Dotan, Efrat

Abstract Background We performed a prospective study evaluating a baseline GA battery and clinical outcomes in fit older adults (age ≥60 years) with AML and normal cardiac and renal function in the recent E-A NCTN E2906 phase 3 study. A patient-reported outcomes (PRO) assessment of Depression, Activities of Daily Living (ADL), Cognitive Function, Social Support (SS) domains, and comorbidity was performed at study registration to evaluate the prevalence of vulnerabilities and their impact on overall survival (OS) and 30-day induction mortality rates (IM) in this cohort selected for fitness to receive IC. Methods E2906 study design and results have been presented previously [n=727, age ≥60 years, randomized 1:1 to ‘standard 7&3‘ & high dose cytarabine (Arm A) vs. single agent clofarabine (CLO, Arm B), as remission induction (Step 1) and consolidation (Step 2)]. There was no difference in composite complete remission (CCR, 50%) or IM (8.5%), and CLO was inferior for OS. A baseline GA was a key secondary protocol objective, offered to all patients, and n=532 (73%) participated. We assessed Geriatric Depression Scale (GDS, none vs. any depressive symptoms, n=524); cognitive screen using Mini-Mental Exam Section (MMES, score 8/8 vs. <8, n=516); ADL & Instrumental ADL (iADL), (need for assistances vs. not n=526); a Medical Outcomes Study SS Survey (MOS-SS, measured as per unit increase, n=527); a Comorbidity survey ( ≤4 vs. ≥5 patient-reported comorbidities, n=530), patient-reported prescription medications use (PM, 0-3 vs. ≥4, n=519); and a survey of Sexual Desire (n=491) and Sexual Activity (n=477) within 4 weeks of AML diagnosis. Association of GA domains with OS, IM, and achievement of CCR was evaluated using the Chi-squared, Fisher's exact, and Wilcoxon rank sum test. Survival analysis was performed using the Cox proportional hazards models, adjusted for treatment arm. All p-values are 2-sided. Results The median age among those participating in GA battery was 67 yrs (range 60-85), including 38% age ≥70. There were 42% females, and ECOG performance status was 0 (28%), 1 (54%), 2 (16%), or 3 (2%). Central Cytogenetic review was classified (ELN2017) as Favorable (3%), Intermediate (66%), and Adverse (31%) risk. There was a notable rate of GA scores outside ‘normal’ clinical cutoff, including Depression (GDS 31%), cognitive and functional impairment [MMSE (37%), ADL (25%) and iADL (32%)], ≥5 Comorbidities (23%), and ≥4 PM's (44%). 81% & 76%, respectively, reported no sexual activity and low/none sexual desire. MOS-SS tended to be high in this cohort [mean (SD) score 87 (17)]. We observed a significant association of GA domains with OS & IM. For OS, absence of depressive symptoms [GDS, Hazard Ratio (HR) 0.79, 95% confidence Intervals (CI) 0.64-0.97, p=0.025)], MMES 8/8 (HR 0.78, 95%CI 0.64-0.96, p=0.016), requiring no assistance with ADLs (HR 0.65, 95%CI 0.52-0.82, p<0.001) and iADLs (HR 0.69, 95%CI 0.57-0.85, p<0.001), and ≤4 Comorbidities (HR 0.68, 95%CI 0.54-0.84, p=0.001) were significant for superior OS; use of ≥4 PM's was associated with inferior OS (HR 1.32, 95%CI 1.09-1.61, p=0.005). There was no association of sexual activity/desire, BMI ≥30 kg/m2, or MOS-SS with OS. IM was significantly higher among those with any depression symptoms (GDS, p=0.005), any ADL (p=0.010) or iADL (p=0.013) impairment, ≥5 comorbidities (p=0.037) and ≥4 PM's (p=0.001); there was no association with MOS-SS or MMES. There was no significant association of GA scores with cytogenetic risk group or with CCR rates. Only ADL independence (p=0.048), and possibly Comorbidity ≤4 (p=0.071), were associated with proceeding to Step 2. Conclusions In this large prospective cohort of fit older adults with AML selected to receive IC, we observed high rates of PRO-assessed GA vulnerability, which was significantly associated with inferior OS and higher IM rates, and (for ADL impairment) lower rates of proceeding to consolidation therapy. This suggests that functional and cognitive impairments are prevalent and can significantly impact outcome even in fit older adults. Despite potential long-term OS advantages of IC previously observed in E2906, efforts to systematically recognize those at higher risk based on GA PROs are needed to help identify patients who may be more appropriate for study of lower intensity treatment options to mitigate impact on IM and OS. SImilarly we plan to evaluate the potential benefit of GA-driven supportive care to improve patients' outcomes.

