The combination of ibrutinib (Imbruvica) and venetoclax (Venclexta) produced rapid and deep responses in previously untreated patients with Waldenström macroglobulinemia but there was a higher-than-anticipated rate of ventricular arrhythmia that prompted stopping treatment, according to data from a prospective phase 2 trial (NCT04273139) presented during the 2022 ASH Annual Meeting.

In the overall patient population (n = 45), the regimen elicited an overall response rate (ORR) of 100%; this included a very good partial response (VGPR) rate of 40% (n = 18), a partial response (PR) rate of 53%, and a minor response rate of 7%. Notably, there would need to be 19 VGPRs for the study to meet its primary end point. The median time to response (TTR) was 1.9 months.

 mutations, the time to response was faster and the VGPR rate was higher than what has been observed with single-agent ibrutinib in the first-line setting, according to lead study author Jorge J. Castillo, MD, clinical director of Bing Center for Waldenström Macroglobulinemia at Dana-Farber Cancer Institute, Boston, MA. In those with 

 wild-type disease, the median TTR was 1.9 months (log-rank, 

Additionally, in the subset of patients with 

 wild-type disease, the doublet elicited an ORR of 100%, which included a VGPR of 50% (n = 14), a PR of 46%, and a minor response of 4%; in those with 

 mutations, the ORR was also 100%, and included a 24% VGPR (n = 4), a 65% PR, and a 12% minor response rate (

“BTK inhibitors are probably one of the most effective agents we have to treat patients with Waldenström,” Castillo said in a presentation of the data. “These therapies give us an indefinite duration of therapy. BCL-2 antagonists have been used in the relapse setting; they have provided a high degree of efficacy; however, the duration of therapy is a little unclear at this time.”

Castillo noted that past study findings have shown that combining the BTK inhibitor ibrutinib with the BCL-2 antagonist, venetoclax, has been shown to be safe and effective in patients with mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL). As a result, the investigators wanted to determine whether similar outcomes could be achieved in those with Waldenström macroglobulinemia.

To this end, the study authors conducted a single-arm, multicenter phase 2 prospective trial with the goal of identifying a treatment regimen that is free from chemotherapy and induces deeper responses. 

The phase 2 study enrolled 45 patients with a median age of 67 years (range, 39-81); 67% of patients were male. Participants were placed on a 24-cycle treatment regimen. Cycle 1 consisted of oral ibrutinib given at a daily (QD) dose of 420 mg. Ibrutinib was continued into cycle 2, with a ramp-up regimen of oral venetoclax, given at 100 mg, 200 mg, and 400 mg QD. In cycles 3 to 24, patients received 420 mg of ibrutinib and 400 mg of venetoclax QD.

At a median follow-up of 11 months, the estimated 12-month progression-free survival (PFS) was approximately 92%. The estimated overall survival rate was approximately 95%.

There were 7 adverse effects (AEs) of grade 4 or 5, with most AEs being grade 2 and 3. The most common grade 2 AEs were muscle/joint pain (n = 14) and reflux (n = 10). The most common grade 3 AE was neutropenia (n = 10).

Castillo noted that there was only 1 patient who experienced disease progression, and that person had achieved a VGPR after 7 cycles. Two deaths occurred due to ventricular arrythmia. As Castillo explained, patients enrolled on the trial experienced high-than-expected rates of ventricular arrythmia.

This finding prompted the investigators to conclude treatment earlier than they had intended.

Castillo noted that the investigators are continuing follow-up of the patients who have now been off therapy since March 2022, when another patient experienced a grade 2 cardiac-related event during a stress test.

However, Castillo said there is still value in continuing to study the combination.

