Tracy T. Batchelor, MD, MPH, co-leader, Neuro-Oncology Program, Dana-Farber Cancer Institute, Neurologist-in-Chief, Department of Neurology, Brigham and Women’s Hospital, Giovanni Armenise - Harvard Professor of Neurology, member, Center Scientific Council, Harvard Medical School, discusses the rationale for investigating tirabrutinib (Velexbru) for the treatment of patients with primary central nervous system lymphoma (PCNSL).

PCNSL is an uncommon B-cell malignancy characterized by high proliferation contained to the brain and cerebrospinal fluid. Most forms of PCNSL are diffuse large B-cell lymphoma, and thus involve frequent mutations in the B-cell receptor pathway, Batchelor begins. These mutations occur at different nodes and cause hyperactivation of the downstream target NFκB, thereby promoting B-cell proliferation, survival, and migration, he details. Utilizing and/or developing agents that target the B-cell receptor signaling axis could therefore interfere with this process and result in cytotoxicity of malignant B cells, Batchelor explains.

The second-generation BTK inhibitor tirabrutinib is one such option, Batchelor states. In March 2023, the FDA granted tirabrutinib orphan drug designation in PCSNL. Early case reports have shown that BTK inhibitors like ibrutinib (Imbruvica) are active and able to produce radiographic responses in PCNSL, Batchelor notes. Tirabrutinib has good CNS bioavailability and could provide more durable responses when utilized in the relapsed/refractory setting, he says.

Tirabrutinib also demonstrated early activity in patients with relapsed/refractory PCNSL in the large, phase 1/2 ONO-4059-02 trial (JapicCTI-173646). Long-term data from this trial demonstrated that patients who received the regimen had an overall response rate (ORR) of 63.6%, supporting its approval in Japan. Results from this trial also supported initiation of the phase 2 PROSPECT study (NCT04947319) of tirabrutinib plus a high-dose methotrexate, rituximab (Rituxan), and temozolomide in newly diagnosed PCNSL in the United States.

Videos

Tracy T. Batchelor, MD, MPH, discusses the rationale for investigating tirabrutinib for the treatment of patients with primary central nervous system lymphoma.

Dr Batchelor on the Rationale for Investigating Tirabrutinib in PCNSL

Although most patients with primary central nervous system lymphoma (PCNSL) experience a response with high-dose methotrexate-based chemotherapy, tirabrutinib (Velexbru) may be a suitable treatment option as unmet needs remain for those with relapsed/refractory disease, according to Lakshmi Nayak, MD. After tirabrutinib demonstrated early success in the phase 1/2 ONO-4059-02 study (JapicCTI-173646) in Japan, the phase 2 PROSPECT study (NCT04947319) has been initiated in the United States.

“This is a rare disease, but it’s very treatable,” Nayak explained. “A tremendous amount of work needs to be done and the number of clinical trials that are currently available for PCNSL in the past few years has increased. We need to solidify our upfront regimen so that we can get to a cure which I believe is possible in this disease with the right treatments.”

Updated data from 3-year follow-up of the ONO-4059-02 study presented at the 2023 ASCO Annual Meeting demonstrated that patients with relapsed/refractory PCNSL (n = 44) treated with tirabrutinib experienced an overall response rate (ORR) of 63.6% (95% CI, 47.8%-77.6%) with a complete response rate of 36.4% (95% CI, 22.4%-52.2%).

Patients receiving 480 mg of tirabrutinib once daily (n = 7) achieved an ORR of 100% (95% CI, 59.0%-100.0%) with a complete response rate of 57.1% (95% CI, 18.4%-90.1%). Additionally, median overall survival (OS) was not yet reached in all patents and the 3-year OS rate was 56.7% (95% CI, 40.9%-69.8%).

, Nayak, an assistant professor of Neurology at Harvard Medical School and the director of the Center for Central Nervous System Lymphoma as well as a senior physician at Dana-Farber Cancer Institute, both in Boston, Massachusetts, discussed the treatment landscape for PCNSL diving into detail on the rare disease and how tirabrutinib may serve as an option for those with relapsed/refractory disease.

Because PCNSL is a rare condition, how is the disease identified in patients?

It is an extremely rare disease, it accounts for approximately 3% to 4% of malignant CNS tumors, and other primary brain tumors are more common than [PCNSL]. A diagnosis is typically made when patients present with neurologic symptoms to the emergency department [ED] or to their local doctors, and an MRI is performed. There are certain characteristics that are suggestive of PCNSL or CNS lymphomas in the brain; however, we always recommend histopathologic confirmation to make the diagnosis.

