BACKGROUND:Fibroblast growth factor receptor 2 (FGFR2) fusions and rearrangements are clinically actionable genomic alterations in cholangiocarcinoma (CCA). Pemigatinib is a selective, potent, oral inhibitor of FGFR1-3 and demonstrated efficacy in patients with previously treated, advanced/metastatic CCA with FGFR2 alterations in FIGHT-202 (NCT02924376). We report final outcomes from the extended follow-up period. PATIENTS AND METHODS:The multicenter, open-label, single-arm, phase II FIGHT-202 study enrolled patients ≥18 years old with previously treated advanced/metastatic CCA with FGFR2 fusions or rearrangements (cohort A), other FGF/FGFR alterations (cohort B), or no FGF/FGFR alterations (cohort C). Patients received once-daily oral pemigatinib 13.5 mg in 21-day cycles (2 weeks on, 1 week off) until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) in cohort A assessed as per RECIST v1.1 by an independent review committee; secondary endpoints included duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. RESULTS:FIGHT-202 enrolled 147 patients (cohort A, 108; cohort B, 20; cohort C, 17; unconfirmed FGF/FGFR alterations, 2). By final analysis, 145 (98.6%) had discontinued treatment due to progressive disease (71.4%), withdrawal by patient (8.2%), or adverse events (AEs; 6.8%). Median follow-up was 45.4 months. The ORR in cohort A was 37.0% (95% confidence interval 27.9% to 46.9%); complete and partial responses were observed in 3 and 37 patients, respectively. Median DOR was 9.1 (6.0-14.5) months; median PFS and OS were 7.0 (6.1-10.5) months and 17.5 (14.4-22.9) months, respectively. The most common treatment-emergent AEs (TEAEs) were hyperphosphatemia (58.5%), alopecia (49.7%), and diarrhea (47.6%). Overall, 15 (10.2%) patients experienced TEAEs leading to pemigatinib discontinuation; intestinal obstruction and acute kidney injury (n = 2 each) occurred most frequently. CONCLUSIONS:Pemigatinib demonstrated durable response and prolonged OS with manageable AEs in patients with previously treated, advanced/metastatic CCA with FGFR2 alterations in the extended follow-up period of FIGHT-202.

the realization of the FAIR (Functional Assessment and Individualized Recommendations) Frailty Clinic, which provides comprehensive geriatric assessments for oncology patients prior to initiation of cancer treatment.Objectives: To demonstrate the growth and success of the FAIR Frailty Clinic as it pertains to collaboration and relationship building.Methods: We collaborated with an established frailty clinic and adapted the model to meet our institutional needs.We created and distributed marketing tools to promote the clinic.We met regularly with various oncology groups to increase exposure, facilitate communication, and incorporate feedback to meet the needs of the referring providers.Word of mouth amongst other specialists and interdisciplinary staff also resulted in clinic referrals.Throughout this process, we tracked patient and subspecialty clinic referral volumes.Results: Since opening October 2019, the number of new patients has grown annually: 25 in year one, 39 in year two, 57 in year three, and 45 seven months into year four.We began receiving referrals from two oncology groups and now take referrals from over five.The clinic initially operated within the outpatient geriatrics clinic.However, increased exposure and credibility has led to the creation of a geriatric oncology clinic and incorporation into the cancer center.Conclusion

SD is prevalent in a large majority of patients studied (58%). In males, higher TD from NVB was associated with better overall SF, better intercourse, and overall satisfaction. While a higher proportion of females had SD, no significant associations were found in females likely due to their small sample size.

withdrawal, 4 years, or study end.We developed a penalized Weibull regression model including demographics, cancer type, and 9 GA measures.For comparison, we constructed a simpler model using routinely collected data (e.g., age, cancer type, stage, self-reported Karnofsky).We assessed model performance by comparing the observed and predicted mean survival time.Results: The 752 trial participants had a four-year survival of 23%.Both the GA and routine data models predicted survival times longer than observed (Figure).Predicted life expectancy was on average overestimated by 1.99 years (GA model) and 1.45 years (routine data model).Conclusion: GA data did not improve prediction of life expectancy over a simpler model.Future work should investigate alternative endpoints (e.g., 1-year mortality), as well as external validation.

