August 2021: Targeted Therapy & Immuno-Oncology

NCCN Guidelines Add Zanubrutinib as Preferred Therapy for Waldenström Macroglobulinemia

Update guidelines from the National Comprehensive Cancer Network (NCCN) for Waldenström macroglobulinemia have added zanubrutinib (Brukinsa) as a preferred regimen. The NCCN Guidelines Version 1.2022 Waldenström Macroglobulinemia/Lymphoplasmacytic Lymphoma (WM/LPL) were updated to include zanubrutinib as a preferred regimen for the primary therapy of WM/LPL along with bendamustine/rituximab, bortezomib/dexamethasone/rituximab, ibrutinib ± rituximab, and rituximab/cyclophosphamide/dexamethasone. Preferred interventions are based on superior efficacy, safety, and evidence.¹ Both zanubrutinib and ibrutinib ± rituximab are considered category 1 recommendations, which means they are based on high-level evidence and there is uniform NCCN consensus that the intervention is appropriate. The other therapies are all category 2A: based on lower-level evidence, but there is still uniform NCCN consensus that the intervention is appropriate.

Zanubrutinib was also added as a category 1 preferred regimen for previously treated WM/LPL.
The other preferred regimens for previously treated WM/LPL are the same as the preferred regimens for primary treatment.

The addition of zanubrutinib to the guidelines was based on the findings from the ASPEN study
published in Blood. The study compared the safety and efficacy of zanubrutinib, a novel highly selective Bruton tyrosine kinase (BTK) inhibitor, with ibrutinib, a first-generation BTK inhibitor.²

In ASPEN, 28% of patients on zanubrutinib and 19% on ibrutinib achieved a very good partial
response (VGPR); no patient achieved a complete response (CR). The study did not meet the primary end point, which was proportion of patients achieving CR or VGPR, but the investigators noted that “there was a trend toward better disease control for zanubrutinib vs ibrutinib.”

Major response rate was similar (77% for zanubrutinib vs 78% for ibrutinib), as was progression-free
survival (85% for zanubrutinib vs 84% for ibrutinib). Patients on zanubrutinib had fewer instances
of atrial fibrillation, contusion, diarrhea, peripheral edema, hemorrhage, muscle spasms, and
pneumonia, as well as adverse events that led to treatment discontinuation.

“This study established that zanubrutinib is highly effective in the treatment of WM; zanubrutinib
is associated with important safety advantages, especially with respect to cardiovascular toxicity,”
the authors wrote.

The data from ASPEN was used in a supplemental new drug application (sNDA) with the FDA for
zanubrutinib in the treatment of WM, which was submitted in February 2021. Health Canada approved zanubrutinib in WM in March based on the findings of ASPEN.

“We are pleased that the FDA has accepted the sNDA for Brukinsa in WM, a rare disease with significant morbidity,” Jane Huang, MD, chief medical officer, Hematology, BeiGene, said in a statement. “BTK inhibitors have transformed the treatment of WM in recent years, but discrepancies in response exist in patients with different subtypes, and toxicity can remain an issue.”³

References
1. NCCN. Clinical Practice Guidelines in Oncology. Version 1.2022. Waldenström macroglobulinemia/lymphoplasmacytic lymphoma. https://
www.nccn.org/guidelines/guidelines-detail?category=1&id=1475
2. 2. Tam CS, OPat S, D’Sa S, et al. A randomized phase 3 trial of zanubrutinib vs ibrutinib in symptomatic Waldenström macroglobulinemia: the ASPEN study.’Blood. 2020;136:2038-2050. doi:10.1182/blood.2020006844
3. BeiGene announces US FDA acceptance of supplemental New Drug Application for Brukinsa (zanubrutinib) in Waldenström’s Macroglobulinemia. News release. BeiGene. Published February 17,
2021. Accessed July 20, 2021. https://ir.beigene.com/news-releases/news-release-details/beigene-announces-us-fda-acceptancesupplemental-new-drug

Investigators Outline Ongoing Studies, Challenges of CAR T-cell Therapy in GBM

With more treatment options needed in glioblastoma multiforme (GBM) to successfully attack disease, attention has been paid to chimeric antigen receptor (CAR) T-cell therapy, which has
shown great promise in hematologic malignancies and is being studied in other settings, including
central nervous system solid tumors, like GBM. In a recent paper, investigators provide a look at
clinical trials currently assessing the potential of treatment for the disease.

Although there’s hope that CAR T-cell therapy can revolutionize the way GBM is treated, there is
still more research to be done, investigators write inCancer Medicine, noting that research on CAR
T-cell therapy in this setting is still in early stages.¹

“Despite the promising results of CAR T technology in hematological malignancies, CAR T cells
for GBM are still in their earlier stage,” wrote the investigators. “Several GBM-associated antigens
have served as the targets of ongoing clinical trials (EGFRvIII, NKG2D, B7-H3, CD147, IL13Ralpha2,
and HER2). Most of the current clinical trials are still in phase 1, testing the safety and efficacy of
mostly second-generation CAR T cells constructed with CD28 and 4-1BB costimulatory intracellular
domains.”

The investigators write that, to date, evidence suggests combined therapy is more effective than
monotherapy in GBM, which not only gives insight into how to enhance the efficacy of CAR T-cell
therapy but also to potentially curtail adverse effects. The investigators outlined various ongoing
trials of CAR T-cell therapy that combine the therapy with other agents in patients with GBM.

With 70% of patients with GBM expressing B7-H3, which is not expressed on normal tissues, 1 ongoing trial is currently assessing the safety and tolerability of B7-H3 CAR T-cell therapy with
temozolomide, with B7-H3 CAR T being injected between temozolomide cycles. Data from the study are expected in 2022.²

EGFRvIII CAR T-cell therapy is being studied in several trials, with an ongoing phase 1 study
assessing the therapy in combination with temozolomide and another assessing EGFRvIII
CAR T following radiosurgery in patients with recurrent GBM.

CAR T-cell therapy in combination with immune checkpoint inhibitors is also being assessed for both recurrent and resistant disease, say the investigators. A phase 1 trial is currently looking at the safety and efficacy of IL13Ralpha2-CRT T cells used alone or in combination with nivolumab and ipilimumab.

Although still in the preclinical stage, Fc-CRs T cells may prove to be a leader in the treatment of
GBM and other solid tumors, say the investigators. As research on CAR T-cell therapy in GBM
progresses, the investigators are also calling attention to the challenges facing the therapy in
the disease, including the highly unstable tumor microenvironment and the variable genetic nature
of the disease.

“The mechanism by which the apparent tumor responses or growth delay in CAR-T cell-treated
GBM are multifactorial. This cannot be attributed to the therapy but could instead result from differences in the natural history of disease between patients,” commented the investigators. “Although there are no direct ways to demonstrate the actual killing of tumor cells by CAR T in situ, previous clinical and preclinical data suggest that CAR-T-EGFRvIII cells induce their action by antigen-directed cytolysis after crossing the blood–brain barrier.”

References

1. Marei HE, Althani A, Afifi N, et al. Current progress in chimeric antigen receptor T cell therapy for glioblastoma multiforme.Cancer Med. Published online June 19, 2021. doi:10.1002/cam4.4064

2. Pilot Study of B7-H3 CAR-T in Treating Patients With Recurrent and Refractory Glioblastoma. Updated May 12, 2020. Accessed July 15, 2021. https://clinicaltrials.gov/ct2/show/NCT04385173.