Kyle Doherty

ADP-A2AFP specific peptide enhanced affinity receptor (SPEAR) T cells were associated with an acceptable safety profile and elicited antitumor activity in patients with advanced hepatocellular carcinoma (HCC), according to data from the third-dose cohort and expansion phase of a phase 1 trial (NCT03132792) that was presented during the 2021 International Liver Cancer Association Conference.

At the data cutoff date of April 15, 2021, 

rate in the 13-patient cohort was 64% and 

1 patient experienced a complete response 

(CR). A total of 6 patients experienced stable 

disease (SD), 4 had SD less than 16 weeks’ 

duration, and 2 had SD of at least 16 weeks’ 

duration. Four patients experienced progressive 

not evaluated because they had not had first 

that are engineered in vitro to express a 

T-cell receptor (TCR) that recognizes with 

high-affinity peptides from [α-fetoprotein],” 

explained lead study author Bruno Sangro, 

MD, PhD, director of the Liver Unit and co-director 

Universidad de Navarra in Pamplona, Spain.

“Based on this principle, this phase 1, first-in-

HCC is testing if patients are compatible for 

the treatment, based on HLA compatibility 

and α-fetoprotein expression. If they are 

eligible, patients are provided an infusion 

of SPEAR T cells after a lymphodepleting 

regimen, with safety and efficacy monitoring 

access to a broader spectrum of intracellular 

and extracellular proteins, giving them the 

-7 to -5/-4 of the trial, patients were given 

a SPEAR T-cell infusion on day 1, followed 

by hospitalization until day 7. Post-infusion 

cytokine monitoring, and T-cell persistence. 

Patients stayed on the trial until disease progression, 

Key eligibility criteria included histologically 

confirmed HCC not amenable to locoregional 

score of 0 to 1. Eligible patients were those 

with progressive disease on, intolerance 

to, or refusing standard systemic therapy. 

Patients also needed to have a Child-Pugh 

score of 6 or less without ascites or encephalopathy 

of tumor α-fetoprotein expression, defined 

by tumor immunohistochemistry analysis or 

serum α-fetoprotein greater than 100 ng/mL.

median transduced cell dose was 5.11 x 10

in 10 patients. Both dose levels were given a 

In the overall cohort, the median age of the 

population was 60 (range, 32-75) and 77% were 

males. Patients had a median of 2 (range, 1-4) 

prior lines of systemic therapy and 4 patients 

had undergone prior liver cancer surgery. Common 

prior liver diseases included cirrhosis (n 

= 6), hepatitis B (n = 3), and hepatitis C (n = 

5). The majority of patients (n = 8) were Barcelona- 

Clinic Liver Cancer stage C at screening.

any grade were neutropenia (54%), leukopenia, 

AEs of at least grade 3 included neutropenia 

(46%), leukopenia (38%), lymphopenia (31%), 

Serious AEs occurred in 4 patients, 2 of 

which were related to T-cell infusion. Febrile 

neutropenia, infusion-related reaction, cytokine 

duct obstruction were observed in 1 patient 

each. There were no grade 4/5 serious AEs.

Most of the AEs were consistent with cytotoxic 

and/or cell therapy. Hepatobiliary AEs were 

most consistent with HCC or underlying disease 

T-cell doses were associated with a decrease 

in serum α-fetoprotein levels. They also noted 

that clinical benefit is associated with sustained 

reduction in serum α-fetoprotein levels.

and dose. Patients receiving the highest 

doses also had the most obvious persistence. 

available post-infusion tumor biopsies and 

was found to be higher in patients with SD.

“SPEAR T cells up to doses of 10 billion 

transduced cells have been associated with 

an acceptable safety profile,” concluded Sangro. 

normalization in serum α-fetoprotein, indicating 

cell therapy can be active in the setting of 

persisted in the periphery in a dose-dependent 

manner and were detected in post-infusion 

Sangro B, Meyer T, Mahipal A, et al. Data from the third dose cohort 

and expansion phase of a phase 1 trial of ADP-A2AFP SPEAR 

T-cells for patients with hepatocellular carcinoma and other cancer 

types expressing alpha-fetoprotein. Presented at: 2021 International 

Liver Cancer Association Conference. September 2-5, 2021. virtual. 

