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Minimal Residual Disease
Frontline Ibrutinib/Venetoclax Combo Leads to High Undetectable MRD Rates in CLL
The first-line combination of ibrutinib (Imbruvica) and venetoclax (Venclexta) led to undetectable minimal residual disease (uMRD) rates of 75% in peripheral blood and 72% in bone marrow in the treatment of patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) <70 years old, according to findings from the MRD cohort of the phase II CAPTIVATE trial.1
The international, multicohort, phase II CAPTIVATE trial involved 164 treatment-naïve patients with CLL who required treatment.
Ibrutinib was administered alone in a lead-in stage at 420 mg daily for 3 cycles. Then, venetoclax was added and escalated to 400-mg daily. uMRD was defined as <0.01% CLL cells by flow cytometry. MRD was measured in the peripheral blood after 6, 9, and 12 cycles of combination therapy and in bone marrow after 12 cycles.
The median participant age was 58 years (range, 28-69), and 32% had del(17p)/TP53 mutation. Twenty percent of patients had chromosome 17p deletion (del[17p]) or TP53 mutations, 17% had 11q deletions, and 59% had unmutated IGHV. The median creatinine clearance was 95.0 mL/min, and 30% of patients had clearance <80 mL/min.1
After 3 cycles of ibrutinib lead-in, hospitalization for tumor lysis syndrome (TLS) was avoided in 76% of at-risk patients. For patients who had high TLS risk at baseline, 90% became medium or low risk, and 74% weren’t hospitalized when initiating venetoclax. No patients with medium or low TLS risk became high risk, lead study author Constantine S. Tam, MBBS, MD, hematologist and disease group lead, Low Grade Lymphoma and Chronic Lymphocytic Leukemia at the Peter MacCallum Cancer Centre, said.
Five patients discontinued ibrutinib before starting venetoclax: 4 due to AEs and 1 due to Richter transformation. Seven patients discontinued the combination treatment: 4 due to AEs, 1 due to disease progression, 1 due to patient withdrawal, and 1 due to investigator decision. Ninety percent (n=152) completed all 12 cycles, with median treatment durations of 14.7 months (range, 0.5-19.9) and 12.0 months (range, 0.8-12.7) for ibrutinib and venetoclax, respectively. No patients died.
uMRD was evaluated in peripheral blood (n = 163) and bone marrow (n = 155). In patients with matched bone marrow samples who had uMRD in peripheral blood at cycle 16, 93% had uMRD in bone marrow.
In the intent-to-treat population, uMRD in peripheral blood and bone marrow was achieved in 74% and 68% of patients, respectively, with ≤12 cycles of combination treatment.
High rates of uMRD were sustained over time in MRD-evaluable patients. The most common AEs with single-agent ibrutinib were diarrhea, arthralgia, fatigue, headache, nausea, upper respiratory tract infection, vomiting, hyperten-sion, and thrombocytopenia, with neutropenia accounting for the majority of grade 3/4 AEs.
The most common AEs for the combination were grade 1/2. Grade 3/4 AEs were most frequent during the first 3 cycles of combination treatment (39%) and then decreased to 15% in the last cycles. Fifty-seven percent of patients experienced grade 3/4 AEs, and serious AEs occurred in 11% of patients.
With the combination, grade 3/4 neutropenia (33%) was an AE of interest. Grade 3/4 atrial fibril-lation, major hemorrhage, febrile neutropenia, and laboratory TLS were infrequent; 2 cases of atrial fibrillation occurred in the ibrutinib lead-in phase, and 1 case was reported during combination treat-ment. Laboratory TLS was reported as an AE in 3 patients, 1 of whom met Howard criteria.
AEs that led to the discontinuation of either ibrutinib lead-in or combination therapy occurred in 11 patients. AEs led to treatment discontinuation in 5% and 4% of patients on ibrutinib and venetoclax, respectively; 14% of patients had AEs that led to dose reductions of ibrutinib therapy, whereas 9% of patients had AEs that led to venetoclax reductions.
The mean plasma area under the curve (AUC; n = 151) for venetoclax was higher when combined with ibrutinib (58.6 μg·h/mL) than when given alone (32.8 μg·h/mL) but was still within the AUC ranges observed with prior study doses. The mean AUC with ibrutinib (n = 112) didn’t change with concurrent venetoclax (646 ng·h/mL) versus single-agent ibrutinib lead-in (641 ng·h/mL). REFERENCES
1. Tam CS, Siddiqi T, Allan JN, et al. Ibrutinib (ibr) plus venetoclax (ven) for first-line treatment of chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL): results from the MRD cohort of the phase 2 CAPTIVATE study. Presented at: 2019 American Society of Hematology Annual Meeting & Exposition; December 7 to 10, 2019; Orlando, FL. Abstract 35. bit.ly/2RvawBV.
2. Wierda WG, Siddiqi T, Flinn I, et al. Phase 2 CAPTIVATE results of ibrutinib (ibr) plus venetoclax (ven) in first-line chronic lymphocytic leukemia (CLL). J Clin Oncol. 2018;36(suppl 15; abstr 7502). doi: 10.1200/JCO.2018.36.15_suppl.7502.
