Enrollment In Part Research Articles

Phase 1/2 study of FOG-001, a first-in-class direct β-catenin:TCF inhibitor, in patients with colorectal cancer, hepatocellular carcinoma, and other locally advanced or metastatic solid tumors.

TPS322 Background: Wnt/B-catenin pathway activation, which is frequently present in most colorectal cancers and a variety of other solid tumors, is associated with poor prognosis and resistance to immunotherapy. FOG-001 is a Helicon peptide that competitively inhibits the interaction between β-catenin and the T-cell factor (TCF) family of transcription factors. Experiments in patient-derived-xenograft (PDX) models of colorectal cancer (CRC) and hepatocellular carcinoma (HCC) have demonstrated that FOG-001 can inhibit tumor growth and promote tumor regression when administered as monotherapy or in combination with immune checkpoint inhibitors or standard of care therapies, including bevacizumab and 5-FU. Methods: This first-in-human, Phase 1/2, multicenter, open-label, dose escalation (Part 1) and dose-expansion (Part 2) study evaluates the safety/tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and anti-tumor effects of FOG-001 as monotherapy and in combination with other anti-cancer therapies. Eligible patients must have received at least one prior systemic anti-cancer therapy and either progressed on, not responded to, or be unfit for available therapies. In Part 1, FOG-001 is administered intravenously, either weekly or every other week, at escalating dose levels evaluated sequentially in a standard 3+3 design as monotherapy in patients with: (1a) microsatellite stable (MSS) CRC or any solid tumor with a documented Wnt/b-catenin pathway activating mutation (WPAM) and (1c) HCC with WPAM. Part 1b will evaluate PD effects in cohorts of approximately six patients with MSS CRC. Upon selection of the preliminary recommended Phase 2 dose from Part 1a for weekly dosing, combination dose escalation (1d) evaluates the safety/tolerability, PK and anti-tumor effects of FOG-001 in CRC patients combined with FOLFOX+bevacizumab, anti-PD-1/PD-L1 (also includes other solid tumors with known WPAM), or trifluridine/tipiracil+bevacizumab. Part 2 dose expansion evaluates FOG-001 monotherapy in MSS CRC, HCC, and other solid tumors with documented WPAM. Combination dose expansion evaluates the combinations initially evaluated in Part 1d. Primary endpoints are safety/tolerability and preliminary anti-tumor effects (objective response rate). Secondary endpoints are PK, PD, and other anti-tumor responses (e.g., best objective response, duration of response, and progression free survival). Enrollment in Parts 1 and 2 is ongoing in the USA. Clinical trial information: NCT05919264 .

Benzodiazepine Utilization in Ischemic Stroke Survivors: Analyzing Initial Excess Supply and Longitudinal Trends.

Benzodiazepines are commonly prescribed for post-acute ischemic stroke for anxiety, insomnia, and agitation. While guidelines discourage use in those aged ≥65 years, little is known about prescription patterns at the national level. We analyzed a 20% sample of US Medicare claims from April 1, 2013, to September 30, 2021. We selected beneficiaries aged ≥65 years discharged alive following an acute ischemic stroke who had traditional Medicare coverage and 6 months' prior enrollment in Parts A (hospital insurance), B (Medical insurance), and D (drug coverage). We excluded those with prior benzodiazepine prescriptions, self-discharges, or discharge to skilled nursing facilities. We examined demographics, comorbidities, first prescription days' supply, cumulative incidences of benzodiazepine first prescription fills within 90 days after discharge, and geographic and yearly trends. We included 126 050 beneficiaries with a mean age of 78 years (SD, 8); 54% were female and 82% were White. Within 90 days, 6127 (4.9%) initiated a benzodiazepine. Among new prescriptions, lorazepam (40%) and alprazolam (33%) were the most prescribed. Most (76%) of first fills had a day's supply over 7 days and 55% between 15 and 30 days. Female initiation rates were higher (5.5% [95% CI, 5.3-5.7]) than male initiation rates (3.8% [95% CI, 3.6%-3.9%]). Rates were highest in the southeast (5.1% [95% CI, 4.8%-5.3%]) and lowest in the midwest (4.0% [95% CI, 3.8%-4.3%]), with a modest nationwide initiation decline from 2013 to 2021 (cumulative incidence difference, 1.6%). Despite a gradual decline in benzodiazepine initiation from 2013 to 2021, we noted excessive supplies in prescriptions post-acute ischemic stroke discharge, underscoring the need for improved policies.

Immune checkpoint inhibitors as subsequent treatment in older adults with non-small cell lung cancer and synchronous brain metastases.

Immune checkpoint inhibitors (ICIs) have become the mainstay treatment for non-small cell lung cancer (NSCLC). However, there is a lack of studies assessing ICIs as subsequent treatment in older adults with NSCLC and brain metastasis (BM). This retrospective cohort study compared the real-world survival of older patients with NSCLC and BM at diagnosis [synchronous BM (SBM)] previously treated with chemotherapy receiving ICI versus chemotherapy as subsequent treatment. Patients with NSCLC and SBM ≥65 years previously treated with chemotherapy were identified using the SEER-Medicare database (2010-2019). Patients receiving new chemotherapy and/or Food and Drug Administration (FDA)-approved ICIs as second/third-line treatment were included, excluding those ever-receiving targeted therapies. Each ICI patient was matched to one chemotherapy patient by time to subsequent treatment (within ±30 days) from diagnosis. Overall survival (OS) time was measured from the start of subsequent treatment to death, censored at disenrollment from Medicare Part A/B, enrollment in Part C, or end of study (December 31, 2019), whichever came first. OS curves were estimated and compared using the Kaplan-Meier (KM) method and log-rank test. Hazard ratio (HR) was estimated using a multivariable-adjusted Cox proportional hazards model. Matched cohorts included 546 patients [273 in each group; median age 71 (range, 65-87) years]. ICI patients were older, more likely non-Hispanic, with squamous cell carcinoma, and liver metastasis compared to chemotherapy. KM estimated better survival in ICI than chemotherapy {median survival: 209 days [95% confidence interval (CI): 160-275] vs. 155 days (95% CI: 135-187); log-rank P<0.001}. ICI was associated with a lower adjusted hazard of death [HR =0.63; 95% CI: 0.52-0.75; P<0.001] compared to subsequent chemotherapy treatment. In this population-based study of older patients with NSCLC and SBM previously treated with chemotherapy, subsequent treatment with ICI was associated with improved survival compared to chemotherapy.

