Noteworthy Studies At ASCO GI Presscast

January 14, 2014 — The 2014 ASCO Gastrointestinal (GI) Symposium will run from January 16-18, 2014, at the Moscone Center West in San Francisco, CA. More than 2500 medical, surgical, and radiologic specialists will attend and learn about the latest translational science and new approaches to diagnosis and management of GI cancers.

A pre-meeting Presscast featured 5 important studies: 3 in difficult-to-treat cancers and 2 focusing on more convenient treatments and improved quality of life.

Anti-Angiogenesis with Ramucirumab

Second-line treatment with the combination of ramucirumab (an anti-angiogenesis inhibitor) plus paclitaxel increased overall survival (OS) by more than 2 months in patients with metastatic gastroesophageal junction (GEJ) and gastric carcinoma, according to results of the Phase III RAINBOW trial. This trial comes on the heels of the REGARD trial, showing that single-agent ramucirumab improved progression-free survival (PFS) in this setting.

Median OS is 4-5 months with currently available second-line therapies. In RAINBOW, ramucirumab plus paclitaxel achieved a median OS of 9.6 months versus 7.4 months with paclitaxel (P=.016). Median PFS was 4.4 months for the combination versus 2.9 months with paclitaxel alone (P=.016).

“These are astonishingly good results in this patient population. The improvement in survival was not only statistically significant, but clinically meaningful as well. The rate of tumor progression was reduced by 36%, and 6-month and 9-month PFS almost doubled [with ramucirumab],” stated lead author Hansjochen Wilke, MD, Kliniken Essen-Mitte, in Essen, Germany.

RAINBOW, the largest gastric cancer second-line therapy trial conducted to date, enrolled 665 patients who progressed within 4 months of standard first-line platinum- and fluoropyrimidine-based combination chemotherapy. Patients were treated until disease progression, unacceptable toxicity, or death.

Currently, only about 30% of patients with advanced gastric cancer receive second-line therapy in the U.S. compared with about 80% in Japan. “We expect that more people will be treated with second–line chemotherapy with this effective new drug,” said Dr. Wilke.

Vaccine Strategy

Updated results of a Phase II randomized trial found that a double hit with 2 vaccines (GVAX followed by CRS-207) markedly improved OS in patients with metastatic pancreatic ductal carcinoma compared to GVAX alone. Median OS was 6.1 months with the combination versus 3.9 months with GVAX alone (P=.0343).

After 1 year, about 24% of patients were alive in the combination arm versus 12% of those in the GVAX-alone arm. Among patients who received 2 doses of GVAX and at least 1 dose of CRS-207, median OS was 9.7 months versus 4.6 months, respectively, (the protocol called for 2 doses of GVAX and 4 doses of CRS-207).

Side effects were related to mode of administration (sub dermal or intra venous) and resolved quickly.

The study enrolled 90 patients with metastatic pancreatic cancer who failed or refused chemotherapy.

“This is the first time a randomized study has shown that immunotherapy is effective in pancreatic cancer. This is just a first step, and we plan to take this approach further,” stated lead author Dung T. Le, MD, Sidney Kimmel Comprehensive Cancer Center in Baltimore, MD.

“This strategy extends survival without encountering the effects of chemotherapy,” stated Smitha Krishnamurthi, MD, Case Western Reserve University, Ohio, who moderated the Presscast.

An additional 3-arm study is being planned to evaluate the combination compared with CRS-207.

CAPTEM (Capecitabine and temozolomide)

The combination of capecitabine and temozolomide (CAPTEM) achieved durable responses and extended PFS in 95% of patients with neuroendocrine tumors (NET) that progressed on standard high-dose octreotide. Responders included patients with carcinoid NET, which are typically chemoresistant.

A few patients in this small study were able to get off their respirators and resume normal activities, and the remissions are long lasting, said lead author Robert L. Fine, Columbia University Medical Center, New York City.

“New treatments are sorely needed for this disease,” said Dr. Fine.