“It could be that these patients really had a higher risk profile. Most of these patients were older individuals over 65 [years]; they were men, they had other cardiac risks, including hypertension, prior history of arrythmias, prior history of coronary artery disease. So maybe it has something to do with that,” Castillo explained. “There is always the idea in which ibrutinib and venetoclax can actually interact with each other and increase the serum levels, and that might induce these arrhythmias … But again, as of today, all that is just pure hypothesis. Now, I think what we see from these experiments, is that the combination is actually very powerful. So I think there is value on continuing [and] evaluating concurrent BTK and BCL2 inhibition.”

Castillo was asked to clarify the use of “very powerful,” as 1 of the moderators noted that there were no complete responses associated with treatment and a VGPR rate of approximately 40%, and why those findings seen in CLL trials perhaps did not translate to Waldenström macroglobulinemia. 

“That was something that we were hoping to see,” Castillo said. “But again, we [are] still unclear if complete responses should be the outcome that we should aim for in these patients. Now I want to remind everybody here that pretty much nobody completed their 24 months of therapy. We had about 40% of patients complete at least a year, [and] about 60% of patients did not complete a year of therapy. So these are the responses that I'm providing at this time, [which] is a median time of [venetoclax and ibrutinib] exposure for about 11 months. So there is always a possibility that we can get into deeper responses with longer treatments.”

Castillo JJ, Sarosiek S, Branagan R, et al. Ibrutinib and venetoclax in previously untreated Waldenström macroglobulinemia. 

. 2022;140(suppl 1):564-565. doi:10.1182/blood-2022-155610

Articles

The combination of ibrutinib and venetoclax produced rapid and deep responses in previously untreated patients with Waldenström macroglobulinemia but there was a higher-than-anticipated rate of ventricular arrhythmia that prompted stopping treatment.

Frontline Ibrutinib/Venetoclax Elicits Responses in Waldenström Macroglobulinemia, But Has Safety Concerns 

The GPRC5D- and CD3-directed bispecific antibody forimtamig led to high response rates in patients with relapsed or refractory multiple myeloma regardless of subcutaneous or intravenous (IV) administration, according to updated findings from a phase 1 dose-escalation study that were presented at 

2022 American Society of Hematology Annual Meeting

The agent, forimtamig, may also elicit long-term treatment responses lasting for at least a median of 10 months, according to the findings.

The trial comprised 108 patients who were administered study drug either intravenously (n = 51; median age, 62 years [range, 27-78]; 54.9% male) or subcutaneously (n = 57; median age, 63 years [range, 46-79]; 50.9% male).

To be enrolled, patients must have presented with relapsed/refractory multiple myeloma and underwent prior treatment with an immunomodulatory agent and a proteosome inhibitor. They also qualified for enrollment if there were no established therapies for their disease, or appropriate or tolerable treatments available.

However, patients were permitted to have previously been treated with CAR T-cell therapies, as well as antibody drug conjugates and bispecific antibodies.

Forimtamig, a GPRC5DxCD3 T-cell engaging bispecific antibody, was administered to patients on a once every 2 weeks schedule for 1 year. The primary end point was to determine the maximum tolerated dose, as well as the recommended phase 2 dose and safety. Additional end points included pharmacokinetics and pharmacodynamics, as well as the immunogenicity and efficacy of the drug.

The median time from initial myeloma diagnosis was 7 years (range, 1.8-24.7) for patients within the IV arm and 5.9 years (range, 0.7-19.0) for the subcutaneous arm. Those in the IV treatment cohort previously received a median of 5 treatments (range, 2-15) compared with a median of 4 in the subcutaneous group (range, 2-14).

More than half of each treatment arm experienced a grade 3/4 adverse effect (AE) following the use of study drug delivered intravenously (68.6%) or subcutaneous forimtamig (73.7%).

Patients in the IV cohort were more likely to experience a serious AE (68.8%) than those who received treatment subcutaneously (61.4%). The occurrence of cytokine release syndrome (CRS) was common in both treatment the IV (82.4%) and subcutaneous (78.9%) arms. However, almost all (97.8%) CRS events were resolved by data cut-off.