A first-in-human, phase 1/2 trial of FOG-001, a β-catenin:TCF antagonist, in patients with locally advanced or metastatic solid tumors.

TPS3175 Background: The Wnt/β-catenin pathway is a frequently activated oncogenic pathway and a well-described driver of many cancers. FOG-001 is designed to be a first-in-class direct inhibitor of β-catenin that blocks β-catenin’s interaction with the T-cell factor (TCF) family of transcription factors. Preclinical studies have indicated FOG-001 can cause tumor growth inhibition and regression by disrupting β-catenin-dependent signaling. FOG-001 is unique from previously reported Wnt/β-catenin pathway modulators as it is designed to directly inhibit TCF transcription factor and β-catenin interaction, the most downstream node in the Wnt pathway. It is hypothesized FOG-001 will abrogate the hyperactivation of the Wnt pathway that is driven by most known pathway mutations. Methods: This first-in-human, Phase 1/2, multicenter, open-label, dose escalation (Parts 1a and 1b) and dose-expansion (Part 2) study is evaluating the safety/tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity of FOG-001 in patients with advanced or metastatic solid tumors. Patients with the following tumor types are eligible: microsatellite stable (MSS) colorectal cancer (CRC) or any solid tumor with documented Wnt pathway activating mutation (WPAM) (Part 1a), MSS CRC only (Part 1b) and MSS CRC, gastric/gastroesophageal (GEJ) cancer, non-small cell lung cancer (NSCLC), and any solid tumors with documented WPAM in Part 2. Patients must have received ≥1 prior systemic anticancer therapy(ies) and be ineligible for curative surgery or curative chemoradiation. In Part 1, FOG-001 is administered at escalating doses via intravenous (IV) infusion on Days 1, 8, 15, and 22 of each 4-week cycle; additional dosing regimens may be explored. After selection of the preliminary recommended Phase 2 dose(s) (pRP2D) and regimen(s) in Part 1, the following cohorts will be enrolled to receive FOG-001 at the pRP2D in Part 2: (2a) MSS CRC; (2b) NSCLC with documented WPAM in adenomatous polyposis coli (APC) or β-catenin; (2c) gastric/GEJ cancer with documented WPAM in APC or β-catenin; and (2d) solid tumors with ≥1 documented WPAM in any predefined Wnt pathway genes. The primary endpoints are safety/tolerability (Parts 1 and 2), and also preliminary antitumor activity (objective response rate) (Part 2). Secondary endpoints are PK, PD, and additional antitumor activity assessments. Enrollment in Part 1 is ongoing. Clinical trial information: NCT05919264 .

Telehealth Expansion and Medicare Beneficiaries’ Care Quality and Access

Understanding the association of telehealth use with health care outcomes is fundamental to determining whether telehealth waivers implemented during the COVID-19 public health emergency should be made permanent. The current literature has yielded inconclusive findings owing to its focus on select states, practices, or health care systems. To estimate the association of telehealth use with outcomes for all Medicare fee-for-service (FFS) beneficiaries by comparing hospital service areas (HSAs) with different levels of telehealth use. This US population-based, retrospective cohort study was conducted from July 2022 to April 2023. Participants included Medicare claims of beneficiaries attributed to HSAs with FFS enrollment in Parts A and B. Low, medium, or high tercile of telehealth use created by ranking HSAs according to the number of telehealth visits per 1000 beneficiaries. The primary outcomes were quality (ambulatory care-sensitive [ACS] hospitalizations and emergency department [ED] visits per 1000 FFS beneficiaries), access to care (clinician encounters per FFS beneficiary), and cost (total cost of care for Part A and/or B services per FFS Medicare beneficiary) determined with a difference-in-difference analysis. In this cohort study of claims from approximately 30 million Medicare beneficiaries (mean [SD] age in 2019, 71.04 [1.67] years; mean [SD] percentage female in 2019, 53.83% [2.14%]) within 3436 HSAs, between the second half of 2019 and the second half of 2021, mean ACS hospitalizations and ED visits declined sharply, mean clinician encounters per beneficiary declined slightly, and mean total cost of care per beneficiary per semester increased slightly. Compared with the low group, the high group had more ACS hospitalizations (1.63 additional hospitalizations per 1000 beneficiaries; 95% CI, 1.03-2.22 hospitalizations), more clinician encounters (0.30 additional encounters per beneficiary per semester; 95% CI, 0.23-0.38 encounters), and higher total cost of care ($164.99 higher cost per beneficiary per semester; 95% CI, $101.03-$228.96). There was no statistically significant difference in ACS ED visits between the low and high groups. In this cohort study of Medicare beneficiaries across all 3436 HSAs, high levels of telehealth use were associated with more clinician encounters, more ACS hospitalizations, and higher total health care costs. COVID-19 cases were still high during the period of study, which suggests that these findings partially reflect a higher capacity for providing health services in HSAs with higher telehealth intensity than other HSAs.

The Prevalence of Incontinence and Its Association With Urinary Tract Infections, Dermatitis, Slips and Falls, and Behavioral Disturbances Among Older Adults in Medicare Fee-for-Service.

