Quality of Life in the Phase 2/3 Trial of N-803 Plus Bacillus Calmette-Guérin in Bacillus Calmette-Guérin‒Unresponsive Nonmuscle-Invasive Bladder Cancer

Open AccessUrology PracticePatient Care1 Mar 2024Quality of Life in the Phase 2/3 Trial of N-803 Plus Bacillus Calmette-Guérin in Bacillus Calmette-Guérin‒Unresponsive Nonmuscle-Invasive Bladder CancerThis article is commented on by the following:Editorial Comment Karim Chamie, Sam S. Chang, Eugene V. Kramolowsky, Mark L. Gonzalgo, Megan Huang, Paul Bhar, Patricia Spilman, Lennie Sender, Sandeep K. Reddy, and Patrick Soon-Shiong Karim ChamieKarim Chamie Department of Urology, University of California, Los Angeles Medical Center, Los Angeles, California , Sam S. ChangSam S. Chang https://orcid.org/0000-0003-2066-9468 Department of Urology, Vanderbilt Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee , Eugene V. KramolowskyEugene V. Kramolowsky Virginia Urology, Richmond, Virginia , Mark L. GonzalgoMark L. Gonzalgo https://orcid.org/0000-0003-0476-0288 Desai Sethi Urology Institute, University of Miami Miller School of Medicine, Miami, Florida , Megan HuangMegan Huang ImmunityBio, Inc, Culver City, California , Paul BharPaul Bhar ImmunityBio, Inc, Culver City, California , Patricia SpilmanPatricia Spilman https://orcid.org/0000-0003-2626-6475 ImmunityBio, Inc, Culver City, California , Lennie SenderLennie Sender ImmunityBio, Inc, Culver City, California , Sandeep K. ReddySandeep K. Reddy ImmunityBio, Inc, Culver City, California , and Patrick Soon-ShiongPatrick Soon-Shiong *Corresponding Author: Patrick Soon-Shiong, MD, ImmunityBio, Inc, 9920 Jefferson Blvd, Culver City, CA 90232 ( E-mail Address: [email protected] https://orcid.org/0000-0002-4682-8298 ImmunityBio, Inc, Culver City, California View All Author Informationhttps://doi.org/10.1097/UPJ.0000000000000517AboutAbstractPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail Abstract Introduction: In the phase 2/3 study QUILT-3.032 (NCT03022825), the ability of the IL-15RαFc superagonist N-803 (nogapendekin alfa inbakicept) plus bacillus Calmette-Guérin (BCG) to elicit durable complete responses in patients with BCG-unresponsive nonmuscle-invasive bladder cancer (NMIBC) was demonstrated. As a secondary end point, patient-reported outcomes (PROs) were assessed. Methods: Both cohort A patients with carcinoma in situ with or without Ta/T1 disease and cohort B patients with high-grade Ta/T1 papillary disease who received N-803 plus BCG therapy completed the EORTC (European Organization for Research and Treatment of Cancer) Core 30 and Quality of Life NMIBC-Specific 24 questionnaires at baseline and months 6, 12, 18, and 24 on study. Scores were analyzed using descriptive statistics, and multivariable analyses were performed to identify baseline variables associated with PROs. Results: On study, mean physical function (PF) and global health (GH) scores remained relatively stable from baseline for cohorts A (n = 86) and B (n = 78). At month 6, cohort A patients with a complete response reported higher PF scores than those without (P = .0659); at month 12, > 3 as compared with ≤ 3 prior transurethral resections of bladder tumor was associated (P = .0729) with lower GH scores. In cohort B, baseline disease type was associated (P = .0738) with PF and race was significantly associated (P = .0478) with GH at month 6. NMIBC-Specific 24 summary scores also remained stable on study for both cohorts. Conclusions: The overall stability of PROs scores, taken together with the efficacy findings, indicates a favorable risk-benefit ratio and quality of life following N-803 plus BCG. Approximately 80% of newly diagnosed bladder cancers are nonmuscle-invasive (NMIBC).1 Intravesical instillation of bacillus Calmette-Guérin (BCG) after transurethral resection of the bladder tumor (TURBT) is standard of care for intermediate- and high-risk NMIBC patients,2-4 but up to 40% of patients will fail BCG therapy and ∼50% will relapse after an initial response.5-7 While currently there is no standard of care for BCG-unresponsive NMIBC,8 therapies approved by the Food and Drug Administration for BCG-unresponsive NMIBC include pembrolizumab, nadofaragene, combined gemcitabine and docetaxel, and