Articles

Phase 1 data indicate that ADP-A2AFP SPEAR T cells are effective and tolerable in patients with advanced hepatocellular carcinoma. 

ADP-A2AFP SPEAR T Cells Demonstrate Efficacy, Tolerability in Advanced HCC

An analysis of the phase 2 NEAR trial (NCT03124433) presented at the 2021 Annual European Association of Urology Congress confirmed that androgen receptor inhibition did not complicate robotic prostatectomy surgical outcomes in patients with prostate cancer.

“Neoadjuvant androgen deprivation therapy has been previously reported to complicate prostatectomy; [however, data on the effect of] neoadjuvant apalutamide prior to robotic prostatectomy has not been described,” Xinyan Yang, MBBS, said in a presentation of the data. “We did not encounter any difficulty because of the neoadjuvant therapy; there was no excessive blood loss and there were desmoplastic changes in the tissue that made the surgery more difficult than usual.” Yang is a medical officer and resident at Singapore General Hospital.

The NEAR trial enrolled 25 patients with biopsy-proven, organ-confined prostate cancer. Patients with intermediate-risk to high-risk disease, as defined per D’Amico criteria, were recruited. Neoadjuvant apalutamide (Erleada) was administered at a dose of 240 mg daily for 12 weeks, after which all patients underwent robotic radical prostatectomy with pelvic lymph node dissection. Yang noted in a discussion that investigators did not perform the surgical technique differently than their routine procedure for this patient population and began with a bilateral seminal vesicle dissection.

Neoadjuvant apalutamide resulted in a statistically significant reduction in serum prostate-specific antigen (PSA) levels over a 12-week duration of treatment (

 < .0001). After prostatectomy, there was a further reduction in PSA levels that was also deemed significant (

 = .001). Moreover, mean quality-of-life scores based on the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Version 3.0 were not significantly reduced (

After prostatectomy, 40% of patients had grade 3 or higher disease per the International Society of Urological Pathology (ISUP) guidelines and all patients had at least stage pT2c disease. The mean nodal yield was 24 (range, 4-49) and 73% of patients had negative margin status. Positive surgical margins were found in 3 patients (27%).

Regarding node status, 70% (n = 21) of patients were N0 and 4 patients were N1. In terms of PSA response after surgery, 84% were at nadir level (0.5 ng/mL) and 16% were above nadir level.

Data from the NEAR trial were compared with outcomes from prospective analysis of a multiracial Asian population of patients from a single institution who underwent prostatectomy without neoadjuvant apalutamide (n = 725). In terms of perioperative outcomes—estimated blood loss (EBL), length of stay (LOS), catheter time, and complication rates—findings showed that prostatectomy with neoadjuvant apalutamide produced similar outcomes.

The mean EBL was 198 mL (range, 50-400) in the neoadjuvant apalutamide study, compared with 215 mL (range, 10-2000) in the study of patients without neoadjuvant apalutamide. The mean length of stay in both groups was 3 days.

The mean catheter time was 8 days (range, 3-14) for patients who received neoadjuvant apalutamide vs 7 days (range, 3-72) in those who did not. By Clavien-Dindo classification, in patients who received neoadjuvant apalutamide, 80% had postoperative events classification of 0 compared with 78.5% of patients not treated with neoadjuvant apalutamide. Similarly, 20% of patients in the neoadjuvant apalutamide group reported a score of 1 or 2 vs 17.6% in the group that did not receive adjuvant therapy. Finally, 0 patients who received neoadjuvant apalutamide had a Clavien-Dindo classification of 3, 4, or 5, compared with 3.8% in those who underwent surgery alone (

Yang presented a case study of a 71-yearold Chinese man with no past medical history. The subject had D’Amico high-risk disease with a preoperative serum PSA of 43 μg/L. The patient also had a Gleason score of 4+4 via biopsy (ISUP grade 4) with clinical T3b bilateral disease.

