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ImportanceSingle-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.ObservationsBetween 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postmarketing requirement to verify clinical benefit, 61 (52%) are pending verification of benefit, and 10 (9%) were withdrawn from the market as of December 31, 2021.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 RelevanceSingle-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.

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.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.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 aged80 years and 51 [8%] of 672 patients aged ≥80 years in the androgen receptor inhibitor groups vs 53 [5%] of 1073 patients aged80 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).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.None.

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.

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.

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.

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.

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.

Supplemental material, sj-docx-1-vmj-10.1177_1358863X211006470 for 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 by Connie Cheng, Michelle Nadeau Nguyen, Afrouz Nayernama, S Christopher Jones, Michael Brave, Sundeep Agrawal, Laleh Amiri-Kordestani and Daniel Woronow in Vascular Medicine

e13572 Background: Improved understanding of the underlying biology of cancer has led to a paradigm shift in cancer drug development and has paved the way for many products to receive accelerated or regular approval based on non-randomized/single arm trials (SATs). Given the high unmet medical need of cancer patients, challenges with lengthy and confounded survival endpoints, and difficulty enrolling rare biomarker-defined subsets of disease, SATs have been used to evaluate a variety of cancer therapies. Unlike time to event endpoints, the objective and clinically relevant endpoint of response rate (RR) and duration of response is interpretable in SATs, as spontaneous tumor shrinkage is not expected. Methods: A search of FDA databases identified all drugs and biologics approved for malignant hematology and oncology indications from January 1, 2001, to December 31, 2020 based on SATs. Data sources included approval letters, U.S. prescribing information, and clinical review documents. The definition of response varied by setting and time period (e.g. RECIST, WHO, IWG, etc.). Results: Between January 1, 2001 and December 31, 2020, FDA granted 153 new indications based on SATs, including 102 accelerated approvals (AAs) and 51 regular approvals (RAs). Overall, 69 approvals (45%) were for new molecular entities and 84 (55%) were expanded indications. Response rate was the most common endpoint used in the trial providing substantial evidence of efficacy to support approval [120/153, (78%)]. The durability of response was also considered to support evidence of clinical benefit. Of the 102 AAs, 38 (37%) have fulfilled their post-marketing requirement (PMR) to verify clinical benefit, 59 (58%) are pending verification of benefit, and 5 (5%) have been withdrawn from the market. Of note, 88% (52/59) of AAs pending verification of benefit occurred in the last 5 years alone (22 AAs in 2020, 8 in 2019, 8 in 2018, 12 in 2017, and 2 in 2016). Between 2001-2020, 58 (38%) new indications were granted for kinase inhibitors, 34 (22%) for immune checkpoint inhibitors (CPIs), and 61 (40%) for drugs with other mechanisms of action including but not limited to antibody-drug conjugates, cytotoxic drugs, and non-CPI monoclonal antibodies. Conclusions: In the last two decades, SATs have been effectively used to study anti-cancer therapies in well-defined patient populations using durable RR as an objective and interpretable clinical endpoint. Although randomized clinical trials remain the gold standard in clinical research, SATs have allowed for rapid advancements in oncology drug development and will continue to serve an important role in bringing new therapies to patients with unmet need.

