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On March 10, 2021, the FDA granted regular approval to tivozanib for treatment of patients with relapsed or refractory (R/R) advanced renal cell carcinoma (RCC) following two or more prior systemic therapies. Approval was based on the TIVO-3 study, a randomized trial of tivozanib versus sorafenib in patients with R/R advanced RCC. In TIVO-3, patients were randomized to receive either tivozanib 1.34 mg orally once daily for 21 consecutive days of every 28-day cycle or sorafenib 400 mg orally twice daily continuously. The primary endpoint was progression-free survival (PFS) per RECIST v1.1. Tivozanib demonstrated efficacy compared with sorafenib with an improvement in PFS [HR, 0.73; 95% confidence interval (CI), 0.56–0.95; P = 0.016]. The estimated median PFS was 5.6 months and 3.9 months in the tivozanib and sorafenib arms, respectively. There was no evidence of a detrimental effect on overall survival: HR, 0.97 (95% CI, 0.75–1.24). The most common grade 3 to 4 adverse reaction on the tivozanib arm was hypertension (24%). Compared with sorafenib, tivozanib was associated with lower rates of grade 3 to 4 diarrhea, rash, and palmar-plantar erythrodysesthesia. Patients receiving tivozanib in TIVO-3 had lower rates of dose reduction, interruption, or permanent discontinuation than those receiving sorafenib.

Published manuscripts supporting 23 of the 26 approvals were retrieved (as of March 2020) and the eligibility criteria specifics for each trial were extracted from each manuscript.

Purpose:In clinical research, eligibility criteria promote patient safety and optimize the evidence generated from clinical trials. However, overly stringent eligibility criteria, including laboratory requirements, may limit enrollment, resulting in delayed trial completion and potentially limiting applicability of trial results to a general practice population.Experimental Design:Starting in 2018, a working group consisting of experts in direct patient care, the FDA, industry, and patient advocacy developed recommendations to guide the optimal use of laboratory reference ranges and testing intervals in clinical trial eligibility criteria and study procedures. The working group evaluated current eligibility criteria across different clinical trial phases and performed a literature review to evaluate the impact of and justification for laboratory test eligibility requirements and testing intervals in clinical trials. Recommendations were developed on the basis of the goals of promoting safety and optimizing the evidence generated, while also expanding eligibility and applicability, and minimizing excess burden of trial participation.Results:In general, we found little variation over time and trial phase in laboratory test requirements, suggesting that these eligibility criteria are not refined according to ongoing clinical experience. We propose recommendations to optimize the use of laboratory tests when considering eligibility criteria.Conclusions:Tailoring the use of laboratory test requirements and testing intervals may increase the number and diversity of patients in clinical trials and provide clinical data that more closely represent the general practice populations.See related commentary by Giantonio, p. 2369

The success of the use of novel therapies in the treatment of advanced urothelial carcinoma has contributed to growing interest in evaluating these therapies at earlier stages of the disease. However, trials evaluating these therapies in the neoadjuvant setting must have clearly defined study elements and appropriately selected end points to ensure the applicability of the trial and enable interpretation of the study results. To advance the development of rational trial design, a public workshop jointly sponsored by the US Food and Drug Administration and the Bladder Cancer Advocacy Network convened in August 2019. Clinicians, clinical trialists, radiologists, biostatisticians, patients, advocates and other stakeholders discussed key elements and end points when designing trials of neoadjuvant therapy for muscle-invasive bladder cancer (MIBC), identifying opportunities to refine eligibility, design and end points for neoadjuvant trials in MIBC. Although pathological complete response (pCR) is already being used as a co-primary end point, both individual-level and trial-level surrogacy for time-to-event end points, such as event-free survival or overall survival, remain incompletely characterized in MIBC. Additionally, use of pCR is limited by heterogeneity in pathological evaluation and the fact that the magnitude of pCR improvement that might translate into a meaningful clinical benefit remains unclear. Given existing knowledge gaps, capture of highly granular patient-related, tumour-related and treatment-related characteristics in the current generation of neoadjuvant MIBC trials will be critical to informing the design of future trials.

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.

