Akce, Mehmet

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.

4097 Background: Given a high recurrence rate, surgical resection for localized intrahepatic cholangiocarcinoma (IHCC) is curative in only 30-35% of patients. BILCAP has established a standard of care for adjuvant therapy with monotherapy capecitabine. Gemcitabine, cisplatin and nab-paclitaxel combination chemotherapy (GAP) was associated with a response rate of 45% in biliary cancer and 20% of patients who were previously inoperable underwent margin negative resection. Based on these data, we conducted a neoadjuvant study of GAP for resectable but high-risk IHCC. Methods: A multi-institutional prospective single-arm phase II trial was conducted for patients with resectable high-risk disease, as defined by tumor size > 5cm, multiple tumors, presence of radiographic major vascular invasion, and lymph node involvement. Patients were administered 4 cycles (3 months) of preoperative GAP (gemcitabine 800 mg/m2, cisplatin 25 mg/m2 and nab-paclitaxel 100 mg/m2 on days 1 and 8 of a 21-day cycle) prior to an attempt at curative-intent surgical resection. The primary endpoint was completion of all therapy, including both preoperative chemotherapy and resection. Secondary endpoints were toxicity, radiologic response according to Response Evaluation Criteria in Solid Tumor (RECIST) criteria, RFS, and OS. Thirty evaluable patients provided 73% power to reject a null therapy completion rate of 50%, with a target completion rate of 70% using a one-sided exact test with a Type I error of 0.05. Results: Thirty-seven patients were screened and 30 evaluable patients were enrolled. The trial was sequentially activated at each of the 4 sites from 09/18-02/21 and the final patient was enrolled in 09/21. Median age was 60.5 years and 40% were female. Twenty-three patients (77%, 90% CI: 60.6-88.5%; p = 0.0026) completed all preoperative chemotherapy and underwent surgical resection. Ten patients (33%) experienced grade 3-4 treatment-related adverse events, the most common being neutropenia and diarrhea; 47% required at least one dose reduction. Partial response rate was 23% and disease control rate was 90% (PD: 10%, PR: 23%, SD: 67%). Of the 23 patients who successfully underwent surgical resection, 2 (9%) had minor postoperative complications. Median size of largest tumor was 5.5cm, median number of tumors was 3, and 39% were lymph node positive. Median length of hospital stay was 4 days. There was zero treatment related mortality. Conclusions: This study met its primary endpoint and demonstrated that neoadjuvant gemcitabine/cisplatin/nab-paclitaxel is feasible and safe prior to resection of intrahepatic cholangiocarcinoma and does not adversely impact perioperative outcomes. Continued follow-up for RFS and OS with this treatment strategy is underway and larger validation studies are planned. Clinical trial information: NCT03579771.

Hepatocellular carcinoma (HCC) is the fastest increasing cause of cancer-related mortality in the United States and is projected to be the third leading cause of cancer-related mortality in the United States by 2030. Main risk factors include alcoholic cirrhosis, chronic hepatitis B, hepatitis C, and nonalcoholic steatohepatitis (NASH). More than half of the patients have advanced-stage disease at presentation. Currently approved frontline systemic therapy options include sorafenib, lenvatinib, and atezolizumab/bevacizumab. Over the past decade, there has been a significant improvement in survival with a median overall survival of 19.2 months reported with first-line treatment with atezolizumab/bevacizumab. Based on positive results of randomized phase III HIMALAYA trial, durvalumab and tremelimumab combination could become another frontline option. Multiple frontline clinical trials with immune checkpoint inhibitor (ICI) or ICI combined with other novel agents are underway. In the frontline setting, identifying predictive biomarkers for ICI-based or tyrosine kinase (TKI)-based therapy is an unmet need. Subsequent treatment is poorly defined in patients with prior ICI-based therapy since all the available second-line and beyond therapy was studied after first-line sorafenib. Frontline systemic therapy is poorly defined in certain subgroups of HCC such as Child–Pugh B and post-transplant recurrent HCC. The landscape of frontline HCC treatment is rapidly changing, and this article reviews the most recent treatment approaches to frontline therapy for advanced HCC.

