Obinutuzumab

Obinutuzumab (Gazyva) was approved by the U.S. Food and Drug Administration (FDA) as a component of four different first-line novel combination regimens used to treat patients with chronic lymphocytic leukemia (CLL)/small lymphocytic leukemia (SLL),¹ and studies with other drug combinations are ongoing. Traditional first-line chemoimmunotherapy regimens are no longer considered the gold standard for most patients with treatment-naive CLL.

Obinutuzumab is a monoclonal antibody that targets the CD20 antigen expressed on normal and malignant B cells. Because stem cells (immature cells in the bone marrow that will develop into various types of cells) do not express the CD20 antigen, healthy B cells can regenerate after treatment.

According to Matthew Davids, MD, MMSc, Director of Clinical Research, Division of Lymphoma at Dana-Farber Cancer Institute, and Associate Professor of Medicine at Harvard Medical School in Boston, obinutuzumab is structurally unique compared with rituximab, which is also an anti-CD20 monoclonal antibody and has been used for many years in the treatment of CLL. Of note, obinutuzumab also enhances greater induction of direct cell death when compared with other anti-CD20 monoclonal antibodies.

“Obinutuzumab is an antibody engineered to have a couple of different effects,” Dr. Davids told JNCCN 360. “One effect is to enhance antibody-dependent cellular cytotoxicity, and the other is to have a direct effect on killing the tumor cells, which is different from rituximab, and relies more on other immune cells and complement to kill tumor cells.”

According to Dr. Davids, researchers hypothesized that obinutuzumab would be an effective antibody in this setting because patients with CLL have dysfunctional immune systems. This is because it can directly kill tumor cells without relying on a patient’s immune system.

Previous Gold Standard for First-Line Treatment in CLL

Chemoimmunotherapy with obinutuzumab/chlorambucil is an established regimen used to treat adults with CLL/SLL without del(17p)/TP53 mutation who are treatment-naive. The regimen was approved in 2013 based on results from the CLL11 trial; obinutuzumab/chlorambucil demonstrated higher response rates compared with rituximab/chlorambucil.² Almost one in three patients in the obinutuzumab arm of that trial experienced a complete response. 

“What was particularly impactful about this study is that an overall survival benefit emerged with obinutuzumab/chlorambucil versus rituximab/chlorambucil, suggesting the ‘hypothetical’ benefit of obinutuzumab was actually important in clinical practice,” said Dr. Davids. “In my mind, the study defined obinutuzumab as the preferred CD20 antibody for most patients with CLL.”

The CLL11 trial defined obinutuzumab as the preferred CD20 antibody for most patients with CLL.

The obinutuzumab/chlorambucil regimen from the CLL11 study became the comparator for subsequent major phase III trials with other novel agents. It was tested head-to-head against three nonchemotherapy-containing regimens in patients with treatment-naive CLL. The initial results of these trials were presented in 2019 and altered the treatment landscape of CLL. That year, obinutuzumab was granted FDA approval as a component of three new combination regimens for the first-line treatment of adults with CLL: venetoclax/obinutuzumab, acalabrutinib/obinutuzumab, and ibrutinib/obinutuzumab.

Novel Treatment Regimens

Findings from the phase III CLL14 trial demonstrated a significant improvement in progression-free survival (PFS) with the 1-year fixed-duration combination of venetoclax and obinutuzumab compared with obinutuzumab/chlorambucil in patients with treatment naive CLL.³ The median PFS was not reached in the venetoclax arm, compared with 35.6 months in the chlorambucil arm. At 3 years, PFS was 81.9% with the venetoclax combination versus 49.5% with obinutuzumab/chlorambucil. At 4 years, 74% of patients treated with venetoclax/obinutuzumab remain progression-free.

In the phase III ELEVATE-TN trial, acalabrutinib combined with obinutuzumab resulted in a significant benefit over obinutuzumab/chlorambucil in the first-line setting.⁴ The median PFS was not reached in the acalabrutinib/obinutuzumab arm compared with 22.6 months with obinutuzumab/chlorambucil. At 2 years, the PFS rate was 93% in patients who received the acalabrutinib combination and 47% in those who received the chlorambucil combination.

“It’s interesting to note that the researchers described a PFS improvement in the acalabrutinib/obinutuzumab arm compared with acalabrutinib alone. This was one of the first times we’ve seen that adding a CD20 antibody to a BTK [Bruton’s tyrosine kinase] inhibitor can potentially improve progression-free survival in CLL,” said Dr. Davids. “This post hoc analysis is essentially hypothesis-generating, since it’s still early, and the PFS difference is small, but it’s an intriguing finding.”