Background To review and summarize all U.S. Food and Drug Administration (FDA) approvals of programmed death (PD)‐1 and PD‐ligand 1 blocking antibodies (collectively referred to as PD‐[L]1 inhibitors) over a 6‐year period and corresponding companion/complementary diagnostic assays. Materials and Methods To determine the indications and pivotal trials eligible for inclusion, approval letters and package inserts available on Drugs@FDA were evaluated for approved PD‐[L]1 inhibitors to identify all new indications granted from the first approval of a PD‐[L]1 inhibitor on September 4, 2014, through September 3, 2020. The corresponding FDA drug and device reviews from the marketing applications for the approved indications were identified through FDA internal records. Two reviewers independently extracted information for the endpoints, efficacy data, basis for approval, type of regulatory approval, and corresponding in vitro diagnostic device test. The results were organized by organ system and tumor type. Results Of 70 Biologic Licensing Application or supplement approvals that resulted in new indications, 32 (46%) were granted based on response rate (ORR) and durability of response, 26 (37%) on overall survival, 9 (13%) on progression‐free survival, 2 (3%) on recurrence‐free survival, and 1 (1%) on complete response rate. Most ORR‐based approvals were granted under the accelerated approval provisions and were supported with prolonged duration of response. Overall, 21% of approvals were granted with a companion diagnostic. Efficacy results according to tumor type are discussed. Conclusion PD‐[L]1 inhibitors are an effective anticancer therapy in a subset of patients. This class of drugs has provided new treatment options for patients with unmet need across a wide variety of cancer types. Yet, the modest response rates in several tumor types signal a lack of understanding of the biology of these diseases. Further preclinical and clinical investigation may be required to identify a more appropriate patient population, particularly as drug development continues and additional treatment alternatives become available. Implications for Practice The number of PD‐[L]1 inhibitors in drug development and the associated companion and complementary diagnostics have led to regulatory challenges and questions regarding generalizability of trial results. The interchangeability of PD‐L1 immunohistochemical assays between PD‐1/PD‐L1 drugs is unclear. Furthermore, robust responses in some patients with low levels of PD‐L1 expression have limited the use of PD‐L1 as a predictive biomarker across all cancers, particularly in the setting of diseases with few alternative treatment options. This review summarizes the biomarker thresholds and assays approved as complementary and companion diagnostics and provides regulatory perspective on the role of biomarkers in oncology drug development., This review provides a regulatory overview on the U.S. FDA approvals of PD‐1 and PD‐L1 inhibitors and highlights complementary and companion diagnostics within the context of each disease and indication.

Nav1.7 is an extensively investigated target for pain with a strong genetic link in humans, yet in spite of this effort, it remains challenging to identify efficacious, selective, and safe inhibitors. Here, we disclose the discovery and preclinical profile of GDC-0276 (1) and GDC-0310 (2), selective Nav1.7 inhibitors that have completed Phase 1 trials. Our initial search focused on close-in analogues to early compound 3. This resulted in the discovery of GDC-0276 (1), which possessed improved metabolic stability and an acceptable overall pharmacokinetics profile. To further derisk the predicted human pharmacokinetics and enable QD dosing, additional optimization of the scaffold was conducted, resulting in the discovery of a novel series of N-benzyl piperidine Nav1.7 inhibitors. Improvement of the metabolic stability by blocking the labile benzylic position led to the discovery of GDC-0310 (2), which possesses improved Nav selectivity and pharmacokinetic profile over 1.

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.

We investigate how the characteristics of firms’ actual controllers influence firms’ access to external finance. Using hand-collected data of actual controllers of Chinese firms, we find that firms...

NBI-921352 (formerly XEN901) is a novel sodium channel inhibitor designed to specifically target NaV1.6 channels. Such a molecule provides a precision-medicine approach to target SCN8A-related epilepsy syndromes (SCN8A-RES), where gain-of-function (GoF) mutations lead to excess NaV1.6 sodium current, or other indications where NaV1.6 mediated hyper-excitability contributes to disease (Gardella and Moller, 2019; Johannesen et al., 2019; Veeramah et al., 2012). NBI-921352 is a potent inhibitor of NaV1.6 (IC50 0.051 µM), with exquisite selectivity over other sodium channel isoforms (selectivity ratios of 756X for NaV1.1, 134X for NaV1.2, 276X for NaV1.7, and >583X for NaV1.3, NaV1.4, and NaV1.5). NBI-921352 is a state-dependent inhibitor, preferentially inhibiting activated (inactivated or open) channels. The state dependence leads to potent stabilization of inactivation, inhibiting NaV1.6 currents, including resurgent and persistent NaV1.6 currents, while sparing the closed/rested channels. The isoform-selective profile of NBI-921352 led to a robust inhibition of action-potential firing in glutamatergic excitatory pyramidal neurons, while sparing fast-spiking inhibitory interneurons, where NaV1.1 predominates. Oral administration of NBI-921352 prevented electrically induced seizures in a Scn8a GoF mouse, as well as in wild-type mouse and rat seizure models. NBI-921352 was effective in preventing seizures at lower brain and plasma concentrations than commonly prescribed sodium channel inhibitor antiseizure medicines (ASMs) carbamazepine, phenytoin, and lacosamide. NBI-921352 was well tolerated at higher multiples of the effective plasma and brain concentrations than those ASMs. NBI-921352 is entering phase II proof-of-concept trials for the treatment of SCN8A-developmental epileptic encephalopathy (SCN8A-DEE) and adult focal-onset seizures.

