1st Line Systemic Therapy Research Articles

NRG-LU002: Randomized phase II/III trial of maintenance systemic therapy versus local consolidative therapy (LCT) plus maintenance systemic therapy for limited metastatic non-small cell lung cancer (NSCLC).

8506 Background: First line therapy options for advanced NSCLC without actionable molecular alterations include immunotherapy (IO) -/+ chemotherapy or chemotherapy alone. NRG-LU002 was a randomized phase II/III study assessing the benefits of local consolidative therapy (LCT) when added to systemic therapy as maintenance in management of oligometastatic NSCLC. Methods: Eligible patients had metastatic NSCLC with 3 or fewer extracranial metastatic sites (excluding primary) exhibiting at least stable disease after 4 cycles of 1st line systemic therapy. Patients were randomized 1:2 to maintenance systemic therapy or LCT (radiation and/or surgery) followed by maintenance systemic therapy until progression, death, or intolerable toxicity. Stratification factors included histology and IO use. In the randomized phase II (RPhII) portion of the study, the primary endpoint was progression-free survival (PFS) with a planned decision analysis after 216 patients were enrolled and 138 PFS events observed. Secondary endpoints included overall survival (OS), quality of life, and toxicity. The RPhII portion was designed to provide at least 95% power to detect a PFS hazard ratio (HR) of 0.60 at 1-sided significance level of 0.15, and the phase III portion warranted only if the estimated HR was less than 0.83. Results: NRG-LU002 accrual was initiated in 4/2017 and suspended in 11/2021 when the RPhII portion sample size was met. Following the planned interim analysis, the study was closed in 12/2023. Overall, 215 patients (81 -LCT arm, 134 +LCT arm) were enrolled from 68 sites with a median age of 65 years (40-86), 77% white, 95% PS 0/1, 78% non-squamous histology, and 90% having received IO-based systemic therapy. Median follow-up among all/surviving patients were 21.9/29.4 months, respectively. With 138 PFS events from both arms, estimated 1-yr and 2-yr PFS rates were 48% (95% CI: 35.9, 59.0) and 36% (95% CI: 24.8, 47.2) in the maintenance systemic therapy arm and 52% (95% CI: 42.5, 59.8) and 40% (95% CI: 31.5, 48.6) in the LCT + maintenance systemic therapy arm, respectively (2-sided log-rank test p-value = 0.66). Corresponding HR was 0.93 (95% CI: 0.66, 1.31). Of 185 patients treated with IO-containing regimens, the PFS HR was 0.90 (95% CI: 0.61, 1.32). OS HR between two arms was 1.05 (0.70, 1.56) among all patients and 1.05 (0.68, 1.63) among IO-treated patients. For adverse events reported as definitely, probably or possibly related to treatment, there were more LCT + maintenance systemic therapy patients with overall grade 2 or higher toxicities (73% vs 84%) and grade 3 or higher pneumonitis (1% vs 10%). Conclusions: LCT added to IO-based 1st line systemic therapy was associated with a PFS HR of 0.90. Reducing toxicity and increasing biologically-driven patient selection may optimize this therapeutic ratio. Clinical trial information: NCT03137771 .

Clinical characteristics and treatment outcomes in Hispanic/Latino patients with advanced renal cell carcinoma at a single institution.

e13738 Background: The incidence of renal cell carcinoma (RCC) is increasing, with an expected 81,610 new cases and 14,390 deaths in 2024. While clinical characteristics in patients with RCC have been well described, studies focusing on minority patients, such as Hispanic and Latino (HL), are limited. The objectives of the current study are to analyze differences in clinical, pathological, and outcome characteristics between HL and non-Hispanic Latino (NHL) pts. with advanced RCC (aRCC) in South Florida. Methods: We retrospectively reviewed clinical and pathological data from pts. with aRCC treated at Sylvester Comprehensive Cancer Center (SCCC) from 2010 to 2023. Descriptive statistics were used to summarize demographic and baseline characteristics. HL vs. NHL groups were compared using chi-square or Fisher’s exact test for categorical variables, and Wilcoxon rank-sum test for continuous variables. Time-to-event outcomes including metastasis-free survival (MFS) and overall survival (OS) were estimated using Kaplan-Meier method, and two groups were compared using the log rank rest. Results: A total of 417 patients diagnosed with aRCC who received care at SCCC were analyzed. HLs comprised 45% while NHLs represented 55% of patients with aRCC. A higher proportion of HLs presented at an earlier age (< 60y.o, 53% vs. 44%), were female (31% vs. 24%), and had a higher proportion of ISUP grade 4 tumors (47% vs. 34.8%). HLs had a significantly shorter metastasis-free survival (HR 1.48 [95% CI: 1.06-2.05]) compared to NHLs. There were no differences in the frequency of AEs from TKI, IO or IO-TKI based therapies between HLs and NHLs. HLs were less likely to achieve an objective response (CR/PR) to 1st-line therapy compared to NHLs (OR 0.54 (95% [CI: 0.31-0.94]), including HLs with non-ccRCC (OR 0.24 [95% CI: 0.07-0.81]). There was no significant correlation between ethnicity and overall survival in pts. treated with systemic therapy. HLs were less likely to achieve CR/PR to 1st-line therapy compared to NHLs (OR 0.54 [95% CI: 0.31-0.94, p=0.030]) in 217 pts. treated with 1st-line therapy, and in 55 with non-cc RCC (OR 0.24 [95% CI: 0.07-0.81, p=0.021]). There was no significant correlation between ethnicity and overall survival in pts. treated with systemic therapy. Conclusions: In our cohort, patients with aRCC presented at an earlier age and we had a higher proportion of females in HLs compared to NHLs. HLs had a higher risk of developing metastases after nephrectomy compared to NHLs and were less likely to achieve an objective response to 1st-line systemic therapy. Our results, suggesting a potentially more aggressive clinical course of aRCC in HLs in our patients, need further validation in a larger cohort. Future studies will incorporate analysis of molecular tumor characteristics, to further understand biological differences explaining outcomes observed in HL vs NHL populations with aRCC.

Comparison of chemotherapy to chemo-immunotherapy as first-line treatment in patients with advanced large cell neuroendocrine carcinomas (LCNECs) of mixed histology: A multi-institutional international retrospective study.