In general, this is a disease of older [individuals] as the median age of diagnosis is 65 or 67 years. When there is a mass in the brain, it is quite suggestive of it being a cancer. We recommend brain biopsies for [individuals] in that context, which can then [help] make the diagnosis of what specific type of cancer it is.

Is underdiagnosis or misdiagnosis common with PCNSL and what challenges occur with diagnosis?

Since this is a rare cancer and occasionally may not present in the brain as a typical mass, that concerns doctors about it being a cancer. In that case, it requires an astute clinician to think about this being in the differential at least. Oftentimes, patients may not present immediately with symptoms because if they’re noticing some memory changes, it could be attributed to age or other factors.

Unless patients have acute deterioration or an acute change such as a seizure or weakness of any 1 side of the body, they may delay in going to the doctor and getting an MRI done.

When the MRI findings are not clear cut and not definitively suggestive of a lymphoma, that’s where it can pose a problem because patients then undergo other kinds of workup to prevent a brain biopsy. In institutions such as ours, neuro-oncology is involved quite quickly, and we work with our neurology team as well as our neurosurgical teams to determine if a brain biopsy is safe because this is a very treatable disease, and we don’t want to cause more adverse effects from a biopsy itself.

Safe biopsies particularly in this time where neurosurgical techniques have evolved and improved tremendously are possible. We recommend for the workup to be done in an expedited manner so that the diagnosis can be made, but awareness [of effects] is important [as well].

What does the typical treatment journey look like for patients after diagnosis?

Many patients who have severe deficits come into the ED [and] if they’re found to have a brain mass—they undergo a biopsy and the diagnosis of lymphoma in the brain is made. At this point, it’s important for us to determine if this is a lymphoma that’s coming from the body [and] has spread to the brain or [if it is] occurring concurrently in the body [and] in the brain, or [if] is it isolated in the nervous system. If it isn’t isolated in the nervous system [we must determine] what compartments of the nervous system are involved.

Once we do an extensive disease evaluation and make the diagnosis of PCNSL, treatment is initiated. We recommend patients to start treatment sooner than later because ‘time is brain’—the sooner we treat the less damage there is. Since this as a very treatable cancer, we can see improvement and resolution of neurologic deficits occur quite rapidly after institution of treatment.

Treatment involves chemotherapy given in the hospital, so patients are moved from the ED to the [inpatient] unit. We treat our patients in the oncology unit where they receive inpatient chemotherapy and high-dose methotrexate forms the backbone of this treatment. There are various other chemotherapy agents as well as antibodies such as rituximab [Rituxan] that are used in combination with high-dose methotrexate.

The specific regimens are dependent on which institution is delivering the treatment because different parts of the country and different parts of the world use a few different guidelines. [However,] we all agree that high-dose methotrexate-based chemotherapy is the best start.

How could tirabrutinib potentially fill an unmet need if approved for this indication?

High-dose methotrexate-based chemotherapy seems to work very well, and most patients achieve a remission or response. However, we notice that approximately 50% to 60% of patients do [experience] recurrence in the first couple of years. Additionally, approximately 15% to 20% of patients don’t respond to high-dose methotrexate-based treatment so we have this group of relapsed/refractory patients.

To reduce the risk of recurrence, we have tried different modalities of treatment. Historically, whole brain radiation [was used and] improved outcomes tremendously. However, the challenge with that was that because [individuals] lived longer, they experienced progressive and irreversible neurotoxicity which manifests in the form of cognitive impairment, memory disorders, and gait disorders. These are irreversible and lead to a significant worsening of quality of life. Therefore, radiation is not commonly [used] in the first-line setting.

Then we investigated the role of high-dose chemotherapy either by itself or in combination with autologous transplant. We now have evidence to show that patients who undergo a thiotepa-based autologous transplant after completion of their high-dose methotrexate-based treatment have improved outcomes and are in a long-term remission. One of the challenges is that this is not suitable for the majority of patients and so far, only patients who are medically fit—younger then 65 or 70 years and can tolerate the rigors of an autologous transplant—can go through this process.

Which brings me to why there remains an unmet need—even though we are able to treat a fraction of the patients very well, the majority of patients are not able to receive such treatment. This is where drugs such as tirabrutinib come into play. We are currently investigating the role of tirabrutinib in the relapsed/refractory setting where if patients don’t respond to methotrexate-based chemotherapy or have progressed after their initial treatment with methotrexate or transplant or any other modalities, they are eligible to receive tirabrutinib.

In the United States, we’re conducting [the PROSPECT] study to look at its efficacy and how long do patients remain in long-term remission? The [next] goal would be to then see tirabrutinib in the upfront setting [and see whether] we can improve outcomes setting by adding it to a high-dose methotrexate-based regimen to [elicit] higher response rates [and] achieve longer durability.