NBI-921352 (formerly XEN901) is a novel sodium channel inhibitor designed to specifically target Na

We describe the synthesis and biological evaluation of a series of novel aryl sulfonamides that exhibit potent inhibition of Na

Na

Purpose: In clinical research, eligibility criteria promote patient safety and optimize the evidence generated from clinical trials. However, overly stringent eligibility criteria, including laboratory requirements, may limit enrollment, resulting in delayed trial completion and potentially limiting applicability of trial results to a general practice population. Experimental Design: Starting in 2018, a working group consisting of experts in direct patient care, the FDA, industry, and patient advocacy developed recommendations to guide the optimal use of laboratory reference ranges and testing intervals in clinical trial eligibility criteria and study procedures. The working group evaluated current eligibility criteria across different clinical trial phases and performed a literature review to evaluate the impact of and justification for laboratory test eligibility requirements and testing intervals in clinical trials. Recommendations were developed on the basis of the goals of promoting safety and optimizing the evidence generated, while also expanding eligibility and applicability, and minimizing excess burden of trial participation. Results: In general, we found little variation over time and trial phase in laboratory test requirements, suggesting that these eligibility criteria are not refined according to ongoing clinical experience. We propose recommendations to optimize the use of laboratory tests when considering eligibility criteria. Conclusions: Tailoring the use of laboratory test requirements and testing intervals may increase the number and diversity of patients in clinical trials and provide clinical data that more closely represent the general practice populations. See related commentary by Giantonio, p. 2369

Among people living with HIV (PWH), there has been an increasing incidence of non-small cell lung cancer (NSCLC) and metabolic abnormalities, including dyslipidemia, which can modulate NSCLC risk. In this article, we evaluate which metabolic risk factors are associated with incident risk among PWH who smoke. This is done through a retrospective cohort study, using data of HIV+ veterans who smoke from the nationwide Veterans Affairs (VA) healthcare system. Data on diagnostic codes, medication, and laboratory values of 33,351 veterans were obtained using the VA&rsquo, s Corporate Data Warehouse and Central Cancer Registry. We calculated NSCLC incidence and utilized Cox regression to determine metabolic factors associated with NSCLC risk. HIV+ cohort was 97.4% male, median age = 47 years and 20,050 (60.1%) well-controlled (&ge, 80% follow-up time undetectable viral load). Crude incidence rates were lower in well-controlled PWH (1.46 vs. 2.06/1000 PY). Metabolic factors associated with incident NSCLC risk included lower BMI at HIV diagnosis and cachexia history in both groups, while HDL and triglycerides were significant in non-well-controlled smokers only. Our findings that lower BMI at HIV diagnosis, history of cachexia among individuals with well-controlled HIV, and cachexia presence at diagnosis are associated with increased risk of developing NSCLC in PWH with a history of smoking have important implications.