The subject’s multiparametric MRI showed significant disease involving both prostatic lobes, with possible right extracapsular extension and involvement of the root of the right seminal vesicle and neurovascular bundle. Surgery began with a posterior dissection, delivering both seminal vesicles and the left vas deferens. The rectoprostatic fascia was incised and the rectum was dissected free. The surgical planes of dissection were preserved despite 12 weeks of neoadjuvant apalutamide, with no increase in tissue desmoplastic reaction.

Pedicle ligation was performed using Hem-o-lok clips. Yang said that to improve postoperative continence rates, an apical dissection— which preserves adequate urethral length—was performed.

Further, nodal dissection was performed routinely and bladder neck reconstruction was conducted using a posterior racket in handle fashion. The vesicourethral anastomosis suture method, a running belt hub and suture to ensure watertight apposition, was also used during reconstruction.

Upon histological examination of the specimen, ypT3bN1 and ISUP grade 4 disease were present, Yang reported. Of the 47 lymph nodes, 2 were positive for adenocarcinoma. The postoperative PSA level at 4 weeks was under 0.03 μg/L. “Perioperative outcomes are comparable to a historical series without neoadjuvant therapy,” Yang concluded, noting that “neoadjuvant apalutamide is well tolerated but associated with a reduction in libido.”

1. Yang XY, Tiwari R, Aslim EJ, et al. Intense androgen receptor inhibition with neoadjuvant apalutamide does not complicate robotic prostatectomy outcomes. Presented at: 36th Annual European Association of Urology Congress; July 8-12, 2021; virtual. Abstract V41. Accessed July 12, 2021. https://virtual.uroweb.org/resource-centre/ EAU21/222528/Abstract/

2. Alvin LWX, Gee SH, Hong HH, et al. Oncological outcomes following robotic-assisted radical prostatectomy in a multiracial Asian population. 

. 2015;9(3):201-209. doi:10.1007/s11701-015- 0516-1

A study has confirmed that androgen receptor inhibition did not complicate robotic prostatectomy surgical outcomes in patients with prostate cancer.

Neoadjuvant Apalutamide Does Not Affect Robotic Prostatectomy Efficacy

In patients with metastatic or locally advanced urothelial carcinoma (mUC) harboring 

 alterations, erdafitinib (Balversa) in combination with cetrelimab (JNJ-63723283) displayed clinically meaningful responses, according to the first results from the phase 2 NORSE trial (NCT03473743) presented by Thomas Powles, MD, during the European Society for Medical Oncology 2021 Virtual Congress.

Erdafitinib plus cetrelimab elicited an overall response rate (ORR) of 68% (95% CI, 43%-87%) in 19 efficacy-evaluable patients, compared with 33% (95% CI, 13%-59%) in 18 patients treated with erdafitinib with pharmacodynamically guided uptitration (UpT). Confirmed complete responses were seen in 4 patients and 1 patient, respectively. The median duration of response (DOR) was 6.9 months (95% CI, 1.6-not evaluable [NE]) in patients treated with erdafitinib plus cetrelimab vs NE (4.4-NE) in the erdafitinib monotherapy group.1

Erdafitinib is an oral pan-FGFR inhibitor and cetrelimab is an immunoglobulin G4 monoclonal antibody specific for PD-1.2

“The standard of care for newly diagnosed mUC is cisplatin-based chemotherapy, however over 50% of patients with mUC are ineligible for cisplatin treatment,” said Powles, director, lead for Solid Tumor Research, and a professor of genitourinary oncology at the Barts Cancer Center in London, England. “Treatment options for patients with newly diagnosed mUC include alterative chemotherapy regimens or anti-PD-(L)1 monotherapy for patients with PD­–L1-postive tumors. There is a significant unmet need for new treatments for patients with mUC who are ineligible for cisplatin.”

