Vadastuximab for AML: Investigator Predicts Changes to Standard Therapy in Near Future

Drug targets CD33 to produce high remission rates

Vadastuximab talirine (SGN-CD33A) is an antibody-drug conjugate that targets the CD33 antigen, which is almost uniformly expressed in acute myeloid leukemia (AML).

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Anjali Advani, MD, Director of Cleveland Clinic’s Inpatient Leukemia Program, discussed findings with vadastuximab from phase I studies at the 2016 American Society of Hematology Annual Meeting in San Diego.

The four abstracts presented at ASH spoke to the effectiveness of vadastuximab for AML in differing treatment phases, across different age groups and in varying therapeutic combinations. Researchers observed the dose-limiting toxicities of the drug and assessed its pharmacokinetic profile and antileukemic activity as well.

“Of the different types of CD33 drugs, this is probably one of the most exciting,” Dr. Advani says. “It is stable and seems to have a good distribution in terms of binding to the cells. And so far, it has demonstrated very little off-target toxicity.”

Monotherapy in older patients with AML

Dr. Advani was senior author of the first abstract, Vadastuximab Talirine Monotherapy in Older Patients with Treatment Naive CD33-positive Acute Myeloid Leukemia, which reported the results of a phase 1 cohort study of vadastuximab monotherapy. Older patients ranging in age from 67 to 89 years received vadastuximab at a dose of 40 mcg/kg. Participants were described as fairly treatment naïve.

“The really encouraging result was that remission rates and major leukemia-free state were extremely high in these patients,” says Dr. Advani. “The drug was fairly well tolerated and toxicity was myelosuppression, mainly platelets and neutrophils.”

What Dr. Advani and other researchers found disappointing was that remissions were short-lived. “While the remission rate was very high, remissions were not durable,” she says.

Vadastuximab did demonstrate favorable antileukemic activity as a single agent with 58percent achieving a complete remission and complete remission with incomplete blood count recovery) in this high-risk, treatment-naive older AML population.. At baseline, patients had a median of 47 percent bone marrow blasts. The rapid clearance of marrow blasts, high rate of minimal residual disease (MRD)-negative remissions and low early mortality rate are encouraging.

These data supported the exploration of vadastuximab in combination with standard induction, consolidation and pre- and post-transplant regimens.

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Induction therapy for patients with AML

For patients under age 65 with newly diagnosed AML, standard induction treatment was continuous infusion cytarabine for seven days and an anthracycline for three days (7+3). Though a high percentage of patients achieve an initial CR by morphologic criteria, some are either primarily resistant to treatment or they achieve a morphologic CR but with flow cytometric or molecular evidence of MRD.

The addition of vadastuximab to 7+3 chemotherapy might result in enhanced and deeper, MRD-negative remissions, and this was the focus of the second abstract, A Phase 1b Study of Vadastuximab Talirine in Combination with 7+3 Induction Therapy for Patients with Newly Diagnosed Acute Myeloid Leukemia (AML).

The results of this study demonstrated that vadastuximab can be safely combined with 7+3 with acceptable count recovery and the recommended phase 2 dose is 20+10 mcg/kg on days 1 and 4.

An alternate schedule of single-day dosing on day 1 is under investigation and enrollment continues. Extramedullary adverse effects, including hepatic toxicity and induction mortality rates, were similar to reported rates for 7+3 alone in this AML population. A high remission rate within the first induction cycle was observed, the majority of which were MRD negative.

Combining a hypomethylating agent with vadastuximab

 In preclinical studies, hypomethylating agent priming followed by vadastuximab resulted in upregulated CD33 expression and increased DNA incorporation of the drug’s active dimer component, with enhanced cytotoxicity.

The third abstract, Vadastuximab Talirine Plus Hypomethylating Agents: A Well-Tolerated Regimen with High Remission Rate in Frontline Older Patients with Acute Myeloid Leukemia (AML), focused on combining vadastuximab with azacitidine (Vidaza ®), a widely used hypomethylating agent.

“By combining vadastuximab with azacitidine, the remission rates looked much better than what we have seen typically with azacitidine alone,” Dr. Advani says. “Again, this was very encouraging and we are waiting for longer follow-up on those results.”

According to Dr. Advani, it’s evident that the drug alone is active, but its remission duration will be very short unless it’s used as a bridge to transplant or is combined with another therapy.

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“As a single agent, for example, it is starting to be looked at as a bridge to transplant,” she says. “That may be a setting where as a single agent it’s fine. But with an elderly population, we are probably going to need to combine it with something like azacitidine.”

Dr. Advani notes plans for a pivotal phase 3 study that will evaluate vadastuximab in combination with azacitidine versus azacitidine alone in an elderly AML population.

Vadastuximab as maintenance therapy

The final abstract, A Phase 1b Study of Vadastuximab Talirine as Maintenance and in Combination with Standard Consolidation for Patients with Acute Myeloid Leukemia (AML), reported on the use of vadastuximab in post-remission therapies for AML patients, including after high-dose cytarabine (HiDAC) and allogeneic stem cell transplant (alloSCT). Both post-remission therapies have led to improved outcomes in younger patients. However, the disease recurrence remains prevalent with about 40 percent five-year overall survival.

Study results indicated that vadastuximab can be safely administered in combination with HiDAC, and as a single-agent maintenance therapy, post-chemotherapy and/or alloSCT.

In the consolidation cohort, in combination with HiDAC, non-hematologic toxicities of vadastuximab were consistent with effects reported with HiDAC alone. As a single agent, vadastuximab administered as maintenance post-chemotherapy and/or alloSCT results in predictable on-target myelosuppression, with mild non-hematologic adverse effects.

Prediction: Changes to standard treatments will come very soon

With all four studies, Dr. Advani was thrilled about the high remission rates but acknowledges that more research is needed to boost remission duration. “We’ll need to look further into combining or sequencing vadastuximab with other agents,” she says, predicting that vadastuximab will ultimately change the treatment paradigm for AML patients.

“This drug (for AML), along with inotuzumab ozogamicin (for ALL), will start to be incorporated in the up-front setting,” she says. “Since these drugs do have some toxicity, such as the myelosuppression, we just have to figure out the right drug, the right dosing, the right timing and how to incorporate them best into treatment.”

She concludes: “I think the biggest thing is that for many years we have had the same treatments and we are likely to see a change very soon here.”