Daratumumab Triplet May Meet Real Clinical Need in Relapsed/Refractory Multiple Myeloma
Jason M. Broderick
A lenalidomide-free triplet therapy could fill a treatment gap for certain patients with multiple myeloma. Adding daratumumab (Darzalex) to carfilzomib (Kyprolis) and dexamethasone (KdD) reduced the risk of disease progression or death by 37% compared with carfilzomib and dexamethasone alone (Kd) in patients with relapsed/refractory multiple myeloma, according to the phase III CANDOR trial.
“Patients treated with KdD achieved deeper responses than patients treated with Kd, with a nearly 10 times higher MRD-negative complete response rate at 12 months versus Kd-treated patients,” said lead study author Saad Z. Usmani, MD, of Levine Cancer Institute in Charlotte, North Carolina.
The open-label CANDOR trial randomized 466 patients with relapsed/refractory multiple myeloma previously treated with 1 to 3 prior therapies 2:1 to either KdD (n = 312) or Kd (n = 154). Prior treatment with anti-CD38 anti-bodies and carfilzomib was allowed, if the patient reached at least a partial response, did not relapse ≤60 days from treatment discon-tinuation, and had a ≥6-month treatment-free interval at the time of initiating study therapy. Overall, 90% of patents had prior bortezomib (Velcade) and 42% of patients had prior lenalidomide (Revlimid). One-third (33%) of patients were lenalidomide refractory.1
“We have limited options for patients who are refractory to lenalidomide, [and] it makes little sense to rechallenge a patient with something they are progressing on just by adding other drugs,” Usmani said.1,2
Two-thirds of the combination regimens approved in this setting include lenalidomide an IMiD. Consequently, establishing a lenalidomide-free therapy is “a real clinical need,” Usmani said.2
Treatments were administered over 28-day cycles. Daratumumab (16 mg/kg) was given on days 1, 8, 15, and 22 of cycles 1 and 2; every 2 weeks during cycles 3 to 6; and every 4 weeks during cycle 7 and beyond. For patient convenience, the first dose of daratumumab was split into two 8-mg/kg doses and administered on cycle 1, day 1 and cycle 2, day 2.1
Carfilzomib and dexamethasone were given at the same dosage and schedule in both arms.
Patients received carfilzomib on days 1, 2, 8, 9, 15, and 16 of each cycle. For cycle 1 only, patients received a 20-mg/m2 loading dose of carfilzomib on days 1 and 2; the proteasome inhibitor was given at 56 mg/m2 for all subse-quent treatments. Dexamethasone was administered at 40 mg on days 1, 8, 15, and 22 of each cycle. When patients received carfilzomib and/or daratumumab infusions, a split dose of 20 mg each of dexamethasone was administered.1
The primary end point was PFS, with key secondary end points including overall response rate (ORR), minimal residual disease (MRD)–negative status, complete response (CR) rate at 12 months, OS, duration of response, and safety.1
Among patients exposed to lenalidomide, the median PFS had not been reached in the KdD arm compared with 12.1 months in the Kd arm (HR, 0.52; 95%, 0.34-0.80). In patients refractory to lenalidomide, the median PFS was not reached versus 11.1 months, respectively (HR, 0.45; 95% CI, 0.28-0.74).1
The ORR was 84.3% with KdD compared with 74.7% with Kd (P = .0040). The rates of CR or better were 28.5% versus 10.4%, respectively. The median time to first response was 1 month in both arms. Among patients receiving KdD, the MRD-negative rate at 12 months was 12.5% compared with 1.3% with Kd.1
The safety analysis included 308 patients in the KdD arm and 153 in the Kd arm. The regimens’ overall safety was similar to single-agent use of these drugs. The median treatment duration was 70.1 weeks in the KdD arm and 40.3 weeks in the Kd arm.1
The rates of grade ≥3 adverse events (AEs) were 82.1 % versus 73.9%, and the rates of serious AEs were 56.2% versus 45.8% in the KdD and Kd arms, respectively. The discontinuation rates due to AEs were 22.4% versus 24.8%, respectively. In the KdD arm, 3.9% of patients had grade ≥3 cardiac failure compared with 8.5% in the Kd arm. Cardiac failure led to carfilzomib discontinuation in 3.9% versus 4.6% of the 2 arms, respectively.1 The 5 treatment-related deaths all occurred in the KdD arm—1 each from pneumonia, sepsis, septic shock, acinetobacter infection, and cardio-respiratory arrest.1
1. Usmani SZ, Quach H, Mateos M-V, et al. Carfilzomib, dexamethasone, and daratumumab versus carfilzomib and dexamethasone for the treatment of patients with relapsed or refractory multiple myeloma (RRMM): primary analysis results from the randomized, open-label, phase 3 study CANDOR (NCT03158688). Presented at: 2019 American Society of Hematology Annual Meeting & Exposition; December 7-10, 2019; Orlando, FL, December 7-10, 2019. Abstract LBA-
2. Triple drug combination delays disease progression in people with stubborn multiple myeloma [news release]. Orlando, FL: American Society of Hematology; December 10, 2019. hematology.org/ Newsroom/Press-Releases/2019/10107.aspx. Accessed December 10, 2019.