116 Background: Constitutively activating KRAS or NRAS muts occur in ̃50% of CRC, increasing RAF-MEK-ERK signaling and causing overexpression of cyclin D1, which binds to cyclin dependent kinase 4/6 (CDK4/6) to drive cell cycle progression. Combination MEK and CDK4/6 inhibitors caused tumor regression in patient-derived xenografts of KRAS mut CRC. We hypothesized that binimetinib and palbociclib (B+P) would improve progression-free survival (PFS) compared to TAS-102 in refractory KRAS/NRAS mut mCRC. Methods: ACCRU-GI-1618 was a multicenter, randomized phase II clinical trial (NCT03981614). Key inclusion criteria were KRAS/NRAS mut mCRC, with prior fluoropyrimidine/ oxaliplatin/ irinotecan/ anti-VEGF therapy. There was a 6-patient safety run-in with binimetinib 30 mg po BID D1-28 and palbociclib 100 mg po daily D1-21. After, patients were randomized 1:1 to B+P vs TAS-102 (stratified by KRAS mut type and prior regorafenib use), with optional crossover at progression. The primary endpoint was PFS; 73 PFS events (from a sample size of 112) provided 90% power to detect improvement of PFS (hazard ratio = 0.5, i.e. median PFS of 2 vs. 4 months) with 1-sided α = 0.05. A prespecified interim analysis for futility was planned after 37 PFS events were observed, with completion of accrual if 1-sided stratified log-rank p-value < 0.551. Hazard ratios (HR) and 95% confidence intervals (CI) are estimated by stratified Cox proportional hazards models. Results: After the safety run-in, 93 patients at 6 sites were randomized; 82 (41 B+P, 41 TAS-102) comprise the primary analysis population (eligible, consented, and started treatment). In this population, median age was 52 years, 50% female, 68% left-sided, 79% with KRAS codon 12/13 mut, 12% with prior regorafenib. Enrollment was halted at interim analysis as the futility boundary was crossed (1-sided p = 0.67). At final analysis, 68 subjects had a PFS event (34 in each arm). Median PFS was 2.1 mo (95% CI 2.0-3.0) with B+P vs 2.1 mo (2.0-2.4) with TAS-102; HR 0.86 (0.52-1.44). 4-mo PFS rate was 22.2% (11.9-41.6) with B+P vs 10.6% (3.8-30.0) with TAS-102. With 37 OS events (14 in B+P arm), median OS was 7.7 mo (5.1-NE) with B+P vs 6.6 mo (4.8-8.9) with TAS-102; HR 0.77 (95% CI 0.39-1.51). TAS-102 had greater grade 3-4 hematologic AEs (46% vs 22%), and B+P had more grade 3-4 non-hematologic AEs (47% vs 32%). Grade 3-4 AEs more common with B+P were fatigue (8% vs 0%), oral mucositis (6% vs 0%), and nausea (4% vs 2%). Though 63% of patients on B+P had acneiform rash, only 2% was grade 3-4. Grade 1-2 diarrhea occurred in 35% of B+P and 24% of TAS-102 patients. No new safety signal was observed. Conclusions: B+P did not significantly improve median PFS or OS compared to TAS-102 in KRAS/NRAS mut mCRC. Subgroup analyses and translational studies are ongoing to determine which subgroups may be more likely to attain 4-mo PFS or identify mechanisms of resistance. Clinical trial information: NCT03981614.

225 Background: ICIs induce durable responses in dMMR CRC patients. However, clinical and molecular biomarkers of response to ICIs have not been well-established. In this study, we investigated impact of specific MMR gene loss, BRAF V600E mutation and clinical characteristics of pts on clinical outcomes of ICIs. Methods: Pts were eligible if they had confirmed dMMR CRC by IHC or MSI-H by PCR and received ICIs between 01/01/2012 and 05/01/2019 at Winship Cancer Institute of Emory University, Mayo Clinic, Vanderbilt or Stanford University. Due to the functional dependency, the groups were categorized as protein loss of MLH1+PMS2 vs MSH2+MSH6. Log-rank test, Cox hazard model and Fisher’s exact test were used for survival outcomes, the best response and the distribution of variables among the subgroups. Results: A total of 66 pts with dMMR CRC were identified and BRAF status was available for 41 pts. ORRs in MLH1+PMS2 and MSH2+MSH6 groups were 72.9% and 56.5% respectively (P = 0.189). At 2 years, PFS rates were 55.6% and 78.2% for MLH1+PMS2 and MSH2+MSH6 groups respectively (P < 0.001). Pts with BRAF V600E mutations had significantly worse outcomes as compared to pts with wild-type BRAF (2-year PFS rate of 35.0% and 73.3% respectively; P < 0.001). Notably pts < 65 had better 2-year disease control rates when compared to > 65 (71.1% and 41.5% respectively; P < 0.001). We also observed worse 2-year PFS rates in pts with liver metastases (P = 0.014). CRC side and tumor volume did not impact 2-year PFS rates in our cohort. Conclusions: Our data suggest that pts with loss of function in MSH2+MSH6 may have better 2 year-PFS rates compared pts with MLH1+PMS2 even though ORR favored MLH1+PMS2 group suggesting that ORR may not reflect the durability of ICI response in dMMR CRC patients. Consistently, pts with BRAF V600E mutation which is associated with MLH1 promoter methylation had significantly worse 2-year PFS rates. Overall, our findings suggest that BRAFV600E mutation, the affected MMR proteins, pt age, and site of metastasis may impact durability of ICI response in dMMR CRC patients.