Purpose/Objective(s) LARC patients with a complete response after NACRT are eligible for organ preservation obviating the need for surgery. MRI evaluation for radiologic complete response (rCR) is essential in determining who is a candidate for organ preservation (OP). We evaluate the ability of MRI, after NACRT, to predict pathologic complete response (pCR). Materials/Methods Patients with LARC (T3-4, N0-2) with post NACRT MRI from 2013 to 2021 were retrospectively identified. MRI and pathology reports were queried for treatment response. Positive (PPV) and negative (NPV) predictive values were calculated and used to test the discriminative ability (ROC curve) of MRI post NACRT. Multivariate logistic regression of post-NACRT MRI characteristics, TN staging, lymph node (LN) size, extramural venous invasion, CEA, smoking pack years, RT dose, total neoadjuvant therapy (TNT), sex, and race were used to identify predictors for rCR and pCR. pCR was defined as no evidence of disease after surgery or flexible sigmoidoscopy with biopsy. Results Of the 69 patients analyzed, 71% were male and 25% were non-white. The median age was 58 years. Overall pCR rate was 41% whereas OP rate (no more than local excision) was 29%. PPV and NPV of MRI for the primary mass were 72% and 77% respectively with an area under ROC curve of 0.74. Higher pre-NACRT CEA (OR=0.92; CI 0.85-0.98, p=0.019) and higher RT dose (OR=0.99; CI 0.99-0.99, p=0.047) were associated with rCR of the primary mass. Complete fibrosis on MRI was associated with pCR of the primary mass (OR=0.15; CI 0.02-0.99, p=0.049). Of the 11 patients that had diffusion restricted mass after NACRT, all were regarded as non-rCR and 8 were non-pCR at surgery/biopsy. PPV and NPV of MRI for LN were 95% and 42% respectively with an area under ROC of 0.79. TNT (OR=0.05; CI 0.002-0.93, p=0.045), higher CEA (OR=0.92; CI 0.84-0.99, p=0.045) and smoking pack years (OR=0.91; CI 0.83-0.99, p=0.029) were associated with rCR and pCR congruence. However, time between post NACRT MRI and surgery/biopsy was not significantly associated with congruence. Conclusion The discriminative ability of MRI to predict pCR of primary rectal mass was middling. Patients with increasing pre-NACRT CEA and received higher RT dose were more likely to achieve rCR. Complete fibrosis on post NACRT MRI was our best predictor of pCR whereas restricted diffusion on MRI correlated with non-pCR. There is room for improvement in OP patient selection by pelvic MRI in the post-NACRT setting.

Cholangiocarcinoma (CCA) tumors have high genomic heterogeneity, with 40%–50% of patients with CCA harboring at least 1 clinically actionable genetic alteration. Fusions or rearrangements in the FGFR2 gene are present in 10%–15% of patients with intrahepatic CCA. Pemigatinib is an oral, potent, selective fibroblast growth factor receptor (FGFR)1, 2, and 3 inhibitor for the treatment of adults with previously treated, unresectable locally advanced/metastatic CCA with an FGFR2 fusion or other rearrangement. Here we report on the final results from an open-label, single-arm, multicenter phase 2 study evaluating the safety and efficacy of pemigatinib in patients with previously treated locally advanced or metastatic CCA (FIGHT-202; NCT02924376). Eligible patients were ≥18 years old, with locally advanced/metastatic or surgically unresectable CCA that progressed after ≥1 prior therapy, a documented FGF/FGFR status, Eastern Cooperative Oncology Group performance status ≤2, and adequate hepatic/renal function. Patients were separated into 3 cohorts based on confirmed FGF/FGFR status (cohort A, FGFR2 fusions or rearrangements; cohort B, other FGF/FGFR genetic alterations; cohort C, no FGF/FGFR genetic alterations). All patients received 13.5 mg pemigatinib once daily (2 weeks on/1 week off) until disease progression or unacceptable toxicity. The primary endpoint was overall response rate (ORR) in cohort A, as confirmed by independent central review. Secondary endpoints included ORR in cohorts B and C, duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety across all cohorts. In total, 147 patients were enrolled (cohort A, n=108; cohort B, n=20; cohort C, n=17; undetermined FGF/FGFR status, n=2). Median (range) age was 59.0 (26–78) years, 57.8% of patients were women, 70.7% were White, and 89.8% had intrahepatic CCA, including 99.1% of patients in cohort A. Median (range) duration of follow-up was 45.4 (19.9–53.7) months. In total, 98.6% of patients discontinued treatment, most commonly for disease progression (n=105/147; 71.4%). In cohort A, ORR (95% CI) was 37.0% (27.9%–46.9%), DCR (95% CI) was 82.4% (73.9%–89.1%), and median DOR (95% CI) was 9.1 (6.0–14.5) months. For cohorts B and C, DCR was 40.0% (19.1%–63.9%) and 17.6% (3.8%–43.4%), respectively. Median (95% CI) PFS was 7.0 (6.1–10.5) months for cohort A, and 2.1 (1.2–4.9) and 1.5 (1.4–1.8) months for cohorts B and C, respectively. For cohorts A–C, median (95% CI) OS was 17.5 (14.4–22.9), 6.7 (2.1–10.6), and 4.0 (2.0–4.6) months. All patients reported treatment-emergent adverse events (TEAEs); the most common were hyperphosphatemia (58.5%), alopecia (49.7%), and diarrhea (47.6%). Most TEAEs were grade 1 or 2 in severity; the most common grade ≥3 TEAE was hypophosphatemia (14.3%). Additionally, 91.8% of patients had a treatment-related AE, 4.1% had a fatal TEAE (all considered unrelated to pemigatinib treatment), and 10.2% discontinued pemigatinib due to a TEAE. In this analysis, pemigatinib continued to demonstrate durable response, prolonged OS, and a manageable safety profile in patients with advanced/metastatic CCA with FGFR2 fusions or rearrangements. These results further highlight the need for molecular testing in patients with CCA.

