A geographic analysis of clinical trial results supporting the use of ramucirumab (Cyramza) in advanced gastric cancer demonstrated that patients in the United States and other Western nations experienced similar survival gains and adverse events as did their counterparts in two other regions of the world. Subgroup results from the RAINBOW trial were presented during the ESMO 16th World Congress on Gastrointestinal Cancer.

Eric Van Cutsem, MD, PhD, who co-chaired the congress, presented findings from RAINBOW, a global double-blinded, phase III trial. “The efficacy and safety from Western patients in Region 1 were similar to patients in the overall population,” said Van Cutsem, of the Digestive Oncology Unit at the Leuven Cancer Institute in Belgium. “Ramucirumab plus paclitaxel should be considered the new second-line standard of care for advanced gastric cancer.”

Ramucirumab is a humanized IgG1 monoclonal antibody vascular endothelial growth factor receptor 2 (VEGFR2) antagonist that blocks the binding of VEGF ligands. The FDA approved the intravenously administered agent as monotherapy for patients with advanced gastric cancer or gastroesophageal junction (GEJ) adenocarcinoma after prior fluoropyrimidine- or platinum-containing chemotherapy based upon data from the REGARD trial.

The RAINBOW trial evaluated the efficacy and safety of paclitaxel with and without ramucirumab in patients with gastric adenocarcinoma or GEJ whose disease progressed during or within 4 months after first-line platinum- and fluoropyrimidine-based combination therapy. Results from an earlier analysis of the trial were submitted to the FDA, with a review pending.

RAINBOW enrolled 665 patients with ECOG PS â‰¤1 and adequate organ function from three areas: Region 1, consisting of the United States, Europe, Israel, and Australia; Region 2, including Mexico, Brazil, Argentina, and Chile; and Region 3, composing Japan, South Korea, Hong Kong, Singapore, and Taiwan.

All patients received paclitaxel at 80 mg/m

 on days 1, 8, 15 of a 4-week cycle; 330 patients were assigned to ramucirumab at 8 mg/kg IV once every 2 weeks (q2w) or placebo (n = 335) until disease progression, unacceptable toxicity, or death.

Van Cutsem compared data from Region 1 patients with findings for participants in the overall population. Region 1 enrolled 398 patients; 198 patients were assigned ramucirumab and 200 received placebo. Baseline characteristics, including baseline tumor characteristics, in the overall population and Region 1 patients were well balanced between treatment arms.

In the overall cohort, RAINBOW met the primary endpoint of overall survival (OS); median OS was 9.6 months for ramucirumab/paclitaxel compared with 7.4 months for placebo/paclitaxel, hazard ratio [HR] = 0.807, 95% CI 0.678-0.962; 

The trial also met the secondary endpoints; median progression-free survival (PFS) was 4.40 months and 2.9 months for ramucirumab and placebo, respectively, HR = 0.635 (

< .0001). The objective response rate (ORR) was 28% with ramucirumab versus 16% with placebo (

 = .0001). Median time to progression (TTP) was 5.5 months with ramucirumab and 3.0 months with placebo (

The secondary endpoint of safety was also met; neutropenia was more frequently reported with ramucirumab but the incidence of febrile neutropenia was comparable between arms.

Region 1 results were consistent with the overall findings. The difference in OS between treatment arms was 2.3 months in the overall population (

 = .0050) months in Region 1. The difference in PFS between treatment arms was 1.5 months and 1.4 months in the overall and Region 1 populations, respectively, (both differences 

Median OS was 8.6 months for ramucirumab/paclitaxel compared with 5.9 months for placebo/paclitaxel (hazard ratio [HR] = 0.726; 95% CI 0.580-0.909; 

= .005). Median PFS was 4.2 months and 2.8 months for ramucirumab and placebo, respectively, (HR = 0.631; 95% CI 0.506-0.786; 

 <.0001). ORR was 26.8% and 13% in the respective arms (

 = .0004). Median TTP was 5.36 months with ramucirumab and 3.15 months with placebo (

Adverse events of grades 3 or 4 severity occurring in more than 5% of Region 1 patients included neutropenia (32.1% vs 14.7%), hypertension (17.9% vs 2.0%), leukopenia (9.7% vs 4.1%), fatigue (10.2% vs 5.1%), asthenia (7.7% vs 2.0%), anemia (6.6% vs 6.1%), abdominal pain (6.6% vs 4.6%), and general physical deterioration, which occurred in 5.6% of patients in both treatment arms.

Eli Lilly and Company, which developed the drug, supported the study.

