12-month Overall Survival Research Articles

Retrospective analysis of digital biomarker predictability of immune checkpoint inhibitor therapy outcomes in patients with NSCLC.

e14713 Background: Immune checkpoint inhibitor (ICI) therapy (pembrolizumab monotherapy and pembrolizumab combined with platinum-based chemotherapy) is recommended as first line for patients with PD-L1 positive advanced or metastatic non-small cell lung cancer (NSCLC) without actionable biomarkers due to incredible improvements in overall survival (OS). Despite this, 15-20% of patients do not respond to ICI therapy in NSCLC. This study examines the effect of body composition features, via analytic morphomics, in conjunction with current clinical and laboratory data to predict ICI response. Methods: This retrospective analysis included 35 patients from the University of Michigan (UM) with newly diagnosed advanced or metastatic NSCLC (adenocarcinoma) receiving single-agent pembrolizumab or in combination with chemotherapy between January 2018 – December 2020. Clinical/ laboratory data included patient gender, age, BMI, neutrophil to lymphocyte ratio (NLR), PDL1 %, and albumin. Analytic Morphomics was performed using proprietary, semi-automated high-throughput CT image processing (mBIOHEALTH, Inc.). Multivariable Cox regression analysis identified clinical and morphomic characteristics predictive of OS at 6 months. Risk models were developed on the UM cohort and tested on an external validation dataset of 24 adenocarcinoma patients from Emory Healthcare who received similar treatment between January 2018 to December 2021. Results: Among the evaluable patients at both sites, 15 (43%) at UM and 19 (79%) at Emory were female, mean age was 66 years at UM and 70 years at Emory, and 6-month OS (95% CI) was 89% (80%, 100%) at UM and 71% (55%, 92%) at Emory. Five regression models with risk scores were assessed with the UM data and then tested with the Emory dataset. Of the five models, 2 matched in their predictability of 6-month OS at both sites. The first, a model of clinical and laboratory features only (age, BMI, PDL1 > = 50%, NLR, and albumin) which had an AUC of 0.79 at UM and 0.66 at Emory. The other utilized an L3 skeletal muscle z-score threshold ( < = -1) alone (previously studied as a measurement of sarcopenia) with an AUC of 0.741 at UM and 0.57 at Emory. Conclusions: Our analysis indicates that the measurement of muscle z-score prior to initiating treatment with ICIs in patients with NSCLC could serve as an indicator for those patients who are unlikely to benefit from therapy. This may be especially important for ICI therapy as skeletal muscle effects the immune function through myokines. Sarcopenia has been associated with immune senescence and thus may play a significant role in decreasing response to ICI therapy. More analysis is warranted with a larger patient population.

Results of a retrospective multicenter study comparing the effectiveness of regorafenib and the rechallenge of chemotherapy in patients (pts) with metastatic colorectal cancer (mCRC).

e15561 Background: Regorafenib is considered the standard third-line therapy of mCRC. However, the modest efficacy and significant toxicity of regorafenib urges the search for new therapeutic approaches. In various countries, the re-challenge of the previously effective treatment regimens is being considered. We compared the effectiveness of various variants of systemic therapy in the third and subsequent lines of the treatment. Methods: We analyzed the prospective database of pts with mCRC from two clinics of the Russian Federation. The statistical hypothesis implied the equivalence of the 6-month overall survival on the repeated chemotherapy (CT) and targeted therapy with the third line regorafenib therapy, provided the equivalence boundaries from 0.8 to 1.25. With α = 0.05, the study power is 80% with 178 patients, 89 people in each group. We conducted statistical analysis with the SPSS statistical software package (v. 20, IBM). Results: In the database, we identified 215 patients with morphologically confirmed metastatic colon cancer who received two or more lines of antitumor drug therapy from 2010 to 2021. Of them, we selected 132 patients with a history of regorafenib therapy, and 83 patients with the re-challenge of CT as the third line of the therapy. Overall survival (OS) in the re-challenge and regorafenib groups did not differ (hazard ratio [HR] 1.01 with 95%CI 0.7-1.45; p = 0.9) and the 6-month OS was 74 and 70%, respectively. Progression-free survival was significantly higher in the re-challenge group (HR 1.94 with 95%CI 1.3-2.7; p < 0.001); In the multifactorial analysis, the re-challenge of previous treatment regimens kept its independent positive effect on progression-free survival (HR 1.9 with 95%CI 1.3-2.8; p = 0.0001) also as index T < 3 (HR 0.7, 95CI 0.55-0,94); ECOG ≥1 a (HR 1.5 with 95%CI 1.16-2.05; p < 0.01) affected PFS negatively. The reduction of the regorafenib dose did not affect PFS (HR 0.9 with 95% CI from 0.9 to 1.0; p = 0.1), its starting dose (HR 0.9 with 95 CI from 0.9 to 1.0; p = 0.2), and a break in the regorafenib treatment (HR 0.9 with 95% CI from 0.5 to 1.8; p = 0.9). Conclusions: Regorafenib and the re-challenge of previously effective CT in the third-line of mCRP therapy show the similar 6-mon. OS. However, progression-free survival is significantly higher in the re-challenge group in third line therapy.