8602 Background: LCNECs are a rare subtype of lung cancer, with limited clinical trial data and an unclear consensus on first-line treatment. Even less is known about the optimal treatment approach for pts with mixed LCNECs, a pathologic subtype where tumors contain both LCNEC histology as well as features of adenocarcinoma, squamous cell, or small cell lung cancer. Methods: We conducted an international multi-institutional retrospective analysis (n=13 institutions) of pts with advanced or metastatic mixed LCNECs who received 1st-line systemic therapy with either chemotherapy alone (chemo) or chemo-immunotherapy (chemoIO) between 2010-2023. Clinical outcomes included progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and treatment-related adverse events (trAEs). Survival comparisons were made via the log-rank test. Results: Seventy-three pts with mixed LCNECs received either chemo (n=42, 57.5%) or chemoIO (n=31, 42.5%). The most common chemo regimens were carboplatin/etoposide (n=27) and cisplatin/etoposide (n=8), while the most common chemoIO was carboplatin/etoposide/atezolizumab (n=19). Median age at 1st-line therapy initiation was 65 (IQR: 60-72). 64% of pts were male (n=47). The majority were former smokers (n=41, 56.2%), with 22 current smokers (30.1%), and 10 non-smokers (13.7%). Mixed histologies included LCNEC/NSCLC (n=45, 56.2%), LCNEC/SCLC (n=17), LCNEC/carcinoid (n=1), and unspecified mixed LCNEC (n=10). Median PFS for chemo was 5 months (95% CI 2.7-9.2) vs. 6 months (95% CI 4.4-8.3) for chemoIO ( p=0.86). Median OS for chemo was 14.2 months (95% CI 10.4-22.5) vs. 17.2 months (95% CI 9.4-27.2) for chemoIO ( p=0.66). The ORR did not differ between chemo (n=18, 45%) and chemoIO (n=15, 48.4%) ( p=0.81). In the chemo group, 60% (n=25) experienced trAEs of any grade, with 23.8% (n=10) experiencing grade 3+ events and four requiring hospitalizations. For chemoIO pts, 61% (n=19) experienced trAEs, with 25.8% (n=8) experiencing grade 3+ events and six requiring hospitalizations. Neutropenia was the most common grade 3+ trAE for both chemo (n=5) and chemoIO (n=4). Overall, there were no significant differences between chemo or chemoIO groups for ORR ( p=0.81), all-grade trAEs ( p=0.88), grade 3+ trAEs ( p=0.84), PFS ( p=0.86), or median OS ( p=0.66). There were no significant differences in median PFS ( p=0.46) or OS ( p=0.99) for pts with mixed LCNEC/NSCLC vs. LCNEC/SCLC. Conclusions: For mixed LCNECs, there was no significant difference in PFS or OS between first-line treatment with chemo vs. chemoIO, suggesting limited benefit from immunotherapy for these pts. Additionally, survival outcomes did not differ between mixed LCNEC/NSCLC and LCNEC/SCLC, suggesting a biology primarily driven by their neuroendocrine component.

Abstract PO4-15-01: A multi-center prospective cohort study to evaluate the presence of circulating tumor cells using the Epic Sciences platform among women with metastatic breast cancer

Abstract Background: The presence of tumor cells (or their components) in the blood of women with a history of early breast cancer has the potential to herald the development of metastatic recurrence at its earliest stages. Such early detection could potentially lead to novel prevention strategies, but it requires a sensitive assay. Objective: To use the Epic Sciences platform to detect and enumerate CTCs in blood samples from patients with an established diagnosis of metastatic breast cancer (MBC), prior to initiation of 1st line systemic therapy in the metastatic setting. Methods: We conducted a multi-center prospective cohort study to evaluate the presence of CTCs using the Epic Sciences platform among patients with a new diagnosis of MBC. Men or women age 18 to 85 were included, irrespective of breast cancer subtype. Patients with a prior or concurrent malignancy whose natural history or treatment had the potential to interfere with the detection of MBC in a liquid biopsy were excluded. A one-time blood draw was performed before patients received any local or systemic therapy in the metastatic setting. In addition, those with recurrent disease must have been off any systemic adjuvant therapy for ≥3 weeks prior to blood collection. Two 5 mL blood samples were obtained for CTC identification and enumeration. CTC identification was based on immunofluorescence analysis using Epic Sciences platform as previously described (Ueno et al 2017). The presence of CTCs was correlated with clinical and pathological features, which were abstracted from medical records and pathology reports. The association between the presence of CTCs and clinical/pathologic characteristics was tested using Fisher’s exact test for categorical variables and t-test or Wilcoxon rank sum tests for numerical variables. All analyses were performed using the R software package. Results: 100 patients were recruited between February 2021 and January 2023 at five academic oncology centres in Ontario and Quebec, Canada. 95 patients had evaluable blood for analysis and 5 did not due to blood age and/or insufficient blood volume. Six patients were excluded after providing a blood sample because tissue biopsy ultimately revealed a 2nd primary tumor (n=4) or benign tissue (n=2). Hence, 89 patients with a clinical diagnosis of MBC and with evaluable blood for CTC analyses were ultimately included in our cohort. The average age of patients was 61 years. Most patients (n=49, 55%) had a prior history of early breast cancer, 38 (43%) had de-novo metastatic disease and prior breast cancer history was unknown for 2 patients. 50 (66%) of patients had visceral metastatic disease. The most common sites of metastases included bone (62%), lung (30%), liver (29%) and lymph nodes (17%). 63 of 89 patients (71%) had detectable CTCs at baseline, prior to any local or systemic treatment in the metastatic setting. The median number of detectable CTCs per 5mL sample was 2 (IQR 8.5) and the range was 0 – 12,798. Twenty nine of 89 (33%) patients had 5 or more CTCs detected per 5ml blood. The proportion of patients with detectable CTCs was numerically highest (n=39/51, 76%) among patients with hormone receptor (HR)+/HER2-ve breast cancer, followed by HER2+ (n=16/22, 73%) and triple negative (n=8/13, 62%) disease. Associations between CTC detection with prior history of early breast cancer, sites of metastatic disease and disease burden will also be presented. Conclusions: Approximately 3 in 4 women with newly diagnosed metastatic breast cancer have detectable CTCs using the Epic Sciences platform prior to initiation of first line systemic therapy. CTCs may be a promising tool for the monitoring of breast cancer recurrence and will be investigated in an ongoing Canadian prospective observational study that aims to elucidate biomarkers of late breast cancer recurrence. Citation Format: Katarzyna Jerzak, Pamela Goodwin, Marguerite Ennis, Christine Brezden-Masley, Nathaniel Bouganim, Mark Basik, Arushi Jain, Giuseppe Di Caro, Rick Wenstrup, Nadine Hartmann, Megan Slade, Ana Elisa Lohmann. A multi-center prospective cohort study to evaluate the presence of circulating tumor cells using the Epic Sciences platform among women with metastatic breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-15-01.

