A couple of months ago, the FDA approved the latest drug to treat chronic myeloid leukemia (CML). Called ponatinib (brand name Iclusig, made by Ariad), the drug is a third-generation tyrosine kinase inhibitor, the latest in a class of agents founded in 2001 with the approval of imatinib (Gleevec, Novartis). Imatinib, followed by dasatinib and nilotinib, and now ponatinib, are tyrosine kinase inhibitors. These drugs block the activity of a mutant kinase that triggers the growth of white blood cells in an uncontrolled way. By plugging up the site at which the kinase binds with ATP (the energy storehouse of the cell, from which the kinase plucks a single phosphate and then transports that phosphate to the next protein in line on the pathway that leads to white blood cell production), these drugs essentially stop the process that defines CML.
Cheerleading new drugs isn’t always warranted. But there is something truly impressive going on with this particular line of medicines. They work well, often with few side effects, and are among the most successful cancer drugs ever made.
How did a rare disease like CML, which strikes about 5,400 people in the U.S. annually, come to have three generations of highly successful treatments? That is a story for another time. (Well, shameless plug, it’s the story told in my forthcoming book, The Philadelphia Chromosome, out this May.) However, the story of ponatinib stands on its own because it is yet another targeted drug that is offering a treatment to patients who would otherwise have died from their disease by now, having run through all other options.
Recently I spoke with Michael Mauro, of Oregon Health & Sciences University (OHSU), who was a lead investigator both on the early lab studies of ponatinib and on the clinical trials that led to its approval. Here’s what he had to say about this new drug and why it matters.
JW: What distinguishes ponatinib from other tyrosine kinase inhibitors for CML?
Michael Mauro: Probably the most significant finding before we gave the drug to patients was that in laboratory studies it was shown to prevent the growth of all mutated clones. So it really held the promise of a drug that could treat more broadly resistant CML, or maybe help stop resistance.
When it went into the clinic, ponatinib was given to patients with multi-drug resistant CML. Among these patients, who had taken on average three or more prior medications, the response rate was very good. The majority responded in a significant fashion. In particular, it could broadly treat chronic phase CML that was resistant to multiple medications.
JW: What are mutated clones?
MM: CML has a mutation in the Abl kinase. But there can be more than one mutation, and depending on what mutations are present, a drug may or may not work. For example, some people with CML have a mutation known as T315I. When that mutation is present, none of the kinase inhibitors available before ponatinib could bind. In the laboratory, ponatinib worked against CML cells with multiple mutations, and also stopped the occurrence of new mutations.
JW: Can you further explain how mutations confer drug resistance?
MM: The binding site on the kinase enzyme works like a lock and key. Mutations in the kinase change the shape of the lock. With each new mutation, the lock changes shape a little more. If the shape is changed in subtle ways, some inhibitors might still work. For others, the change is too severe. For example, the T315I mutation is a very dramatic alteration in the lock, so none of the keys worked for patients with this mutation. But ponatinib does work for these patients. T315I is one example, but the significance of this drug extends beyond that one mutation. In preclinical and clinical studies, there was not one mutation against which ponatinib did not work.
JW: Is there any reason why patients with the T315I mutation seemed to do particularly well on this drug in the clinical trial?
MM: It’s true that patients with this mutation had a dramatically better response rate compared to the overall population of the clinical trial, although the average response rate among the entire population was also very good. The reason for this increased rate of response may be because these patients had had fewer prior treatments, or because they were younger. The mutation was just one part of the story.
Here are some of the results of the clinical trials of ponatinib:
• Among 43 patients with chronic CML (the earliest stage, with a life expectancy of 4-6 years in the absence of treatment), 98% (42) had a complete hematologic response; 72% (30) had a major cytogenetic response; and 44% (18) had a major molecular response [more about what these responses mean another time].
• Among 12 patients with the T315I mutation, 100% (12) had a complete hematologic response and 92% (11) had a major cytogenetic response
• The full report is published here.
The “pivotal” phase II trial was known as PACE, for Ponatinib Ph+ ALL and CML Evaluation (Ph+ refers to the Philadelphia chromosome, the spontaneous genetic mutation that triggers CML in the first place). This trial served as the basis for FDA approval.
• 49% (126 out of 258 evaluable patients) had a major cytogenetic response, 41% (105/258) had a complete cytogenetic response, and 26% (68/265) had a major molecular response.
• Here is the full chart of response rates. You can see that among patients with the T315I mutation, the response rates were higher than for the overall population, but the population size isn’t large enough to be considered truly rigorous.
Back to the Q&A…
JW: What is it about the chemical structure of ponatinib that allows it to work so broadly?
MM: Imatinib (the first tyrosine kinase inhibitor for CML) binds to a certain receptor in a leukemia cell. It is active against the target, bcr/abl, when the target is in its normal configuration. It’s a very tight-fitting drug. The contact points have to be exactly right.
All of the other inhibitors of this kind are built on the backbone of imatinib. With the second-generation drugs, the chemical had fewer requirements – fewer contact points. The kinase flips back and forth between active and inactive states. For imatinib, the kinase needs to be in an active state, like a door opening that allows the drug to get in. For some of the second-generation drugs, that requirement is removed. The chemical structure retains some of imatinib, but it’s altered slightly. The same is true for ponatinib.
