An actuary might note that if you were in residency at the time when the 7+3 protocol of cytarabine and daunorubicin was first used to treat acute myelogenous leukemia, chances are you are considering retirement just about now.
Sadly, not very much has happened in AML through the bulk of your career.
This has been changing over the past year. AML is not alone. In recent years, large numbers of new drugs have gone through FDA. How are these drugs changing oncology? Most physicians can answer this question within their own subspecialty, but keeping track of changes in another field, even one that is closely related, is hard to do.
In this issue, The Cancer Letter presents a case study in AML that examines change as it occurs—focusing on the roles of FDA, The Leukemia & Lymphoma Society, industry, and academic oncologists have played in developing new therapies.
Since last April, FDA has approved five agents for the treatment of front-line and relapsed AML, with the most recent of these approvals announced last week.
More drugs are in the pipeline and more applications are in the hopper at FDA.
Also, a clinical trial called “Beat AML Master Trial,” sponsored by LLS, is trying to live up to its name by using next-generation sequencing to match patients with treatments—and, possibly, to produce data that FDA would deem sufficiently convincing to support application for approval.
Insiders predict that soon, you will likely see that the entity that now goes under the name AML is made up of a cluster of distinct diseases that will have separate treatments.
It’s a victory of genetics and structural biology that enables chemists to develop drugs that could suppress signals in the leukemic cells that are driving them out of control.
Albert Deisseroth
“There are many. I don’t have the exact number of clinical trials and targets, but there are probably at least 15 and probably more subtypes of AML. Some will be able to be treated the same way, but many will have different paths that ultimately lead to a targeted therapy,” said John Byrd, one of the principals of Beat AML, Distinguished University Professor, the D. Warren Brown Professor of Leukemia Research at The Ohio State University, a member of the NCI Leukemia Steering Committee, chair of the Leukemia and Correlative Science Committee within the Alliance for Clinical Trials in Oncology.
“For some, targeted therapy may not be the path; it may be immunotherapy,” Byrd said. “But I think, really, what’s going to limit us in our exploitation of the science of AML now is the ability to get sufficient patients on clinical trials to ultimately isolate these small groups of patients that respond really well to targeted therapy.”
A conversation with Byrd appears here.
Since changes in the field have just begun, it’s too early to measure the impact these new therapies are having on what’s defined as CML. But efficacy is there, and it’s dramatic in some subsets of patients. In the case of Tibsovo, for example, complete remission plus complete remission with partial hematological recovery was at 32.8 percent.
Indeed, the agency has been at the table where key strategic decisions at AML are made, and it’s thinking creatively. In the case of the most recent approval—Tibsovo (ivosidenib), sponsored by Agios Pharmaceuticals Inc.—FDA accepted data from a single-arm trial to give the agent a full approval.
The agency decided that reduction of transfusions of blood or platelets due to AML constituted a patient benefit. A year ago, the agency granted full approval of enasidenib (IDHIFA), co-sponsored by Agios and Celgene Corp., based on similar endpoints.
Tibsovo is approved for relapsed or refractory AML associated with the isocitrate-dehydrogenase-1 (IDH1) mutation, and IDHIFA is associated with an isocitrate dehydrogenase-2 (IDH2) mutation. Both drugs have to be used with FDA-approved tests.
“I think it speaks to where the FDA is, but I think it also speaks to the compelling data we’ve been able to demonstrate,” David Schenkein, CEO of Agios, said to The Cancer Letter. “The primary endpoint for both our studies, which led to the two approvals was the percentage of patients who have a complete remission. And in this setting, one would expect the complete remission rate with chemotherapy to be about 10 percent.
“And so, we’re seeing with Tibsovo a little over 33 percent complete remissions. So, that’s the primary endpoint. But the secondary endpoint, because of the way the drug works, such a novel way of differentiating or repairing the leukemic cell, led to these transfusion benefits,” Schenkein said.
“The FDA has historically always believed that a reduction in the need of transfusions is a direct measure of clinical benefit. So, the combination of the compelling results, a complete remission rate, together with the transfusion improvement data, and safety profile, is what led to the full approvals, which is unusual, based on a non-randomized trial.”
