This year is shaping up to be a promising period in the development of oncology therapeutics as the FDA moved briskly to review and approve new drugs, including several agents hailed as breakthroughs in personalized medicine and cancer care.
At press time, the FDA had approved 8 new cancer medicines and 9 new oncologic indications for existing drugs. The group includes 2 drugs, Xalkori (crizotinib) and Zelboraf (vemurafenib), which were approved with companion diagnostic tests, and Yervoy (ipilimumab), the first in a new class of immune-boosting anticancer agents.
The FDA said priority and streamlined review procedures helped expedite approvals across all therapeutic classes, with the average time to review a new drug dropping to 1.1 years. The time from submission to approval was much shorter for some of the most-heralded oncology drugs: 3.6 months for Zelboraf, 4.2 months for Zytiga (abiraterone acetate), and 4.9 months for Xalkori.
The new therapy options are presenting both opportunities and challenges for clinicians. In this report, leading oncology specialists discuss considerations for fitting some of the new drugs into patients’ treatment plans.Hematologic MalignanciesPathways Research Points Way to 2 Agents
Two new drugs approved this year for the treatment of hematologic malignancies illustrate the evolving understanding of the signaling pathways that promote cancers.
Adcetris (brentuximab vedotin), the first drug the FDA has approved for treating patients with Hodgkin lymphoma since 1977, is an antibody-drug conjugate that selectively targets CD30, a cell membrane protein overexpressed in the disorder.
It is approved for patients with Hodgkin lymphoma whose disease has progressed after autologous stem cell transplant or after 2 prior chemotherapy treatments for those who cannot receive a transplant. It also may be used for patients with anaplastic large cell lymphoma whose disease has progressed after 1 chemotherapy treatment.
In addition to its approved uses, the drug might also open new windows of opportunity to treat other patients, according to Paul A. Hamlin, MD, clinical director of the Lymphoma Outpatient Unit at Memorial Sloan- Kettering Cancer Center in New York City. Hamlin said that as the drug’s efficacy is better understood, Adcetris might serve as first-line therapy in older patients for whom standard chemotherapy poses a greater risk.
“We know the toxicity of standard chemotherapy is sometimes too great [for these patients], and if we could incorporate a very active agent and eliminate [the need to use] bleomycin, which can cause significant pulmonary damage, we may be able to improve the outcome in a group of patients where we actually don’t do as well as we do in younger patients,” Hamlin said.
Additionally, Hamlin said there might be other lymphomas where Adcetris can help.
“We’re not limited to solely Hodgkin lymphoma,” Hamlin said. “We’re limited to these diseases that have adequate CD30 present on their surface.”
For example, Hamlin said that T-cell lymphomas are “notoriously difficult” to treat. However, CD30 is expressed in many of these cancers.
Another new hematologic agent, Jakafi (ruxolitinib) is an oral inhibitor of JAK1 and JAK2, both members of the JAK family of nonreceptor tyrosine kinase inhibitors. Dysregulation of these signaling pathways has been linked to myelofibrosis, a condition in which scar tissue replaces healthy bone marrow, forcing the liver and spleen to work to produce new blood cells.
The FDA approved Jakafi based on 2 studies. The first study showed that 41.9% of patients receiving the drug had at least a 35% reduction in spleen size, compared with only 0.7% of patients receiving the placebo by week 24 of the study (P
<.0001). In the second study, 28.5% of patients in the Jakafi arm experienced a reduction in spleen size ≥35%. No patients receiving best available therapy (ie, hydroxyurea, a chemotherapy agent, or glucocorticoids) experienced the same kind of reduction (P
“Jakafi represents another example of an increasing trend in oncology where a detailed scientific understanding of the mechanisms of a disease allows a drug to be directed toward specific molecular pathways,” said Richard Pazdur, MD, director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research, in a press release.
Clinicians Face Challenges Integrating New Therapeutics
The options for treating patients with prostate cancer are mushrooming, presenting fresh questions for clinicians seeking to select and combine therapies for the best possible outcomes.
In April, the FDA approved Zytiga (abiraterone acetate), an oral CYP17 inhibitor, for use in combination with prednisone in patients with metastatic castration-resistant prostate cancer who have received prior docetaxel therapy.
In recent months, positive trial data have been reported about Alpharadin (radium-223 chloride), which emits alpha radiation targeted to bone metastases, and MDV3100, an androgen receptor signaling inhibitor.
These developments come on top of the 2010 approvals of Jevtana (cabazitaxel), an injectable microtubule inhibitor, and Provenge (sipuleucel-T), a vaccine custom-made for each patient.
In an interview with OncologyLive, Daniel P. Petrylak, MD, discussed key points in evaluating therapies.
What are the challenges facing clinicians?
It's a very difficult issue. We have some drugs that are approved in very, very similar clinical niches. For example, there is cabazitaxel as well as abiraterone, and now MDV3100, which will probably be approved as therapy post-docetaxel, so there are 3 drugs in the space. Then there is Alpharadin, which will probably be approved for patients ineligible for docetaxel, as well as those patients who have failed docetaxel. And, if you consider the fact that you can administer Provenge to patients who fail docetaxel, that's 5 different agents.
How do we sequence them? We don't understand the biology as well as we should. We need good tests to tell us which drug or treatment is the best one to use in a given situation. Right now, it's a bit of guesswork. If a patient is rapidly progressive, one tends to go toward chemotherapy, although there's really no evidence to use that at this particular point. That's just basically what a lot of clinicians are accustomed to using. If you've had chemotherapy and you've tolerated it poorly, one would tend to go to some of the other hormonal agents such as abiraterone or MDV3100.
Is it frustrating to have new tools but many questions?
I'm happy that we have all these drugs. If you look back to a review that I wrote with Alan Yagoda in 1993, we were labeled as being nihilist because we said nothing worked at that point. We went from that to Taxotere [docetaxel] in 2004. Our study supported the approval of that drug for castration-resistant disease. So that's a big leap at that point. In an 11-year period, the field changed. And then for seven years it's been quiescent and now we've had this explosion of new drugs.
So I'm really happy for the patients. It's up to us to figure out how to use these drugs properly, and I think I have good confidence that we'll be able to do that.