The structure of ponatinib enables the drug to work against other targets, not just the bcr/abl kinase that triggers CML.It also blocks VEGF (vascular endothelial growth factor) and FLT3. FLT3 is associated with acute myeloid leukemia, which is why the drug was also tested for that disease. VEGF is present in many cancers.
JW: What is the significance of a molecular remission?
MM: A molecular remission is often predictive of a survival benefit because it’s such a deep indicator of the disease disappearing. When blood counts normalize, as indicated by a hematologic response, that points to a disease remission. When you sample the bone marrow and see the Philadelphia chromosome disappearing, that’s an even greater depth of remission. When you sample the entire system to look for any cells with RNA made from DNA that has the Philadelphia chromosome – the molecular response – that is the deepest level of remission. A molecular response measures leukemia burden in thousands… is the leukemia burden a thousand times smaller in a treater versus untreated patient?
This level of response takes time to develop. In the trials of ponatinib, we saw these responses occur fairly rapidly, which may seem odd to hear. Why would the molecular remissions occur faster with one drug versus another? When the disease is resistant, the drugs either work or they don’t. In this case, the drug worked for almost all patients in the studies and the responses tended to be fairly rapid.
JW: What does the advent of ponatinib reveal about how to create effective targeted drugs? Are there any lessons learned here?
MM: Ponatinib is really building on history. It was borne out of necessity and data. Imatinib (Gleevec) was unprecedented. It was a small molecule that worked against a selected targeted. No one thought it would be a comprehensive treatment, but it was. Just as the drug was gaining traction, we saw that there are mutations that can arise that prevent the drug from binding. So you go back to the lab and ask: How can we overcome this mutation? You have to make the chemical as slick and as strongly binding as possible.
This drug, and other kinase inhibitors, are really an evolution, not an epiphany. It wasn’t, “Oh we didn’t get this right the first time, what should we have done?” It’s really, “What were the problems with the other drug and how can we fix that?”
Mutations in CML cells happen whether you give these drugs or not. They are fast-growing, unstable cells and these genetic errors happen. A study in our laboratory found that among patients with advanced forms of Philadelphia chromosome-positive leukemia who had never had other treatments, 30% had mutations that were resistant to imatinib or other drugs.
Some people think that if you give these medications, you kill off the grass and the weeds grow. That’s not how mutations occur. It’s more like popcorn popper. Mutations happen.
JW: For a newly diagnosed patient, does it make sense to start with Gleevec and then move to other inhibitors if this drug stops working? Or is the prevalent thinking to start with the latest drug?
MM: There is a healthy debate in the field. All of these drugs yield good results. The data on dasatinib and nilotinib showed that if these drugs put more patients into remission compared to imatinib, but they didn’t lead to a huge shift in practice. Some people continue to use imatinib first because its side-effect profile is so mild and it’s the one we know best, especially when more serious complications arise.
I think the benefits outweigh the risks of using a new drug. Over the years, we’ve learned that if a patient doesn’t have a good response to imatinib, we can improve on the outcome, but it might not be as good as if the patient had started on a more recent drug first.
We need to move forward cautiously. The current official recommendation is that all of these drugs are reasonable first-line choices. It’s an individual decision for each patient that needs to consider what side effect you might predict and what other medications the patient is taking that might interact with this one.
The biggest issue is getting patients into remission, and getting them there quickly. But we always need to exercise caution.
JW: Is it possible to profile patients for what mutations are present and make a decision based on what you see?
MM: No. For one thing, the mutations are not always there at the beginning. You’re looking for a needle in a haystack, and you need to clear away the haystack before you see them, and sometimes new needles appear as the haystack shrinks. A drug-resistant mutation may be present at the start, but you usually can’t see it. We are not very good at profiling patients at the start of their care. It’s one of our biggest challenges: we don’t have a tool that allows us to discern which drug would be best for which patient. All we can say is the odds of response.
JW: Any stories you can share from your experience treating patients with ponatinib?
MM: One of my patients is a middle-aged woman who I’d been treating for at least ten years. She’d been through five clinical studies at our center – she’d tried imatinib, interferon, arsenic trioxide, sunitinib, and nothing worked. She had nagging symptoms from CML, including being cold all the time due to anemia. She enrolled on the phase I trial at a starting dose of 4 mg (the approved dose is 45 mg, so she had just one tenth that amount). She started to respond even at very low doses. She worked up to 15 mg, then 30, and she went into a complete molecular remission. She’s had some side effects, but overall she is feeling so much more … normal. Her long battle was so worth it.
With another patient, the story was more internal. He was a younger man, didn’t know much about CML, and didn’t care very much, it was more of an irritation for him because it was still in the early stages and wasn’t causing many symptoms. He had all sorts of mutations, and had taken imatinib only. I treated him on the phase I trial, and it was like he was starting fresh with treatment again, after having no response to imatinib. He went into a very orderly remission. I wanted to say to him, “Do you realize how lucky you are? You dodged a bullet.” He had never had any problems from his disease, but they would have come if he didn’t respond to this drug. We were able to switch gears just in time to a highly experimental drug with unknown side effects. For him, as a recently diagnosed patient, he didn’t realize the significance.
The mechanism behind CML: The Philadelphia chromosome translocation and bcr/abl kinase by Piotr Zurek.