Results from the phase 1b portion of the trial established the recommended phase 2 dose (RP2D) as erdafitinib 8-mg UpT plus 240-mg cetrelimab. At the April 2020 data cutoff, the confirmed ORR in 11 evaluable patients treated at the RP2D was 55% and the disease control rate (DCR) was 100%. In the overall patient population (N = 22), treatment-emergent adverse events (TEAEs) occurred in 91% of patients and 32% of patients experienced serious TEAEs.2

The phase 2 portion of the NORSE trial enrolled a total of 53 patients and randomized them 1:1 to receive either erdafitinib monotherapy (n = 26) or erdafitinib plus cetrelimab (n = 27). The safety analysis set consisted of 24 patients in each arm and the efficacy-evaluable set was made up of 18 and 19 patients in the monotherapy and combination arms, respectively.

In the monotherapy arm, erdafitinib was administered at a dose of 8 mg with pharmacodynamically UpT up to 9 mg. In the combination group, once-daily erdafitinib was given at a dose of 8 mg in plus 240 mg cetrelimab intravenously every 2-weeks for cycles 1 to 4 and 480 mg every 4 weeks thereafter.

To be eligible for the ongoing trial, patients needed to be at least 18 years old with a confirmed diagnosis of mUC and measurable disease. Patients also needed to have a select 

 alteration (mutation or fusion), no prior systemic therapy for mUC, and be ineligible for cisplatin.

The primary end points of the trial are ORR and safety. Key secondary end points include DCR, DOR, and time to response. No formal statistical comparisons between arms were prespecified.

The median age of patients treated with erdafitinib alone was 75 (range, 45-92) and 73% of patients were males. In terms of ECOG performance status, most patients registered a 0 or 1 (77%) and 23% scored a 2. Most patients in this arm had an unknown PD-L1 status (54%) and a lower tract primary tumor location (76%). 

 mutations (88%) were the dominant alteration and no patients had both mutations and fusions.1

In the combination group, the median age was 69 (range, 56-91) and 74% of patients were male. Again, ECOG performance status was mostly 0 to 1 (63%) and lower tract was the primary tumor location in 85% of patients. 

 alterations were more evenly distributed in this arm: 67% of patients had mutations, 26% had fusions, and 1 patient had both.1

Both trial arms had impressive DCRs, patients treated with erdafitinib monotherapy experienced a 100% DCR (95% CI, 82%-100%) and the combination arm achieved a DCR of 90% (95% CI, 67%-99%). The median time to response was 2.3 months (range, 1-6) and 1.8 months (range, 1-4), respectively. Responses are ongoing in 28% of the monotherapy cohort and in 53% of the combination cohort.1

Patients in both treatment arms experienced durable reductions in the sum of target lesion diameters over time. The median of the maximum reduction in the sum of target lesion diameters was 28% in the erdafitinib group and 51% in the erdafitinib plus cetrelimab cohort.1

In general, the safety profile of erdafitinib plus cetrelimab was similar to that of erdafitinib alone. TEAEs of any grade occurred in 96% of the safety populations of both arms. Grade 3/4 TEAEs occurred in 38% of the monotherapy arm and in 50% of the combination arm. There was also 1 death due to respiratory failure in the erdafitinib plus cetrelimab cohort that was determined to be related to cetrelimab.1

The most frequent TEAEs of any grade in the monotherapy arm were stomatitis (63%), hyperphosphatemia (58%), diarrhea (50%), and anemia (25%). In the combination arm, hyperphosphatemia and dry mouth were most common (both 58%), followed by stomatitis (54%) and diarrhea (42%).1

The incidence of TEAEs of interest was mostly similar between arms, with the exception of immune-related TEAEs. Immune-related TEAEs of any grade occurred at a rate of 50% in the combination arm compared with 4% in the monotherapy group. Common immune-related TEAEs in the erdafitinib plus cetrelimab group consisted of diarrhea and increased lipase (13% each) and stomatitis and anemia (8% each).1

“These are the first data on erdafitinib plus cetrelimab in patients with mUC with 

 alterations who are ineligible for cisplatin-based therapy,” concluded Powles. “Preliminary findings suggest that adding cetrelimab to erdafitinib may improve ORR and depth of response in this population. These data suggest a potential positive interaction between erdafitinib and cetrelimab, possibly mediated by priming the immune environment via neoantigen release in patients with 

 alterations to increase the response to immune checkpoint blockade.”

