ECC 2013: Late Breaking Clinical Trials: EXPERT-C Trial results

Report by Esther Drain – Cetuximab resulted in a significant improvement in survival in TP53 WT, high-risk Rectal Cancer.
Neoadjuvant chemotherapy before standard chemotherapy was associated with promising long-term outcomes in high-risk rectal cancer patients and in TP53 wild type patients with high-risk rectal cancer, the addition of cetuximab resulted in a significant improvement in survival. These were the conclusions from 2 related presentations by Dr F Sclafani at the ECC 2013 conference in Amsterdam.

In the first presentation Sclafani explained that neoadjuvant chemoradiotherapy (CRT) or short course radiotherapy (RT) followed by TME is a standard treatment for locally advanced rectal cancer and although the local recurrence rate is less than10%, systemic relapse still occurs in around 25-30% of patients. Until now alternative multimodality strategies have in most cases failed to demonstrate a significant advantage over standard CRT. There is an acknowledged lack of validated prognostic or predictive biomarkers to guide optimal treatment selection for patients.

Dr Sclafani from the Royal Marsden Hospital in London presented an updated survival analysis of the EXPERT-C trial, a randomized phase II trial of neoadjuvant capecitabine and oxaliplatin (CAPOX) and chemoradiotherapy (CRT) with or without cetuximab in MRI-defined high risk rectal cancer patients.

EXPERT-C was a multicentre, randomised phase II trial of neoadjuvant CAPOX and CRT ± cetuximab in patients with MRI defined high-risk rectal cancer patients.Dr Sclafani explained

“ We have shown previously that the addition of cetuximab did not result in a significant improvement in complete response (CR) and progression-free survival (PFS). However, in the initial analysis, a statistically significant overall survival (OS) benefit was observed in the group of KRAS/BRAF wild type (WT) patients. We now report the survival outcomes with extended follow-up.”

Between October 2005 and July 2008, 164 eligible patients were randomly assigned to 4 cycles of CAPOX followed by capecitabine CRT, surgery, and 4 cycles of adjuvant CAPOX (n=81) or the same regimen plus weekly cetuximab (CAPOX-C, n=83). The primary endpoint was CR in KRAS/BRAF WT patients (n=90). PFS and OS in KRAS/BRAF WT and overall populations were secondary endpoints and estimated by using the Kaplan–Meier method.

After a median follow-up of 63.1 months (95%CI: 61.0–65.3) 52 events were observed, 28 in the CAPOX arm and 24 in the CAPOX-C arm. In the KRAS/BRAF WT group, the 5-year PFS rates were 67.8% (95%CI: 53.9–81.7) and 80.0% (95%CI: 68.2–91.8) for CAPOX and CAPOX-C, respectively (p=0.21). No difference in local and distant relapse rates between the two arms was found. The 5-year OS rates were 72.3% (95%CI: 59.0–85.6) and 84.3% (95%CI: 73.5–95.1) (p=0.20). In the entire population, the 5-year PFS rates were 64.8% (95%CI: 54.2–75.4) and 72.0% (95%CI: 62.2–81.8) for CAPOX and CAPOX-C, respectively (p=0.36). The 5-year OS rates were 68.5% (95%CI: 58.3–78.7) and 77.8% (95%CI: 68.8–86.8) (p=0.13). Irrespective of the treatment received, pathologic CR (pCR) was associated with a significant improvement in relapse-free survival (92.6% vs 73.7%, p=0.04) and OS (96.3% vs 77.3%, p=0.02).

Dr Sclafani concluded that neoadjuvant chemotherapy before standard CRT was associated with promising long-term outcomes in high-risk rectal cancer patients. Based on the absence of improvement in any of the study endpoints, cetuximab did not appear to be the optimal companion targeted agent to further increase the efficacy of this strategy. pCR was demonstrated to be a reliable surrogate end point for rectal cancer trials even in the context of intensified pre-operative regimens including induction chemotherapy.

In a related second presentation Sclafani highlighted thatfunctional p53 may predict response of rectal cancer (RC) to chemoradiotherapy (CRT). Moreover, evidence has recently emerged suggesting an association between p53 function and activity of anti-EGFRs. Sclafani explained that the researchers retrospectively analysed TP53 in EXPERT-C, a randomised phase II trial of neoadjuvant CAPOX and CRT ± cetuximab (Cmab) in MRI-defined high-risk RC.

