ASH 2020: Clinical Updates

In APOLLO, Subcutaneous Daratumumab With Pomalidomide Cuts Progression, Death Risk By 37% in Relapsed MM

A version of daratumumab injected under the skin, when added to the oral medications pomalidomide and dexamethasone (D-Pd), cut the risk of disease progression or death by 37% compared with Pd alone in patients who have had at least 1 relapse with multiple myeloma, according to study results presented during the 62nd American Society of Hematology (ASH) Annual Meeting and Exposition.¹

Findings from the phase 3 APOLLO trial, which examined the formulation of daratumumab and hyaluronidase-fihj, were presented during ASH, which took place December 5-8, 2020, in a virtual format due to the coronavirus disease 2019 (COVID-19) pandemic.

Daratumumab is an immunotherapy that targets the CD38 protein, which is heavily expressed in multiple myeloma cells. The therapy binds to the protein and blocks tumor cell growth, causing cancerous cells to die. The subcutaneous formulation of daratumumab is approved in various combinations to treat transplant-eligible and refractory multiple myeloma; however, it is not yet approved in combination with pomalidomide (Pomalyst, Celgene), which is anti-angiogenic and acts as antimmunomodulator.

Janssen, which sells daratumumab as Darzalex, filed submissions with FDA and European regulators on November 12, 2020, based on the new results.²

The study’s lead investigator, Meletios A. Dimopoulos, MD, professor and chairman of the Department of Clinical Therapeutics at the National and Kapodistrian University of Athens School of Medicine in Greece, touted the subcutaneous formulation of daratumumab during a press briefing on APOLLO. He said the average time to inject the drug in APOLLO was 5 minutes; Janssen reports that administration can take between 3 and 5 minutes.

Dimopoulos highlighted that using the subcutaneous version can spare a patient 2 hours or more at a hospital or infusion center. “This is an improvement in the quality of life of the patient,” he said, noting this is especially true during the early stretch of the regimen when daratumumab is given weekly.

“Also, it saves valuable time in the chemotherapy or the outpatient treatment unit,” Dimopoulos said.

APOLLO randomized 304 patients to receive either D-Pd or Pd alone; the average age of patients in the D-Pd arm was 67 years and the average age in the Pd arm was 68 years. Patients had multiple myeloma for just over 4 years, and a slightly higher share of patients in the Pd arm was considered high risk. Trial participants had received at least 1 prior line of therapy, including lenalidomide and a proteasome inhibitor, and had responded to the treatment but then progressed. Those with just 1 prior line of therapy were refractory to lenalidomide.

Among key findings from APOLLO:²

1. The study achieved its primary end point, significantly improving progression-free survival (PFS), with a hazard ratio (HR) of 0.63 (95% CI, 0.47-0.85; P = .0018).
2. Patients in the D-Pd arm had a median PFS of 12.4 months, compared with 6.9 months for those in the Pd arm.
3. Other results showed that patients taking D-Pd had a better rate of overall response (69% vs 46%), very good partial response or better (51% vs 20%) and complete response (25% vs 4%).
4. A higher share of patients in the D-Pd arm achieved minimal residual disease negativity (9% vs 2%).

Among patients taking the subcutaneous version of daratumumab, 6% had infusion-related reactions, which were all grade 1 or 2, and 2% had local injection site reactions, all grade 1. Dimopoulos said these rates are far less than would be seen with infusion-related reactions, which can include upper respiratory tract reactions, including bronchospasm. An occasional patient develops hypotension; to avoid this, patients are typically premedicated during the first infusion, causing the initial session to last up to 8 hours. This creates a significant burden for patients and caregivers, he said.

In fact, he said, there are very few circumstances when intravenous administration of daratumumab would still be preferred.

Rates of patients who stopped treatment due to treatment-related adverse events were similar: 2% for D-Pd vs 3% for Pd.

Dimopoulous noted that the phase 3 APOLLO results build on what was already known about daratumumab and pomalidomide as single agents in separate trials. He highlighted that the combination of both therapies has now been shown to be even more effective within the context of a randomized trial. “This is a particularly useful regimen for an increasing number of patients with myeloma who progress on lenalidomide maintenance or continuous [therapy],” he said.

APOLLO was one of several trials at ASH that featured innovative treatments for multiple myeloma, an incurable blood cancer that affects plasma cells, causing tumors to grow in the bone marrow. Approximately 32,000 people receive a diagnosis of multiple myeloma in the United States this year, and 13,000 people will die from the disease.³ Patients with multiple myeloma sometimes have no symptoms and the first sign of disease is often a bone fracture; symptoms can include fatigue, pain, low red blood cell counts, or renal decline.

