We often think of cancer conferences as places to look back on finished work, but they’re also where new ideas ignite. And in late 2022, that’s what happened at the American Society of Hematology (ASH) annual meeting.
There, a group of Stanford physicians and scientists from Foresight Diagnostics (Boulder, CO) shared study findings around the use of a new minimal residual disease (MRD) test that claimed to detect cancer cells not killed by chemotherapy or other cancer treatments in patients with large B-cell lymphoma (LBCL). Using ultrasensitive detection, their platform found tiny traces of cancer not detectable by conventional methods, including PET/CT scans, the current standard following first-line treatment for LBCL.
That got the attention of Dr. Zachary Roberts, EVP, Research and Development and Chief Medical Officer at the CAR-T biotech Allogene Therapeutics, headquartered in South San Francisco, California. Two years later, we have what may be the start of a “fundamental shift” in cancer care through a new clinical trial called ALPHA3.
The pieces fall into place for a pivotal trial
Soon after the ASH presentation, Roberts had begun to explore the use of CAR-T in earlier lines as part of a consolidation regimen in newly diagnosed LBCL patients with a goal to prevent relapse and improve cure rates. Roughly six in 10 patients are cured after first-line (1L) chemotherapy, known as R-CHOP, or other standard regimens, but physicians don’t know who will or won’t relapse until the lymphoma has returned. Patients who respond to 1L R-CHOP are typically monitored post treatment every 3-6 months using the current standard of care known as “watch and wait.” This means that if the disease recurs, it may have been progressing undetected for some time, at which point it becomes harder to treat.
“At that point, [some] patients can experience a catastrophic relapse event where the disease comes back and is sort of galloping along,” Roberts said at a fireside chat during this year’s STAT Summit in Boston. “You can have relapses in the brain, or other very difficult situations.”
Roberts hypothesized that administering CAR-T at the end of treatment could consolidate a patient’s remission and potentially prevent relapse altogether. Now, armed with an investigational ultra-sensitive MRD test (Foresight CLARITY™) that can be used to select the patients who will likely experience recurrence, Roberts saw a path to an efficient treatment plan that concentrates CAR-T only in the patient population who needs it and leaves everyone else alone.
When Roberts saw Foresight’s data from ASH 2022, it sparked an “aha moment” for him — what if he could pair new MRD technology as a companion diagnostic with Allogene’s “off-the-shelf” CAR-T? With their powers combined, Foresight and Allogene could come together to improve the lives of relapse-likely survivors by capitalizing on the 1L consolidation window.
“I remember thinking, ‘This is the opportunity to run this trial,’” Roberts said in a STAT Brand Studio multimedia lounge interview at the Summit. The two organizations started discussing the partnership in early 2023, just months after ASH. This summer, the ALPHA3 trial officially launched. “It’s been a very productive and fruitful collaboration between the two companies ever since then.”
Finding cancer at one-part-per-million sensitivity
ALPHA3 is enrolling patients with LBCL who are likely to relapse after first-line treatment. Such relapses can be not only aggressive but can occur quickly following completion of therapy. Of the 30% of patients who achieve remission but whose cancer returns after 1L treatment, relapse can occur within weeks of their final infusion. To get ahead of a potential impending relapse, trial investigators are testing participants for MRD soon after completion of their 1L treatment course, which is typically six rounds of R-CHOP or a similar chemoimmunotherapy regimen. With innovations by Foresight in circulating tumor DNA (ctDNA) detection — those shared at ASH 2022 — the result of the MRD test, in hand shortly thereafter, may now predict in days what once took months to detect and, within ALPHA3, may now capitalize on the critical 1L consolidation window.
For patients considering participation in this trial, there are multiple potential upsides to consider. If a patient tests negative for MRD, the result may provide peace of mind because relapse is probably unlikely. If they test positive, these patients are then potentially eligible for the ALPHA3 trial. If they are randomized into the arm for treatment, they will receive Allogene’s CD19 CAR-T product candidate, cemacabtagene ansegedleucel (cema-cel), an investigational product that may be curative and consolidate remission. If they are in the arm that uses the current standard of care, they will be monitored more closely than they might be otherwise, which allows them to be very proactive in managing their disease. All three potential paths for this trial can be significantly beneficial to patients.
“Up until this point, ctDNA-MRD hasn’t had the sensitivity required to design a trial such as this because you need to have very high limits of detection in order to adjudicate whether patients actually have the disease or are true negatives,” noted John Truesdell, chief business officer of Foresight Diagnostics, in the lounge interview. “We believe the sensitivity of the CLARITY assay meets these limits of detection required.”
Foresight’s platform can find cancer DNA at a rate of less than one part per million, thanks to new iterations of the technology that can detect disease during periods of low and previously undetectable tumor burden. “This gives the capability to see microscopic level of disease in order to select patients for the ALPHA3 trial,” he added.
“This knowledge will fundamentally alter how we follow these patients over time,” Roberts said. “If we can come in and mop up that residual disease so that patients never experience that relapse in the first place, that would be a massive step forward for these patients.”
Expanding CAR-T access for close-to-home care
Another distinguishing feature of ALPHA3 is that it doesn’t take away the R-CHOP workhorse that is successful for most people. This is important to clinicians, who are comfortable with R-CHOP and ideally would rather not escalate care unnecessarily in a patient who would have been cured by R-CHOP alone. ALPHA3 is the only pivotal trial currently enrolling that adds preemptive action solely in high-risk patients instead of escalating care for everyone. If successful, this strategy will benefit patients and could potentially help to reduce overall costs to the healthcare system.
This makes ALPHA3 a good fit for the community setting — and the fact that it utilizes an allogeneic product does, too.
As opposed to autologous products, allogeneic drugs like cema-cel do not require extracting and reinfusing a patient’s own cells, nor the complex product-by-product manufacturing involved in the interim. Instead, allogeneic therapies are developed from healthy donors well in advance and are therefore ready-made for people who need them “off-the-shelf.”
In turn, the provider can access the CAR-T and administer it right away, without the infrastructure and resource burdens of autologous products. With this lower lift, ALPHA3 opens up a whole new universe of community-based sites and participants.
More than 8 in 10 first-line cancer patients get treated in such centers, as opposed to the large health systems where they may have to drive farther to see providers. Receiving more sophisticated autologous treatments at large centers has traditionally meant tradeoffs for patients, Roberts noted.
“When those patients unfortunately relapse, they’re faced with a choice: ‘Do I pick up and go to the big city that maybe is hundreds of miles away to get access to this advanced therapy? Or do I roll the dice and stay with my local doctor…?’” he said
Contrast that legacy model with the possibilities unlocked from ALPHA3: With a ready-made, allogeneic CAR-T, patients get both things: a chance at effective, cutting-edge treatments, delivered near home.
“Many of the first clinical trial sites have been community oncology practices that have never had a CAR-T program before,” he said. “And these are large network practices who treat hundreds of patients a year. So this is their first time really taking that step in providing access to CAR-T — and they get to keep their patients within the community practice.”
“This is really a fundamental shift in how this complex modality is administered to patients.”