4516 Background: Immunotherapy-based combination therapies (IO-X) are standard of care for metastatic RCC (mRCC) in the frontline setting. Limited data is available on the role of cytoreductive nephrectomy prior to IO-X in patients (pts) with mRCC (Bakouny, et al. GU ASCO 2020). We assessed the correlation between nephrectomy prior to IO-X and overall survival (OS) in pts with de novo mRCC. Methods: We pooled data from trials submitted for FDA review of a checkpoint inhibitor combination as first-line treatment for pts with mRCC. We only included trials with available data for stage at initial diagnosis (dx) to identify pts with stage IV disease at initial dx and to exclude those with nephrectomy in the non-metastatic setting. Kaplan-Meier method was used to estimate median OS in pts with de novo mRCC with and without nephrectomy prior to IO-X. Results: Five trials met inclusion criteria, all of which evaluated IO in combination with a kinase inhibitor. Data for stage at initial dx was available in 1708 pts who received IO-X. The majority of pts were male (72%) and White (80%). Among the 849 pts (50%) with stage IV RCC at initial dx, 523 pts (62%) had nephrectomy prior to IO-X. All pts had clear cell histology; Sarcomatoid differentiation was present in tumor pathology of 25% and 10% of pts with and without prior nephrectomy, respectively. Proportion of pts with favorable, intermediate and poor risk disease was 10%, 70% and 20%, respectively. OS appeared better in those with stage IV disease at dx who had prior nephrectomy compared to pts without nephrectomy (Hazard ratio (HR) = 0.53, 95% CI: 0.42, 0.68), even after adjusting for age and prognostic risk group (HR = 0.59, 95% CI: 0.46, 0.75) (see table). Conclusions: In this retrospective exploratory analysis, nephrectomy prior to IO-X in pts with new dx of stage IV RCC appeared to be associated with improved OS, even when controlling for age and prognostic risk group. The decision for nephrectomy is affected by factors such as medical comorbidities which could not be completely controlled. Results should be considered hypothesis generating.[Table: see text]

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]

12038 Background: The FDA has approved three androgen receptor (AR) inhibitors for nonmetastatic castration-resistant prostate cancer (nmCRPC) based on improvements in metastasis-free survival (MFS). MFS is an earlier endpoint, defined as the time from randomization to either imaging-detectable distant disease or death. This pooled analysis examines MFS, time to initiation of cytotoxic chemotherapy (TTCyto), and safety outcomes in men over 80 treated with AR inhibitors. Methods: Data was pooled from three randomized controlled studies (n=4117) of AR inhibitors for nmCRPC. The treatment effect of AR inhibitors on MFS and TTCyto across age groups was evaluated using Kaplan-Meier estimates and a Cox proportional hazards regression model. Hazard Ratios for MFS and TTCyto were adjusted for baseline ECOG, total Gleason score, PSA doubling time, and prior bone-targeting therapy. Results: For patients age 80 years or older (n=675) who were treated with AR inhibitors, the hazard ratio was 0.38 (95% CI 0.29, 0.49) with an estimated median MFS of 40 months (95% CI 36, 41) versus 22 months (95% CI 18, 29) for those treated with placebo (n=348). For patients

5045 Background: Although recent evidence has suggested that patients who receive antibiotics (ABX) during the course of ICI treatment might decrease overall survival (OS) (1), our previous analysis did not support a difference in OS in urothelial cancer patients who did and did not use ABX during the course of ICI treatment without regard to timing (2). This updated analysis aims to addresses the question of timing; specifically, use of ABX in the 30-day window pre- or post- initiation of ICI treatment. Methods: We pooled data from 7 trials that led to drug approval and which included 1747 patients with advanced urothelial cancer treated with an ICI. Five trials enrolled patients who received prior platinum and 2 enrolled cisplatin-ineligible patients. Concomitant medication datasets were searched for systemic ABX use. The association between ABX use and survival was evaluated using Kaplan-Meier estimates and Cox proportional hazards regression models stratified by study. Results: Overall, 56% of patients were exposed to antibiotics (ABX+) and 43% were not exposed (ABX-). In an exploratory analysis, median OS was similar between arms: 9.7 vs. 9.3 months in ABX+ vs. ABX- patients, respectively (HR 0.96). However, OS results differed in the 27% of patients who were exposed to antibiotics in the 30-day window pre- or post- initiation of ICI treatment, for whom median OS was 4.7 months vs. 11.5 months in the ABX+ vs. ABX- patients, respectively (HR 1.8). This remained true after controlling for baseline risk prognostic factors (Bajorin and Bellmunt scores). Similar trends were observed for progression-free survival (PFS). Conclusions: Patients treated with ABX while on therapy with an ICI for urothelial cancer had similar OS outcomes to those not treated with ABX. However, in an exploratory analysis looking at ABX use in the 30-day window pre- or post-initiation of ICI treatment, OS appeared decreased in ABX+ vs ABX- patients. Our exploratory analyses appear to show an association of OS/PFS with timing of antibiotics. References: 1) Routy B, Science (2017) 2) Weinstock C, ASCO 2019, abstract. [Table: see text]

