AML Paradigm Shift: Doctors Welcome Many New Approvals And Approaches
Executive Summary
This year's ASH meeting reflected a peak of development success, with many new approvals and many more in the pipeline.
What a difference a few years made for acute myeloid leukemia R&D, as evidenced at the action-packed American Society of Hematology (ASH) annual meeting.
At the ASH meeting in December 2016, the treatment landscape was very limited, but the pipeline was plentiful, including a variety of drugs in late-stage development. (Also see "AML Pipeline Update: Pharmas Pursue Big Breakthroughs In Niche Spaces" - Scrip, 6 Jan, 2017.)
About 21,000 new cases of AML are diagnosed every year in the US. Patients who are younger (in their 40s to 60s) may be eligible for high-intensity chemotherapy with the "7+3" induction regimen – standard since the 1970s – and have a chance at complete remission, but fewer than half are actually candidates for that.
Hypomethylating agents have long been approved in Europe for AML and are used off label in the US for this disease type – SuperGen/Otsuka Holdings Co. Ltd.'s Dacogen (decitabine) and Celgene Corp./Nippon Shinyaku's Vidaza (azacitidine).
Development activity of new drugs has been intense, with a heavy focus on frontline treatment of older patients who can't tolerate high intensity chemotherapy, relapsed/refractory disease and genetic mutations across lines of therapy.
Between late-2016 and this year's ASH meeting, held Dec. 1-4 in San Diego, eight new drugs were approved by the US FDA for acute myeloid leukemia (see chart), including Agios Pharmaceuticals Inc.'s IDH inhibitors Tibsovo (ivosidenib) and Idhifa (enasidenib), the latter of which is partnered with Celgene, and Roche/AbbVie Inc.'s BCL-2 inhibitor Venclexta, which was already approved for chronic lymphocytic leukemia (CLL). (Also see "More Good News For AML As Pfizer And AbbVie/Roche Drugs Get FDA Okay" - Scrip, 22 Nov, 2018.)
The latest to hit a home run in the US was Astellas Pharma Inc.'s FLT3 inhibitor Xospata (gilteritinib), cleared on Nov. 28 for relapsed or refractory AML with FLT3 mutations, based on a single-arm study that showed a 21% complete response with or without recovery of blood count (CR/CRi) rate. (Also see "First Approval Globally For Gilteritinib, In Japan For AML" - Scrip, 28 Sep, 2018.)
Xospata is the first FLT3 inhibitor approved for relapsed AML, but Novartis AG' kinase inhibitor Rydapt (midostaurin) was previously approved in April 2017 for use in combination with chemotherapy for frontline FLT3-mutated AML.
In addition to Xospata, Daiichi Sankyo Co. Ltd.'s FLT3 inhibitor quizartinib is under FDA review for approval as a single agent for relapsed/refractory AML, with a user fee date in May. (Also see "Daiichi's Phase III Quizartinib Data Pave Way In Niche AML Market" - Scrip, 18 Jun, 2018.) Data from the pivotal QuANTUM-R study were presented at the ASH meeting, reaffirming expectations for approval.
In comparison with gilteritinib and quizartinib, midostaurin is a less specific FLT3 inhibitor, which results in more off-target activity and side effects, commented Cleveland Clinic AML specialist Aaron Gerds. Also, the response rates for midostaurin in relapsed AML had not been as good as hoped for, Gerds told Scrip.
Updated data from the single arm studies supporting Venclexta's approval in combination with low dose cytarabine (LDAC) and hypomethylating agents for first-line AML in patients not eligible for intense chemotherapy were presented at the ASH meeting and were a highlight for AML experts (see sidebar).
Venetoclax is a pretty easy addition, given physicians' familiarity using it in CLL for a couple of years, and it has the advantage of having been tested with hypomethylating agents, said Robyn Scherber, an MD Anderson hematologist.
But approaches targeting particular mutations have also matured. The two main mutations targeted so far are FLT3, which is present in 30% to 40% of cancers, and IDH, present in 25%.
"The whole field is changing by leaps and bounds," Scherber said.
There has been a boom of new therapeutics from the genomics revolution, with recognition that AML is a widely-dispersed type of disease, Gerds said.
"Although we call it one disease, it's really a large collection of a bunch of different diseases," Gerds added.
In collaboration with the FDA, the Leukemia & Lymphoma Society (LLS) developed the "Beat AML" umbrella study in newly-diagnosed AML as a means of rapidly testing (with results in seven days) molecular subtypes and directing patients to appropriate targeted treatment. (Also see "AML Master Protocol For Precision Medicine Developed By Nonprofit And US FDA" - Pink Sheet, 21 Dec, 2016.) The protocol was unveiled at the 2016 ASH meeting and the LLS announced at the 2018 event that the program was progressing well and that a precision medicine approach is feasible.