Karolina Faysman, RN, MSN, AOCNP
UCLA Medical Center
FORTUNATELY, ADVANCES IN medical and pharmaceutical technology have allowed improvement in progression free survival (PFS) and thus, overall survival (OS) rates in patients diagnosed with this incurable disease. New strategies in treating patient with multiple myeloma drastically improved PFS and OS. Triplet therapy and ongoing continuous therapy have become foundation of successful therapy for this disease. Regimens include combination therapy with the immunomodulatory agents, protease inhibitors, steroids and monoclonal antibodies.
Recent clinical trials demonstrated superior results with addition of daratumumab (a monoclonal antibody) to the doublet regimens or replacing an immunomodulatory agents, such as lenolidomide for patients who either intolerable or refractory to this category of drugs. Addition of daratumumab to carfilzomib and dexamethasone combination, Improvement in progression free survival, overall response rate and minimal residual disease rates have been shown across all of the clinical trials. The addition of this monoclonal antibody did not demonstrate statistically significant changes in safety or tolerability profiles.
The schedule of the treatment is as follows:
• Daratumumab (16 mg/kg) was given on days 1, 8, 15, and 22 of cycles 1 and 2; every 2 weeks during cycles 3 to 6; and every 4 weeks during cycle 7 and beyond
• Carfilzomib and dexamethasone were administered at the same dosage and schedule in both arms. Patients received carfilzomib on days 1, 2, 8, 9, 15, and 16 of each cycle. For cycle 1 only, patients received a 20-mg/m2 loading dose of carfilzomib on days 1 and 2; the proteasome inhibitor was given at 56 mg/m2 for all subsequent treatments thereafter.
Dexamethasone was administered at 40 mg on days 1, 8, 15, and 22 of each cycle. During weeks when patients received carfilzomib and/or daratumumab infusions, a split dose of 20 mg each of dexamethasone was administered.
Chronic Lymphocytic Leukemia
Acalabrutinib Alone or in Combination Improves PFS in Frontline CLL
Acalabrutinib (Calquence) as a single agent or in combination with obinutuzumab (Gazyva) led to a significant improvement in progression-free survival (PFS) compared with obinutuzumab plus chlorambucil in treatment-naïve patients with chronic lymphocytic leukemia (CLL), according to results from the phase III ELEVATE CLL TN trial presented at the ASH annual meeting.
At a median follow-up of 28.3 months, the combination of acalabrutinib, a Bruton tyrosine kinase (BTK) inhibitor, with obinutuzumab led to a 90% reduction in the risk of disease progression or death compared with the chemoimmunotherapy regimen of obinutuzumab plus chlorambucil (HR, 0.10; 95% CI, 0.06-0.17; P <.0001). When used as monotherapy, acalabrutinib also showed a significant benefit in PFS compared with obinutuzumab/chlorambucil (HR, 0.20; 95% CI, 0.13-0.30; P <.0001).
Obinutuzumab combined with chlorambucil was a standard frontline option for patients with CLL prior to the introduction of the BTK inhibitor ibrutinib (Imbruvica). In November 2019, the FDA approved acalabrutinib for the treatment of patients with CLL or small lymphocytic lymphoma, based partially on data from the ELEVATE TN trial as well as from the ASCEND trial, which evaluated acalabrutinib compared with either rituximab (Rituxan) or idelalisib (Zydelig) in previously treated patients with CLL.
ELEVATE TN STUDY DETAILS
In the randomized, multicenter, open-label, phase III ELEVATE TN (ACE-CL-007) trial (NCT02475681), investigators evaluated the safety and efficacy of acalabrutinib alone or in combination with obinutuzumab versus obinutuzumab/chlorambucil in 535 treatment-naïve patients with CLL.
Patients were randomized 1:1:1 into 3 arms: obinutuzumab plus chlorambucil (n = 177); acalabrutinib 100 mg twice daily in combination with obinutuzumab until disease progression or unacceptable toxicity (n = 179); and single-agent acalabrutinib 100 mg twice daily until disease progression or unacceptable toxicity (n = 179). Patients were stratified by chromosome 17p deletion status, ECOG performance status of 0 to 1 versus 2, and geographic region.
Crossover from the obinutuzumab/chlorambucil arm to acalabrutinib monotherapy was permitted after independent review committee (IRC)–confirmed disease progression; therefore, these patients were not included in the PFS data presented at 2019 ASH. An interim analysis was planned after the occurrence of approximately 111 IRC-assessed PFS events in the combination arms, or after 24 months if the required number of events was not met by this time.