e19101 Background: Efficient and thoughtful collection of PROs in randomized cancer trials is necessary, especially when comparing drugs with differing administration schedules. Assessment timing for PROs can dramatically influence results. We sought to better understand how different assessment schedules affect interpretation of toxicity using PRO data. Methods: We reviewed 3 randomized trials in advanced/metastatic RCC with a control arm of sunitinib administered 4 weeks on/2 weeks off. All 3 trials used FACT Kidney Symptom Index (FKSI-19 or -DRS) and one also used EORTC QLQ-C30. For each trial, we chose patient-reported diarrhea and bone pain due to their strong association with the therapeutic intervention and the disease, respectively. Results: For the first 12 weeks, all trials had PRO assessments at baseline but had differing schedules thereafter. PRO assessment in Trial 1 was every 3 weeks; Trial 2: week 6 and week 12; Trial 3: every 3 weeks on the investigational arm and at weeks 4, 6, 10 and 12 on the sunitinib arm. Notably, all assessments for Trial 2 were after 2-week sunitinib washout while Trials 1 and 3 had assessments before and after washout. The table shows the percentage of patients who experienced any worsening from baseline in diarrhea and bone pain in the first 2 assessments. In each trial, more patients had worsening following periods of treatment versus washout on the sunitinib arm, with no such fluctuation on the non-sunitinib arms. The pattern was more apparent for diarrhea (treatment-related) than for bone pain (disease-related). Conclusions: Patients’ recall of symptoms may vary depending on the timing of PRO assessments in relation to drug administration and may be more prominent with respect to treatment-related symptoms, as disease-related symptoms are less impacted by drug toxicity and washout. Clinical protocols should carefully consider PRO assessment timing in relation to drug administration to improve interpretation of toxicity. Higher fidelity PRO data can be obtained with weekly collection of symptoms during the first few months of cancer clinical trials. [Table: see text]

This article summarizes the data supporting FDA approval of atezolizumab and pembrolizumab for the treatment of patients with advanced urothelial carcinoma ineligible for cisplatin‐based chemotherapy and the subsequent revision of the indications for both agents., 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.

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.

4557 Background: Previous data has suggested that patients treated with anti-PD-1/L1 antibodies who receive antibiotics during their therapy might have dramatically decreased progression-free and overall survival 1,2. This has clinical implications for management of patients with suspected bacterial infection while on treatment with these agents. We assessed the relationship between antibiotic use and tumor response rate, progression-free survival, and overall survival in a large dataset of patients with urothelial cancer treated with anti-PD-1/L1 antibodies. Methods: We examined seven trials that led to drug approval and which included 1747 patients with metastatic or locally advanced urothelial cancer treated with an anti-PD-1/L1 antibody. Five trials enrolled patients who had received prior platinum-based therapy and two enrolled patients who were cisplatin-ineligible. Six were single arm trials and one was a randomized controlled trial whose control arm is not included in these analyses. Concomitant medication datasets were searched for systemic antibiotic used by each patient while on treatment. Results: Overall, 51% of patients (n=892) were exposed to antibiotics (ABX+) and 49% (n=855) were not exposed (ABX-). In these exploratory analyses, small numeric differences in OS, PFS, and ORR were seen in ABX+ vs. ABX- patients. Median OS was 9.23 vs. 9.86 months, median PFS was 105 vs 101 days, and ORR was 20% vs. 21% in ABX+ vs. ABX- patients, respectively. Conclusions: Patients who were treated with antibiotics while on therapy with an anti-PD-1/L1 antibody for urothelial cancer had similar outcomes to those who were not treated with antibiotics. Numeric differences in outcomes were not significant and did not duplicate previous analysis demonstrating a median OS that was doubled in ABX- patients1. Our exploratory analyses do not appear to demonstrate a clear need for practitioners to avoid antibiotic use in patients treated with PD-1/L1 agents for fear of significantly impacting clinical outcomes. References: 1) Tinsley et. al., ASCO annual meeting 2018, abstract 3010 2) Routy et. al., Science 05 Jan 2018: Vol. 359, Issue 6371. [Table: see text]

