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he outlook has never been better for patients with chronic myeloid leukemia (CML). Clinicians have an increasingly wide choice of drugs, between imatinib (Gleevec), dasatinib (Sprycel), nilotinib (Tasigna), bosutinib, and very likely ponatinib too, if it receives U.S. Food and Drug Administration (FDA) approval later this year.
The 17th Congress of the European Hematology Association (EHA), recently held in Amsterdam, The Netherlands, presented a wealth of new data on these second- and third-line tyrosine kinase inhibitors (TKIs).
"It's phenomenal. The overall survival has improved, with 93 to 95% of patients alive after 7 to 8 years of follow-up," said Daniel DeAngelo, MD, associate professor of medicine at Harvard Medical School, and clinical director of Adult Leukemia at the Dana-Farber Cancer Institute, Boston, Massachusetts, in an interview with Medscape Medical News. "There has been a dramatic improvement in outcome over the decade."
Data Round-Up on New Drugs
The EHA saw long-term follow-up and comparison data on bosutinib, dasatinib, nilotinib, and ponatinib presented.
Dasatinib data (Bristol-Myers Squibbs) showed that first-line treatment at 100 mg resulted in faster and deeper response rates compared with imatinib 400 mg, according to 3-year follow-up of the DASISION (Dasatinib versus Imatinib Study in Treatment-Naïve CML-CP Patients) trial. The median time to complete cytogenic response (CCyR) for dasatinib was 3.2 months, versus 6.0 months for imatinib. The median time to major molecular response (MMR) was 15 versus 36 months, respectively. By 3 years, MMR was achieved in 68% of dasatinib-treated patients and in 55% of imatinib-treated patients (P < .0001). Long-term follow-up for 5 years is planned as part of the original DASISION study design.
Pfizer's BELA trial compared bosutinib with imatinib and reported that after at least 30 months of follow-up, 79% of patients on bosutinib showed CCyR versus 81% on imatinib; 61% on bosutinib versus 52% on imatinib achieved MMR; and 30% on bosutinib versus 22% on imatinib achieved complete molecular response (CMR), according to an intent-to-treat analysis. The BELA trial is a phase 3 open-label comparison of the efficacy and safety of bosutinib combined with imatinib in patients with newly diagnosed chronic phase CML.
Nilotinib data (Novartis) showed superior results compared with imatinib in newly diagnosed patients in the ENESTnd 3-year follow-up. A significantly lower rate of progression to accelerated/blast phase CML, lower rates of mutation, and significantly higher rates of MMR and molecular response were observed for nilotinib versus imatinib. Differences in rates of molecular response between nilotinib and imatinib increased over time. Another study presented at EHA showed that nilotinib induced deeper molecular responses versus continued imatinib in patients with CML with detectable disease after 2 years on imatinib as seen in the ENESTcmr 12-month results.
Data on ponatinib (Ariad), an investigational pan-BCR-ABL inhibitor, showed that 54% of chronic-phase CML patients who were pretreated and were refractory to other TKIs, including 70% with a T315I mutation, achieved a major CyR (MCyR). CCyR was achieved by 44% of patients. The median follow-up of chronic phase CML patients is 10.1 months. Data were updated from the pivotal PACE trial in CML patients who were resistant or intolerant to dasatinib or nilotinib, or who had the T315I mutation.
Imatinib Sets the Stage
Imatinib was the first oral targeted drug in cancer therapy and the first in CML. "Imatinib sets the bar very high," reflects Dr. DeAngelo, "but that doesn't mean it's the best drug."
Patients who experience significant side effects, develop resistance to imatinib, or become intolerant warrant discontinuation of the drug. "These categories represent a small number of patients, but it is important to have alternative second- and now third-generation drugs available for patients," added Dr. DeAngelo.
In 2006, dasatinib received U.S. Food and Drug Administration (FDA) approval for CML in patients who were refractory or intolerant to imatinib; in 2010, it received approval for use in patients newly diagnosed with CML. Nilotinib (Tasigna) received FDA approval for previously treated CML in 2007, and for newly diagnosed patients in 2010. These 2 drugs represent the first 2 second-generation drugs for CML. They are more potent inhibitors of BCR-ABL than imatinib, and they exhibit significant activity against all resistant mutations except the T315Imutation.
Bosutinib Holds Long-Term Promise
Bosutinib is another second-generation TKI. Dr. Carlo Gambacorti, MD, hematologist-oncologist, from the University of Milano Bicocca, Monza, Italy, who presented findings at the EHA, commented on the BELA comparison trial with imatinib and noted that results reflected findings with other second-generation TKIs in that you get faster and deeper molecular remissions. "This translates into a reduced number of progressions to accelerated or blast/crisis phase, usually within the first year of treatment," said Dr. Gambacorti in an interview with Medscape Medical News.
At 30 months, 4% of patients in the bosutinib group progressed to accelerated or blast/crisis phase, compared with 6% of those taking imatinib. Overall survival at 30 months was achieved by 97% of patients in the bosutinib group versus 95% in the imatinib group, with 5 of 250 versus 10 of 252 drug-related deaths in each group, respectively.