References

1. Dimopoulos MA, Terpos E, Boccadoro M, et al. Apollo: Phase 3 randomized study of subcutaneous daratumumab plus pomalidomide and dexamethasone (D-Pd) versus pomalidomide and dexamethasone (Pd) alone in patients with relapsed/refractory multiple myeloma (RRMM). Presented at: 62nd American Society of Hematology Annual Meeting and Exposition; December 5-8, 2020; Virtual. Accessed December 15, 2020. https://ash.confex.com/ash/2020/webprogram/Paper135874.html

2. Seeking approval of Darzalex Faspro (daratumumab and hyaluronidase-fihj)/Darzalex (daratumumab) subcutaneous (SC) formulation in combination with pomalidomide and dexamethasone for patients with relapsed or refractory multiple myeloma. News release. PR Newswire. November 12, 2020. Accessed December 5, 2020. https://www.prnewswire.com/news-releases/janssen-submits-applications-in-us-and-eu-seeking-approvalof-darzalex-faspro-daratumumab-and-hyaluronidase-fihjdarzalex-daratumumabsubcutaneous-sc-formulation-in-combination-with-pomalidomide-and-dexamethasonefor-pat-301171825.html

3. Myeloma. American Cancer Society: Cancer facts and statistics. Accessed November 2020. https://cancerstatisticscenter.cancer.org/#!/cancer-site/Myeloma

Zanubrutinib Studies Highlight Efficacy, Tolerability in MZL, CLL, SLL

Zanubrutinib, the second-generation Bruton tyrosine kinase (BTK) inhibitor sold as Brukinsa (BeiGene), fared well in a series of studies presented during the 62nd American Society of Hematology Annual Meeting and Exposition.

Overall, the drug’s selling point—fewer off-target effects—seemed to hold up, as patients were able to stay on the drug for long periods or, as seen in one study, take it successfully after they could not tolerate other BTK inhibitors. However, serious adverse events (AEs) do occur, and a small number of patients stopped taking the drug across the studies due to adverse events.

Results presented on December 6, 2020, demonstrated effectiveness in patients with marginal zone lymphoma (MZL) and treatment-naïve patients with chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) with 17p deletion. Additionally, results from a phase 2 study presented December 7, 2020, showed that zanubrutinib was able to maintain or improve clinical outcomes in patients with B-cell malignancies who had stopped taking ibrutinib or acalabrutinib.

Zanubrutinib is FDA-approved in mantle cell lymphoma (MCL) for patients who have received at least 1 prior therapy. Besides MZL and CLL/SLL, it is being studied in other blood cancers including follicular lymphoma, B-cell malignancies, and Waldenström macroglobulinemia (WM).

The phase 2 results presented December 7, 2020, were an outgrowth of a phase 2 study in WM, according to Ian Flinn, MD, PhD, of Tennessee Oncology, the senior author on the new study. In the original study, patients were randomized to take either zanubrutinib or ibrutinib.

“We found that there was much less of the adverse events, such as atrial fibrillation, seen with zanubrutinib than with ibrutinib, and this held true for many of the other adverse events associated with ibrutinib,” Flinn said. “We thought that trying this drug in patients who could no longer take ibrutinib, that maybe we could keep people on therapy with zanubrutinib that could not be on ibrutinib. And that was really the case here,” he continued.

Arm C, Phase 3 SEQUOIA Trial.¹ Jennifer Brown, MD, PhD, of the Dana-Farber Cancer Institute, presented follow-up results from the nonrandomized “Arm C” of the randomized, open-label, phase 3 SEQUOIA trial, which examined zanubrutinib monotherapy in treatment-naïve patients with CLL or SLL with del(17p). As seen in the ASPEN trial for WM, she said, zanubrutinib is “designed to maximize BTK occupancy and minimize off-target inhibition of TEC and EGFR kinases.”

Despite the more favorable safety profile of zanubrutinib, 5 patients in the study stopped treatment due to AEs and 2 patients died, including 1 who developed pneumonia related to therapy.

Results reported at ASH 2019 were based on a follow-up of 10 months, but new results included 21.9 months of follow-up; the complete response (CR) rate increased from 1.9% to 6.4% during that time. Progression-free survival at 18 months (PFS) was 90.6% (95% CI, 83.3-94.9), and the overall response rate (ORR) was 94.5%. The drug’s tolerability remained consistent with what has been reported in previous studies. Overall survival at 18 months was 95.4% (95% CI, 89.3-98.1). PFS at 18 months among patients with unfavorable characteristics was 88% for those with unmutated IGHV and 94% for those with complex karyotype status.