4556 Background: Registrational trials of PD-1/PD-L1 inhibitor therapy help inform clinicians and patients about the expected outcomes of patients receiving these drugs. However, the clinical trial population does not reflect all patients with the underlying disease. There have been ongoing efforts to expand eligibility criteria for clinical trial enrollment that are expected to mitigate some of these factors. We reviewed four registrational trials of PD-1/PD-L1 inhibitor therapy to better understand why patients were deemed ineligible for trial enrollment and whether expanded eligibility criteria may have addressed the reasons for ineligibility. Methods: We reviewed four trials that led to approval of PD-1/PD-L1 inhibitor therapy. These trials screened 1931 and enrolled 1253 patients with metastatic or locally advanced urothelial cancer who had previously received platinum-based therapy. We examined the datasets to determine patient demographics and reasons for trial ineligibility. Results: There were no differences in the demographics characteristics of patients who were eligible or ineligible for study treatment. However, when compared to the SEER database the screened population was younger, and minorities were under-represented. Causes of patient ineligibility included: 1) Lack of Tumor Tissue/PD-L1 Low Tumor Staining (23%), 2) Underlying Disease characteristics were not met (19%), 3) Laboratory Abnormalities (18%), 4) Excluded Co-morbid Conditions (16%), 5) Poor Performance Status (15%), 6) Refused Consent (10%), 7) Other (7%), and 8) Incorrect Prior Therapy (5%). Conclusions: Clinical trial accrual should be representative of all patients with the underlying disease. Changes in trial eligibility criteria such as less stringent requirements concerning tumor tissue (when possible), co-morbid conditions, laboratory abnormalities, and performance status may improve patient accrual. These, when added together, formed the majority of the reasons for clinical trial ineligibility.

4549 Background: To assess the relationship between tumor response rate, overall survival, and the development of related adverse events of special interest (AESIs) or related immune-mediated adverse events (imAEs) in patients with urothelial cancer treated with anti-PD-1/L1 antibodies. Methods: We examined seven trials that led to drug approval and which included 1747 patients with metastatic or locally advanced urothelial cancer treated with an anti-PD-1/L1 antibody. Five trials enrolled patients who had received prior platinum-based therapy and two enrolled patients who were cisplatin-ineligible. The datasets were searched for AESIs, related AESIs, imAEs, and related imAEs. The relationship to study drug was determined by the Investigator. Immune-mediated adverse events were defined as AESIs treated with topical or systemic corticosteroids. Results: In these exploratory analyses, a related AESI was reported in 64% of responding patients and in 34% of patients who did not respond to the anti-PD-1/L1 antibody while a related imAE occurred in 28% and 12% of patients who did and did not respond to study drug, respectively. In a responder analysis, an increase in overall survival was seen in patients with related AESIs compared to those with no related AESI [hazard ratio (HR) 0.42; 95% CI: 0.37, 0.49]. Fifty-seven percent of responding patients with a related AESI reported a related AESI prior to documentation of response. Conclusions: Patients who responded to treatment with an anti-PD-1/L1 antibody were more likely to report a related AESI or related imAE. This relationship did not appear to be due to the increased duration of exposure in responding patients. Systemic corticosteroid use did not appear to affect the duration of response.

