Survival outcomes in older men with non-metastatic castration-resistant prostate cancer treated with androgen receptor inhibitors: a US Food and Drug Administration pooled analysis of patient-level data from three randomised trials.

BACKGROUND: Little is known about the benefit-risk profile of second-generation androgen receptor inhibitors in older men with non-metastatic castration-resistant prostate cancer. We aimed to examine the efficacy and safety of second-generation androgen receptor inhibitors in men aged 80 years or older with non-metastatic castration-resistant prostate cancer. METHODS: We searched for all randomised controlled clinical trials evaluating second-generation androgen receptor inhibitors in patients with non-metastatic castration-resistant prostate cancer submitted to the US Food and Drug Administration before Aug 15, 2020, and pooled data from three trials that met the selection criteria. All three trials enrolled patients who were aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0-1, castration-resistant prostate cancer, prostate-specific antigen (PSA) 2·0 µg/L or greater, PSA doubling time of 10 months or less, and no evidence of distant metastatic disease on conventional imaging per the investigator's assessment at the time of screening. All patients had histologically or cytologically confirmed adenocarcinoma of the prostate without neuroendocrine differentiation or small-cell features. All patients who were randomly assigned to androgen receptor inhibitor or placebo groups in these trials were considered assessable and were included in this pooled analysis. We evaluated the effect of age on metastasis-free survival and overall survival across age groups (<80 years vs ≥80 years) in the intention-to-treat population. Safety analyses were done in patients who received at least one dose of study treatment. FINDINGS: Between Oct 14, 2013, and March 9, 2018, 4117 patients were assigned to androgen receptor inhibitor (apalutamide, enzalutamide, or daralutamide; n=2694) or placebo (n=1423) across three randomised trials. The median follow-up duration for metastasis-free survival was 18 months (IQR 11-26) and for overall survival was 44 months (32-55). In patients aged 80 years or older (n=1023), the estimated median metastasis-free survival was 40 months (95% CI 36-41) in the androgen receptor inhibitor groups and 22 months (18-29) in the placebo groups (adjusted hazard ratio [HR] 0·37 [95% CI 0·28-0·47]), and the median overall survival was 54 months (50-61) versus 49 months (43-58), respectively (adjusted HR 0·79 [0·64-0·98]). In patients younger than 80 years of age (n=3094), the estimated median metastasis-free survival was 41 months (95% CI 36-not estimable [NE]) in the androgen receptor inhibitor groups and 16 months (15-18) in the placebo groups (adjusted HR 0·31 [95% CI 0·27-0·35]), and the median overall survival was 74 months (74-NE) versus 61 months (56-NE), respectively (adjusted HR 0·69 [0·60-0·80]). In patients aged 80 years or older, grade 3 or worse adverse events were reported in 371 (55%) of 672 patients in the androgen receptor inhibitor groups and 140 (41%) of 344 patients in the placebo groups, compared with 878 (44%) of 2015 patients in the androgen receptor inhibitor groups and 321 (30%) of 1073 patients in the placebo groups among patients younger than 80 years. The most common grade 3-4 adverse events were hypertension (168 [8%] of 2015 patients aged <80 years and 51 [8%] of 672 patients aged ≥80 years in the androgen receptor inhibitor groups vs 53 [5%] of 1073 patients aged <80 years and 22 [6%] of 344 patients aged ≥80 years in the placebo groups) and fracture (61 [3%] and 36 [5%] in the androgen receptor inhibitor groups vs 15 [1%] and 11 [3%] in the placebo groups). INTERPRETATION: The findings of this pooled analysis support the use of androgen receptor inhibitors in older men with non-metastatic castration-resistant prostate cancer. Incorporating geriatric assessment tools in the care of older adults with non-metastatic castration-resistant prostate cancer might help clinicians to offer individualised treatment to each patient. FUNDING: None.

Arterial aneurysm and dissection with systemic vascular endothelial growth factor inhibitors: A review of cases reported to the FDA Adverse Event Reporting System and published in the literature.

