Allogene Therapeutics Teases April ALPHA3 Data as cema-cel Targets MRD+ LBCL in Remission

Key Points

• Allogene expects an initial ALPHA3 readout in April reporting whether its CD19 allogeneic CAR T candidate, cema-cel, clears MRD at day 45 in MRD-positive LBCL patients randomized to cema-cel versus observation (12 patients per arm), with preliminary safety and outpatient administration details.
• The company has set a futility bar targeting a 25% to 30% absolute difference in MRD clearance between arms (noting an expected ~20% spontaneous clearance in observation); deltas near ~11% would likely be considered insufficient by stakeholders.
• ALPHA3 integrates ultrasensitive ctDNA MRD testing (partnering with Foresight, now part of Natera), finds ~20% of frontline-remission patients are MRD-positive, involves ~50% community sites, and emphasizes the potential advantage of an off-the-shelf product for faster, mostly outpatient treatment versus autologous CAR T.

Allogene Therapeutics NASDAQ: ALLO Chief Medical Officer Zach Roberts said the company expects to report initial data in April from its ALPHA3 study, a frontline consolidation trial evaluating its off-the-shelf allogeneic CD19 CAR T-cell therapy, cema-cel, in large B-cell lymphoma (LBCL). Roberts discussed the trial’s design, what the upcoming “futility analysis” will assess, and how minimal residual disease (MRD) testing is being integrated into patient selection.

ALPHA3 design focuses on MRD-positive patients in remission

Roberts described cema-cel as an off-the-shelf allogeneic CAR T targeting CD19 that has been evaluated clinically for several years. He said a prior phase 1 study in third-line relapsed/refractory LBCL produced “very good results,” which the company published in the Journal of Clinical Oncology last year. He characterized the efficacy as comparable to approved autologous CAR T products and said safety was similar, with cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) described as similar or “numerically improved.”

In early 2024, Allogene shifted development of cema-cel from the third-line setting to ALPHA3, which Roberts called a first-of-its-kind study in lymphoma. Under ALPHA3, newly diagnosed LBCL patients receive standard frontline therapy outside the trial. Those who achieve remission then receive an ultrasensitive MRD test using circulating tumor DNA (a PCR-based blood test), which Roberts said is more sensitive than CT scans for detecting residual disease. Patients who are MRD positive—indicating residual tumor not seen on imaging—are randomized to either standard-of-care observation (“watching and waiting”) or treatment with cema-cel.

April readout to center on MRD clearance at day 45

Roberts said the April update will report whether cema-cel can eradicate MRD in these patients. Specifically, the company plans to compare the rate of MRD clearance (MRD-positive to MRD-negative) between the observation arm and the cema-cel arm. He noted the analysis includes 12 patients per arm and will assess MRD status at day 45 post-randomization to avoid bias from staggered enrollment.

He also said Allogene expects to provide some safety information with the data, though it may not be exhaustive. Roberts emphasized safety as a key consideration because patients are in remission, adding that the company aims for convenient administration and that ALPHA3 is being conducted with outpatient management, including lymphodepletion and infusion in outpatient infusion clinics for most patients.

How Allogene is setting the “bar” for the futility analysis

Roberts said MRD status is “highly prognostic,” describing MRD-positive patients as having a high likelihood of relapse and MRD-negative patients as having a strong chance of durable remission. For the upcoming futility analysis, he said Allogene is targeting a 25% to 30% absolute difference in MRD clearance between arms. He added that the observation arm is expected to have a non-zero clearance rate, citing historical data suggesting roughly 20% MRD clearance without intervention.

To contextualize the target, Roberts pointed to several comparisons:

• Frontline chemoimmunotherapy benchmarks: He cited the POLARIX trial for Polivy R-CHOP, describing a modest ~6.5% absolute improvement in two-year progression-free survival versus R-CHOP, and framed this as requiring treatment of 17 patients to prevent one PFS event.
• Second-line autologous CAR T trials: He referenced ZUMA-7 and TRANSFORM (Yescarta and Breyanzi versus transplant), stating there was about a 30% “delta” in response and complete remission rates in positive trials, and described MRD as a proxy for response.
• An MRD-guided bladder cancer trial: Roberts discussed a study published in the New England Journal of Medicine in muscle-invasive bladder cancer, where MRD-positive patients were randomized to placebo or a checkpoint inhibitor. He said a post-hoc analysis showed an 11% MRD clearance difference (14% placebo vs. 25% treatment) despite positive disease-free and overall survival outcomes.

Asked what would constitute a “no-go” scenario if the MRD clearance delta falls below 25% to 30%, Roberts said it is difficult to specify a single number and noted multiple stakeholders—including investigators—will evaluate whether the signal is compelling enough to support enrolling patients. He suggested 11% would likely be challenging for the community to accept in LBCL, and reiterated that the company is anchoring to the 25% to 30% goal.

Enrollment and site mix include significant community participation

Roberts said Allogene has “largely worked through” early enrollment challenges that led to a timeline adjustment about a year ago. He attributed the slow start primarily to workflow: patients in remission after standard frontline therapy are “not thought of to be clinical trial patients,” and clinicians required training and materials to routinely incorporate MRD testing and trial discussions. He said once these practices were established, MRD testing and screening became routine across potentially eligible patients, and the company is applying these “best practices” to new sites as they come onboard.

Regarding site mix, Roberts said about 50% of listed trial sites could be characterized as community practices, including some that have never administered CAR T previously and historically opted out of offering autologous CAR T, instead referring patients elsewhere.

MRD testing momentum and the patient pathway

Roberts characterized MRD testing in lymphoma as early but rapidly developing, calling it “a better test than PET-CT” and easier to administer because it avoids radiation exposure and scanner logistics. He said Allogene selected Foresight Diagnostics as its diagnostic partner based on supporting data when ALPHA3 was designed, and noted that Foresight was acquired by Natera in December, which he said could accelerate MRD adoption. He also cited growth of clonoSEQ (Adaptive Biotechnologies) in lymphoma practices.

In describing the patient journey, Roberts said approximately four out of five patients tested in ALPHA3 are MRD negative, while about one in five are MRD positive. For MRD-positive patients who enter the trial, cema-cel treatment includes standard lymphodepletion with fludarabine and cyclophosphamide followed by a single infusion, with inpatient versus outpatient administration left to the physician and patient; he said most are managed as outpatients.

Roberts also discussed the urgency of the MRD-positive setting, stating that roughly one-third of MRD-positive patients progress within about three months and that the median time to relapse is about six months or less from the last dose of chemotherapy. He argued that the off-the-shelf nature of cema-cel could be advantageous versus autologous manufacturing timelines and suggested that chronic therapies could be less attractive to patients who have been told their disease is potentially curable.

Looking beyond the April readout, Roberts said Allogene expects to provide more detail on the timing of future efficacy analyses, including an interim event-free survival (EFS) analysis and the primary EFS readout, while reiterating the company’s expectation to complete enrollment by the end of next year.

About Allogene Therapeutics NASDAQ: ALLO

Allogene Therapeutics is a clinical-stage biotechnology company focused on developing allogeneic, or “off-the-shelf,” chimeric antigen receptor T-cell (CAR T) therapies to treat a range of hematologic malignancies and solid tumors. The company leverages gene-editing technologies to generate universally compatible engineered T cells, aiming to overcome the limitations of patient-specific CAR T approaches such as manufacturing delays, variable product quality and treatment resistance.

The company's pipeline includes multiple allogeneic CAR T candidates targeting key antigens in blood cancers.

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