2565 Background: PD-1/L1 inhibitor therapy has become the standard of care for many advanced solid tumors. A notable limitation of PD-1/L1 inhibitor therapy is the concern for AESI that are likely to be immune related. It is unclear whether a history of autoimmune events is a predisposing risk making these adverse events more likely. We aimed to evaluate the association between autoimmune-associated PMH and AESI on PD-1/L1 inhibitors. Methods: We pooled data across seven pivotal trials for PD-1/L1 inhibitors in urothelial cancer (UC) identifying patients with AESI submitted from 2016 - 2017. AESI were determined using a pooled preferred term list for each trial. Information collected from trials included PMH, AESI events and toxicity grade. Results: In total, 1747 immunotherapy treated patients were identified, with 1068 (61%) having an AESI and 277 (26%) having an autoimmune-related PMH. The most common autoimmune-associated events in the PMH were thyroid disorders (64%), asthma (23%), atopic dermatitis/eczema (6%), irritable bowel syndrome (5%), and psoriasis (4%). AESI occurred in 68% of patients with an autoimmune-related PMH and 60% of patients without an autoimmune-related PMH. The most common AESI in patients with an autoimmune-related PMH were diarrhea (35%), rash (27%), renal disorder (27%), and pruritis (23%). The most common AESI in the general trial population were diarrhea (28%), pruritis (26%), rash (25%), increased creatinine (14%), and elevated AST and ALT (10% and 9%). The majority of events were Grade 1-2 (87% in patients with an autoimmune-related PMH and 84% in the general trial population). Conclusions: Pooled clinical trial data shows a slight numeric increase in AESIs in patients with autoimmune-associated PMH. Limitations include potential lack of consistency of PMH documentation and adverse event reporting. There did not appear to be a pattern of association between PMH and type of AESI event. Grades of AESI events in the population with autoimmune-associated PMH were similar to the general trial population. This suggests that PD-1/L1 inhibitors may be safely administered to patients with UC and a PMH of some autoimmune-associated events. Further exploration is needed.

Background: In developmental dysplasia, Pavlik harness treatment of hips with a positive Ortolani sign fails in up to 40% of such patients; however, no study has described factors for failure associated with ultrasonographic parameters. The goal of this study was to describe unique ultrasonographic markers in hips with a positive Ortolani sign that are associated with Pavlik harness failure. Methods: A retrospective review was performed of all patients less than six months old who were treated for developmental dysplasia of the hip with a Pavlik harness from 1991 to 2005 at a single institution. Inclusion criteria for this study were patients with a hip that was dislocated but reducible (a positive Ortolani sign), treatment with a Pavlik harness, and an ultrasound examination performed within four weeks after the initiation of treatment. The initial coronal ultrasound studies were graded with use of the Graf classification, the percentage of femoral head coverage, labral morphology, and two new measurements: superior femoral head displacement relative to the labrum and total femoral head displacement. Results: Eighty-five patients with 115 hips fitting the inclusion criteria were identified. Pavlik harness treatment was successful in seventy-two hips (63%) and failed in forty-three hips (37%). Increased beta angle, decreased femoral head coverage, an inverted labrum, decreased superior femoral head displacement relative to the labrum, and decreased total femoral head displacement were significantly correlated with Pavlik harness failure (p < 0.001 for all). A finding of 0° of superior femoral head displacement relative to the labrum was seen in 98% of the hips with successful Pavlik harness treatment. Total femoral head displacement of less than −30° was found in 89% of the hips with a failure of Pavlik harness treatment. Conclusions: We identified two new objective measurements on static ultrasound examinations of the hip that are associated with the outcome of Pavlik harness treatment in patients with developmental dysplasia and a positive Ortolani sign. A femoral head positioned below the labrum is strongly associated with success of the Pavlik harness treatment, whereas a hip with a femoral head that is located substantially superior and lateral to the labrum is associated with Pavlik harness treatment failure. The presence of a deficient cartilaginous anlage and an inverted labrum may provide a pathoanatomical explanation for Pavlik harness treatment failure. Level of Evidence: Prognostic Level II. See Instructions to Authors for a complete description of levels of evidence.

