Table S4 shows incidence of new peripheral neuropathy over time in EV monotherapy pooled data

Figure S1 is a schematic diagram of key datasets supporting the FDA’s efficacy review for accelerated approval of enfortumab vedotin plus pembrolizumab for cisplatin-ineligible patients with locally advanced or metastatic urothelial cancer

Figure S2 is a schematic diagram of key datasets supporting the FDA’s safety review for accelerated approval of enfortumab vedotin plus pembrolizumab for cisplatin-ineligible patients with locally advanced or metastatic urothelial cancer

Table S5 shows the percentage of patients with resolution of neuropathy at last assessment of neuropathy in EV-103 and EV monotherapy pooled data

Table S3 shows incidence of new peripheral neuropathy over time in patients receiving combination treatment in EV-103

Table S1 shows selected laboratory abnormalities ≥ 20 % (All Grades) in EV-103

Table S2 presents a summary of exposure and safety data by performance status in patients receiving combination treatment in EV-103

BACKGROUND:Retrospective analyses of studies of IO-containing combinations for advanced renal cell carcinoma (RCC) suggest that depth of response is associated with overall survival but have methodological limitations. We investigated the relationship of week 12 depth of response as a continuous variable with overall survival. METHODS:Pooling data from patients with treatment-naïve advanced RCC enrolled in randomized IO-containing frontline advanced RCC trials submitted to the US Food and Drug Administration that included week 12 imaging assessment, we developed 36-month overall survival prediction models based on week 12 depth of response (reduction from baseline in target lesion diameter) using Cox proportional hazards with natural spline in an IO combination group and a sunitinib group. To avoid guarantee-time bias, only patients in follow-up at the week 12 scan were included. Overall survival was defined from the week 12 imaging date. RESULTS:Among the 4 trials that met our inclusion criteria, 1364 patients in the IO combination group and 1267 patients in the sunitinib group had week 12 imaging. Depth of response and 36-month overall survival were correlated throughout the entire range of depth of response in both treatment groups, with no plateau in overall survival as depth of response approached complete response. Across this range, estimated 36-month overall survival was higher in the IO combination group. CONCLUSIONS:Deeper response was associated with better 36-month overall survival in this pooled exploratory analysis of treatment-naïve patients with advanced RCC treated with IO combination or sunitinib. Further work characterizing the relationship between depth of response and overall survival at the trial level may advance understanding of the utility of depth of response as a pharmacodynamic response biomarker or early endpoint in signal-seeking trials and to facilitate efficient drug development.

Background Retrospective analyses of studies of immune-oncology (IO)-containing combinations for advanced renal cell carcinoma (aRCC) suggest that depth of response (DepOR) is associated with overall survival (OS), but have methodologic limitations. We investigated the relationship of Week 12 DepOR as a continuous variable with OS. Methods Pooling data from patients with treatment (tx)-naïve aRCC enrolled in randomized IO-containing frontline aRCC trials submitted to FDA that included Week 12 imaging assessment, we developed 36-month (mo) OS prediction models based on Week 12 DepOR (reduction from baseline in target lesion diameters) using Cox proportional hazards with natural spline in IO combination and sunitinib (SUN) groups. To avoid guarantee-time bias, only patients in follow-up at Week 12 scan were included. OS was defined from Week 12 imaging date. Results Among the 4 trials meeting inclusion criteria, 1364 patients in IO combination and 1267 patients in SUN group had Week 12 imaging. DepOR and 36-month OS were correlated throughout the entire range of DepOR in both tx groups, with no plateau in OS as DepOR approached complete response. Across the range of DepOR, estimated 36-mo OS was higher in IO combination group. Conclusion Deeper response was associated with better 36-month OS in this pooled exploratory analysis of tx-naive aRCC patients treated with IO combination or SUN. Further work characterizing the relationship between DepOR and OS at the trial level may advance understanding of the utility of DepOR as a pharmacodynamic response biomarker or early endpoint in signal-seeking trials and to facilitate efficient drug development.