Dr. Davids told JNCCN 360 that the previous data sets are comparable, and head-to-head data do not exist yet. As a result, the question of preferred first-line treatment between fixed-duration versus continuous therapy is still unanswered. However, individualizing therapy should be based on factors such as age and comorbidities. For example, a patient with significant cardiovascular comorbidities might fare better on venetoclax/obinutuzumab, whereas a patient with difficulty traveling for infusions might do well with BTK-inhibitor monotherapy.

Additionally, the phase III iLLUMINATE trial of patients with treatment-naive CLL showed that the combination of ibrutinib and obinutuzumab significantly improved PFS over obinutuzumab/chlorambucil.⁵ The median PFS was not reached in the ibrutinib-containing group compared with 19 months in the chlorambucil-containing arm. Overall response rates were 88.5% with ibrutinib and 73.3% with chlorambucil. Complete responses were seen in 19.5% and 7.8% of patients with ibrutinib/obinutuzumab and obinutuzumab/chlorambucil, respectively. However, this study did not contain an ibrutinib monotherapy arm, so the benefit of adding obinutuzumab to ibrutinib over ibrutinib monotherapy remains unknown.

Obinutuzumab Dosing and Administration

Obinutuzumab is administered as an intravenous (IV) infusion for a total of six 28-day cycles, so most patients will complete their treatment in about 6 months. According to Dr. Davids, this is part of a fixed-duration treatment regimen with venetoclax that may be appealing to both patients and providers.

On the days they receive obinutuzumab, patients should expect to spend most of the days at the clinic or infusion center. For the first cycle, obinutuzumab is dosed as 100 mg on day 1, 900 mg on day 2, and 1,000 mg on day 8 and day 15. For cycles 2 through 6, each dose is the same (1,000 mg on day 1). Split dosing is done to reduce the severity of patients’ side effects when first starting obinutuzumab. Premedications, such as steroids, acetaminophen, and antihistamines, are given just before the infusion to reduce the occurrence of infusion-related reactions.

If a planned dose is missed, the missed dose should be administered as soon as possible, and the dosing schedule should be adjusted accordingly. If appropriate, patients who do not complete the day 1 cycle 1 dose may proceed to the day-2 cycle-1 dose.

Sandra Stewart, PA, a physician assistant at NewYork-Presbyterian/Weill Cornell in New York City, has extensive experience caring for patients receiving obinutuzumab. “For the first treatment, we give obinutuzumab in a split dose over 2 days, to prevent or minimize infusion-related reactions and/or tumor-lysis syndrome,” she told JNCCN 360. “We see more reactions in patients with heavy disease burdens or massive splenomegaly. As with most monoclonal antibodies, reactions can include fevers, chills, rigors, hives, and rash.”

Infusion-Related Reactions

“For the first infusion,” Ms. Stewart continued, “we always provide acetaminophen and antihistamines. For patients with a large disease burden, we often add a steroid. If the patient has a reaction, we stop the infusion until it resolves or provide as-needed medication that can improve the symptom, and then restart treatment.”

According to Ms. Stewart, the dose of obinutuzumab given as first-line therapy for CLL remains the same regardless of the drug combination being administered, and dosing is rarely impacted by performance status. However, she added, a poor performance status can make treatment planning more difficult. If the patient is deemed stable enough to proceed with obinutuzumab, Ms. Stewart’s institution’s protocol is to administer the full dose.

Infusion-related reactions at the start of treatment can be challenging, particularly for older patients, Dr. Davids pointed out. Severe reactions such as hypotension and anaphylaxis are rare, but low-grade reactions (ie, mild chills, rash) can be experienced by up to half of patients. Splitting the first dose over 2 days and using prophylactic medications help to mitigate the severity of these reactions, he said. However, it is important to warn patients about these potential reactions to eliminate surprises and reassure them that the risk of these reactions drops significantly after the first dose. “It’s unusual to see infusion-related reactions with later doses of obinutuzumab,” he said.

It’s unusual to see infusion-related reactions with later doses of obinutuzumab.