The US Food and Drug Administration (FDA) has approved multiple systemic vascular endothelial growth factor (VEGF) inhibitors since 2004 to treat various malignancies. Inhibition of the VEGF signaling pathway can result in impairment of vascular wall integrity through medial degeneration and endothelial dysfunction, potentially resulting in arterial (including aortic) aneurysm/dissection. We performed a postmarketing review to evaluate arterial aneurysm/dissection as a potential safety risk for patients with cancer treated with VEGF inhibitors. We searched the FDA Adverse Event Reporting System (FAERS) database and literature for reports of arterial (including aortic) aneurysm/dissection with VEGF inhibitors currently approved by the FDA for a cancer indication. We identified 240 cases of arterial aneurysm/dissection associated with VEGF inhibitors. The median time to onset of an arterial aneurysm/dissection event from the initiation of a VEGF inhibitor was 94 days (range 1-1955 days). Notably, 22% (53/240) of cases reported fatal outcomes related to arterial aneurysm/dissection. We determined the drug-event association as probable in 15 cases that lacked relevant confounding factors for arterial aneurysm/dissection, which is supported by unremarkable computed tomography (CT) findings prior to starting VEGF inhibitor therapy, despite nondrug-associated background arterial aneurysm/dissection generally demonstrating preexisting arterial abnormalities. FAERS and literature case-level evidence suggests that VEGF inhibitors may have contributed to arterial aneurysm/dissection, as a class effect, based on short onset relative to natural history of disease and biologic plausibility. Cardiovascular and oncology healthcare professionals should be aware of this rare, but life-threatening safety risk associated with VEGF inhibitors.

FDA Approval Summary: Atezolizumab or Pembrolizumab for the Treatment of Patients with Advanced Urothelial Carcinoma Ineligible for Cisplatin-Containing Chemotherapy.

The U.S. Food and Drug Administration (FDA) granted accelerated approval to atezolizumab and pembrolizumab in April and May 2017, respectively, for the treatment of patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-containing chemotherapy. These approvals were based on efficacy and safety data demonstrated in the two single-arm trials, IMvigor210 (atezolizumab) and KEYNOTE-052 (pembrolizumab). The primary endpoint, confirmed objective response rate, was 23.5% (95% confidence interval [CI]: 16.2%-32.2%) in patients receiving atezolizumab and 28.6% (95% CI: 24.1%-33.5%) in patients receiving pembrolizumab. The median duration of response was not reached in either study and responses were seen regardless of PD-L1 status. The safety profiles of both drugs were generally consistent with approved agents targeting PD-1/PD-L1. Two ongoing trials (IMvigor130 and KEYNOTE-361) are verifying benefit of these drugs. Based on concerning preliminary reports from these trials, FDA revised the indications for both agents in cisplatin-ineligible patients. Both drugs are now indicated for patients not eligible for any platinum-containing chemotherapy or not eligible for cisplatin-containing chemotherapy and whose tumors/infiltrating immune cells express a high level of PD-L1. The indications for atezolizumab and pembrolizumab in patients who have received prior platinum-based therapy have not been changed. This article summarizes the FDA thought process and data supporting the accelerated approval of both agents and the subsequent revision of the indications. IMPLICATIONS FOR PRACTICE: The accelerated approvals of atezolizumab and pembrolizumab for cisplatin-ineligible patients with advanced urothelial carcinoma represent the first approved therapies for this patient population. These approvals were based on single-arm trials demonstrating reasonable objective response rates and favorable durations of response with an acceptable toxicity profile compared with available non-cisplatin-containing chemotherapy regimens. However, based on concerning preliminary reports from two ongoing phase III trials, the FDA revised the indication for both agents in cisplatin-ineligible patients. Both are now indicated either for patients not eligible for any platinum-containing chemotherapy or not eligible for cisplatin-containing chemotherapy and whose tumors have high expression of PD-L1.

Cytoreductive nephrectomy in the era of immune checkpoint inhibitors: a US Food and Drug Administration pooled analysis.

