With acquired resistance patterns emerging for nearly every agent, hematologic experts are looking closely at sequencing patterns, but more work needs to be done in aggressive malignancies in which mutations associated with resistance may be present before therapy even begins.
Outsmarting cancer has been the long game in oncology drug development. With acquired resistance patterns emerging for nearly every agent, hematologic experts are looking closely at sequencing patterns, but more work needs to be done in aggressive malignancies in which mutations associated with resistance may be present before therapy even begins, according to Mark Levis, MD, PhD.1
“Acquired resistance is inevitable. You’ve got point mutations, clonal shift, synthetic resistance, alternate pathways, and the microenvironment [to consider],” said Levis, program leader of Hematologic Malignancies and Bone Marrow Transplant Program at Sidney Kimmel Comprehensive Cancer Center and a professor of oncology at Johns Hopkins University in Baltimore, Maryland. “Sequencing therapies can be an effective and tolerable, but sequencing is probably going to be more effective in those indolent malignancies or more indolent malignancies where you can switch and play Whac-a-Mole…the more aggressive malignancies are more problematic.”
Levis presented his lecture during the 27th Annual International Congress on Hematologic Malignancies®: Focus on Leukemias, Lymphomas, and Myeloma. For the discussion, Levis considered a small molecule that binds to or inhibits an oncoprotein or an immunotherapy directed against a cell surface protein to be the definition of targeted therapy.
“The first targeted agent was rituximab [Rituxan] that I can recall, but we didn't think of it [like that],” Levis said. “I remember when [colleagues] came back from ASH telling us about rituximab, we didn’t call it a targeted agent, we didn’t quite know what to make of it. And the first time I recall targeted agents being used as a term was with imatinib [Gleevec] a few years later.”
The landscape in hematologic malignancies has grown to encompass BCR-ABL inhibitors, Bruton tyrosine kinase (BTK) inhibitors, IDH1 inhibitors, FLT3 inhibitors and more since the introduction of rituximab. Acquired resistance, according to Levis, does follow some patterns.
“The common one, which quickly emerged, [is that resistance mechanisms] will sterically impede a drug from binding a mutation in cysteine residue, in the case of an irreversible drug, or outright loss of the target as a clever trick. Clonal shift is a similar theme but a little bit different where a new clone emerges frequently lacking the target altogether. Synthetic resistance I label as a version of we’ve heard of, synthetic lethality, where a cancer cell becomes susceptible to a targeted agent because of a mutation in an alternate pathway. The same thing can occur with resistance, it’s a bit more mysterious. Finally, cancer stem cells are hiding in their microenvironment and that alone provides intrinsic resistance,” Levis explained.
Just as quickly as advances were made, cancer “rained on the parade,” Levis said. He cited a paper from 2001 from Druker et al, noting the success of a BCR-ABL inhibitor in chronic myeloid leukemia (CML).2 The study authors noted the safety and efficacy of imatinib showcased the “potential for development of anticancer drugs based on the specific molecular abnormality present in a human cancer.”2
However, just 1 year later in 2002, Shah et al showed the point mutations identified in BCR-ABL which sterically interfere with imatinib binding.3 “We instantly found ways in which resistance to imatinib emerged with these point mutations that sterically interfered with imatinib binding and we learned about the activation loop and the kinase domain of these targets. But what was more striking about this publication back then, these mutations were already present before we started the drug. This wasn’t something that developed while on the drug, we were simply selecting this clone out and the seeds of destruction were already present.”
Levis turned to FLT3-ITD mutations in acute myeloid leukemia (AML) to highlight the challenges with targeted therapy. “FLT3 is a particularly nasty version of the disease,” Levis said. “Patients have 2 different kinds of mutations in ITD and TKD, which results in a pretty aggressive version of disease—very high white counts lead to a tendency to relapse and lower overall survival. So of course, we were trying to inhibit this.”
Occurring in approximately 20% of non-acute promyelocytic leukemia AML, ITD mutations are much more aggressive with TKD mutations being much less common and having less prognostic impact.4 “We need to understand the whole signaling pathway here. It’s a receptor tyrosine kinase, which dimerizes with this cytokine, the FLT3 ligand,” Levis explained. “It comes from the bone marrow, stroma or T cells, and it comes from within the leukemia cells produce it as well and activate the receptor, but the receptor can be activated by mutation. And you phosphorylated we can follow that with a Western blot. And then you get this activation of downstream [effect] activating these growth factor pathways, the so-called RAS pathway being the most common one.”
Levis noted that by inhibiting FLT3, the feedback mechanism is activated, and the cells start producing more of the ligand, which can block the inhibitor. “It’s shifting the receptor back on and spitting the inhibitor out,” Levis said. He added that whenever a rise in ligand is noted following chemotherapy or as feedback to the inhibition, “that’s a very simple basic mechanism that's going to occur to try and circumvent the effects of your inhibitor.”
Developing agents to address these niches has been an ongoing process met with challenges. For example, the development of quizartinib, a FLT3-ITD inhibitor that is under review at the FDA for patients with newly diagnosed FLT3-ITD AML5, demonstrated success in for patients in the phase 3 QuANTUM-First trial (NCT02668653). However, even though quizartinib is a type II inhibitor, which are generally active against activation loop mutations, Levis noted that there was an emergence of FLT3-TKD mutations among patients on the agent. This makes awareness and knowledge of biology of the disease of paramount importance. “You have to understand the whole picture of the cytokines how the resistance is emerging, what you're doing with your drugs, to understand [what] awaits the patient in this setting,” Levis said.
The process Levis describes addresses the root of the problem first—develop a better inhibitor. “We’re going to [try to] inhibit all those little kinase mutations at the same time…this drug is a better inhibitor, it does in fact, inhibit a lot of those kinds of resistance conferring mutations [and] is better than salvage chemotherapy. But what we then saw was the emergence of RAS pathway mutations. We didn’t get FLT3 mutations, it wasn’t so much cytokine rebound, you got the emergence of RAS pathway mutations…. And so by the end of 10 months of response, or 6 months [of response], we have 2 different clones [waiting]…. These are the mutations that are cropping up quickly.”
Andre Goy, MD, MS, the moderator of the session, and physician in chief of Hackensack Meridian Health Oncology Care Transformation Services, and chairman, chief physician officer, and lymphoma division chief at John Theurer Cancer Center at Hackensack University Medical Center in New Jersey, added, “In acute leukemias, we do not have that luxury of just [inhibiting] the next thing, and the next thing. And part of the problem is the instability of the originating clone, and/or the microenvironment, because the interesting thing is in some of these examples, these new clones have a completely different mutation, and it continues emerging. So, how do we prevent that from happening? That’s key.”