Abstract 4606: Combinatorial effects of a sequence of trabectedin (T) and CD13-targeted tissue factor tTF-NGR on human vascular endothelial cells (HUVEC) and in soft tissue sarcoma (STS) models

Abstract Trabectedin represents a standard treatment option for relapsed or refractory soft tissue sarcomas. CD13 is a neutral aminopeptidase expressed on remodeling and invasive endothelial cells such as in the tumor vasculature. CD13-targeted tissue factor (tTF-NGR) is a recombinant pro-coagulatory fusion protein which accumulates in the tumor vasculature leading to tumor vascular occlusion and ultimately to tumor infarction. Giving both compounds in sequence could trap trabectedin inside tumors and thus increase its efficacy. This vice versa can optimize the activity of tTF-NGR. To prepare a multicenter clinical trial of a combination of trabectedin and tTF-NGR in patients with advanced soft tissue sarcomas refractory to 1st line systemic therapy (TRABTRAP), preclinical experiments on the mechanism of action of this combination, its efficacy and pharmacokinetics (PK) were performed. We first tested the pro-apoptotic function of trabectedin on human vascular endothelial cells (HUVEC) and human HT1080 sarcoma cells in vitro. Trabectedin significantly (p<.0001) increased the presence of phosphatidylserine (PS) on the outer leaflet of the phospholipid bilayer of the cell membrane in a dose- and time-dependent manner. The resulting optimized phospholipid milieu significantly potentiated the pro-coagulatory efficacy of tTF-NGR within the factor X:factor VIIa:tTF-NGR:CD13 complex on the outer cell membrane when compared to cultures without trabectedin (p<.05). This effect was specifically dependent on the presence of PS as it could be abolished by masking PS via preincubation with annexin V, whereas corticosteroids had no effect on the pro-coagulatory response of HUVEC in the presence of tTF-NGR. In an in vivo HT1080 human sarcoma xenograft model in athymic mice, systemic combination treatment of trabectedin followed by tTF-NGR (n=11) inhibited tumor growth to a greater extent than either compound alone (trabectedin n=9, tTF-NGR n=9) and compared to a saline control (n=8). The terminal half-life of tTF-NGR infused intravenously over 1 hour, was 9 hours (phase I trial). To further characterize the duration of tTF-NGR presence upon binding to the endothelial cell surface molecule CD13, we performed flow cytometry and fluorescence labeling experiments with tTF-NGR and HUVEC in vitro. After coincubation with HUVEC, the cells rapidly internalized the tTF-NGR:CD13 complex into the cytoplasm of the cells (approx. 50% of the labeled tTF-NGR after 3 h at 37oC), a process which exposed the protein to intracellular degradation. The multicenter TRABTRAP trial is actively recruiting patients (EudraCT 2020-005858-21). Citation Format: Caroline Brand, Stefanie Pavelka, Kathrin Hessling, Heike Hintelmann, Andrew F. Berdel, Sebastian Bäumer, Nicole Bäumer, Georg Lenz, Christoph Schliemann, Wolfgang E. Berdel, Christian Schwöppe. Combinatorial effects of a sequence of trabectedin (T) and CD13-targeted tissue factor tTF-NGR on human vascular endothelial cells (HUVEC) and in soft tissue sarcoma (STS) models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4606.

Phase III randomized trial of stereotactic ablative radiotherapy (SAbR) for oligometastatic advanced renal carcinoma (EA8211-SOAR).

TPS489 Background: Optimal strategies for managing oligometastatic renal cell carcinoma (RCC) are unclear. While systemic therapy is the accepted standard, Stereotactic Ablative Radiation (SAbR) is a promising alternative based on retrospective and limited prospective data1-3. SAbR may spare patients from systemic therapy toxicity, but progression of occult micrometastasis remains a concern. This prospective ECOG-ACRIN phase 3 randomized trial will compare SAbR to systemic therapy for oligometastatic RCC. Co-primary endpoints are overall survival (OS) and toxicity. Methods: Patients with RCC (any histology except for sarcomatoid) with an ECOG performance 0-2, International Metastatic RCC Database Consortium (IMDC) favorable and intermediate-risk, and 2-5 extracranial metastases are eligible. The exclusion criteria include prior systemic therapy (except for adjuvant therapy) and brain metastases. Patients with intact primary are eligible after definitive treatment of the primary site. Stratification factors include 1) number of metastases (2-3 vs 4-5), 2) histology (clear cell vs non-clear cell), 3) IMDC (0 vs 1-2), 4) prior adjuvant systemic therapy (yes vs no), and 5) time from treatment of primary disease (<1yr vs >1yr). Patients will be randomized to up front systemic therapy (the type of systemic therapy will be chosen at the discretion of the investigator) versus SAbR (and additional SAbR of up to a total of 6 metastasis while disease remains amenable) followed by systemic therapy. Co-primary endpoints are OS and toxicity (≥grade 3). Target accrual goal is 472 patients which will provide 85% power to test non-inferiority in OS from a non-inferiority hybrid design, assuming a null hazard ratio of 1.24 and alternative hazard ratio of 0.85. If it is concluded that SAbR arm has non-inferior OS, superiority in toxicity will be tested. Secondary endpoints include health-related quality of life (QOL) as measured with NFKSI-19 and EQ-5D-5L and progression free survival (PFS). Exploratory endpoints include PFS of 1st line systemic therapy, local control with SAbR and cost-effectiveness. The trial has been open for enrollment since September 2023.

Characterization of outcomes and genomic alterations (GA) in combined hepatocellular carcinoma-cholangiocarcinoma (cHCC-CCA).