Real-world efficacy and safety of donafenib-based therapies in patients with unresectable hepatocellular carcinoma: A retrospective study.

e16169 Background: According to the results of phase III ZGDH3 study, donafenib has significantly improved overall survival (OS) versus sorafenib in first-line treatment for patients with unresectable hepatocellular carcinoma (uHCC). The present study aimed to evaluate the efficacy and safety of donafenib-based therapies in patients with uHCC regardless of first- or later-line systemic therapy. Methods: This single-center retrospective study involved 30 patients with histopathologically/cytologically or clinically confirmed uHCC at Sun Yat-sen Memorial Hospital, Sun Yat-sen University between August 2021 and February 2022. Eligible patients underwent donafenib-based therapies until disease progression, death, or unacceptable toxicity. The primary endpoint was progression-free survival (PFS) per the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Secondary endpoints included OS, objective response rate (ORR), disease control rate (DCR), and safety. Tumor response was determined according to the RECIST v1.1 and modified (m)RECIST. Results: Of these eligible 30 patients, the median age was 55 years (range, 27–73), 93% were male, 93% with HBV and 63% were BCLC C. Donafenib was commonly used as a monotherapy (17%) or in combination with immune checkpoint inhibitors (ICIs), transarterial therapy, both, or other treatments. Twenty (67%) patients underwent donafenib-based therapies as a first-line treatment, of which 15 (75%) underwent a triple combination of donafenib, ICIs, and transarterial therapy. By the cutoff date of January 2023, the median PFS and OS were not yet reached; the 6-month PFS and OS rates were 70.0% and 90.0%, respectively, and the 12-month PFS and OS rates were 66.5% and 86.5%, respectively. The ORR and DCR for all patients were 43.3% and 73.3%, respectively, based on both RECIST v1.1 (CR 4 [13.3%], PR 9 [30.0%], SD 9 [30.0%]) and mRECIST (CR 5 [16.7%], PR 8 [26.7%], SD 9 [30.0%]). Among the 20 patients who underwent donafenib-based first-line systemic therapy, the ORRs according to RECIST v1.1 and mRECIST were both 55.0%, and higher ORRs (73.3% per RECIST v1.1 and mRECIST) were observed in 15 patients who underwent donafenib, ICIs, and transarterial therapy. Overall, 15 (50.0%) patients had more than one treatment-related adverse event (TRAEs) and the most common AEs were hand-foot skin reaction (26.7%), rash (10.0%), and gingival bleeding (10.0%). Grade 3 AEs occurred in 16.7% of patients. No TRAE led to death in the study. Conclusions: This study indicated that donafenib-based therapies, particularly donafenib in combination with ICIs plus transarterial therapy, show promising antitumor activity in patients with uHCC, and no new safety signals were observed in real-world settings. Clinical trial information: ChiCTR2200063822 .

OniLon: Phase II trial of trifluridine/tipiracil (TAS-102) and nanoliposomal irinotecan (nal-IRI) in advanced colorectal cancer.

