Kyle Doherty

Findings from the phase 2 NORSE trial showed that combining the TKI erdafitinib (Balversa) with the anti–PD-1 immune checkpoint inhibitor cetrelimab (JNJ-63723283) led to strong clinical activity in patients with metastatic or locally advanced urothelial carcinoma (mUC) harboring 

The results, which were shared during the 2021 ESMO Congress, showed that the TKI/immunotherapy combination reached 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.

Erdafitinib is an oral pan-FGFR inhibitor and cetrelimab is an immunoglobulin G4 monoclonal antibody specific for PD-1.

“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 Thomas Powles, MD, 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.”

1. 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.

2. 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

Articles

The TKI/immunotherapy combination demonstrated strong clinical activity in patients with metastatic or locally advanced urothelial carcinoma (mUC) harboring FGFR alterations. 

Erdafitinib combined with cetrelimab shows promise in bladder cancer

Study findings presented during the 2021 AUA annual meeting showed that large surface area microparticle docetaxel (LSAM-DTX; NanoDoce) is safe with early signs of clinical activity in patients with high-risk non–muscle invasive bladder cancer (NMIBC).

Among the 19 patients who received LSAM-DTX at any dose level in the phase 1/2 trial (NCT03636256), 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 Max Kates, MD, 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 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 cystoscopically 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.”

1. 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.

Phase 1/2 data showed that large surface area microparticle docetaxel is safe with early signs of clinical activity in patients with high-risk non–muscle invasive bladder cancer.

Large surface area microparticle docetaxel shows promise in NMIBC

Now that pivotal trials have demonstrated a survival benefit with PSMA-targeted therapy in metastatic prostate cancer, researchers are hoping to deliver the exciting new approach earlier in the disease course. Accordingly, findings presented at the 2021 American Urological Association Annual Meeting showed early promise with neoadjuvant 177Lu-PSMA imaging and therapy in patients with locally advanced, high-risk disease.

Specifically, 177Lu-PSMA imaging and therapy followed by radical prostatectomy exhibited a favorable safety profile and early signs of efficacy. In the prospective, open-label, single-arm trial (NCT04297410), 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 presenting author Michael Frumer, MD, a physician in the department of urology at Rabin Medical center in Petah 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.”

1. 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.

Now that pivotal trials have demonstrated a survival benefit with PSMA-targeted therapy in metastatic prostate cancer, researchers are hoping to deliver the exciting new approach earlier in the disease course.

Kyle Doherty

Articles

Erdafitinib combined with cetrelimab shows promise in bladder cancer

Large surface area microparticle docetaxel shows promise in NMIBC

PSMA-targeted therapy shows early promise in locally advanced prostate cancer