458 Background: Hepatobiliary cancers comprise a heterogeneous spectrum of invasive carcinomas involving the liver and bile ducts. Due to its rarity, the prognosis and clinical outcomes data are poorly understood. This study aims to provide insight into the response to therapeutic options and GA in patients (pts) with cHCC-CCA. Methods: We conducted a retrospective analysis of clinical outcomes data and GA at MD Anderson (MDA) from 2009 to 2023 in pts with cHCC-CCA. Pt characteristics were compared using Fisher’s exact test and Mann-Whitney U. Progression-free survival (PFS) and overall survival (OS) were assessed using Kaplan-Meier and the log-rank test. Results: 40 pts with cHCC-CCA were analyzed. Hepatitis B and C were the most common etiologies (Table). 25.0% had portal vein tumor thrombus and 72.0% had advanced disease (M1/N1) at diagnosis. Radiographic washout was seen in 55.9%. Elevation of CA19-9, AFP, and both was in 42.5, 57.5, and 30.0%. Cirrhosis at diagnosis was 35.0%. Pts who underwent surgery (n=10) had significant OS benefit (55.6 vs. 14.1 m, p<0.001). Y90 (n=4)/radiation therapy (n=10) provided significant OS benefit in pts who did not undergo surgery (23.3 vs 10.9 m; p=0.012). 34 pts received 1st line systemic therapy: 10 pts received gemcitabine/cisplatin (GC) combined with immunotherapy (GCI): GC + nivolumab (n=5), durvalumab (n=3), or atezolizumab/bevacizumab (AB, n=2). GCI was compared to other regimens (OR, n=24) including chemotherapy alone (GC, FOLFIRI, FOLFOX), HCC-directed therapy alone (AB, lenvatinib, nivolumab), or chemotherapy plus lenvatinib or bevacizumab with mPFS of 7.0 vs. 2.9 m (p=0.014) showing significant PFS benefit. Pts who received GCI trended to better OS compared to OR (18.9 vs. 12.0 m, p=0.380). 2 pts treated with GC+AB had complete responses to date at 36.0 and 14.0 m. Of 31 pts who underwent GA testing, the 2 most frequent GAs were TP53 (38.7%) and TERT (35.5%) mutations. Neither impacted OS: TP53 15.8 vs. 17.6 m (p=0.746); TERT 9.8 vs. 23.3 m (p=0.355). Conclusions: GCI had survival benefit compared to OR in cHCC-CCA. Pts who present with early stage of disease should be evaluated early for surgical resection or maximize local therapy in the case of nonresectable disease to improve survival. [Table: see text]

First-Line Treatment for Advanced Hepatocellular Carcinoma: A Three-Armed Real-World Comparison.

There are several existing systemic 1st- line therapies for advanced hepatocellular carcinoma (HCC), including atezolizumab/bevacizumab (Atez/Bev), sorafenib and lenvatinib. This study aims to compare the effectiveness of these three 1st-line systemic treatments in a real-world setting for HCC, focusing on specific patient subgroups analysis. A total of 177 patients with advanced HCC treated with Atez/Bev (n = 38), lenvatinib (n = 21) or sorafenib (n = 118) as 1st line systemic therapy were retrospectively analyzed and compared. Primary endpoints included objective response rate (ORR), progression-free survival (PFS) and 15-month overall survival (15-mo OS). Subgroups regarding liver function, etiology, previous therapy and toxicity were analyzed. Atez/Bev demonstrated significantly longer median 15-month OS with 15.03 months compared to sorafenib with 9.43 months (p = 0.04) and lenvatinib with 8.93 months (p = 0.05). Similarly, it had highest ORR of 31.6% and longest median PFS with 7.97 months, independent of etiology. However, significantly superiority was observed only compared to sorafenib (ORR: 4.2% (p < 0.001); PFS: 4.57 months (p = 0.03)), but not comparing to lenvatinib (ORR: 28.6% (p = 0.87); PFS: 3.77 months (p = 0.10)). Atez/Bev also resulted in the longest PFS in patients with Child-Pugh A and ALBI 1 score and interestingly in those previously treated with SIRT. Contrary, sorafenib was non inferior in patients with impaired liver function. Atez/Bev achieved longest median PFS and 15-mo OS independent of etiology and particularly in patients with stable liver function or prior SIRT treatment. Regarding therapy response lenvatinib was non-inferior to Atez/Bev. Finally, sorafenib seemed to perform best for patients with deteriorated liver function.

Abstract B022: Clinical outcomes in NF2-mutated RCC treated with contemporary immunotherapy regimens

Abstract Background: Neurofibromin-2 (NF2) encodes the cell scaffolding protein merlin, which is involved in the Hippo tumor suppressor pathway. Somatic loss of function NF2 alterations in renal cell carcinoma (RCC) are associated with poor prognosis and can also molecularly define a subset of unclassified renal cell carcinomas without a standard of care treatment. While immuno-oncology (IO) combination regimens such as ipilimumab/nivolumab (IO/IO) or PD-1 inhibitor with a VEGFR-targeted therapy (IO/VEGFR) are the standard of care for clear cell RCC, efficacy of IO-based regimens for NF2 mutated RCC remains unknown. We report the first comparison of clinical responses to IO/IO, IO/VEGFR, or other systemic therapies for NF2-mutated RCC. Methods: NF2-mutated RCC patients receiving systemic therapy at Memorial Sloan Kettering Cancer Center were retrospectively identified by screening of our targeted exome sequencing (MSK-IMPACT) database. Groups are defined by 1st line systemic therapy regimens: IO/IO, IO/VEGFR, and other (VEGFR-targeted monotherapy, IO monotherapy, everolimus/bevacizumab, and chemotherapy). PFS-2 is defined as time from start of 1st line to progression on next therapy, or death. ORR, PFS, and PFS-2 were measured by an independent RECIST radiologist (CD). PFS, PFS-2, and OS are estimated using the Kaplan-Meier method. Results: Histologic subtypes in the overall cohort were unclassified (N=25), clear cell (N=7), and papillary (N=3). ORR of IO containing regimens in any line of treatment (N=29) was 57% (95% CI 37, 75). In the 1st line setting, 8 patients received IO/IO, 12 received IO/VEGFR, and 15 received other regimens with an ORR of 38% (95% CI 9, 76), 75% (95% CI 43, 95), and 23% (95% CI 5, 54), respectively. Thirty-three patients were included for PFS and PFS-2 analysis and 34 for OS with a median duration of follow-up of 40 months. Median PFS is 11 months (95% CI 4, 19; 26 events), median PFS-2 is 14 months (95% CI 9, 25; 25 events) and median OS is 27 months (95% CI 13, 65; 21 events). PFS, PFS2, and OS did not differ by 1st line treatment group. Among patients who received any IO exposure in the 1st line versus patients who received non-IO-based therapy, there was no significant difference in median PFS (12 (95% CI 5, 22) vs 5 (95% CI 2,21) months, p=0.39), PFS2 (17 (95% CI 9, 28) vs 13 (95% CI 3, 25) months, p=0.49), or OS (27 (95% CI 13, 73) vs 26 (95% CI 4, NE), p=0.90). OS did not differ by tumor histologic subtype; however, sample size limits power to detect differences. Conclusion: In comparison to clear cell RCC, prognosis for patients with NF2-mutated RCC remains poor. IO-based therapy has activity in treating NF2-mutated RCC; patients may derive benefit even if first exposure to IO occurs ≥2nd treatment line. There was no significant difference in PFS, PFS2, or OS based on 1st line regimen for patients with NF2-mutated RCC. Further investigation of inhibitors specifically targeting downstream effectors of the Hippo pathway are warranted. Citation Format: Kelly N. Fitzgerald, Cihan Duzgol, Andrea Knezevic, Rachel Jacobi, Ritesh R. Kotecha, David H. Aggen, Maria I. Carlo, Neil J. Shah, Martin H. Voss, Darren R. Feldman, Robert J. Motzer, Chung-Han Lee. Clinical outcomes in NF2-mutated RCC treated with contemporary immunotherapy regimens [abstract]. In: Proceedings of the AACR Special Conference: Advances in Kidney Cancer Research; 2023 Jun 24-27; Austin, Texas. Philadelphia (PA): AACR; Cancer Res 2023;83(16 Suppl):Abstract nr B022.