			Wilke H, Clingan P, Ananda S, et al. RAINBOW: A global, phase 3, double-blind study of ramucirumab plus paclitaxel versus placebo plus paclitaxel in the treatment of gastric cancer following disease progression: Western population subgroup. Presented at: 16th World Congress on Gastrointestinal Cancer; June 25-28, 2014; Barcelona, Spain. Abstract O-0006.

			Fuchs CS, Tomasek J, Yong CJ, et al. Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial [published online October 3, 2013]. 

View more from the 2014 World GI Congress

Articles

A geographic analysis of clinical trial results supporting the use of ramucirumab in advanced gastric cancer demonstrated that patients in the United States and other Western nations experienced similar survival gains and adverse events as did their counterparts in two other regions of the world.

Ramucirumab Benefit for US Patients With Gastric Cancer Mirrors Global Results

Treatment with regorafenib significantly improved overall survival (OS) and progression-free survival (PFS) in an Asian population of patients with previously treated metastatic colorectal cancer (mCRC), according to results from the phase III CONCUR trialÂ presented at the ESMO 16th World Congress on Gastrointestinal Cancer.

During his presentation, study author Jin Li, MD, PhD, from the Fudan University Shanghai Cancer Center, Shanghai, China, noted that regorafenib is the first small molecule multikinase inhibitor to demonstrate a survival benefit in patients with mCRC who progressed following standard therapy.Â 

Results from the 204 patient CONCUR trial confirm the safety and efficacy of regorafenib that was demonstrated in the pivotal phase III CORRECT trial. The rationale to conduct theÂ CONCUR trial in a more diverse population of patients of Asian descent with mCRC was derived from a subpopulation of the CORRECT trial that included 15% of patients who were of Asian descent (mostly Japanese).

CONCUR was a randomized, double-blind, placebo-controlled phase III study that enrolled patients with mCRC from 25 centers in mainland China, Hong Kong, Taiwan, Republic of Korea, and Vietnam.Â Patients with stage IV adenocarcinoma of the colon or rectum who experienced disease progression within 3 months of completing standard treatment were eligible. Patients must have undergone a minimum of two prior treatment lines of fluoropyrimidine, oxaliplatin, or irinotecan; previous anti-VEGF and anti-EGFR treatments were allowed, but not required for eligibility.Â 

Patients were stratified by metastatic site (single vs multiple) and by time from diagnosis of metastatic disease to randomization (<18 months vs â‰¥18 months) and randomized 2:1 to receive regorafenib at 160 mg daily during the first 3 weeks of each 4-week cycle plus best supportive care (BSC) or placebo plus BSC until disease progression, unacceptable toxicity, or withdrawal of consent.

The trial’s primary endpoint was OS, and secondary endpoints were PFS, tumor response, disease control rate (DCR) and safety. Reported 

Regorafenib was administered to 136 patients, and 68 patients received placebo; patient demographics and baseline characteristics were well balanced between these arms. Median patient age was 57 years. ECOG PS 1 was recorded in 75% of patients, and PS 0 was recorded in 25% of patients. Anti-EGFR or anti-VEGF therapies had not been previously received by 41% of patients, and the majority (75%) of patients had received three or more treatments for mCRC.

Significantly improved OS and PFS were demonstrated with regorafenib over placebo. Median OS was 8.8 months and 6.3 months in the regorafenib and placebo arms, respectively (hazard ratio [HR] = 0.550; 95% CI: 0.395-0.765; 

PFS was improved to a median of 3.2 months with regorafenib compared with 1.7 months with placebo (HR = 0.311; 95% CI: 0.222-0.435; 

 <.0001). The DCR also favored regorafenib over placebo with 52% and 7%, respectively.

The most commonly reported grade 3 or 4 treatment-related adverse events with regorafenib were hand-foot skin reaction, hypertension, and hyperbilirubinemia, which were reported by 16%, 12%, and 12% of patients in the regorafenib arm, respectively. The occurrence of hand-foot skin reaction and hypertension are consistent with other reports of regorafenib in patients of Asian descent.

	Li J, Qin S, Yau T, et al. CONCUR: aÂ randomized, double blind, placebo-controlled phase 3 study of regorafenib monotherapy in Asian patient with previously treated metastatic colorectal cancer.Â Presented at: 16th World Congress on Gastrointestinal Cancer; June 25-28, 2014; Barcelona, Spain. Abstract O-0023

Treatment with regorafenib significantly improved OS and PFS in an Asian population of patients with previously treated mCRC.

