Caroline Seymour

A patient with heavily pretreated testicular cancer achieved a complete response (CR) to BNT211-01, an investigational CAR T-cell therapy directed against the antigen Claudin-6 (CLDN6), according to findings from a phase 1/2a trial (NCT04503278) presented during the 2022 ESMO Congress.

The patient had previously received 6 lines of chemotherapy and remained in an ongoing CR at the data cutoff for the study analysis. Further, the patient had a large tumor mass at baseline that displayed an “impressive regression” at 6 weeks following CAR T-cell therapy and became PET-negative over time, lead study investigator Andreas Mackensen, MD, said during the meeting presentation.

Overall, the study explored BNT211-01 across patients with various CLDN6-positive relapsed/refractory advanced solid tumors and found that the CAR T-cell therapy displayed clinical activity both as a monotherapy and in combination with a CLDN6-encoding mRNA vaccine.

At the data cutoff of June 15, 2022, the overall response rate (ORR) was 33% among 21 efficacy-evaluable patients. The ORR comprised the 1 patient with testicular cancer who had a CR, along with 6 patients who achieved a partial response. There were also 7 patients who achieved stable disease and the disease control rate (DCR) was 67%.

“BNT211-01 is a CAR T-cell product candidate that targets the CLDN6, a tight junction associated membrane protein,” said Mackensen, a professor in the Department of Internal Medicine 5—Hematology/Oncology at the University Hospital Erlangen in Germany. “CLDN6 is an ideal CAR antigen [because] it has an extracellular loop that can be targeted by T cells, is absent in healthy adult tissue since it is silenced during organogenesis, and is expressed in various cancer, such as testicular cancer and ovarian cancer.”

Patients with testicular cancer expressed CLDN6 at a rate of approximately 93%, and it is present in a little over half of patients with ovarian cancer (56%).

The phase 1/2a trial followed a 3+3 design with bifurcation. Patients an ECOG performance status of 1 or less and measurable disease by RECIST 1.1 criteria were eligible. CLDN6-positivity was defined as at least 50% of tumor cells being CLDN6-high.

In part 1 of the phase 1 portion, patients received BNT211-01 monotherapy at a dose of 1 x 107 CAR T cells (dose level 1; n = 3) or 1 x 108 CAR T cells (dose level 2; n = 6). In part 2 of phase 1, 4 patients received dose level 1 of BNT211-01 plus the CLDN6-encoding mRNA vaccine and 9 patients received dose level 2 in combination with the vaccine.

Apheresis and CAR T manufacturing were performed at day –18 or earlier. Patients then underwent lymphodepletion with cytarabine plus fludarabine on days –5 to –3. CAR T-cell infusion was performed on day 1. Patients also given the vaccine were administered the first dose on day 4. The first 5 vaccine treatments occurred every 3 weeks, followed by a treatment every 6 weeks thereafter.

The median age of the total safety population (n = 22) was 46 years (range, 25-68) and most patients were male (n = 15). The population was heavily pretreated with a median of 4 (range, 3-9) prior lines of therapy.

The study group of patients with testicular cancer treated at study dose level 2 with lymphodepletion (n = 7) experienced a better response than the overall population, achieving an ORR of 57% with a DCR of 85%. The ORR for the total population of patients with testicular cancer who received either BNT211-01 dose with lymphodepletion was 45% with a DCR of 54%.

Regarding safety, 20 patients in the safety population experienced a grade 3 or higher treatment-emergent adverse effect (TEAE). A single case of grade 1 immune effector cell-associated neurotoxicity syndrome was reported, and it quickly resolved.

Cytokine release syndrome (CRS), a common TEAE accompanying CAR T-cell treatments, was present in 10 patients (45%). Increased levels of interleukin 6 were present in patients with CRS. All instances of CRS were grade 3 or less and were manageable with tocilizumab (Actemra), if needed.

Dose-limiting toxicities (DLTs) were observed in 2 patients, including 1 treated at dose level 2 alone and 1 treated at dose level 2 in combination with the CLDN6-encoding mRNA vaccine. The DLTs consisted of prolonged pancytopenia after lymphodepletion for the patient treated with the CAR T-cell monotherapy and hemophagocytic lymphohistiocytosis for the patient treated with the combination, though this toxicity occurred before administration of the CLDN6-encoding mRNA vaccine. Eight total patients died during the trial, all from disease progression.

