Colorectal cancer is the fourth leading cause of cancer deaths in the United States. More than 143,400 men and women will be diagnosed with colorectal cancer in the USA this year, and an estimated 51,690 Americans will die from this cancer, according to the National Cancer Institute (NCI).

Refractory metastatic colorectal cancer (mCRC) represents a daunting treatment challenge with poor survival rates. But the available treatment options have expanded rather dramatically in recent months, thanks to the FDA’s approvals of two drugs. Zaltrap (ziv-aflibercept) was approved in August for use with FOLFIRI (folinic acid, fluorouracil and irinotecan) chemotherapy, and Stivarga (regorafenib) monotherapy was approved on September 27 – a full month ahead of schedule.

The FDA had granted both drugs Priority Review of the Biologics License Application (BLA) status for expedited approval. The agency grants Priority Review designations only when preliminary data suggests a drug can offer a significant improvement over current treatment options.

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Zaltrap (also known as VEGF Trap), marketed by Sanofi Oncology and Regeneron Pharmaceuticals, was approved for patients with mCRC for whom oxaliplatin-based treatment has failed. Zaltrap is recombinant human fusion protein that competes with vascular endothelial growth factors (VEGF-A and VEGF-B) and placental growth factor (PIGF) to inhibit tumor angiogenesis. Data from the multinational, randomized, double-blind phase 3 VELOUR trial showed that Zaltrap plus FOLFIRI was associated with longer survival times than FOLFIRI plus placebo after failure of oxaliplatin-regimen failure, regardless of prior bevacizumab history or tumor KRAS mutation status (HR 0.817;P=0.0032).

Stivarga, an oral multi-kinase inhibitor marketed by Bayer Health Care and Onyx Pharmaceuticals, was shown in the phase 3 CORRECT trial to be associated with significantly improved overall survival over placebo (6.4 months vs 5.0 months; HR 0.77;P=0.0052). 

“Patients who didn’t have any therapeutic options left, this was the space where Stivarga was explored in the CORRECT trial,” Dirk Laurent, MD, Bayer’s vice president for global clinical development, oncology, told The Advisor Blog.

Zaltrap and Stivarga are “completely different molecules” that address different patient populations, Dr. Laurent explained.

Stivarga will carry a black-box FDA label warning stemming from severe and fatal cases of liver toxicity among clinical trial participants. 

“It is not a contraindication, but patients treated with Stivarga have to have regular liver function tests,” Dr. Laurent said. “The observations are very detailed and there are recommendations about how to modify treatment if needed.”

In many such cases, Stivarga dose can be reduced, though in some cases, it will be necessary to discontinue Stivarga therapy permanently, Dr. Laurent acknowledged.

Stivarga also has shown promise in clinical trials to prolong progression free survival for metastatic and unresectable gastrointestinal stromal tumor (GIST), Dr. Laurent was quick to note. Those trial data suggest Stivarga is helpful “whether patients were third-line or fourth, or higher,” said George D. Demetri, MD, Director of the Center for Sarcoma and Bone Oncology at the Dana-Farber Cancer Institute in Boston.

Bayer applied a New Drug Application with the FDA in August for that application as well.

“We hope that based on those trials, the FDA will make a decision very soon,” Dr. Laurent said.

Readers, we want to hear from you!

  • Do you agree with the rapid FDA approval of both Zaltrap and Stivarga?
  • Do you intend to prescribe Zaltrap or Stivarga to your mCRC patients?