Amy Burd, vice president of research strategy at the LLS, told Scrip that the goal for the initiative now is to get pharmaceutical companies on board for testing novel-novel targeted drug combinations, but she acknowledged that it can be "complicated" to do this in practice.
The Beat AML study includes evaluation and testing of 12 different types of mutations in AML patients, including IDH1/2, FLT3, TP53+ and MLL-rearranged.
"In 10, 15 years, we're going to be looking back at studies like the Beat AML study and saying this is how it all started – this is how the major sea change in the field really happened," Gerds said.
Similarly, Scherber said there is more understanding now than ever before about the biology of the cancer and how to target therapies, which means more hope and options for patients, especially those not eligible for a transplant or who had a relapse.
"Our real challenge now is going to be to find the timing of these drugs and really be able to figure out what gives patients the most bang for the buck in terms of therapy early on and what is better to put later on in the treatment cycle," Scherber said.
In addition to the newly-approved drugs, a wide variety of different mechanisms are in early-stage development, as the sampling of early-stage news at the ASH meeting below shows:
Amgen's Bispecific AMG 330: A "Work-In-Progress"
Amgen Inc. reported some complete responses for its anti-CD33 bispecific T-cell engager antibody AMG 330 in a first-in-human Phase I dose escalating study of 40 heavily relapsed/refractory AML patients at the ASH meeting.
The company established the BiTE technology platform through the 2014 FDA approval of the CD19-targeted Blincyto (blinatumomab) for acute lymphoblastic leukemia (ALL). Amgen has been actively developing other BiTE candidates and a second-generation technology platform for different blood cancers and also for solid tumors. (Also see "Interview: Amgen's BiTE Platform Becomes A Feast As More Molecules Enter The Clinic" - Scrip, 6 Mar, 2018.)
The CD33 target is expressed almost uniformly in AML cells, David Reese, executive vice president of R&D, explained in an interview prior to the meeting.
In the first-in-human study, two patients achieved a CR at a dose of 240 µg/d, and two patients achieved a CRi – one at the 240 µg/d dose and one at a 120 μg/d dose.
The complete responses did not last past one treatment cycle, the company reported, but Reese views the program as a "work-in-progress" and the data as a good start.
"My assessment of this study is that we're just coming into the range of dose and intensification of dose where we're hoping to see much greater efficacy. But what we've seen so far, I think, is quite encouraging," the exec said.
As for safety, six patients dropped out due to treatment-related adverse events. The rates of serious adverse events overall and related to the treatment were 73% and 19%, respectively. These included cytokine release syndrome, febrile neutropenia and thrombocytopenia. No treatment-related deaths were reported.
Reese said the adverse event profile was very consistent with expectations in trials of patients with advanced or relapsed AML.
"Some of these patients, depending on the nature of the disease and the relapse, may have only a few weeks to months to live. So it's a very sick population of patients for which there aren't a lot of effective therapies available right now," Reese said.
The company is working on intensifying dosing and scheduling for the AMG 330 program.
ImmunoGen's "Intriguing" Anti-CD123 Data
ImmunoGen Inc. highlighted Phase I data for two different antibody drug conjugates (ADCs) at the ASH meeting – the anti-CD123 IMGN632 and anti-CD33 IMGN779 – in AML and blastic plasmacytoid dendritic cell neoplasm (BPDCN).
Immunogen's IMGN632 joins a novel humanized anti-CD123 antibody to one of the company's novel DNA-alkylating indolino-benzodiazepine cancer-killing agent (IGN) payloads through a peptide linker.
In a Phase I dose-ranging study, there was a 26% objective response rate (ORR) across multiple doses in 23 evaluable, heavily pretreated AML patients, including two complete remissions and four CRis. Two of three patients with BPDCN had an ORR after a single dose.
ImmunoGen concluded that adverse events were consistent with underlying disease and that the drug was tolerable, safe and efficacious at doses up to 0.3 mg/kg. In higher dose groups, one case of prolonged neutropenia was reported and there were two cases of the dreaded veno-occlusive disease (VOD), though these were reversible.
ImmunoGen's IMGN779 ADC joins a humanized anti-CD33 antibody with an IGN payload using a cleavable disulfide linker.
The company presented data from a Phase I dose-ranging study of the drug in relapsed AML.
As with IMGN632, adverse events were consistent with underlying disease with no evidence of cumulative toxicity after multiple doses. One case of VOD was reported at a high dose.
Anti-leukemia activity was seen at doses ≥0.39 mg/kg in weekly and biweekly schedules. Out of 29 evaluable patients, 41% had at least a 30% reduction in bone marrow blasts, including two with a CR or CRi.
The company said that it is continuing development work for IMGN632 and IMGN779 to identify the right dose and schedule for Phase II. Jazz Pharmaceuticals PLC has an option to license both programs. (Also see "Jazz Raising Hematology/Oncology Reach Further With ImmunoGen Deal" - Scrip, 30 Aug, 2017.)