Regorafenib Offers Effective Option for Asian Patients With mCRC

Adding ruxolitinib (Jakafi) to capecitabine as a second-line treatment for patients with metastatic pancreatic cancer significantly improved survival for a subgroup with a high degree of local and systemic inflammation compared with capecitabine plus placebo, according to phase II trial results presented at the ESMO 16th World Congress on Gastrointestinal Cancer.

The results from the RECAP trial confirm the role of inflammation in promoting cancer and the importance of the JAK-STAT pathway, which ruxolitinib inhibits, as a therapeutic target in metastatic pancreatic cancer, said lead author Herbert I. Hurwitz, MD, in presenting the findings at the conference, held June 25-28 in Barcelona, Spain.

Ruxolitinib, which is supplied in tablet form, inhibits JAK1/JAK2 kinases and blocks signaling mediated by many proinflammatory cytokines. Initially approved by the FDA in 2011, ruxolitinib is indicated for treatment of patients with intermediate or high-risk myelofibrosis.

Two phase III clinical trials, JANUS 1 and JANUS 2, are evaluating ruxolitinib among patients with pancreatic cancer with inflammation scores of 1 or 2 as measured by the modified Glasgow Prognostic Score (mGPS), according to Hurwitz, a professor of Medicine at Duke University School of Medicine in Durham, North Carolina. He said mGPS also is being used as a selection criterion in trials evaluating ruxolitinib in colorectal, non-small cell lung, and breast cancers.

The RECAP trial enrolled 127 patients who progressed after treatment with gemcitabine; all patients were treated with 1000 mg/m

 capecitabine twice daily on days 1 through 14 of a 21-day cycle. A cohort of 64 patients also received 15-mg doses of ruxolitinib twice daily on days 1-21 and 63 patients received placebo.

The primary endpoint was overall survival (OS), and secondary endpoints included progression-free survival (PFS) and objective response rate (ORR). Reported 

In the overall patient population, a trend toward improved OS at 12 months favoring the ruxolitinib combination over capecitabine/placebo that did not reach statistical significance was seen (hazard ratio [HR] = 0.79; 95% CI 0.53—1.18), and PFS (HR = 0.75; 95% CI, 0.51-1.10; 

 = .14). The confirmed ORR was 7.8% in the ruxolitinib arm compared with 0% in the placebo arm.

However, preplanned subgroup analysis of data from patients with high serum C-reactive protein (CRP) and albumin levels told a stronger story. Subgroup analysis of a cohort of 60 patients with CRP levels greater than the group median of 13 mg/L showed statistically significant OS improvement (HR = 0.47; 95% CI, 0.26-0.85; 

 = .01) and a trend toward improved PFS (HR = 0.62; 95% CI, 0.35-1.10;

 = .10) among the 31 patients receiving ruxolitinib. Patients with CRP ≤13 mg/L who received ruxolitinib also showed improved OS (HR = 0.89) and PFS (HR = 0.82), but the differences between arms did not reach statistical significance.

The subgroup analysis also revealed improved survival rates at 3 months and 6 months of 48% and 42%, respectively, in the ruxolitinib arm, compared with 29% and 11%, respectively, in the placebo arm.

Outcome evaluated by mGPS showed patients with higher inflammation scores achieved improved survival with ruxolitinib. Significantly improved OS was achieved by patients with a score of 2 with ruxolitinib (HR = 0.49). OS decreased as the mGPS score decreased; patients with a score of 1 demonstrated slight improvements (HR = 0.71), but almost no benefit was observed in patients with a score of 0 (HR = 0.91).

The greatest gains in OS were seen in analyses of inflammation measures were combined. OS was prolonged in 70 patients with mGPS of 1 or 2 plus CRP >10 mg/L (HR = 0.60; 

 = .063) and in 36 patients with mGPS 2, CRP >10 mg/L, and albumin <35 g/L (HR = 0.49; 

Hurwitz noted that mGPS has been well characterized as a clinical measure in cancer. “Importantly, more than 50 clinical studies across multiple tumor types in over 25,000 patients support the prognostic value of the GPS,” said Hurwitz.

Adverse events of grade 3 or grade 4 severity were reported by 75% of patients in the ruxolitinib arm compared with 82% of patients in the placebo arm. Grade 3/4 anemia was observed more often with ruxolitinib than with placebo (15.3% vs 1.7%), respectively, and grade 3/4 neutropenia and thrombocytopenia occurred in 1.7% of ruxolitinib treated patients versus 0% of patients receiving placebo.

“Ruxolitinib demonstrated clinical utility—something we can really do for our patients,” commented Discussant Jordan D. Berlin, MD, clinical director of the GI Oncology Program at Vanderbilt-Ingram Cancer Center in Nashville, Tennessee. “If we reduce inflammation and cancer cachexia, it could prolong the patient’s life and give us a chance to treat the cancer itself.”

The Incyte Corporation, which markets ruxolitinib in the United States, sponsored the RECAP study.

	Hurwitz H, Uppal N, Wagner SA, et al. Results from a phase 2 study of ruxolitinib or placebo with capecitabine as second-line therapy in patients with metastatic pancreatic cancer: the RECAP trial. Presented at: 16th World Congress on Gastrointestinal Cancer; June 25-28, 2014; Barcelona, Spain. Abstract O-0026.

Adding ruxolitinib to capecitabine as a second-line treatment for patients with metastatic pancreatic cancer significantly improved survival for a subgroup with a high degree of local and systemic inflammation compared with capecitabine plus placebo.

Ruxolitinib Combo Improves Outcomes in Metastatic Pancreatic Cancer

Adding cetuximab to concurrent chemoradiotherapy did not improve overall survival in patients with adenocarcinoma or squamous cell carcinoma of the esophagus according to findings of RTOG 0436, a randomized phase III trial presented by David Ilson, MD, of Memorial Sloan Kettering Cancer Center, at the 16th World Congress of Gastrointestinal Cancer on June 26, 2014.

The trial evaluated adjunct cetuximab when added to concurrent chemoradiation in patients who were undergoing nonoperative management of esophageal carcinoma. Patients with squamous cell or adenocarcinoma that was proven by biopsy (T1N1M0; T2-4 AnyN M0; Any T/N M1a) were randomized to weekly concurrent cisplatin (50 mg/m

) for 6 weeks plus daily radiation 50.4 gy/1.8 gy fractions with or without weekly cetuximab. Patients received 400 mg/m

 of cetuximab on day 1 followed by weekly doses of 250 mg/m

The results demonstrate that cetuximab or other EGFR targeted therapies added to chemoradiation does not improve overall survival (OS) in unselected patients with esophageal cancer, said Ilson.

But the trial did show that “6 weeks of cisplatin/paclitaxel was sufficient to achieve clinical complete response (cCR) at 8 weeks, suggesting that the 2 additional weeks usually administered may not be necessary,” said Ilson.

Achieving cCR after 8 weeks of treatment, Zubrod performance scale score of 0, and tumor size less than 5 cm were identified as independent predictors for OS at 2 years.

Cisplatin, 5-FU, and radiotherapy were established as the standard treatment for non-operable esophageal cancer in 2003 (Cooper et al. 

 2003). Overexpression of EGFR has been identified by immunohistochemistry in 60% to 80% of adenocarcinoma and squamous cell cancers of the esophagus (Bonner. 

 2006), leading investigators to evaluate whether cetuximab, which targets EGFR, could be effective in extending OS in these patients.

The trial enrolled 344 patients, with 328 patients meeting eligibility criteria. Patients were stratified by histology, tumor size (< 5 cm versus ≥ 5cm), and the status of celiac lymph nodal involvement. Patient characteristics were similar for both treatment arms with median follow-up for all patients was 15.4 months.

Patient accrual was halted upon interim analysis in May 2012 for patients with adenocarcinoma and in January 2013 for patients with squamous cell carcinoma, and with the publication of negative results from the SCOPE trial (Crosby et al. 

The trial’s primary endpoint of OS was not met: OS at 2 years was similar between treatment arms, hazard ratio (HR) = 0.92 (P = .72). The secondary endpoint was also not met; the cCR rate was 56% versus 59% without and with cetuximab, respectively (

Results show that cCR was also similar between treatment arms by histology; patients with adenocarcinoma (n=203) had a 12 and 24 month OS of 65% and 43% with cetuximab compared with 64% and 41% with sole chemoradiotherapy, respectively (

 = .37). OS at 12 and 24 months for the 125 squamous cell carcinoma patients was 62% and 46% with cetuximab and 67% and 43% without cetuximab, respectively (

However, when OS was evaluated by multivariate analysis, Zubrod performance score of 0 (versus 1 or 2) and cancer lesion size <5 cm (versus 5 cm or greater) was associated with prolonged OS (

OS rates at 12 and 24 months for patients achieving cCR were 79% and 58% compared with 53% and 30% for patients experiencing residual disease (

Treatment related adverse events were similar between treatment groups and consistent with previously establish profiles for each agent.

Ilson emphasized the need for identification of biomarkers in esophageal cancer and recommended that future trials of targeted agents should be conducted only in selected population of patients with esophageal cancer.

In response to an audience question, Ilson said that BRAF did not play a role in esophageal cancer, due to extremely low expression in these tumors. “It is simply not there,” he said.

The trial was supported by RTOG CA21661 and CCOP CA3742 NCI grants and Bristol Myers Squibb.

	Ilson et al. A Phase III Trial of Cisplatin, Paclitaxel and Radiation with or without Cetuximab in the Nonoperative Treatment of Esophageal Cancer. Presented at: the ESMO 16th World Congress on Gastrointestinal Cancer; June 25-28, 2014; Barcelona, Spain. Abstract O-0005.

Adding cetuximab to concurrent chemoradiotherapy did not improve overall survival in patients with adenocarcinoma or squamous cell carcinoma of the esophagus

Adding Cetuximab to Chemoradiation in Non-operable Esophageal Cancer Does Not Improve Survival

Four independent prognostic factors for improved overall survival (OS) in patients with locally advanced pancreatic cancer (LAPC) emerged from an analysis of the LAP 07 phase III trial presented at the ESMO 16th World Congress on Gastrointestinal Cancer. Based on these factors, a risk scale was developed that could be useful for stratifying and treating patients.

Lead author Dewi Vernerey, MSc, Methodological and Quality of Life in Oncology Unit, University Hospital, Besançon, France, discussed the grim reality of pancreatic cancer, noting that 30% of patients present with disease that is locally advanced. He added that pancreatic cancer disease mortality in Europe increased from 73,439 deaths in 2009 to 82,300 deaths in 2014, an increase of approximately 12%.

Vernerey presented results from a data analysis from LAP 07, an international multicenter, randomized phase III trial. In LAP 07, investigators evaluated whether continued chemoradiotherapy improved OS in patients with inoperable LAPC whose tumors were determined to be controlled following 4 months of induction gemcitabine-based chemotherapy. LAP 07 found no advantage for continued chemotherapy versus no treatment in OS (

In Vernerey et al’s analysis, thirty-five baseline characteristics from demographics, radiological, disease history, and biological parameters of 370 patients from LAP 07 comprised the variables evaluated by univariate and multivariate analysis to identify independent factors prognostic for OS.

Univariate analysis narrowed the characteristics to WHO tumor status 2, age at diagnosis, blood pressure, ASAT, albumin, the presence of pain, tumor size, and poorly differentiated histology grade as potential prognostic variables (all 

Upon multivariate analysis, age (HR = 1.01; 95% CI, 1.00-1.03; 

 = .0418), tumor size (HR = 1.01; 95% CI, 1.00-1.02; 

 = .0033), increased albumin (HR = 0.96; 95% CI, 0.94-0.98; 

 = .0001), and the presence of pain (HR = 1.36; 95% CI, 1.08-1.71; 

 = .0094) emerged as independent prognostic factors of OS.

Using these four variables, a prognostic score scale for risk of death in patients with LAPC was devised, with scale scores ranging from 0 to 4. Based on the scale, three risk groups for death were identified: lower risk (0, 1), intermediate risk (1, 2), and higher risk (2, 3).

Patients were stratified using the scale, with 17, 166, and 187 patients identified for the lower, intermediate, and higher risk groups, respectively. By global rank test, the three risk groups were associated with a median OS of 18.8, 13.4, and 11.8 months, respectively (

“Nomogram development and this simple score should allow patient stratification that can direct treatment management and design of future clinical trials,” said Vernerey. He added that external validation of this score using a cohort from the large ARCAD (Aide et Recherche en Cancérologie Digestive) database is ongoing.

	Vernerey D, et al. Prognosis model for overall survival in locally advanced pancreatic cancer (LAPC): an ancillary study of the LAP 07 trial. Presented at: the ESMO 16th World Congress on Gastrointestinal Cancer; June 25-28, 2014; Barcelona, Spain. Abstract O-0002.

Four independent prognostic factors for improved overall survival in patients with locally advanced pancreatic cancer emerged from an analysis of the LAP 07 phase III trial.

Virginia Powers, PhD

Articles

Ramucirumab Benefit for US Patients With Gastric Cancer Mirrors Global Results

Regorafenib Offers Effective Option for Asian Patients With mCRC

Ruxolitinib Combo Improves Outcomes in Metastatic Pancreatic Cancer

Adding Cetuximab to Chemoradiation in Non-operable Esophageal Cancer Does Not Improve Survival

Prognostic Scale Developed for Overall Survival in Locally Advanced Pancreatic Cancer