STUDY DESIGN Multicenter analysis of 3 groups of patients who underwent surgical treatment for adolescent idiopathic scoliosis (AIS). OBJECTIVE.: To evaluate 3 surgical approaches to determine the modality that has the greatest influence on improving thoracic kyphosis. SUMMARY OF BACKGROUND DATA AIS is characterized by thoracic hypokyphosis which may be restored to normal to varying degrees with surgery. METHODS A multicenter retrospective AIS surgical database was reviewed. Patients with only a structural main thoracic curve (Lenke 1, 2, or 3), and instrumentation of only the main thoracic curve were included. Lateral radiographs were analyzed to determine sagittal plane measurements before surgery, after surgery at 6 to 8 weeks, 1 year, and 2 years. The 3 groups were compared and statistical significance was defined as P < 0.05. RESULTS Three groups were analyzed: (1) ASF group (n = 135), Anterior spinal fusion and instrumentation, (2) PSF-Hybrid group (n = 86), PSF with proximal hooks, +/- apical wires and distal pedicle screws, and 3) PSF-Hooks group (n = 132), PSF with only hooks. All groups had similar preoperative coronal main thoracic curve magnitudes (ASF: 50.6 degrees , PSF-Hybrid: 49.1 degrees , PSF-Hooks: 52.0 degrees ) and thoracic kyphosis (ASF: 23.7 degrees , PSF-Hybrid: 19.3 degrees , PSF-Hooks: 21.9 degrees ). After surgery, the T5-T12 kyphosis was greater in the ASF group (25.1 degrees ) compared with PSF-Hooks (19.0 degrees ) and PSF-Hybrid (18.5 degrees (P < 0.05). At 1 year, thoracic kyphosis (T5-T12) remained greater in the ASF group (28.8 degrees ) compared with PSF-Hooks (22.6 degrees ) and PSF-Hybrid (20.2 degrees ) (P < 0.05), and was also greater at 2 years (29.9 degrees vs. 23.8.8 degrees and 19.7 degrees ) (P < 0.05). Kyphosis at the thoracolumbar junction was not seen in the PSF-Hybrid group. Lumbar lordosis increased only in the ASF group in response to the increase in thoracic kyphosis. CONCLUSION ASFI is the best method to restore thoracic kyphosis when compared with posterior approaches using only hooks or a hybrid construct in the treatment of thoracic adolescent idiopathic scoliosis.

A retrospective chart and radiograph review in a consecutive series of patients at a single institution.To compare 2 methods of placing vertebral body screws in thoracoscopic anterior spinal fusion and instrumentation with respect to radiographic, clinical, and perioperative variables.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.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.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 (P0.05). 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) (P0.05) 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).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.

Appropriate cancer pain documentation is one of the quality measures in the American Society of Clinical Oncology (ASCO) Quality Oncology Practice Initiative (QOPI). MedStar Washington Cancer Institute has participated in QOPI since 2008, and documenting a plan of care for moderate to severe pain (which was defined as a pain score of ≥ 4 on a scale of 0 to 10, with 10 being the worst) was identified as an area for improvement.We undertook a structured approach to improve documentation of the plan of care for moderate/severe pain with support from ASCO's Quality Training Program. Our team used standard plan-do-study-act (PDSA) methodology to achieve our goal of 90% documentation. We used a statistical process control chart (p chart) to determine whether our process was under control and to monitor the improvement in the documentation of pain management.The baseline rate of a documented plan of care for pain was 70%. In January 2014, we implemented action plans including an electronic health record trigger for a pain score of ≥ 4, education for fellows and midlevel providers, and establishment of a faculty consensus on documenting management of pain unrelated to cancer. After these interventions, the pain documentation rate improved to 90%.After one cycle of PDSA, we achieved our goal of a 90% pain documentation rate. To sustain our project, we continued to monitor the pain documentation rate quarterly in 2014 and continue the process of education and orientation to new staff, rotating residents, and fellows.

Using magnetic resonance imaging (MRI), evaluate the correlation of acromion angulation with thickening of the coracoacromial ligament (CAL) and narrowing of the subacromial space resulting in impingement upon the rotator cuff tendons.Eighty-nine shoulder MRI studies performed on a 3T scanner were retrospectively analyzed by two blinded independent reviewers. Measurements of the acromion angle (delta angle), CAL thickness and distance between the CAL and humeral head were obtained. The data were categorized into two groups, delta angle less that and greater than 7.5°. The presence or absence of full thickness (FT) or near full thickness (NFT) rotator cuff tears was noted.In group 1, the acromion angle varied from -6.8 to 6.8° (1.7±3.5°) with a CAL thickness of 0.91±0.20 mm and a subacromial distance of 6.47±0.88 mm. Group 2 acromion angle varied from 7.6° to 46.8° (18.0°±8.1°) with a CAL of 1.77±0.51 mm and a subacromial distance of 4.52±0.82 mm. The difference in CAL thickness and subacromial distance were significantly different between the two groups (P.001). In Group 1, 3 out of 51 patients had a FT or NFT tear of the rotator cuff compared to 20 out of 38 in Group 2 (P.001). There was no significant interobserver variability.Steep acromion angulation is associated with CAL thickening and narrowing of the subacromial space. Patients with a steep acromion angle had a statistically increased incidence of rotator cuff tears.