Powles TB, Chistyakov V, Beliakouski V, et al. Erdafitinib (ERDA) or ERDA plus cetrelimab (CET) for patients with metastatic or locally advanced urothelial carcinoma (mUC) and fibroblast growth factor receptor alterations (FGFRa): first phase (Ph) 2 results from the NORSE study. Presented at: European Society for Medical Oncologists 2021 Virtual Congress. September 16-21, 2021. Virtual. Abstract LBA27.

Siefker-Radtke AO, Loriot Y, Siena S, et al. 752P Updated data from the NORSE trial of erdafitinib (ERDA) plus cetrelimab (CET) in patients (pts) with metastatic or locally advanced urothelial carcinoma (mUC) and specific fibroblast growth factor receptor (FGFR) alterations. 

. 2020;31(suppl 4):S584-S585. doi:10.1016/j.annonc.2020.08.824

In patients with metastatic or locally advanced urothelial carcinoma harboring FGFR alterations, erdafitinib (Balversa) in combination with cetrelimab displayed clinically meaningful responses. 

Encouraging Efficacy Seen With Erdafitinib plus Cetrelimab in mUC

Administration of direct intramural injection and intravesical instillations of large surface area microparticle docetaxel (LSAM-DTX; NanoDoce) to patients with high-risk non-muscle invasive bladder cancer (NMIBC) was found to be safe with preliminary efficacy signals, according to phase 1/2 study findings presented by Max Kates, MD, during the American Urological Association 2021 Annual Meeting.

Among the 19 patients who received LSAM-DTX at any dose level, the 3-month complete response (CR) rate was 68%. The 6-month durability in 13 evaluable patients who had a CR at 3 months was 62% and the 12-month durability in this group was 31%.

“LSAM-DTXs are large surface area microparticles of pure drug in powder form,” explained Kates, the director of the Bladder Cancer Program and an assistant professor of urology at the Johns Hopkins University School of Medicine in Baltimore, Maryland. “The microparticles are formed using supercritical precipitation technology, then suspended in saline prior to use. The uniqueness of this technology relative to other particle engineering technologies is that it maintains a relatively large particle size of about 3.5 microns. [This size] enhances tumor infiltration and entrapment while at the same time also substantially increasing surface area, allowing for continuous drug release for more than 4 weeks after intratumoral delivery.

“Meanwhile, clearance of drug from the site of administration was shown in preclinical studies to be gradual at subtoxic levels.”

Kates added that, in the dose-escalation group, 54% experienced no recurrence after 3-months and 2 patients had a CR after 6-months. The maximum dose of approximately 15 mg LSAM-DTX via intratumoral injection and approximately 75 mg via intravesical therapy was given to a 6-patient dose-confirmation cohort. All patients in this cohort achieved a CR at 6-months and 4 patients showed durability at 12 months. One patient in this group was lost to follow-up and was not a confirmed failure.

Kates and colleagues evaluated LSAM-DTX in 19 patients with high-risk NMIBC. LSAM-DTX in saline suspension was administered via direct intratumoral injection into resection bed post transurethral resection of a bladder tumor (TURBT) and multiple intravesical instillations. The safety of LSAM-DTX was the primary end point. Preliminary efficacy and immune effects were secondary end points.

Patients included in the trial (NCT0363625) were adults with pathologically- or cytologically-confirmed high-risk NMIBC and urothelial carcinoma. Patients needed to have a life expectancy of at least 6 months and an ECOG performance status of 0-2 at study entry. Eligible patients also needed to have adequate marrow, liver, and renal function and have all visible tumors removed during TURBT.

Ineligible patients included those with metastatic disease and a previous (within 12 months) or concurrent history of a non-bladder malignancy, except for non-melanoma skin cancer. Those undergoing intravesical therapy within 4 weeks prior to consent or with upper tract and urethral disease within 18 months were excluded. Patients with known hypersensitivity to any of the study drug or reconstitution components or those had participated in the treatment phase of another clinical trial within 3 months were also not allowed into the trial.