PURPOSE The US Food and Drug Administration (FDA) approved talazoparib with enzalutamide for first-line treatment of patients with homologous recombination repair (HRR) gene-mutated metastatic castration-resistant prostate cancer (mCRPC). PATIENTS AND METHODS The approval was based on the HRR gene-mutated (HRRm) population of TALAPRO-2, a randomized, double-blind trial that randomly assigned 1,035 patients with mCRPC to receive enzalutamide with either talazoparib or placebo. Two cohorts enrolled sequentially: an all-comer population (Cohort 1), followed by an HRRm-only population (Cohort 2). The independent primary end points were radiographic progression-free survival (rPFS) per blinded independent central review (BICR) in Cohort 1 (all-comers) and in the combined HRRm population (all HRRm patients from Cohorts 1 and 2). Overall survival (OS) was a key secondary end point. RESULTS A statistically significant improvement in rPFS by BICR was demonstrated in both the all-comers cohort and the combined HRRm population, with hazard ratio (HR) of 0.63 (95% CI, 0.51 to 0.78; P < .0001) and 0.45 (95% CI, 0.33 to 0.61; P < .0001), respectively. In an exploratory analysis of the 155 patients with BRCA-mutated ( BRCAm) mCRPC, rPFS HR was 0.20 (95% CI, 0.11 to 0.36). In the non-HRRm/unknown stratum of Cohort 1 (n = 636), the rPFS HR was 0.70 (95% CI, 0.54 to 0.89). OS was immature. CONCLUSION Despite a statistically significant rPFS improvement in the all-comer cohort, FDA did not consider the magnitude of rPFS clinically meaningful in the context of the broad indication, combination treatment, and safety profile. Approval was therefore limited to patients with HRRm mCRPC, for whom there was a statistically significant and clinically meaningful improvement in rPFS and favorable OS results. This represents the first approval for the first-line treatment of patients with HRRm mCRPC.

Abstract On April 3, 2023, the FDA granted accelerated approval to enfortumab vedotin-ejfv (EV) plus pembrolizumab for treatment of patients with locally advanced or metastatic urothelial carcinoma who are ineligible for cisplatin-containing chemotherapy. Substantial evidence of effectiveness was obtained from EV-103/KEYNOTE-869 (NCT03288545), a multicohort study. Across cohorts, a total of 121 patients received EV 1.25 mg/kg (maximum of 125 mg) intravenously on days 1 and 8 of a 21-day cycle plus pembrolizumab 200 mg intravenously on day 1 of each 21-day cycle until disease progression or unacceptable toxicity. The major efficacy outcome measures were objective response rate (ORR) and duration of response (DoR), determined by blinded independent central review using RECIST v1.1. The confirmed ORR in 121 patients was 68% (95% confidence interval, 59–76), including 12% with complete responses. The median DoR for the 82 responders was 22 months (range: 1+ to 46+). The safety profile of the combination comprised adverse reactions expected to occur with the corresponding monotherapies, but with overall increased frequency of adverse reactions, including skin toxicity, pneumonitis, and peripheral neuropathy. The article summarizes the data and the FDA thought process supporting accelerated approval of EV + pembrolizumab, as well as additional exploratory analyses conducted by the FDA.

4559 Background: The International Metastatic RCC Database Consortium (IMDC) risk model was developed for prognosis of patients with mRCC treated with vascular endothelial growth factor (VEGF)-targeted monotherapy in the first-line setting. Efficacy in trials of anti-VEGF therapy has been generally consistent across risk groups, including for overall survival (OS). For trials of immunotherapy combinations, the small numbers of OS events for the favorable risk group in each trial limited reliable conclusions; however, there was a suggestion of possible differential effects on OS between favorable risk and other risk groups. Methods: We pooled individual patient data (n=3447) from four phase III randomized trials of combinations of immunotherapy + immunotherapy (n=1) or immunotherapy + anti-VEGF therapy (n=3) submitted to the US Food and Drug Administration in support of marketing applications. All trials calculated IMDC risk group for each patient and used a control arm of sunitinib. We combined intermediate and poor prognostic groups (“intermediate/poor”) and compared their OS to that of the favorable risk group using Kaplan-Meier and Cox Proportional Hazards methods. Results: In this pooled analysis, treatment with combination immune checkpoint therapy did not demonstrate an improvement in OS compared to sunitinib in the favorable risk group (HR 0.953; 95% CI: 0.72, 1.27). An improvement in OS was observed in the intermediate/poor risk group (HR 0.696; 95% CI: 0.62, 0.78). Conclusions: Our analysis of OS in patients treated with immunotherapy combinations compared to sunitinib suggests possible differential benefit in the favorable risk compared to the intermediate/poor risk group. These results are not conclusive and considered exploratory due to the relative immaturity of OS in the favorable risk group. Follow-up for survival continues in each study to allow for more definitive results.[Table: see text]

