Roundup of Second-Generation Targeted Therapies for CML

CHICAGO-The second-generation targeted therapies designed to treat chronic myelogenous leukemia (CML) continue to look good but none yet has scored the home run needed to dethrone imatinib. That was the conclusion of studies presented here at the ASCO Annual Meeting.

The newly described data show that once-daily dasatinib dosing is preferred over the currently approved twice-daily schedule and that the agent works in the first-line setting. Also, nilotinib is well tolerated and induces rapid cytogenetic responses. Two new agents appear safe and have early evidence of efficacy in previously treated patients.

The best dose of dasatinib, based both on efficacy and side effects seems to be 100 mg per day, said the Discussant for the papers, Charles Schiffer, MD, Professor of Medicine and Oncology and Director of Multidisciplinary Leukemia and Lymphoma Medical Oncology at the Karmanos Cancer Institute at Wayne State University.

Companies rush to trial often having done inadequate Phase I trials. That is not the case with dasatinib, but what almost never happens are secondary trials to discover the ideal dose and schedule. I think this was a very important trial. I think the nilotinib data are holding up with a large number of patients, he continued. It is clearly an alternative therapy for people who have failed imatinib therapy, and the data are reminiscent, except for a different side effect profile, of the data presented with dasatinib.

Dasatinib Dosing

Dasatinib is currently approved in the US for the treatment of CML patients who are intolerant or resistant to imatinib therapy. The approved dose of the drug is 70 mg twice daily, which results in a continuous inhibition of the Bcr-Abl kinase that is the root cause of CML.

Figure. Charles Schi...

However, researchers have seen hints in the clinic that twice-daily dosing increased the incidence of side effects, including pleural effusions, relative to once-daily dosing. Also, in vitro tests suggested that intermittent blockade of Bcr-Abl by dasatinib was adequate to kill tumor cells.

To find out which dose and schedule were better for patients, Neil P. Shah, MD, Assistant Professor in Residence at the University of California, San Francisco, and colleagues randomly assigned 670 patients with chronic-phase CML who were resistant or intolerant to imatinib to one of four doses. Two study arms tested once-daily doses of 100 mg and 140 mg and two arms tested 50 mg and 70 mg twice-daily doses.

With a median duration of 11.5 months, there was no statistically significant difference in the response rate between the trial arms. Patients had an 88% to 92% rate of complete hematologic response in the four trial arms. Additionally, 58% to 64% of the patients in the trial had a major cytogenetic response, and 46% to 50% achieved a complete cytogenetic response.

Similarly, the rate of response appeared similar between the arms, with 17% to 22% of patients achieving a major molecular response by six months.

Progression-free survival was significantly better in the 100 mg daily arm compared with the 70 mg twice daily arm, with progression defined as development of accelerated- or blast-phase disease as well as loss of a complete hematologic or major cytogenetic response.

Specifically, 16 of 165 patients (10%) on the once-daily 100 mg regimen had disease progression, compared with 30 of 167 patients (18%) on the standard dose. The other two arms were in between, with 22 and 23 patients progressing out of 167 and 163 total patients.

Side Effects

As expected from previous smaller trials, Grade 3 or 4 side effects were less common in patients treated with the once-daily 100 mg dose compared with those who received the twice-daily 70 mg dose, but most of the differences were not statistically significant.

The one nonhematologic toxicity that did reach statistical significance was congestive heart failure (CHF) which occurred in four patients in the twice-daily arm and none in the once-daily arm. (The 50 mg twice-daily arm had one patient with CHF and the 140 mg once-daily had two.)

Anemia was not statistically different between the two arms at 10% in the 100 mg once-daily and 17% of patients affected in the 70 mg twice-daily arm, and neutropenia was similar at 34% and 43%, respectively. Thrombocytopenia was statistically different at 22% in the 100 mg once daily arm and 38% in the standard doing arm.