STUDY DESIGN: A retrospective review comparing patients who had postoperative ketorolac and those who did not following posterior spinal fusion and instrumentation (PSFI) for adolescent idiopathic scoliosis (AIS). OBJECTIVE: To analyze the effect of postoperative ketorolac on the incidence of pseudoarthrosis in postoperative AIS patients. SUMMARY OF BACKGROUND DATA: Ketorolac (Toradol, Roche Laboratories, Nutley, NJ) is a nonsteroidal antiinflammatory drug that is an effective adjunct to manage postoperative pain. It has been previously demonstrated to inhibit spinal fusion in adult patients undergoing a L4 to sacral fusion. To our knowledge, there are no large studies analyzing this effect following PSFI for AIS. METHODS: An IRB-approved retrospective medical record review was performed from 1994 to 2000 of patients undergoing a PSFI for AIS at a single institution. Segmental spinal instrumentation (Texas Scottish Rite Hospital) and iliac crest bone graft were used in both groups. Demographic and operative data were recorded. Patients were divided into those who had postoperative ketorolac (K group) and those who did not (NK group). Patients who had a surgically confirmed pseudoarthrosis were identified and the K group and NK group were statistically compared. RESULTS: There were 161 patients in the NK group and 158 in the K group. There were no differences with respect to age (14.4 vs. 14.2 years), gender (83.9% vs. 84.8% females), levels fused (9.8 vs. 9.7), or preoperative curve magnitude (57.9 degrees vs. 58.9 degrees ). In the K group, the number of doses of ketorolac administered was 6.7 for an average of 26.7 mg for a duration of 46 hours after surgery. Patients in the K group were more likely to have Motrin (average 5.8 doses) compared with the NK group (average 0.7 doses) (P < 0.01). No patient in the K group had a history of cigarette smoking compared with 2 patients in the NK group, both of whom went on to solid arthrodesis. The overall incidence of pseudoarthrosis was 2.5% for all patients. There was no difference in the incidence of pseudoarthrosis comparing the K (1.9%) and the NK group (3.1%)(P = 0.7). When the single rod posterior implants were excluded, there was no difference between the K (0.7%) and NK groups (1.8%) (P = 0.58). CONCLUSION: Ketorolac does not increase the incidence of developing a pseudoarthrosis when used as an adjunct for postoperative analgesia following a PSFI for AIS using segmental spinal instrumentation and iliac crest bone graft. The differences seen here compared with adults may be due to the greater healing potential in these young patients. We recommend utilization of ketorolac after surgery to supplement pain management when necessary.

218 Background: Appropriate cancer pain documentation is one of the quality indicators in American Society of Clinical Oncology (ASCO)’s Quality Oncology Practice Initiative (QOPI). Medstar Washington Cancer Institute (MWCI) has participated in QOPI since 2008. Documentation of plan of care for moderate/severe pain defined as a pain score of ≥4 on a numeric pain scale was 69%, (compared to QOPI aggregate of 79%) during the fall 2011 round which led to a quality improvement project with an aim of ≥ 90%. Methods: MWCI created a team of physicians, nurses and administrative staff. We attended ASCO’s quality training workshop from October 2013 to March 2014 for guidance. We implemented a Plan Do Study Act (PDSA) methodology for our quality improvement project. We created a process map, cause and effect diagram and Pareto chart based on survey of physicians citing common reasons for lack of documented plan of care for pain. Results: Baseline rate of documented plan of care for pain control in November 2013 was 70%. In January 2014, we implemented action plans to increase the awareness of pain documentation (Electronic Health Record (HER) trigger for pain ≥ 4, fellows and mid level education and faculty consensus on documenting management for pain unrelated to cancer). After intervention, the pain documentation rate was improved to 90.2% (Table). Conclusions: After one cycle of PDSA, we achieved our goal of pain documentation rate. In order to sustain our project, we will continue to monitor the pain documentation rate quarterly in 2014 and continue the process of education and orientation to new staff as well rotating residents and fellows. [Table: see text]