The U.S. Food and Drug Administration (FDA) granted accelerated approval to rucaparib in May 2020 for the treatment of adult patients with deleterious BRCA mutation (germline and/or somatic)-associated metastatic castrate-resistant prostate cancer (mCRPC) who have been treated with androgen receptor-directed therapy and a taxane. This approval was based on data from the ongoing multicenter, open-label single-arm trial TRITON2. The primary endpoint, confirmed objective response rate, in the 62 patients who met the above criteria, was 44% (95% confidence interval [CI]: 31%–57%). The median duration of response was not estimable (95% CI: 6.4 to not estimable). Fifty-six percent of patients had a response duration of >6 months and 15% >12 months. The safety profile of rucaparib was generally consistent with that of the class of poly-(ADP-ribose) polymerase enzyme inhibitors and other trials of rucaparib in the treatment of ovarian cancer. Deaths due to adverse events (AEs) occurred in 1.7% of patients, and 8% discontinued rucaparib because of an AE. Grade 3–4 AEs occurred in 59% of patients. No patients with prostate cancer developed myelodysplastic syndrome or acute myeloid leukemia. The trial TRITON3 in patients with mCRPC is ongoing and is planned to verify the clinical benefit of rucaparib in mCRPC. This article summarizes the FDA thought process and data supporting this accelerated approval. Implications for Practice The accelerated approval of rucaparib for the treatment of adult patients with deleterious BRCA mutation (germline and/or somatic)-associated metastatic castrate-resistant prostate cancer who have been treated with androgen receptor-directed therapy and a taxane represents the first approved therapy for this selected patient population. This approval was based on a single-arm trial demonstrating a confirmed objective response rate greater than that of available therapy with a favorable duration of response and an acceptable toxicity profile. The ongoing trial TRITON3 is verifying the clinical benefit of this drug.

On December 18, 2019, the FDA granted accelerated approval to enfortumab vedotin-ejfv (PADCEV; Astellas and Seattle Genetics) for treatment of patients with locally advanced or metastatic urothelial cancer who have previously received a programmed cell death protein 1 or programmed death ligand 1 inhibitor, and a platinum-containing chemotherapy in the neoadjuvant/adjuvant, locally advanced or metastatic setting. Substantial evidence of effectiveness for this application is obtained from Cohort 1 of the single-arm, multicenter Study EV-201. Patients received enfortumab vedotin (EV) 1.25 mg/kg (up to a maximum dose of 125 mg) intravenously on days 1, 8, and 15 of 28-day cycles until disease progression or unacceptable toxicity. Confirmed objective response rate in the 125-patient efficacy population determined by blinded independent central review was 44% [95% confidence interval (CI), 35.1–53.2], with complete responses in 12%. Median response duration was 7.6 months (95% CI, 6.3–not estimable). Grade 3–4 adverse reactions occurred in 73% of patients. Hyperglycemia, peripheral neuropathy, ocular disorders, skin reactions, infusion site extravasations, and embryo-fetal toxicity are labeled as warnings and precautions for EV. The article summarizes the data and the FDA thought process supporting accelerated approval of EV. This approval may be contingent upon verification and description of clinical benefit in confirmatory trial(s).

BACKGROUND Despite advances in diagnosis and treatment of both HIV and Burkitt lymphoma (BL), persons living with HIV remain at high risk for BL. We conducted this study to evaluate if there have been any changes in the risk of or survival after BL diagnosis among persons living with HIV during the antiretroviral era. SETTING Veterans living with HIV (VLWH) and age-matched HIV-negative controls receiving care between 1999 and 2016 were retrospectively identified using Veterans Health Administration electronic medical records. METHODS We identified BL diagnoses through Veterans Health Administration Cancer Registry review and International Classification of Diseases, Ninth/Tenth Revisions, codes, and we extracted demographic, lifestyle, and clinical variables from electronic medical record. We estimated hazard ratios (HR) and 95% confidence intervals (CIs) for BL risk and survival using Cox proportional models. RESULTS We identified 45,299 VLWH. Eighty-four developed BL (incidence rate = 21.2 per 100,000 person years; CI: 17.1 to 26.3). Median CD4 count at BL diagnosis was 238 cells per milliliter (SD: 324.74) and increased over time. Survival was truncated in VLWH with BL (P < 0.05). The risk of BL in VLWH was 38% less in blacks compared with whites (HR: 0.620; CI: 0.393 to 0.979; P = 0.0401). VLWH with an undetectable viral load for at least 40% of follow-up were 74% less likely to develop BL (HR: 0.261; CI: 0.143 to 0.478; P < 0.0001) and 86% less likely to die after diagnosis (HR: 0.141; CI: 0.058 to 0.348; P < 0.0001). CONCLUSIONS BL incidence among VLWH did not improve between 2000 and 2016. Survival after BL diagnosis in VLWH remains dismal as compared with their HIV-negative counterparts, although veterans with prolonged periods of undetectable viral load had improved prognosis.

