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Combination Treatments Improve Outcomes in Problematic GI Cancers

Carlson, Robert H.

doi: 10.1097/01.COT.0000444386.49340.3f


Three trials of combination therapies presented at the Gastrointestinal Cancers Symposium reported improvements in prognosis for patients diagnosed with historically difficult-to-treat cancers. All three were discussed during a presscast news conference in advance of the meeting.

In gastroesophageal junction and gastric adenocarcinomas, the Phase III RAINBOW study showed increased survival with use of ramucirumab plus paclitaxel when compared with paclitaxel alone, for patients with metastatic disease that had progressed after first-line chemotherapy.

In pancreatic cancer, updated results of a Phase II study evaluating a new cancer vaccine combination in patients with previously treated, metastatic disease showed that immunotherapy can be effective.

And in neuroendocrine tumors, a combination of capecitabine and temozolomide was associated with a response rate of 43 percent and a 54 percent rate of stable disease in patients with treatment-resistant, metastatic disease.

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GEJ, Gastric Cancers

The RAINBOW trial (IMCL CP12-0922), a global, Phase III study of 665 patients, compared the experimental targeted vascular endothelial growth factor receptor 2 inhibitor ramucirumab plus paclitaxel with paclitaxel alone as second-line therapy in metastatic gastroesophageal junction (GEJ) and gastric adenocarcinoma (Abstract LBA7).



In the study reported at the symposium, median overall survival was 9.7 months for patients receiving the combination compared with 7.4 months for those receiving paclitaxel—“an astonishingly good result in such a challenging patient population,” said Hansjochen Wilke, MD, Director of the Department of Oncology and Hematology and the Center of Palliative Care at Kliniken Essen-Mitte in Germany.

Ramucirumab plus paclitaxel represents a potential new treatment option for patients with previously treated gastric cancer, where there are few effective therapies that extend life. “A two-month survival gain for patients with gastric cancer receiving second-line therapy is a big improvement.” he said.

In the trial, which was sponsored by Eli Lilly and Company, patients were treated in 200 centers in approximately 30 countries. All had been refractory to or had disease progression after first-line therapy with platinum and fluoropyrimidine.

Wilke said that RAINBOW and the recently published REGARD trial (Fuchs et al: Lancet 2014;383:31-39), in which ramucirumab increased survival compared with best supportive care alone, demonstrate that the drug, which received Priority Review status by the Food and Drug Administration in October as a second-line single agent for advanced gastric cancer, is an effective treatment for metastatic or locally advanced gastric and GEJ cancer.

The trial reported at the GI Symposium showed an overall response rate of 28 percent with ramucirumab-paclitaxel versus 16 percent for paclitaxel alone. Median progression-free survival was 4.4 months for ramucirumab-paclitaxel versus 2.9 months for paclitaxel alone. And, patients who received the combination also reported a reduction in pain and had other improvements in quality of life.

The most common side effects of ramucirumab-paclitaxel were neutropenia, leukopenia, hypertension, anemia, fatigue, abdominal pain, and asthenia. Although neutropenia was more frequently reported in the ramucirumab-paclitaxel group, the incidence of febrile neutropenia was comparable to treatment with paclitaxel alone, he said.

He said the researchers now intend to retrospectively analyze tumor samples collected as part of the study to identify biomarkers defining subgroups of patients more likely to benefit from ramucirumab, as well as investigate ramucirumab in the first-line setting.



The moderator of the news conference, Smitha S. Krishnamurthi, MD, Associate Professor of Medicine at Case Western Reserve University, noted that RAINBOW is the largest study of second-line treatment for metastatic GEJ and gastric adenocarcinoma, and the only one to demonstrate an improvement in overall survival as well as a relatively high response rate of 28 percent for the combination therapy.

“Gastric cancer is more common worldwide than in the U.S., but it remains a poor-prognosis cancer throughout the world,” she said. “So we are excited to have what appears to be an active drug for the second-line setting that can be used instead of supportive care or in addition to chemotherapy for patients who can tolerate chemotherapy. We are anxiously awaiting the word from the FDA about approval of ramucirumab, which is expected later this year.”

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Pancreatic Cancer

The use of two distinct vaccines as second-line therapy for advanced pancreatic ductal adenocarcinoma produced very encouraging results, according to researchers from Johns Hopkins University Sidney Kimmel Comprehensive Cancer Center (Abstract 177).

An updated report of the Phase II study evaluating the GVAX and CRS-207 vaccines as combined immunotherapy platforms in patients with previously treated, metastatic disease showed a doubling of the one-year survival probability compared with GVAX alone.

Immunotherapy for pancreatic ductal adenocarcinoma is likely to require synergistic combinations, said the first author, Dung Thi Le, MD, Assistant Professor of Medicine. The use of two vaccines is intended to stimulate an immune response against pancreas tumor cells, first with GVAX inducing a broad response against multiple tumor proteins and then with CRS-207 boosting immune response against the mesothelin protein, she explained.

GVAX consists of irradiated, GM-CSF-secreting, allogeneic cell lines—in this case pancreatic cells—given intradermally to produce a broad antigenic response. GVAX is given with low-dose cyclophosphamide to inhibit regulatory T-cells.

