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.
Indication: For patients with metastatic or inoperable melanoma whose tumors have a gene mutation called BRAF V600E. Approved with a companion diagnostic test, the cobas 4800 BRAF V600E Mutation Test.
Approval: Based on results from a phase III clinical trial of 675 patients with late-stage melanoma with the BRAF V600E mutation who had not been previously treated. Patients were randomly assigned to receive vemurafenib or dacarbazine . Objective responses were seen in nearly half of patients treated with vemurafenib but only in 6 percent of patients treated with dacarbazine.
The median survival of patients treated with vemurafenib has not been reached, while the median survival for those who received dacarbazine was 8 months.
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.
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.
Brentuximab vedotin (Adcetris)
Indication: For patients with Hodgkin lymphoma, the approval covers use of brentuximab in patients whose disease has progressed after receiving an autologous stem cell transplant or after two rounds of chemotherapy in patients who are not eligible for a stem cell transplant. For anaplastic large cell lymphoma (ALCL), the drug is approved for patients whose disease has progressed after one chemotherapy treatment.
Approval: For Hodgkin lymphoma, based on the results of a single-arm, 102-patient phase II trial. Nearly three-quarters of patients had an objective response and one-third had a complete response. The estimated 1-year survival rate was 88 percent.
For ALCL, based on results from a single-arm trial of 58-patients whose disease had returned following treatment or never responded to the first-line treatment. In that trial, 86 percent of patients had an objective response and 57 percent had a complete response.
In the case of crizotinib, only 3 to 5 percent of patients with NSCLC harbor the ALKtranslocation . (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 .
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
Indication: For patients with advanced or metastatic non-small cell lung cancer (NSCLC) whose tumors have the ALK gene fusion. Approved with a companion diagnostic test, the Vysis ALK Break Apart FISH Probe Kit.
Approval: Based on two single-arm studies that enrolled 255 patients with late-stage ALK-positive NSCLC. Most patients had previously received chemotherapy.
Objective response rate in the two trials was 50 percent and 61 percent, respectively, with durations of response (time without tumor regrowth) of 42 and 48 weeks, respectively.
Possible side effects: Nausea, diarrhea, vomiting, and vision disorders, such as blurred vision and visual field defects.
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.
The approval of these three and several other new cancer drugs in the last year has generated a great deal of excitement. But there is also a mounting concern about their high cost. Crizotinib, for example, costs $9,600 per month. Brentuximab costs $13,500 per dose. The price of vemurafenib and iplimumab , another melanoma drug, are in the same ballpark, as is sipuleucel-T (Provenge), which was approved last year to treat metastatic prostate cancer. For 1 year of treatment with many of these drugs, the cost is $100,000 or more.
Pfizer, Roche (which owns development and distribution rights to vemurafenib), and Seattle Genetics have all established patient assistance programs to help cover the cost of the drugs for those who are under- or uninsured.
The available data suggest that such help is needed. A study published earlier this year found that as patient co-pays for cancer drugs rose, the likelihood of patients filling even the initial prescription fell.
In addition to the burden of high drug costs on individual patients, costs are expanding for society as a whole. A recent NCI study estimated that Americans spent $125 billion on cancer treatment in 2010 and the authors projected that costs could reach nearly $180 billion by 2020.
Numerous factors influence drug prices, including well-documented issues related to development and regulatory approval. When it's possible, the ability to limit trials to a smaller group of patients whose tumors have specific molecular markers may bring down development costs, which could translate to lower prices, Dr. Kurzrock said. But that's not a certainty.
From a population-wide perspective, such targeted drugs may offer potential savings, Dr. Allen stressed. In the case of drugs like vemurafenib and crizotinib, he said, "we'll be saving money by not giving them to patients who we know won't benefit."