BACKGROUND: This pooled analysis of patient-level data from trials evaluated the clinical outcomes of patients with metastatic renal cell carcinoma with or without cytoreductive nephrectomy before a combination of immune checkpoint inhibitor and antiangiogenic therapy. METHODS: Data from 5 trials of immune checkpoint inhibitors plus antiangiogenic therapy were pooled. Only patients with stage 4 disease at initial diagnosis were included to ensure that nephrectomy was performed for cytoreductive purposes and not to previously treat an earlier stage of disease. The effect of cytoreductive nephrectomy before immune checkpoint inhibitor therapy on outcomes was evaluated using the Kaplan-Meier method and a Cox proportional hazards regression model, adjusted for age, sex, risk group, performance status, and the presence of sarcomatoid differentiation. RESULTS: A total of 981 patients were included. The estimated median progression-free survival with and without nephrectomy was 15 and 11 months, respectively; the adjusted hazard ratio was 0.71 (95% confidence interval = 0.59 to 0.85). The estimated median overall survival with and without nephrectomy was 46 and 28 months, respectively; the adjusted hazard ratio was 0.63 (95% confidence interval = 0.51 to 0.77). Objective response was 60% of patients with vs 46% of patients without cytoreductive nephrectomy. CONCLUSIONS: Patients with metastatic renal cell carcinoma who undergo cytoreductive nephrectomy before immune checkpoint inhibitor plus antiangiogenic therapy had improved outcomes compared with patients without cytoreductive nephrectomy. Selection factors for cytoreductive nephrectomy may be prognostic and could not be fully controlled for in this retrospective analysis. Prospective determination of and stratification by prior cytoreductive nephrectomy may be considered when designing clinical trials to assess the impact of this factor on prognosis.

FDA Approval Summary: Enfortumab Vedotin plus Pembrolizumab for Cisplatin-Ineligible Locally Advanced or Metastatic Urothelial Carcinoma.

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.

Efficacy of Poly(ADP-ribose) Polymerase Inhibitors by Individual Genes in Homologous Recombination Repair Gene-Mutated Metastatic Castration-Resistant Prostate Cancer: A US Food and Drug Administration Pooled Analysis.

PURPOSE: We performed a pooled analysis of multiple trials of poly(ADP-ribose) polymerase inhibitors (PARPi) in metastatic castration-resistant prostate cancer (mCRPC) to investigate the efficacy of PARPi in each individual homologous recombination repair (HRR) mutated (m) gene. PATIENTS AND METHODS: We pooled patient-level data from trials of PARPi in mCRPC that reported mutation status in individual HRR genes. Any HRR gene with available data across all the randomized trials of PARPi in first-line mCRPC was selected. The hazard ratios (HRs; 95% CI) for radiographic progression-free survival (rPFS; by blinded independent review) and overall survival (OS) of a PARPi plus an androgen receptor pathway inhibitor (ARPI) relative to placebo plus an ARPI in the pool of three randomized trials in first-line mCRPC were calculated using Kaplan-Meier estimates and a Cox proportional hazards model. RESULTS: In ATMm (N = 268), rPFS HR was 1.05 (0.74 to 1.49) and OS HR was 1.18 (0.82 to 1.71). In BRCA1m (N = 64), rPFS HR was 0.51 (0.23 to 1.1) and OS HR was 0.74 (0.34 to 1.61). In BRCA2m (N = 422), rPFS HR was 0.31 (0.23 to 0.42) and OS HR was 0.66 (0.49 to 0.89). In CDK12m (N = 164), rPFS HR was 0.50 (0.32 to 0.80) and OS HR was 0.63 (0.39 to 0.99). In CHEK2m (N = 172), rPFS HR was 1.06 (0.67 to 1.66) and OS HR was 1.53 (0.95 to 2.46). In PALB2m (N = 41) rPFS HR was 0.52 (0.23 to 1.17) and OS HR was 0.78 (0.34 to 1.8). CONCLUSION: In this pooled analysis, benefit from PARPi appeared greatest for patients with BRCA1m, BRCA2m, CDK12m, and PALB2m. Given limitations of this exploratory analysis, the apparent lack of benefit from PARPi in patients with CHEK2m or ATMm should be further explored in future clinical trials.

A Pooled Analysis of Treatment-Free Survival in Advanced Renal Cell Carcinoma.

