Studies Confirm Regorafenib Benefit in Pre-Treated Metastatic Colorectal Cancer

BARCELONA-LUGANO, 3 July 2015 – The phase IIIb CONSIGN study has confirmed the benefit of regorafenib in patients with previously treated metastatic colorectal cancer (mCRC), researchers announced at the ESMO 17th World Congress on Gastrointestinal Cancer 2015 in Barcelona.(1) The safety profile and progression free survival were similar to phase III trial results.

CONSIGN was a prospective, observational study that was initiated to allow patients with mCRC access to regorafenib before marketing authorisation and to assess safety, which was the primary endpoint. The randomised phase III CORRECT trial previously showed that regorafenib significantly improves survival in patients with pre-treated mCRC and led to regulatory approval.

“We began CONSIGN at the suggestion of the authorities and to fulfil the wishes of patients and doctors for a larger expanded access,” said lead study author Prof Eric Van Cutsem from University Hospitals Leuven, Belgium. “Today we report on safety and progression-free survival in a large cohort of patients that more closely resembles daily clinical practice than the pivotal registration trial.”

CONSIGN included more than 2,800 patients at 188 sites in 25 countries who received regorafenib for a median of 2.5 months. Grade >3 adverse events occurred in 80% of patients. The estimated progression-free survival was 2.7 months and was similar across KRAS wild type and mutant subgroups.

Van Cutsem said: “This study in a real world population of patients with pre-treated mCRC shows a similar safety profile and progression-free survival with regorafenib as shown in the randomised CORRECT trial. The findings add to our knowledge of how to select patients and how to manage toxicities. We need to establish clear guidelines on the management of adverse events to make taking the drug more tolerable for patients.”

Commenting on the data, Dr Dirk Arnold, ESMO spokesperson, director of the Department of Medical Oncology, Klinik für Tumorbiologie in Freiburg, Germany, said: “CONSIGN confirms the efficacy and safety data of the randomised phase III CORRECT and CONCUR trials. The merit of CONSIGN is that it translates phase III data into the clinical routine since patients had similar characteristics and pre-treatment to what we see in daily practice.”

The adverse events reported in CONSIGN were within the scope of expectation and comparable to the CORRECT trial, added Arnold. “There were no surprising findings in terms of toxicity,” he said. “All of the adverse events were quite class specific and also likely manageable.”

He added: “CONSIGN depicts what we would expect from an observational trial in this setting. It shows that we have further treatment options for mCRC patients pre-treated with chemotherapy, and that this comes at the cost of a specific, but manageable toxicity profile.”

Regarding the next step in this research area, Arnold said: “Biomarkers have been extensively investigated in the randomised trials but until now nothing has been found that would allow prediction of the benefit of regorafenib for a specific group of patients. I would suggest having a further look at the data in the observational CONSIGN study to see if there are clinical characteristics that identify patients who could benefit more or less from this treatment.”

Less pre-treatment may explain larger gain of overall survival with regorafenib in CONCUR trial compared to CORRECT trial

An analysis of the characteristics and outcomes of patients in the CONCUR and CORRECT trials has confirmed the clinical benefit of regorafenib in patients with previously treated metastatic colorectal cancer.(2) Overall survival improved in Asian and non-Asian patients and adverse events were similar across the two trials.

Commenting on the data, Dirk Arnold said: “Patients in the CORRECT trial were more heavily pretreated than patients in the CONCUR trial. For example, all patients in CORRECT had pretreatment with anti-VEGF and about 50% had pre-treatment with an anti-EGFR. In the CONCUR trial about 60% of patients had pre-treatment with any of these two compounds, and 40% were not pre-treated with a targeted biological treatment.”

He continued: “The differences in pre-treatment may be responsible for the better outcome of patients getting active treatment in the CONCUR trial compared to the CORRECT trial. The hypothesis could be made that less pre-treatment allows a larger gain of overall survival by adding a drug like regorafenib in this setting.”

Arnold concluded: “The main difference between the two trials is that all patients in CONCUR were of Asian origin whereas only 15% of patients had an Asian background in CORRECT. It’s not clear whether it is ethnicity or pre-treatment that brings the difference in benefit, but very likely it’s the pre-treatment.”

TAS-102 improves survival across KRAS gene status in metastatic colorectal cancer

A subgroup analysis of the phase III RECOURSE trial in metastatic colorectal cancer has shown that TAS-102 was associated with improved overall survival and progression-free survival in patients with KRAS wild type and mutant tumours.(3) The overall survival benefit in patients with KRAS mutant tumours did not reach statistical significance.

