At ASH: Novel Targeted Therapies for Tough-to-Treat Blood Cancers

By Neil Canavan

 

Significant progress in new treatments – cures even – is being reported for some blood cancers. Advances in patient management highlighted at ASH 2015 include recently approved, or near-term for approval treatments options for patients with acute myeloid leukemia (AML; midostaurin); chronic lymphocytic leukemia (CLL; idelalisib, venetoclax); and multiple myeloma (MM; midostaurin).

“This is an enormously exciting time,” said Robert Hromas, MD, chairman of the Department of Medicine at the University of Florida, Gainesville, FL, speaking at a press conference at the ASH 2015 meeting. “In my career alone we’ve made advances where, once, I lost everybody with multiple myeloma, but now… I haven’t lost anyone in 6 years.”

The reason? Targeted therapies. We now live in the era of molecular medicine where innovative drugs are increasingly designed to exploit a specific genetic defect. “My father has CML, a disease caused by a broken gene,” Dr. Hromas explained. “With a targeted therapy he has done extremely well, and new treatments will provide improved survival advantages for patients.”

Thanks to the blockbuster, Gleevec, and the next generation versions of this agent, many, if not most patients with CML are well served. The same cannot be said for numerous other leukemia subtypes (CLL, ALL, AML), as well as multiple myeloma (MM). However, clinical investigators presenting at ASH 2015 beg to differ. 

 

At ASH: Novel Targeted Therapies for Tough-to-Treat Blood Cancers (continued)

Acute Myeloid Leukemia (AML)

There hasn’t been a new drug approval in AML in decades, but if the data hold, the FLT3 inhibitor, midostaurin, will interrupt that streak.

“FLT3 is an activating mutation that occurs in about 30% of patients with AML,” said Richard Stone, MD, of the Dana-Farber Cancer Institute, Boston, MA, reporting on this study with midostaurin. “And, about three quarters of these patients have the ITD (internal tandem duplication) or TKD (tyrosine kinase domain) mutation, which has a particularly poor prognosis.”

In the CALGB 10603 Phase 3 trial, standard-of-care chemotherapy, plus or minus midostaurin, was given to newly-diagnosed AML patients with the FLT3 mutation (N=717).

“This is very much of a real world trial,” said Dr. Stone. “We’re taking patients right from diagnosis on forward.”

Results of this investigation showed that after a follow up of 57 months, the median overall survival (OS) was 74.7 months in the midostaurin plus chemotherapy arm vs 25.6 months for the chemotherapy alone arm (P=0.008). Treatment with midostaurin was also favored by patients in the comparative rates of event-free survival (P=0.003).

This benefit was also seen for the more dire FLT3 molecular subtypes, prompting Dr. Stone to suggest that, “Midostaurin plus chemotherapy should be studied in FLT3 wild type and/or older AML patients.”  

Commenting on the results, Mark Levis, MD, Johns Hopkins University, Baltimore, MD, noted that FLT3 has been targeted before. “We’ve been trying to develop FLT3 inhibitors for some time—at least 6 have made it as far as Phase 3 trials.”

So how is midostaurin any different from those that have come before? “Its advantage against some of the other compounds is the fact that it’s active in both ITD and TKD mutations,” said Dr. Levis, and further, it’s multi-targeted. “What we’ve learned about AML in the last few years from whole genome sequencing is that the disease at diagnosis is more polyclonal.” So, an agent that is highly selective against FLT3 would be more effective in the relapse setting, which tends to be more clonal, than in treatment-naive patients, where Dr. Levis suggested midostaurin should be positioned. 

Multiple Myeloma (MM)

Recently FDA-approved daratumumab for the treatment of MM is an antibody drug targeted to the cell surface glycoprotein CD38. “This target is highly expressed in myeloma cells,” said Torben Plesner, MD, Vejle Hospital, Vejle, Denmark. The drug has several distinctive killing mechanisms. “First, by immune-mediated (killing) via complement or other innate mechanism; second, by directly engaging multiple myeloma cells; and third, by the immunomodulatory function of daratumumab that eliminates T-regs — cells that suppress the immune response,” explained Dr. Plesner.

