FDA Approves New Drugs to Treat Skin, Blood, and Lung Cancers

Article from NCI

LD-lungsIn the last 2 weeks of August, the Food and Drug Administration (FDA) approved three new cancer drugs: vemurafenib (Zelboraf), for patients with unresectable or metastatic melanoma whose tumors harbor a specific genetic mutation in the BRAF gene; brentuximab vedotin (Adcetris), for some patients with Hodgkin lymphoma and anaplastic large cell lymphoma; and crizotinib (Xalkori), for patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) whose tumors have a gene fusiontranslocation involving the ALK gene. caused by a chromosomal

The three drugs were approved all well in advance of the time allotted for their review. By comparison, from the beginning of 2010 until the week of August 15, 2011, the agency had approved just six new cancer drugs.

Some common themes ran through the approvals. Crizotinib and brentuximab, for example, were accelerated approvals, meaning that they were approved because clinical trials showed an improvement in a surrogate endpoint, such as tumor response, that is reasonably likely to predict clinical benefit. Both drugs have to be tested in confirmatory trials to verify their safety and clinical effectiveness.

Crizotinib and vemurafenib, meanwhile, were approved with companion diagnostics for each drug. These companion tests are used to identify patients who are most likely to benefit from the drugs, based on the presence of a specific genetic abnormality or other molecular marker.

All three drugs also have one more important feature in common, stressed Dr. Richard Pazdur, director of the Office of Oncology Drug Products in FDA’s Center for Drug Evaluation and Research: “They all appear to have a more favorable benefit-to-risk analysis than conventional chemotherapy agents.” The greater benefit-to-risk ratio “reflects a true understanding of the biology of the disease,” Dr. Pazdur continued.

Although targeting specific genetic aberrations is not a new therapeutic approach, greater knowledge of the underlying biology of many cancers means that “there are more targets out there, and researchers better understand how to hit [those targets] and the ramifications of hitting them,” said Dr. Jeff Allen, executive director of Friends of Cancer Research, an advocacy organization that promotes research collaborations. “To see that coming to clinical benefit with greater frequency is very encouraging.”

In addition, all three drugs have demonstrated or strongly suggested that they are effective for diseases for which effective treatments have been difficult to find. Brentuximab, for instance, is the first new drug approved for Hodgkin lymphoma in 30 years.

A Refined Approach

Dr. Paul Bunn, a lung cancer expert from the University of Colorado Medical Center, said during a press briefing on crizotinib that the drug’s approval represents “a new paradigm for drug development, where a small but well-defined fraction of people get a very well-defined drug.”

The same holds true for vemurafenib. The FDA based its approval for both drugs on trials that included only patients who harbored the molecular aberrations that the drugs target.

In the case of crizotinib, only 3 to 5 percent of patients with NSCLC harbor the ALK translocation. (A recent study suggests, however, that as many as 8 percent of patients with the adenocarcinoma type of NSCLC may have the translocation.) Even though the percentage of patients with the translocation is small, as many as 16,000 NSCLC patients per year may be candidates for the drug, said Dr. Mark Kris of Memorial Sloan-Kettering Cancer Center during the briefing.

The subset of melanoma patients who are candidates for vemurafenib is substantially larger; about half of patients with metastatic melanoma harbor the BRAF mutation.

Such a sizable subset of patients who are candidates for a new molecularly tailored therapy will likely be more of an exception than the rule, said Dr. Razelle Kurzrock, chair of the Department of Investigational Cancer Therapeutics at the University of Texas M. D. Anderson Cancer Center.

For common cancers like lung cancer, Dr. Kurzrock added, it is particularly unlikely that a large percentage of patients will be found to carry a specific genetic alteration. “Common cancers may be more common because there are more pathways for developing the disease than in less common and rarer cancers,” she said.

Had crizotinib been developed in the more traditional manner, Dr. Kurzrock said, with the trials including any patient with NSCLC rather than just those with the ALK translocation, the drug could very well have been abandoned because of poor response rates.

Essential Companions

When there is a marker that clearly identifies a subset of patients who may benefit from a drug, “companies have become very proactive in the development of companion diagnostics,” said Dr. Helen Chen of NCI’s Division of Cancer Treatment and Diagnosis.

From fairly early in the development process of vemurafenib and crizotinib, in fact, the drugs’ developers, Pfizer and Plexxikon, began working with diagnostics companies to develop tests that would identify appropriate patients to include in clinical trials.

“There has been a great deal of concern in the oncology community about the difficulty of developing diagnostics along with the drug,” said Dr. Pazdur. “These are both excellent examples that it can be done…. You can develop your in vitro diagnostic [test] with the drug simultaneously and move through the approval process fairly easily.”

Go Forth and Multiply

The rapid development and approval of these drugs can have a multiplier effect. Crizotinib’s approval is particularly important, Dr. Kurzrock believes. “It provides a real incentive to look for these small subsets of patients, because now it’s been shown that it can really pay off.”

It can also accelerate the continued development of the approved agents. Brentuximab is already being tested in patients with earlier-stage Hodgkin lymphoma, as well as in CD30-positive non-Hodgkin lymphoma. And vemurafenib will be tested in trials in combination with a recently approved drug for advanced melanoma, the immunotherapy drug ipilimumab (Yervoy).

With numerous patients experiencing complete disappearance of their tumors, at least for a time, in the clinical trials that led to these new approvals, all three drugs are already helping patients.

Jeff Wigbels took his first dose of crizotinib last October. His lung cancer had spread to multiple places in his body, including his throat. He had to eat through a tube, he explained during the briefing on the drug’s approval.

A week after taking the first dose, some friends came to visit him. They ordered pizza. And he could eat it.

“It was an amazing experience for me that [the drug] could work that quickly,” he said.

Carmen Phillips

For more information, visit National Cancer Institute