PURPOSE: A clinically meaningful attribute of some immune-oncology (IO) regimens is potential durable clinical benefit during a treatment-free interval. We characterize treatment-free survival (TFS) with and without ongoing toxicity in trials of frontline IO-VEGF tyrosine kinase inhibitor (TKI) combinations in patients with advanced renal cell carcinoma (aRCC). EXPERIMENTAL DESIGN: Individual patient data were pooled by treatment arm from randomized trials submitted to the FDA evaluating IO-TKI combination in treatment-naïve aRCC with at least 30 months of median follow-up. OS, TFS, TFS with and without toxicity, and time to all protocol therapy cessation were assessed. TFS was estimated by 30-month restricted mean times, defined as area between Kaplan-Meier curves for two time-to-event endpoints originating at randomization: time to all protocol therapy cessation and time to subsequent systemic therapy initiation or death. RESULTS: Three trials met criteria for analysis; 1,183 patients received IO-TKI versus 1,184 on control arms receiving TKI alone (sunitinib, SUN). IO-TKI and SUN groups spent 9% {2.7 months [95% confidence interval (CI), 1.8-3.5]} and 10% [2.9 months (95% CI, 2.1-3.8)] of the 30-month period alive and treatment-free, respectively. Mean TFS without grade ≥3 toxicity was 1.7 and 2.3 months in IO-TKI and SUN groups, respectively. CONCLUSIONS: In this post hoc partitioned survival analysis, TFS and TFS without toxicity appeared similar in the IO-TKI group compared with the SUN group. These findings may reflect contin-uation of TKI until progression per protocol design in all trials and discontinuation of IO after 2 years in two trials. See related commentary by Stadler and Karrison, p. 3098.

A U.S. Food and Drug Administration-pooled Analysis of Frontline Combination Treatment Survival Benefits by Risk Groups in Metastatic Renal Cell Carcinoma.

BACKGROUND: While frontline immuno-oncology/tyrosine kinase inhibitor (IO/TKI) combination therapy has established a benefit in metastatic renal cell carcinoma (mRCC), this may differ by International Metastatic RCC Database Consortium (IMDC) risk grouping. Looking at individual trials, we noted an apparently smaller magnitude of benefit for favorable-risk disease. OBJECTIVE: We aimed to assess treatment benefit by risk groupings, especially in favorable-risk, augmenting patient numbers via a pooled analysis. DESIGN, SETTING, AND PARTICIPANTS: We pooled four frontline mRCC trials of IO/TKI combinations including 3,098 patients (839 favorable-risk) with approvals from 2019 to 2021. INTERVENTION: All trials used IO/TKI combinations as the treatment option and sunitinib as the control. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We analyzed progression-free survival (PFS) and overall survival (OS) by IMDC groupings. To specifically address the favorable-risk group, we combined all others into an intermediate/poor-risk group. RESULTS AND LIMITATIONS: In this exploratory analysis adjusted for baseline covariates, IO/TKI combinations have yet to demonstrate an OS benefit in favorable-risk (hazard ratio [HR] 1.24; 95% confidence interval [CI]: 0.86, 1.78) despite demonstrating an OS benefit in the intermediate/poor-risk group (HR 0.64; 95% CI: 0.55, 0.75). In contrast, IO/TKI demonstrated a PFS benefit for both the favorable-risk (HR 0.63; 95% CI: 0.50, 0.79) and the intermediate/poor-risk (HR 0.52; 95% CI: 0.45, 0.60) group. For objective response rate, a smaller difference was observed between the combination and sunitinib arms in favorable-risk (68.2% vs 49.9%) versus intermediate/poor-risk (59.9% vs 36.5%) groups, while the difference in complete response rate was larger for favorable-risk (15.3% vs 6.0%) versus intermediate/poor-risk (9.1% vs 3.4%) groups. CONCLUSIONS: The frontline IO/TKI combination therapy benefit was shown to be greater in the intermediate/poor-risk group than in the favorable-risk group. The OS benefit observed with IO/TKI for mRCC has yet to be demonstrated for favorable-risk patients; longer follow-up is needed. PATIENT SUMMARY: Patients with intermediate/poor-risk metastatic renal cell carcinoma derive an overall survival benefit from immuno-oncology/tyrosine kinase inhibitor combinations, while data for favorable-risk remain immature.

Use of Single-Arm Trials for US Food and Drug Administration Drug Approval in Oncology, 2002-2021.

