Expert Highlights CAR-T and Other Treatment Advances Across Hematologic Malignancies

Mazyar Shadman, MD, MPH

Now that the CD19-targeted CAR T-cell therapies axicabtagene ciloleucel (axi-cel; Yescarta) and tisagenlecleucel (Kymriah) have shown durable responses in the relapsed/refractory settings of non-Hodgkin lymphoma, researchers are hopeful that earlier exposure may heighten the curative potential of the modality, explained Mazyar Shadman, MD, MPH.

Both constructs are indicated for patients with relapsed/refractory large B-cell lymphoma who have received ≥2 lines of systemic treatment, but a handful of trials are investigating axi-cel and tisagenlecleucel in earlier settings. One such trial is the single-center, phase II ZUMA-12 trial (NCT03761056). In the study, patients with high-risk large B-cell lymphoma will receive a single infusion of axi-cel at a target dose of 2 × 10⁶ CAR T cells/kg.

Furthermore, the CD19-targeted product lisocabtagene maraleucel (liso-cel; JCAR017) is being compared with standard of care, high-dose therapy, and transplant, in patients with relapsed/refractory aggressive B-cell lymphomas in the phase III TRANSFORM trial (NCT03575351).

“The field is looking at different indications in diffuse large B-cell lymphoma (DLBCL), new histologies, and different targets; there's a lot of work to do,” said Shadman, assistant member, Clinical Research Division, Fred Hutchinson Cancer Research Center. “For most of these lymphomas, the goal is cure.”

As in DLBCL, curative strategies in chronic lymphocytic leukemia (CLL) are entering the clinic in the form of chemotherapy-free and time-limited treatment. In the phase III CLL14 trial, 88.2% of patients who received the combination of venetoclax (Venclexta) and obinutuzumab (Gazyva) in the frontline setting remained progression-free at 2 years, 1 year after stopping treatment, versus 64.1% of those who received obinutuzumab and chlorambucil.^1,2

In an interview during the 2019 OncLive^® State of the Science Summit^™ on Hematologic Malignancies, Shadman, who is also an assistant professor, Medical Oncology Division, Department of Medicine, University of Washington, and an attending physician, Hematologic Malignancies, Seattle Cancer Care Alliance, discussed earlier use of CAR T-cell therapy in lymphoma, the impact of approved products on future development, and recent data with chemotherapy-free and time-limited therapy in CLL.

OncLive^®: What are some of the CAR T-cell products that are on the rise?

Shadman: We have seen great results in the lymphoma world. We now have two approved CAR T-cell constructs that target CD19 for patients with diffuse large B-cell lymphoma (DLBCL) or similar histologies in the relapsed setting for patients who have received 2 lines of treatment. We're seeing great responses. We have reasonable follow-up now showing that some of those responses are durable.

Now, like anything else in oncology, it's time to bring this treatment to earlier lines of therapy; that will be the focus moving forward. In large cell lymphoma, moving these treatments earlier has been the focus for the past few years. There are studies that are testing the therapy in the second-line setting. Second-line treatment for large cell lymphoma is still chemoimmunotherapy followed by high-dose treatment and autologous stem cell transplant.

The question is whether we could do better with CAR T-cell therapy, and there are randomized studies that are investigating that possibility. That's very exciting. For example, there are trials with liso-cel. Liso-cel is not approved yet, but we are actively participating in a study that is looking at that opportunity.

The same thing is true in the first-line setting. We now have studies with axi-cel in the first-line setting in high-risk patients with DLBCL, who are classified as high risk according to different definitions. If patients don’t achieve a complete remission after a few cycles of therapy, then we try CAR T-cell therapy instead of waiting until they fail 2 or more lines of treatment.

It’s important that we bring these treatments to earlier lines of therapy [with curative intent]. We're happy to see this happening in this field. Follicular lymphoma is following this trend. There were a few small subgroup reports from the 2019 ASCO Annual Meeting in mantle cell lymphoma (MCL) and secondary central nervous system lymphoma; these are very important. Of course, there are other trials targeting more than CD19, such as studies that are looking at targeting CD20. At Fred Hutchinson Cancer Research Center, we have an in-house CAR T-cell therapy targeting CD20 that we are very excited about.

What is the biggest challenge that has to be overcome in this space?

As with any other therapy, toxicity is always the priority. You want to make sure your patients are safe and we're making progress in that regard. We're learning more about how to manage the toxicity [with CAR T] and how to decrease the risk of these toxicities, namely cytokine release syndrome and neurotoxicity. From a practical standpoint, it is becoming a crowded space to bring new CAR T-cell products or combinations into. Having an FDA-approved CAR T-cell therapy is great, but it also sets the bar much higher for bringing a new CAR T-cell therapy to patients. It’s a good problem to have, but it will slow down enrollment on clinical trials or [research regarding] sequencing strategies. Although clinical research will be a little bit slower than before, I'm sure with a large group of investigators it will be feasible.