Within the ORR, 6 patients (5.5%) had CRs, 1 (0.9%) had a CR with incomplete bone marrow recovery, 1 (0.9%) had nodular partial response (PR), 94 (86.2%) had PRs, and 1 (0.9%) had PR with lymphocytosis. Additionally, 93.1% maintained response at 12 months, and 87.7% maintained response at 18 months.

The most common AEs were confusion (20.2%), upper respiratory tract infection (19.3%), diarrhea (17.4%), and nausea (14.7%); less common were back pain, constipation, rash, cough, neutropenia, arthralgia, and pneumonia. More than half (52.3%) of patients had an AE of grade 3 or higher, with the most common being neutropenia, pneumonia, falls, and hypertension. More than a third (38.5%) of patients had a serious AE.

Phase 2 MAGNOLIA Trial.² Initial results from the single-arm, open-label study showed that zanubrutinib was generally well-tolerated among older, high-risk patients with MZL who had received at least 1 prior line of anti-CD20 treatment. The trial included 68 patients, with an average age of 70 years and a median of 2 prior treatments; more than 30% had refractory disease and nearly 40% had nodal MZL.

Data cut off occurred on August 14, 2020. With a median follow-up time of 10.7 months, 66 patients were eligible for zanubrutinib efficacy evaluation. Results show:

1. The ORR was 74.2% (95% CI, 62.0-84.2), with 16 complete responses (24.2%) and 33 partial responses (50.0%).
2. The ORR was strong across high-risk subgroups, including patients who were at least 75 years of age (ORR 88.9%); those with refractory disease (ORR 71.0%); and those with nodal MZL (ORR 84.0%).
3. Median follow-up time for progression-free survival (PFS) was 9.13 months; PFS rates at 6 and 9 months were 80.0% and 67.0%, respectively.

Nearly all patients (95.6%) had a treatment-related adverse event, with 38.2% having an event of grade 3 or higher. The most common events were neutropenia, diarrhea, pyrexia, thrombocytopenia, anemia, and pneumonia. Two patients stopped taking the drug due to treatment-related AEs, including 1 patient with a pre-existing cardiovascular condition who suffered a fatal heart attack.

Zanubrutinib After Other BTK Ibhibitors.³ Mazyar Shadman, MD, PhD, of the Fred Hutchison Cancer Center and the University of Washington in Seattle, presented phase 2 results of zanubrutinib therapy in patients who had previously taken ibrutinib or and 32 patients reached an assessment milestone in time for the data cutoff: 20 patients with CLL, 5 with SLL, 2 with MCL, and 5 with WM. All but 2 patients had taken ibrutinib previously, either as monotherapy or as part of a combination regimen. The median time on a prior BTK inhibitor ranged from 6.41 months for patients with MCL to 12.91 months for patients with WM, though some were on treatment for less than 2 months.

Researchers reported the following:

1. Of the 66 ibrutinib intolerant events that occurred with the first BTK inhibitor, 58 did not recur with zanubrutinib.
2. Of the 25 grade 3 intolerant events that occurred on prior therapy, only 2 recurred on zanubrutinib.
3. None of the four grade 4 events recurred.
4. Eight intolerant events occurred with zanubrutinib; 7 were at a lower severity than with prior therapy, while 1 was of the same severity. These were all bleeding events.

No patients have developed disease progression. Clinical assessments show that 44% of patients are doing as well as they were on prior therapy, while 50% have experienced improved responses. After a median follow-up of 3.5 months, 31 patients remain in the study. The patient no longer in the study did not drop out due to an AE.

References

1. Brown JR, Robak T, Ghia P, et al. Efficacy and safety of zanubrutinib in patients with treatment-naïve (TN) chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) with del(17p): follow-up results from arm C of thežSEQUOIA (BGB-3111-304) trial. Presented at: 62nd American Society of Hematology Annual Meeting and Exposition; December 5-8, 2020; Virtual. Accessed December 15, 2020. https://ash.confex.com/ash/2020/webprogram/Paper134280.html

2. Opat S, Tedeschi A, Linton K, et al. Efficacy and safety of zanubrutinib in patients with relapsed/refractory marginal zone lymphoma: initial results of the MAGNOLIA (BGB-3111-214) trial. Presented at: 62nd American Society of Hematology Annual Meeting and Exposition; December 5-8, 2020; Virtual. Accessed December 15, 2020. https://ash.confex.com/ash/2020/webprogram/Paper134611.html