The purpose of this study was to examine the prevalence of urinary (UI), fecal (FI), and dual incontinence (DI) in older adults and their association with urinary tract infections, dermatitis, slips and falls, and behavioral disturbances based on Medicare fee-for-service (FFS) claims data. Retrospective analysis. Data from administrative claims from the CMS Medicare Limited Data Set (5% sample) for all months in 2018 were reviewed. The analysis was limited to FFS Medicare beneficiaries, with minimum of 3-month enrollment in Parts A and B who were at least 65 years old. This cohort included 1.2 million beneficiaries in the United States. We used diagnosis codes to identify members with incontinence and grouped these members into 3 categories (UI only, FI only, and DI). We also divided claims based on 4 sites of care (nursing home, skilled nursing facility, home health, and self- or family care). We then determined the prevalence of (1) urinary tract infections (UTIs), (2) dermatitis, (3) slips and falls, and (4) behavioral disturbances for each type of incontinence. We found that 11.2% of Medicare members had a claims-based diagnosis of incontinence in 2018. On average, those diagnosed with incontinence experienced 5 times more UTIs, 2 times as many dermatitis events, more than twice as many slips and falls, and 2.8 times more behavior disturbances compared to those without an incontinence diagnosis. For those with DI, the prevalence of the 4 outcomes was significantly higher (between 22% and 185%) compared to those with UI only. Findings show that Medicare beneficiaries diagnosed as incontinent experience a much higher prevalence of UTIs, dermatitis, slips and falls, and behavioral disturbances compared to those without a diagnosis of incontinence. Our results suggest that incontinence may be an important indicator diagnosis for multiple other conditions and, if not well-managed, may challenge the desire for those who are incontinent to age at home.

Abstract C034: First in Human phase 1/2a trial of a macrocyclic ATR inhibitor (ATRN-119) in patients with advanced solid tumors

Abstract Background: ATRN-119 is an oral and highly selective nanomolar inhibitor of Ataxia Telangiectasia and Rad3- related (ATR) kinase, an enzyme that is activated by replication stress and DNA damage and prevents the collapse of DNA replication forks into double strand breaks. ATRN-119 is being studied in advanced solid tumors with dysregulated components of the DNA damage response (DDR) based on the hypothesis that these tumors will be more susceptible to ATR inhibition. Single agent ATRN-119 demonstrates increased cytotoxicity in vitro against a broad spectrum of human colon, breast, pancreatic, sarcoma, ovarian and prostate cancer cell lines that harbor genomic alterations of DDR genes. In vivo, ATRN-119 has demonstrated tumor growth inhibition in human castration-resistant prostate cancer and human colon cancer cell line-derived xenografts (CDX) mice models, and in BRCA mutant high grade serous ovarian cancer patient derived xenografts (PDXs). Trial design: This is a first-in-human Phase 1/2a open-label study (NCT04905914) to evaluate safety, tolerability, pharmacokinetics (PK), and preliminary e!cacy of oral daily ATRN-119 in subjects with advanced solid tumors, conducted in 2 parts. Part 1 consists of a 3+3 dose escalation design at up to 6 dose levels to evaluate the tolerability, PK, dose limiting toxicity (DLT) and maximum tolerated dose (MTD) of repeated daily doses of ATRN-119. Enrollment in Part 1 is ongoing. Subjects must be ≥12 years old with advanced solid tumor, have documented DDR mutations, or advanced Merkel cell carcinoma, must have failed at least one prior standard treatment, have ECOG performance status of 0 or 1, with a life expectancy &amp;gt; 3 months. Primary objective is safety/tolerability and secondary objective is efficacy. After determination of the MTD or maximum feasible dose (MFD) in Part 1, Part 2 will enroll up to 30 additional subjects. The trial is currently recruiting across 4 locations in the United States. Clinical trial identification: ClinicalTrials.gov Identifier: NCT04905914 Citation Format: Fiona Simpkins, Reva Schneider, Amit Mahipal, Patricia LoRusso, Crystal Miller, Eric Brown, Mike Carleton, Joachim Gullbo, Nadeem Q Mirza. First in Human phase 1/2a trial of a macrocyclic ATR inhibitor (ATRN-119) in patients with advanced solid tumors [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C034.

Will Survival Improve By Treating Multiple Myeloma Patients at MRD Relapse? the Remnant Study