BACKGROUND: Despite recent drug development for non-muscle invasive bladder cancer (NMIBC), few therapies have been approved by the US Food and Drug Administration (FDA), and there remains an unmet clinical need. Bacillus Calmette-Guerin (BCG) supply issues underscore the importance of developing safe and effective drugs for NMIBC. OBJECTIVE: On November 18–19, 2021, the FDA held a public virtual workshop to discuss NMIBC research needs and potential trial designs for future development of effective therapies. METHODS: Representatives from various disciplines including urologists, oncologists, pathologists, statisticians, basic and translational scientists, and the patient advocacy community participated. The workshop format included invited lectures, panel discussions, and opportunity for audience discussion and comment. RESULTS: In a pre-workshop survey, 92% of urologists surveyed considered the development of alternatives to BCG as a high drug development priority for BCG-naïve high-risk patients. Key topics discussed included definitions of disease states; trial design for BCG-naïve NMIBC, BCG-unresponsive carcinoma in situ, and BCG-unresponsive papillary carcinoma; strengths and limitations of single-arm trial designs; assessing patient-reported outcomes; and considerations for assessing avoidance of cystectomy as an efficacy measure. CONCLUSIONS: The workshop discussed several important opportunities for trial design refinement in NMIBC. FDA encourages sponsors to meet with the appropriate review division to discuss trial design proposals for NMIBC early in drug development.

PURPOSE This article summarizes the US Food and Drug Administration (FDA) review of the data leading to approval of olaparib plus abiraterone for the treatment of patients with deleterious or suspected deleterious BRCA-mutated ( BRCAm) metastatic castration-resistant prostate cancer (mCRPC), as determined by an FDA-approved companion diagnostic test. PATIENTS AND METHODS Approval was based on the results from PROpel, a double-blind trial that randomly assigned 796 patients with mCRPC to abiraterone plus prednisone or prednisolone with either olaparib or placebo. The primary end point was radiographic progression-free survival (rPFS) per investigator assessment. RESULTS There was a statistically significant improvement in rPFS for olaparib plus abiraterone versus placebo plus abiraterone, with a median rPFS of 25 versus 17 months and a hazard ratio (HR) of 0.66 (95% CI, 0.54 to 0.81) in the intention-to-treat population. In an exploratory analysis of the subgroup of 85 patients with BRCAm mCRPC, the HR for rPFS was 0.24 (95% CI, 0.12 to 0.45) and the HR for overall survival (OS) was 0.30 (95% CI, 0.15 to 0.59). In an exploratory analysis of the subgroup of 711 patients without an identified BRCA mutation, the HR for rPFS was 0.77 (95% CI, 0.63 to 0.96) and the HR for OS was 0.92 (95% CI, 0.74 to 1.14). Adding olaparib to abiraterone resulted in increased toxicity, including anemia requiring transfusion in 18% of patients. CONCLUSION In patients with mCRPC, efficacy of the combination of olaparib plus abiraterone was primarily attributed to the treatment effect in the BRCAm subgroup, the indicated population for the approval. For patients without BRCAm, the FDA determined that the modest rPFS improvement, combined with clinically significant toxicities, did not demonstrate a favorable risk/benefit assessment.