In the Phase 1/2 GEN503 trial, daratumumab was combined with the standard-of-care combination of lenalidomide/dexamethasone (LEN/DEX) in a cohort of relapsed and refractory MM patients (N=32).

Prior to this study, single-agent therapy with daratumumab demonstrated an overall response rate (ORR) of 31% with a median OS of 19.9 months; and the LEN/DEX doublet demonstrated an ORR of 60.6% and a median progression-free survival (PFS) of 11months. In the GEN503 study, the combination of all three agents surpassed the previous benchmarks demonstrating an ORR of 81% and OS was 90% at 18 months.

Regarding adverse events, there were no surprises: “We saw no new safety signals with the addition,” said Dr. Plesner. The most common events were neutropenia (84%), cough (50%), diarrhea (44%), and muscle spasm (44%).

Phase 3 investigations with the triplet are ongoing. 

At ASH: Novel Targeted Therapies for Tough-to-Treat Blood Cancers (continued)

Ixazomib

Seemingly, a direct competitor to daratumumab—ixazomib, a proteosome inhibitor, plus LEN/DEX, represents an all-oral therapeutic option for MM.

In the Phase 3 TOURMALINE-MM1 investigation, the ixazomib/LEN/DEX triplet was tested in a population of relapsed and/or refractory MM patients vs LEN/DEX alone (N=722; of note, 70% of this cohort had already received an approved proteosome inhibitor).

The primary endpoint was PFS. After a median follow up of 15 months, a 35% improvement in PFS was observed (20.6 months in the triplet arm vs 14.7 in the doublet arm; P=0.012).

“The responses were very quick for the triplet combination,” reported study investigator, Philippe Moreau, MD, University Hospital of Nantes, Nantes, France. “The median time to response occurred at 1.1 months, with a median duration of response of 20.5 months (vs 15.0 months for the control arm).”

For adverse events, “There was more thrombocytopenia with ixazomib, but it did not impact the treatment plan.” Of note, peripheral neuropathy was not an issue in this trial, a potential advantage for patients since the already-approved proteosome inhibitor, bortezomib, is associated with a peripheral neuropathy rate of 30%. Further, bortezomib is an injected drug; ixazomib is an oral medication.

Chronic Lymphocytic Leukemia (CLL) 

First up, idelalisib is a first-in-class PI3k delta enzyme inhibitor previously approved for CLL patients who can’t receive standard-of-care chemotherapy due to toxicity. As reported by Andrew Zelenetz, MD, PhD, Memorial Sloan Kettering Cancer Center, New York, NY, idelalisib was used in combination with rituximab and bendamustine (R/B), in a cohort of relapsed/refractory CLL patients in a Phase 3 trial (N=416).

“This study asks whether idelalisib could be added to a standard-of-care in this setting,” said Dr. Zelenetz.

Results were striking. After a planned interim analysis in October 2015, the study was stopped due to obvious efficacy.

“There was a highly statistically significant improvement in PFS of 23.1 months vs 11.1 months (P<0.0001),” reported Dr. Zelenetz. “The numbers for the doublet (R/B control arm) are as expected, so this represents a substantial increase in PFS.”

The benefit was observed across all CLL risk groups. Improvement in OS was also seen: 34% of patients receiving the doublet vs 51% of individuals in the idelalisib cohort were alive after a median follow up of 12 months (P=0.008).

As far as toxicity goes, the triplet had more treatment discontinuations: 26% of patients discontinued the triple vs 13% for the combination. Yet the question to ask is, would efficacy remain and toxicity lessen with the subtraction of bendamustine?