A conversation with Schenkein appears here.
Albert Deisseroth, a medical officer and associate director of the FDA Division of Hematology Products, said the pace of development of AML drugs reminds him of the recent revolution in the treatment of lung cancer.
“It’s a victory of genetics and structural biology that enables chemists to develop drugs that could suppress signals in the leukemic cells that are driving them out of control,” Deisseroth said to The Cancer Letter.
“This seems to be following a pattern that we witnessed in the area of lung cancer, where the discovery of genetic changes led to targeted therapy that has clearly transformed how we think of lung cancer and created opportunities for new types of therapy for patients with lung cancer,” Deisseroth said. “I am seeing the same process and pattern emerging in the area of AML.”
AML is not a huge indication—about 20,000 new cases a year in the U.S. When you split this into 15 or more subsets, some of these subsets will be very small. Will there be enough of an incentive for drug companies to develop compounds for such populations?
“When I started my career, drug companies were interested in developing drugs for big, common diseases,” said Ruben Mesa, a member of the LLS board and director of the Mays Cancer Center, the newly named home to the UT Health San Antonio MD Anderson Cancer Center. “We continue to have an evolving benefit that really started with imatinib, where even in small populations, if you have a targeted therapy and it’s efficacious, the economics are viable for biotech companies to develop therapies. In the past, you’d have said a subset of relapsed/refractory AML with a particular definition is an orphan disease.”
Here is the list of recently approved AML therapies:
The first new AML therapy approved in decades is midostaurin (Rydapt ), on April 28, 2017. This marked the first significant advance for AML patients in 40 years. The drug, sponsored by Novartis, is approved in combination with chemotherapy for a subset of patients with a mutation called FLT3. Midostaurin is not part of LLS’s Beat AML Master Trial; the study includes a different FLT3 inhibitor.
Celgene and Agios’s enasidenib (IDHIFA) was approved on Aug. 1, 2017, for AML patients with the IDH2 mutation, which impacts 12 percent of AML patients. This therapy is part of the Beat AML trial; the FDA approval was for relapsed and refractory AML patients; it is being studied as a first-line treatment in the trial.
CPX-351 (Vyxeos), sponsored by Jazz Pharmaceuticals, is a reformulation of two standard chemotherapies that optimizes the ratio and delivery of the drugs. It was approved Aug. 3, 2017 for patients with secondary AML, a high-risk subtype that has a very poor prognosis and occurs in 10-20 percent of AML patients. Vyxeos was originally developed by Celator Pharmaceuticals, which was acquired by Jazz in 2016.
Pfizer’s gemtuzumab ozogamicin (Mylotarg), for treatment of adults with newly diagnosed AML both in combination with chemotherapy and on its own, and for the treatment of patients aged two years and older who have experienced a relapse or who have not responded to initial treatment. Mylotarg is approved for patients whose AML cells express a specific protein, CD33, commonly found on the surface of the cancer cells. The drug was approved on Sept. 1, 2017.
Ivosidenib (Tibsovo), sponsored by Agios Pharmaceuticals, was approved on July 20 for AML patients who have relapsed or do not respond to standard chemotherapy and have the IDH1 genetic marker, which is found in approximately six to 10 percent of the 20,000 people in the U.S. diagnosed with AML each year.
LLS holds the IND for the master protocol trial, which it operates through a separate entity, Beat AML LLC. The corporation employs a contract research organization, pays Foundation Medicine for sequencing, hires other contractors, and distributes money to the academic centers that accrue patients to the trial.
We continue to have an evolving benefit that really started with imatinib, where even in small populations, if you have a targeted therapy and it’s efficacious, the economics are viable for biotech companies to develop therapies.
Ruben Mesa
The trial will end up costing at least $55 million, which includes funding from pharmaceutical companies and private donors, said Amy Burd, vice president for research strategy at LLS. The trial is part of a broader series of ALS programs at LLS, which will commit a total of $125 million to this area of research.