The pre-specified analysis investigated outcome and toxicity in relation to KRAS and BRAF mutant status. The latter group was too small to allow meaningful conclusions.
Commenting on the data, Dirk Arnold said: “Overall there were no large differences in efficacy or in the incidence of adverse events according to KRAS status. However, patients with wild type status had a better outcome than those with mutant status. That underlines our knowledge that the mutation confers a poorer prognosis, now also proven in largely pre-treated patients, and not that TAS-102 is less effective in these patients.”

He added: “There were no differences in adverse events between mutant and wild type groups. This is also not surprising because as far as we know the mechanism of action of TAS-102 is not correlated to KRAS or BRAF mutational status.”

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References
1. Abstract LBA-05 ‘Results from the large, open-label phase 3b CONSIGN study of regorafenib in patients with previously treated metastatic colorectal cancer’ will be presented by Eric Van Cutsem during Session X: Presentation of Selected Abstracts: Colorectal Cancer on Friday 3 July, 8:00.
2. Abstract O-0011 ‘Characteristics and outcomes of patients enrolled in the CORRECT and CONCUR phase 3 trials of regorafenib for metastatic colorectal cancer (mCRC) will be presented by Axel Grothey during Session X: Presentation of Selected Abstracts: Colorectal Cancer on Friday 3 July, 8:00.
3. Abstract O-0010 ‘KRAS and BRAF gene subgroup analysis in the Phase 3 RECOURSE trial of TAS-102 versus placebo in patients with metastatic colorectal cancer’ will be presented by Howard Hochster during Session X: Presentation of Selected Abstracts: Colorectal Cancer on Friday 3 July, 8:00.

LBA-05
Results from the large, open-label phase 3b CONSIGN study of regorafenib in patients with previously treated metastatic colorectal cancer   
E. Van Cutsem1, F. Ciardiello2, J-F. Seitz3, R. Hofheinz4, U. Verma5, R. Garcia-Carbonero6, A. Grothey7, A. Miriyala7, J. Kalmus8, JA. Shapiro9, A. Falcone10, A. Zaniboni11 1Leuven Cancer Institute, University Hospitals Leuven, Leuven, Belgium, 2Seconda Universita Degli Studi Di Napoli, Naples, Italy, 3Aix-Marseille University, Marseille, France, 4Universitaetsmedizin Mannheim, Mannheim, Germany, 5University of Texas Southwestern Medical Center, Dallas, Texas, 6Hospital Universitario Virgen del Rocío Instituto de Biomedicina de Sevilla (IBIS), Sevilla, Spain, 7Mayo Clinic, Rochester, Minnesota, 8Bayer Pharma AG, Berlin, Germany, 9Bayer HealthCare Pharmaceuticals, Whippany, New Jersey, 10Department of Translational Research and New Technologies In Medicine, University of Pisa, Pisa, Italy, 11U.O. Oncologia Medica, Casa di Cura Poliambulanza, Brescia, Italy
Introduction: Regorafenib is an oral multikinase inhibitor that targets tumor angiogenesis, oncogenesis, and the tumor microenvironment. The CORRECT phase 3 trial showed that regorafenib significantly improves survival compared with placebo in patients with previously treated metastatic colorectal cancer (mCRC) and led to regulatory approval in this setting. CONSIGN (NCT01538680) was initiated to allow patients with mCRC access to regorafenib before marketing authorization and to characterize the safety of regorafenib in a large cohort of patients (primary objective).
Methods: CONSIGN was a prospective, open-label, single-arm study carried out at 188 sites in 25 countries. Patients with mCRC who progressed after approved standard therapies and had ECOG performance status (PS) 0─1 received regorafenib 160 mg once daily for the first 3 weeks of each 4-week cycle. Treatment was continued until disease progression, death, or unacceptable toxicity; treatment beyond progression was at the investigator’s discretion. The primary endpoint was safety. Progression-free survival (PFS) (per investigator assessment) was the only efficacy variable assessed.
Results: A total of 2872 patients were assigned to treatment from April 2012 to December 2013. The cut-off date for this analysis was January 2, 2015. The safety analysis includes 2864 patients who received treatment. Patients were a median 62 years of age, 53% had an ECOG PS of 1, and 47% had an ECOG PS of 0. Fifty-one percent of patients had a KRAS mutation; 96% had received ≥2 prior regimens for metastatic disease. The median duration of treatment was 2.5 months (range 0─30). NCI-CTCAE v4.0 grade ≥3 adverse events (AEs) occurred in 80% of patients (Table). Grade 5 treatment-emergent AEs occurred in 16% of patients, but were deemed drug-related in 0.5%. Grade ≥3 treatmentemergent hepatobiliary disorders occurred in 4% of patients. Treatment-emergent laboratory toxicities with grades ≥3 included increased bilirubin (13%), increased aspartate aminotransferase (AST; 7%), increased alanine aminotransferase (ALT; 6%), anemia (4%), thrombocytopenia (2%), and neutropenia (1%). One non-fatal case of severe drug-induced liver injury according to International DILI Working Group criteria (Aithal et al. 2011) was identified. Estimated median PFS was 2.7 (95% CI: 2.6‒2.7) months (2.8 months KRAS wild-type, 2.5 months KRAS mutant).
Conclusion: In this large, prospective study in patients with previously treated mCRC, the safety profile of regorafenib was consistent with data from phase 3 trials in mCRC. PFS was in the range of that reported with regorafenib in this setting and similar across KRAS wild-type and mutant subgroups.