In terms of pharmacokinetics, a strong persistence of CAR T cells was reported for over 100 days. A few patients also displayed persistence for over 200 days.

“Some patients showed long-term CAR T-cell persistence for more than 200 days post CAR T-cell infusion,” Mackensen said. “The process of generation of CLDN6 CAR T-cells has now been switched to an automated process and dose escalation is ongoing. The recommended phase 2 dose will be identified for the automated product [in the future].”

1. Mackensen A. BNT211-01: A phase I trial to evaluate safety and efficacy of CLDN6 CAR T cells and CLDN6-encoding mRNA vaccine-mediated in vivo expansion in patients with CLDN6-positive advanced solid tumours. Presented at: 2022 ESMO Congress; September 9-13, 2022; Paris, France. Abstract LBA38

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The patient had previously received 6 lines of chemotherapy treatment and was still in an ongoing complete response at the time of the study analysis.

Testicular cancer patient has complete response to CAR T-cell therapy

Findings from the phase 2 BIONIKK trial (NCT02960906) presented at the 2022 ESMO Congress identified biomarkers of enhanced efficacy outcomes with nivolumab (Opdivo) and ipilimumab (Yervoy) as a first-line treatment for patients with metastatic renal cell carcinoma (RCC).

Specifically, the presence of more than 2 tertiary lymphoid structures (TLSs) coupled with increased density of Ki-67 and PD-1 positivity was linked to an increased response rate and prolonged progression-free survival (PFS) with the upfront immunotherapy combination.

Several treatment cohorts were evaluated in the trial. Within 15 days of screening, patients were grouped into 1 of 4 molecular subsets. Patients in subsets 1 and 4 were randomly assigned to 3 mg/kg of intravenous (IV) nivolumab every 2 weeks or 3 mg/kg of IV nivolumab plus 1 mg/kg of IV ipilimumab every 3 weeks for 4 cycles followed by 240 mg of nivolumab every 2 weeks. Those in subsets 2 and 3 were randomly assigned to the combination or 50 of oral sunitinib for 4 weeks on, 2 weeks off, or 800 mg of oral pazopanib once daily.

With nivolumab alone (n = 38), patients with more than 2 TLSs achieved an objective response rate (ORR) of 73% (n = 8) vs 15% (n = 4) in those with fewer than 2 TLSs (chi-square P = .00195; HR for PFS, 0.31; 95% CI, 0.12-0.83; P = .015). With the combination (n = 76), 69% (n = 20) and 40% (n = 19) of patients experienced response with more than 2 and fewer than 2 TLSs, respectively (chi-square P = .0291; HR for PFS, 0.81; 95% CI, 0.44-1.46; 

“TLS >2 identify responders to nivolumab and nivolumab plus ipilimumab, and Ki-67- and PD-1–positive cell density identifies patients with longer PFS,” lead study author Maxine Meylan, PhD, research fellow at Dana-Farber Cancer Institute, said. “Patients with TLS >2 and high Ki-67 and PD-1 positivity have high response rates to nivolumab plus ipilimumab and longer PFS.”

BIONIKK is a hypothesis-generating, noncomparative, per-molecular group randomized phase 2 trial.

The trial enrolled patients at least 18 years of age with treatment-naïve, metastatic clear cell RCC with an ECOG performance status between 0 and 2 and frozen tumor tissue. Patients with active brain metastases were excluded from enrollment.

Treatment was continued until disease progression, death, or end of study.

A total of 160 samples underwent immunohistochemical and immunofluorescence staining to assess TLS, PD-1, and Ki-67 level.

The primary end point was investigator-assessed objective response per RECIST v1.1 criteria. Key secondary end points were PFS, overall survival, time to subsequent therapy, time to objective response, and duration of response.