You also spoke about CLL. Could you discuss the impact of the phase III CLL14 trial?

At the 2019 ASCO Annual Meeting, we saw the results of the German CLL14 study, which was a randomized trial for patients with previously untreated CLL. Since last year, we had a press release indicating that the study was positive, but we didn't have access to the data. Now, it's published in manuscript. These are the most important data we have in CLL since the 2018 ASH Annual Meeting; it’s had a significant impact on how we treat patients in the frontline setting. The study led to the FDA approval of venetoclax (Venclexta) for the frontline treatment of patients with CLL. Right now, we have access to venetoclax to treat patients with CLL per the FDA label for basically any patient with the disease. However, this study specifically looked at the combination of venetoclax with obinutuzumab, which is a CD20-directed monoclonal antibody.

Is the combination preferred for specific patients in the frontline setting?

The study was designed to include patients with comorbidities and patients who did not have perfect kidney function. In theory, that would be the target population for the combination. However, the combination is approved for all patients with CLL, regardless of the inclusion criteria of the study. We have experience using venetoclax in the first-line setting, so while this study was designed for a specific subpopulation, I believe every patient will see a benefit from it.

That doesn't mean that is the preferred treatment option. There are other great options. There should be a discussion between the physician and the patient to talk about different treatment approaches. Chemoimmunotherapy is pretty much gone from the first-line setting, but there are still specific populations who can benefit from different types of chemoimmunotherapy. We have entered the chemotherapy-free era, and we have more than 1 great drug available. The question is how to pick between them, a question that has to do with the safety profile and patient preference. For example, are patients more interested in a fixed duration of treatment or are they OK with taking a medication for a longer period of time? We are getting to a point where we're combining these drugs and doing even better [than ever before].

Is venetoclax showing as much potential in other hematologic malignancies?

The drug is being tested in different diseases. For myeloma, there is a hold on clinical trials due to some toxicity concerns. There’s currently no indication for it. We know it's an active drug in MCL; it's being studied in combination. Venetoclax induces cell death.

In CLL, for example, some of the high-risk patients have genetic abnormalities that make the CLL cells resistant to the normal death mechanisms in the cancer cells. Since venetoclax works differently, by inducing apoptosis related to BCL-2—a protein that's highly expressed in CLL—we have great responses even in high-risk patients, who, by standard definition, should not respond to treatments like that. The same principle applies to lymphoid malignancies, specifically MCL. Venetoclax has an indication in CLL as well as acute myeloid leukemia, but we're looking forward to seeing data with venetoclax in other diseases as well.

Will the field place more emphasis on fixed durations of treatment?

Last year, if I had a patient who had an option of receiving chemoimmunotherapy or an oral drug like ibrutinib (Imbruvica), they would choose chemoimmunotherapy because it's a fixed duration of treatment. After 6 months or so, they would enjoy their remission, which could last for years.

Now, we have a nonchemotherapy drug that gives patients the opportunity of potentially having a fixed duration of treatment. I say “potentially” because studies, such as CLL14 or MURANO, were designed to give venetoclax in combination with a CD20-targeted antibody for 1 and 2 years, respectively. However, we don't know what happens after these patients stop treatment. In the MURANO study, we have short-term follow-up data that suggest that patients who achieve a deep remission may be free of relapse for a long time.

Just the fact that we hope we can get to that treatment-free and disease-free timepoint is very promising. We never thought about it with BTK inhibitors or PI3K inhibitors; these drugs are just not designed to induce deep remissions that could translate to long-term remissions. In theory, venetoclax could do that. We need to wait and see longer follow-up. It's important for a patient, it's important for a physician, and it’s important for the health system to have a limited duration of treatment. That’s the goal.

References

1. Fischer K, Al-Sawaf O, Bahlo J, et al. Effect of fixed-duration venetoclax plus obinutuzumab (VenG) on progression-free survival (PFS), and rates and duration of minimal residual disease negativity (MRD—) in previously untreated patients (pts) with chronic lymphocytic leukemia (CLL) and comorbidities. J Clin Oncol. 2019;37(suppl; abstr 7502).
2. Fischer K, Al-Sawaf O, Bahlo J, et al. Venetoclax and obinutuzumab in patients with CLL and coexisting conditions. N Engl J Med. 2019;380(23):2225-2236. doi: 10.1056/NEJMoa1815281.