Evaluation of total tumor volume reduction ratio in initially unresectable colorectal liver metastases after first line treatment

Background: Total tumour volume is predictive factor for hepatic resection in some solid tumours, but its significance in colorectal liver metastases has not been fully investigated. liver is most frequent location of distant metastasis for colorectal cancer, which is 1 of most common cancers to cause cancer-related deaths globally. For colorectal liver metastases, hepatic resection is widely recognized as most effective therapy &amp; only possibly curative operation. assessment of tumour burden can depend significantly on total tumour volume. Aim: In this review, we sought to assess the total tumour volume decrease ratio in colorectal liver metastases that were initially unresectable following 1st-line therapy, Summary: After receiving 1st-line systemic therapy, decreased ratio of TTV had been reliable predictor of conversion result &amp; long-term prognosis in studied cases with originally unresectable CRLM.

Toxicity profile, palliative care and hospice utilization of geriatric patients with hepatocellular carcinoma treated with atezolizumab plus bevacizumab in the veteran health administration.

e24022 Background: Over the last decade, the incidence of Hepatocellular carcinoma (HCC) has increased in the geriatric population. Atezolizumab plus Bevacizumab (A+B) has become an established systemic therapy for patients with HCC. Even with the aging population and elevated prevalence of HCC amongst Veterans, limited studies have explored the safety of A+B in geriatric patients. This study aims to investigate the toxicity profile of A+B in the geriatric population as well as Palliative Care and Hospice utilization within the Veteran Health Administration (VHA). Methods: Data were extracted from the electronic medical records (EMR) for adults (deceased and living) with ICD9 and ICD10 HCC codes that received 1st line systemic therapy with A+B within the VHA between December 1, 2019, and March 1, 2023. Descriptive statistics were used to summarize baseline characteristics, toxicity profile and Palliative Care and Hospice enrollment between 3 populations aged &lt; 65, 65-69, and &gt; 70 years. A significant p-value of ≤0.05 was used. Results: In total, 332 patients were included in the study; 206 were deceased. Approximately 70% of patients were &gt; 65 years. The majority in each age group were non-Hispanic white males, ECOG ≥1, CPS class A and BCLC score of C. Veterans &gt; 70, significantly had less cirrhosis caused by viral hepatitis(p &lt; 0.0001) and no prior local therapy (p = 0.002). There was no significant difference in either median A+B doses, cessation of therapy due to toxicities or median reported toxicities of any grade, as reported in Table 1. Most common toxicities in all age groups were fatigue, decreased appetite, proteinuria and transaminitis. There was a significant difference in Hospice enrollment in deceased patients (p = 0.027), with Veterans &gt; 70 years more likely to enroll in Hospice. Conclusions: This is the first known study that reports geriatric advanced HCC patients with A+Z toxicities in VHA patients. This study demonstrates that A+Z can be used safely in geriatric patients. Further quality improvements projects need to be implemented to improve number and timing Hospice utilization.[Table: see text]

Real-world data: Clinical characteristics and outcomes of patients with advanced hepatocellular carcinoma treated with atezolizumab plus bevacizumab in Veteran Health Administration.

2651 Background: Advanced Hepatocellular carcinoma (HCC) is an aggressive tumor, and most patients have a poor prognosis. Recent clinical trials have demonstrated improved survival with molecularly targeted treatment and immunotherapy. Atezolizumab plus Bevacizumab (A+B ) is the recommended first-line treatment for advanced HCC based on the phase 3 IMbrave 150 trial. However, in a real-life setting, many patients do not meet the inclusion criteria of this landmark trial. This study proposes a retrospective review of outcomes of advanced HCC patients receiving A + B in Veterans Health Administration (VHA). Methods: Patients with advanced HCC receiving 1st line systemic therapy with A+ B at the VHA between Dec 1, 2019, to Mar 1, 2022, were selected from the electronic medical records (EMR) using ICD-9 and ICD-10 codes. Abstractors reviewed EMR and followed from their index date of A+ B initiation until death or their last VHA visit, with the study period ending on Jan 31, 2023. The Chi-Squared test was used to compare rates, and the Mann-Whitney test was used to compare medians. Results: A total of 332 patients met the study criteria. The median age was 67 yrs., 99% were males, 63% non-Hispanic White, 26% were Black, 66 % had ECOG ≥ 1, 84% had CPS class A, 16% had CPS class B and C, 62% had grade 2 ALBI score, 56% had viral hepatitis-caused HCC, 80 % had cirrhosis, and 67% had prior local therapies. The outcomes are shown. Conclusions: In our real world, despite having similar PFS as the phase 3 IMbrave 150 trial, our OS at 12 months was lower (52% vs. 67%), given that we had more elderly patients with moderate liver dysfunction and 40% were non-white. This study provides actual outcomes in clinical practice where patients do not match the study population of the pivotal trial. [Table: see text]

