Ahn, Daniel H.

Abstract Background: Sarcopenia is one of the early pathological features of cancer cachexia, yet the effect of sarcopenia on clinical outcomes in patients with advanced HCC is unclear. Our objective was to determine the effect of Sarcopenia on response to systemic therapy with advanced HCC. Methods: Patients with unresectable and advanced liver cancer were retrospectively evaluated between 2010 to 2019. Skeletal muscle area (SMA) was computed with a previously validated computed tomography (CT) body composition AI algorithm. The skeletal muscle index (SMI) was derived from the skeletal muscle area (SMA) (cm2) divided by patient height (m2) calculated from images at the level of L3 on pretreatment CT. Sarcopenia cutoffs for females was less than 39 cm2/m2 SMI or less than 50 cm2/m2 SMI for males. Patients’ demographics, systemic treatment response, toxicity, progression-free survival (PFS) and overall survival (OS) were compared between first-line therapy groups. Kaplan-Meier and Cox proportional hazards regression were used for survival analysis comparisons. Results: A total of 146 patients with advanced HCC were assessed from Mayo Clinic Arizona and Emory University. Seventy-six patients received immunotherapy as first-line treatment and seventy patients received TKI as first-line therapy. Sarcopenia at baseline was assessed in a total of 91 patients at first-line systemic treatment: n=48 with immunotherapy (IO) and n=43 with tyrosine kinase inhibitor (TKI). Sarcopenia was more prevalent in male patients (p=0.009), and in patients with low BMI (p=0.02). When comparing those with sarcopenia at baseline, higher response rate was observed in patients treated with IO without sarcopenia (47% versus 15%, p=0.019), this was not observed in TKI group. Interestingly, median PFS and OS was not significantly changed in patients with or without sarcopenia treated with IO or TKI on first-line therapy. Conclusions: Sarcopenia was associated with reduced response rate (RR) in patients treated with IO, but not in TKI groups. Both didn’t translate into deleterious effect in PFS and or OS. Further research with sufficient adjustments for confounding factors is warranted to better elucidate the prognostic value of sarcopenia in these patients. Citation Format: Gehan Botrus, Pedro Luiz Serrano Uson Junior, Heidi Kosiorek, Mehmet Akce, Isabela Chang, Zhubene Mesbah, Eric Yancey, Daniel Blezek, Jason Klug, Lana Khalil, Puneet Raman, Mohamad Sonbol, Mitesh Borad, Daniel Ahn, Tanios Bekaii-Saab. Prognostic impact of Sarcopenia on clinical outcomes in advanced hepatocellular carcinoma (HCC) treated with systemic therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6274.

e16042 Background: Current second-line (2L) therapies for patients (pts) with advanced/metastatic esophageal squamous cell carcinoma (adv/met ESCC), including docetaxel, paclitaxel and irinotecan, have demonstrated modest survival gains. The National Comprehensive Cancer Network added the use of anti-programmed cell death protein-1 (PD-1) therapies (e.g., pembrolizumab, nivolumab) in the 2L to their guidelines in 2020. A real-world evidence study of 2L therapy for adv/met ESCC patients reported a median (95% CI) overall survival (OS) of 201 (153-249) days but did not include recently approved anti-PD-1 agents. Other studies of 2L anti-PD-1 therapy relied on claims data without the ability to report survival. Limited studies exist for 2L ESCC real-world treatment patterns. Herein, we characterize the real-world treatment patterns and OS for a recent cohort of US pts initiating an anti-PD-1 2L therapy. Methods: Pts (≥ 18 years of age) from the United States diagnosed with adv/met ESCC and initiating an anti-PD-1 2L therapy between January 1, 2011 and February 28, 2021 were selected using the electronic health record (EHR)-derived de-identified Flatiron Health database. Pt characteristics and descriptive treatment patterns were reported. Duration of therapy (DoT; start of therapy until last administration) was computed and OS (start of therapy until death or last recorded medical activity) was estimated by the Kaplan Meier method. Results: 60 pts were included who initiated an anti-PD-1 2L therapy. At 2L initiation, the median age was 66 years, 65% were male, 53% were white, 82% had a history of smoking, and 53% had stage IV disease. The median DoT was 92 days and median OS was 303 days with variability across agents (Table) . Of the 60 pts, a total of 21 (35%) initiated 3L therapy (8 initiated an anti-PD-1; 13 initiated a non-anti-PD-1). Of the 39 (65%) pts who did not initiate a 3L therapy, 16 (41%) died within 60 days of the final 2L administration, 12 (31%) lacked 60 days of follow-up observation, and the remaining 11 (28%) patients had no further 2L treatment. Conclusions: Compared to prior real-world analyses, use of anti-PD-1 therapy in the 2L for patients with advanced/metastatic ESCC may be associated with survival gains over other approved non-anti-PD-1 therapies. However, future real-world studies are needed to directly compare PD-1 inhibitors with other 2L therapies.[Table: see text]