The median age of the population was 72 (range, 56-82) and consisted mostly of men (n = 14). Most patients were white (n = 18), and 12 reported prior treatment with Bacillus Calmette-Guerin immunotherapy. In terms of staging, most patients had carcinoma in situ (CIS; n = 8). Seven, 3, and 1 patients had Ta, T1, and T1 with CIS disease, respectively.

The trial utilized a 3 + 3 dose-escalating design in 13-patients where 4 concentrations of LSAM-DTX (3 mg to 15 mg) were administered via direct intratumoral injection cytoscopically into and around the resection bed after TURBT. This was followed by an intravesical instillation of LSAM-DTX at 50-75 mg in 25 mL of suspension. One month later, responders received a 6-week induction course and a 3-week maintenance course, for a total of 9 intravesical instillations.

Both LSAM-DTX injections and instillations were well-tolerated, with no attributable local or systemic SAEs, except for a kidney stone in 1 patient. There were 203 treatment-emergent adverse events observed overall. Kates called pharmacokinetic results for systemic LSAM-DT absorption “unremarkable.”

Investigators obtained tissue suitable for immune cell analysis from 5 patients before treatment with LSAM-DTX and at the end of treatment. Samples were analyzed using multiplex immunofluorescence to evaluate potential immune effects from the treatment. Investigators observed increased density of immune effector cells in the tumor microenvironment (TME) compared with pretreatment levels.

“This is really fascinating because it speaks to the hypothesis that direct injection of a cytotoxic chemotherapy into the resection bed, followed by therapeutic instillations leads to a recruitment of immune effector cells to the TME,” remarked Kates.

All 5 of the samples showed an increased density of T cells pre to post LSAM-DTX treatment and all patients also displayed increased density of macrophages, including PD-L1+. Most of the patients (n=3) also had an increase in natural killer (NK) cell density. Variable changes in the density of myeloid and myeloid-derived suppressor cells were reported.

“The increase in PD-L1 expression, increase in NK cells, and decrease in suppressor cells are all very interesting, and may warrant further clinical research in combination with immune checkpoint inhibitors or other immunotherapies aimed at increasing tumor response,” concluded Kates. “Clearly, we have learned that by enhancing chemotherapeutic delivery and efficacy, we also may be getting an enhanced antitumor immune effect. This interplay will need to be studied and expanded on further.”

Kates M, Mansour A, Lamm D, et al. Initial Results from a phase 1/2 trial of large surface area microparticle docetaxel for high-risk non-muscle invasive bladder cancer.Paper presented at the 2021 American Urological Association Annual Meeting; September 10-13, 2021; virtual. Abstract LBA02-02.

Administration of direct intramural injection and intravesical instillations of large surface area microparticle docetaxel may be safe and effective in high-risk non-muscle invasive bladder cancer using a particular technique.

Direct and Multifaceted LSAM-DTX Treatment May Be Safe and Effective in NMIBC

In patients with locally advanced high-risk prostate cancer treatment with neoadjuvant lutetium prostate-specific membrane antigen (PSMA) followed by radical prostatectomy was shown to be safe, according to results from a clinical trial (NCT04297410) presented by Michael Frumer, MD, during the American Urological Association 2021 Annual Meeting.

The prospective, open-label, single-arm trial showed that all 11 patients treated with lutetium who underwent a radical prostatectomy had a biochemical response. Positive surgical margins were reported in 27% (3/11) of patients. At 3-months after surgery, all patients had achieved continence recovery.

“High-risk localized prostate cancer remains a therapeutic challenge,” said Frumer, a physician in the department of urology at Rabin Medical center inPetah Tikva, Israel. “The introduction of theranostics [has brought about] new treatment opportunities. Treatment with lutetium-PSMA is based on the ability of PSMA ligand that is labeled with the radioisotope 177-lutetium to bind specifically to PSMA-expressing prostate cancer cells to cause cellular damage. Recently, the efficacy of lutetium PSMA has been demonstrated in castrate-resistant metastatic prostate cancer.”