Background: Although many new treatment options have become available, multiple myeloma (MM) is still considered an incurable disease. The importance of achieving minimal residual disease (MRD) negativity in MM patients has become clearer in recent years. Multiple studies show that bone marrow based MRD assessment is one of the strongest prognostic factors, and deeper responses correlate with more favorable outcomes. The REMNANT study will evaluate if treating at MRD relapse after first line (1.L) treatment prolongs progression-free survival (PFS) and overall survival (OS) in MM patients. Methods: The REMNANT study (RElapse from Mrd Negativity As iNdication for Treatment) is an academic, multicenter, open-label, randomized phase 2/3 study of newly diagnosed (ND) MM patients eligible for autologous stem cell transplant (ASCT). The study has a population-based approach with few exclusion criteria, implying that patients with kidney failure, amyloidosis, plasma cell leukemia and other comorbidities are enrolled. To increase enrollment in part 2, patients who have received 1.L treatment outside the REMNANT study can be enrolled directly if they are &amp;gt;CR/MRD negative. 391 NDMM patients (age 18-75 years) eligible for ASCT will be enrolled in part 1 (phase 2) of the study and receive standard of care Norwegian 1.L treatment; 4 pre-transplant induction and 4 post-transplant consolidation cycles of bortezomib, lenalidomide and dexamethasone (VRd). After induction, patients will undergo tandem or single transplant, depending on toxicity and response to first transplant. All patients receive lenalidomide maintenance. Following 1.L treatment 176 patients achieving MRD negative (Euroflow NGF 10 -5) complete response will be enrolled in part 2 (phase 3) of the study. Patients will be randomized in a 1:1 ratio to receive second line treatment (2.L) at MRD relapse in arm A or at PD in arm B. At loss of MRD negativity in arm A or at PD in arm B, 2.L treatment will be daratumumab, carfilzomib and dexamethasone until PD. The primary endpoint of part 1 (phase 2) of the study is the number of patients who achieve MRD negative (Euroflow NGF 10 -5) complete response 30-45 days post consolidation. Secondary endpoints includes response rates, safety evaluations and patient-reported outcome. The co- primary endpoints in part 2 (phase 3) are PSF and OS from randomization to progressive disease or death on 2.L treatment. We will also compare different methods for measuring MRD: NGF Euroflow, Next Generation Sequencing, mass spectrometry and PET-CT. We want to evaluate how the different methods compare when it comes to sensitivity and outcome (PFS and OS). Results: As of July 18 th 2023, 291 patients are enrolled in part 1 and 97 in part 2 (23 directly enrolled). Baseline characteristics, safety summary and preliminary results can be found in Table 1. The ORR on first line treatment is 95% and 65 of 152 patients (45%) were &amp;gt;CR and MRD negative at the post-consolidation visit. Patients achieving &amp;gt; VGPR but not CR MRD negativity post consolidation are followed for up to 24 months on lenalidomide maintenance, and 11 of 74 patients (15%) in follow-up have converted to &amp;gt;CR/MRD negativity at a median time of seven months (range 2-16). Nine patients have started 2.L treatment in part 2 (phase 3), eight in arm A (MRD guided) and one in arm B (control arm). Median time to loss of MRD negativity among the eight patients in arm A was four months (range 1-6). The most common adverse events were infections, occurring in 24% of patients (any grade). During 1.L treatment, 61 patients have left the study. Seven patients have died, 27 discontinued due to disease progression, 12 patients have withdrawn from the study and seven discontinued due to adverse events. 59% of the patients who progressed during 1. L treatment had high-risk cytogenetics (with gain1q and/or del17p and/or t(4;14)). Conclusion: Standard of care Norwegian first line treatment has an ORR of 95%. The MRD negativity rate among patients who have finished 1.L treatment was 43% (65 of 152). The median time to loss of MRD negativity in arm A (MRD guided) was 4 months.

Safety and Efficacy of Bezuclastinib (CGT9486), a Novel, Highly Selective, Potent KIT D816V Tyrosine Kinase Inhibitor, in Patients with Advanced Systemic Mastocytosis (AdvSM): Results from Part 1 of the Phase 2 Apex Trial

Background: Systemic mastocytosis (SM) is a rare disease characterized by the aberrant proliferation of mast cells (MC). In about 95% of adult patients, SM is driven by a gain-of-function mutation (D816V) in exon 17 of KIT. Advanced SM (AdvSM) is a life-threatening form of SM and includes three subtypes: aggressive SM (ASM), SM with an associated hematologic neoplasm (SM-AHN), and Mast Cell leukemia (MCL). Bezuclastinib is an oral, potent, and selective tyrosine kinase inhibitor (TKI) with activity against KIT D816V. Preliminary results from the on-going Apex study in patients with AdvSM (NCT04996875) were presented previously (DeAngelo et al. [abstract] In: Blood (ASH) 2022; 140 (Supplement 1): 1512-13). Methods: Apex is a randomized Phase 2, open-label, multicenter trial in adult patients diagnosed with AdvSM per 2022 WHO criteria with a baseline serum tryptase of ≥20 ng/mL. In Part 1, patients were randomized 1:1:1:1 to bezuclastinib 50mg BID, 100mg BID, 200mg BID, or 400mg QD. Patients with a history of prior TKI therapy (e.g., avapritinib, midostaurin) are permitted in the trial. Data from Part 1 informed dose selection for Part 2 of the trial. The primary efficacy endpoint for this trial is overall response rate (complete response [CR], CR with incomplete hematologic recovery [CRh], partial response [PR] and clinical improvement [CI]) as assessed by a central review committee based on mIWG-MRT-ECNM response criteria. Results: As of April 2023, Part 1 was fully enrolled with 33 AdvSM patients. Patients were randomized to 50mg BID (n=8), 100mg BID (n=8), 200mg BID (n=8), or 400mg QD (n=9). Disease subtypes included ASM (n=7), MCL (n=2), and SM-AHN (n=24); AHN subtypes included CMML (n=18), MDS (n=3), MPN (n=1), and MDS/MPN-U (n=2). The majority of patients were male (64%), ECOG PS 0-1 (82%) and KITD816V positive at baseline (91%). At baseline, 67% of patients were TKI-naïve; 33% had prior midostaurin, and 15% had prior avapritinib. Median (range) BM MC burden, serum tryptase, and KIT D816V VAF at baseline were 30% (5-90), 163 ng/mL (35-1578), and 7% (0-47), respectively. Of the 33 patients enrolled, 25 patients (76%) had C-findings evaluable per mIWG-MRT-ECNM criteria; 20 patients (61%) were positive for SRSF2/ASXL1/RUNX1 mutation which are associated with poor survival in SM. Conclusion: Enrollment in Part 1 of the Apex trial is complete. Patients enrolled in Part 1 of the Apex trial are generally representative of the population of patients with AdvSM based on patient characteristics and markers of disease. Part 1 includes a small subset of patients with prior use of TKIs. Safety, clinical activity, and clinical objective response for all patients in Part 1 will be presented.

Adherence to hormonal therapy after surgery among older women with ductal carcinoma in situ: Implications for breast cancer-related adverse health events.