Baseline characteristics were similar across the 3 treatment arms. The median patient age was 70.5 years, 63% of patients had unmutated IGVH, 47% had Rai stage III or IV disease, 18% had 11q deletion, and 14% had 17p deletion or TP53 mutation. Most patients (93.6%) had an ECOG performance status of 0 to 1. High-risk features were evenly distributed.
The treatment discontinuation rates were 20.7%, 20.1%, and 18.1% in the acalabrutinib/obinutuzumab, acalabrutinib monotherapy, and obinutuzumab/chlorambucil arms, respectively. The most common reason for patients discontinuing treatment was adverse events (AEs), which led to treatment discontinuation in 11.2%, 8.9%, and 14.1% of patients, respectively.
Two deaths were reported on the acalabrutinib combination arm, 3 deaths on the single-agent acalabrutinib arm, and 1 death in the chemoimmunotherapy group. The median duration of treatment in both acalabrutinib-containing arms was 27.7 months versus 5.6 months in the obinutuzumab/chlorambucil arm, and 79.3% of patients in both acalabrutinib-containing arms were still on acalabrutinib monotherapy at the time of publication.
The primary end point was IRC-assessed PFS compared between the acalabrutinib/obinutuzumab and obinutuzumab/chlorambucil arms. Secondary end points included IRC-assessed PFS compared between the acalabrutinib-alone and obinutuzumab/chlorambucil arms, as well as IRC-assessed overall response rate (ORR), time to next treatment, overall survival (OS), and safety.
The PFS benefit with both acalabrutinib-containing regimens was found to be consistent across prespecified subgroups, irrespective of high-risk disease characteristics.
OS showed a trend toward favoring both the acalabrutinib/obinutuzumab arm (HR, 0.47; 95% CI, 0.21-1.06; P = .0577) and the single-agent acalabrutinib arm (HR, 0.60; 95% CI, 0.28-1.27; P = .1556) compared with obinutuzumab/chlorambucil; however, this benefit was not statistically significant. The estimated 2-year OS rates were 95%, 95%, and 92% with acalabrutinib/obinutuzumab, acalabrutinib alone, and chemoimmunotherapy, respectively.
Thirty-one percent of patients who were randomized to obinutuzumab/chlorambucil experienced disease progression, and 82% of this subgroup crossed over to receive the BTK inhibitor alone.
Additionally, the IRC-assessed ORR was significantly higher with acalabrutinib/obinutuzumab (93.9%; 95% CI, 89.3-96.5) compared with chemoimmunotherapy (78.5%; 95% CI, 71.6-89.9; P <.0001). The acalabrutinib combination ORR comprised a 13% complete response (CR) rate and an 81% partial response (PR) rate; 2% of patients achieved stable disease (SD).
In the single-agent acalabrutinib arm, the ORR was 85.5% (95% CI, 79.6-89.9) with a 1% CR rate, an 85% PR rate, and a 5% SD rate. There was no significant difference in ORR between the single-agent acalabrutinib and obinutuzumab/chlorambucil arms, according to Sharman. The obinutuzumab/chlorambucil arm exhibited a 5% CR rate, a 74% PR rate, and a 9% SD rate.
Sharman noted that because of the study design, in which continuous BTK inhibitor therapy was compared with fixed-duration chemoimmunotherapy, there was an imbalance in the reporting of AEs that occurred within 30 days of the last dose due to the longer reporting period in the BTK inhibitor arms.
Serious any-grade AEs were observed more frequently with acalabrutinib/obinutuzumab (38.8%) compared with acalabrutinib alone (31.8%) and obinutuzumab/chlorambucil (21.9%). The rates of grade ≥3 AEs were 70.2%, 49.7%, and 69.8%, respectively. Twelve grade 5 AEs were observed in the chemoimmunotherapy arm, 7 in the acalabrutinib monotherapy arm, and 5 in the acalabrutinib combination arm; these were pulled from the entire treatment-emergent and non–treatment-emergent period.
The most common (≥15%) any-grade AEs in the acalabrutinib/obinutuzumab and single-agent acalabrutinib arms were headache (39.9% vs 36.9%, respectively), diarrhea (38.8% vs 34.6%), neutropenia (31.5% vs 10.6%), fatigue (28.1% vs 18.4%), contusion (23.6% vs 15.1%), arthralgia (21.9% vs 15.6%), cough (21.9% vs 18.4%), upper respiratory tract infection (21.3% vs 18.4%), nausea (20.2% vs 22.3%), and dizziness (18.0% vs 11.7%). Grade ≥3 neutropenia was highest with obinutuzumab/chlorambucil (41.4%), followed by acalabrutinib/obinutuzumab (29.8%) and acalabrutinib alone (9.5%).
The most common (≥2%) serious AEs with acalabrutinib/obinutuzumab, acalabrutinib, and obinutuzumab/chlorambucil were pneumonia (6.7% vs 2.8% vs 1.8%, respectively), infusion-related reaction (2.2% vs 0% vs 1.2%), anemia (1.7% vs 2.2% vs 0%), febrile neutropenia (1.7% vs 1.1% vs 4.1%), and tumor lysis syndrome (0.6% vs 0% vs 4.7%). These events were consistent with those in the previously established safety profile of these of agents, Sharman said.