"The comparator imatinib is a very effective drug, and most patients are well served by it. However, the small number who fail imatinib show a better response to bosutinib," pointed out Dr. Gambacorti.
It is notable that a small proportion of patients could not tolerate bosutinib and discontinued in the first few weeks. "Most discontinued because the physician was unfamiliar with the drug or the management of gastrointestinal effects like nausea and vomiting, but these can be effectively treated."
Because of these dropouts, the trial did not reach its primary endpoint of CCyR at 12 months but did show significant differences in MMR and CMR at 12 months. "The CMR is theoretically the response which could open the door for drug discontinuation," Dr. Gambacorti commented, and he added that no serious adverse toxicity was seen with bosutinib, unlike with other second-generation TKIs.
Reflecting more generally on CMR, Dr. Gambacorti stated that if a patient remained in CMR for an extended time, the patient would be likely to have a normal life expectancy, based on other data on imatinib. "This is the first disease in which we can return a patient to normal life expectancy. Patients on bosutinib with CMR at 24 months may have a similarly positive outlook."
Dr. Gambacorti concluded that bosutinib is most likely to be used in the approximately 20% of patients who do not respond well when taking imatinib. "In patients with a bad prognosis, bosutinib, like other second-generation TKIs, is likely to return over 50% of them to cytogenetic remission," said Dr. Gambacorti. "This is where these drugs are going."
However, he stood by the effectiveness of imatinib as first-line therapy. "It's difficult to beat a Ferrari, especially when it is a Ferrari that does not harm the patient," Dr. Gambacorti commented.
Ponatinib: A T315I Inhibitor
Ponatinib is a third-generation pan-BCR-ABL inhibitor drug. It marks another turning point in the therapeutic history of CML in that, in addition to other cases of refractory CML, it is under investigation for the treatment of patients with the gatekeeper T315I mutation, for which no other drug is currently available.
The study presented at this year's EHA represented patients who had failed treatment with a second-generation drug—dasatinib or niliotinib. Most had failed imatinib too.
"Imatinib, dasatinib, nilotinib, and bosutinib all fail to be effective in patients with the T315I mutation," commented Dr. DeAngelo. "Also, there are other mutations which render nilotinib ineffective, and others which render dasatinib ineffective; however, these mutations are sensitive to ponatinib."
Ariad, the company developing ponatinib, expects to file for regulatory approval of ponatinib in the European Union and in the United States in the third quarter of 2012 for patients who have failed dasatinib and nilotinib; it will also include patients who have the T315I mutation.
At some point in the near future, a randomized clinical trial (RCT) of ponatinib versus imatinib will be conducted in newly diagnosed patients; additional information will be obtained on toxicity profiles, and this will potentially lead to a first-line indication.
Asked where he would envisage using ponatinib if approval is granted, Dr. DeAngelo said, "Ponatinib offers a new approach in patients who fail dasatinib or nilotinib, as we currently have no good alternative option for them. With the exception of low-risk chronic phase CML, I typically use one of the second-generation TKIs as first line in the majority of my patients."
Dr. DeAngelo added that if a patient progressed while receiving imatinib and was found to have a T315I mutation, he would move straight to ponatinib. Mutation analysis still is not recommended in treatment-naïve patients.
Head-to-Head Comparisons
Three head-to-head RCTs have compared the following treatment agents: imatinib and niliotinib, imatinib and dasatinib, and imatinib and bosutinib. This information was presented at EHA.
Commenting on the dasatinib-imatinib trial results (3-year follow-up of the DASISION trial), Dr. DeAngelo said that dasatinib seemed to be better tolerated. "There was, in general, a slightly greater number of patients with pleural effusions in the dasatinib arm, but all other side effects were higher in the imatinib arm. Patients had a more rapid time to response, achieving complete cytogenetic remission on dasatinib, which was almost twice as fast," he said.
Furthermore, he added that more patients on dasatinib achieved an MMR. "On the face of it, dasatinib appears to be superior with these endpoints to imatinib."
Dr. DeAngelo said that the bosutinib BELA trial was powered to look at CCyR, and it was found identical to imatinib, but MMR was better in the bosutinib group. "Bosutinib had a higher MMR and complete molecular response rate, but the endpoint of CCyR was identical at 79% for bosutinib and 80% for imatinib. My assumption is that the drug is more active than imatinib, but CCR rate was the study's primary endpoint, and there was no difference," he said.
Dr. DeAngelo added that more patients experienced diarrhea in the bosutinib than in the imatinib group, but greater numbers of musculoskeletal issues and cases of edema were reported in the imatinib group. "It works in patients who fail imatinib, but also has a different toxicity profile to dasatinib and nilotinib. It would [be] good to have this as another treatment option."
Dr. DeAngelo has disclosed that he sat on the Novartis advisory board and received an honorarium from Ariad. Dr. Gambacorti has received research funding from Pfizer.