valrubicin.9-11 Radical cystectomy is an option for these patients,12 or it may be suggested they consider participation in a clinical trial. To address the need for a safe, effective therapeutic option for BCG-unresponsive NMIBC patients that provides an opportunity for avoidance of radical cystectomy,12,13 a phase 2/3 clinical trial was conducted wherein intravesical BCG was used in combination with the interleukin-15 superagonist nogapendekin alfa inbakicept (also known as N-803 or Anktiva).14-16 In the study QUILT-3.032, patients with BCG-unresponsive bladder carcinoma in situ (CIS) with or without Ta/T1 papillary disease (cohort A) and those with high-grade Ta/T1 papillary NMIBC (cohort B) were treated with the investigational therapeutic combination of intravesical N-803 plus BCG. As reported in Chamie et al16 based on data from the January 15, 2022, cutoff, a complete response (CR) was achieved in 71% of cohort A patients with a median duration of 26.6 months, with a high (89.2%) rate of cystectomy avoidance. In cohort B, the median disease-free survival was 19.3 months. The efficacy findings for QUILT-3.032 demonstrate N-803 plus BCG's ability to elicit CRs with a persistence of effect, but given the chronic nature of NMIBC—particularly in the absence of a CR—and the requirement for repeated treatment and endoscopic examinations in this patient population, patient-reported outcomes (PROs) are also an important consideration.17 As part of protocol design for QUILT-3.032, participants were asked to complete both cancer- and NMIBC-specific quality of life (QoL) questionnaires to facilitate more meaningful comparison of N-803 plus BCG therapy to other available therapies and potentially identify variables that may affect PROs. Here, we present findings from the May 16, 2022, cutoff from these questionnaires along with multivariable analyses. Methods Study Participants and Treatment QUILT-3.032 (NCT03022825) is an ongoing registrational, pivotal, open-label, single-arm,18 3-cohort, multicenter trial (32 clinical trial sites) of intravesical N-803 (ImmunityBio, Inc) plus BCG or N-803 alone in patients with BCG-unresponsive NMIBC.16 In cohorts A and C, patients were enrolled with histologically confirmed BCG-unresponsive CIS with or without Ta/T1 papillary disease; cohort B enrolled patients with histologically confirmed BCG-unresponsive high-grade Ta/T1 papillary NMIBC. Other details of patient inclusion (and exclusion) criteria for enrollment can be found in Chamie et al,16 and the study protocol provided with the Supplementary Materials (https://www.urologypracticejournal.com). Treatments and Assessments Patients in cohorts A and B were treated with intravesical N-803 (400 μg per instillation) plus intravesical BCG (50 mg per instillation). Patients in cohort C received intravesical N-803 monotherapy (400 μg per instillation). All patients received intravesical treatment via a urinary catheter weekly for 6 consecutive weeks during the induction treatment period. Response assessments were completed every 3 months through month 24 and every 6 months from month 24 to month 60 for all cohorts. Cystoscopy was performed at each response assessment. If a CR was not observed at the required week 12 assessment, patients were offered the option of Reinduction Comprising an Additional 6 Weeks of Treatment QoL Assessment QoL was assessed by the EORTC (European Organization for Research and Treatment of Cancer; www.qol.eortc.org) QoL Questionnaire Core 30 (QLQ-C30) and QoL NMIBC-Specific 24 Questionnaire (QLQ-NMIBC24) in cohort A, B, and C patients. The QLQ-C30 is a 30-question widely used cancer-specific health-related QoL questionnaire that comprises a global health (GH) status scale, 5 functional scales (physical, role, emotional, cognitive, and social) and 9 symptom scales/items (fatigue, nausea and vomiting, pain, dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). It allows assessment of the patient's perception of their state of well-being, including their ability to perform activities that reflect physical, psychological, and social well-being; as well as the patient's satisfaction with levels of functioning and disease control.19,20 The QLQ-NMIBC24 is a 24-item questionnaire