I think we can confidently say at this time that 100 mg once daily is the optimal dose schedule for patients with chronic stage CML, Dr. Shah said. This is an important trial because it provides the first evidence that transient inhibition of a target with a tyrosine kinase inhibitor can preserve the efficacy of more continuous inhibition and simultaneously improve tolerability.

Figure. Neil P. Shah...

The results open the door for intravenous delivery of tyrosine kinase inhibitors that work like dasatinib and for even less frequent dosing and inhibition, he added.

I was a little reluctant to switch patients to once daily until I had seen these data and the number of time follow-up we have now-I think [better] adherence on the whole is the reason for decreased progression in once- daily therapy, he said.

Dasatinib as First-Line Therapy

Although the vast majority of CML patients have a cytologic response to imatinib, most continue to have low levels of the Bcr-Abl gene, which remain detectable by polymerase chain reaction (PCR) assay. Researchers have thought that because dasatinib binds the Bcr-Abl target 300 times more tightly than imatinib does, that the newer drug may induce deeper and faster remissions in newly diagnosed patients.

To find out, Ehab L. Atallah, MD, a leukemia fellow at the University of Texas M. D. Anderson Cancer Center, and colleagues designed a trial to treat previously untreated chronic-phase CML patients with either 100 mg once daily or 50 mg twice daily dasatinib.

The planned enrollment for the trial is 50 patients per arm; thus far 35 patients have enrolled and 34 are evaluable for response, with a median follow-up time of nine months. Given the small number of patients, Dr. Atallah did not divide the responses by treatment arm.

Overall, 85% of the patients have had a complete cytogenetic response. Of the 21 patients who have been on dasatinib therapy for 12 months or more, 95% have had a complete response. Moreover, 27% of the patients treated for one year have had a major molecular response, which was the primary endpoint of the trial. Thus far only one patient has failed therapy.

Although the numbers of patients in the trial are still quite small and there has been a relatively short duration of treatment, Dr. Atallah said the response rate compares favorably to what physicians at M. D. Anderson have seen historically with imatinib in previously untreated CML patients.

Figure. Ehab L. Atal...

Side effects were similar to what has been seen in previous dasatinib trials, with three patients having Grade 3 headache and three with Grade 3 skin reactions. Thrombocytopenia was the most common Grade 3 or 4 hematologic toxicity and occurred in 11 patients. Six patients had Grade 3 or 4 anemia and three had Grade 3 or 4 neutropenia.

Nearly half of the patients (43%) in this trial required some sort of break in therapy. The median duration of dose interruption was 12 days, but one patient was off therapy for 135 days and is expected to go off study shortly, Dr. Atallah said.

Four patients required a dose interruption due to myelosuppression, three for pleural effusion, three for rash, two for headaches and two for fever.

The Chair of the session, Ellin Berman, MD, Acting Chief of the Leukemia Service at Memorial Sloan-Kettering Cancer Center, said that given the large number of dose reductions, dasatinib presents more difficult management compared with imatinib, which has a much lower interruption rate.

Nilotinib Phase II Data

Nilotinib, like dasatinib, is a second-generation inhibitor of Bcr-Abl. The drug is currently in Phase II and III trials. During the session at the ASCO Meeting, Gianantonio Rosti, MD, a researcher at the Institute of Hematology and Medical Oncology, Sergnoli, in Bologna, Italy, presented results from a large Phase II trial testing nilotinib in chronic-phase patients who have relapsed from imatinib or are intolerant of it.

A total of 320 patients have enrolled in the trial and were started on a dose of 400 mg of nilotinib twice daily. Fifty-one patients (16%) have had a dose escalation to 600 mg twice daily and 165 patients had dose interruptions.

Currently the median duration of nilotinib therapy is 314 days, with a range of one to 624 days, Dr. Rosti said. Of the patients who have been treated for six months or longer, 76% have had a complete hematologic response, 56% have had a major cytogenetic response and 40% have had a complete cytogenetic response.