Herein, we report the discovery and optimization of a series of orally bioavailable acyl sulfonamide NaV1.7 inhibitors that are selective for NaV1.7 over NaV1.5 and highly efficacious in in vivo models of pain and hNaV1.7 target engagement. An analysis of the physicochemical properties of literature NaV1.7 inhibitors suggested that acyl sulfonamides with high fsp3 could overcome some of the pharmacokinetic (PK) and efficacy challenges seen with existing series. Parallel library syntheses lead to the identification of analogue 7, which exhibited moderate potency against NaV1.7 and an acceptable PK profile in rodents, but relatively poor stability in human liver microsomes. Further, design strategy then focused on the optimization of potency against hNaV1.7 and improvement of human metabolic stability, utilizing induced fit docking in our previously disclosed X-ray cocrystal of the NaV1.7 voltage sensing domain. These investigations culminated in the discovery of tool compound 33, one of the most potent and...

The sodium channel NaV1.7 has emerged as a promising target for the treatment of pain based on strong genetic validation of its role in nociception. In recent years, a number of aryl and acyl sulfonamides have been reported as potent inhibitors of NaV1.7, with high selectivity over the cardiac isoform NaV1.5. Herein, we report on the discovery of a novel series of N-([1,2,4]triazolo[4,3-a]pyridin-3-yl)methanesulfonamides as selective NaV1.7 inhibitors. Starting with the crystal structure of an acyl sulfonamide, we rationalized that cyclization to form a fused heterocycle would improve physicochemical properties, in particular lipophilicity. Our design strategy focused on optimization of potency for block of NaV1.7 and human metabolic stability. Lead compounds 10, 13 (GNE-131), and 25 showed excellent potency, good in vitro metabolic stability, and low in vivo clearance in mouse, rat, and dog. Compound 13 also displayed excellent efficacy in a transgenic mouse model of induced pain.

Heat seeking is cool Mosquitoes seek hosts using several cues, one of which is body heat. Greppi et al. hypothesized that cooling-activated receptors could be used for locating mammalian hosts if they were rewired downstream for repulsion responses (see the Perspective by Lazzari). A gene family conserved in insects and known to be responsible for sensing changes in temperature in fruit flies was the starting point. Genome-wide analyses and labeled CRISPR-Cas9 mutants allowed visualization of the receptor in neurons of Anopheles gambiae mosquitoes' antennae and assessment of adult female mosquitoes with a disrupted copy of the receptor. This ancestral insect temperature regulatory system has been repurposed for host-finding by malaria mosquitoes. Science , this issue p. 681 ; see also p. 628

Background Although declining rates of incident AIDS-related Kaposi sarcoma (KS) have been reported, KS incidence rates have noted race/ethnic, age, and geographic diversity. We performed a comprehensive assessment of recent secular trends in AIDS-related KS incidence in the United States. Methods We identified incident KS diagnosed in men aged 20-54 years (who comprise most AIDS-related KS in the United States) using the US Cancer Statistics registry data. Joinpoint analysis assessed for trends in age-adjusted incidence rates between 2000 and 2014 calculating average annual percentage changes (AAPCs) with 95% confidence intervals. Heat maps were generated to compare age-adjusted HIV incidence rates with KS incidence rates. Results Age-adjusted KS incidence rates nationwide decreased from 1.44/100,000 to 0.95/100,000 between 2000 and 2014. Observed rate changes varied across subgroups; eg, there were significant decreases in 30-44 years (AAPC = -5.4%), particularly in Whites and Blacks, significant increases among 20-29 years (AAPC = 2.7), primarily in Blacks, and stable rates among 45-54 years (AAPC = -0.03). In Southern United States, the incidence rates among Blacks did not significantly change. The states with highest average age-adjusted rates over the study period were Georgia (2.71/100,000), New York (2.16/100,000), California (2.02/100,000), Florida (1.90/100,000), and Texas (1.39/100,000), with significantly decreasing trends over time, except Georgia where rates increased (AAPC = 1.8). Conclusions Although KS incidence rates have decreased nationally, age, racial, and geographic disparities persist, including increasing risk among younger Black men and particularly elevated rates in some southern states and urban areas. Further research is needed to address racial and geographic AIDS-related KS disparities.

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]

Checkpoint inhibitors have become standard therapy for multiple cancers, and their use will increase in the next year as regulatory approvals for additional indications are expected. It is essential for clinicians to be aware of the potential for rare immune-related adverse effects. Here, we report the case of a new diagnosis of myasthenia gravis (MG) after the use of nivolumab for squamous cell carcinoma of the bladder. A review the literature identified 10 cases of MG diagnosed after programmed cell death protein 1 inhibitor therapy. This is the first case, to our knowledge, reported in association with bladder cancer. The precise diagnosis of MG has important implications on management, as treatment with steroids can transiently worsen myasthenia in nearly 50% of cases.

