The FDA approved more new oncology drugs in 2011 than it has in a single year in more than a decade, thanks in part to priority review and streamlined evaluation procedures. While this is good news for patients, oncology and hematology specialists must tackle the challenges posed by integrating new therapies into treatment plans. Leading specialists give their perspectives on key issues.
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.
Pathways 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 <.0001).
“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.
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.
Breaking New Ground on Several Fronts
In August, the FDA approved Xalkori (crizotinib) for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) that is anaplastic lymphoma kinase (ALK)-positive. The abnormal ALK gene is detected by the Vysis ALK Break Apart FISH Probe Kit, a test the FDA also approved.
Paul A. Bunn, Jr, MD, professor of Medicine and the James Dudley Chair in Cancer Research at the University of Colorado, Denver, said that Xalkori, the first new drug approved for lung cancer by the FDA in more than 6 years, provides a model for future drug development in cancer care. Bunn said Xalkori represents a paradigm shift in NSCLC because it is a move away from a one-size-fits-all approach to biomarker-based treatment decisions.
The abnormal ALK gene causes cancer to develop and grow. An estimated 1% to 7% of patients with NSCLC have this genetic abnormality, and they are usually nonsmokers. Xalkori is an oral adenosine triphosphate (ATP)-competitive small-molecule dual inhibitor of mesenchymal epithelial transition growth factor and ALK tyrosine kinases, both of which are indicated in cancer.
In the past, Bunn said, treatment decisions in lung cancer were made primarily on clinical grounds, (eg, age, performance status, and comorbid conditions). Histology and molecular features were not considered and cytology and small biopsies were used for diagnosis, with a diagnosis of “NSCLC not otherwise specified” considered, adequate, he said.
“Now we need to know the precise histologic type and the molecular features before selecting therapy,” Bunn said. “In many instances, an additional biopsy is necessary. And at the time of progression on targeted therapies, we often need another biopsy to determine the cause of resistance to select the next therapy.”
Moving Forward With Novel Therapies
By any account, this year has been a watershed year for the development of melanoma drugs. The FDA approved 3 drugs for the treatment of metastatic melanoma: Sylatron (peginterferon alfa-2b), Yervoy (ipilimumab), and Zelboraf (vemurafenib). Before 2011, the last time a new drug was approved to treat metastatic melanoma was in 1998, when the FDA approved interleuken-2.
“Yervoy and Zelboraf are major advances in the field,” said Stuart H. Packer, MD, clinical director, Medical Oncology Service, Montefiore Einstein Center for Cancer Care, Bronx, New York. “These 2 drugs, along with interleukin, are the drugs doctors now have in their arsenal when they treat patients with metastatic melanomas.”
Zelboraf is a selective inhibitor of the activated BRAF V600E gene, which is found in 70% of malignant melanomas. It was approved along with a companion diagnostic test, the cobas 4800 BRAF V600 Mutation Test. Zelboraf is supplied as a tablet for oral administration.
Packer said the biomarker test presents an advantage for Zelboraf. “As a practitioner, you can have some confidence that there is a possibility the drug is going to work,” he said.
In addition, Yervoy may take longer to work in some patients. “It takes a while for the immune system to get geared up. Patients sometimes get worse before they get better,” he said.
Both drugs have exhibited the ability to improve overall survival. More than 20% of patients who received Yervoy in the pivotal trial lived at least 2 years, and some of them much longer, while the median survival time for patients in the Zelboraf trial had not yet been reached when the drug was approved in August.
To determine which option is best for a patient with metastatic melanoma, Packer said every patient should be tested for the BRAF V600E gene. If the test is positive, Zelboraf is recommended as the first line of defense. If the test is negative, Yervoy is recommended.
The drawback to using interleukin-2 is its significant toxicity, and Packer said it is only used with patients who doctors feel can tolerate the adverse events.
Existing Agents Prove Helpful in New Ways
Two new drugs represent “major breakthroughs” in the treatment of pancreatic neuroendocrine tumors, according to one of the key investigators. In May, the FDA approved new indications for Afinitor (everolimus) and Sutent (sunitinib malate) so that they can be used in patients with advanced neuroendocrine tumors that cannot be surgically removed and for cancer that has metastasized. These are the first new drugs to be approved for this type of cancer in nearly 30 years.