Objectives: Real-world data (RWD) from the clinical care of patients captured through Electronic Health Records (EHRs) is a valuable resource for research. Understanding the relationship between characteristics and outcomes of patients treated in the real world and in oncology clinical trials by producing evaluable trial-like populations from RWD can advance clinical and regulatory knowledge. Methods: RWD from the Flatiron Health EHR-derived, de-identified, longitudinal database were compared with pooled patient-level data from the three randomized controlled trials (RCTs) supporting regular approval of CDK4/6 inhibitors for patients with previously untreated hormone receptor-positive, HER- metastatic breast cancer (mBC). The RCT group included patients who received aromatase inhibitor (AI) monotherapy (RCT-control), and an experimental group (RCT-experimental) that received a cyclin dependent kinase 4/6 (CDK4/6) inhibitor + AI. The real-world control group (rwCG) of patients initiating AI monotherapy was selected using the key eligibility criteria across the RCTs. Patients from the rwCG were matched to the RCT-control and the RCT-experimental patients, respectively. Matching (1:1) was performed through the propensity score (PS) method adjusting for baseline covariates of age, race, site of disease, ECOG PS, and metastatic disease (recurrent, De novo). Multiple imputation (MI) was adopted to impute missing ECOG PS in the rwCG due to the high percentage of missingness. Progression-free survival (PFS) and overall survival (OS) were analyzed for the following groups: A) rwCG and RCT- control B) rwCG and RCT-experimental and C) RCT-control and RCT-experimental. To assess the feasibility of RCT control arm replication, we assessed whether the trial replication hazard ratio (HR) estimates from analysis B were within the published trial estimates’ 95% confidence intervals (CIs). HR and their 95% CIs were estimated using Cox proportional hazard model. Results: A total of 1292 patients were selected from the EHR-derived database to comprise the rwCG and 1827 patients were pooled across the RCTs (1106 for RCT-experimental and 721 patients for RCT-control). With MI, 520 rwCG patients were matched to the RCT-control for analysis A, and 658 rwCG patients were matched to the RCT-experimental for analysis B. The results are summarized in Table 1. The point estimate of the PFS HR comparing the rwCG to the RCT-experimental was within the 95% CIs for three RCTs. For OS, the point estimate of the HR was within the 95% CI for MONALESSA-2 but not for PALOMA-2. Conclusion: PFS and OS appeared longer in the RCT-control than in the rwCG, and the difference was more pronounced in OS. While it appears that there is greater similarity for PFS than for OS based on the results of the matched analysis of RCT- experimental vs. rwCG, evaluation of PFS results are limited by substantial differences in assessment and outcome definitions for progression between RCT-control (RECIST) and rwCG. Despite PS matching, there are apparent differences between patients treated in RCTs and routine practice, highlighting the importance of clinical setting, trial selection, study design, and use of randomization. There are still outstanding feasibility questions on the evaluation of OS and further research is required to understand factors potentially impacting the outcomes between RCTs and RWD. Table 1: Estimated Treatment Effects in PFS and OS, rwCG vs RCT-control vs RCT-experimental Citation Format: Christy Osgood, Jiaxin Fan, Xin Gao, Catherine Keane, Jonathan Bryan, James P. Roose, Erik Bloomquist, Aracelis Torres, Shrujal Baxi, Nathan Nussbaum, Fatima Rizvi, Shenghui Tang, Irene Nunes, Julia Beaver, Donna R. Rivera, Lynn Howie, Prashni Paliwal, Laleh Amiri-Kordestani. Feasibility of generating an external control comparator using RWD by matching with previously conducted RCTs: CDK4/6 Inhibitors for the treatment of Metastatic Breast Cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-13-03.

e16532 Background: Retrospective analyses of individual studies of immune-oncology-containing combinations (IOC) for advanced renal cell carcinoma (aRCC) suggest that depth of response (DepOR; % reduction from baseline in sum of target lesion diameters) is associated with overall survival (OS). However, these analyses are limited by use of DepOR categories with a small number of patients and guarantee-time bias. We therefore sought to investigate the relationship of week 12 DepOR as a continuous variable with OS, hypothesizing not only complete but also deep partial responses might portend favorable longer-term survival. Methods: We pooled data from patients with treatment (tx)-naïve aRCC enrolled in randomized IO-based frontline aRCC trials submitted to FDA that included a Week 12 imaging assessment. We developed 36-month (mo) overall survival (OS) prediction models based on Week 12 DepOR per Independent Review Committee using Cox proportional hazards with natural spline in the IO-TKI combination (IOC) and sunitinib (SUN) groups. To avoid guarantee-time bias, OS was defined from date of an individual patient’s 12-week imaging, among the subset of patients who were alive and in follow-up at the Week 12 scan. Results: Four trials met inclusion criteria (KEYNOTE-426, JAVELIN Renal 100, CheckMate 9ER, CheckMate 214); in total, there were 1364 patients in the IOC group and 1267 patients in the SUN group. Eligibility criteria, baseline patient characteristics, and endpoints were similar both between the trials and between tx groups. Deepest response occurred at median 31 weeks (interquartile range [IQR], 18-55) in the IOC group and 29 weeks (IQR range, 17-48) in the SUN group. At Week 12, 34.7% of patients had DepOR of at least 30%; median DepOR was 27.6% (interquartile range [IQR] 8.7 to 43.4%) in the IOC and 13.7% (IQR 2.5 to 26.3%) in the SUN group. DepOR and 36-month OS were correlated throughout the entire range of DepOR in both tx groups; at each DepOR, the IOC group had slightly higher 36-mo OS over SUN. We saw similar results modeling 24-month OS compared to 36-month OS. Conclusions: This pooled exploratory analysis suggests that deeper response is associated with better 36-month OS in patients treated with IOC or SUN and slightly higher probability of 36-month OS for any given DepOR for IOC vs. SUN. We saw no plateau in OS as DepOR approached complete response. However, caution should be used when interpreting DepOR at the tails due to sparse data. Further work characterizing the relationship between DepOR and OS at the trial level may advance understanding of the utility of DepOR as an early endpoint in signal-seeking trials and to facilitate efficient drug development. Additionally, identifying patients with favorable long-term prognosis based on DepOR provides hypotheses for new trial designs.