Evidence from randomized clinical trials (RCTs) shows that receipt of hormonal therapy after surgery for estrogen receptor-positive ductal carcinoma in situ (DCIS) reduces the risk of DCIS and contralateral invasive breast cancer (IBC) but not death from breast cancer. RCTs examined homogeneous samples, and therefore whether this evidence can be generalized to diverse populations is unclear. Population-based data from four state cancer registries (California, New Jersey, New York, and Texas) were analyzed on women aged 65 years and older newly diagnosed with DCIS who underwent surgery with or without radiation during the years 2006-2013. Registry records were merged with Medicare enrollment in Parts A and/or B and D (prescription drugs) and associated claims. Whether adherence to hormonal therapy was associated with adverse breast cancer-related health events was analyzed. Achieving excellent adherence did not affect death from breast cancer. In contrast, the risk of developing a subsequent breast tumor was 6.24 percentage points (breast-conserving surgery [BCS] with radiation therapy [RT]) and 10.54 percentage points (BCS alone) lower for women with excellent versus low adherence (p<.00001). For excellent versus good adherence, the reduced risk among women who had BCS with and without RT was approximately 3 and 5 percentage points, respectively. A similar pattern emerged for the risk of IBC among women who achieved excellent versus good or low adherence, whereas good versus low adherence comparisons were not significant. This analysis of a diverse population-based cohort of women with DCIS demonstrates that achieving excellent adherence to hormonal therapy is critical to minimizing the occurrence of developing subsequent breast tumors. Our analysis of a diverse population-based cohort of women with ductal carcinoma in situ demonstrates that achieving excellent adherence to hormonal therapy is critical to minimizing the occurrence of developing subsequent breast tumors.

Real-World Survival of First-Line Immune Checkpoint Inhibitor Treatment Versus Chemotherapy in Older Patients With Non-Small-Cell Lung Cancer and Synchronous Brain Metastases.

This study assessed real-world survival among older patients with non-small-cell lung cancer (NSCLC) and brain metastases (BMs) at diagnosis (synchronous BM [SBM]) receiving first-line immune checkpoint inhibitors (ICIs) compared with chemotherapy only. Patients with NSCLC and SBM age 65 years or older at diagnosis from 2010 to 2019 SEER-Medicare database and received US Food and Drug Administration-approved ICIs (pembrolizumab/nivolumab/ipilimumab/atezolizumab/durvalumab/cemiplimab) and/or chemotherapy (platinum-based doublets/taxane/pemetrexed/gemcitabine) as first-line systemic treatment were included, excluding those with no cranial radiation or ever being treated with targeted therapies. Overall survival time was from the start of systemic treatment (ICI/chemotherapy) to death, censored at disenrollment from Medicare part A/B, enrollment in part C, or end of the study period (December 31, 2019). Kaplan-Meier (KM) survival curves were compared between treatment groups using the log-rank test. Multivariable Cox proportional hazards (CPH) model was used to estimate hazard ratio (HR) between groups, adjusting for patients' sociodemographic and clinical characteristics. The study included 1,481 patients (1,303 chemotherapy and 178 ICI). The median (range) age was 71 (65-91) years. First-line ICI patients were more likely to be older, live in urban areas, and less likely to be non-White than the chemotherapy group. KM estimates showed that survival curves initially overlapped but diverged approximately 6 months after initiating first-line systemic treatment (median survival [95% CI]: ICI, 190 [131 to 303] days versus chemotherapy, 189 [177 to 201] days), with ICI showing a better survival than the chemotherapy group (log-rank test P < .0001). First-line ICI was associated with a lower risk of death compared with chemotherapy in adjusted CPH model (HR [95% CI], 0.67 [0.55 to 0.80]; P < .0001). Among older patients with NSCLC and SBM, first-line ICI use was associated with improved survival occurring 6 months after treatment initiation compared with chemotherapy only.

Abstract CT050: A phase 2, multi-center, open-label, dose-finding study evaluating telomere targeting agent THIO sequenced with cemiplimab in patients with advanced NSCLC

Abstract Background: The modified nucleoside 6-thio-2'-deoxyguanosine (THIO) is a first-in-class direct telomere-targeting agent that is preferentially incorporated in telomeres of telomerase-positive cells, leading to telomere uncapping and cancer cell death. Preclinical evidence indicates that THIO pretreatment sensitizes non-small cell lung cancer (NSCLC) cells to cemiplimab, a PD-1 inhibitor approved as 1L treatment for patients with locally advanced/metastatic NSCLC with ≥50% PD-L1 expression. The THIO-101 trial is designed to evaluate safety and efficacy of THIO followed by cemiplimab in patients with advanced NSCLC who have developed resistance or relapsed after prior immune checkpoint inhibitor (ICI) therapy. Trial Design: THIO-101 enrolls adult patients with stage 3/4 NSCLC, who have progressed or relapsed after treatment with an ICI alone or in combination with platinum-based therapy. Using a 3+3 design, the safety lead-in (Part A) is enrolling up to 6 patients in the first cohort to receive a total dose of THIO 360 mg IV (120 mg QD, D1-3) followed by a fixed dose of cemiplimab 350 mg on D5 Q3W. If ≥2 patients experience dose-limiting toxicities, a second cohort will receive a total dose of THIO 180 mg IV (60 mg QD, D1-3) followed by cemiplimab. In the dose- finding portion of the study (Part B), patients will be randomized 1:1:1 in a Simon 2-stage design (n=41 per arm) to receive THIO 360 mg [if cleared in Part A], 180 mg, or 60 mg followed by cemiplimab. Sequential THIO and cemiplimab treatment may be continued Q3W for up to 1 year, or until disease progression, unacceptable toxicity, or withdrawal of consent. The primary endpoints are safety, objective response rate, and disease control rate (CR, PR, and SD). Secondary endpoints include duration of response, progression-free survival, and overall survival; exploratory endpoints include PK/PD parameters (type I IFN, IL-6, CRP) and assessment of tumor telomerase status by IHC. Investigators will assess disease progression per RECIST v1.1 and/or iRECIST, with radiographic scans performed on D1 of cycles 3 and 5 and every 9-12 weeks thereafter. Adverse events are evaluated according to NCI CTCAE v5.0. The trial is enrolling patients at sites in Europe and Australia. The trial has completed enrollment in Part A without DLTs and opened enrollment in Part B. NCT05208944; EUDRA CT Number, 2021-005136-34 Citation Format: Mihail Obrocea, Brenton Seidl, Rohit Joshi, Melissa Moore, Vlad Vitoc, Bin Yao, Sergei Gryaznov. A phase 2, multi-center, open-label, dose-finding study evaluating telomere targeting agent THIO sequenced with cemiplimab in patients with advanced NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT050.