The median time required for patients to have a major cytogenetic response was 2.8 months, and the median duration of the response has not been reached. Thus far 19 patients (6%) have progressed on therapy.

Nilotinib appears to be well tolerated, with diarrhea the most common Grade 3 or 4 nonhematologic side effect, affecting 2.8% of patients. Grade 3 or 4 headache occurred in 2.5% of patients, arthralgia in 2.2%, and Grade 3 or 4 myalgia and fatigue each occurred in about 2% of patients.

Grade 3 or 4 hematologic toxicities were common in nilotinib-treated patients, with thrombocytopenia occurring in 33% of patients, neutropenia in 31%, and anemia in 9%.

Laboratory tests indicated that pancreas and liver functions were affected with the drug, with about 15% of patients having Grade 3 or 4 lipase elevation, 13% hypophosphatemia, and 12% glycemia.

Unlike imatinib, however, the drug does not seem to induce fluid retention. None of the patients experienced Grade 3 or 4 peripheral edema, although 12% of patients had Grade 1 or 2 edema. There was one case each of Grade 3 pericardial effusion and pleural effusion, and two cases of Grade 3 pulmonary edema.

Bosutinib and INNO-406 in Phase I Trials

Two other drugs being developed for the treatment of imatinib-resistant or -intolerant patients, bosutinib (SKI-606) and INNO-406, are currently in early-phase trials. Carlo Gambacorti-Passerini, MD, Professor of Clinical Medicine at San Gerardo Hospital in Monza, Italy, reported on the bosutinib data during the oral session and Adam Craig, MD, PhD, Vice President and Chief Medical Officer of Innovive Pharmaceuticals in New York presented a poster study on INNO-406.

In a Phase I/II trial of bosutinib, 110 patients with chronic- or advanced-phase CML who were intolerant or resistant to imatinib were treated with the new agent. Of those, 14 had prior treatment with dasatinib and 13 with prior nilotinib. The median duration of treatment is still quite short, at just 2.8 months.

Of the 45 evaluable patients who had been previously treated with imatinib, but no other targeted therapy, 40 had a complete hematologic response, 11 had a complete cytogenetic response and 16 achieved a major cytogenetic response. Of the 15 evaluable patients who had prior imatinib therapy and another targeted agent, five had a complete hematologic response and three have had major cytogenetic responses.

Figure. Carlo Gambac...

Diarrhea was the most common side effect, with 75 patients (68%) experiencing any grade and eight (7%) having Grade 3 or 4 diarrhea. Nausea and vomiting were also common, although only three had Grade 3 nausea and 4 had Grade 3 vomiting. Two patients had Grade 3 fluid retention, but pleural effusion occurred in only four patients, with one having Grade 3.

As with the other drugs in this group, thrombocytopenia was the most common hematologic toxicity, with Grade 3 or 4 occurring in 10 patients (9%) patients. Four patients (3.6%) experienced Grade 3 or 4 neutropenia and four (3.6%) had Grade 3 or 4 anemia.

Meanwhile, 29 patients enrolled in the Phase I trial testing INNO-406. Twenty-four of the patients have been previously treated with imatinib and a second Bcr-Abl inhibitor. Of the five patients previously treated only with imatinib, three showed some clinical benefit from INNO-406. One patient had a minor cytogenetic response, one had complete hematologic response that lasted more than three months, and one had a complete hematologic response along with a major cytogenetic response.

Fifteen of the patients previously treated with imatinib and another Bcr-Abl inhibitor are currently evaluable. Of those, four derived some benefit from INNO-406. One patient with accelerated-phase CML had a complete hematologic response and went on to a bone marrow transplant.

Two patients, one with chronic-phase disease and one with accelerated-phase, have had a complete hematologic response, and another patient with chronic-phase disease had an unspecified molecular response.