PURPOSE The US Food and Drug Administration approved fam-trastuzumab deruxtecan-nxki (DS-8201a, T-DXd) for the treatment of adult patients with unresectable or metastatic human epidermal growth factor receptor 2 (HER2)-low (immunohistochemistry 1 + or immunohistochemistry 2+/in situ hybridization–) breast cancer who have received a prior chemotherapy in the metastatic setting or developed disease recurrence during or within 6 months of completing adjuvant chemotherapy. PATIENTS AND METHODS Approval was based on DESTINY-Breast04, a phase III, randomized, open-label, multicenter trial in patients with unresectable or metastatic HER2-low breast cancer, determined at a central laboratory. A total of 557 patients were randomly assigned (2:1) to receive either T-DXd 5.4 mg/kg intravenously once every 3 weeks (n = 373) or physicians' choice of chemotherapy (n = 184). RESULTS The study met its primary efficacy end point of progression-free survival (PFS) by blinded independent central review assessment in the hormone receptor–positive (HR+) cohort (N = 494) with an estimated hazard ratio (HR) of 0.51(95% CI, 0.40 to 0.64; P < .0001). Key secondary end points were also met, including PFS in the intent-to-treat population with an HR of 0.50 (95% CI, 0.40 to 0.63; P < .0001), overall survival (OS) in the HR+ cohort with an HR of 0.64 (95% CI, 0.48 to 0.86; P = .0028) and OS in the intent-to-treat with an HR of 0.64 (95% CI, 0.49 to 0.84; P = .0010). The safety profile of T-DXd was consistent with previously approved indications, and no new safety signals were observed in this study population. CONCLUSION The approval of T-DXd in HER2-low metastatic breast cancer was based on statistically significant and clinically meaningful PFS and OS improvements observed in the DESTINY-Breast04 trial and represents the first approved therapy specifically for the treatment of HER2-low metastatic breast cancer.

On December 10, 2021, the FDA expanded the indications for ribociclib to include male patients for the treatment of hormone receptor-positive, HER2-negative advanced or metastatic breast cancer. Ribociclib is now indicated in combination with an aromatase inhibitor (AI) as initial endocrine-based therapy in adult patients, or with fulvestrant as initial endocrine-based therapy or following disease progression on endocrine therapy (ET), in postmenopausal women or in men. The efficacy of ribociclib + AI for male patients was primarily based on previous favorable benefit-risk assessments of ribociclib from MONALEESA-2 and MONALEESA-7 trials, and supported by COMPLEEMENT-1, an open-label, single-arm, multicenter clinical trial, in which 39 male patients (n = 3,246 total patients) received ribociclib + letrozole + goserelin/leuprolide. The overall response rate (ORR) based on confirmed responses in male patients with measurable disease at baseline was 46.9% [95% confidence interval (CI), 29.1-65.3], consistent with an ORR of 43.6% (95% CI, 41.5-45.8) in the overall population. Overall, adverse reactions occurring in male patients were similar to those occurring in female patients treated with ribociclib + ET. The efficacy of ribociclib + fulvestrant for male patients was primarily based on the previous findings of a favorable benefit-risk assessment from the MONALEESA-3 trial, supported by FDA review of clinical data of a limited number of male patients treated in clinical practice receiving ribociclib + fulvestrant. The known mechanism of action, biologic rationale, and clinical information available adequately demonstrate that the efficacy and safety of ribociclib + AI/fulvestrant are similar in male and female patients. This article summarizes the FDA's decision-making and data supporting the approval of ribociclib in male patients with breast cancer, and discusses regulatory insights.

In the era of precision oncology, use of circulating tumor DNA (ctDNA) is emerging as a minimally invasive approach for the diagnosis and management of patients with cancer and as an enrichment tool in clinical trials. In recent years, the US Food and Drug Administration has approved multiple ctDNA-based companion diagnostic assays for the safe and effective use of targeted therapies and ctDNA-based assays are also being developed for use with immuno-oncology-based therapies. For early-stage solid tumor cancers, ctDNA may be particularly important to detect molecular residual disease (MRD) to support early implementation of adjuvant or escalated therapy to prevent development of metastatic disease. Clinical trials are also increasingly using ctDNA MRD for patient selection and stratification, with an ultimate goal of improving trial efficiency through use of an enriched patient population. Standardization and harmonization of ctDNA assays and methodologies, along with further clinical validation of ctDNA as a prognostic and predictive biomarker, are necessary before ctDNA may be considered as an efficacy-response biomarker to support regulatory decision making.