Specific AEs of clinical interest were reported for acalabrutinib. Any-grade atrial fibrillation was observed in 6 (3.4%) patients on acalabrutinib/obinutuzumab; 1 instance was grade ≥3. Seven cases of atrial fibrillation were observed on the single-agent acalabrutinib arm. Hypertension, bleeding, infections, and second primary malignancies, excluding nonmelanoma skin cancer, were other AEs of interest observed with the BTK inhibitor.
Sharman JP, Banerji V, Fogliatto LM, et al. ELEVATE TN: phase 3 study of acalabrutinib combined with obinutuzumab (O) or alone versus O plus chlorambucil (Clb) in patients (Pts) with treatment-naïve chronic lymphocytic leukemia (CLL). Presented at: 2019 American Society of Hematology Annual Meeting & Exposition; December 7-10, 2019; Orlando, FL. Abstract 31. ash.confex.com/ash/2019/webprogram/Paper128404.html.
Novel Antibody Elicits Complete Remissions in NHL After CAR Relapses
Anita T. Shaffer
Mosunetuzumab, a novel bispecific antibody, generated durable responses in patients with highly refractory non-Hodgkin lymphomas (NHLs), including complete remissions (CRs) in 22.2% of those who had previously received chimeric antigen receptor (CAR) T-cell therapy, according to study results presented at the 2019 ASH.1
The agent represents a promising therapy for patients whose disease has recurred after receiving CAR therapy or is progressing too rapidly to be treated with personalized gene therapy, said lead investigator Stephen J. Schuster, MD.
“Unlike CAR T-cell therapy, mosunetuzumab is an off-the-shelf immunotherapy product that can be given to patients without having to genetically modify their autologous T-cell immunotherapies. Although CAR agents represent a significant advance in treating refractory B-cell malignancies, Schuster said, two-thirds of patients with lymphomas do not respond. He also said the process of producing and obtaining insurance approval for CAR therapy delays treatment by several weeks. “A month or 2 months doesn’t sound long, but it’s an eternity when you have a patient with a very fast-paced disease,” he said. Stephen J. Schuster, MD T cells,” Schuster, director of the lymphoma program at Abramson Cancer Center at the University of Pennsylvania (UPenn) in Philadelphia, said in a statement.
The therapy exhibited a tolerable safety profile, with mostly low-grade occurrences of cytokine release syndrome (CRS) and neurological adverse events (AEs), said Schuster, who is also the Robert and Margarita Louis-Dreyfus Professor in Chronic Lymphocytic Leukemia and Lymphoma Clinical Care and Research at UPenn.
Mosunetuzumab is a humanized antibody that contains 2 antigen-recognition sites: CD3, a T-cell surface antigen and CD20, a tumor-associated antigen exclusively expressed on B cells.2 “In binding to the T cells, it’s capable of inducing T-cell activation and, when engaged with a B cell, it will cause a death of the target cell and eliminate those cells,” Schuster said at a press briefing.
The 2 FDA-approved CAR therapies, tisagenlecleucel (Kymriah) and axicabtagene ciloleucel (Yescarta), are CD19-directed genetically modified autologous T-cell immunotherapies. Although CAR agents represent a significant advance in treating refractory B-cell malignancies, Schuster said, two-thirds of patients with lymphomas do not respond.
He also said the process of producing and obtaining insurance approval for CAR therapy delays treatment by several weeks. “A month or 2 months doesn’t sound long, but it’s an eternity when you have a patient with a very fast-paced disease,” he said.
“To be able to use the cellular immunotherapeutic approach [with mosunetuzumab] rapidly in patients who need this approach because traditional immunochemotherapy is no longer working is, I think, a very important aspect,” Schuster added. “An off-the-shelf product that has alternative B-cell targets to CD19, which the approved CAR T-cell products address, is necessary.”
STUDY FINDINGS DETAILED
At the briefing, Schuster reported efficacy results for 191 evaluable patients treated with mosunetuzumab monotherapy during the ongoing phase I/Ib dose-escalation GO29781 study (NCT02500407) in late-line relapsed/refractory B-cell NHLs. The data are from group B of the study, in which patients received mosunetuzumab intravenously with stepped-up dosing on days 1, 8, and 15 of cycle 1, and then as a fixed dose on day 1 of each subsequent 21-day cycle (maximum 17 cycles).
In 67 participants with indolent NHL, the ORR was 62.7% (n = 42), including 43.3% (n = 29) with a CR, for dosing cohorts ranging from 2.8 mg to 13.5 mg. Twenty-four patients remain in CR up to 26 months after initial treatment.
Notably, patients who previously received CAR T-cell therapy were among those who responded to mosunetuzumab. Among 18 evaluable patients in this cohort, the ORR was 38.9% (n = 7), including a 22.2% CR rate (n = 4). Investigators also observed an expansion of lymphocytes, including residual CAR T cells in 2 of 8 patients and CRs with and without CAR T-cell expansions.
