Expert Point of View: Manish Shah, MD


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Manish Shah, MD

The implications of RAINBOW are that targeting the angiogenesis pathway in gastric and gastroesophageal junction adenocarcinoma is now validated, and ramucirumab plus paclitaxel is a viable, safe, effective treatment option following first-line therapy.

—Manish Shah, MD

Manish Shah, MD, Director of Gastrointestinal Oncology and Associate Professor of Medicine at New York–Presbyterian/Weill Cornell Medical Center in New York, discussed the findings of the RAINBOW trial at the 2014 Gastrointestinal Cancers Symposium.

Dr. Shah noted that in this “well sized” study, the addition of ramuricumab to paclitaxel significantly improved overall survival. “The curves split early, at just over 2 months, and stayed separated for over 1 year.”

Outcome Differences in Asian Populations

Comparing studies of bevacizu­mab (primarily, AVAGAST) and the ­RAINBOW study of ramucirumab, Dr. Shah noted that outside of the Asian populations, “we see more dramatic benefit with bevacizumab [Avastin] (for overall survival, hazard ratio [HR] = 0.67 outside of Asia vs 0.97 for Asians), and we see a similar hazard ratio outside of Asia in RAINBOW (0.73 outside of Asia vs 0.99 for Asians).”

He further pointed out, “For progression-free survival, we see a slight difference distinguishing these two antibodies”: Hazard ratios were more impressive with ramucirumab, especially in the Asian subset. For AVAGAST, the progression-free survival hazard ratio for Asians was 0.92, whereas for the RAINBOW study, the hazard ratio for progression-free survival was 0.63.  “This may be an important difference,” he suggested. “Outside of Asia, the hazard ratios for progression free survival are similar in Europe and North American populations for both studies.”

Biomarkers are clearly needed, he added. For the VEGF-A inhibitor bevacizumab, potential candidates include plasma VEGF-A and neuropilin-1, a coreceptor for VEGF receptor signaling. Overall survival was most favorable in patients with high VEGF-A levels (HR = 0.72) and low neuropilin-1 levels (HR = 0.75), compared to low and high levels, respectively, he indicated.

“The implications of RAINBOW are that targeting the angiogenesis pathway in gastric and gastroesophageal junction adenocarcinoma is now validated, and ramucirumab plus paclitaxel is a viable, safe, effective treatment option following first-line therapy,” Dr. Shah concluded.

Disease Biology

Whether VEGF receptor-2 inhibition is different from inhibition of VEGF-A remains to be determined, he added.

“We have also learned that disease biology is important, as shown by gastric cancer heterogeneity,” Dr. Shah added. “We have shown that the epidemiology of the disease is different across the world, and where the studies are done will affect the types of patients in the various ‘buckets’ of disease subtypes. This may make a difference as we move on with targeted therapies.”

The “impressive” fact is that more than 5,000 gastric cancer patients have been treated with targeted therapies within just the last few years, he said, but much remains to be learned—mainly why targeted agents are ineffective in some patients and in some settings. Using biospecimens and advanced molecular analyses, researchers can now turn their focus on how these treatments work, and more importantly, why they sometimes do not. ■

Disclosure: Dr. Shah reported no potential conflicts of interest.


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