Importance: Single-arm trials have allowed for transformative therapies to be made available to patients expeditiously. However, using single-arm trials to support drug approval presents several challenges that must be carefully considered. Observations: Between January 1, 2002, and December 31, 2021, the US Food and Drug Administration granted 176 new malignant hematology and oncology indications based on single-arm trials, including 116 accelerated approvals (AAs) and 60 traditional approvals. Overall, 87 approvals (49%) were for new molecular entities or original biologics and 89 (51%) were supplemental indications. Response rate (RR) was the most common end point used to support approval in these single-arm trials (173 of 176 [98%]). Of the 116 AAs based on single-arm trials, 45 (38%) fulfilled their postmarketing requirement to verify clinical benefit, 61 (52%) are pending verification of benefit, and 10 (9%) were withdrawn from the market as of December 31, 2021. Most (56 of 61 [92%]) AAs based on single-arm trials pending verification of benefit occurred during the previous 5 years and have ongoing confirmatory trials as of December 2021. Conclusions and Relevance: Single-arm trials have been a common development strategy to support regulatory approval as early-stage expansion cohorts with promising durable RRs have become more prevalent. In the appropriate context, single-arm trials using durable RRs can allow patients expedited access to novel therapies and will continue to serve a role in advancing drug development in oncology. However, single-arm trials have a smaller noncomparative safety data set, inability to use time-to-event end points, and other limitations that require careful consideration within the context of the disease and available therapies. The randomized clinical trial remains the preferred approach in clinical investigation.

FDA Approval Summary: Lutetium Lu 177 Vipivotide Tetraxetan for Patients with Metastatic Castration-Resistant Prostate Cancer.

On March 23, 2022, the FDA approved Pluvicto (lutetium Lu 177 vipivotide tetraxetan, also known as 177Lu-PSMA-617) for the treatment of adult patients with prostate-specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer (mCRPC) who have been treated with androgen receptor pathway inhibition and taxane-based chemotherapy. The recommended 177Lu-PSMA-617 dose is 7.4 gigabecquerels (GBq; 200 mCi) intravenously every 6 weeks for up to six doses, or until disease progression or unacceptable toxicity. The FDA granted traditional approval based on VISION (NCT03511664), which was a randomized (2:1), multicenter, open-label trial that assessed the efficacy and safety of 177Lu-PSMA-617 plus best standard of care (BSoC; n = 551) or BSoC alone (n = 280) in men with progressive, PSMA-positive mCRPC. Patients were required to have received ≥1 androgen receptor pathway inhibitor, and one or two prior taxane-based chemotherapy regimens. There was a statistically significant and clinically meaningful improvement in overall survival (OS), with a median OS of 15.3 months in the 177Lu-PSMA-617 plus BSoC arm and 11.3 months in the BSoC arm, respectively (HR: 0.62; 95% confidence interval: 0.52-0.74; P < 0.001). The most common adverse reactions (≥20%) occurring at a higher incidence in patients receiving 177Lu-PSMA-617 were fatigue, dry mouth, nausea, anemia, decreased appetite, and constipation. The most common laboratory abnormalities that worsened from baseline in ≥30% of patients receiving 177Lu-PSMA-617 were decreased lymphocytes, decreased hemoglobin, decreased leukocytes, decreased platelets, decreased calcium, and decreased sodium. This article summarizes the FDA review of data supporting traditional approval of 177Lu-PSMA-617 for this indication.

Advancing Clinical Trial Design for Non-Muscle Invasive Bladder Cancer.

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.

Clinical Evidence Generation During a Pandemic: Lessons Learned for Sustaining Progress.

ABSTRACT: Because of significant adaptations forced by the COVID-19 pandemic, resultant changes within health care delivery and clinical research introduced the potential for evaluation of novel evidence generation approaches in oncology. On July 26 and 27, 2021, the National Academies of Science, Engineering, and Medicine, National Cancer Policy Forum hosted a virtual workshop entitled "Cancer Care and Cancer Research in the Context of the COVID-19 Pandemic: A Workshop on Lessons Learned." This workshop examined changes in cancer care and cancer research that occurred in response to the COVID-19 pandemic and considered lessons learned from that experience. The goal was to identify what changes could improve the delivery of high-quality cancer care and the conduct of cancer clinical trials in the postpandemic era, with an emphasis on health equity. How can we sustain the valuable lessons learned that might accelerate progress and enhance clinical evidence generation for patients and clinicians? In this overview, we discuss ways in which the COVID-19 experience has catalyzed research efficiencies as well as fostered a broader array of trial design and research methods that may facilitate improved cancer drug development during the pandemic and beyond.