“We tend to use obinutuzumab in combination with other medications, but we stick with the standard dosing regardless of which other drug it is being used with. We generally give obinutuzumab first, as it quickly and effectively debulks a large amount of disease, so we can safely add in other medications, such as venetoclax,” Ms. Stewart observed. “It’s amazing to see the dramatic drop in white blood cell count after just one dose. Even with how quickly obinutuzumab drops the white blood cell count, tumor-lysis syndrome (TLS) is rare. Nevertheless, we provide tumor-lysis prophylaxis with at least allopurinol prior to administration of these regimens.” [Editor’s Note: Patients who receive obinutuzumab may be at risk for TLS within 12 to 24 hours of their first dose. TLS is caused by massive tumor cell destruction when the body releases high amounts of potassium, phosphate, and nucleic acids and can lead to life-threatening sequelae or death unless appropriately and immediately treated.]

Obinutuzumab Regimens: Adverse Effects

Cytotoxic chemotherapy-based regimens are often difficult for patients to tolerate (particularly those with multiple comorbidities or those considered “unfit”). However, because monoclonal antibodies such as obinutuzumab target specific cells alone, they may be less toxic to healthy cells. This is an advantage of treatment with an antibody because patients with CLL tend to have multiple comorbidities.

“Luckily, there aren’t many clinical challenges with obinutuzumab,” said Ms. Stewart. “It’s been shown to have great efficacy with minimal side effects, and it’s very well tolerated by our patients. We monitor patients closely for any possible side effects, but we don’t see many [with this agent],” she told JNCCN 360.

However, it’s important to note that prescribing information for obinutuzumab⁶ contains a black box warning about hepatitis B reactivation and progressive multifocal encephalopathy. Other common adverse events of any grade reported in CLL clinical trials (≥ 30%) include lymphocytopenia, leukopenia, neutropenia, thrombocytopenia, infection, hypoglycemia, and hyperkalemia.

“With this drug, side effects are most common during the first cycle, when the schedule is a little more intensive,” Dr. Davids said. “But overall, this is a well-tolerated antibody.”

With obinutuzumab, side effects are most common during the first cycle, when the schedule is a little more intensive.

Obinutuzumab Combinations in CLL: Future Research

CLL17 is a large study currently under way in Europe that will compare ibrutinib monotherapy with both venetoclax/obinutuzumab and ibrutinib/venetoclax (ClinicalTrials.gov identifier NCT04608318). Both ECOG and Alliance have ongoing trials of the triple regimen ibrutinib/venetoclax/obinutuzumab versus the doublet regimen ibrutinib/obinutuzumab in younger and older patient populations, respectively (NCT03701282; NCT03737981).

Another phase III study, CLL311 (NCT03836261), is comparing acalabrutinib/venetoclax/obinutuzumab with acalabrutinib/venetoclax and an investigator’s choice of chemoimmunotherapy. Although the obinutuzumab-based regimen demonstrated efficacy in patients with CLL in a smaller phase II study led by Dr. Davids, the phase III trial will determine whether obinutuzumab is necessary as part of the drug triplet compared with the acalabrutinib/venetoclax doublet.

“Certainly, it would be easier for patients not to have infusions, so this study could potentially lead to acalabrutinib/venetoclax as a new option for standard of care,” predicted Dr. Davids.

DISCLOSURES

Matthew Davids, MD, MMSc, has received research funding from AbbVie, Ascentage Pharma, AstraZeneca, Genentech, MEI Pharma, Novartis, Pharmacyclics, Surface Oncology, TG Therapeutics, and Verastem and has served as a consultant to AbbVie, Adaptive Biotechnologies, AstraZeneca, BeiGene, Bristol Myers Squibb, Eli Lilly, Genentech, Janssen, Merck, Pharmacyclics, Research to Practice, Takeda, TG Therapeutics, and Verastem.

Sandra Stewart, PA, reported no conflicts of interest.

References

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4. Sharman JP, Egyed M, Jurczak W, et al. Acalabrutinib with or without obinutuzumab versus chlorambucil and obinutuzumab for treatment-naive chronic lymphocytic leukaemia (ELEVATE TN): a randomised, controlled, phase 3 trial. Lancet 2020;395:1278–1291.
5. Moreno C, Greil R, Demirkan F, et al. Ibrutinib plus obinutuzumab versus chlorambucil plus obinutuzumab in first-line treatment of chronic lymphocytic leukaemia (iLLUMINATE): a multicentre, randomized, open-label, phase 3 trial. Lancet Oncol 2019;20:43–56.
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