CRS-207 is live-attenuated Listeria monocytogenes, which expresses mesothelin and stimulates innate and adaptive immunity. “Using whole cells allows presentation of a wide variety of tumor-associated antigens to the immune system,” Le said. “GM-CSF serves to attract and direct cells to the vaccine site that will then pick up the antigens and present them to the immune system that activates tumor specific T cells. And Listeria is unique in that it is able to stimulate both innate and adaptive immunity.”

Patients with pancreatic ductal adenocarcinoma whose disease progresses after first-line treatment have median survival of four to six months with second-line therapy, and two to four months with third-line therapy. Le said the best reported median survival for metastatic pancreatic cancer, 11 months, was with first-line treatment using FOLFIRINOX, but the toxicity precludes treatment for only the most fit patients.

In a Phase I study of CRS-207, three pancreatic ductal adenocarcinoma patients who had received prior GVAX lived 15 months or longer. And In this Phase II study, 90 patients with pancreatic ductal adenocarcinoma were randomly assigned to receive GVAX followed by CRS-207 versus GVAX alone. The majority of patients received at least one prior course of chemotherapy.



At a planned interim analysis of this GVAX/CRS-207 study, median overall survival was 6.1 months with the two-vaccine therapy versus 3.9 months for GVAX alone. Approximately 24 percent of patients in the combination arm were alive at one year versus 12 percent with GVAX alone.

A separate analysis of patients who received at least three doses of vaccine (approximately 70 percent of patients) showed that those in the combination arm who received two doses of GVAX and at least one dose of CRS-207 had a median overall survival of 9.7 months vs. 4.6 months with GVAX alone.

This study was sponsored by Aduro Bio Tech and Johns Hopkins University.

Le noted that a large Phase II study is about to open comparing the combination with CRS-207 alone vs. chemotherapy as second-line or further therapy for metastatic pancreatic cancer. GVAX/CRS-207 will also be tested with immune checkpoint inhibitors such as ipilimumab and anti-PD-1/PD-L1. In addition, a study testing GVAX/ipilimumab as maintenance treatment for patients whose disease became stable on FOLFIRINOX has recently opened.

“These are exciting results in a poor-prognosis cancer,” Krishnamurthi said. “This is a Phase II study, but it is the first randomized study of immunotherapy in pancreatic cancer demonstrating a doubling of survival without the side effects of chemotherapy. And it is the first time a randomized study has shown that immunotherapy is effective in pancreatic cancer.”

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Neuroendocrine Tumors

Treatment of neuroendocrine tumors with the combination of two oral drugs, capecitabine and temozolomide, showed a response rate of 43 percent and a stable disease rate of 54 percent in a Phase II study of patients with carcinoid, pituitary, and pancreatic tumors (Abstract 179 ).

The clinical benefit rate adds up to 97 percent, said the lead author, Robert Fine, MD, Director of Experimental Therapeutics at Herbert Irving Comprehensive Cancer Center of New York Presbyterian Hospital-Columbia University Medical Center.

He also reported an ongoing progression-free survival rate of greater than 22 percent.

Krishnamurthi said the study is of interest because although it was small—just 28 patients—and not randomized, the capecitabine-temozolomide combination (called CAPTEM) achieved responses in neuroendocrine tumors that are typically resistant to chemotherapy, including responses in five of 12 carcinoid patients (41 percent).

Fine said the highest percentage of tumors in the carcinoid subgroup—well-differentiated neuroendocrine tumors—tend to be chemoresistant, with response rates lower than 10 percent; and carcinoid response rates are lower than three percent.



He said ocreotide has been the standard of care for many years, and although the tyrosine kinase inhibitors everolimus and sunitinib are now being used, response rates are still less than 10 percent, although the stable disease rate is about 60 percent. Slow cytokinetic growth apparently allows neuroendocrine tumors to be treatment resistant, he noted.

The interim study results show that among the 12 patients with carcinoid tumors, four had a partial response rate (33%) and one had a complete response. Stable disease rates were 60 percent for typical carcinoid and 50 percent for atypical carcinoid tumors. “It's interesting that all the carcinoids responded to treatment,” he said, adding that the duration of progression-free survival is 23.9 months, and overall survival is still accumulating.

Among three patients with pituitary tumors there was one partial response and two complete responses—“These were end-stage patients who were intubated because of spinal-cord compression from their tumor,” he said. “They both had complete responses, got off-machine, and now are still free of tumor, close to four years out now and on continual treatment.”

Among 11 patients with pancreatic neuroendocrine tumors the partial response rate was 36 percent with 55 percent stable disease. And two patients with medullary thyroid tumors had stable disease but no responses.

Toxicities were “extraordinarily light,” he said: The most common Grade 3/4 toxicity was lymphopenia in one-third of patients, but with no consequence: There were no hospitalizations, opportunistic infections, or deaths in the study, which was sponsored by Columbia University.

Fine said a cooperative group trial is now underway with capecitabine-temozolomide, comparing it with temozolomide alone in pancreatic neuroendocrine cancer.

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4 Co-sponsors

The meeting is cosponsored by the American Gastroenterological Association Institute, the American Society of Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.

© 2014 by Lippincott Williams & Wilkins, Inc.
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