First-line lenvatinib plus pembrolizumab plus chemotherapy versus chemotherapy in advanced/metastatic gastroesophageal adenocarcinoma (LEAP-015): Safety run-in results.

411 Background: LEAP-015 (NCT04662710) is a randomized, open-label, 2-part, phase 3 study of the safety and efficacy of lenvatinib + pembrolizumab + chemotherapy as a first-line treatment for advanced/metastatic gastroesophageal adenocarcinoma. We report findings from part 1, the safety run-in, of LEAP-015. Methods: Eligible patients had untreated, HER2-negative, locally advanced unresectable or metastatic gastroesophageal adenocarcinoma, measurable disease per RECIST v1.1, and ECOG performance status 0 or 1. In part 1, patients received induction with IV pembrolizumab 400 mg Q6W (×2) + oral lenvatinib 8 mg QD + investigator choice of chemotherapy (capecitabine + oxaliplatin [CAPOX] Q3W ×4 or 5-fluorouracil + leucovorin + oxaliplatin [mFOLFOX6] Q2W ×6) and consolidation with pembrolizumab 400 mg Q6W for ≤16 doses + lenvatinib 20 mg QD; dose-limiting toxicities (DLTs), defined as selected prespecified grade ≥3 adverse events (AEs) or any-grade thromboembolic events, were evaluated for 21 days after the first dose of study intervention. If ≥3 DLTs occurred in either oxaliplatin-containing regimen, then enrollment in part 2 may be delayed to allow for the examination of safety data and to consider design changes. In part 1, the primary end point was safety and tolerability in all patients. Preliminary efficacy was also assessed in part 1. Objective response and disease control rate were assessed per RECIST version 1.1 by blinded independent central review. Results: In part 1, 15 pts received ≥1 dose of lenvatinib + pembrolizumab + chemotherapy. 1 DLT of grade 3 asthenia occurred in the CAPOX cohort and 1 DLT of grade 4 neutropenia occurred in the FOLFOX cohort. Median time from first dose to data cutoff (Oct 13, 2021) was 7 mo (range, 7-9). Treatment-related AEs occurred in 14 patients (93%), with grade 3/4 events in 8 patients (53%). 4 patients (27%) discontinued any drug because of a treatment-related AE, and no patient discontinued all drugs because of a treatment-related AE. No patients died because of a treatment-related AE. No grade ≥3 immune-mediated AEs or infusion reactions occurred. Objective response was reported in 11 of 15 patients (73%; 95% CI, 45-92) who received ≥1 dose of treatment. Disease control rate was reported in 14 of 15 patients (93%; 95% CI, 68-100) who received ≥1 dose of treatment. Conclusions: In the safety run-in of LEAP-015, lenvatinib + pembrolizumab + chemotherapy was associated with a manageable safety profile in the first-line treatment of advanced/metastatic gastroesophageal adenocarcinoma. Preliminary antitumor activity was observed for lenvatinib + pembrolizumab + chemotherapy. Part 2 will evaluate the efficacy and safety of lenvatinib + pembrolizumab + chemotherapy versus chemotherapy in this same patient population and patient accrual is ongoing. Clinical trial information: NCT04662710 .

Association between hospital-physician vertical integration and medication adherence rates.

To test the association between vertical integration of primary care providers (PCPs) and adherence rates for anti-diabetics, renin angiotensin system antagonists (RASA), and statins. Medicare Part B outpatient fee-for-service claims and Medicare Part D event data from 2014 to 2017. We estimated difference-in-differences regressions, comparing changes in adherence among patients with PCPs who converted from independent to integrated to changes among patients whose PCPs remained independent or integrated during the study period. To test for heterogenous impacts by patient demographics, we estimated triple difference regressions that included additional interaction terms by comorbidity rates, age group, and race/ethnicity. We extracted Medicare claims for adults with continuous enrollment in Parts B and D during the study period. The proportion of patients who had a vertically integrated PCP increased by approximately 23% over the study period. Changes in adherence did not differ significantly between patients based on whether their PCP became integrated (Statins: 0.18, 95% CI -0.13, 0.49; RASA: -0.13, 95% CI -0.46, 0.19; Anti-Diabetics: -0.20, 95% CI -0.78, 0.38). Among patients with PCPs who became integrated, there were significant decreases in adherence for patients who were Black, Asian, Hispanic, or Native American, above 80 years old, and had greater comorbidities for all three classes. While there were no average changes in adherence following vertical integration of PCPs, health equity worsened, with significant declines in adherence for Black, Asian, Hispanic, and Native American patients, patients over 80 years old, and patients with greater comorbidities. These findings suggest that integration may reduce clinicians'incentives to compete based on the quality of care delivered. Given the price increases associated with integration, integration may be a net welfare loss.