4130 Background: KRAS is mutationally activated in over 90% of pancreatic ductal adenocarcinoma (PDAC). Compared to pts with KRAS mutation, KRAS wild-type (wt) PDAC seem to have better response to therapy and may harbor potentially actionable molecular alterations. Here, we analyze the molecular profile and clinical outcome of a cohort of pts with KRAS wt PDAC. Methods: A retrospective review was conducted on pts with PDAC who underwent CLIA-certified Next Generation Sequencing (NGS) testing at Mayo Clinic between December 1, 2018 and December 1, 2021. Pts with KRAS wt PDAC with available reports were included. Their genomic drivers, RNA expression, demographics, disease characteristics, therapies offered, and clinical outcome data were collected. The study was approved by the institutional IRB. Results: Of the 241 eligible pts, 8% (19) has KRAS wt PDAC. Among those, 2 pts had no mutation identified by the gene/molecular panel used. Of the 17 pts (89%) with identified alterations, mutations found in ³ 2 pts were TP53 (53%), CDKN2A (16%) and CDKN2B/ERBB2/PTEN/MSH3/RNF43/FBXW7/KMT2D/GNAS (11% each). Chromosomal rearrangements were identified in 5 (26%): CADPS2-BRAF, GP2-ERBB2, PTPRK-RSPO3, EML4-NTRK3 and TFG-MET. RNA expression results were available in 12 pts: common overexpression were ERBB2 (27%) and MET/NRAS/MYC/CCDN1/CCNE1/AR (18% each); and the under-expression MGMT (18%). Among the 13 pts with available MSI status via NGS, 2 (11%) were MSI-high (both had high TMB [28.4 and 23.7 m/MB]) while all others were TMB < 10 m/MB. The median age at diagnosis was 61 years (68% males). 8/19 (42%) were Stage IV at diagnosis with 15/19 (79%) pts ultimately diagnosed with metastatic disease. Among metastatic pts, median lines of treatment received was 2.5 (range:0-4). 4 pts received FOLFIRINOX (FFX), 2 gemcitabine/ nab-paclitaxel (GP) and tumor response were comparable to previously reported results. 1 received 1st-line pembrolizumab and remained on therapy at the time of analysis. The median length of follow up from diagnosis was 29 months. A patient with TFG-MET re-arrangement previously progressed on FFX and GP was treated using a MET inhibitor, and achieved significant CA19-9 drop and pancreas tumor shrinkage at 1st restaging, with ongoing response. Conclusions: The molecular profile of KRAS wt PDAC is highly heterogeneous and difficult to generalize. Novel approaches (e.g., basket trials) are needed to develop therapy for this rare PDAC subgroup.

4009 Background: Survival outcomes are historically poor in patients (pts) with advanced/metastatic iCCA, with median overall survival (mOS) times of approximately 1 year with first-line gemcitabine plus cisplatin and approximately 6 months with second-line chemotherapy. Futibatinib, a highly selective, irreversible FGFR1–4 inhibitor, demonstrated efficacy with durable responses in pts with iCCA harboring FGFR2 fusion/rearrangements in the pivotal FOENIX-CCA2 phase 2 study (NCT02052778). At the primary analysis of this trial (data cutoff: October 1, 2020), an objective response rate (ORR) of 41.7% was observed, with a median duration of response (mDOR) of 9.7 mo. Here, we report updated efficacy (including mature OS data) and safety data from the final analysis with an additional 8 mo of follow-up. Methods: FOENIX-CCA2 was a single-arm phase 2 study that enrolled pts with advanced/metastatic iCCA with FGFR2 fusion/rearrangement and progressive disease (PD) after ≥1 prior treatment (tx; including gemcitabine plus platinum-based chemotherapy). Pts received futibatinib 20 mg once daily until PD/intolerability. The primary endpoint was ORR per RECIST v1.1 by independent central review. Secondary endpoints were DOR, disease control rate (DCR), progression-free survival (PFS), OS, safety, and patient-reported outcomes. Results: At the time of the final data cutoff (May 29, 2021), median follow-up was 25.0 mo, and 96/103 pts (93%) had discontinued tx. The median number of tx cycles was 13.0 for a median tx duration of 9.1 mo. The confirmed ORR was 41.7% (43/103) and thereby the same as of the primary analysis, as was the DCR (at 82.5%). The ORR was consistent across pt subgroups. The mDOR was 9.5 mo, and 74% of responses lasted ≥6 mo. mPFS was 8.9 mo, with a 12-mo PFS rate of 35.4%. Mature mOS was 20.0 mo, with a 12-mo OS rate of 73.1% . No new safety signals were identified. Common tx-related adverse events (TRAEs) included hyperphosphatemia (85%), alopecia (33%), dry mouth (30%), diarrhea (28%), dry skin (27%), and fatigue (25%). TRAEs resulted in tx discontinuation in 4 pts (4%). No tx-related deaths occurred. Quality of life was maintained from baseline to tx cycle 13. Conclusions: Findings from the final analysis of FOENIX-CCA2 confirm the results of the primary analysis and reinforce the durable efficacy and continued tolerability of futibatinib in previously treated pts with advanced/metastatic iCCA harboring FGFR2 fusion/rearrangements. Mature OS data were consistent with data from the primary analysis and far exceed historical data in this patient population. Clinical trial information: NCT02052778.