“Not only is this is a major breakthrough in the field,” said James C. Yao, MD, associate professor in the Department of Gastrointestinal Medical Oncology at The University of Texas MD Anderson Cancer Center in Houston, who coauthored the definitive Afinitor study. “The results are telling us more about the biology of the disease. We are identifying the mutation involved, and hitting a very specific abnormality present in the tumors, with fairly significant results. This pathway will open the door for further improvement in the future,” Yao said.
The Afinitor study enrolled 410 patients with advanced, low-grade or intermediate-grade pancreatic neuroendocrine tumors. Progression-free survival was 11 months for patients treated with Afinitor and 4.6 months for patients treated with placebo. Approximately 34% of patients treated with Afinitor were alive and free of cancer progression at 18 months, compared with 9% of patients treated with placebo.
To evaluate Sutent, researchers conducted a phase III clinical trial in 171 patients who had experienced cancer progression. Progression-free survival was 11.4 months among patients treated with Sutent and 5.5 months among patients treated with placebo.
Yao described the new treatment options as an evolving story. “More and more people are going to use everolimus and other less-toxic treatments early on in the disease and save the more toxic therapies for later in the disease,” he said.
Head and Neck Cancers
Caprelsa (vandetanib) is the first approved treatment for patients with metastatic medullary thyroid cancer (MTC) who are not candidates for surgery and have disease that is advancing and causing symptoms. It is a tyrosine kinase inhibitor with multiple targets.
The drug, which is administered orally, was approved on the basis of a single, randomized study among 331 participants that demonstrated a median progression-free survival of at least 22.6 months in the vandetanib arm versus 16.4 months for those on placebo (Epub ahead of print November 21, 2011. J Clin Oncol).
To prescribe the drug, physicians must register with a Risk Evaluation and Mitigation Strategy program.
Eric J. Sherman, MD, a medical oncologist at Memorial Sloan-Kettering Cancer Center in New York City, discussed the drug during the 7th Annual Multidisciplinary Symposium on Head and Neck Cancer, a Physicians’ Education Resource (PER) conference held in Philadelphia on November 19.
“One of the concerns the FDA had was an increase in QTc interval and whether that can lead to further cardiac events,” said Sherman in an interview. “Very few people actually had a cardiac event in the study, but it still was a major concern of the FDA. Because of that concern, the FDA mandated that in order to be able to prescribe vandetanib, physicians would need to undergo registration, which basically involves a short online course.”
“It’s still not clear when it is the perfect time to start [Caprelsa] because people with metastatic medullary thyroid carcinoma, even those who have some progression, can live quite a number of years before any event,” said Sherman. “It shouldn’t be started just because someone has metastatic disease, and it shouldn’t be started just because tumor markers are increasing. However, it is very reasonable to start when there is a significant progression (not minor) on the scans or when symptoms due to the disease develop.”
For late-stage head and neck cancers, a category that includes cancers of the nasal cavity, sinuses, lips, mouth, salivary glands, throat, or larynx, oncologists can now consider Erbitux (cetuximab) in combination with chemotherapy.
In 2006, Erbitux gained approval as a treatment for advanced squamous cell carcinoma of the head and neck in combination with radiation therapy, or as a single agent after prior platinum-based therapy. Studies showed prolonged survival and delay in tumor growth compared with radiation therapy alone (N Engl J Med. 2006;354:567-578).
The study that led to its latest approval demonstrated that patients treated with cetuximab and chemotherapy (cisplatin or carboplatin and 5-fluorouracil) had a median overall survival of 10.1 months compared with 7.4 months on chemotherapy alone (N Engl J Med. 2008;359:1116-1127).
Everett E. Vokes, MD, chairman of the Department of Medicine and physician-in-chief at the University of Chicago Medical Center in Illinois, said the study of cetuximab combined with chemotherapy represents “a major breakthrough” for that patient population because it was the first to show an increase in survival.
“That is really where there is measurable impact directly derived from cetuximab at this point,” said Vokes, who also spoke at the PER conference.