FP.22 Results from the end of Part A of the ongoing 3-part DEVOTE study to explore higher doses of nusinersen in SMA

DEVOTE is an ongoing 3-part, Phase 2/3 study evaluating the safety/tolerability, efficacy, and pharmacokinetics of higher doses of nusinersen in participants with SMA. Part A is an open-label study in later-onset SMA; participants receive 3 loading doses of 28mg nusinersen at 14-day intervals followed by 28mg maintenance doses every 4 months. Part B is a pivotal, randomized, double-blind, active-controlled study of up to 126 participants with infantile- or later-onset SMA randomized (1:2) to receive the approved 12-mg dosing regimen or 2 loading doses (50mg) 14 days apart followed by maintenance doses (28mg) every 4 months. Part C will enroll ∼40 participants who have been receiving the approved nusinersen dosing regimen for ≥1 year. Part C participants will receive 1 loading dose (50mg) followed by maintenance doses (28mg) every 4 months. The primary objective of DEVOTE Part A is to evaluate the safety and tolerability of higher doses of nusinersen in treatment-naïve participants with SMA. Enrollment in Part A is complete (N=6) and the final results from Part A are reported. Age at SMA symptom onset was 8–36 months and age at screening was 6.1–12.6 years; three (50%) participants were ambulatory at screening. AEs were reported in four (67%), with no AEs assessed as related to nusinersen. Among the six participants, four (67%) participants experienced ≥1 AEs related to lumbar puncture. There were no clinically relevant changes related to nusinersen in blood chemistry, hematology, urinalysis, vital signs, physical or neurological exams, or ECGs. Final safety and efficacy results will be reported. DEVOTE is currently enrolling participants in Part B and Part C. Results from DEVOTE (NCT04089566) will provide valuable information on the efficacy and safety of higher doses of nusinersen in a range of participants with SMA.

1223P First-line lenvatinib (Len) + pembrolizumab (Pembro) + chemotherapy (Chemo) vs chemo in advanced/metastatic gastroesophageal adenocarcinoma: LEAP-015 safety run-in

LEAP-015 (NCT04662710) is a randomized, open-label, 2-part, phase III study of the safety and efficacy of len + pembro + chemo as a first-line treatment for advanced/metastatic gastroesophageal adenocarcinoma. We report findings from part 1, the safety run-in, of LEAP-015. Eligible patients (pts) had untreated, HER2-negative, locally advanced unresectable or metastatic gastroesophageal adenocarcinoma, measurable disease per RECIST v1.1, and ECOG performance status 0 or 1. In part 1, pts received induction with IV pembro 400 mg Q6W (×2) + oral len 8 mg QD + investigator choice of chemo (capecitabine + oxaliplatin [CAPOX] Q3W ×4 or 5-fluorouracil + leucovorin + oxaliplatin [mFOLFOX6] Q2W ×6) and consolidation with pembro 400 mg Q6W for ≤16 doses + len 20 mg QD; dose-limiting toxicities (DLTs), defined as selected prespecified grade ≥3 adverse events (AEs) or any-grade thromboembolic events, were evaluated for 21 days after the first dose of study intervention. If ≥3 DLTs occurred in either oxaliplatin-containing regimen, then enrollment in part 2 was delayed to allow for examination of safety data and to consider design changes. In part 1, the primary end point was safety and tolerability in all pts. In part 1, 15 pts received ≥1 dose of len + pembro + chemo. 1 DLT of grade 3 asthenia occurred in the CAPOX cohort and 1 DLT of grade 4 neutropenia occurred in the FOLFOX cohort. Median time from first dose to data cutoff (Oct 13, 2021) was 7 mo (range, 7-9). Treatment-related AEs occurred in 14 pts (93%), with grade 3/4 treatment-related AEs in 8 pts (53%). 4 pts discontinued any drug because of a treatment-related AE and no pt discontinued all drugs because of a treatment-related AE. No pt died because of a treatment-related AE. No grade ≥3 immune-mediated AEs or infusion reactions occurred. In the safety run-in of LEAP-015, len + pembro + chemo was associated with a manageable safety profile in the first-line treatment of advanced/metastatic gastroesophageal adenocarcinoma. Part 2 is currently enrolling and will evaluate the efficacy and safety of len + pembro + chemo vs chemo in this same pt population.

Characterizing platinum sensitivity among Medicare FFS patients with limited versus extensive-stage small cell lung cancer receiving NCCN category 1 preferred regimens.

e20601 Background: There is limited research evaluating real-world platinum sensitivity and treatment patterns among patients with limited vs. extensive stage small cell lung cancer (SCLC). Methods: We identified patients with SCLC in 2017 using ICD-10 diagnosis (Dx) and drug codes in the 2016-20 Medicare Parts A/B/D 100% Research Identifiable Files. Patients had 1+ lung cancer Dx and continuous enrollment in Parts A/B/D from the month prior to first Dx in 2017 (index) through 2020 or death. Patients with evidence of end-stage renal disease, prior lung or any metastatic cancer Dx within 12 months of index, lung resection/lobectomy, or use of a drug indicated only for non-SCLC or lung neuroendocrine cancer per NCCN guidelines were excluded. Use of systemic therapies cisplatin (ci), carboplatin (ca), etoposide intravenous (etIV), atezolizumab (at), durvalumab (du) and irinotecan (ir) were observed. Patients included in our study were treated with first-line NCCN Category 1 preferred regimens: ca/etIV, ca/etIV/at, ca/etIV/du, ca/ir, ci/etIV, ci/etIV/du, or ci/ir. First line of therapy (LoT1) was defined based on the first claim for a first-line regimen administered within 90 days following or up to 14 days before index. The end of LoT1 was defined as the earliest of death, 32 days after the last administration, or the start of a second line of therapy (LoT2). Patients initially treated with ca/etIV/at, ca/etIV/du, ca/ir, ci/etIV/du, or ci/ir regimens were flagged with extensive stage disease. Patients not receiving these regimens were classified as limited stage disease if they had 15+ days of radiation therapy over a 6-week period during or within 60 days of LoT1. Patients were deemed platinum sensitive (PS) if we did not observe a LoT2, hospice, or death within 6 months of LoT1. Uncategorizable patients were flagged Status Unknown (SU). All other patients were deemed platinum refractory (PR). Results: We identified 3,772 SCLC patients receiving NCCN Category 1 preferred regimens: 43% (1,607) had limited stage, and 57% (2,165) had extensive stage at index. Among patients with extensive stage, 71% (1,541) were PR compared with 34% (548) of patients with limited stage. On average, patients with extensive stage had fewer platinum cycles in LoT1 than those with limited stage. Conclusions: More platinum refractory patterns were observed among Medicare FFS patients with extensive stage SCLC than among patients with limited stage SCLC. Patients with extensive stage SCLC also underwent fewer platinum cycles in their first line of therapy.[Table: see text]

GRN300–001: Phase 1/1B evaluation of the safety, pharmacokinetics, and efficacy of GRN-300, a salt-inducible kinase inhibitor, alone and in combination with paclitaxel, in recurrent ovarian, primary peritoneal, and fallopian tube cancers.