Background: Pneumonitis (Pn) is a potentially life-threatening adverse event of some anticancer drugs. We compared treatment associated pneumonitis (TAP) related to immune checkpoint inhibitors (ICI) or chemotherapies (chemo) in advanced non-small cell lung cancer (aNSCLC) patients (pts) with and without (+/-) past medical history (PMH) of Pn, using data from clinical trials (CT) and real world data (RWD). Methods: Pts with PMH Pn in 8 aNSCLC CT comparing ICI to chemo, were identified using terms pneumonitis, acute interstitial pneumonitis, pneumonitis chemical, and interstitial lung disease. aNSCLC pts treated with ICI (+/- chemo) or chemo [without concurrent radiation therapy (RT)] were identified using RWD from a community health system; Pn was defined using terms in ICD-9 and ICD-10 including pneumonitis or associated concepts in the Unified Medical Language System. RWD pts were selected using core eligibility criteria from CT. In CT and RWD, Pn incidence proportion was calculated for 4 subgroups: pts (+/-) PMH of Pn and treated with ICI vs chemo. Pn diagnosis type, including RT Pn, was assessed. Results: In CT and RWD, a higher incidence of TAP was observed among aNSCLC pts with PMH of Pn compared to those without PMH of Pn, among ICI and chemo groups (Table 1). In CT pts without PMH of Pn, ICI associated Pn was more common than chemo associated Pn. Similar rates of TAP were observed in the CT and RWD. In RWD, Pn at any time was strongly associated with RT in ICI and chemo groups, with 73% of all diagnoses of Pn due to RT. Conclusion: PMH of Pn in pts with aNSCLC is associated with a greater risk of TAP for ICI and chemo groups, in CT and RWD. RWD data suggests RT to be a frequent cause of Pn. Only in CT data, and only for pts without PMH Pn, was there a demonstrated difference in TAP incidence between ICI and chemo groups. Additional research (e.g. inclusion of pts treated with tyrosine kinase inhibitors) is warranted to optimize treatment for cancer pts with PMH of Pn. Pneumonitis incidence and 95% CI among aNSCLC patients treated with immunotherapy and chemotherapyCT patients treated with immune checkpoint inhibitors +/-chemo (N=3723)CT patients treated with chemotherapies (N=2768)RWD patients treated with immune checkpoint inhibitors +/-chemo (N=615)RWD patients treated with chemotherapies (N= 647)patients with past medical history of pneumonitis (N=48 for CT; N=33 for RWD)5/30 (16.7%;7.3-33.6%)2/18 (11.1%;3.1-32.8%)3/21 (14.3%;5.0-34.6%)1/12 (8.3%; 0.4-35.4%)patients without past medical history of pneumonitis (N=6443 for CT; N=1229 for RWD)164/3693(4.4%; 3.8-5.2%)27/2750(1.0%; 0.7-1.4%)17/594 (2.9%; 1.8-4.5%)14/635 (2.2%; 1.3-3.7%)All patients (N=6491 for CTs; N=1262 for RWD)169/3723(4.5%; 3.9-5.3%)29/2768(1.0%; 0.7-1.5%)20/615 (3.3; 2.1-5.0%)15/647(2.3; 1.4-3.8%) Citation Format: Qi Liu, Chenan Zhang, Yutao Gong, Hao Zhu, Elaine Chang, Cheryl Cho-Phan, Jonathan Hirsch, Michael A. Thompson, Gideon Blumenthal, Shiew Mei Huang, Thomas D. Brown. Pneumonitis incidence in patients with non-small cell lung cancer treated with immunotherapy or chemotherapy in clinical trials and real-world data [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT086.