specifically for patients with NMIBC that assesses 11 domains: urinary symptoms, malaise, future worries, bloating and flatulence, intravesical treatment issues, risk of contaminating partner, sexual intimacy, sexual enjoyment, sexual function, male sexual problems, and female sexual problems. For scoring the QLQ-C30 and QLQ-NMIBC24, raw scores of each domain were calculated by averaging the response scores of comprised items in each domain. A linear transformation was then performed to standardize the raw scores, such that scores for each domain range from 0 to 100. Higher scores indicate higher (better) levels of GH status or functioning, or higher (worse) levels of symptoms. For scoring the QLQ-C30 and QLQ-NMIBC24, raw scores of each functional/symptom domain were calculated by averaging the response scores of comprised items in each domain. A linear transformation was then performed to standardize the raw scores, such that scores for each domain range from 0 to 100. Higher scores indicate higher (better) levels of GH status or functioning, or higher (worse) levels of symptoms.21 Summary scores for GH and physical function (PF) were compared for all patients at 0, 6, 12, 18, and 24 months (questionnaires were not completed at month 3), and for those with CR vs without a CR at 0, 6, and 12 months. Eleven summary scores and 3 individual questions—"do you feel ill or unwell?," "do you feel pain or burning when urinating?," and do you have "worries about repeated bladder treatments?"—from the QLQ-NMIBC24 were also compared at 0, 6, and 12 months. To assess the influence of baseline clinical variables such as age (<65 or ≥65 years), gender (female or male), race (White, non-White), baseline disease type (for cohort A, CIS, CIS/Ta, CIS/T1, and in addition for cohort B, papillary T1), baseline Eastern Cooperative Oncology Group (ECOG) status (0, 1-2), number of prior prestudy BCG doses (<12, ≥12), prior cancer therapy (BCG, BCG plus other therapy), and number of prior TURBTs (≤3, >3), as well as the nonbaseline variable of CR or no CR on GH, PF, and 11 summary scores from the QLQ-NMIBC24, multivariable analyses were performed. In the multivariable regression model used, change from baseline score was the dependent variable, baseline QoL score was included as a covariate, and baseline clinical variables were included as independent variables. The multivariable analyses were conducted on month 6 and 12 scores and significance was established as a P value < .1. The rate of questionnaire completion was determined and, as additional non-PROs that nonetheless reflect QoL, utilization of health care including hospitalizations, opioid use, peripheral red blood cell infusions, and palliative procedures were also recorded. For the QoL and other findings reported here, the data cutoff was May 16, 2022. Missing Data For instances of missing specific items or questions, summary scores were calculated according to the EORTC Scoring Manual, that is, if ≥ half of the component items are missing, the summary score was recorded as missing; otherwise, it was calculated based on the average of the nonmissing item values. Should entire forms be missing, no imputation was performed. Trial Oversight The trial was designed by the sponsor ImmunityBio. Ethics bodies at each participating institution approved the protocol and any amendments. The study was conducted in accordance with the International Conference on Harmonization for Good Clinical Practice guidelines22 and with the principles of the Declaration of Helsinki. Written consent was given by all study participants before enrollment. Data were gathered by study investigators and analyzed by Biostatistics at ImmunityBio. The sponsor, ImmunityBio, vouches for the data. Results The demographics of participants that contributed to the PROs reported here are listed in Supplementary Table S1 (https://www.urologypracticejournal.com). The mean age of cohort A (n = 88) participants was 72.6 years, 88% were male, 90% were White, and 82% had a baseline ECOG status performance of 0. The mean age of cohort B participants (n = 79) was 71.6 years, 73% were male, 89% were White, and 76% had a baseline ECOG status performance of 0. For cohort A, PRO completion rate was