TPS5616 Background: Salt-induced kinase 2 (SIK2) is a serine-threonine kinase that regulates centrosome splitting, activation of PI3 kinase and phosphorylation of Class IIa HDACs. SIK2 is overexpressed in 30% of ovarian cancers and associated with decreased progression-free survival (Ahmed et al., 2010). Treatment with GRN-300, an orally bioavailable small-molecule inhibitor of SIK2, was shown to improve the response to paclitaxel in human ovarian cancer cells grown in culture and in immunocompromised mice (Zhou et al., 2017). Methods: Part 1 of the study will evaluate the safety, MTD, RP2D (Recommended Phase 2 Dose), and PK of daily GRN-300 monotherapy. For the dose-escalation enrollment of patients with advanced solid tumors of any histology, four dose levels of GRN-300 are planned: 100, 200, 300, and 400 mg BID. Subsequently, GRN-300 will be administered at the determined RP2D in an ovarian cancer expansion cohort. Part 2 will evaluate the safety, PK, and preliminary clinical activity in an open-label study of the combination of GRN-300 and paclitaxel weekly x3. Paclitaxel will be administered in one of two different dosing levels: 60 mg/m2 initially, then dose escalated to 80 mg/m2. In the combination regimen, GRN-300 will be administered at the RP2D dose as determined in Part 1 of this study. The two dose findings will be conducted independently using the BOIN design (Liu 2015, Yuan 2016). Study drug may be administered per protocol for continuous 28-day cycles until disease progression, adverse events, or other criteria as described in the protocol. Tumor biopsies and blood plasma samples including peripheral blood mononuclear cells (PBMCs) will be collected for exploratory biomarker analysis to predict and to monitor responses to GRN-300 treatment. Major eligibility criteria At least 18 years of age. Recurrent or persistent, locally non-resectable or metastatic ovarian, primary peritoneal or fallopian tube epithelial cancer (advanced solid tumors of any other histology only for the monotherapy dose escalation enrollment in Part 1) In Part 2, diagnosis of recurrent or persistent, locally non-resectable or metastatic ovarian, primary peritoneal or fallopian tube epithelial cancer for which treatment with paclitaxel is indicated. Received at least one prior second-line treatment. The first 3 dose groups (100, 200, and 300 mg BID of GRN-300) have been completed without DLT and preliminary PK analysis indicate dose proportionality. Enrollment to dose group 4 (400 mg BID) began in February 2022. Clinical trial information: NCT04711161.

CYCLONE 2: A phase 2/3, randomized, placebo-controlled study of abiraterone acetate plus prednisone with or without abemaciclib in patients with metastatic castration-resistant prostate cancer.

TPS198 Background: Despite recent advances, nearly all patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) experience disease progression and cancer-specific mortality. Persistent or reactivated androgen receptor (AR) signaling and/or activation of pathways in cross-talk with AR signaling are key drivers of mCRPC progression. Evidence suggests that AR signaling promotes translation of D-type cyclins resulting in cyclin-dependent kinase 4 and 6 (CDK4&amp;6) activation and cell cycle progression. Abemaciclib is an oral selective inhibitor of CDK4&amp;6 dosed on a continuous schedule, that is FDA-approved in combination with endocrine therapy or as monotherapy to treat HR+, HER2- metastatic breast cancer pts. Preclinical studies with prostate cancer cell lines and xenograft models showed that abemaciclib induces cell cycle arrest and tumor growth inhibition. The hypothesis is that addition of abemaciclib to AR targeted therapy may be an effective treatment for mCRPC pts. Methods: CYCLONE 2 (NCT03706365) is a phase 2/3, randomized, double-blind, multicenter, placebo-controlled study to assess the safety and efficacy of abemaciclib in combination with abiraterone acetate plus prednisone (AA+P) in pts with mCRPC. CYCLONE 2 is an adaptive study which is designed in three parts. Part 1 is a 30-patient safety lead-in to determine the recommended phase 2 dose (RP2D; 150 mg or 200 mg, twice daily) of abemaciclib in combination with AA (1000 mg, once daily) + P (5 mg, twice daily). In part 2, 150 pts are randomized 1:1 to AA+P with abemaciclib at the RP2D or placebo. The study expands to enroll an additional 170 pts in Part 3 if prespecified expansion criteria are met at a planned adaptive interim analysis performed by an independent data monitoring committee (IDMC). Pts with mCRPC evidenced by radiographic and/or PSA progression during continuous ADT are eligible. Prior docetaxel for mHSPC is permitted. Systemic anti-cancer therapy for mCRPC and prior novel hormonal agents are exclusionary. The primary objective is radiographic progression free survival (rPFS; per RECIST1.1 for soft tissue and PCWG3 for bone). Secondary objectives include safety, objective response rate, duration of response, time to symptomatic and PSA progression, overall survival, and pharmacokinetics. Status: Enrollment in Part 1 &amp; 2 is completed. Based on the recommendation from the IDMC, Part 3 was opened in June 2021 and enrolls pts from about 112 sites across 12 countries. Clinical trial information: NCT03706365.

A Phase 3 Study of the Hepcidin Mimetic Rusfertide (PTG-300) in Patients with Polycythemia Vera

A Phase 3 Study of the Hepcidin Mimetic Rusfertide (PTG-300) in Patients with Polycythemia Vera