Results from

O-0010
KRAS and BRAF gene subgroup analysis in the Phase 3 RECOURSE trial of TAS-102 versus placebo in patients with metastatic colorectal cancer
H. Hochster1, S. Hager2, J.M. Pipas3, N. Tebbutt4, S. Laurent5, C. Gravalos6, M. Benavides7, F. Longo Munoz8, F. Portales9, F. Ciardiello10, S. Siena11, K. Yamaguchi12, K. Muro13, T. Denda14, Y. Tsuji15, A. Ohtsu16, E. Van Cutsem17, R.J. Mayer18, on behalf of the RECOURSE Study Group 1)Yale Cancer Center, New Haven, Connecticut, USA 2)California Cancer Associates for Research and Excellence, Fresno, California,USA 3) Dartmouth Hitchcock Medical Center, Lebanon, New Hampshire, USA   4)Austin Hospital, Melbourne, Australia   5) University Hospital Ghent, Ghent, Belgium     6)Hospital Universitario 12 de Octubre, Madrid, Spain      7)Hospital Regional Universitario Carlos Haya, Málaga, Spain     8)Ramón y Cajal University Hospital, Madrid, Spain     9)Institut Régional du Cancer, Montpellier, France    10)Seconda Universita Degli Studi Di Napoli, Naples, Italy     11)Ospedale Niguarda Ca’ Granda, Milano, Italy     12)Saitama Cancer Center, Saitama, Japan     13)Aichi Cancer Center Hospital, Nagoya, Japan      14)Chiba Cancer Center, Chiba, Japan    15)Tonan Hospital, Sapporo, Japan     16)National Cancer Center, Kashiwashi, Japan    17)Leuven Cancer Institute, University Hospitals Leuven, Leuven, Belgium 18)Dana-Farber Cancer Institute, Boston, Massachusetts
Introduction: TAS-102 is comprised of an antineoplastic thymidine-based nucleoside analog, trifluridine, and the thymidine phosphorylase inhibitor, tipiracil hydrochloride, at a molar ratio of 1:0.5 (weight ratio, 1:0.471). The efficacy and safety of TAS-102 in patients with metastatic colorectal cancer refractory/intolerant to standard therapies were evaluated in the RECOURSE trial; enrollment criteria included ≥2 prior lines of standard chemotherapy (including prior fluoropyrimidine, oxaliplatin, irinotecan, bevacizumab, and an anti-EGFR antibody in patients with KRAS wild-type [WT] tumors). Primary results of RECOURSE demonstrated a significant improvement in overall survival (OS) and progression-free survival (PFS) with TAS-102 vs placebo (hazard ratio [HR] = 0.68 and 0.48 for OS and PFS, respectively; both P < 0.0001).We report on the efficacy and safety in the RECOURSE trial based on KRAS and BRAF mutation gene status.
Methods: These prespecified analyses of RECOURSE compared efficacy and safety of TAS-102 vs placebo in subgroups of patients who had tumors that were WT or mutant, and status was determined according to site practice. Patients were initially stratified by status; status was collected if available. The primary endpoint (OS) and key secondary efficacy endpoint (PFS) were evaluated using univariate and multivariate analyses for stratification (eg, status) and prespecified (eg, status) factors.
Results: Of the 800 RECOURSE patients, 394* (49.3%) had KRAS WT tumors (63.7% male, mean age 62.0 years); 406* (50.8%) had KRAS mutant tumors (59.1% male, mean age 61.1 years). Treatment groups were well balanced with respect to KRAS status, including KRAS mutation types. BRAF status was provided for approximately 15% of intent-totreat patients: 116 (14.5%) had BRAF WT, 8 (1.0%) had BRAF mutant tumors. OS favored TAS-102 vs placebo across both KRAS subgroups, although this difference did not achieve statistical significance in the KRAS mutant group (Table). Results for PFS also favored TAS-102 across KRAS gene status. The small number of patients with BRAF status identified, especially BRAF mutant, precludes any meaningful analysis. There were no overall differences in incidence of adverse events (AEs), ≥ Grade 3 AEs, or serious AEs for patient subgroups based on KRAS status, and no consistent differences in incidence of specific AEs and clinical laboratory abnormalities. In the TAS-102 group, patients with KRAS mutant vs WT tumors had a higher incidence (≥5%) of diarrhea (35.2% vs 28.5%), asthenia (21.6% vs 14.6%), and decreased appetite (43.2% vs 34.6%); patients with KRAS WT tumors had a higher incidence of decreased neutrophil (30.4% vs 25.3%) and white blood cell count (31.5% vs 23.4%). Statistical analysis was not planned for AEs. The small BRAF status sample size makes it difficult to draw any conclusions regarding differences in incidence of AEs or clinical laboratory abnormalities.
Conclusion: As in the overall RECOURSE study group, TAS-102 was associated with improved OS and PFS vs placebo in patients with KRAS WT and mutant tumors, along with a favorable safety profile. Survival benefit in patients with KRAS mutant tumors showed borderline statistical significance. Although similar results were obtained with respect to BRAF status, the small patient sample size precludes evaluation.