The trial design was described where 164 eligible patients received 4 cycles of CAPOX followed by capecitabine CRT, surgery, and 4 cycles of adjuvant CAPOX (n=81) or the same regimen plus Cmab (CAPOX-C, n=83). Progression-free survival (PFS) and overall survival (OS) were estimated by using the Kaplan-Meier method. TP53 mutations (exons 4-9) were screened for by Capillary Electrophoresis-Single Strand Conformational Analysis. Comparison of the treatment arms was performed using a log-rank analysis. A significant interaction between treatment and TP53status was tested (Cox regression) and adjusted for prognostic variables and KRAS status in a multivariate model.

Sclafani presented the results that showed TP53 was analysed in 199 samples (102 biopsies, 97 resections). 90 (45.2%) had a mutation and 109 (54.8%) were wild-type (WT). Of 144 assessable patients, 69 (47.9%) were TP53 WT and 75 (52.1%) TP53 mutant (MUT).

After a median follow-up of 65 months, no difference in PFS (HR 1.21, p=0.59) and OS (HR 0.97, p=0.94) were observed between TP53 MUT patients treated with CAPOX or CAPOX-C. In contrast, in the group of TP53 WT patients, the addition of Cmab was associated with a statistically significant advantage in PFS (HR 0.23, p=0.02) and OS (HR 0.16, p=0.02). A statistically significant interaction between TP53 status and Cmab effect was found for both PFS (p=0.023) and OS (p=0.036). In multivariate analyses, this interaction remained significant even after adjusting for significant prognostic factors and KRAS status.

Sclafani concluded that In TP53 WT, high-risk RC, the addition of cetuximab resulted in a significant improvement in survival. TP53 emerged as a strong, independent predictive biomarker for cetuximab.

	CAPOX	CAPOX-C	HR (95%CI)	P value
TP53 WT (n=40) (n=29)
5-yr PFS	65.0 (50.3–79.7)	89.3 (77.9–100)	0.23 (0.07–0.78)	0.02
5-yr OS	67.5 (53.0–82.0)	92.7 (82.9–100)	0.16 (0.04–0.70)	0.02
TP53 MUT (n=35) (n=40)
5-yr PFS	60.9 (44.2–77.6)	52.3 (36.8–67.8)	1.21 (0.60–2.46)	0.59
5-yr OS	67.1 (51.2–83.0)	67.3 (52.8–81.8)	0.97 (0.44–2.13)	0.94

 

Abstract number: 2168 Analysis of EXPERT-C, a randomized phase II trial of neoadjuvant capecitabine and oxaliplatin (CAPOX) and chemoradiotherapy (CRT) with or without cetuximab in MRI-defined high risk rectal cancer patients
F. Sclafani(1), D. Cunningham(1), J. Tabernero(4), B. Glimelius(5), A. Cervantes(6), C. Peckitt(1), D. Tait(1), G. Brown(1), D. Gonzalez De Castro(1), I. Chau(1)

Abstract number: 7  : LATE BREAKING ABSTRACT: TP53 status may predict benefit from cetuximab in high-risk, locally advanced rectal cancer: Results of the EXPERT-C trial

F. Sclafani(1), D. Gonzalez(2), D. Cunningham(1), S. Hulkki Wilson(2), C. Peckitt(3), J. Tabernero(4), B. Glimelius(5), A. Cervantes(6), G. Brown(7), I. Chau(1)

(1)   The Royal Marsden NHS Foundation Trust, Medicine GI and Lymphoma Unit, Surrey and London, United Kingdom

(2)   The Royal Marsden NHS Foundation Trust, Molecular Diagnostics, Surrey and London, United Kingdom

(3)   The Royal Marsden NHS Foundation Trust, Research & Development Statistic Unit, Surrey and London, United Kingdom

(4)   Vall d’Hebron University Hospital, Medical Oncology, Barcelona, Spain

(5)   Akademiska Sjukhuset Uppsala, Department of Oncology Radiology and Clinical Immunology, Uppsala, Sweden

(6)   Institute of Health Research Hospital Clinic of Valencia, Hematology and Medical Oncology, Valencia, Spain

(7)   The Royal Marsden NHS Foundation Trust, Radiology, Surrey and London, United Kingdom: