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ESMO Gastrointestinal Cancers Congress

Heinz-Josef Lenz, MD, the co-director of the Colorectal Center and GI Oncology Program at the USC Norris Comprehensive Cancer Center, discusses the potential predictive impact of traditionally wild-type 

 mutations in metastatic colorectal cancer (mCRC).

To date, Lenz notes, KRAS testing has been restricted to codons 12 and 13; however, the phase II PEAK trial suggests that testing should now include codons 61, 117, and 146. This trial examined the affects of non-traditional (wild-type) activating 

 mutations on the clinical activity of EGFR inhibitors. Overall, Lenz suggests, testing for these additional codons could help screen 20% more patients with mCRC for treatment with EGFR inhibitors.

PEAK is a phase II trial and these data have not yet been validated, Lenz points out. As such, analyses will be applied to the FIRE-3 and the CALGB 8045 trials to see if these findings can be further validated. If they can, this could have a dramatic impact on how patients with mCRC are screened and treated, Lenz believes. This method could help to more accurately select patients who will benefit from EGFR inhibitors.

Heinz-Josef Lenz, MD, from the USC Norris Comprehensive Cancer Center, discusses the potential predictive impact of KRAS and NRAS mutations in metastatic colorectal cancer.

Dr. Lenz Explores KRAS/NRAS Mutations in Colorectal Cancer

A simple and inexpensive blood test is being developed that can be used to screen patients for premalignant colorectal cancer (CRC) lesions which, once perfected, will be a real “game changer,” predict researchers at ESMO 15th World Congress on Gastrointestinal Cancer.

“My laboratory just published this work a week ago,” C. Richard Boland, MD, chief of gastroenterology, Baylor University Medical Center, Dallas, Texas, told 

. “And if it works, people who won’t have a colonoscopy, sigmoidoscopy, or won’t get their stool tested year after year might well have a blood test. What we want is to find a test that will be good enough that a person can be reassured that they do not need a colonoscopy for maybe a year, and that will change everything.”

 (2013;105(12):849-859), investigators from the Gastrointestinal Cancer Research Laboratory at Baylor University Medical Center set out to determine whether several oncogenic microRNAs that negatively regulate tumor-suppressor genes could be used as potential serum biomarkers in human CRC.

Investigators first screened expression in medium from two CRC cell lines to determine whether microRNA-21 and microRNA-31 are secretory microRNAs. They then analyzed serum from 12 patients with CRC and 12 controls to see if microRNA-21 was released into the blood stream. The same team then went on to validate expression of candidate microRNAs in serum samples from a cohort of 186 CRC patients; 60 postoperative patients; 43 patients with advanced adenomas, and 53 control subjects.

In this validation cohort, Boland and his colleagues found that microRNA-21 levels were statistically significantly elevated in preoperative serum from both patients with adenomas as well as those with CRC (

<.001 for both groups). Importantly, they also found that the expression of the same microRNA dropped in postoperative serum in patients who had undergone curative surgery (

<.001) and that serum microRNA levels “robustly distinguished” patients with adenomas and CRC from controls.

Furthermore, high levels of microRNA-21 expression in both serum and tissue were significantly associated with tumor size, distant metastases, and poor survival. “The sensitivity of the test for colon cancer is still only 82%—and for advanced adenomas it’s 72%&mdash;so it’s not ready to be marketed yet,” Boland said. “But we can look at other microRNAs. In fact, we already have data that suggests other microRNAs may be involved in CRC and could be good predictors of what’s going on. So, we can build on what we have and we’re already starting a prospective trial.”

In the meantime, Boland reminded delegates at the World GI Congress that colonoscopy is still the “gold standard” for CRC screening and is recommended in the United State for all patients aged 50 years and over. However, the test does have significant shortcomings—it’s invasive, it can cause bleeding and perforation (though uncommon), and there is considerable variability in terms of quality of the test done and subsequent impact from the test on patient outcomes.

“Colonoscopy may still be the best test, but it’s far from perfect. Besides, people won’t do it—they have to do the prepping; they understand the dangers of colonoscopy; and the test is expensive,” Boland noted. “So, it’s my belief that when we have our first good blood test to screen for colon cancer, it will be a microRNA-based test. And while people will still need to have a good colonoscopy to locate the lesion, a microRNA test has the potential to be a simple, inexpensive test and one of the easier ones to do in any molecular laboratory.”

A simple and inexpensive blood test is being developed that can be used to screen patients for premalignant colorectal cancer lesions which, once perfected, will be a real game changer.

Simple, Inexpensive Blood Test Poised to Be a Real "Game Changer" in CRC Screening

Better responders within a cohort of patients from the VELOUR study derive enhanced benefit from aflibercept when combined with FOLFIRI, a post-hoc analysis of the study shows. Findings were presented during a poster session at the ESMO 15th World Congress on Gastrointestinal Cancer in Barcelona, Spain.

Ian Chau, MD, Royal Marsden Hospital, Sutton, United Kingdom, and colleagues reported that median overall survival (OS) in the intent-to-treat (ITT) population was 13. 50 months for aflibercept plus FOLFORI-treated patients compared with12.06 months for placebo plus FOLFORI patients (

 = .0032). In the subgroup categorized as “better responders,” median OS was 16.2 months for those who received additional aflibercept compared with a median OS of 13.1 months for placebo plus FOLFIR patients. The subgroup of “better responders” constituted two-thirds of all patients in both arms of the study, the investigators noted.

“The difference in survival between treatment arms also increased over time,” the authors stated. They also noted that there was a significant improvement in progression-free survival (PFS) with aflibercept compared with placebo in both the ITT population and in the better responders subgroup. In the ITT population, mean PFS was 6.9 months in the aflibercept plus FOLFIRI arm compared with a median PFS of 4.6 months for the placebo plus FOLFIRI arm—a 25% improvement in PFS time in favor of aflibercept (hazard ratio = 0.75; 

In the better responders subgroup, the median PFS was 7.2 months for the aflibercept plus FOLFIRI arm versus 4.8 months for placebo plus FOLFIRI for a median difference of 2.4 months between the two treatment arms.

		Median Overall Survival in Patients With and Without Prior Bevacizumab Therapy

There was also no difference in median OS among VELOUR patients who had received prior bevacizumab treatment compared with those who had not (

Investigators also noted that in the ITT population, the overall response rate (ORR) consisting of both complete and partial responses was 19.8% for the aflibercept plus FOLFIRI cohort compared with 11.1% for their placebo counterparts. For the better responders subgroup, the ORR was 23.7% among those who received additional aflibercept versus 11% for placebo controls.

The most commonly reported adverse events (AEs) in the aflibercept plus FOLFIRI arm were gastrointestinal-related issues. This was true for both the overall VELOUR population and for the better responders subgroup. Grade 3 and higher AEs in the aflibercept plus FOLFIRI arm included diarrhea, stomatitis, fatigue, hypertension, and neutropenia. However, the authors noted that the AEs in the better responders subgroups closely approximated those in the ITT population and were consistent with expected anti-VEGF class effects.

“The addition of aflibercept to FOLFIRI chemotherapy in patients with metastatic CRC that is resistant to or has progressed after an oxaliplatin-containing regimen resulted in clinically meaningful survival gains in the better responders subgroup,” the investigators concludes. “And these statistically significant and clinically meaningful efficacy benefits in the better responders subgroup were obtained without any compromise in safety.”

	Chau I, et al. A VELOUR post hoc subset analysis: prognostic groups and treatment outcomes in patients with metastatic colorectal cancer treated with aflibercept and FOLFIRI. Presented at: ESMO 15th World Congress on Gastrointestinal Cancer; July 3-6, 2013; Abstract P-0196.

Better responders within a cohort of patients from the VELOUR study derive enhanced benefit from aflibercept when combined with FOLFIRI, a post-hoc analysis of the study shows.

Better Responders in VELOUR Derive Enhanced Benefit From Aflibercept

Ramucirumab, a novel monoclonal antibody that targets vascular epithelial growth factor receptor-2 (VEGFR-2), significantly prolongs survival in patients with advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma following progression on first-line therapy—the first single biologic agent to do so, according to a randomized phase III study presented July 4, 2013 at the European Society for Medical Oncology 15th World Congress on Gastrointestinal Cancer in Barcelona, Spain.

Joseph Tabernero, MD, PhD, of Vall d’Hebron University Hospital, Barcelona, and multicenter colleagues in the REGARD trial found that ramucirumab significantly prolonged overall survival (OS) by 22% (

 = .0473) as well as progression-free survival (PFS) by 52% (

<.0001) compared with placebo in patients with metastatic gastric or GEJ adenocarcinoma following progression on first-line platinum or fluoropyrimidine-containing regimens or both.

“These results confirm VEGFR-2 as a viable therapeutic target in gastric cancer,” Tabernero said, “and ramucirumab represents a potential new second-line standard of care in this patient population.”  

For the study, 355 patients were randomized to either ramucirumab (8 mg/kg IV) or placebo, given every 2 weeks until disease progression or intolerable toxicity. Approximately two-thirds of patients were >65 years of age at randomization. The primary tumor was gastric in approximately75% of patients, the remainder being at the GE junction. A significant proportion of patients in both arms also had three or more metastatic sites prior to randomization.

Few to no patients achieved a complete response (CR) but 2.9% of ramucirumab patients achieved a partial response (PR) as did 2.6% of placebo patients. Disease stabilized in more than twice as many patients in the active therapy arm (~45%) compared with approximately 20% among placebo controls. Disease control (CR plus PR plus stable disease) was also achieved in almost half of patients on active therapy versus 23% for controls (

Tabernero reported that median OS was 5.2 months for patients receiving ramucirumab compared with 3.8 months for placebo. At 6 months, 42% of patients on ramucirumab were still alive compared with 32% of placebo controls. At 12 months, 18% and 12% of patients were alive on active versus control therapy, respectively. The median interlude before patients progressed was 2.1 months for the ramucirumab arm compared with 1.3 months for placebo, Tabernero added.

At 12 weeks, 40% of patients on active treatment still had not progressed compared with only 10% of placebo patients. Both the OS and the PFS benefit seen with the VEGFR-2 inhibitor appeared consistent across all subgroups analyzed and after adjustment for other prognostic factors. Following discontinuation of treatment in REGARD, 29% of patients formerly treated with ramucirumab went on to chemotherapy compared with approximately 37% of those formerly on placebo.

Overall, investigators felt that ramucirumab had an acceptable safety profile. Rates of grades 3 and 4 fatigue and anemia were 6.4% for each event in patients on active therapy, but these events were more common among placebo patients (9.6% and 7.8%, respectively). Rates of hypertension and bleeding or hemorrhage were higher for those receiving active therapy, but no specific treatment effects were seen in >10% of patients on active therapy.

	Tabernero J, et al. REGARD phase III, randomized trial of ramucirumab in patients with metastatic gastric or GEJ adenocarcinoma following progression on first-line chemotherapy. Presented at: ESMO 15th World Congress on Gastrointestinal Cancer; July 3-6, 2013; Abstract 0-0008.

Ramucirumab significantly prolongs survival in patients with advanced gastric or gastroesophageal junction adenocarcinoma following progression on first-line therapy.

Novel VEGFR-2 Inhibitor Prolongs Survival in Advanced Gastric/GEJ Adenocarcinoma

Paul Ruff, MD, director of Medical Oncology at the University of Witwatersrand, Johannesburg, South Africa, elaborates on factors that can be utilized to select an appropriate antiangiogenic therapy as a second-line treatment in metastatic colorectal cancer (mCRC).

Whether to switch from bevacizumab to aflibercept in the second-line of treatment for patients with mCRC is an important concept that warrants further investigation. This remains particularly clear with recent evidence suggesting that switching the chemotherapy backbone while continuing bevacizumab in the second-line manifests in more efficacious results, Ruff suggests.

The antiangiogenic therapy utilized can be personalized on an individual basis, Ruff notes. As an example, patients who progress slowly on first-line bevacizumab plus chemotherapy are better candidates for continuing this regimen. In this case, aflibercept should be reserved for later lines of treatment. However, for patients with more aggressive, rapidly progressive disease a switch to aflibercept in the second-line may be warranted.Â Â 

While no formal comparison currently exists, Ruff states, aflibercept may be more appropriate for actively progressing patients with mCRC in the second-line setting than bevacizumab.

Paul Ruff, MD, from the University of Witwatersrand, Johannesburg, South Africa, elaborates on factors that can be utilized to select an appropriate antiangiogenic therapy as a second-line treatment in metastatic colorectal cancer.

Dr. Ruff on Selecting Anti- Angiogenic Agents in mCRC

Treatment with weekly nab-paclitaxel plus gemcitabine remains a strong independent predictor of both overall survival (OS) and progression-free survival (PFS) in patients with metastatic pancreatic cancer compared with gemcitabine alone, even after correcting for all confounding prognostic variables, a new analysis of the MPACT study shows.

Josep Tabernero, MD, PhD, of Vall d’Hebron University Hospital, Barcelona, Spain, and multicenter colleagues found that after correcting for known prognostic factors in metastatic pancreatic cancer, treatment with weekly nab-paclitaxel plus gemcitabine improved OS by 28% and PFS by 34% relative to gemcitabine alone in predominantly stage IV metastatic pancreatic cancer patients who had received no prior treatment for metastatic disease (

Tabernero reported these findings July 3, 2013 at the European Society of Medical Oncology 15th World Congress on Gastrointestinal Cancer in Barcelona

“In order to understand what the real impact of the addition of nab-paclitaxel is, we needed to consider other well-known prognostic factors that are usually evaluated in pancreatic cancer,” Tabernero explained in an interview with 

“The data show that by introducing all these variables in our multistep model, the addition of nab-paclitaxel to gemcitabine continues to be the most important factor. So this is another statistical model to show that there is no bias related to other confounding factors and that the treatment effect is the most significant one.”

For the MPACT trial, 842 patients with metastatic pancreatic cancer were randomized to receive nab-paclitaxel, 125 mg/m

 on days 1, 8, and 15 every 4 weeks (that is, every week for 3 weeks, with the 4th week off) or the same dose of gemcitabine alone weekly for 7 weeks followed by 1 week of rest, and then on days 1, 8, and 15 every 4 weeks from cycle 2 onwards. Patients were also stratified by region, presence of liver metastases, and Karnofsky performance status (KPS ≥70).

At 36 months, median OS in the intent-to-treat (ITT) population was 8.5 months in the combination arm compared with 6.7 months for the gemcitabine alone arm (

“KPS, presence of liver metastases, age, region, and number of metastatic sites were the most important predictors of survival,” Tabernero said.

On univariate analysis, the baseline for cancer antigen 19-9 (CA19-9), a tumor marker for pancreatic cancer, also significantly predicted OS in the overall cohort. However, after correction for an array of other prognostic factors on multivariate analysis, CA19-9 no longer emerged as significant predictor of OS.

For the PFS analysis, MPACT investigators found that the region of Australia; being 65 years of age and older; a KPS of 70-80, and the presence of liver metastases were all significant predictors of worse PFS.

“The safety profile of this regimen is also acceptable and manageable compared to other regimens, so this study suggests that nab-paclitaxel plus gemcitabine should definitely be considered as one of the most important treatment options for this disease,” Dr. Tabernero concluded.

	Taberner J, Von Hoff DD, Moore MJ, et al. Phase III trial (MPACT) of weekly nab-paclitaxel plus gemcitabine in metastatic pancreatic cancer: influence of prognostic factors of survival. Presented at: ESMO 15th World Congress on Gastrointestinal Cancer; July 3-6, 2013; Abstract 0-001.

Treatment with weekly nab-paclitaxel plus gemcitabine remains a strong independent predictor of both OS and PFS in patients with metastatic pancreatic cancer compared with gemcitabine alone.

Nab-paclitaxel Plus Gemcitabine a Strong Predictor of Survival in Metastatic Pancreatic Cancer

Patients who express low levels of a critical gene involved in transporting gemcitabine into pancreatic tumor cells have virtually no overall survival (OS) advantage from treatment with the drug in the adjuvant setting, according to research presented at the ESMO 15th World Congress on Gastrointestinal Cancer in Barcelona, Spain.

Christophe Louvet, MD, PhD, Hopital Saint Antoine, Paris, France, reviewed a series of studies in which patients with pancreatic cancer who received gemcitabine following surgical resection of the tumor had dramatically different outcomes based on whether they were high- or low- to moderate-expressers of the human equilibrative nucleoside transporter (hENT1) protein responsible for activating gemcitabine. In the French-Belgium experience, for example, (

Marechal R et al. Gastroenterology, 2012 ;143(3) :664-74)

, a total of 434 evaluable patients were assigned to either adjuvant treatment following surgical resection of their tumor or no adjuvant treatment.

Those who were assigned to adjuvant treatment received either gemcitabine or a non-gemcitabine regimen consisting of radiotherapy alone or radiotherapy plus 5-fluorouracil (5-FU). At 60 months follow-up, OS in patients who had high levels of hENT1 expression and who had received gemcitabine had a 66% longer survival time versus those with low- to moderate-hENT1 expression (

The same clinically meaningful difference in OS was also seen in moderate to high-expressers of deoxycytidine kinase (dCK) where high dCK expression was associated with a 43% longer survival time compared with low-dCK expressers. dCK is involved in the activation of gemcitabine once inside the tumor cell.

In contrast, no difference in OS was seen among the French-Belgium cohort who received non-gemcitabine adjuvant therapy regardless of their level of hENT1 or dCK expression. In the randomized ESPAC1/3 trial presented by 

 at ASCO this year, “investigators found exactly the same thing,” Louvet observed. Again stratified into high- versus low-hENT1 expressers, median survival was 26.2 months in high-hENT1 expressers following treatment with gemcitabine versus 17.1 months among those who expressed low levels of the same protein (

Again in contrast, median OS between high hENT1 expressers at 25.6 months and low hENT1 expressers at 21.9 months was not statistically significant following adjuvant treatment with 5-FU (

 = .0362). “Unfortunately, we still have problems diagnosing hENT1 and we cannot be sure which antibody test is best to test patients for hENT1 expression,” Louvet said.

However, looking at results from several different trials of pancreatic cancer patients—the RTOG in primary tumor patients and two meta-analyses&mdash;Louvet estimated that approximately two-thirds of patients with pancreatic cancer are low- to null-expressers of hENT1. Given this, “we can say that gemcitabine might be considered as placebo for two-thirds of pancreatic cancer patients in the adjuvant setting because gemcitabine is unable to enter the tumor cell,” Louvet said.

It also suggests that the majority of pancreatic cancer patients who receive any sort of couplet regimen containing gemcitabine following surgical resection are really only receiving single-agent therapy, he added.

In the future, Louvet argued that pancreatic cancer patients should be stratified into high- versus low- to moderate-hENT1 expressers; based on their levels of expression, gemcitabine would be a good choice for those with high levels of hENT1 expression whereas FOLFIRINOX would be a better choice for those with low to moderate levels of hENT1 expression.

“Adjuvant treatment with 6 months of gemcitabine remains the 2013 gold standard after pancreatic cancer resection,” Louvet concluded. “But in the very near future, treatment will be based on molecular approaches in order to customize treatment and improve overall outcomes of patients with pancreatic cancer.”

Patients who express low levels of a critical gene involved in transporting gemcitabine into pancreatic tumor cells have virtually no overall survival advantage from treatment with the drug in the adjuvant setting.

Gemcitabine Response Depends on Gene Expression in Patients With Pancreatic Cancer

Alan P. Venook, MD, a professor in the Department of Medicine (Hematology/Oncology) at the University of California, San Francisco, describes factors that contribute to the geographic variations seen in therapies utilized to treat cancer in the United States and Europe.

Primarily, pharmaceutical companies determine where they will pursue the development of new agents. As an example, the angiogenesis inhibitor bevacizumab was largely development in the US. In contrast, Venook notes, the antiangiogenic agent aflibercept was developed largely in Europe and, as a result, it is not used as frequently in the US.

The treatments utilized by physicians are driven by other regional differences, Venook suggests. In the US, treatment selection is driven by guidelines and the pharmaceutical industry has less of an impact. However, the reverse is true in Europe. Overall, when comparing the two, it is unclear which is the best option, Venook believes. However, it is clear that collaboration between the regions helps foster better treatment of patients.

Alan P. Venook, MD, from the University of California, San Francisco, describes factors that contribute to the geographic variations seen in therapies utilized to treat cancer in the United States and Europe.

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