San Francisco—The current pattern of drug development in lymphoma is unfocused and requires better prioritization. So says Anas Younes, MD, Professor of Cancer Medicine and Director of Clinical and Translational Research for Lymphoma/Myeloma at The University of Texas MD Anderson Cancer Center, speaking here at the Oncology Congress.
“There is a clear need for new drugs. We need to get out of the CHOP scaffold and ABVD backbone. These are 30-year-old regimens. We‘ve just added rituximab. We need to get something different that will improve the cure rate of these patients.”
The addition of rituximab to the chemotherapy regimens increased overall survival for lymphoma patients, but nearly half still remain uncured and require second-line therapy. The good news is that there are other agents in development. The bad news, Dr. Younes argues, is that the current approach to clinical trials in lymphoma hinders the identification and development of truly effective agents.
Challenge 1: Enrolling Patients
“The biggest problem is not a lack of new agents or identification of molecular targets. The biggest challenge is enrolling patients in a timely manner on clinically meaningful trials,” he said.
To illustrate the problem, he collected information from the National Institutes of Health website, clinicaltrials.gov, and did some simple calculations. He found that between January 2009 and March 2010, researchers activated 238 lymphoma trials in the United States. Only 14 trials were randomized Phase III trials. “This tells us that very few agents that go through Phase I and Phase II graduate to Phase III,” Dr. Younes said. “They are not making it, either because of toxicity or lack of efficacy.”
Moreover, the number of patients needed for these trials exceeds the number available, he continued. On average, 74,000 people are diagnosed with lymphoma each year, and about 3% will participate in trials. “With 238 trials, you end up having nine patients per trial, so good luck. No matter how good the trial is, if it is not enrolling, it is not going to go anywhere.
“That is our biggest challenge,” he said. “We have too many drugs. We are diluting our efforts with too many clinical trials; some of them probably ask marginal questions that may not be very important. We really need to prioritize the questions we ask to advance the field. Otherwise we will be stuck with R-CHOP for the next 30 years.”
Challenge 2: Narrow Indications
The US Food and Drug Administration has approved five new drugs for lymphoma since 2005. However, all of the agents are palliative and none increase overall survival. To do that the community needs to develop agents with narrower indications, according to Dr. Younes.
“I think the era of one drug to treat all is going to disappear, it has to disappear. Giving R-CHOP to everyone, we are stuck with a 45 to 50 percent cure rate. It is not going to be 100 percent no matter what you do. You start to have to select the patients. If you can cure a patient with R-CHOP, that's okay; it's not so bad. But for the other patients, using R-CHOP delays other therapies and is toxic. We need to try to identify the other patients upfront and give them what they need.”
Targeted therapies can be aimed at either the oncogenic processes that drive tumor cell survival and growth, or they can be aimed at non-oncogenic processes. Surprisingly, progress in lymphoma has come from targeting non-oncogenic proteins, like CD-20. And that past success means that investigators and clinicians should keep an open mind with regard to what targets might be valuable in the future in this disease setting, he said.
Dr. Younes noted that antibodies against other non-oncogenic targets, including CD-22 and CD-23, are in development. Thus far, antibodies conjugated to toxins seem to induce higher response rates than naked antibodies.
For example, a naked CD-22 antibody, epratuzumab, induced an 18% response rate in indolent or follicular lymphomas, while the same antibody linked to a toxin, CMC-544, induced a 69% response rate. Response rates were also higher with the conjugated antibody in diffuse large B-cell lymphoma and Hodgkin lymphoma.
“So it seems like a conjugated toxin approach is interesting and a producing higher response rate. Of course, we need to show this in focused clinical trial to see if it would lead to potential approval,” said Dr. Younes, who also discussed some of these issues in a recent article in Nature Reviews in Clinical Oncology (“Beyond chemotherapy: new agents for targeted treatment of lymphoma,” published online on 12/14/10).
Targeted Oncogenic Pathways
Meanwhile, targeting oncogenic pathways is an approach that is working in many cancers, not just lymphoma. And many of the oncogenic pathways that are active in lymphoma—NF∼B, PI3K/AKT/mTOR, and JAK/STAT, for example—are active in other cancers as well. And there are agents in development that target these pathways.
The problem is that response rates in lymphoma rarely exceed 30%, because the disease is so heterogeneous. And that relatively low response rate leaves drug developers in an awkward spot. If an agent is from a big company with a substantial pipeline, the group can drop it and forego future trials in lymphoma. If, however, it is a small company and with few agents in development, the team has to continue pursuing development and will try combining it with another agent.
“The knee-jerk response is to combine it with either rituximab or bendamustine, which leads to extremely unfocused trials that just combine agents to see what happens,” Dr. Younes said. “And that leads to a dilution of clinical trials, and which is why we cannot move the field forward. We cannot continue to do these unfocused trials.”
Challenge 3: Treat According to Molecular Defect
The way forward, Dr. Younes contends, is more focused trials in preselected patients. Otherwise, researchers will continue to be left with low response rates and response durations that are limited to six months or less.
“To maximize patient benefit from novel agents, you really need to identify predictive biomarkers to select patients. And you need to start to design rational combinations based on these preselected criteria to improve the impact.”
A recent example demonstrating the power of preselection comes from lung cancer. Approximately 5% of non-small cell lung cancer tumors have a translocation in the anaplastic large cell lymphoma kinase (ALK) gene. “If you preselect these patients, you get a response rate of more than 50%, which is remarkable,” Dr. Younes said.
It is not yet clear whether the ALK inhibitor will work in lymphoma patients, despite being first identified in this disease setting. Yet, that is exactly the point, says Dr. Younes. “These oncogenic pathways should be targeted across different types of cancer, regardless of the cell of origin.”
To test whether this approach will work in practice, researchers at MD Anderson, the National Cancer Institute, the Mayo Clinic, and the University of Nebraska have set up a collaborative effort. The group plans to try treating patients based not on histology, but on the oncogenic pathways that are affected. To identify these patients, the team will use gene expression signatures and pool them across different lymphoma histologies.
“This is a testable hypothesis,” Dr. Younes said. “We are moving now toward testing this in a prospective way. If we can prove this is efficient, then this could be a new model of drug development in lymphoid malignancies.”