The study enrolled a total of 12 patients with high-risk, locally advanced prostate cancer, 7 who had Gleason Grade Group (GGG) 4 disease and 5 with GGG 5 disease. Investigators administered two 7.4 GBq lutetium treatments, one at 8 weeks prior to radical prostatectomy followed by pelvic node dissection and one at 6 weeks prior. The goal of the trial was to evaluate for the first time the safety and immediate oncological outcomes of lutetium PSMA followed by radical prostatectomy.

The median age of the population was 66 (range, 60-68). The median baseline PSA was 11.4 ng/dL. Of the 12 patients who received lutetium-PSMA treatment, 11 underwent surgery.

Periprostatic adhesions were encountered during surgery without any intraoperative complications in 2 patients. The median surgical length was 220 minutes (range, 165-250), and the median estimated blood loss was 300 mL (IQR 200, 400). Median PSA levels decreased by 28% during treatment and the median hospital stay was 4 days (range, 3-4).

Regarding safety, the only adverse event (AE) reported during the treatment was fatigue occurring in 2 patients. Investigators did not record any incidence of dry mouth or blood count changes. A single patient experienced fever postoperatively. Treatment-related histological changes were noted in 4 of the 6 final surgical specimens. No blood count changes, or dry mouth were reported during treatment with lutetium-PSMA.

Postoperatively, pneumonia was reported in 1 patient. Another patient experienced a postoperative urine leak with conservative management.

“Neoadjuvant lutetium-PSMA followed by radical prostatectomy appears to be safe in patients with locally advanced high-risk prostate cancer,” concluded Frumer. “While longer oncological outcomes are pending, continence recovery seems to be unaffected by lutetium treatment.”

Frumer M, Rosenbaum E, Kedar D, et al. MP15-20: Neo-adjuvant 177Lu-PSMA-I&T radionuclide in high-risk prostate cancer before radical prostatectomy: a feasibility trial. Poster presented at: the American Urological Association 2021 Annual Meeting, virtual. September 10-13, 2021. Abstract MP15-20.

Prospective clinical trial results of lutetium-PSMA suggest the therapy is safe for patients with locally advanced high-risk prostate cancer.

Lutetium-PSMA Displays a Favorable Safety Profile in Locally Advanced High-Risk Prostate Cancer 

A phase 3 trial (NCT04824092) has been initiated to explore the potential of a triplet regimen of tafasitamab-cxix (Monjuvi), lenalidomide (Revlimid), and R-CHOP (rituximab [Rituxan], cyclophosphamide, doxorubicin, vincristine, and prednisone) as a treatment options for patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL). 

According to an abstract presented by Umberto Vitolo, MD, the director of the Hematology 2 section at University-Hospital in Turin, Italy, presented during the European Hematology Association 2021 Virtual Congress, the triplet may have synergistic potential.

The Front-MIND study will evaluate the safety and efficacy of the Fc-modified, humanized CD19-targeting monoclonal antibody in combination with lenalidomide and R-CHOP versus tafasitamab plus R-CHOP in patients with previously untreated high-intermediate and high-risk DLBCL. The study will enroll an estimated 880 patients from 350 locations in America, Europe, and Asia.

“Preliminary data from the First-MIND study suggest that tafasitamab plus or minus lenalidomide and R-CHOP is tolerable in patients with treatment‑naïve DLBCL,” study authors wrote in the abstract presented during the meeting. “The phase 3 Front-MIND study will provide further evaluation of clinical benefits and safety in a high-intermediate and high-risk population of patients with newly diagnosed DLBCL.”

To be eligible for the trial, patients must be aged at least 18 to 80 years with previously untreated, local biopsy-proven, CD20-positive DLBCL. Patients must have an international prognostic index (IPI) score of at least 3 if they are aged 60 years or older and an IPI score of 2 to 3 if they are aged 60 years or younger. Patients must also have an ECOG performance score of 0 to 2. Patients with transformed lymphoma will be excluded from the trial.

Patients will be randomized 1:1 based on stratification factors, which include IPI score, disease risk, and geographic region. The experimental arm will be made up of 6 cycles that are 21 days each. Tafasitamab will be administered intravenously at a dose of 12 mg/kg on days 1, 8, and 15. Lenalidomide will given orally on days 1 to 10 at a dose of 25 mg, with R-CHOP given throughout.