3590 Background: Co-occurring alterations (COAs) in the HER2 and MAPK pathway are rare in mCRC. RAS, HER2 and BRAF alterations have been associated with resistance to EGFR inhibitor therapy (EGFR-mab). Typical co-occurring mutually exclusive gene mutations such as in KRAS and BRAF have been reported. This study aims to evaluate the prevalence of co-occurring alterations in the MAPK pathway or across MAPK/ HER2 and correlate to outcomes in patients with mCRC treated with EGFR-mab. Methods: This is a retrospective study of patients with mCRC within the Mayo Clinic database who have available blood-based NGS Guardant 360 data (September 2017-November 2021) and contained co-alterations in the MAPK pathway or across MAPK/ HER2. MSI-high cases were excluded. Typical-RAS was defined as alterations in codons 12, 13, 59, 61, 117, and 146 of KRAS, HRAS, and NRAS. Atypical-RAS alterations were considered mutations at other codons of these genes. Patient characteristics, specific mutations, and outcome data were assessed. Results: 692 patients (pts) with mCRC were identified and 66 (9.5%) of those had COAs detected. 59/66 pts had clinical data available. Median age was 52 years, 55.9% were male, and 61.0% had left-sided tumors. The frequency of detected alterations was: BRAF-V600E (7.3%), BRAF-non-V600E (7%), BRAF-amplification (3.04%), RAS-typical (39.5%), RAS-atypical (2.1%), HER2 amp (0.5%), HER2-mutation (1.2%) and PIK3CA (13%). COAs are described in the table. Twenty-three pts received EGFR-mab; COAs developed in 19 of them after progression on EGFR-mab. Four pts received EGFR-mab with documented COAs at baseline with none of them responding to treatment. Conclusions: COAs in MAPK and MAPK/ HER2 pathway are not uncommon in pts with mCRC emphasizing on the importance and feasibility of blood based NGS vs. selected gene testing. In pts with prior EGFR-mab treatment, COAs were detected after progression on treatment in the majority of pts, suggesting a mechanism of secondary treatment resistance. Further data including prospective validation is warranted. [Table: see text]

2583 Background: MT-5111 is a 55kD engineered toxin body (ETB) targeting HER2 in solid tumors that binds to an epitope distinct from trastuzumab and pertuzumab, offering potential combination strategies with other HER2-targeting agents. MT-5111 may demonstrate efficacy in patients (pts) resistant to other HER2-targeting agents, as its mechanism of action induces direct cell kill via enzymatic and permanent ribosome destruction. Methods: This is a phase 1 study in adults with advanced HER2+ solid tumors. The dose-escalation portion (Part A) enrolls pts into sequential dose cohorts, followed by Part B expansion cohorts for HER2+ breast cancer (BC), gastroesophageal adenocarcinoma (GEA), and any other HER2+ cancer (CA). MT-5111 is dosed weekly IV over 30 min in each 21-day treatment (tx) cycle until disease progression, unacceptable toxicity, death or withdrawn consent. Results: As of Jan 2022, 27 pts had enrolled in Part A cohorts (0.5 to 10 µg/kg/dose) with completed DLT assessments: 9 (33%) pts were male and 18 (67%) female, median age 67 and a median of 4 prior systemic and 2 prior HER2-targeting tx. Common tissue types were BC (9/30%), biliary CA (6/22%), GEA (4/15%). The following safety data reflect 33 treated pts to date including ongoing 13 µg/kg/dose Part A and 10 µg/kg/dose BC expansion cohorts. No Grade (G) 4/5 tx-emergent adverse events (AEs) or DLTs occurred. Tx-related AEs occurred in 17 (52%) pts, most commonly G1/2 fatigue (8/24%). 3 pts had G1 troponin elevations without clinical signs or symptoms of cardiac distress: 1 at 6.75 µg/kg/dose, 2 at 10 µg/kg/dose. 2 pts (3 and 4.5 µg/kg/dose) had reversible G2 and G1, respectively, infusion-related reactions (IRR)s. A comparison of cytokines from baseline to on-treatment timepoints reveals no evidence of significant changes, even in pts with IRR. Best response per RECIST thus far was stable disease (SD) in 7 pts or non-CR/non-PD in 2 pts: 1 pt had SD for 12 weeks (wks) (4.5 μg/kg, pancreatic CA); 1 pt (1 μg/kg/dose, BC) had non-CR/non-PD for 30 wks; 1 pt (10 μg/kg/dose, GEA) has ongoing SD for 18 wks. AUClast data match PK simulations in non-human primate studies. Cmax at 10 µg/kg/dose is ≥5 times the IC50 values of high HER2 expressing gastric CA and BC cell lines while approaching the IC50 of a moderately HER2 expressing liver CA cell line. Conclusions: MT-5111 is well tolerated to-date with no clinically significant immuno/cardiotoxicity. Dose escalation is ongoing at a dose of 13µg/kg, expected to be required for efficacious exposure. Clinical trial information: NCT04029922.