Abstract 235: Establishing clinical utility for genomic profiling with plasma cell free DNA in urothelial carcinoma

Abstract Purpose: Genomic profiling in urothelial carcinoma (UC) conventionally uses tissue DNA. However, tissue biopsy is so invasive that it can be difficult in some cases. Cell-free DNA (cfDNA) assay is a minimally invasive tool obtaining a comprehensive genomic information reflecting a tumor heterogeneity. Recently, the investigation of cfDNA assay in UC is widely conducted, but its clinical utility remains largely unknown. We aimed to establish plasma cfDNA assay and clarify its clinical role in UC. Method: Blood and matched tissue were obtained from 48 cases with advanced UC before 1st line systemic therapy or radical surgery. For genomic profiling of all samples, we applied a customed targeted DNA-sequencing strategy capturing 54 UC-relevant genes. Somatic mutations were required to be supported by a minimum variant allele frequency (VAF) of 0.5% in plasma cfDNA and 5% in tissue DNA. All mutation calls were filtered against matched leukocyte DNA. The result of mutational analysis was validated with digital PCR. The proportion of tumor-derived cfDNA (circulating tumor DNA (ctDNA) fraction) was estimated. We investigated the association between genomic profile and molecular subtyping with RNA sequencing and immunohistochemistry (IHC). Result: Fifty-five somatic mutations were detected in 22 cfDNA samples (22/48, 45.8%). Twenty-six of all somatic mutations identified in cfDNA (26/55, 47.3%) were concurrently present in tumor tissues. In 14 mutations randomly selected from all of those detected in cfDNA, VAF of digital PCR was statistically consisted with the result of NGS (p&amp;lt;0.001, R2=0.95). Furthermore, digital PCR showed that mutations detected in cfDNA alone were cleared via radical surgery. And those were found in another tissue sample from the same patient. Of the 22 cases, 6 had a ctDNA fraction greater than 2% of total cfDNA. High ctDNA fraction was associated with advanced clinical tumor stage, high PD-L1 expression in tumor tissue by IHC and basal molecular subtype (p = 0.04, 0.02, &amp;lt;0.01, respectively). Conclusions: We established cfDNA assay for genome profiling in advanced UC. The result of validation using digital PCR suggested that cfDNA assay can identify the mutation which cannot be detected in tissue sample as a tumor heterogeneity. Additionally, cfDNA assay generate the information for classifying UC cases by molecular subtypes and predicting the expression of immune checkpoint molecules. Further investigation is needed as a promising minimally invasive assay to predict an immunotherapy responsiveness against metastatic UC. Citation Format: Yuki Kita, Takayuki Sumiyoshi, Takeshi Sano, Akihiro Hamada, Toru Sakatani, Kenji Nakamura, Hideaki Takada, Ryousuke Ikeuchi, Takayuki Goto, Atsuro Sawada, Shusuke Akamatsu, Takashi Kobayashi. Establishing clinical utility for genomic profiling with plasma cell free DNA in urothelial carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 235.

Comparative outcomes of metastatic prostate cancer (mPC) patients (pts) with DNA damage response gene alterations (DDR-a): A single-center experience.

169 Background: DDR-a are prevalent in mPC pts. The clinical behaviour of these pts is not well defined. We sought to investigate how DDR-a affects prognosis and treatment outcomes in mPC pts. Methods: Eligible pts were age ≥18 with mPC who had undergone germline (G) and/or somatic (S) next generation sequencing (NGS) at the Cross Cancer Institute 2016-2021. Pts were considered DDR-a if a pathogenic/likely pathogenic variant (P/LP-v) in a DDR gene was identified on G or S NGS; patients were considered DDR-p if no P/LP-v was identified on S NGS. Data from electronic medical records were collected. The primary endpoint was overall survival (OS) from diagnosis of mPC. Secondary endpoints included: OS and progression free survival (PFS) from initial diagnosis of prostate cancer (PC); PSA response after 12 weeks, and PFS and OS from the start time of 1st and 2nd line therapies. Time based endpoints were analyzed using the Kaplan-Meier (KM) method, and log-rank statistics were used to compare the KM curves. PSA responses were compared using chi-squared testing. Results: 23 DDR-a and 48 DDR-p pts were identified. The most frequent DDR-a were BRCA2 (n=11) and ATM (n=6). Baseline characteristics including age at diagnosis were similar between the two groups. 1st line systemic therapy was androgen deprivation therapy (ADT) alone in 73.9% of DDR-a and 77.0% of DDR-p. 2nd line therapy was abiraterone or enzalutamide in 65% of DDR-a and 92% of DDR-p. Olaparib was received by 52% of DDR-a pts. No difference in OS from mPC (65.7 vs 51.0 mos, p=0.487), OS from initial diagnosis (94.1 vs 88.9 mos, p=0.865), PFS on 1st line therapy (33.2 vs 31.0 mos, p=0.847), OS on 1st line therapy (85.6 vs 78.6 mos, (p=0.799) PFS on 2nd line therapy (8.4 vs 13.1 mos, p=0.569) or OS on 2nd line therapy (32.5 vs 35.8 mos, p=0.901) was seen for DDR-a vs DDR-p, respectively. PSA responses to 1st and 2nd line therapies were similar and will be presented as waterfall plots. Conclusions: In this single-center cohort, no difference in clinical characteristics or outcomes were seen in DDR-a compared to DDR-p pts. While this study is limited by small numbers and retrospective nature, it adds to the growing literature characterizing the clinical behaviour of DDR-a mPC. Collaborative efforts are required to better define this molecular cohort of pts.

Long-term quality of life in patients with metastatic esophagogastric cancer receiving first-line systemic therapy.