high, being 90% at most time points; for cohort B, the QLQ-C30 completion rate declined only slightly after baseline with a greater decline in the completion rate for the QLQ-NMIBC24 (Supplementary Table S2, https://www.urologypracticejournal.com). For the summary of QLQ-C30 questions concerning GH, for both cohorts A and B there was a modest decrease in the mean from baseline at month 6 all that became less by month 12 for cohort B and month 24 for cohort A (Figure 1, A). There was a modest decrease in PF for cohort A at months 12, 18, and 24; PF remained stable for cohort B (Figure 1, B). Figure 1. Global health (GH) and physical function (PF) summary scores. GH (A) and PF (B) summary scores for all participants in cohorts A and B. GH (C) and PF (D) summary scores for all (black), responder (green), and nonresponder (red) cohort A participants at baseline and months 6 and 12. N numbers at each time point are color-coded. Data are graphed as mean and SD. When cohort A responders (those with a CR) were compared with nonresponders, they showed less of a decrease in GH and PF summary scores on study (Figure 1, C and D, respectively), although both parameters were higher at baseline for responders. We note a similar comparison was not made for cohort B because disease-free survival, rather than response to therapy, was the primary outcome for cohort B. Multivariable Analyses of QLQ-C30 Summary Scores In cohort A at month 6, achievement of a CR was associated with higher PF scores as compared with to no CR (P = .0659), and at month 12, > 3 prior TURBTs was associated with lower GH scores as compared with ≤ 3 prior TURBTs (P = .0729; Table 1). For cohort B at month 6, race was significantly associated with GH (P = .0478) and PF was lower for those with CIS/T1 disease as compared with papillary Ta disease (P = .0738). No other baseline variable had significant or a trend for a significant level of association. Table 1. Multivariable Analysis of Global Health and Physical Function Variable Cohort A Cohort B GH PF GH PF Mo 6 Mo 12 Mo 6 Mo 12 Mo 6 Mo 12 Mo 6 Mo 12 P value Est P value Est P value Est P value Est P value Est P value Est P value Est P value Est Age (<65 [ref], ≥65 y) .6428 −2.79 .9199 1.23 .9853 −0.10 .9723 0.32 .9920 −0.08 .6504 3.73 .9907 0.05 .9728 0.26 Sex (F [ref], M) .6077 −4.83 .9638 −0.68 .9110 0.9100 .7454 −3.70 .7828 2.03 .8428 −1.55 .5096 −2.59 .1654 −10.23 Race (White [ref], non-White) .7674 2.69 .8969 −2.39 .3249 −7.07 .9101 −1.30 .0478 24.65 .3752 12.20 .2218 7.96 .4586 9.39 Baseline disease typea CIS/T1 .9474 0.56 .696 7.05 .7149 2.73 .2477 14.53 .8769 2.54 .0738 −15.83 Baseline disease typea CIS/Ta −10.13 .3498 −11.46 .8636 −0.95 .7906 −2.58 Baseline disease type CISb .4144 −18.92 .7492 3.96 Baseline disease typeb T1 .9084 −0.85 .7661 2.54 .2606 −4.45 .8916 1.04 Baseline ECOG (0 [ref], 1-2) .7968 1.90 .5252 −8.82 .8443 −1.34 .2787 −12.16 .1121 −12.82 .9413 −0.79 .8389 0.85 .8024 −2.51 No. prior BCG doses (<12 [ref], ≥12) .4691 −4.45 .1803 16.35 .6797 2.23 .2417 10.65 .8007 1.60 .5319 4.65 .4530 −2.60 .6190 3.39 Prior cancer therapyc .3063 −4.81 .5207 6.58 .2233 −5.00 .9606 0.36 .3413 7.09 .2604 9.74 .2418 4.65 .6643 −3.38 No. prior TURBTs (≤3 [ref[, >3) .5769 −2.71 .0729 −17.69 .4839 3.2 .6346 −3.78 .5417 −4.08 .6270 −3.74 .5611 −2.10 .6559 3.23 CRd or no CR [ref] .3324 5.36 .4396 8.3 .0659 9.18 .489 5.98 Abbreviations: BCG, bacillus Calmette-Guérin; CIS, carcinoma in situ; CR, complete response (not baseline); ECOG, Eastern Cooperative Oncology Group; Est, estimate; F, female; GH, global health; M, male; PF, physical function; ref, reference; TURBT, transurethral resection of bladder tumor. Bolded P values indicate < .05 level of significance. Cohort A (reference group is CIS). Cohort B (reference group is high Ta). BCG only (reference), BCG + other therapy. CR vs no CR not performed for cohort B. QLQ-NMIBC24 Summary Scores For cohort A overall, summary scores for the QLQ-NMIBC24 questionnaire concerning urinary symptoms, malaise, future worries, bloating and flatulence, intravesical treatment issues, sexual function, sexual intimacy, risk of contaminating partner, sexual enjoyment, and sexual problems (male, female) remained stable from baseline to months 6 