Previous, nonselective FGFRi have validated FGFR2 f/r as a target in CCA by achieving an objective response rate (ORR) of ∼20-40% with duration of response (DOR) ∼5-9 months. However, off-target toxicity and emergence of polyclonal FGFR2 resistance limit their efficacy. RLY-4008 is the first highly selective, potent FGFR2 inhibitor designed to target both driver alterations and FGFR resistance mutations. Here we present the initial efficacy of RLY-4008 in pts with a FGFR2 f/r, FGFRi-naïve CCA.

ZW49 is a novel ADC comprised of a HER2-targeting bispecific antibody (directed against 2 non-overlapping HER2 epitopes) attached to a proprietary auristatin toxin with a protease-cleavable linker. The results from this ongoing, first-in-human, dose escalation (DE) and dose expansion (DX) study (NCT03821233) are presented. DE: In a 3+3 design, patients (pts) with HER2+ cancers were dosed with ZW49 IV QW (3 weeks on, 1 off; 1-1.75 mg/kg), Q2W (1-2 mg/kg) or Q3W (2-3 mg/kg). DX: Pts with centrally confirmed HER2+ cancers and measurable disease received ZW49 at the recommended dose(s)(RD[s]) determined in DE. Primary endpoints are safety and tolerability assessments; secondary endpoints include response assessments per RECIST v1.1. As of 10 Mar 2022, 76 pts (DE [51] and DX [25]; female: 58%; median age: 59 years [range, 24-83]) have been treated with ZW49. Overall, the most common histologies were gastric (28%) and breast (22%) cancers; 70% received prior HER2-targeted therapy; median number of prior metastatic therapies was 3 (range: 1-16). A RD of 2.5 mg/kg was identified for the Q3W schedule. One dose-limiting toxicity of Grade [Gr] 2 keratitis > 14 days was observed in 1 pt and resolved to Gr 1 (2.5 mg/kg Q3W DX cohort). 68 (89%) pts had treatment-related adverse events (TRAEs); majority were Gr 1 or 2 in severity. The most common TRAEs (≥ 20% pts) included keratitis (42%), alopecia (25%), and diarrhea (21%). 7 (9%) pts had Gr ≥ 3 TRAEs, including 2 Gr 4 events (infusion-related reaction [1 pt] and decreased neutrophil count [1 pt]). Serious TRAEs were reported in 3 pts, leading to 1 discontinuation (D/C); 2 other pts had D/C due to TRAE. No interstitial lung disease nor TR deaths were reported. Among 29 response-evaluable pts treated with ZW49 at 2.5 mg/kg Q3W, the confirmed objective response rate across multiple cancer types was 28% and disease control rate was 72%. ZW49 has a manageable safety profile with encouraging single-agent antitumor activity in heavily pretreated pts with HER2+ cancers. Enrollment continues at 1.75 mg/kg QW in DE and 1.5 mg/kg QW in DX.

TPS4185 Background: Evidence-based data is lacking to guide the care of older adults with newly diagnosed metastatic pancreatic cancer (mPCA). As a result, treatment approach and the selection of chemotherapy regimens are often extrapolated from data from younger patients. Furthermore, vulnerable older adults are often treated with dose adjusted regimens with limited data to support this practice. EA2186 is a phase II randomized controlled trial, and the first prospective study aiming to define the optimal treatment approach of vulnerable older adults with newly diagnosed mPCA. Methods: Patients aged 70 years and over with histologically confirmed pancreatic adenocarcinoma, evidence of metastatic disease, ECOG PS 0-2 and adequate organ function, who are considered vulnerable are eligible for this trial (accrual target 184). This study utilizes a screening geriatric assessment which characterize patients as fit, vulnerable or frail by evaluating functional status, cognition and co-morbidities. Vulnerable patients according to this screening assessment are those with mild abnormalities in functional status, comorbidities and/or cognition, or older than 80 years of age. Those patients will be randomized to receive either modified Gemcitabine/Nab-Paclitaxel or dose-reduced 5-Fluorouracil Leucovorin and Liposomal Irinotecan every 2 weeks. A comprehensive geriatric assessment (GA) and quality of life (QOL) evaluation are completed prior to initiation of therapy for all randomized patients. Follow up will continue until disease progression or withdrawal, with repeated GA and QOL assessments at each disease evaluation. Overall survival is the primary objective, with secondary objectives including progression free survival, and response rate. Enrolled patients will be stratified by age 70-74 vs ≥75, and ECOG PS 0-1 vs 2. Additional endpoints of interest for older adults include: evaluation of risk factors identified through GA, and capturing toxicities of interest for this patient population (i.e. hospitalization, deterioration in PS, and falls). Correlative studies include assessment of pro-inflammatory biomarkers or aging in the blood (IL-6 and CRP) as well as imaging evaluation of sarcopenia and body composition as predictors of treatment tolerance. Clinical trial information: NCT04233866.