The control arm will receive tafasitamab placebo intravenously on days 1, 8, and 15 over the course of six 21-day cycles. Lenalidomide placebo will be given on days 1 to 10. The control group will also be given R-CHOP.

The primary end point of the trial is investigator-assessed progression-free survival. Secondary end points will include investigator-assessed event-free survival and overall survival. Preplanned central nervous system prophylaxis with intravenous high-dose methotrexate will be allowed after response assessment at the conclusion of treatment. Patients have follow-up from their end of treatment visit until the end of the study. Clinical evaluation will occur every 3-6 months, with imaging every 3-12 months, up to 60 months.

In addition, a large set of translational studies are planned, which aim to analyze the relationship between potential biomarkers and efficacy. The approximate duration of the Front-MIND study from the patient’s first visit to last will be 5 years.

In preclinical studies, tafasitamab enhanced 

 antibody-dependent cell-mediated cytotoxicity and phagocytosis. Tafasitamab plus rituximab and tafasitamab plus lenalidomide were also shown to increase anti-tumor activity vs either single agent alone.

Preliminary safety data from the phase 1b portion of the First-MIND trial were presented at the 62nd Annual ASH Meeting. At the time of analysis, data for 24 patients in the safety run-in phase were available. A total of 137 events were reported for patients in the tafasitamab/lenalidomide/R-CHOP arm (n = 11) and 111 events were reported for the 13 patients in the tafasitamab/R-CHOP arm. Neutropenia grade 3 or higher was observed 46% and 54% of patients, respectively, and grade 3 or higher thrombocytopenia was observed 18% and 8%, respectively. Other events of interest—diarrhea, fatigue and vomiting—were comparable between the 2 arms.

Investigators reported 23 serious adverse effects: 12 in the triplet arm and 11 in the control arm. No treatment-associated deaths occurred.

Tafasitamab plus lenalidomide was previously examined in the L-MIND study (NCT02399085). The combination was found to be well tolerated and achieved an overall response rate of 55% in 71 patients (95% CI, 43%-67%) with a complete response rate of 37% and a partial response rate of 18%. The median duration of response was 21.7 months (range, 0-24).

Based on these data, in July 2020, the FDA granted accelerated approved for tafasitamab in combination with lenalidomide for the treatment of adult patients with relapsed or refractory DLBCL not otherwise specified, including DLBCL arising from low-grade lymphoma, and who are not eligible for autologous stem cell transplant.

1. Vitolo U, Nowakowski GS, Burke JM, et al. FRONT-MIND: a phase III, randomized, double-blind, placebo-controlled study comparing efficacy and safety of R-CHOP + tafasitamab + lenalidomide vs R-CHOP alone for newly-diagnosed high-risk DLBCL. Presented at: EHA 2021 Virtual Congress; June 9-17, 2021. Abstract PB1451. Accessed June 13, 2021. 

https://s3.eu-central-1.amazonaws.com/m-anage.com.storage.eha/temp/eha21_abstract_bodies/200930.html.pdf

2. Belada D, Nowakowski GS, Bergua Burgues JM, et al. A Phase Ib, open-label, randomized study to assess safety and preliminary efficacy of tafasitamab (MOR208) or tafasitamab + lenalidomide in addition to R-CHOP in patients with newly diagnosed diffuse large B-Cell lymphoma: analysis of the safety run-in phase. 

. 2020;136(suppl 1):27-28. doi:10.1182/blood-2020-139788

3. FDA grants accelerated approval to tafasitamab-cxix for diffuse large B-cell lymphoma. FDA. Updated August 3, 2020. Accessed June 13, 2021. 

https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-tafasitamab-cxix-diffuse-large-b-cell-lymphoma

A phase 3 trial has been initiated to explore the potential of a triplet regimen of tafasitamab-cxix, lenalidomide, and R-CHOP as a treatment options for patients with newly diagnosed diffuse large B-cell lymphoma. 