FDA Oncology Center of Excellence Project Renewal: Engaging the Oncology Community to Update Product Labeling for Older Oncology Drugs.

The FDA conducts independent reviews of scientific data obtained with investigational drug products to ensure that they are safe and effective. As a result of this process, FDA-approved product labeling is generated that is considered one of the most trusted sources of information for use of an approved drug. But FDA approval is only the beginning of the life cycle of a new drug; the first oncology drugs now have more than 7 decades of clinical experience in the postmarketing setting. Due, in part, to lack of incentives, some companies may not seek inclusion of new data, other than new safety information, in FDA-approved product labeling. Ensuring that product labeling provides adequate directions for use is important for all drugs, including older therapies that may form the backbone of many standard combination regimens for pediatric and adult cancers. Project Renewal is an FDA Oncology Center of Excellence pilot program that leverages expertise from the clinical and scientific oncology communities to review published literature and generate a drug-specific product report summarizing data that may support updates to FDA-approved product labeling. This article provides a broad overview of Project Renewal's collaborative pilot process for identifying and assessing literature supporting potential labeling updates, while engaging the oncology community to increase awareness of FDA's evidentiary standards and deliberative processes used when considering the addition of new indications and dosing regimens to product labeling.

Eligibility and Radiologic Assessment for Adjuvant Clinical Trials in Kidney Cancer.

PURPOSE: To harmonize the eligibility criteria and radiologic disease assessment definitions in clinical trials of adjuvant therapy for renal cell carcinoma (RCC). METHOD: On November 28, 2017, US-based experts in RCC clinical trials, including medical oncologists, urologic oncologists, regulators, biostatisticians, radiologists, and patient advocates, convened at a public workshop to discuss eligibility for trial entry and radiologic criteria for assessing disease recurrence in adjuvant trials in RCC. Multiple virtual meetings were conducted to address the issues identified at the workshop. RESULTS: The key workshop conclusions for adjuvant RCC therapy clinical trials were as follows. First, patients with non-clear cell RCC could be routinely included, preferably in an independent cohort. Second, patients with T3-4, N+M0, and microscopic R1 RCC tumors may gain the greatest advantages from adjuvant therapy. Third, trials of agents not excreted by the kidney should not exclude patients with severe renal insufficiency. Fourth, therapy can begin 4 to 16 weeks after the surgical procedure. Fifth, patients undergoing radical or partial nephrectomy should be equally eligible. Sixth, patients with microscopically positive soft tissue or vascular margins without gross residual or radiologic disease may be included in trials. Seventh, all suspicious regional lymph nodes should be fully resected. Eighth, computed tomography should be performed within 4 weeks before trial enrollment; for patients with renal insufficiency who cannot undergo computed tomography with contrast, noncontrast chest computed tomography and magnetic resonance imaging of the abdomen and pelvis with gadolinium should be performed. Ninth, when feasible, biopsy should be undertaken to identify any malignant disease. Tenth, when biopsy is not feasible, a uniform approach should be used to evaluate indeterminate radiologic findings to identify what constitutes no evidence of disease at trial entry and what constitutes radiologic evidence of disease. Eleventh, a uniform approach for establishing the date of recurrence should be included in any trial design. Twelfth, patient perspectives on the use of placebo, conditions for unblinding, and research biopsies should be considered carefully during the conduct of an adjuvant trial. CONCLUSIONS AND RELEVANCE: The discussions suggested that a uniform approach to eligibility criteria and radiologic disease assessment will lead to more consistently interpretable trial results in the adjuvant RCC therapy setting.

Regulatory Considerations for Contribution of Effect of Drugs Used in Combination Regimens: Renal Cell Cancer Case Studies.

The development and review of combination drug regimens in oncology may present unique challenges to investigators and regulators. For regulatory approval of combination regimens, it is necessary to demonstrate the contribution of effect of each monotherapy to the overall combination. Alternative approaches to traditional designs may be needed to accelerate oncology drug development, for example, when combinations are substantially superior to available therapy, to reduce exposure to less effective therapies, and for drugs that are inactive as single agents and that in combination potentiate activity of another drug. These approaches include demonstration of activity in smaller randomized trials and/or monotherapy trials conducted in a similar disease setting. This article will discuss alternative approaches used in the development of approved drugs in combination, based on examples of recent approvals of combination regimens in renal cell carcinoma.