What is the mechanism of action of tirabrutinib?

On histopathology [results], PCNSL looks [almost] indistinguishable from any other diffuse large B-cell lymphoma in the body. On gene expression profiling, we know now that it fits into the activated B-cell–like subtype of diffuse large B-cell lymphomas. [Further,] with comprehensive genomic analysis, we now recognize that this is a distinct disease with unique mutations which allows for specific targets.

We’ve known that PCNSLs exhibit near uniform toll-like receptor signaling as a result of mediated mutations and B-cell receptor signaling. The B-cell antigen receptor signaling pathway is very active in PCNSL and its downstream target is Bruton tyrosine kinase [BTK]. Tirabrutinib targets BTK and this may be one of the mechanisms in which it works; however, we have seen responses with tirabrutinib in the absence of 

 mutations. We have yet to learn its specific mechanism of action in PCNSL.

What early data have been seen with tirabrutinib so far?

Before the [ongoing] PROSPECT study, data from the study of tirabrutinib conducted in Japan…supported the approval [of the agent] for relapsed/refractory PCNSL in Japan. There’s emerging data of tirabrutinib in the Japanese population the response rate was very profound at approximately 60% to 64%, which is encouraging and with their long-term data it seems that there’s a reasonable group of patients that do tend to have long-term remission. We do need longer follow-up, and we’re waiting to see how the drug performs in the [PROSPECT] population.

What safety signals of the agent have been observed so far?

Tirabrutinib is considered a second-generation irreversible selective inhibitor of BTK, and we expected that the adverse event profile would be slightly different and better than the first-generation drugs. There are a fair number of patients who experience rashes, that seems to be the most common adverse event, which is not unexpected, and it seems that most of these rashes could be managed.

The other safety signal was that patients were developing neutropenia [and were at-risk] for infections. This was [also] expected and patients can be followed to prevent life-threatening infections; the risk is there but high-risk infections are uncommon with this drug. In the Japanese study they did not see cardiac toxicities and one of the concerns with BTK inhibitors is the possibility developing cardiac arrhythmias, the most common of which is atrial fibrillation. Emerging data are important for us to see if this is seen in the United States population and in the general population.

What are the institution-specific patient care pathways that are used at Dana-Farber?

We see patients in 2 possible ways: one is the newly diagnosed patient who comes in through the Brigham and Women’s Hospital ED or patients who are referred to us once they are diagnosed or [have] relapsed/refractory [disease].

In the newly diagnosed setting, neuro-oncology team gets involved very quickly. For outpatients, we see them within 24 hours [and] we offer appointments that quickly so that we can work with our inpatient teams to start treatment as soon as possible. We institute treatment with high-dose methotrexate-based chemotherapy. Our [go-to] regimen is a combination of high-dose methotrexate with rituximab and temozolomide which we use for 6 to 8 cycles, followed by high-dose cytarabine. We monitor patients after starting treatment at 1 month to see their initial response to the chemotherapy, and if they have a favorable response further on, we monitor patients with MRIs every 2 months until they’ve completed their induction chemotherapy.

If patients have a good response and are candidates for additional high-dose chemotherapy with thiotepa followed by a transplant, we refer them to our transplant team so that they can be evaluated. We also follow National Comprehensive Cancer Network (NCCN) guidelines. As such we [want to] offer all patients who are candidates a clinical trial. We have a few trials for upfront management [including an arm of] the PROSPECT study that allows for tirabrutinib with the high-dose methotrexate/rituximab/temozolomide regimen [in newly diagnosed patients]. In the relapsed/refractory setting, we offer tirabrutinib in other clinical trials that we have available before considering the standard-of-care regimen.

Asai K, Narita Y, Nagane M, et al. Final three-year follow-up analysis of phase I/II study on tirabrutinib in patients with relapsed or refractory primary central nervous system lymphoma. 

. 2023;41(suppl 16):7548. doi:10.1200/JCO.2023.41.16_suppl.7548

Articles

Lakshmi Nayak, MD, discusses the treatment landscape for patients with primary central nervous system lymphoma and how tirabrutinib may serve as an option for those with relapsed/refractory disease.

Tirabrutinib Aims to Fill Gap in the PCNSL Treatment Landscape

Katsunori Asai, MD, PhD, Department of Neurosurgery, Osaka International Cancer Institute, Osaka, Japan, discusses the evaluation of tirabrutinib (ONO-4059) in patients with relapsed/refractory primary central nervous system lymphoma (PCNSL) in a phase 1/2 study (JapicCTI-173646).