306 Background: Thus far, evidence that quality of life (QoL) remains stable during 1st line systemic therapy of patients with metastatic esophagogastric cancer (mEGC) originates from randomized clinical trials (RCTs). Outcomes from a population-based study provides inside into the effect of systemic therapy on HRQoL in daily clinical practice. The aim of this study was to assess QoL of patients with mEGC at baseline, during 1st line, at progression and after disease progression. Methods: Patients diagnosed with mEGC (2014-2020) receiving 1st line systemic therapy registered in the Prospective Observational Cohort study of Oesophageal-gastric cancer Patients (POCOP) were included. QoL was measured with the EORTC QLQ-C30 and -OG25 at baseline, during 1st line therapy, at progression and after disease progression. Results: Of the 263 included patients, 123, questionnaires were available at baseline, 161 during 1st line, 77 at progression and 89 after progression. Results of the mixed effect models showed that global health status and four functioning scales deteriorated after progression as compared to baseline. Largest improvements during 1st line treatment were observed for odynophagia (mean change -17.3), anxiety (-14.9), dysphagia (-11.7) and eating restrictions (-11.1). Trouble with taste deteriorated at all three time points. Conclusions: In accordance to RCTs, QoL outcomes remained relatively stable or improved during 1st line therapy in patients with esophagogastric cancer. Deterioration of functioning scales were mainly observed after progression. [Table: see text]

Effect of adrenergic receptor antagonists on clinical outcomes in metastatic renal cell carcinoma.

e16520 Background: Adrenergic receptors (ADR) have a well-established role in kidney physiology, suggesting a possible role of ADR signaling in renal cell carcinoma (RCC). Preclinical studies have shown a possible anti-tumor effect of both alpha-adrenergic blockers (AB) and beta-adrenergic blockers (BB) on renal cancer cells. However, the literature is conflicting regarding the effect on clinical outcomes. In addition, there is no comprehensive analysis of what role these medications have specifically in RCC patients with metastatic disease. In this single health system retrospective study, we evaluate the effect of AB or BB prescription on cancer-specific outcomes in patients with metastatic RCC. Methods: Clinical data was abstracted from the electronic health record and the institutional cancer registry at The Mount Sinai Health System to include patients with RCC diagnosed with metastatic disease ( de novo or relapsed) between 2016-2020. Follow up data was recorded until a data lock of 4/1/2021. Multivariate Cox regression was used to evaluate the association of AB and BB prescription on overall survival (OS) for the entire cohort and progression free survival (PFS) for patients who received any first line therapy. Multivariate logistic regression was used to evaluate association of these medications with overall response rate (ORR) of first line therapies with available data on initial response. Analyses were controlled for clinical risk factors including age at diagnosis, sex, race, treatment plan including immunotherapy, and medical history of benign prostatic hyperplasia, hypertension, or heart failure. Data was analyzed using R version 4.1.0. Results: 133 patients were identified for inclusion in the study. 61% of cases are de novo metastatic and 39% are relapsed from previously resected disease. 71% are clear cell histology, 3.8 % are papillary, and the rest are unspecified/other. 84 patients (63%) received at least a 1st line systemic therapy. AB or BB prescription alone is not associated with OS, PFS, or ORR. However, prescription of both AB and BB is associated with worse OS (HR 2.94 95% CI 1.13-7.68), worse PFS (HR 7.70 95% CI 1.80-33.0), and decreased odds of responding to 1st line therapy (OR 0.06 95% CI 0.00-0.55) on multivariate analysis. Conclusions: The data suggests that the concurrent use of both an AB and BB in patients with metastatic RCC leads to worse clinical outcomes. What remains unclear is if there is a negative synergistic effect of these medications on RCC pathophysiology or if the prescription of these medications is associated with another negative confounding clinical factor. Since these medications are commonly utilized for cardiovascular disease, multivariate analyses attempted to control for these comorbidities. Future studies may add to this data by cataloging the severity of heart failure and doses of AB and BB medications used in a RCC cohort.

AdvanTIG-203: A randomized phase 2 study comparing anti-TIGIT ociperlimab plus tislelizumab versus tislelizumab plus placebo as second-line treatment in patients with advanced or recurrent esophageal squamous cell carcinoma (ESCC) expressing programmed death-ligand 1 (PD-L1).

TPS370 Background: The programmed death-1 (PD-1)/PD-L1 pathway plays an important role in tumor induced immunosuppression. PD-L1 overexpression is observed in approximately 30–60% of esophageal cancers and is associated with poor prognosis. Anti-PD-1 agents demonstrate moderate efficacy in PD-L1-positive esophageal cancer in terms of response rate and overall survival, however, long-term outcomes remain poor due to primary and secondary resistance driven by tumor immune escape. The T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT) is upregulated on T-cells and natural killer cells in multiple solid tumors, which can inhibit anticancer immune responses. Ociperlimab (BGB-A1217) is a novel, humanized, monoclonal antibody that binds TIGIT with high specificity and affinity, blocking the interaction with its ligands on tumor cells. Preclinical and clinical studies suggest that dual targeting with anti-TIGIT and anti-PD-1 antibodies produces synergistic immune cell activation and enhanced antitumor activity. Methods: AdvanTIG-203 is a Phase 2, global, randomized, double-blind, placebo-controlled study (NCT04732494) of patients with unresectable, locally advanced, recurrent or metastatic ESCC, who progressed on or after 1st line systemic therapy and whose tumors express PD-L1 (visually-estimated combined positive score ≥ 10%). After stratification by Eastern Cooperative Oncology Group performance status (0 or 1), number of metastatic sites (≤ 1 or ≥ 2) and region (Asian or non-Asian), 280 patients will be randomized (1:1) to either ociperlimab 900 mg intravenous (IV) plus tislelizumab 200 mg IV every 3 weeks (Q3W), or tislelizumab plus placebo Q3W, until disease progression (per RECIST v1.1), unacceptable toxicity, death or withdrawal of consent. Co-primary endpoints are investigator-assessed overall response rate (ORR) and overall survival (OS) in the intention-to-treat population. A sample size of 280 patients was estimated to provide approximately 94.8% power to detect a 20% difference in ORR at a one-sided significance level of 0.025. With 198 deaths, the study was estimated to provide approximately 86% power to detect a hazard ratio of 0.65 for OS. Secondary endpoints are ORR by independent review, progression-free survival, duration of response, disease control rate, and clinical benefit rate per investigator and independent assessment, cancer-specific health-related quality of life (HRQoL), and safety. Exploratory endpoints include but are not limited to expression of TIGIT, CD226, CD155, CD112, and PD-L1, pharmacokinetics, immunogenicity, and generic HRQoL measures. Clinical trial information: NCT04732494.

