Science Editor

Chronic myelogenous leukemia – and its first-generation treatment imatinib (Gleevec, Novartis AG) have been changing the face of cancer research, and cancer drug development, from the outset.

The mutation that underlies most cases of CML – a genetic translocation known as the Philadelphia chromosome – was "the first genetic mutation found in any human cancer," Jorge Cortes told reporters at a press conference at the 2010 ASH annual meeting in Orlando, Fla. And so, imatinib was the first drug that was developed to target a specific molecular mutation.

Imatinib has won its developers the gratitude of all those whose cancer it has transformed from death sentence to chronic disease, as well as worldly accolades such as the 2009 Lasker Prize. And rightly so: Results with imatinib have been "outstanding," Cortes said.

But "we still have some patients that do not achieve a good outcome" with imatinib – either because they are nonresponders or because they develop resistance to imatinib and second-generation agents Tasigna (nilotinib, Novartis) and Sprycel (dasatinib, Bristol-Myers Squibb Co.).

At the firehose of information that is the American Society of Hematology annual meeting, Cortes presented new clinical data on an investigational drug, Ariad Pharmaceuticals Inc.'s ponatinib, that may be successful where the other agents fail.

The 74 patients in the study showed what Cortes termed "an excellent rate of response." Roughly two-thirds of patients had a major cytogenetic response, and half the patients achieved a complete cytogenetic response. Considering the patients in the trial already were resistant to two or three receptor tyrosine kinase inhibitors, Cortes said, "that is an outstanding response."

Scientifically, ponatinib is interesting because resistance to the drug does not develop in vitro under culturing conditions that allow resistance to develop frequently to imatinib and, though less often, to nilotinib and dasatinib as well.

With ponatinib, Cortes said, "when you incubate [cells] at clinically achievable concentrations, we have not seen the emergence of such mutations," adding that this lack of resistance in cell culture gave the investigators "a lot of hope" that it might be true in the clinic as well. Of course, developing drugs to which no resistance will emerge has been a longstanding, and so far unsuccessful, dream for cancer and infectious disease alike.

But another encouraging aspect of the trial is ponatinib's effect on existing mutations: The drug was effective in patients with a particular mutation, the T315I mutation, that none of the currently approved agents are effective against (though some other drugs in clinical trials appear to be) and that was once characterized as "the mutation from hell" by a researcher.

The trial results reported at ASH included nine patients with a T315I mutation who were currently evaluable for a response. All had both a complete hematological response and a major cytogenetic response, with eight of the cytogenetic responses being complete as well.

The FDA's Oncologic Drugs Advisory Committee has said it will not approve drugs for T315I mutations unless there is diagnostic for it. Cortes acknowledged that "obviously, that's going to be a major challenge that we face in the future. . . . The message from the FDA told us that [developing a companion diagnostic] would be very important." Development of such a diagnostic test, he said, is ongoing.

Based on the results of the trial, a pivotal study already is under way. That trial again will enroll "patients that have no other options," Cortes said. But he added that ponatinib would be "attractive to explore" in earlier-stage and front-line settings. Such earlier use, he said, would be "the logical progression in the research on this drug."

In an analyst note, Jefferies & Co. Inc.'s Eun K. Yang pointed out that recruitment for such front-line trials "would be difficult given the high success rates of current front-line therapies." And as imatinib itself goes generic in 2015, price differentials may add to those troubles.

But despite those factors, the overall tenor of the report was positive: Yang predicted possible 2018 sales of ponatinib of more than half a billion dollars, upgrading Jefferies rating for Ariad to "buy."

Data on Seattle Genetics Inc.'s brentuximab vendotin (SGN-35) and Rituxan (rituximab, Genentech Inc./Roche AG and Biogen Idec Inc.) also were presented over the weekend at a press conference titled "Lymphoma: Improving Quality of Life Through Innovative and Alternative Treatment Strategies."

British researchers showed that treating patients with rituximab when they first receive a diagnosis of follicular lymphoma defers chemotherapy for on average of 2.5 years.

The initial strategy to deal with follicular lymphoma is often watchful waiting. Starting chemotherapy immediately in patients who have a follicular lymphoma diagnosis but no symptoms other than swelling in the armpit or groin, does not prolong life, and the therapy itself will lead to significant side effects. So "we know from previous experience that there's no sense in starting treatment early for patients who have no symptoms," Kirit Ardeshna of University College London told reporters.

Rituxan depletes B cells, which are the culprits in lymphoma, and so the team "wanted to see whether we could extend watchful waiting further."

In 462 patients, there was a "highly significant difference" in the time it took for follicular lymphoma to advance to the point where treatment became necessary. Only 20 percent of patients who took rituximab, but over half of those on a watchful waiting approach, have started chemotherapy or radiotherapy.

Ardeshna said there was no overall survival difference "yet," with 95 percent of patients still alive in all groups three years after the trial started.

While rituximab itself is not risk-free, Ardeshna noted that there were few side effects: seven infections, five allergic reactions and four cases of neutropenia. "You can't say it's harmless," he said. "But it's easy to give and well tolerated."

The same press conference saw the presentation of new data on Seattle Genetics' and partner Millennium: the Takeda Oncology Co.'s brentuximab vedotin in patients with relapsed Hodgkin's lymphoma.

The data showed that in 102 patients, who had been failed by a median of 3.5 prior treatments, almost all patients, or 94 percent, achieved "any kind of tumor reduction," and a third went into complete remission.

Side effects were better than expected. Though 55 percent of patients experienced neuropathy, there were few Grade 3 and no Grade 4 events. Ten percent of patients had to come off the study, while another 9 percent reduced their doses.

The data suggested that brentuximab vedotin will be "a very exciting choice for Hodgkin's patients," press conference moderator Ginna Laport told reporters. "For this agent to show a 30 percent complete remission rate . . . with fairly good tolerability is a big breakthrough."

Seattle Genetics agreed. The company said that it would submit a biologics license application in the first quarter of 2011 to seek FDA approval. Millennium has initiated discussions with European regulators to support the submission of a marketing authorization application in the first half of 2011.

Some analysts, however, appeared less smitten with the data. While Needham & Co. reiterated a "buy" recommendation for Seattle Genetics, Canaccord Genuity reiterated a "sell" recommendation, stating that "consensus sales estimates for SGN-35 are unrealistically high, in our view."

And while J.P. Morgan had a more positive view, calling the data "very good," its analysts stuck with their "neutral" rating because "prevailing expectations were already quite high" for the drug.