FDA clears first new weight-loss pill in 13 years

The Food and Drug Administration has approved Arena Pharmaceutical's anti-obesity pill Belviq, the first new prescription drug for long-term weight loss to enter the U.S. market in over a decade.

Despite only achieving modest weight loss in clinical studies, the drug appeared safe enough to win the FDA's endorsement, amid calls from doctors for new weight-loss treatments.

The agency cleared the pill Wednesday for adults who are obese or are overweight with at least one medical complication, such as diabetes or high cholesterol. The drug should be used in combination with a healthy diet and exercise.

Obesity Society President Patrick O'Neil said he's encouraged by the drug's approval because it underscores the notion that lifestyle changes alone are not enough to treat obesity.

"This is good news because it tells us that the FDA is indeed treating obesity seriously," said O'Neil, who teaches at Medical University of South Carolina and was the lead researcher on several studies of Belviq. "On the other hand, it's not the answer to the problem — or even a big part of the answer."

Even if the effects of Belviq are subtle, experts say it could be an important first step in developing new treatments that attack the underlying causes of obesity.

"The way these things tend to work is you have some people who do extremely well and other people don't lose any weight at all. But if we had 10 medicines that were all different and worked like this, we would have a real field," said Dr. Louis Aronne, director of the weight loss program at Weill-Cornell Medical College.

The FDA denied approval for Arena's drug in 2010 after scientists raised concerns about tumors that developed in animals studied with the drug. The company resubmitted the drug with additional data earlier this year, and the FDA said there was little risk of tumors in humans.

Arena and its partner Eisai Inc. of Woodcliff Lake, N.J., expect to launch the drug in early 2013.

With U.S. obesity rates nearing 35 percent of the adult population, many doctors have called on the FDA to approve new weight loss treatments.

But a long line of prescription weight loss offerings have been associated with safety problems, most notably the fen-phen combination, which was linked to heart valve damage in 1997. The cocktail of phentermine and fenfluramine was a popular weight loss combination prescribed by doctors, though it was never approved by the FDA.

In a rare move, the FDA explicitly stated in a press release that Belviq "does not appear to activate" a chemical pathway that was linked to the heart problems seen with fen-phen.

The FDA said the drug acts on a different chemical pathway in the brain, which is believed to reduce appetite by boosting feelings of satiety and fullness.

Belviq is one of three experimental weight-loss drugs whose developers have been trying for a second time to win approval, after the FDA shot them all down in 2010 or early 2011 because of serious potential side effects.

Vivus Inc.'s Qnexa is thought to be the most promising of the drugs, achieving the most weight loss. But the FDA has delayed a decision on that pill until July.

Shares of San Diego-based Arena Pharmaceuticals Inc. jumped $2.54, or 28.7 percent, to close at $11.39. Shares of Mountain View, Calif.-based Vivus rose $1.94, or 7.4 percent, to $28.33. Shares of Orexigen Therapeutics Inc., the third drugmaker with an obesity pill before the FDA, rose 20 percent to close at $4.92.

Arena's studies showed that patients taking Belviq, known generically as lorcaserin, had modest weight loss. On average patients lost just 3 to 3.7 percent of their starting body weight over a year. About 47 percent of patients without diabetes lost at least 5 percent of their weight or more, which was enough to meet FDA standards for effectiveness. By comparison, average weight loss with Qnexa is 11 percent, with more than 83 percent of patients losing 5 percent of their weight or more.

The FDA said patients should stop taking Belviq after three months if they fail to lose 5 percent of their body weight. Patients are unlikely to see any significant weight loss by staying with the drug.

Side effects with the drug include depression, migraine and memory lapses.

In May a panel of expert advisers to the FDA voted 18-4 to recommend approval of Arena's drug, concluding that its benefits "outweigh the potential risks when used long term" in overweight and obese people.

Experts say the challenge of weight loss drug development lies in safely turning off one of the body's fundamental directives: to eat enough food to maintain its current weight.

While several drugs are available for short-term weight loss, until Wednesday there was only one FDA-approved prescription drug for long-term weight loss: Xenical from Roche, which is seldom prescribed because of unpleasant digestive side effects and modest weight loss. Belviq is the first new prescription drug approved to treat obesity since Xenical's approval 13 years ago.

Other safety failures for diet pills have continued to pile up in recent years.

Four years ago Sanofi-Aventis SA discontinued studies of its highly anticipated pill Acomplia due to psychiatric side effects, including depression and suicidal thoughts. In 2010, Abbott Laboratories withdrew its drug Meridia after a study showed it increased heart attack and stroke.