Schuster described a 58-year-old woman with relapsed/refractory follicular lymphoma (FL) who had received 8 prior lines of systemic treatment that included CD19-directed CAR T-cell therapy. The patient achieved a CR after 3 cycles of mosunetuzumab therapy and remains in CR after more than 8 months.
“This is not an ongoing therapy forever,” Schuster said. “This is a therapy that patients receive until they’re in remission and then it’s discontinued. Three-quarters of the remission patients are off therapy.”
In the population evaluable for safety, the study has enrolled 270 patients; the median age is 62.0 years (range, 19-96), and 61.2% had a baseline ECOG performance score of 1. The safety population comprises 66.7% with aggressive NHLs, including diffuse large B-cell lymphoma (DLBCL), transformed FL, mantle cell lymphoma, and 31.5% with FL and other indolent NHL types. The median number of prior system therapies was 3 (range, 1-14). In terms of prior therapies, 28.5% of patients had received autologous stem cell transplantation, and 71.9% were refractory to their last prior therapy.
Of 30 patients who had received prior CAR T-cell therapy, 22 (73.3%) were refractory to that treatment. This group had received a median 5 lines of prior systemic therapies (range, 3-14).
In the safety analysis, the incidence of all grades of CRS was 28.9% among all participants (N = 270) and 26.7% among those who previously received CAR therapy (n = 30). The majority of these events were of grade 1 or 2 severity, occurred mostly in cycle 1 of therapy, and had a median duration of 2 days (range, 1-59). There were 3 grade 3 CRS occurrences in the total population (1.1%) and 1 in the prior CAR cohort (3.3%). A total of 8 patients received tocilizumab (Actemra) as supportive care and most CRS events (96.6%) were resolved by the clinical cutoff date.
In all, neurological AEs were observed in 43.7% of patients in the total population and 43.3% in the CAR cohort. The most common neurological AEs included headache (15.6%), insomnia (9.3%), and dizziness (9.3%) and were of grades 1 and 2 severity. The incidence of grade 3 neurological AEs was 3.7% in the broad population and 10.0% in the CAR group.
APPROACH HOLDS MUCH PROMISE
In addition to the refractory setting, Schuster sees potential for mosunetuzumab to be used either before or after CAR T-cell therapy. He noted that 3 of 4 patients in the GO29781 study responded to retreatment with mosunetuzumab, including 1 person who remains in CR. “It suggests that over time, there was some diminution of the immune response and then the ability to restimulate it,” he said. “It’s not something that we’ve seen with CAR T cells.”
“[Overall], the safety with regard to cytokine release syndrome and neurological adverse events is almost identical whether the patients have had prior CAR T-cell therapy or not,” Schuster said. “What’s interesting is [that] these 2 adverse events are much more frequent during CAR T-cell therapy.”
Additionally, Schuster said, treatment with mosunetuzumab does not preclude subsequent CAR treatment. “This could be a bridging approach that doesn’t require chemotherapy, that actually stimulates and invigorates T cells, and [that] then [can] be used to make a CAR T-cell product,” he said. Mosunetuzumab, which is being developed by Genentech, also is being studied in combination therapies.
In addition to the monotherapy arm reported at the conference, the GO29781 trial will have an expansion phase in which patients receive mosunetuzumab in combination with the PD-L1 inhibitor atezolizumab (Tecentriq), according to the ClinicalTrials.gov website. The international trial aims to enroll 665 participants. In another phase I study, mosunetuzumab is being evaluated in combination with polatuzumab vedotin-piiq (Polivy), a CD79b-directed antibody-drug conjugate with and without bendamustine and rituximab (Rituxan) in patients with relapsed/ refractory DLBCL and FL (NCT03671018).
1. Schuster SJ, Bartlett NL, Assouline S, et al. Mosunetuzumab induces complete remissions in poor prognosis non-Hodgkin lymphoma patients, including those who are resistant to or relapsing after chimeric antigen receptor T-Cell (CAR-T) therapies, and is active in treatment through multiple lines. Presented at: American Society of Hematology Annual Meeting; December 7-10, 2019; Orlando, FL. Abstract 6.
ash.confex.com/ash/2019/webprogram/Paper123742.html. 2. Mosunetuzumab. NCI Drug Dictionary. cancer.gov/publications/dictionaries/cancer-drug/def/774847. Accessed December 7, 2019.
Korie Bigbee, NP
Nurse Practitioner at City of Hope
For the nursing providers, these findings validate the importance of knowing how to manage these patients with a broader scope. It’s imperative that inpatient nurses perfect our art of assessment so that we are able to recognize signs of toxicity, report them, and be familiar with what treatments will be prescribed. This especially is essential when the patient is on protocol, as avoiding deviations in the studies are paramount.