ISI Evercore analyst Umer Raffat found the IMGN632 (anti-CD123) data more interesting and "intriguing" than IMGN779, based on the complete responses reported. In a Dec. 5 overview of the meeting, Raffat said that targeting CD123 makes biological sense, but noted that there have been some failures in the space.
FDA placed a complete clinical hold on Johnson & Johnson/Genmab AS's bispecific JNJ-63709178 in 2016 due to safety concerns.
A Phase III study of J&J's CD123-targeted talacotuzumab, an antibody developed with technology from Xencor Inc., was terminated seven months after it started. (Also see "J&J Immunology Growth Now Hinges On Stelara, Tremfya After RA Setback" - Scrip, 17 Oct, 2017.)
A clinical hold was placed on Cellectis SA's CD123 chimeric antigen receptor T-cell (CAR-T) program in the fall of 2017 after a death was reported, but the study later resumed with a lower dose. (Also see "A Cellectis Trial Death Points To Challenges Ahead For CAR-T" - Scrip, 5 Sep, 2017.)
Leerink Swann analyst Jonathan Chang said in a Dec. 2 note that the ImmunoGen AML data are early, though they do shed more light on efforts to identify optimal dosing and scheduling. He expects investor focus will remain on the company's lead ADC candidate mirvetuximab soravantansine, which is in Phase III, with data due in the first half of 2019.
Celyad Provides CAR-T Update
There is a lot of interest in CAR-T approaches and immunotherapy in general for AML, which have been applied successfully in ALL, Gerds noted. However, in ALL CD19 is simpler to target, whereas the AML targets are present on normal as well as abnormal cells, he said.
Celyad SA was among the companies presenting the CAR-T approach at ASH, with early data for its NKG2D-targeted CAR-T therapy CYAD-01. (Also see "Next-Generation CAR-Ts Tackle First-Generation Safety, Solid Tumor Challenges" - Scrip, 21 Apr, 2018.)
Preliminary data in relapsed/refractory AML patients enrolled in the Phase I THINK trial exceeded expectations, the company said, as there was anti-leukemic activity in five out of eight patients treated with CYAD-01 without preconditioning therapy. Three had an ORR and in two the disease stabilized, with a decrease in relevant bone marrow blasts.
The drug was also well-tolerated, Celyad said.
Celyad recently amended the THINK study protocol, adding a cohort with a more frequent dosing schedule. Preliminary data are expected in the first half of 2019.
GlycoMimetics' Uproleselan Works On Chemo Resistance
Glycomimetics Inc. believes that the gathering data – including updated Phase I/II results presented at ASH – support a role for its E-selectin antagonist uproleselan (GMI-1271) in chemo combinations for AML to prevent resistance and improve safety.
E-selectin is expressed in the bone marrow microvasculature and binds to the E-selectin ligand on AML cells. Upregulation of E-selectin is associated with poor prognosis.
"E-selectin plays a critical role in binding cancer cells within vascular niches in the bone marrow, which prevents the cells from entering circulation where they can be more readily killed by chemotherapy," according to the company.
Also, in animal studies, the drug "appeared to also protect normal cells from some of the side effects of chemotherapy," including mucositis, which in humans can be so severe that patients are unable to take liquids by mouth, GlycoMimetics said.
Uproleselan by itself has no single-agent activity, as would be expected based on its mechanism of action, but it is critically involved in the development of drug resistance, CEO Rachel King explained in an interview.
"Mechanistically it is actually quite differentiated from other approaches in AML – and we think the data is beginning to speak to the value on that," King said.
The Phase I/II study presented at ASH included 25 older, newly-diagnosed patients and 66 with relapsed/refractory disease.
The treatment-naïve patients got the drug in combination the 7+3 chemo combination and the relapsed/refractory patients took it with the mitoxantrone, etoposide, cytarabine (MEC) chemotherapy combination.
In the treatment-naïve patients, the CR/CRi rate was 72%. Five of nine evaluable patients evaluated for minimal residual disease (MRD) were negative (56%).
Researchers were satisfied with tolerability and no cases of Grade 3+ mucositis were reported. The one-year survival rate was 52% overall and 60% in those who were MRD-negative.
In the 66 relapsed/refractory patients, the CR/CRi rate for all doses was 39%. Eleven of 16 patients evaluable for MRD were negative (69%). E-selectin detectable blasts were detectable in all patients.
Researchers were satisfied with tolerability; the rate of Grade 3/4 mucositis was 2%. King noted that the rate of Grade 3/4 mucositis for the regimen without uproleselan would typically be about 20%.
The one-year survival rate was 35% overall and 73% in those who were MRD-negative.
Two Phase III studies of the drug in combination with conventional chemotherapy are under way. The company is sponsoring a trial in relapsed/refractory AML and the National Cancer Institute is testing it in older patients newly diagnosed with AML.