*Per assignment on CRF.

KRAS and BRAF

O-0011
Characteristics and outcomes of patients enrolled in the CORRECT and CONCUR phase 3 trials of regorafenib for metastatic colorectal cancer (mCRC)
A. Grothey1, E. Van Cutsem2, A. Wagner3, J. Kalmus1, S. Qin4, R. Xu5, T.W. Kim6, J. Li7 1)Mayo Clinic, Rochester, Minnesota  2)Leuven Cancer Institute, University Hospitals Leuven, Leuven, Belgium  3)Bayer Pharma AG, Berlin, Germany  4)PLA Cancer Center, Nanjing Bayi Hospital, Nanjing, China   59Sun Yat-Sen University Cancer Center, Guangzhou, China 6) University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea  7)Fudan University Cancer Hospital, Shanghai, China
Introduction: The international CORRECT trial (NCT01103323) showed that regorafenib improves overall survival (OS) vs placebo in patients with previously treated mCRC. The CONCUR trial (NCT01584830) confirmed the survival benefit for regorafenib in Asian patients.We examined the characteristics of patients in the two trials.
Methods: The designs of both phase 3 trials were similar, except that CONCUR included only Asian patients and prior use of biologic targeted therapy was not mandatory. Patients were randomly assigned 2:1 to regorafenib 160 mg or placebo for the first 3 weeks of every 4-week cycle. The primary endpoint was OS.
Results: CORRECT involved 760 patients from North America, Europe, Australia, and Asia (n = 4 Chinese; n = 100 Japanese), whereas CONCUR included 204 patients from Asian countries (n = 172 Chinese; n = 0 Japanese). In CONCUR, patients had fewer treatment lines for metastatic disease, a higher proportion of patients were PS1, and overall 40% had no prior biologic targeted therapy (Table). The most frequent drug-related grade ≥3 adverse events in CORRECT were hand–foot skin reaction (HFSR, 17%), fatigue (10%), diarrhea and hypertension (7% each). In CONCUR, the most frequent drug-related grade ≥3 adverse events were HFSR (16%), hypertension (11%), hyperbilirubinemia, hypophosphatemia, and alanine aminotransferase increase  (7%, each).
Conclusion: CONCUR and CORRECT confirm the clinical benefit of regorafenib in patients with previously treated mCRC and a statistically significant improvement in OS in Asian and non-Asian patients. Adverse events were mostly similar across both trials and consistent with the known safety profile of regorafenib.

Characteristics and outcomes

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