Both forms of forimtamig were effective. The overall response rate was 71.4% among those treated with IV forimtamig and 63.6% in those who received study drug subcutaneously.

Of note, the lead study author, Carmelo Carlo-Stella, MD, PhD, section chief of Lymphoid Malignancies and Cancer Therapeutics at Humanitas Clinical and Research Center—IRCCS in Italy, highlighted the duration of response in both arms.

In the IV arm, the median duration of response was 10.8 months (range, 0.0-17.6). As for the subcutaneous arm, patients derived a median duration of response of 12.5 months (range, 1.2-12.5).

As of Oct. 21, 2022, 23 of 35 patients in the IV arm continued demonstrating a treatment response. That response continued in 25 of 35 patients in the subcutaneous cohort.

Carlo-Stella concluded and explained that ongoing studies are evaluating ways to optimize both the subcutaneous and intravenous dosing of forimtamig.

Carlo-Stella C, Mazza R, Manier S, et al. RG6234, a GPRC5DxCD3 T-cell engaging bispecific antibody, is highly active in patients (pts) with relapsed/refractory multiple myeloma (RRMM): updated intravenous (IV) and first subcutaneous (SC) results from a phase 1 dose-escalation study. Presented at: 64th American Society of Hematology Annual Meeting and Exposition; December 10-13, 2022; New Orleans, Louisiana. Abstract 161.

The GPRC5D- and CD3-directed bispecific antibody forimtamig led to high response rates in patients with relapsed or refractory multiple myeloma regardless of subcutaneous or intravenous administration, according to updated findings from a phase 1 dose-escalation study.

Forimtamig Produces High ORR With IV and Subcutaneous Delivery in Relapsed/Refractory Multiple Myeloma 

Glofitamab administered as a fixed 12-cycle regimen 7 days after obinutuzumab (Gazya) pretreatment elicited high, early, and durable responses in patients with relapsed/refractory mantle cell lymphoma (MCL) who had undergone prior BTK inhibitor therapy, according to follow-up data presented by Tycel J. Phillips, MD, at the 2022 American Society of Hematology (ASH) Annual Meeting.

 The addition of obinutuzumab to this regimen also mitigated the incidence and severity grade of cytokines release syndrome (CRS) in this patient population.

The readout of these results follows the data published last year showing that the use of a step-up-dosing regimen of glofitamab after obinutuzumab treatment elicited high response rates in patients with MCL whose disease had stopped responding to BTKis.

“We see high overall response rates, irrespective of the obinutuzumab dose given as far as pretreatment,” said Phillips, an assistant professor within the Division of Hematology Oncology at University of Michigan Rogel Cancer Center in Ann Arbor, during the presentation.

The study population comprised 37 patients (median age, 72.0 years [range: 41–84]; 73.0% male) who received pretreatment with obinutuzumab at either a dosage of 1000 mg (n = 16) or 2000 mg (n = 21).

Patients enrolled in the study had received a median of 3 prior lines of therapy (range: 1–5). More than half of the study population (64.9%) had prior treatment with a BTKi, and 7 patients had previously received lenalidomide (Revlimid).

Most of the patients (62.2%) did not derive a response from their first treatment and/or their most recent treatment (73.0%). The median time since receipt of last treatment was 1.9 months (range: 0.1–107.5).

At a median follow-up of 8.0 months, the findings demonstrated that median time to first treatment response was 51 days (range: 29-234). Additionally, the overall response rate among the patient population at first assessment was 73%, with a complete response rate of 48.6%.

The responses, Phillips noted, were long-lasting in the patient population.

For instance, the median duration of complete response was 10.0 months (95% CI, 4.9–NE) and 20 of the 27 patients who achieved a complete response remained in remission at data cut-off.

“Of note, no progression of disease was reported after the end of treatment in patients [who achieved] response at [the] end [their] of treatment,” he said.