The study included 28 patients with various subtypes of NET. CAPTEM achieved tumor shrinkage in 43% of patients and stopped tumor growth in 54%. High response rates were observed in carcinoid and pituitary NET, typically very difficult to treat tumor subtypes.

Among 12% of those with carcinoid tumors, 41% had tumor shrinkage; the typical response to chemotherapy in this subgroup is 0%-4%. Among the 4 patients with pituitary tumors, CAPTEM achieved 2 complete remissions, 1 partial remission (75% reduction in tumor size), and 1 had stable disease for 5 years.

The most recent data capture shows that median PFS approaches 30 months and more than 4 years for 25% of patients. Median OS is longer than 25 months.

Toxicities were minimal, said Dr. Fine.

The combination versus temozolomide alone is now being studied in a cooperative group trial.

“Although small and not randomized, this trial is of great interest because CAPTEM achieved responses in patients we consider chemoresistant,” said Dr. Krishnamurthi.

Oral Capecitabine

Oral capecitabine achieved equivalent outcomes as standard continuous infusional 5-FU when combined with neoadjuvant radiation in patients with stage II or III rectal cancer, according to mature results of NSAPB R-04. The study also found that oxaliplatin is of no additional benefit when added to either drug and is associated with increased overall toxicity.

The study randomized 1608 patients who were receiving 5 weeks of neoadjuvant radiation therapy to 1 of 4 arms: 5-FU; 5-FU + oxaliplatin; capecitabine; capecitabine + oxaliplatin. Results showed no significant differences in loco-regional control rates and other 5-year outcomes, including disease-free survival and OS, among all 4 treatment arms.

“This study shows you can use an oral drug, capecitabine, or continuous infusional 5-FU plus radiation, with indistinguishable outcomes. The same was true for oxaliplatin, but the side effects, especially increased grade 3 and 4 diarrhea, suggest that this drug should not be used in combination with radiotherapy in the preoperative rectal cancer setting,” stated lead author Carmen J. Allegra, MD, University of Florida in Gainesville.

“Doctors should be reassured that they are not giving less effective therapy if they prescribe capecitabine. Oral capecitabine is certainly far more convenient for patients than placing an intravenous port for 5-FU and wearing a pump on their belts for 5 weeks.”

Extended RAS Testing

A retrospective analysis of a large Phase III study supports the use of extended KRAS testing in patients with metastatic colorectal cancer (mCRC) to identify subgroups that should be treated with panitumumab and other EGFR inhibitors. The study showed that tumors that contain RAS mutations beyond KRAS exon 2 are unlikely to benefit from the addition of panitumumab to second-line FOLFIRI chemotherapy.

“Testing for RAS mutations will allow doctors to better select patients and only recommend panitumumab treatment to those most likely to benefit. These results confirm that it is RAS status that matters, not just KRAS, when determining if panitumumab therapy could be beneficial. These findings will spare patients with a RAS mutation the costs and side effects of a treatment that will not improve their outcomes,” stated lead author Marc Peeters, MD, PhD, Antwerp University Hospital, Edegem, Belgium.

The study was based on tumor samples from 1186 patients enrolled in a large, international Phase III study evaluating the addition of panitumumab to FOLFIRI as second-line therapy.

Forty-five percent of the patient population had mutated KRAS exon 2. Extended RAS testing revealed mutations that predicted for response to panitumumab in another 18%.

Among patients treated with both panitumumab and FOLFIRI, median OS and median PFS were improved in those with wild-type RAS tumors versus those with RAS mutations: median OS was 16.2 months versus 11.8 months, respectively, and median PFS was 6.4 months versus 4.8 months, respectively. The addition of panitumumab to FOLFIRI was of no added survival benefit versus FOLFIRI alone in those who received panitumumab plus chemotherapy: median OS 11.8 months versus 11.1 months, respectively; median PFS was 4.8 months versus 4.0 months, respectively.

“These findings support extended RAS testing as standard of care for metastatic CRC to identify patients who will benefit from panitumumab,” said Dr. Krishnamurthi.

By Alice Goodman

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