4110 Background: Neuroendocrine tumors (NET) comprise around 2% of all malignant tumors of the gastrointestinal system. The genomic landscape of NET has not been well studied. The aim of this study was to confirm the feasibility of next generation sequencing (NGS) using ctDNA in NET and characterize common alterations in the genomic profile. Methods: Molecular alterations in 114 plasma samples from 114 patients with NET using clinical-grade NGS of ctDNA (Guardant360Ò) across multiple institutions were evaluated. The test detects single nucleotide variants in 54-73 genes, copy number amplifications, fusions, and indels in selected genes. Results: A total of 114 NET patients were evaluated, of which 64 (56.1%) were female. Mean age was 59.7 years with a range between 23-89 years. ctDNA NGS testing was performed on 114 plasma samples; 1 patient had testing performed twice. Genomic alterations were defined in 94 (n = 94/114, 82.5%) samples with a total of 289 alterations identified after excluding variants of uncertain significance (VUSs) and synonymous mutations. Alterations were identified in at least one sample from 83 patients; TP53 associated genes were most commonly altered (n = 83/289, 28.7%), followed by KRAS (n = 22, 7.6%), PI3CA (n = 15, 5.2%), CCNE1 (n = 15, 5.2%), BRAF (n = 13, 4.5%), MYC (n = 12, 4.1%), ERBB2 (n = 11, 3.8%), APC (n = 10, 3.5%), EGFR (n = 10, 3.5%), MET (n = 10, 3.5%), PTEN (n = 9, 3.1%), RB1 (n = 9, 3.1%), CDK6 (n = 7, 2.4%), AR (n = 5, 1.7%), ARID1A (n = 5, 1.7%), FGFR1 (n = 5, 1.7%), and PDGFRA (n = 5, 1.7%). Other genomic alterations of low frequency, but clinical relevance included: CDK4 (n = 4, 1.3%), NF1 (n = 4, 1.3%), RAF1 (n = 4, 1.3%), GNAS (n = 3, 1.0%), KIT (n = 3, 1.3%), BRCA2 (n = 2, 0.7%), CCND2 (n = 2, 0.7%), CTNNB1 (n = 2, 0.7%), JAK2 (n = 2, 0.7%), NRAS (n = 2, 0.7%), SMAD4 (n = 2, 0.7%), and TERT (n = 2, 0.7%). Alterations in AKT1, ALK, ATM, BRCA1, CCND1, CDKN2A, FGFR2, MTOR, RHOA, SMO and STK11 were all reported once (n = 1, 0.3%). Conclusions: Evaluation of ctDNA is feasible among individuals with NET. Liquid biopsies are not invasive and can provide personalized options for targeted therapies in NET patients.

e15029 Background: ICIs induce durable responses in dMMR CRC pts with overall response rates (ORR) of 30-50%. Even though the loss of expression of any MMR gene predicts ICIs response, it is unknown if ORRs are similar across all MMR genes (MLH1, PMS2, MSH2, and MSH6). In this study, we analyzed the impact of each specific MMR gene loss and clinical characteristics of pts with best response to ICIs. Methods: Pts were eligible if they had confirmed dMMR CRC by IHC or microsatellite instability-high (MSI-H) by PCR, and received ICIs between 01/01/2012 and 10/01/2018 at Winship Cancer Institute of Emory University, Mayo Clinic or Vanderbilt University Medical Center. Due to the pattern of frequent concurrent loss and functional dependency, the groups were categorized as MLH1 ±PMS2 vs. MSH2 ±MSH6. Cox proportional hazard model and Fisher’s exact test were used for the best response and the distribution of variable among the subgroups. Results: A total of 45 pts with dMMR CRC were identified. ORRs in MLH1 ±PMS2 and MSH2 ±MSH6 groups were 68% and 57.1% respectively without statistical difference (Table). Pts with age < 50 and 50-65 years old had better ORRs compared to pts with age >65 (58.3%, 85.7% and 42.1% respectively, P=0.036). Left-sided tumors had a trend toward higher ORRs compared to right-sided tumors (83.3% vs 51.5% P=0.086). Gender and BRAF status were not predictors of response. BRAF mutations were more common in right-sided tumors (29.6% vs 11.1% respectively) and in older patients. Conclusions: Our data suggest that MSI-H CRC pts aged 50-65 treated with ICIs, have improved ORR compared to pts > 65; pts with left-sided tumors have a trend toward improved ORR compared to those with right sided tumors. [Table: see text]