Outcome in patients of hormone receptor (HR) positive (Her 2) negative metastatic breast cancer treated with palbociclib – A real-world experience

Objectives: We present real-world outcome with the use of palbociclib in patients with HR-positive Her2-negative breast cancer treated at single center in India. Material and Methods: We conducted a medical audit of consecutive patients with HR-positive Her2-negative metastatic breast cancer, who were treated with palbociclib at our center between November 2016 and May 2020. Palbociclib was commenced at a dose of 125 mg orally once daily and a schedule of 21 days on therapy followed by 7 days off therapy was followed. Survival analysis included the Kaplan–Meier method using Statistical Package for the Social Sciences software (Version 26). HRs were calculated using Cox proportional hazard regression models and 95% confidence intervals (CIs) for the incidence estimates. Results: A total of 67 female patients were commenced on treatment with palbociclib between November 2016 and May 2020. The median age was 55 years (range 29–78 years). A total of 51 (76%) of these patients were postmenopausal and the remaining 16 were premenopausal. Baseline metastatic disease involved one organ/site in 23 (34%), two organs/sites in 32 (48%), three or more in 12 (18%). Bony metastasis alone was seen in 17 (25%) patients, visceral alone in 30 (45%), and the remaining 20 had both bony and visceral metastases. For these 67 patients, palbociclib was commenced as 1st line systemic therapy in 24 (36%) cases. Amongst the remaining 43 cases, it was 2nd line in 21 (31%); 3rd line and beyond in 22 (33%). Median PFS was 16.1 months (95% CI: 9.6–22.8) and median OS was 20.7 months (95% CI: 14.1–27.3). Median PFS for palbociclib use in first line was 18.7 months (95% CI: 4.6–32.9) while in subsequent lines, it was 13.8 months (95% CI: 9.8–17.9; log-rank P = 0.228). Median OS in patients who received palbociclib in first line was 23.2 months (95 % CI 20.1–26.3) and for those why received it in subsequent lines was 16.3 months (95 % CI: 12.5–20.1; P = 0.069). In total population, best response on imaging was CR in 11 (16%) cases (06 in 1st line setting and 05 in subsequent line setting); PR in 33 (49%); SD in 03; and progressive disease in 20. Median PFS with bone only metastasis: 20.9 months (95 % CI: 5.9–36.0), while with visceral metastasis 16.1 months (95% CI: 9.8–22.5; P = 0.537). Median OS with bone only metastasis: 22.7 months (95% CI: 17.8–27.5), while with visceral metastasis, it was 18.5 months (95% CI: 13.6–23.4; P = 0.314). Conclusion: Palbociclib is a useful addition in the management of HR +ve Her2 –ve breast cancer patients. Its benefit is confirmed in our real-world setting, both in the first and subsequent lines of therapy and the data are on similar lines as the global real-world data on palbociclib effectiveness.

Novel and Promising Systemic Treatment Approaches in Mesothelioma.

There was limited progress in the development of novel systemic approaches in the treatment of advanced malignant mesothelioma for years following the publication of the pivotal phase III trial of Vogelzang et al. that established the cisplatin/pemetrexed regimen as a standard 1st-line systemic therapy. Since then, over the last several years, a significant step forward has been made, with incorporation of immune checkpoint inhibitors and anti-angiogenic agents. In addition, better appreciation of mesothelioma biology has allowed detection of novelmolecular therapeutic targets. All the above-mentioned strategies, along with the additional promising approaches represented by adoptive T cell therapy, dendritic cell therapy, cancer vaccines, oncoviral therapy, and agents targeting mesothelin are discussed in this review. The clinical research to identify effective biologic targets and treatment combinations in malignant mesothelioma is ongoing.

Systemic treatment of patients with inoperable and metastatic Merkel cell carcinoma: A multicenter study.

e21521 Background: Merkel cell carcinoma (MCC) is an uncommon, aggressive neuroendocrine skin cancer. The prognosis in the unresectable and metastatic setting is very poor. Distant metastases develop in more than 30%. Chemotherapy (CHT), the previous mainstay of treatment, is associated with the high response rates (RR) of limited duration. The main cytotoxic drugs have been platinum derivatives, taxoids, anthracyclines, and etoposide. The standard systemic treatment for this disease has changed in the last few years. Immunotherapy (IO) is currently the basis of systemic therapy in the metastatic setting. This study aimed to analyze outcomes for unresectable and metastatic MCC pts treated in routine clinical practice, mostly before the era of IO availability. Methods: We conducted the retrospective analysis of data from 36 MCC pts in unresectable (n= 23) and metastatic (n=13) settings treated in three oncological centers, diagnosed between 01/2010 and 12/2019, with data cut-off on 31/12/2020. The data collected included epidemiological and clinical information. Survival analyses were performed using the Kaplan-Meier method and log-rank test. Results: The median patient age at diagnosis was 72 years (57-88); 58.3% were male. The most common primary tumor (PT) locations were lower limbs (41.7%), head and neck (30.6%), and upper limbs (16.7%). In 63.9% the PT was located in the sun-exposed skin. The most common location of distant metastases were nonregional lymph nodes (n=9) and lungs (n=3). Thirty-six pts received 1st line CHT with the median progression-free survival (mPFS) of 5.3 months (95%CI 2.88-7.7) and objective response of 61.1%, with 13.9% complete responses (CR). The most commonly used regimens were platinum-based and anthracycline-based regimens (n=26). Disease progression (PD) was observed in 91.7% of pts treated with 1st line CHT. Twenty-one pts received 2nd line therapy, IO (n=14), or CHT (n=7), with PD in 19 pts (90.6%), mPFS 2.83 months (95% CI 0.59-5.06) and RR of 33.3% (0% CR). 13 pts were treated with avelumab (AVE), all in the 2nd line, with RR of 38.5% (0% CR). The mPFS in the 2nd line was 5 months (95%CI 0-11.46) on AVE compared to 2.82 (95%CI 0.46-5.19) on CHT (HR 0.65, 95%CI 0.25-1.70, p=0.378). During 1st line systemic therapy, 16 pts underwent palliative surgery (n=7, 19.4%) or received radiation therapy (RT) (n=9, 25%), and during 2nd line, one patient was treated with surgery, and five pts received RT. The median overall survival was 10.38 months (95% CI 2.90-17.87). Local treatment did not improve the treatment outcomes in the 1st (p=0.119) nor 2nd line (p=0.821). Conclusions: Our results confirm the poor prognosis of pts with unresectable and metastatic MCC. The response rates and median PFS for CHT in the 1st and 2nd line setting are consistent with historical data. The treatment with AVE in the 2nd line allows achieving better results, similar to the results reported in the clinical trials.