3. Shadman M, Sharman JP, Levy MY, et al. Phase 2 study of zanubrutinib in patients with relapsed/refractory B-cell malignancies intolerant to ibrutinib/acalabrutinib. Presented at: 62nd American Society of Hematology Annual Meeting and Exposition; December 5-8, 2020; Virtual. Accessed December 15, 2020. https://ash.confex.com/ash/2020/webprogram/Paper134621.html

NCCN Recommends Zanubrutinib as First-Line, Second-Line Therapy in CLL, SLL

The National Comprehensive Cancer Network (NCCN) has recommended zanubrutinib, a tyrosine kinase inhibitor sold as Brukinsa (BeiGene), for treatment of chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL).

While zanubrutinib is approved by the FDA for the treatment of adult patients with mantle cell lymphoma (MCL), recent NCCN guidelines updated on December 3 now recommend the indication as both a first-line and second-line treatment in CLL/SLL.

• First-line therapy of zanubrutinib as a single agent is recommended for the treatment of CLL/SLL with 17p deletion (del 17p) and TP53 mutations in patients with contraindication to other Bruton tyrosine kinase (BTK) inhibitors who have indications for treatment.
• For second-line treatment and subsequent therapy, the NCCN recommends the indication as a single agent for the treatment of CLL/SLL with or without del(17p) and TP53 mutations in patients with intolerance or contraindication to other BTK inhibitors who have indications for retreatment.

As payers view the NCCN guidelines as a gold standard for making reimbursement decisions, the question lingers whether to adhere to the NCCN guidelines while the FDA has not approved zanubrutinib for the treatment of CLL/SLL. The distinction of the del(17p) mutation as a high- risk genetic characteristic associated with overall survival may warrant the push for treatment of CLL/SLL as those with CLL have a shorter life expectancy than age- and sex-matched populations.

Findings from the arm C, phase 3 SEQUOIA Trial presented at the 62nd American Society of Hematology Annual Meeting and Exposition indicate that zanubrutinib was well tolerated and effective among patients with CLL/SLL with 17p deletion. Including more than 21.9 months of follow-up, treatment-naïve patients with CLL or SLL with del(17p) administered zanubrutinib as a monotherapy exhibited an increased complete response rate from baseline (1.9% to 6.4%).

Additionally, progression-free survival at 18 months was 90.6% (95% CI, 83.3%-94.9%), and the overall response rate was 94.5%, with the drug’s tolerability remaining consistent with what has been reported in previous studies.

So, how do payers handle a situation when the NCCN updates treatment guidelines ahead of an FDA approval? Erin Lopata PharmD, MPH, vice president, Market Access Experience Team, PRECISIONvalue said in an email that both payers and providers “are challenged with keeping up-to-date with advances and updates in this therapeutic area.”

Most payers, she said, consider the NCCN Guidelines “as a recognized compendium to support coverage decisions for oncology products.” While many will limit coverage to FDA-approved indications, a Category 1 or 2a recommendation for a non-approved indication will generally bring coverage, she wrote.

“The new recommendation may trigger a payer policy change for the drug, where the NCCN-supported indication is added to the pharmacy or medical policy clinical criteria. Other payers may have an overarching policy that allows for authorization based on NCCN guideline recommendations,” she wrote. “Additionally, if the payer utilizes a pathway to manage oncology agents, the pathway may also need to be updated to direct approvals of the NCCN-supported indication.”

Studies have produced conflicting findings. A 2018 analysis published in BMJ of 113 NCCN recommendations found that the NCCN frequently recommends beyond FDA-approved indications and that the evidence for these recommendations was weak.¹ But a later study in the Annals of Oncology,² examining the levels of evidence used in recommendations within NCCN guidelines formed prior to FDA approvals, found the strength of the evidence supporting these recommendations was “robust, with a significant subset of these drugs later becoming FDA approved or supported by randomized controlled trials.”

References

1. Wagner J, Marquart J, Julia R, et al. Frequency and level of evidence used in recommendations by the National Comprehensive Cancer Network guidelines beyond approvals of the US Food and Drug Administration: retrospective observational study. BMJ. 2018;360:k668

2. Kurzrock R, Gurski LA, Carlson RW, et al. Levels of evidence used in recommendations by the National Comprehensive Cancer Network guidelines beyond Food and Drug Administration approvals. 2019; Ann Oncol. 30:1647–1652. doi:10.1093/annonc/mdz232.