PCNSL is an uncommon and aggressive variant of extra-nodal non-Hodgkin lymphoma (NHL) that typically occurs in the brain and cerebrospinal fluid without evidence of systemic spread. Analysis of driver genes for this tumor type have implicated BTK as a therapeutic target, supporting the investigation of BTK inhibitors for this patient population.

In this phase 1/2 study, 44 Japanese patients with relapsed/refractory PCNSL received the highly potent and selective second-generation oral BTK inhibitor tirabrutinib at dose levels of 320 mg (n = 20), 480 mg (n = 7), or 480 mg while fasting (n = 17). The trial's primary end point was overall response rate (ORR), and the data cutoff date for the final analysis was April 27, 2022.

Interim data from this trial were previously reported with 14.9 months of median follow-up and led to the agent's approval in Japan for the treatment of patinets with relapsed or refractory PCNSL.

Data from a final 3-year follow-up analysis of the study demonstrated that the agent produced durable responses in this population, with an ORR of 63.6% in all patients, 60.0% for those given the 320 mg dose, 100% for those given the 480 mg dose, and 52.9% for the 480-mg fasting group, Asai reports. Moreover, the duration of response (DOR) in all patients was 9.2 months. In the 320-mg, 480-mg, and 480-mg fasting groups, the median DOR was 3.7 months, 10.2 months, and 12.1 months, respectively.

Median overall survival (OS) was not reached all patient groups and the 480-mg fasting group. Three-year OS rates were 56.7% and 52.9% in the overall population and 480-mg fasting group, respectively. Regarding progression-free survival (PFS), the total population had a median PFS of 2.9 months and a 36-month PFS rate of 13.9%, Asai states. These measures were 5.8 months and 19%, respectively, in the 480-mg fasting group, he adds. Safety findings were consistent with the agent's previously reported profile.

Tirabrutinib was granted an orphan drug designation by the FDA for this patient population in March 2023. The agent is currently under investigation in the ongoing phase 2 PROSPECT trial (NCT04947319).

Disclosures: Dr. Asai reports having received institutional research funding from Ono Pharmaceuticals.

Katsunori Asai, MD, PhD, Department of Neurosurgery, Osaka International Cancer Institute, Osaka, Japan, discusses the use of tirabrutinib in patients with relapsed/refractory primary central nervous system lymphoma according to a phase 1/2 study (JapicCTI-173646). 


 Dr Asai on Final Results From a Phase 1/2 Trial of Tirabrutinib in R/R PCNSL

Lakshmi Nayak, MD, senior physician, director, Center for Central Nervous System (CNS) Lymphoma, Center for Neuro-Oncology, Dana-Farber Cancer Institute, assistant professor, Neurology, Harvard Medical School, discusses the diagnosis of patients with primary CNS lymphoma (PCNSL).

PCNSL is a rare variant of extra-nodal non-Hodgkin lymphoma (NHL), Nayak begins. It accounts for about 4% of malignant CNS tumors, and its incidence has risen significantly in recent years, she reports. PCNSL is typically present in the brain and cerebrospinal fluid without evidence of systemic spread. The eyes and spinal cord can also be involved in this disease, although this is less frequent.

Most patients with PCNSL will first visit the emergency room or their general practitioner with worsening neurologic symptoms, Nayak says. Symptoms can include focal neurologic deficits, mental and behavioral changes, headaches, nausea, vomiting, papilledema, or seizures. These patients will then undergo baseline staging, which includes magnetic resonance imaging (MRI) of the brain, Nayak continues. The MRI scan will typically identify a single homogenously enhancing mass lesion in the supratentorial area with frontoparietal lobe involvement. Other tools recommended to assess the extent of disease are ophthalmologic evaluation, and CSF evaluation.

The majority of patients who develop PCNSL are 60 years of age or older, and the median age of diagnosis is around 65 years old, Nayak notes. Importantly, advanced age has been identified as an independent prognostic factor for worse patient outcomes for this disease. PCNSL can also develop in individuals who are immunocompetent or immunosuppressed due to HIV/AIDS, organ transplant, or immunosuppressive agents. Notably, the presence of a mass legion is more likely to be cancer rather than a different abnormality, she explains. However, histopathologic confirmation of the diagnosis through stereotactic biopsy is recommended to confirm diagnosis, Nayak concludes.

Lakshimi Nayak, MD, discusses the diagnosis of patients with primary CNS lymphoma.

Clinical Updates in Primary CNS Lymphoma | Supplements and Featured Publications

Dr Batchelor on the Rationale for Investigating Tirabrutinib in PCNSL

Tirabrutinib Aims to Fill Gap in the PCNSL Treatment Landscape

Dr Asai on Final Results From a Phase 1/2 Trial of Tirabrutinib in R/R PCNSL

Dr Nayak on the Identification of Primary CNS Lymphoma