Most of the adverse events (AEs) of any grade (94.6%) were related to the use of glofitamab. Serious AEs were reported in 78.4% of the overall patient population, with 62.2% being attributed to glofitamab. There were 10 patient deaths on the trial; however none were attributed to either obinutuzumab or glofitamab, according to Phillips.

Three patient deaths were attributed to COVID-19 infection, 1 was cardiac-related and the remaining deaths were due to disease progression.

The most common AEs of any grade among the overall patient population included, but were not limited to, cytokine release syndrome (75.7%), neutropenia (45.9%), and anemia (32.4%).

Phillips noted that most of the cytokine release syndrome events were grade 1 or grade 2 (29.7% for each).

As for the other AEs of interest, 24 patients developed an any-grade infection or infestation. Neutropenia was also a commonly occurring AE, with 45.9% of patients reporting an occurrence of any grade.

“Glofitamab monotherapy with fixed treatment duration of 12 cycles, induced high CR rates in heavily pretreated patients with mantle cell lymphoma,” Phillips noted. “The CR rates were early and were durable; glofitamab was well tolerated and there was no treatment discontinuation due to adverse events. [CRS] events were manageable and predominantly low.”

Phillips concluded by noting that there are plans for a phase 3 study assessing glofitamab monotherapy in patients with relapsed/refractory mantle cell lymphoma. He noted that the trial will be a randomized study investigating glofitamab vs a standard-of-care choice treatment arm, but said he was unable to disclose the third treatment arm at this time.

Phillips TJ, Dickinson M, Morschhauser F, et al. Glofitamab monotherapy induces high complete response rates in patients with heavily pretreated relapsed or refractory mantle cell lymphoma. Presented at: 64th American Society of Hematology Annual Meeting and Exposition; December 10-13, 2022; New Orleans, Louisiana. Abstract 74.

Phillips TJ, Dickinson M, Morschhauser F, et al. Glofitamab step-up dosing induces high response rates in patients (pts) with relapsed or refractory (R/R) mantle cell lymphoma (MCL), most of whom had failed prior Bruton's tyrosine kinase inhibitor (BTKi) therapy. 

Glofitamab administered as a fixed 12-cycle regimen 7 days after obinutuzumab pretreatment elicited high, early, and durable responses in patients with relapsed/refractory mantle cell lymphoma who had undergone prior BTK inhibitor therapy.

Glofitamab/Obinutuzumab Regimen Produces Early, Durable Responses in Relapsed/Refractory Mantle Cell Lymphoma

, may be predictive of response to maintenance avelumab (Bavencio) in patients with advanced or metastatic urothelial carcinoma, according to findings from an analysis peripheral blood samples taken in the JAVELIN Bladder 100 trial (NCT02603432). 

, a transcription factor with known roles in B-cell maturation and participation in T-cell dependent humoral immunity, was strongly associated with the T-effector signature.

 is a gene we don’t know a huge amount about,” Thomas B. Powles, MBBS, MRCP, MD, director, Barts Cancer Centre at St. Bartholomew’s Hospital in London said during the presentation of the data at the 2022 ESMO Congress. “Nevertheless, it does seem to be important regulation of B cells and may or may not be involved in tertiary lymphoid structures [TLSs].”

expression in the tumor was linked to a survival benefit with maintenance avelumab. The benefit was highest in patients who had 

 and a tumor mutation burden (TMB) above the median threshold of 7.66 nonsynonymous SNVs per Mb (HR, 0.69; 95% CI, 0.51-0.93).

loop in the blood samples was also associated with a better survival benefit associated with maintenance avelumab (HR, 0.62; 95% CI, 0.36-1.08).

Of note, Powles highlighted that the absence of the 

loop may pinpoint a benefit in patients who have a low TMB.