Eligibility and Radiologic Assessment in Adjuvant Clinical Trials in Bladder Cancer.

Objective: To harmonize eligibility criteria and radiographic disease assessments in clinical trials of adjuvant therapy for muscle-invasive bladder cancer (MIBC). Methods: National experts in bladder cancer clinical trial research, including medical and urologic oncologists, radiologists, biostatisticians, and patient advocates, convened at a public workshop on November 28, 2017, to discuss eligibility, radiographic entry criteria, and assessment of disease recurrence in adjuvant clinical trials in patients with MIBC. Results: The key workshop conclusions for adjuvant MIBC clinical trials included the following points: (1) patients with urothelial carcinoma with divergent histologic differentiation should be allowed to enroll; (2) neoadjuvant chemotherapy is defined as at least 3 cycles of neoadjuvant cisplatin-based combination chemotherapy; (3) patients with muscle-invasive, upper-tract urothelial carcinoma should be included in adjuvant trials of MIBC; (4) patients with severe renal insufficiency can enroll into trials using agents that are not renally excreted; (5) patients with microscopic surgical margins can be included; (6) patients should undergo a standard bilateral lymph node dissection prior to enrollment; (7) computed tomographic (CT) imaging should be performed within 4 weeks prior to enrollment. For patients with renal insufficiency who cannot undergo CT imaging with contrast, noncontrast chest CT and magnetic resonance imaging of the abdomen and pelvis with gadolinium should be done; (8) biopsy of indeterminate lesions to evaluate for malignant disease should be done when feasible; (9) a uniform approach to evaluate indeterminate radiographic lesions when biopsy is not feasible should be included in any trial design; (10) a uniform approach to determining the date of recurrence is important in interpreting adjuvant trial results; and (11) new high-grade, upper-tract primary tumors and new MIBC tumors should be considered recurrence events. Conclusions and Relevance: A uniform approach to eligibility criteria, definitions of no evidence of disease, and definitions of disease recurrence may lead to more consistent interpretations of adjuvant trial results in MIBC.

The awl-staple versus guidewire method for placing vertebral screws in thoracoscopic anterior spinal fusion and instrumentation for adolescent idiopathic scoliosis.

STUDY DESIGN: A retrospective chart and radiograph review in a consecutive series of patients at a single institution. OBJECTIVE: To compare 2 methods of placing vertebral body screws in thoracoscopic anterior spinal fusion and instrumentation with respect to radiographic, clinical, and perioperative variables. SUMMARY OF BACKGROUND DATA: Placing vertebral body screws in thoracoscopic anterior spinal fusion and instrumentation for adolescent idiopathic scoliosis can be performed using 2 methods: the awl/staple technique and the guidewire method. There are no current studies that have compared both of these techniques. METHODS: Two groups of patients were analyzed depending on the method of screw placement: The AS group (n=15) used the awl/staple method and the GW group (n=27) used the guidewire method. Surgical times and estimated blood loss were obtained from the medical record. Fluoroscopy times were obtained from the radiology technician. Preoperative posteroanterior standing, bending, and immediate postoperative radiographs were examined to determine the primary curve magnitude, postoperative curve correction, curve flexibility, and the Lenke classification. RESULTS: The AS group had significantly less fluoroscopy times (156.6+/-71.4 vs. 328.4+/-171.6 s) and operative times (416.1+/-65.4 vs. 505.6+/-61.8 min) compared with the GW group (P<0.05). When calculating the duration per fusion level, the AS group was also shorter for fluoroscopy times (27.1+/-13.2 vs. 49.3+/-24.5 s/level) (P<0.05) and surgical times (72.0+/-15.2 vs. 76.9+/-9.8 min/level) (P=0.10). There was a trend toward a lower incidence of screw plow or pullout (0.0% vs. 14.8%) for the AS group (P=0.157). CONCLUSIONS: The awl/staple technique is the preferred technique for placing vertebral body screws when performing thoracoscopic anterior spinal fusion/instrumentation because it has shorter fluoroscopy times, surgical times, and a lower incidence of screw plow/pullout than the traditional guidewire method.