Decisions that involve the trial are made by a group of four scientists: Burd, Byrd, Brian Druker, director of Knight Cancer Institute at Oregon Health & Science University and JELD-WEN Chair of Leukemia Research, and Ross Levine, the Laurence Joseph Dineen Chair in Leukemia Research and director of the Center for Hematologic Malignancies at Memorial Sloan Kettering Cancer Center.
With just a dozen clinical trial sites, the trial is more manageable than an NCI-sponsored study that might have a hundred sites or more. This trial has smaller groups as well, but is full cooperative with the NCI effort, and hopefully will inform ideal agents to test in larger patient groups. Both byrd and Levine actively contribute to both the NCi and LLS effort.
“The difference here is that the decision-making is more nimble, probably, than the cooperative groups,” Burd said to The Cancer Letter. That acknowledged, Burd recognizes that the study may have to expand to about 20 sites, and arms will have to be added for researchers to attempt to define combinations of novel drugs.
“Our real push at the moment would be to go to combination therapies,” Burd said. “We certainly believe that it’s going to take a combination of drugs to have the durable, curative responses that we are looking for. That’s the next step for us.”
The following cancer centers are enrolling patients in The Leukemia & Lymphoma Society’s Beat AML study:
The Ohio State University Comprehensive Cancer Center
Memorial Sloan Kettering Cancer Center
Oregon Health & Science University Knight Cancer Institute
Harold C. Simmons Comprehensive Cancer Center at University of Texas Southwestern
University of Chicago Comprehensive Cancer Center
University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center
Huntsman Cancer Institute, University of Utah
Mayo Clinic Cancer Center (Rochester, MN)
Mayo Clinic Cancer Center (Jacksonville, FL)
Mayo Clinic Cancer Center (Phoenix, AZ)
UCLA Health
Winship Cancer Institute, Emory University
Since Beat AML consists of single-arm studies, there is no real stopping rule for the entire enterprise, and the number of arms that can be added is limited only by scientific curiosity and the sponsors’ willingness to play.
One of the principles we had across all the stakeholders was that no one was in this for the credit. We needed to put our egos aside and work together, and that would be the only way we could instill change.
Amy Burd
“One of the principles we had across all the stakeholders was that no one was in this for the credit,” Burd said. “We needed to put our egos aside and work together, and that would be the only way we could instill change.”
Unlike many studies by cooperative groups, Beat AML is gearing to produce data that may support registration.
“We start out with a small number of patients to make early go/no-go decisions. If you achieve the CR rate that you expect, then we have a discussion with FDA to expand out the study to something that could be registrational without doing a randomized study,” Burd said. “We are looking for really large signals. We are not looking for something that’s incremental. But it’s something where we have to weave in a synthetic control arm for the natural history of the disease to determine whether we can get to registration without doing a randomized trial.”
The planning for Beat AML started in June 2014, when LLS noted that it was devoting about 26 percent of its research budget to the disease. “This prompted me and some of the other scientists at the department to take a pause and question what was really happening in the field and—more importantly—how we can better prioritize our dollars to have a real impact, especially considering that the standard of care at that point hadn’t changed in 40 years,” Burd said.
Burd put together a meeting of key researchers, including Levine, Druker and Byrd. “This was where the idea for the trial was born,” she said.
“We then had a meeting with FDA in the fall of 2014, and continued to have these discussions on how the field was challenged and how we could improve the outcome for patients with AML and get drugs approved.”
Next, LLS put together a larger gathering, about 30 people, at the 2014 annual meeting of the American Society of Hematology. That meeting sparked the eventual discussions that produced the concept for a trial that would drive innovation in AML. FDA, too, gave a nod to the idea.
At the 2015 annual meeting of the American Society of Clinical Oncology, the trial’s designers met with representatives of 27 pharma and biotech firms, and soon thereafter filed an IND. In July 2016, the society received a safe-to-proceed letter from FDA and the study began in November 2016.
As the study was being designed, LLS and the academics involved consulted NCI and FDA. At the time, NCI was just starting to climb out of a long financial crunch.
Early on, a decision was made that if NCI were to start some version of an AML trial, LLS would abort its plans for Beat AML.
“Our goal was all about the patients, it’s about finding the drugs and helping the patients,” Burd said.