Additional results showed that higher density of PD-L1– and Ki-67–positive cells was associated with improved ORR and PFS with nivolumab. The ORR was 40% (n = 6) with nivolumab in patients with high expression vs 26% (n = 5) in those with low expression (chi-square 

 = .633); with the combination, these rates were 56% (n = 25) and 45% (n = 14), respectively (chi-square 

However, the median PFS was not different between cohorts of high or low expression with nivolumab alone (HR, 0.73; 95% CI, 0.32-1.65; 

 = .44). Only with the combination, did patients with high expression level outperform those with low expression (HR, 0.49; 95% CI, 0.28-0.88; 

Finally, the investigators showed that the presence of both high TLS and PD-1/Ki-67 positivity enhanced response rates and PFS for the combination. In this population, the ORR was 81% (n = 17) vs 40% (n = 21) in those without both markers (chi-square test 

 = .00319). Moreover, the PFS was favorable in the population with more than 2 TLSs and Ki-67 positivity vs those without (HR, 0.53; 95% CI, 0.26-1.07; 

Notably, 95% of patients enriched with both markers (n = 20) who received treatment with the combination did not experience early progression within the first 6 months of therapy vs only 64% (n = 34) of those without both markers.

Meylan added that preliminary peripheral blood mononuclear cell analysis indicated that select circulating CD4 T-cell populations were also associated with response.

“Validation of these markers on immunotherapy and TKI/immunotherapy [combinations] is ongoing,” the study authors concluded.

1. Meylan M, Sun CM, Elaidi RT, et al. In-situ and circulating immune markers predict nivolumab +/- ipilimumab efficacy in frontline metastatic clear cell renal cell carcinoma: key ancillary analyses from the BIONIKK randomized trial. Ann Oncol. 2022;33(suppl 7):S660-S680. doi:10.1016/annonc/annonc1072

The presence of more than 2 tertiary lymphoid structures coupled with increased density of Ki-67 and PD-1 positivity was linked to an increased response rate and prolonged progression-free survival.

Study identifies biomarkers of enhanced nivolumab/ipilimumab efficacy in renal cell carcinoma

Combination treatment with the IL15RaFc superagonist N-803 (Anktiva) and BCG was associated with prolonged complete responses (CRs) and disease-free survival (DFS) in patients with BCG-unresponsive non–muscle invasive bladder cancer with carcinoma in situ (CIS) and papillary histology, according to a recent study.

The findings, from the phase 2/3 QUILT-3.032 trial (NCT03022825), were presented at the 2022 AUA Annual Meeting.

At a median follow-up of 23.9 months in patients with CIS, the CR rate was 71% (95% CI, 60.1%-80.5%). The 12- and 24-month CR rates were 60% (95% CI, 45%-72%) and 52% (95% CI, 40%-65%), respectively.

At a median follow-up of 20.7 months in patients with papillary disease (n = 77), the median DFS was 23.6 months. The 12-, 18-, and 24-month DFS rates were 57% (95% CI, 44%-68%), 53%, and 48% (95% CI, 34%-60%), respectively.

“In animal models the combination of BCG plus IL15 further augments that T- and NK-cell response and results in memory T cells, and for that we designed phase 2/3 QUILT-3.032 study,” lead study author Karim Chamie, MD, MSHS, associate professor of urology at UCLA, said during the presentation.

QUILT-3.032 enrolled patients with historically confirmed BCG-unresponsive disease with persistent or recurrent CIS, with or without recurrent Ta/T1 disease, within 12 months of receiving sufficient BCG.

The population was divided into 2 cohorts: those with CIS (n = 83; cohort A) and those with papillary histology (n = 77; cohort B).

In the study, patients received 50 mg of intravesical BCG plus 400 µg of N-803 every week for 6 cycles followed by 6 cycles of maintenance therapy in patients who achieved CR for up to 2 years with the option to extend therapy. Patients who did not achieve CR but experienced response were allowed to receive another 6 cycles of re-induction with the combination.

The primary end point was CR at any time; secondary end points included duration of CR, cystectomy avoidance, and time to cystectomy. Safety end points included serious adverse effects (AEs) and immune AEs.

Regarding baseline demographics, the median age was 72.8 years in cohort A and 71.7 years in cohort B. Most patients were male and above the age of 65 years in cohorts A (87% and 84%) and B (74% and 74%), respectively. Most patients in cohorts A and B had an ECOG performance status of 0 (82% and 77%), followed by 1 (18% and 17%), and 2 (0% and 6%), respectively. The mean number of prior transurethral resections of the bladder tumor was 4 in both cohorts.

In terms of disease type, most patients in cohort A had CIS (70%), followed by CIS/Ta (19%), CIS/T1 (11%), high-grade Ta (0%), T1 (0%), and Ta/T1 (0%) disease. In cohort B, most patients had T1 (44%), followed by high-grade Ta (43%), CIS/T1 (5%), Ta/T1 (4%), and CIS/Ta (1%), and CIS (1%) disease.