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]

5081 Background: Time to treatment discontinuation (TTD) has been proposed as a potential pragmatic real-world data (RWD) endpoint, and was closely correlated with progression-free survival (PFS) in pooled analyses of non-small cell lung cancer (NSCLC) and breast cancer trials across therapeutic classes (Blumenthal, Ann Onc 2019; Gao, SABCS Abstract P5-14-02). Methods: We analyzed data from all randomized patients (pts) in the phase 3 trials submitted to FDA 2016-18 evaluating a combination therapy (Rx) of an immuno-oncology agent and another systemic Rx (IO-X) versus sunitinib (SUN) for treatment-naïve advanced renal cell carcinoma (RCC). Protocols specified treatment until progression, but treatment beyond progression was allowed. TTD was defined as the time from the start of Rx to time of treatment discontinuation of both drugs in combination Rx or SUN. We measured TTD in treatment-defined subgroups (IO-X and SUN) and across all pts, and pt-level correlation (Pearson’s r) between TTD and PFS and between TTD and overall survival (OS). We also determined rates of disparity between TTD and PFS greater than 3 months. Results: Of 3758 pts (IO-X, n=1878; SUN, n=1880), 3190 pts (85%) had a TTD event, and 1899 pts (51%) had a PFS event. Median TTD was longer among pts receiving IO-X than SUN (12.3 versus 8.0 months). Regardless of drug class, more pts had early (TTD shorter than PFS by ≥ 3 months) TTD events than late TTD (13.4% versus 6.4%, overall). We found higher correlation between TTD and PFS in pts receiving SUN ( r = 0.89) than pts receiving IO-X ( r = 0.72). Overall, TTD was more closely associated with PFS ( r = 0.80) than with OS (0.61). Conclusions: Observed correlations of TTD to PFS were stronger compared to the correlation of TTD to OS. This may be expected because OS is farther removed in time from TTD than is PFS. In contrast to TTD in NSCLC, more than twice as many pts in RCC trials had early TTD than late TTD, regardless of Rx group, which may indicate earlier discontinuation with combination Rx due to additive toxicity. Limitations include the censoring of PFS and OS and the post-hoc nature of this analysis. [Table: see text]

9541 Background: Previous studies have suggested that tumor growth rate (g), estimated using prostate-specific antigen values, is associated with overall survival (OS) in prostate cancer (Wilkerson, 2016). We performed a retrospective pooled analysis in non-small cell lung cancer (NSCLC) to investigate the extent to which g values estimated using radiological tumor measurements in clinical trials are associated with survival. Methods: We identified 24 randomized clinical trials submitted to FDA between 2013 and 2019 investigating either immune checkpoint inhibitor (ICI) or targeted therapy (TT) in pts with metastatic NSCLC. Of 9934 patients (pts) enrolled, 5532 pts (2401, 1189, and 1942 pts treated with ICI, TT, and chemotherapy respectively) had sufficient data to derive a valid g. The g was evaluated by both type and line of therapy. Pts were then grouped according to quartiles of g, with Q1 being the lowest. We calculated OS and progression-free survival (PFS) for each group via the Kaplan-Meier method, and used the Cox model for group comparison. Results: Median g was 9.7E-4, 1.4E-3, and 2.2E-3/day, and median OS was 34.2, 21.3, and 15.3 months (mo), in pts treated with TT, ICI, and chemotherapy, respectively, regardless of lines of therapy. When treated with the same type of therapy, pts receiving 2nd line therapy had a higher median g than those receiving 1st line. The median survival and log-rank hazard ratios for pts treated with 1st line ICI monotherapy are shown in the Table. Conclusions: TT is associated with the lowest median g, followed by ICI, and then chemotherapy, perhaps due to patient selection, better inherent biology/natural history, or favorable results of TT on selected tumors. Regardless, we found that g is inversely associated with survival, across treatment types. This relationship is also observed in pts treated with the same type and line of therapy (for example, 1st line ICI), where Q1 has the longest survival, followed by Q2, Q3, and then Q4. In summary, our exploratory analysis suggests that g derived from radiological tumor measurements in NSCLC may relate to survival. Prospective studies are needed to evaluate if g might be an earlier endpoint compared to classical response criteria. [Table: see text]