PURPOSE This investigation sought to evaluate the prognostic value of pretreatment of circulating tumor DNA (ctDNA) in metastatic biliary tract cancers (BTCs) treated with platinum-based first-line chemotherapy treatment. MATERIALS AND METHODS We performed a retrospective analysis of 67 patients who underwent ctDNA testing before platinum-based chemotherapy for first-line treatment for metastatic BTC. For analysis, we considered the detected gene with highest variant allele frequency as the dominant clone allele frequency (DCAF). Results of ctDNA analysis were correlated with patients' demographics, progression-free survival (PFS), and overall survival (OS). RESULTS The median age of patients was 67 (27-90) years. Fifty-four (80.6%) of 67 patients evaluated had intrahepatic cholangiocarcinoma; seven had extrahepatic cholangiocarcinoma, and six gallbladder cancers. Forty-six (68.6%) of the patients were treated with cisplatin plus gemcitabine, and 16.4% of patients received gemcitabine and other platinum (carboplatin or oxaliplatin) combinations, whereas 15% of patients were treated on a clinical trial with gemcitabine and cisplatin plus additional agents (CX4945, PEGPH20, or nab-paclitaxel). TP53, KRAS, FGFR2, ARID1A, STK11, and IDH1 were the genes with highest frequency as DCAF. The median DCAF was 3% (0%-97%). DCAF > 3% was associated with worse OS (median OS: 10.8 v 18.8 months, P = .032). Stratifying DCAF in quartiles, DCAF > 10% was significantly related to worse PFS (median PFS: 3 months, P = .014) and worse OS (median OS: 7.0 months, P = .001). Each 1% increase in ctDNA was associated with a hazard ratio of 13.1 in OS when adjusting for subtypes, metastatic sites, size of largest tumor, age, sex, and CA19-9. CONCLUSION DCAF at diagnosis of advanced BTC can stratify patients who have worse outcomes when treated with upfront platinum-based chemotherapy. Each increase in %ctDNA decreases survival probabilities.

Abstract Purpose: This phase Ib/2 trial investigated pembrolizumab-containing trimodality therapy in patients with gastroesophageal junction (GEJ) adenocarcinoma. Patients and Methods: Patients with GEJ adenocarcinoma (cT1–3NanyM0) received neoadjuvant pembrolizumab-containing chemoradiation (CROSS regimen) followed by surgical resection and adjuvant pembrolizumab. The primary endpoints were tolerability in the first 16 patients and pathologic complete response [pCR (ypT0N0)]. Secondary endpoints included progression-free survival (PFS) and overall survival (OS). An independent propensity-score-matched cohort (treated with CROSS without immunotherapy) was used for comparison. Exploratory analyses included immune biomarkers in the tumor microenvironment (TME) and plasma. Results: We enrolled 31 eligible patients, of whom 29 received all expected doses of neoadjuvant pembrolizumab and 28 underwent R0 resection. Safety endpoints were met. The primary efficacy endpoint was not met [7/31 (22.6%) achieved pCR]. Patients with high [i.e., combined positive score (CPS) ≥ 10] baseline expression of programmed death (PD)-L1 in the TME had a significantly higher pCR rate than those with low expression [50.0% (4/8) vs. 13.6% (3/22); P = 0.046]. Patients with high PD-L1 expression also experienced longer PFS and OS than propensity-score-matched patients. Among trial patients with PD-L1 CPS &lt; 10, unprespecified analysis explored whether extracellular vesicles (EV) could identify further responders: an elevated plasma level of PD-L1–expressing EVs was significantly associated with higher pCR. Conclusions: Adding pembrolizumab to trimodality therapy showed acceptable tolerability but did not meet the pre-specified pCR endpoint. Exploratory analyses suggested that high PD-L1 expression in the TME and/or on EVs may identify patients most likely to achieve tumor response.