The mean number of prior BCG doses was 16.6 in cohort A and 12.3 in cohort B.

Additional efficacy findings from cohort A demonstrated that the median duration of response (DOR) was 24.1 months (95% CI, 9.9–not reached). The percentage of patients whose DOR was at least 12, 18, and 24 months was 62% (95% CI, 48.0%-73.5%), 55% (95% CI, 40.1%-67.3%), and 52% (95% CI, 37.0%-64.9%), respectively.

In cohort A, the cystectomy rate was 7% in responders and 15% overall.

The 12-, 18-, and 24-month rates of bladder cancer–specific progression-free survival were 92% (95% CI, 83.4%-96.4%), 91% (95% CI, 81.2%-95.4%), and 91% (95% CI, 81.2%-95.4%, respectively. The bladder cancer–specific overall survival rate was 100%.

Regarding the efficacy in cohort B, 95% of patients (n = 73) avoided radical cystectomy, meeting the secondary end point for the cohort.

Notably, the efficacy of the combination was retained across all subgroups in both cohorts.

Regarding safety, the combination was well tolerated across both cohorts. Grade 1 and 2 treatment-related AEs (TRAEs) included dysuria (22%), pollakiuria (19%), hematuria (18%), fatigue (16%), micturition urgency (12%), chills (7%), bladder spasm (6%), pyrexia (5%), urinary tract infection (5%), noninfective cystitis (4%), nocturia (3%), diarrhea (3%), nausea (2%), positive bacterial test (2%), cystitis (2%), influenza-like illness (2%), and urinary tract pain (2%).

Grade 3 TRAEs occurring in less than 1% of patients included arthralgia, bacteremia, dysuria, encephalopathy, escherichia bacteremia, hematuria, myalgia, pain in extremity, pollakiuria, sepsis, urinary tract infection, and decreased urine flow.

The rate of serious TRAEs was 1%, there were no immune-related AEs, and only 3% of patients underwent a treatment-related discontinuation.

Notably, the activity of N-803 was localized to the bladder, and there were no systemic IL-15 levels per pharmacokinetic analysis.

Chamie K. IL-15RaFc superagonist N-803 with BCG in BCG-unresponsive non-muscle invasive bladder cancer (NMIBC) CIS and papillary cohorts. Presented at: 2022 AUA Annual Meeting; May 13-16, 2022. New Orleans, LA. PLLBA-01.

At a median follow-up of 20.7 months in patients with papillary disease (n = 77), the median DFS was 23.6 months.

N-803 plus BCG yields prolonged complete responses and DFS in NMIBC

 Interdisciplinary Prostate Cancer Congress® and Other Genitourinary Malignancies, Leonard G. Gomella, MD, explained how the ever-expanding application of genetic and genomic testing has launched the game-changing precision medicine era in prostate cancer. 

“Precision medicine is here for prostate cancer. It’s not a fantasy anymore. We’re using it every day more and more,” said Gomella.

Genomic or genetic germline testing is done to inform treatment decisions and screening in an individual and their family members for other at-risk cancers, Gomella said. Almost all the genes that are associated with inherited prostate cancer are found in the DNA damage response and repair pathway and include 

, the latter of which increases individual and familial risk for other hereditary cancers, including breast, ovarian, pancreatic, colon, gastric, and Lynch syndrome.

“The DNA damage response genes increase the risk of developing prostate cancer and, more importantly, aggressive, life-threatening, metastatic prostate cancer,” Gomella said, adding the disease is typically defined by a Gleason score of 8 or higher, positive nodes, metastases, and poor survival.

 gene mutation have a 2.6-fold increased risk of developing aggressive prostate cancer during their lifetime, and that risk is increased 8.6-fold by the age of 65 years.

“If you identify someone who has an inherited germline mutation, you really need to pay attention to that patient,” Gomella said, adding that germline mutations are found in more than 11% of prostate cancer cases and up to 25% of metastatic castration-resistant cancers.

, although uncommon, is an androgen receptor gene mutation that is the most significant inherited gene for prostate cancer and one that is almost always found in aggressive cancers in family members diagnosed before the age of 55 years.