“Remember, these low TMB patients aren't supposed to be responding to therapy,” he said. “But indeed, if you have 

 low, which is high gene expression, and low TMB, we can pick out a group of patients who are supposed to be the TMB low non-responders, and we can identify them as responders. And we can do this from blood tests, not from tissue, which I think is cool.”

The median survival probability for the 22 patients who received avelumab and did not have 

 but a low TMB was 36.99 months versus 13.6 months in the 18 patients who only received best supportive care.

TLSs, ectopic lymphoid tissue that arises in inflamed tissues including cancer, have been generating quite a bit of interest, according to Powles.

“They’re characterized by B-cell and T-cell zones and are attracting attention in urothelial cancer,” Powles said. “They’re essentially balls of active immune cells … And [the] characterization of these tertiary lymphoid structures is an area of interest.”

To determine whether blood-based biomarkers could potentially provide insight into which patient populations may best benefit from immune checkpoint inhibitors such as avelumab, the investigators used the EpiSwitch platform to analyze white blood cell chromatin loops associated with tumor immune activity.

This analysis was conducted using peripheral blood samples that were collected from 496 patients enrolled onto the trial after non-progression with first-line chemotherapy and before patients were randomized to either avelumab plus best supportive care or best supportive care only.

One of the main questions posed by the investigators, according to Powles, was what role does 

play in determining patient outcomes and they looked for the chromatin loop in the blood as well as the genetic expression of the tumor.

“We looked at whole blood, we looked at PBMCs and we looked at the structure of chromatin,” Powles explained. “Chromatin has a really important role in DNA packaging. And it also therefore has a really important role in transcriptome extender and gene expression. The chromatin allows loops, these loops are associated with activation of transcription. And these loops can result in dynamic changes, of course, to protein expression.”

Powles stressed that there are several limitations with the trial, including that the analysis was exploratory in nature. Additionally, the investigators still need to validate the findings to confirm its feasibility to be used in the clinic.

Nonetheless, Powles concluded the presentation explaining the significance of the findings of the exploratory analysis of the peripheral blood samples.

“I think it’s reasonable to say that we showed TLS appear relevant in terms of outcome in the JAVELIN 100 trial,” he stated. “And these TLSs, along with the immuno signature helped us identify from the circulating white cells, 

 as a key chromatin loop, and indeed gene expression, which may be relevant in predicting outcome for the future. … I think it's also reasonable to say that moving forward, the predisposition to form TLS in response to inflammatory stimuli may be a host factor influencing response to immune checkpoint inhibition, and therefore bringing the circulating and tumor-based biomarkers together is a really exciting area for the future.”

Powles T, Sridhar SS, Bellmunt J, et al. Genomic biomarkers in peripheral blood (PB) from patients (pts) enrolled in the JAVELIN Bladder 100 trial of avelumab first-line (1L) maintenance in advanced urothelial carcinoma (aUC). 

. 2022;33(suppl 7):LBA74. doi:10.1016/annonc/annonc1089

The absence of POU2F2, may be predictive of response to maintenance avelumab in patients with advanced or metastatic urothelial carcinoma, according to findings from an analysis peripheral blood samples taken in the JAVELIN Bladder 100 trial.

POU2F2 May Be Predictive of Survival Benefit With Maintenance Avelumab in Urothelial Carcinoma 

Deep and early responses were yielded with a single infusion of ciltacabtagene autoleucel (cilta-cel) in patients with previously treated, relapsed/refractory multiple myeloma, according to data from the phase 2 CARTITUDE-2 (NCT04133636) study presented virtually during the 

Treatment with a target dose of cilta-cel at 0.75 x 106/kg resulted in an overall response rate (ORR) of 95% (95% CI, 75-100) with a stringent complete response rate (sCR) of 75% (95% CI, 51-91), and a very good partial response rate or better of 85% (95% CI, 62-97).

After a median follow-up of 5.8 months, the median time to first response with cilta-cel was 1 month (range, 0.7–3.3) and the median time to best response was 1.9 months (0.9–5.1). As of the January 2021 data cutoff, a median duration of response had not yet been reached.