and 12 (Figure 2, A). Figure 2. Quality of Life Nonmuscle-Invasive Bladder 24 Questionnaire (QLQ-NMIBC24) summary scores. A (A) and B (B) summary scores at 0 6, and 12 months on study the questions listed on of are Data are graphed as mean and SD. For cohort B, summary scores remained with sexual problems for female participants at months 6 and 12 (Figure 2, for month numbers were and significance was not achieved (Supplementary Table https://www.urologypracticejournal.com). In response to the QLQ-NMIBC24 you feel ill or there was an of the response at month 6 for cohort A but responses to baseline levels at months 12, 18, and 24; responses remained stable in cohort B Table 2. or Cohort A Cohort B Baseline 6 12 24 Baseline 6 12 24 No. at No. A No. 3 5 3 a No. 0 0 0 0 0 0 No. 0 0 0 0 0 0 0 0 0 For the QLQ-NMIBC24 you had any pain or a burning when the of patients at from baseline at all time 12, 18, and 24 Supplementary Table in both cohorts A and B. In response to the you about repeated bladder or cohort A patient responses remained stable at ∼50% at month 24 when the had from at baseline to and that response to (n = with (n = (Supplementary Table https://www.urologypracticejournal.com). In cohort B, the at from (n = at baseline to (n = at month 6 and (n = at month 12, but to (n = and 80% (n = at months and While baseline QoL scores were assessed for cohort C patients (n = to the of efficacy of N-803 there were only 3 and cohort C by months 6 and 12 of the study, The data is not as the numbers Multivariable Analysis of QLQ-NMIBC24 Summary Scores variables were significantly associated with QLQ-NMIBC24 summary scores In cohort A age was associated with urinary and intravesical treatment at month 12. gender was associated with urinary at month 12 and sexual at month 6. Race was associated with and reported sexual at month 6. in cohort A, sexual was also associated with disease type and number of prior TURBTs at month disease type was also associated with of bloating and at month 12. of a CR was associated with scores for questions to sexual including sexual function, intimacy, and problems. Table Multivariable Analysis of Quality of Life Nonmuscle-Invasive Bladder 24 Questionnaire Summary Scores Variable Cohort A Cohort B P 6 Est P 12 Est P 6 Est P 12 Est Age ≥65 Sex Baseline ECOG BCG + other Age ≥65 No. prior (≤3, Baseline disease type T1 Baseline ECOG Baseline disease CIS/T1 Intravesical BCG + other Age ≥65 Sex Baseline disease type T1 function Age ≥65 No. prior (≤3, Sex CR [ref] or no CRd Sex Baseline disease CIS/T1 Baseline disease type CIS/Ta [ref] No. prior (≤3, CR [ref] or no CRd Baseline disease type CIS/Ta No. prior (≤3, BCG + other problems, Baseline disease type CIS Baseline ECOG Baseline disease type CIS/Ta CR [ref] or no CRd Abbreviations: BCG, bacillus Calmette-Guérin; CIS, carcinoma in situ; CR, complete response (not baseline); ECOG, Eastern Cooperative Oncology Group; Est, estimate; F, female; M, male; ref, reference; TURBT, transurethral resection of bladder tumor. vs BCG CIS vs CIS/Ta CIS/T1 CR (not there were more significant in cohort A PROs in to sexual there were more significant in cohort B PROs future and intravesical treatment Health As in Supplementary Table were during the of the study, to for cohort A and to for cohort B up to 12 months. to bladder cancer after months 6 to in cohort A and after month to 3 in cohort B, although was baseline at time during this period. procedures to at months to 11 in both cohorts A and B, in The of stability of GH and PF during the of the study is similar to that reported by et and by for BCG combination N-803 plus BCG intravesical therapy is at as as treatment with BCG not achievement of a CR was associated with higher patient-reported GH and PF scores and the higher not scores at baseline for those that on to a CR overall health at baseline that may the opportunity of a Analysis of baseline clinical variables that be associated with achievement of a CR is Summary scores for the NMIBC-specific an important assessment for for this patient population, also remained stable through 12 months. The to these questions may a in and in patients with NMIBC disease with those the less CIS disease in cohort A in sexual function