The number of adverse events reported was limited in this relatively small patient group, with three patients (10%) having a Grade 1 or 2 QTc prolongation. Grade 3 AST or ALT elevation occurred in three patients (10%). One had acute renal failure following tumor lysis syndrome, and one had intrahepatic cholestasis, grade 4, which was a dose-limiting toxicity. The researchers did not report any hematologic toxicities.

All of the speakers, including Dr. Schiffer, have received some form of research support or honoraria from the companies developing these drugs.

The State of CML Therapy

The most recent data from the IRIS trial, which was designed to test imatinib as first-line therapy in chronic-phase CML patients, shows that 93% of patients are progression-free at five years, Charles Schiffer, MD, noted during his discussion of the newer compounds. What is notable is that there are very few relapses after the second year. So this is wonderful therapy that we are trying to improve upon.

That said, approximately 15% of CML patients do not achieve a complete cytogenetic response with imatinib and another 1% to 2% are intolerant of it. Interestingly, many of the patients who are intolerant of imatinib, succeed on one of the other agents, said Dr. Schiffer, which suggests that the mechanism of intolerance is unrelated to Bcr-Abl inhibition.

So if all of the agents are able to induce relatively similar responses, how will physicians choose between them? In addressing this question, Dr. Schiffer noted the likelihood that it is unlikely that large head-to-head trials to look at long-term endpoints will be done.

This almost never happens with successful drugs, he said. (Novartis, the company that makes both imatinib and nilotinib, is planning a Phase III trial to compare the rate of major molecular response in previously untreated CML patients with their two agents.)

A quick walk through the Exhibit Hall at the ASCO meeting, though, suggests that companies think that marketing will have an impact on physicians' choices, Dr. Schiffer said.

Side-effect profile likely will be clinically important and help guide physicians' drug choice-for example, he said, I probably wouldn't choose nilotinib for someone who has a history of pancreatitis or dasatinib for someone with a history of congestive heart failure.

It is not yet clear whether some of the agents will be more effective in one stage of disease than the other drugs are, or whether their inhibition of enzymes other than the Bcr-Abl target will be important. I think we have no idea whether some of the responses are aided or abetted with Src inhibitor [by dasatinib and bosutinib, for example] or Lyn inhibition [by INNO-406]. But I think it is very important, he said.

Some of the agents are known to work better against specific mutations in the Bcr-Abl gene, but nearly half of the time, no mutation is found in patients who become resistant to imatinib. Thus, which drug will be best for these patients remains unclear.

Cost is going to continue to be an issue, and one that physicians need to really pay attention to, he added. The pharmaceutical industry seems to be the only industry that when you have multiple competitive products, the prices don't change. There is no Southwest Airlines in the pharmaceutical industry. Perhaps it would be nice if there was one.

This is particularly true because experts are concerned that with the very high cost and very high copays attached to these drugs that patients may not be taking their full doses. Patients might just be cutting back on their drug. It is like hypertension; it is invisible to them, he said. If they stretch their copay, they are going to lose some of their efficacy.

What Would It Take to Dethrone Imatinib as First-Line Standard Therapy?

So what would it take to dethrone imatinib as the first-line standard therapy? A drug would have to show increases in overall survival and progression-free survival, and that would take years, he said. Alternatively, if any of these drugs induce such a deep remission that patients can stop therapy, that would be enormously important.

Right now, many centers have stopped performing transplants on CML patients, yet patients cannot stop their therapy. And fertility is becoming a big issue amongst these patients.

To illustrate the state of the field, Dr. Schiffer described a clinical dilemma not unfamiliar to leukemia physicians: A 40-year-old patient has to switch to dasatinib and is now having a good response to therapy. But he has a donor match. Should he be transplanted or continue on dasatinib?

This is like year one with imatinib, Dr. Schiffer said, noting that it is still unclear how long a patient is likely to respond to a second-generation drug. We have tended to recommend transplant for these patients in our institution. This could cause vigorous debate amongst us, but should not cause vigorous debate that this is an important question to which we do not have a definitive answer.

-RST