For outpatient nurses, being able to recognize long-term effects of treatment is impudent, understanding follow-up protocols, signs of concern when we are triaging their symptoms and learning how to focus on survivorship since these patients are living longer. We all must teach the patients and their family members what symptoms are critical and which ones can wait until the next clinical appointment. That being said, we cannot educate our patients and families if we ourselves are unaware. We must take the initiative to read our facilities standard operating procedures for these regimens, ask rounding physicians/mid-levels questions and/or read the study protocols. We may not be the principal investigator on these new emerging immunotherapies, but we are for sure on the frontline. If we aren’t armed with knowledge, we have defeated ourselves. .
R2 Regimen Maintains PFS Benefit in Older Patients With Indolent NHL
The combination of lenalidomide (Revlimid) and rituximab (Rituxan; R2) showed a 34% reduction in the risk of disease progression or death compared with rituximab plus placebo in patients ≥70 years old with indolent non-Hodgkin lymphoma (NHL), according to findings of a subgroup analysis of the phase III AUGMENT trial presented at 2019 ASH.1 Although the result was not found to be statistically significant, investigators said the regimen was beneficial for this population.
The progression-free survival (PFS) benefit was more pronounced in patients with follicular lymphoma (FL) who were ≥70 years old (HR, 0.49; 95% CI, 0.250.99; P = .043). Additionally, the regimen’s safety profiles were similar to that of the overall study population of patients with indolent NHL.
“These data show that R2 maintained efficacy improvements versus rituximab/placebo in patients aged ≥70 years, despite higher unfit status and lower overall lenalidomide treatment and exposure compared with the overall population,” lead study author Martin Trněny, MD, professor of medical oncology and director of the stem cell transplantation and lymphoma programs at General University Hospital, Charles University in Prague, Czech Republic, said in a presentation during the meeting. “R2 is an effective and available treatment option for patients with indolent NHL, including those with advanced age.”
In May 2019, the FDA approved the R2 regimen for use in patients with previously treated FL and marginal zone lymphoma (MZL). The decision was primarily based on results of the phase III AUGMENT study, in which the combination reduced the risk of disease progression or death by 54% versus rituximab alone in patients with relapsed/refractory (R/R) indolent NHL.2
“Because advanced age at diagnosis is a risk factor in patients with indolent non-Hodgkin lymphoma, we performed post hoc subgroup analyses by age from AUGMENT, and data here focused on patients aged more than 70 years,” Trněny said, explaining the rationale for the subgroup analyses. The double-blind trial included 358 patients with R/R FL or MZL in need of treatment. Across the study, 295 patients had FL and 63 had MZL. Participants had to have received ≥1 prior chemotherapy, immunotherapy, or chemoimmunotherapy regimen and could not be rituximab refractory.
Patients were randomized to rituximab at 375 mg/m2 on days 1, 8, 15, and 22 of cycle 1 and day 1 of cycles 2 through 5, plus either 20 mg of lenalidomide (n = 178) or placebo (n = 180) daily on days 1 through 21 every 28 days for up to 12 cycles.
In the intent-to-treat (ITT) population, patient characteristics at baseline were well balanced overall between the 2 arms. The median age was 63 years; over 70% of patients had advanced-stage disease at study entry. About 50% of patients had high tumor burden per the Groupe d’Etude des Lymphomes Folliculaires criteria. Around 83% of patients in each arm had FL, with the remaining 17% having MZL; 34.5% of patients had a Follicular Lymphoma International Prognostic Index (FLIPI) score ≥3.
The post hoc analysis stratified patients who were ≥70 years (n = 91) and received R2 (n = 47) or placebo (n = 44). Here, the median age was 75 years, and 55% of patients on R2 had an ECOG performance status of 1 to 2 versus 36% of patients who received rituximab plus placebo. Additionally, about half of patients in each arm had a FLIPI score ≥3 and about three-fourths had FL.
In the ITT population, 57% of patients on R2 had received 1 prior systemic regimen; 17%, 2; and 25%, ≥3. In the control arm, the corresponding rates were 54%, 23%, and 23%, respectively. Eighty-five percent of patients in the R2 arm and 83% in the placebo arm had prior rituximab. About 75% of patients in each arm had received a prior rituximab-containing chemotherapy regimen. Thirty-seven percent of patients in the R2 arm and 42% in the placebo arm had progressed within 2 years of their last regimen.
In the ≥70-years subgroup, 53% of patients on R2 received >1 prior systemic therapy compared with 39% of those who received rituximab; furthermore, 36% and 14% of patients, respectively, relapsed ≤2 years following their initial diagnosis. Trněny explained that these were notable differences between the 2 arms. However, 85.5% of patients received prior rituximab and 66% received a prior rituximab-containing regimen. Fifteen percent of patients on R2 were refractory to their last regimen versus 7% randomized to receive rituximab with placebo.
Although the median number of treat-ment cycles was 12 for both the ≥70-years subgroup and the overall population, fewer patients aged ≥70 years completed 12 cycles of lenalidomide at 57% versus 71% in the total population. Additionally, more of the older patients started lenalido-mide at the lower 10-mg dose (35%) versus 14% in the overall population because of low creatinine clearance. The average daily lenalidomide dose was 14.4 mg daily compared with 17.0 mg daily, respectively, and the median relative dose intensity was 86% versus 95% for the ≥70-year subgroup and total population, respectively.