“When moving into the curative-intense setting, we want to use it as a radiation sensitizer or as a chemotherapy sensitizer, so we add it to what we know to be curative modalities at this point,” Vokes continued. “The landmark study that was done was a comparison of radiation versus radiation and cetuximab. And the survival with cetuximab was improved, statistically and clinically. But in terms of where that leaves us as clinicians or the patient, it’s really in the middle of nowhere because radiation alone is not something we use frequently.”
“I think if I’m a community oncologist and I stick to evidence-based medicine, then I will give it with first-line chemotherapy for patients who have recurrence,” he said. “That is the indication with chemotherapy. Every other use with chemotherapy or chemoradiation upfront would be on experimental trials.”
Medications Address Pain and Bone Mass
Two fast-acting forms of fentanyl were approved by the FDA this year for the management of breakthrough cancer pain. Abstral, a transmucosal tablet, was approved in January, and Lazanda, a nasal spray, was approved in June.
“These types of analgesics are another step forward in helping improve functioning in patients with breakthrough pain,” said Srinivas R. Nalamachu, MD, the principal Abstral investigator, of the International Clinical Research Institute in Overland Park, Kansas.
He has researched the long-term effectiveness and tolerability of sublingual fentanyl for the treatment of breakthrough cancer pain. “More than anything else, the development of these drugs is important because of the quick onset of pain relief,” said Nalamachu. “It is very fast, under 15 minutes, and patients can get relief and quickly get back to doing the things they need to do in their lives.”
Abstral is approved for patients with cancer aged ≥18 years who already use opioid pain medication around the clock and are experiencing periodic breakthrough pain. The recommended initial dose of the drug is a single 100-μg tablet. If adequate analgesia is achieved within 30 minutes of administration, subsequent episodes of breakthrough pain should be treated with the same dose.
If adequate analgesia is not achieved after the initial dose, the patient may use a second Abstral dose after 30 minutes as directed by a healthcare provider. No more than 2 doses of Abstral may be used to treat an episode of breakthrough pain, and patients must wait at least 2 hours before treating another episode of breakthrough pain.
Adverse events associated with the use of Abstral include nausea, drowsiness, headache, and constipation. The FDA has also warned that the risk of death had been cited in studies of similar immediate-release fentanyl products. However, the deaths occurred as a result of improper patient selection and/or improper dosing, the FDA said.
Lazanda is supplied as a nasal spray, and, like Abstral, the appropriate dose must be determined by dose titration and is based on the individual patient’s effective and tolerable dose.
Nalamachu said that being able to offer fentanyl in various formulations is important in tailoring treatment to patients’ needs. A patient with a head or neck cancer, for example, can suffer from a dry mouth, and thus is not a good candidate for transmucosal tablets, he said, adding, “and a patient with allergy problems is not the best candidate for the nasal spray.”
Also in the supportive care category are new uses for Prolia (denosumab), which has been approved as a treatment to increase bone mass in patients at high risk for fracture receiving androgen deprivation therapy (ADT) for nonmetastatic prostate cancer or adjuvant aromatase inhibitor (AI) therapy for breast cancer.
The approvals were based on results from 2 international, randomized, double-blind, placebocontrolled trials in patients receiving ADT for nonmetastatic prostate cancer or adjuvant AI therapy for breast cancer. Treatment with Prolia resulted in a statistically significant effect on bone mass density as compared with placebo in patients with nonmetastatic prostate or breast cancer at 24 months and 12 months, respectively. In men with prostate cancer, Prolia also significantly reduced the incidence of new vertebral fractures at 36 months.
“The study showed not only improvement in bone mineral density, but also a decrease in the incidence of fractures, which is important for maintaining the quality of life of the patient,” said Neal D. Shore, MD, the medical director of the Carolina Urologic Research Center, Myrtle Beach, South Carolina. “Bone complications disrupt a patient’s life, cause disability, pain, and hospitalization. A decrease in fractures improves the quality of life, and also lowers the cost to the healthcare system. A fracture of the hip can be extremely costly.”
Another important plus is that denosumab does not require an intravenous infusion or the need for dose adjustment for renal function. The recommended dose and schedule is 60 mg subcutaneously every 6 months. “Denosumab is also a benefit for the patient in terms of time and discomfort,” Shore said. “It is very simple and quick to administer, and relatively painless.”
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