Importance Neoadjuvant therapy (NT) is an increasingly used treatment strategy for patients with localized pancreatic ductal adenocarcinoma (PDAC). Little research has been conducted on cancer care delivery during NT, and the standards for optimal delivery of NT have not been defined. Objective To develop consensus best practices for delivering NT to patients with localized PDAC. Design, Setting, and Participants This study used a modified Delphi approach consisting of 2 rounds of voting, and a series of virtual conferences (from October to December 2023) to reach expert consensus on candidate best practice statements generated from a systematic review of the literature and expert opinion. An interdisciplinary panel was formed including 47 North American experts from surgical, medical, and radiation oncology, radiology, pathology, gastroenterology, integrative oncology, anesthesia, pharmacy, nursing, cancer care delivery research, and nutrition as well as patient and caregiver stakeholders. Main Outcome and Measures Statements that reached 75% agreement or greater were included in final consensus statements. Results Of the 47 participating panel members, 27 (57.64%) were male, and the mean (SD) age was 47.6 (8.2) years. Physicians reported completing training a mean (SD) 14.6 (8.6) years prior and seeing a mean (SD) 110.6 (38.4) patients with PDAC annually; 35 (77.7%) were in academic practice. Final consensus was reached on 82 best practices for delivering NT. Of these, 38 statements focused on pre-NT practices, including diagnosis and staging (n = 15), evaluation and optimization (n = 20), and decision-making (n = 3); 29 statements defined best practices during NT, including initiation (n = 3), delivery of therapy (n = 8), restaging practices (n = 12), and management of complications during NT (n = 6); and 15 best practices were identified to guide treatment post-NT, focusing on surgery (n = 7), pathology (n = 4), and follow-up (n = 3). Conclusions Using a modified Delphi consensus technique, best practice guidelines were developed focusing on the optimal standards for delivering NT to patients with localized PDAC. Given the prognostic importance of completing multimodality therapy, efforts to standardize and optimize the delivery of NT represent an immediate opportunity to decrease care variation and improve outcomes for patients with PDAC. Future research should focus on validating and implementing best practice standards into clinical practice.

Ampullary cancers refer to tumors originating from the ampulla of Vater (the ampulla, the intraduodenal portion of the bile duct, and the intraduodenal portion of the pancreatic duct), while periampullary cancers may arise from locations encompassing the head of the pancreas, distal bile duct, duodenum, or ampulla of Vater. Ampullary cancers are rare gastrointestinal malignancies, and prognosis varies greatly based on factors such as patient age, TNM classification, differentiation grade, and treatment modality received. Systemic therapy is used in all stages of ampullary cancer, including neoadjuvant therapy, adjuvant therapy, and first-line or subsequent-line therapy for locally advanced, metastatic, and recurrent disease. Radiation therapy may be used in localized ampullary cancer, sometimes in combination with chemotherapy, but there is no high-level evidence to support its utility. Select tumors may be treated surgically. This article describes NCCN recommendations regarding management of ampullary adenocarcinoma.