and those with the more high-grade papillary disease in cohort B to more on future and intravesical treatment The absence of comparison of PROs for patients BCG plus N-803 combination therapy to BCG alone may be a of the data We that QUILT-3.032 was designed as a trial based on the of the Food and Drug the of additional BCG monotherapy in BCG-unresponsive BCG monotherapy group not be the findings may be but nonetheless The patient-reported QoL assessment in QUILT-3.032, together with the relatively rate reported in Chamie et that of were to with only 3 3 the of N-803 plus BCG combination therapy. When efficacy is also not only the 71% CR rate but also the high of cystectomy avoidance of at 24 months in patients with a CR, treatment of BCG-unresponsive NMIBC with N-803 plus BCG can be as a favorable risk-benefit 1. and treatment of bladder 2. in the treatment of bladder and of repeated of intravesical bacillus therapy for bladder Intravesical therapy for the treatment of bladder a and The of transurethral resection on and in patients with bladder cancer treated with intravesical bacillus 6. and in individual patients with Ta T1 bladder cancer using EORTC risk a combined of patients from EORTC The of BCG in bladder an assessment of and therapies for bladder cancer after bacillus a and for bladder and ongoing clinical Intravesical therapy for BCG-unresponsive bladder a open-label, clinical trial. intravesical gemcitabine and for the treatment of bladder Bladder 12. cancer-specific survival in patients with bladder cancer and a BCG BCG an to the to clinical in bladder Bladder are for effective BCG superagonist in and superagonist in BCG-unresponsive bladder outcomes in bladder a Life Department of Health and Food and Drug for Drug and Research and for and Research for Bladder and for Food and Drug data for the EORTC QLQ-C30 health-related quality of life questionnaire based on and the The Organization for Research and Treatment of Cancer a for in clinical in Cancer and of the EORTC QLQ-NMIBC24 questionnaire to assess patient-reported outcomes in bladder The International Conference on Harmonization Good Clinical Practice Radical cystectomy intravesical BCG for high-risk high-grade bladder from the study. Quality of life in patients for bladder of effective intravesical therapies on quality of life in patients with bladder a The QUILT-3.032 study was by ImmunityBio, of All with an ImmunityBio, Inc, are of ImmunityBio, is a for ImmunityBio, The other have to Ethics In of the principles of the Declaration were All patients provided Author is the on the clinical and are and and performed on QoL data from the graphed and and the of the and designed the study. All contributed to of and the Data All data or analyzed during this study are included in this article (and by and A 2, Comment Materials by and bladder Author Karim Chamie Department of Urology, University of California, Los Angeles Medical Center, Los Angeles, California by this Sam S. Chang Department of Urology, Vanderbilt Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee by this Eugene V. Kramolowsky Virginia Urology, Richmond, Virginia by this Mark L. Gonzalgo Desai Sethi Urology Institute, University of Miami Miller School of Medicine, Miami, Florida by this Megan Huang ImmunityBio, Inc, Culver City, California by this Paul Bhar ImmunityBio, Inc, Culver City, California by this Patricia Spilman ImmunityBio, Inc, Culver City, California by this Lennie Sender ImmunityBio, Inc, Culver City, California by this Sandeep K. Reddy ImmunityBio, Inc, Culver City, California by this Patrick Soon-Shiong ImmunityBio, Inc, Culver City, California *Corresponding Author: Patrick Soon-Shiong, MD, ImmunityBio, Inc, 9920 Jefferson Blvd, Culver City, CA 90232 ( E-mail Address: [email protected] by this All The QUILT-3.032 study was by ImmunityBio, of All with an ImmunityBio, Inc, are of ImmunityBio, is a for ImmunityBio, The other have to Ethics In of the principles of the Declaration were All patients provided Author is the on the clinical and are and and performed on QoL data from the graphed and and the of the and designed the study. All contributed to of and the Data All data or analyzed during this study are included in this article (and