Cilta-cel, formerly JNJ-68284528, is a second-generation CAR T-cell therapy with 2 BCMA-targeting, single-domain antibodies designed to confer avidity. Previous data that were published from the phase 1b/2 CARTITUDE-1 trial demonstrated that single infusion of cilta-cel was associated with deep and durable response among heavily pretreated patients with relapsed/refractory disease.

The primary objective of this cohort of the phase 2 CARTITUDE-2 trial was to assess minimal residual disease (MRD) negativity at 10–5 threshold among patients who were refractory to lenalidomide or relapsed after one to three prior lines of therapy. Additional secondary outcomes included ORR, duration of response (DOR), time and duration of MRD negativity and incidence and severity of adverse events (AEs).

Patients received the targeted dose of cilta-cel 5 to 7 days after the beginning of lymphodepletion (daily cyclophosphamide at 300 mg/m2 and fludarabine at 30 mg/m2 for 3 days).

A total of 20 patients (median age, 60 years; 65% male) received the single-infusion CAR T-cell therapy. One of the patients was treated in an outpatient setting. Twelve of the patients had received fewer than 3 lines of therapy, and the remaining 8 received 3 prior lines of therapy.

All the patients had been previously treated with a proteasome inhibitor (PI), an immunomodulatory drug (IMiD) and dexamethasone. Almost all (95%) of the patients were exposed to alkylating agents and 65% received daratumumab (Darzalex).

All patients (n = 4) with MRD-evaluable samples were MRD negative at the January 2021 cutoff and more samples are being evaluated.

In terms of safety, hematologic AEs that occurred in 20% or more of the patients included neutropenia (95%), thrombocytopenia (80%), anemia (65%), lymphopenia (60%) and leukopenia (55%). Moreover, cytokine release syndrome occurred in 85% of patients, of which 10% were considered grade 3 or 4.

“The safety profile was manageable, including in the one patient that was treated in the outpatient setting,” said study author Mounzer E. Agha, MD, director, Mario Lemieux Center for Blood Cancers, clinical director of Hematopoietic Stem Cell Transplantation, UPMC Hillman Cancer Center, during a recorded presentation of the data. “There were no cases of movement and neurocognitive adverse events.”

Agha noted that one death occurred 100 days after the infusion of cilta-cel due to COVID-19 infection and was assessed as treatment-related by the investigators.

“Early and deep responses were observed with a single infusion of cilta-cel in lenalidomide refractory patients with multiple myeloma who received one-to three prior lines of therapy,” he concluded.

The CAR T-cell therapy is being evaluated in other cohorts of the CARTITUDE-2 in earlier line settings, as well as in the phase 3 CARTITUDE-4 study in patients with one to three prior lines of therapy.

Agha ME, Cohen AD, Madduri D, et al. CARTITUDE-2: Efficacy and safety of ciltacabtagene autoleucel (cilta-cel), a BCMA-directed CAR T-cell therapy, in patients with progressive multiple myeloma (MM) after one to three prior lines of therapy. 

Deep and early responses were yielded with a single infusion of ciltacabtagene autoleucel in patients with previously treated, relapsed/refractory multiple myeloma.



Ryan McDonald

Articles

Frontline Ibrutinib/Venetoclax Elicits Responses in Waldenström Macroglobulinemia, But Has Safety Concerns

Forimtamig Produces High ORR With IV and Subcutaneous Delivery in Relapsed/Refractory Multiple Myeloma

Glofitamab/Obinutuzumab Regimen Produces Early, Durable Responses in Relapsed/Refractory Mantle Cell Lymphoma

POU2F2 May Be Predictive of Survival Benefit With Maintenance Avelumab in Urothelial Carcinoma

Deep Responses Yielded by Cilta-Cel in Relapsed/Refractory Multiple Myeloma