12047 Background: Metastatic colorectal cancer (mCRC) is a leading cause of death, particularly in older adults. Regorafenib (REGO) is an FDA-approved oral multi-kinase inhibitor for refractory mCRC based on the CORRECT trial results, but older adults were underrepresented with a median age of 61 (54–67). This study aimed to evaluate REGO safety in older adults with mCRC and assess the feasibility of using geriatric assessment (GA) to predict toxicity risk. Methods: 27 subjects (PTs) enrolled (median age 73, range 65-85) and started at 120mg of REGO for 21 days of a 28-day cycle with provider discretion to escalate to full dose of 160mg after cycle 1. GA was conducted at enrollment, 4 weeks later, and then every 3 months to monitor for any deterioration. GA assessed 8 geriatric domains (comorbidity, functional status, physical performance, cognition, psychological state, nutrition, medication review, and social support) using validated tools. Primary objective was to assess grade 3-5 toxicity rate, with secondary objectives evaluating REGO efficacy and exploring baseline GA and toxicity risk associations. Kaplan-Meier method was used to estimate median overall survival (OS) and progression-free survival (PFS) from date of consent. Continuous GA measures were compared using non-parametric Wilcoxon rank-sum test, and binary GA measures were compared using Fisher’s exact test. Results: Of 27 PTs enrolled, 15 were male, 12 were female, and 19 identified as white. At baseline, 77.7% of PTs had at least 3 (1-9) GA impairments. Physical performance (80.8%), comorbidity (75%), and cognition (69.2%) were the most prevalent impaired GA domains. 40% required dose reduction by end of cycle 2, and none escalated to full dose. 55% of PTs completed cycle 3. Main reasons for drug discontinuation were disease progression (80%) and toxicity (12%). 74.1% of PTs experienced at least one treatment-related grade 3-4 toxicity. Fatigue (33%), hypertension (30%), and hand-foot syndrome (15%) were the leading grade 3-4 toxicities. Median OS was 5.6 months (95% CI: 3.6-12.2m), and median PFS was 2.8 months (95% CI: 2.5-3.4m). There was no significant difference in baseline GA measures between those who experienced toxicities and those who did not. No statistically significant toxicity risk was associated with any baseline GA impairment. The prevalence of impaired mini-nutritional assessment increased over 4 weeks (58% to 91%, p < 0.01), and median Short Physical Performance Battery (SPPB) scores decreased (7 to 6, p = 0.03). Conclusions: The study found that older adults with mCRC had comparable survival with REGO but experienced high toxicity. This may be ameliorated by recently published step-wise REDOS dosing method and should be considered in older adults with mCRC. The study confirms the feasibility of implementing GA within clinical trials. More data is needed on the role of GA in predicting toxicity with targeted therapies. Clinical trial information: NCT02466009 .

4009 Background: Oncogenic FGFR2 alterations (fusions/rearrangements (f/r), amplifications, mutations) represent a broad therapeutic opportunity as they drive multiple solid tumors, particularly cholangiocarcinoma (CCA). However, off-isoform toxicity and on-target resistance limit the benefit of approved pan-FGFR inhibitors (FGFRi). RLY-4008 is the first potent, highly selective, oral FGFR2 inhibitor designed to overcome these limitations by targeting FGFR2 driver alterations and resistance mutations. Here, we present updated dose escalation results from ReFocus (NCT04526106), a seamless Phase I/II, open label study evaluating the safety and preliminary efficacy of RLY-4008 in patients (pts) with advanced, FGFR2-altered solid tumors. Methods: Adult pts received RLY-4008 BID, QD, QD discontinuous on a 4-week (wk) cycle following a Bayesian Optimal Interval design. Treatment-related adverse events (TRAEs), PK, ctDNA and anti-tumor activity (RECIST v1.1) were assessed. Results: As of 30 Jan 23, 116 pts (82 f/r, 27 mutation, 6 amplification) received RLY-4008 at doses of 20-200 mg/day, including 91 with CCA. 50% had prior FGFRi, and median lines of prior therapies was 3 (1-15). 28/46 ct-DNA-evaluable pts with CCA with prior FGFRi had ≥1 baseline resistance mutation, most commonly at FGFR2 N549X (23/46) or V564X (17/46). RLY-4008 had favorable PK with doses ≥40 mg QD providing FGFR2 occupancy ≥90%. 70 mg QD was the RP2D based on PK, safety, anti-tumor activity and exposure-dependent tumor regressions in FGFRi-naïve CCA f/r pts. Anti-tumor activity was observed in CCA and solid tumors across doses and FGFR2 alterations with radiographic tumor reductions in 74 (64%), SD/PR in 83 (72%), including 4/4 (100%) FGFRi-naïve CCA f/r pts at RP2D achieving confirmed PR. Clinically meaningful disease control and durable responses were observed in pts with FGFR2 f/r CCA. Overall, median treatment duration was 24 wks (range <1-108 wks). 105 pts discontinued (PD (81%), AE (3%), other (7%)). Across doses, most common TRAEs were low-grade PPE (57%), stomatitis (56%), dry mouth (38%), alopecia (28%), and dry eye (22%). No grade 4/5 TRAEs were observed. Conclusions: These encouraging dose escalation data confirm the broad therapeutic potential of highly selective FGFR2 targeting with RLY-4008 by demonstrating encouraging initial efficacy across FGFR2-altered solid tumors and genomic alterations, with a differentiated safety profile that avoids FGFR1- and FGFR4-related toxicity. Phase 2 of ReFocus continues across solid tumors and with registrational intent in FGFRi-naïve, FGFR2 f/r CCA. Clinical trial information: NCT04526106 . [Table: see text]