“It’s interesting to consider if bendamustine was necessary here,” said Dr. Zelenetz, “But that can’t be answered with this trial design.”

Venetoclax

Venetoclax is an oral agent that selectively inhibits BCL2, which is a protein highly expressed in CLL cells, and through which cell death via apoptosis can be triggered—independent of p53 activity.

In a pivotal Phase 2 international trial, venetoclax monotherapy was tested in a population of relapse/refractory CLL patients with 17p deletion (N=107).

“This is a very special population with the most dismal outcomes,” said study investigator, Stephan Stilgenbauer, MD, University of Ulm, Ulm, Germany. “These patients are resistant to conventional therapy.”

The reported ORR for this study was 79.4%, with 7.7% experiencing a complete response, a result Dr. Stilgenbauer described as “remarkable.”

Additionally, the treatment allowed for rapid recovery of the patient’s immune system. “With the exception of 4 patients, there was a normalization of lymphocyte count—with a dramatic disease reduction—at a median of 22 days.”

Given these results, Dr. Stilgenbauer suggested that venetoclax was well positioned for a place in novel combinations. 

At ASH: Novel Targeted Therapies for Tough-to-Treat Blood Cancers (continued)

 

 

There was plenty to report on at ASH when it came to cancer immunotherapies, but these data are largely from early stage investigations, and so were omitted here in favor of the more practice-changing presentations. That said, credit where credit is due:

“We presented the first demonstration that CD19 CAR therapy would work at ASH back in 2003,” says Michel Sadelain, MD, PhD, director of the Center for Cell Engineering at Memorial Sloan Kettering Cancer Center, and cofounder of the immunotherapy powerhouse, Juno. “We showed T-cells targeted to CD19 cured leukemias and lymphomas in mice—the first ever such demonstration.  Yet, it was not accepted for oral presentation,” which would have been a clear and public validation of the importance of the new technology. “It was a just a poster.”

At ASH 2015, 12 years later, there are over 120 abstracts on CAR therapies, and another hundred with “checkpoint” in the title. “So, in the end we kind of like it that it was just a poster in a back room,” says Dr. Sadelain. “It tells the story of how far we’ve come.”

Indeed, CARs have traveled from the back room all the way to the front page with the recently reported case study by the immunotherapy company Cellectis, a case where an 11-month old baby girl with advanced acute lymphoblastic leukemia (ALL) achieved a molecular remission after being treated with an allogeneic CD19 CAR.

This is not the first time CARs have been successfully used in pediatric ALL, but the first time an allogeneic T-cell product—a potential off-the-shelf drug—was tested in a human being. An off-the-shelf CAR would be an industry game changer and a revolution writ large in cancer care.

Prior to this single case, only autologous CARs have been used to treat patients. In brief: T-cells are removed from the patient, augmented with the CD19 targeting moiety, and returned to same patient—medicine cant get more personalized that that.

“What Cellectis and others have done,” explains Dr. Sadelain, “is take advantage of these new gene editing technologies that we’re all so excited about (CRISPR, for one). This allows for the “unfanging” of T-cells, as Dr. Sadelain puts it—the genetic removal of the T-cell receptor that the T-cell was born with (from the donor) that would otherwise trigger either rejection of the cellular transplant in the CAR recipient, or inappropriate attack on the recipient’s healthy tissue by the CAR T-cells, a condition called graft vs host disease, which can be deadly.

“From the data (on the poster) presented at ASH—which was minimal—it’s a little hard to say how well that has been achieved, but I’ll trust that Cellectis and others can at some point do a real good job on that,” Dr. Sadelain says.

What is certain right now is that the little girl in question is, at the time of this writing, cancer-free.

(For more on CARs see: https://www.obroncology.com/blog/2015/06/baby-can-you-drive-my-car-t-great-potential-and-excitement-but-questions-remain)

Credits:  All 2015 ASH photos are courtesy of The American Society of Hematology.

 

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