Prostate cancer–specific genetic testing panels on the market include ProstateNext by Ambry Genetics, the Prostate Cancer Panel by GeneDx and Invitae, and the Hereditary DNA Repair Panel for Prostate Cancer by NeoGenomics. General cancer panels that also screen for relevant gene mutations include Myriad’s myRisk and Color Genomics/Genome Dx’s Hereditary Cancer Panel.

The use of such panels is first informed by a patient’s family history, said Gomella, who emphasized to urologists that asking about an individual’s history of inherited prostate cancer should be augmented by any history of breast and ovarian cancer, melanoma, and Lynch syndrome.

After such information has been gathered, a genetic counselor can be brought in to discuss testing options, result types, cancer risks, insurance complications, and reproductive implications.

Current guidelines recommend genetic testing/counseling in the event of:

At least 2 cases of prostate cancer in close relatives 55 years of age or younger regardless of risk category

At least 3 first-degree relatives with prostate cancer regardless of risk

Aggressive prostate cancer with a Gleason score above 7

At least 2 cases of breast, ovarian, and/or pancreatic cancer in a close relative

Metastatic prostate cancer or metastatic castration-resistant prostate cancer (mCRPC)

Somatic tumor sequencing with mutations in hereditary cancer genes

Family history of cancer at an early age of diagnosis

“Looking for genetic risk has become baked into our management of prostate cancer today,” Gomella said. “Germline and somatic testing are complementary. One does not replace the other. They should both be considered in the management of many patients with prostate cancer.”

When it comes to determining whether to biopsy patients for prostate cancer, several things can be used, including prostate-specific antigen (PSA) kinetics, the Prostate Health Index score, OPKO 4K, Prostarix, Select MDx, ExoDx, MyProstate Score, PCA3, as well as MRI and ultrasound, the Prompt Prostate Genetic Score, germline testing, and online calculators.

In terms of whether to perform a repeat biopsy, Gomella cited the ConfirmMDx, Prostate Score Mitomic Test, MyProstate Score, OPKO 4K, and PCA3 as helpful options.

“Whatever test you’re comfortable with is the most important,” Gomella said. “[At Jefferson Health,] we rotate different tests to give our residents exposure to the different potential assays that are available.”

Following biopsy, several tissue tests can be used to determine disease aggressiveness, including ConfirmMDx, Decipher, Prolaris, and the Oncotype DX genomic prostate score test.

“[These tests] are used after the biopsy. This is taking the biopsy of someone with known prostate cancer and deciding whether this a cancer, based on the characteristics beyond Gleason score, PSA, and digital rectal exam, that can be watched or [one] that requires further testing,” Gomella said.

Turning to treatment implications, Gomella explained that in the setting of heavily pretreated metastatic castration-resistant prostate cancer, in the presence of a germline or somatic 

mutation or homologous recombination repair gene mutation, patients may be eligible to receive rucaparib (Rubraca) or olaparib (Lynparza),

 respectively, and in the presence of high microsatellite instability/mismatch repair deficiency or tumor mutational burden greater than 10 mut/Mb, pembrolizumab (Keytruda).

“Many of the new treatments under study today are associated with precision medicine with the identification of a precise marker that can be used to guide treatment,” Gomella concluded.

Gomella L. The evolution of biomarkers and genetics in the management of prostate cancer. Presented at: New York GU 

 Interdisciplinary Prostate Cancer Congress® and Other Genitourinary Malignancies; March 11-12, 2022; virtual. Accessed March 12, 2022.

Rubraca highlights of prescribing information. FDA. Updated December 2016. Accessed March 15, 2022. https://bit.ly/3Ibfx9b

Lynparza highlights of prescribing information. FDA. Updated May 2020. Accessed March 15, 2022. https://bit.ly/2WLJt7u

Keytruda highlights of prescribing information. FDA. Updated March 2021. Accessed March 15, 2022. https://bit.ly/37zl8tu

The applications for germline and somatic genetic testing in prostate cancer have skyrocketed, carving out an important role in screening, diagnosis, and treatment.

Caroline Seymour

Articles

Testicular cancer patient has complete response to CAR T-cell therapy

Study identifies biomarkers of enhanced nivolumab/ipilimumab efficacy in renal cell carcinoma

N-803 plus BCG yields prolonged complete responses and DFS in NMIBC

Dr. Gomella explains the evolving precision medicine paradigm in prostate cancer