AbstractAlthough adults aged 65 years or older make up a strong majority of cancer patients, their underrepresentation in cancer clinical trials leads to the lack of representative data to guide evidence-based therapeutic decisions in this patient population. The Trial Design Working Group, convened as part of the workshop titled, Engaging Older Adults in the National Cancer Institute Clinical Trials Network: Challenges and Opportunities, recommended study designs and design elements that could improve accrual of older adults in National Cancer Institute–funded clinical trials. These include trials that are specifically designed to enroll older adults, trials that include a cohort of older patients (parallel cohort, stratified cohort, or embedded cohort), and trials with pragmatic design elements to facilitate enrollment of older adults. This manuscript provides brief descriptions of the recommended designs, examples of successful trials, and considerations for implementation of these designs.As with any clinical trial, the scientific questions and trial objectives should drive the study design, the selection of endpoints and intervention, and eligibility criteria. When designing trials that include older adults, the heterogeneity of fitness levels is an important consideration as fitness can influence accrual rates and outcomes. Appropriately incorporating geriatric assessments can help identify the optimal subset of older patients for inclusion and minimize selection bias. Incorporating pragmatic design elements to reduce the burden on trial participants as well as on accruing sites and retaining essential elements to ensure that the main goal of the trial can be accomplished can enhance enrollment without compromising the integrity of trials.

Abstract INTRODUCTION: Oncogenic FGFR2 alterations (fusions/rearrangements, amplifications, mutations) are key drivers in cholangiocarcinoma (CCA) and multiple solid tumors. Current pan-FGFR inhibitor (FGFRi) therapy is limited by off-isoform toxicity and acquired FGFR2 kinase domain resistance mutations. RLY-4008 is a highly selective and potent oral inhibitor designed to target both FGFR2 driver and resistance mutations. We initiated a first-in-human study in advanced solid tumors patients (pts) to define the safety, pharmacokinetics (PK) and efficacy of RLY-4008 (NCT04526106). METHODS: Adult pts received RLY-4008 QD or BID on a 4-week cycle following a BOIN escalation design. Adverse events (AEs), PK, ctDNA and anti-tumor activity (RECIST 1.1) were assessed. RESULTS: As of 16AUG21, 45 pts (35 CCA; 10 other) have been treated with RLY-4008 at total daily doses of 30-200 mg (18 pts BID; 27 pts QD). 44 pts had oncogenic FGFR2 alterations (26 fusions/13 mutations/5 amplifications). The median number of prior anti-neoplastic therapies was 3 (range 1-15). 94% (33/35) of CCA pts had prior chemotherapy and 69% (24/35) had prior FGFRi. 56% (9/16) CCA pts with prior FGFRi and evaluable ctDNA had ≥1 FGFR2 resistance mutation at baseline, most commonly at positions 549 (8/9), 617 (3/9), or 564 (2/9). RLY-4008 had rapid absorption (Tmax 1-7h), half-life to support QD dosing (18-34 h), dose-dependent exposure (AUC; Cmax) and predicted FGFR2 occupancy &gt;85% across dose levels. The MTD has not been defined, and QD dose exploration continues to select the optimal biologically efficacious dose. AEs occurring in &gt;20% of pts include stomatitis (49%), palmar-plantar erythrodysesthesia (PPE, 38%), dry mouth (29%), and nail toxicities (22%), majority of which were ≤Gr 2. 6 pts had Gr 1-2 retinopathy, which resolved in all cases. 5 AEs were considered dose limiting toxicities: 4 in BID (rash/PPE/mucositis/hyperbilirubinemia) and 1 in QD (retinopathy). No Gr 4/5 drug-related AEs were seen. 25 pts remain on treatment (range 1-37 weeks). RLY-4008 showed broad anti-tumor activity across dose levels and FGFR2 alterations with radiographic tumor reductions of ≥10% in 59% pts (19/32; -11% to -83%). Activity was seen in FGFRi-naïve, FGFR2-fusion+ CCA with PRs in 50% of pts (3/6, 2 confirmed and 1 pending confirmation; -56% to -83%). Activity was also seen in FGFRi pre-treated FGFR2-fusion+ CCA pts (N=16) with 16 SD, including 9 pts with tumor reduction ≥10% (from -12% to -35%). Of the FGFRi pre-treated FGFR2-fusion+ CCA patients with detectable FGFR2 resistance mutations in ctDNA at baseline, 78% (7/9) were undetectable at C2D1. CONCLUSION: RLY-4008 demonstrates promising safety, tolerability, and clinical activity in FGFR2-altered solid tumor pts, including those who progressed on prior FGFRi therapy. Consistent with the FGFR2-selective mechanism, minimal off-isoform toxicity (FGFR1-hyperphosphatemia; FGFR4-diarrhea) was seen. These encouraging data validate selective targeting of FGFR2 and suggest that RLY-4008 has potential to overcome resistance to FGFRi. Citation Format: Lipika Goyal, Mitesh Borad, Vivek Subbiah, Amit Mahipal, Suneel Kamath, Kabir Mody, Robin Katie Kelley, Richard Kim, Vaibhav Sahai, Anthony El-Khoueiry, Efrat Dotan, Oleg Schmidt-Kittler, Jinshan Shen, Kai Yu Jen, Alicia Deary, Wei Guo, Mahesh Padval, Cori Ann J. Sherwin, Charles Ferte, Beni Wolf, Alison M. Schram. First results of RLY-4008, a potent and highly selective FGFR2 inhibitor in a first-in-human study in patients with FGFR2-altered cholangiocarcinoma and multiple solid tumors [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P02-02.

