (n=87), objective response was significantly improved by addition of cetuximab to FOLFOX4 (58% versus 29%; odds ratio 3.33 [95% confidence interval 1.36-8.17]; P=0.0084); although limited by population size, there also appeared to be trends favouring the cetuximab arm in terms of PFS and overall survival in the RAS wild-type group compared with the RAS evaluable group. There was no evidence that patients with other RAS mutations benefited from cetuximab, but small numbers precluded precise estimations of treatment effects. In the combined population of patients with any RAS mutation (KRAS exon 2 or other RAS), a clear detrimental effect was associated with addition of cetuximab to FOLFOX4.ConclusionPatients with RAS-mutant mCRC, as defined by mutations in KRAS and NRAS exons 2-4, derive no benefit and may be harmed by the addition of cetuximab to FOLFOX4. Restricting cetuximab administration to patients with RAS wild-type tumours will further tailor therapy to maximise benefit.

Dataset Information

Patients with RAS wild-type right-sided unresectable liver-confined mCRC also benefit from cetuximab plus chemotherapy in first-line treatment.

Publications

Patients with RAS wild-type right-sided unresectable liver-confined mCRC also benefit from cetuximab plus chemotherapy in first-line treatment.

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