Notably, 70% of patients in the ≥70-years group required dose interruptions due to treatment-emergent adverse events (TEAEs) compared with 20% of those on rituximab/placebo. In the overall population, the rates were 66% and 29%, respectively. Dose reductions due to TEAEs with R2 occurred in 35% of both the subgroup and the over-all population; 20% of patients ≥70 years discontinued R2 due to a TEAE compared with 9% of those in the total study group.
In the ITT population, the median PFS per independent central review (ICR) was 39.4 months (95% CI, 22.9–not evaluable [NE]) with R2 versus 14.1 months (95% CI, 11.4-16.7) with rituximab alone (HR, 0.46; 95% CI, 0.34-0.62; P <.0001), at a median follow-up of 28.3 months. By investigator assessment, the median PFS was 25.3 months (95% CI, 21.2-NE) versus 14.3 months (95% CI, 12.4-17.7), respectively (HR, 0.51; 95% CI, 0.38-0.69; P <.0001). .38-0.69; P <.0001).In all patients ≥70 years, the median PFS was 24.9 months (95% CI, 16.4–not reached [NR]) and 14.3 months (95% CI, 11.3-27.7) for R2 and rituximab/placebo, respectively (HR, 0.66; 95% CI, 0.37-1.18; P = .1576), which Trněny noted was not statistically significant.
FOLLICULAR LYMPHOMA FINDINGS
The PFS benefit by IRC was more pronounced for patients ≥70 years with FL (n = 66), with a median PFS of 28.0 months (95% CI, 16.4-NR) for R2 and 14.3 months (95% CI, 11.3-27.7) for rituximab/placebo (HR, 0.49; 95% CI, 0.25-0.99; P = .043).
“When we analyzed the FL subset, you can see a significant improvement in with regard to PFS in terms of a risk reduction in death or progression of 51%,” Trněny said.
ICR-assessed response rates for the ≥70-year subgroup were comparable with the total population. For patients ≥70 years, the ORRs were 81% and 59% for R2 and ritux-imab plus placebo, with complete response (CR) rates of 26% and 16%, respectively, and the rest made up of partial responses. In the overall group, the ORRs were 78% and 53% for R2 and rituximab/placebo; the CR rates were 34% and 18%, respectively.
The median OS was not reached in both arms for all patients ≥70 years (HR, 0.79; 95% CI, 0.21-2.93) and those in the FL subgroup ≥70 years (HR, 0.24; 95% CI, 0.03-2.18). Overall survival (OS) data across the entire population showed that at a median follow-up of 28.3 months, the HR for OS was 0.61 (95% CI, 0.33-1.13).
The time to next lymphoma treatment for all patients ≥70 years was also not reached in either arm and not statistically significant (HR, 1.02; 95% CI, 0.50-2.09; P = .9586). It was also not reached for the ≥70-years-old FL group (HR, 0.52; 95% CI, 0.20-1.31; P = .0156). In the entire study population, this was not reached with R2 and was 32.2 months with rituximab/placebo (HR, 0.54; 95% CI, 0.38-0.78).
Placebo (HR, 0.54; 95% CI, 0.38-0.78). Previously reported safety for the overall population showed that the most common all-grade adverse events (AEs) occurring in patients with MZL/FL were neutropenia (58%), diarrhea (31%), constipation (26%), cough (24%), fatigue and rash (22% each), pyrexia (21%), leukopenia and pruritus (20% each), upper respiratory tract infections and abdominal pain (18% each), anemia (16%), and headache and thrombocytopenia (15% each).
For patients ≥70 years, no significant differences in safety and serious AEs were reported compared with the ITT population. Most grade 3/4 TEAEs were hematologic, comprising neutropenia, leukopenia, and anemia. One patient on R2 ≥70 years old experienced febrile neutropenia, and 1 died on the rituximab/placebo arm due to pneumonia. Four secondary primary malignancies were observed in both arms, Trněny concluded.
1. Trněny M, Leonard JP, Zhang H, et al. Subgroup analyses of elderly patients aged ≥ 70 years in AUGMENT: a phase III random-ized study of lenalidomide plus rituximab (R2) vs rituximab plus placebo (R-placebo) in patients with relapsed/refractory (R/R) indolent non-Hodgkin lymphoma (iNHL). Presented at: 2019 Ameri-can Society of Hematology Annual Meeting & Exposition; December 7-10, 2019; Orlando, FL. Abstract 347. bit.ly/353kfmQ.
2. Leonard JP, Trněný M, Izutsu K, et al. AUGMENT: a phase III ran-domized study of lenalidomide plus rituximab (R2) vs rituximab/placebo in patients with relapsed/refractory Indolent non-Hod-gkin lymphoma. Blood. 2018;132(suppl 1):445. doi: 10.1182/