The NCCN Guidelines for Older Adult Oncology address specific issues related to the management of cancer in older adults, including screening and comprehensive geriatric assessment (CGA), assessing the risks and benefits of treatment, preventing or decreasing complications from therapy, and managing patients deemed to be at high risk for treatment-related toxicity. CGA is a multidisciplinary, in-depth evaluation that assesses the objective health of the older adult while evaluating multiple domains, which may affect cancer prognosis and treatment choices. These NCCN Guidelines Insights focus on recent updates to the NCCN Guidelines providing specific practical framework for the use of CGA when evaluating older adults with cancer.

4086 Background: Pemigatinib (PEMI), a potent, selective, oral FGFR1-3 inhibitor, has shown efficacy and safety in patients (pts) with CCA and FGFR2 rearrangements/fusions in FIGHT-202 (NCT02924376; objective response rate [ORR], 35.5%; duration of response [DOR], 7.2 months [mo]). Overall survival (OS: 21.1 mo) was not mature in the primary report (Abou-Alfa. Lancet Oncol 2020; cutoff: Mar 22, 2019); herein we report matured efficacy and safety data from FIGHT-202 (cutoff: Apr 7, 2020). Methods: Pts (≥18 y) with known FGF/FGFR alterations and progression after ≥1 prior therapy had FGFR2 rearrangements/fusions (cohort A), other FGF/FGFR alterations (B), or no FGF/FGFR alterations (C). Pts received PEMI 13.5 mg QD (21-d cycle; 2 wks on, 1 wk off) until progression or toxicity. Primary endpoint: independent, centrally confirmed ORR (cohort A); secondary endpoints: ORR (cohorts B, C; cohorts A and B combined); DOR, disease control rate (DCR), progression free survival (PFS), OS, and safety. A post-hoc analysis in cohort A evaluated mOS in responders (pts with complete response [CR] or partial response [PR]) vs non-responders (pts with progressive disease [PD] or stable disease (SD]). Results: At cutoff, 147 pts were enrolled (cohort A, n=108; B, n=20; C, n=17; FGF/FGFR status undetermined, n=2); median follow-up was 30.4 (range, 4.9–38.7) mo and median treatment duration was 5.9 (0.2–36.5) mo. In cohort A, 9.3% of pts remained on therapy at cutoff; in cohorts B and C, all pts had discontinued. Pts discontinued mainly for PD (67.6%, 75%, and 64.7% in cohorts A, B, and C respectively). Independent, centrally confirmed ORR was 37.0%; mOS was 17.5 mo (95% CI, 14.4-22.9) in cohort A (Table 1). mOS for responders (n=40) vs non-responders (n=68) was 30.1 (95% CI, 21.5-NE) mo vs 13.7 (9.6-16.1) mo. Overall, most common all-cause treatment-emergent adverse events (TEAEs) were hyperphosphatemia (58.5%; grade ≥3, 0%), alopecia (49.7%; 0%), diarrhea (46.9%; 3.4%), fatigue (43.5%; 5.4%), nausea (41.5%; 2%), and dysgeusia (40.8%; 0%); 10.2%, 13.6% and 42.2% of pts discontinued, had dose reduction, and treatment interruption due to TEAEs, respectively. Conclusions: These results reinforce the primary data, showing continued, durable responses and sustained tolerability in pts receiving PEMI for CCA harboring FGFR2 rearrangements/fusions. Notably, the matured OS is longer than historical data; OS for responders was more than twice as long vs for non-responders. Clinical trial information: NCT02924376. [Table: see text]