38 Background: FDA approved 3 androgen receptor inhibitors for nonmetastatic castration-resistant prostate cancer (nmCRPC) based on global randomized trials with control arms of placebo + ADT. Despite similar enrolled populations, grade 1 or higher investigator-reported, Common Terminology Criteria for Adverse Events (CTCAE)-graded fatigue ranged 11-25% in the placebo arms. We sought to characterize variability in investigator-reported, CTCAE-graded fatigue across geographic regions and compare this with the variability in patient-reported fatigue. Methods: Data from patients receiving ≥ 1 placebo dose were reviewed from control arms of 3 nmCRPC double-blind, placebo-controlled trials submitted to FDA. We determined worst grade clinician-reported (ClinRO) CTCAE fatigue, and most severe fatigue reported by patient-reported outcome (PRO) for each patient at any time during treatment or within 30 days of last dose in each trial by geographic region: North America/Western Europe (NAWE) versus rest of the world (ROW). We compared variability in fatigue rates to those of a more objective AE, CTCAE-defined anemia. Results: NAWE enrollment comprised 46-75% of placebo cohorts. Median age was comparable across trials and regions. ClinRO CTCAE fatigue was higher in NAWE (15-33%) compared to ROW (8-14%) in each of the 3 placebo cohorts (see Table). Rates of PRO fatigue varied by region (50-73% in NAWE compared to 42-59% in ROW), and the regional differential was present at baseline. Anemia rates were similar in NAWE and ROW in each trial ( < 5%) per CTCAE. Conclusions: CTCAE reporting of fatigue, a subjective symptom, was inconsistent across sites. Anemia, an objective AE, was more consistently reported. ROW investigators less frequently reported fatigue compared to NAWE investigators. Reasons for this are unclear, but could include cultural and language factors. PRO fatigue was relatively consistent across trials and regions. These results should be interpreted with caution, as we acknowledge the limitations of cross-trial comparison.[Table: see text]

Herein, we report the discovery and optimization of a series of orally bioavailable acyl sulfonamide Na

Nivolumab is a standard treatment option in several advanced malignancies, but safety and efficacy are still unknown in patients with human immunodeficiency virus (HIV) infection. We describe a case series of people living with HIV (PLWH) receiving nivolumab in the Veterans Health Administration (VA) and report responses and toxicities. We identified all PLWH who received nivolumab at any VA facility since 2000 in the Corporate Data Warehouse (CDW), which provides nationwide research access to VA electronic medical records. We identified 16 HIV-infected nivolumab recipients. The median number of nivolumab doses received was 6 (range, 1-32). Changes in CD4 count during therapy were variable, with 70% (7/10) of patients experiencing increases. Half of PLWH were treated for non-small-cell lung cancer; 2 for Hodgkin lymphoma (HL), 2 for renal cell carcinoma, and 4 for off-label cancers. For non-small-cell lung cancer, 7 patients had evaluable responses. Although 5 of 7 patients immediately progressed, 1 had a partial response and 1 had stable disease, which were both durable. Two of 16 (14%) PLWH had complete responses; both with HL (2/2 HL, 100%). The prevalence of immune-related adverse effects was 40% overall (6/15); 27% (4/15) had pneumonitis. To our knowledge, this is the largest case series reporting outcomes with nivolumab in PLWH. Outcomes were comparable with those seen in studies of HIV-uninfected patients, and particularly interesting for HL. The reason for the high proportions of immune-related adverse effects is unclear, but needs to be confirmed in larger studies.

BACKGROUND: Protease inhibitors (PIs) may inhibit Kaposi sarcoma (KS) carcinogenesis. However, PI-based antiretroviral therapy (ART) is rarely a first-line choice in people living with HIV (PLWH) because of cost and toxicities. This is the first systematic review to assess KS incidence stratified by ART type. METHODS: We searched PubMed to identify original, full research reports of KS incidence in ART-treated adult PLWH, stratified by ART class, published between 1996 and 2017. For overlapping cohorts, we included only the most recent study and supplemented data with earlier relevant analyses. We described study design, sociodemographic characteristics, statistical adjustment factors, and KS incidence. RESULTS: We identified three unique retrospective cohort studies, and supplemented one of the studies with results from six prior subgroup reports, which included 242,309 PLWH and 3570 incident KS cases. Overall, KS crude incidence decreased by a factor of 10 between untreated and ART-treated PLWH; CD4-adjusted KS incidence decreased by ~50%, with either non-nucleoside reverse transcriptase inhibitor (NNRTI)- or PI-based ART. A single study measured a cumulative dose-/time-dependent effect of ART, which reported a relative risk reduction in only the cohort receiving boosted PI-based ART. Other studies defined ART categories by first-line therapy only. CONCLUSIONS: The risk of incident KS was significantly reduced regardless of ART class even after adjusting for CD4 count. The quality of evidence (i.e., most studies categorizing users by first-line ART) does not permit KS risk reduction comparisons across ART types. Given the limited number and retrospective nature of these studies, prospective data is indicated.

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