3580 Background: TAS-102 (FTD/TPI) is a combination of a nucleoside analogue and a thymidine phosphorylase inhibitor, and has showed activity in 5FU-resistant CRC. Nal-IRI achieves higher intra-tumor concentrations than irinotecan (Iri; 142-fold) and its major metabolite, SN-38 (9-fold). This resulted in superior anti-tumor activity compared to free Iri in multiple tumor xenografts. Furthermore, multiple clinical trials have established the activity of nal-IRI in combination with 5FU in pancreaticobiliary cancers. The combination of nal-IRI with the more potent nucleoside analogue TAS-102 may thus result in a more effective systemic therapy. We conducted this study to define the safety and efficacy of the combination of TAS-102 and nal-IRI in advanced CRC. Methods: Eligible patients (pts) on this investigator-initiated phase II study had advanced CRC and must have had disease progression on at least one prior therapy. Additional inclusion criteria - measurable disease, ECOG PS 0-1 & adequate organ function. Based on previously published dose escalation phase I data, the pts were treated at the recommended phase II dose of TAS-102 (given orally at 35mg/m2 bid on days 1-5) and nal-IRI (60mg/m2 IV on day 1) in 14-day cycles. The primary endpoint was objective response rate (ORR) = complete (CR) + partial (PR) response per RECIST v1.1. Multiple secondary endpoints included safety/tolerability, progression-free survival (PFS), overall survival (OS), disease control rate (DCR) and duration of response (DoR). Results: Twenty-two pts were enrolled, of whom 20 were evaluable for response. Male - 50%; ECOG PS 1 – 75%; African Americans – 38%; median age - 58yrs (interquartile range [IQR] 49-67). Median line of prior therapy was 1 (IQR 1-2) and 13.6% (3 pts enrolled during the dose escalation phase) had received prior Iri. 47.6% received concurrent Bevacizumab. ORR was 15% (3 PR, 0 CR). 60% had stable disease (SD) as best response; DCR of 75%. mPFS - 9.7 mos (95% CI: 5.6, 14.2); mOS - 10.1 mos (95% CI: 7.3, 15.9). 12-month PFS and OS rates were 34.6% and 39.5% respectively. At a median follow up of 11.9 mos, DoR was yet to be determined and 50% of the pts had maintained response for 12 mos. Median duration of progression free among pts with SD was 7.6 mos (95% CI: 4.6, 13.2), with a 12-month survival rate of 47.7% (95% CI: 15.5%, 74.5%). Median time to response (TTR) was 4.8mos. Most common treatment related toxicities included fatigue and neutropenia (G3; 27.3% each); anemia and leucopenia (G3; 18.2% each). Other G3 AEs included febrile neutropenia, diarrhea, hypokalemia, lymphopenia and nausea (4.5% each). Conclusions: We demonstrated that the combination of TAS-102 and nal-IRI had an acceptable safety profile, and showed antitumor activity in patients with advanced CRC. Additional biomarker analyses such as survival correlation with UGT1A1 phenotype and RAS mutational status are ongoing. (NCT03368963). Clinical trial information: NCT03368963 .

Donafenib combined with anti-PD-1 antibodies plus transarterial therapy for initially unresectable hepatocellular carcinoma.

e16135 Background: Given its clear efficacy and high safety demonstrated in the phase 3 ZGDH3 study, donafenib has been recommended by the Chinese guidelines for the first-line treatment of unresectable hepatocellular carcinoma (uHCC). Recently, combination therapies have shown favorable results. However, triple therapy with donafenib, anti-PD-1 antibodies, and transarterial therapy has not yet been investigated. Thus, we aimed to investigate the efficacy and safety of triple therapy with donafenib, anti-PD-1 antibodies, and transarterial therapy in patients with uHCC. Methods: A single-center, retrospective study was performed based on the medical records of consecutive patients diagnosed with HCC who were not suitable for curative surgery or local ablation at Zhujiang Hospital of Southern Medical University from June 2021 to October 2022. Patients with ≥18 years, Child-Pugh score ≤7, ECOG PS ≤1, no prior systemic therapy, having at least one measurable lesion (per mRECIST) were enrolled. Patients were treated with donafenib 200 mg orally twice daily, anti-PD-1 antibodies intravenously every three weeks, and transarterial therapy until disease progression or unacceptable toxicity. Endpoints include objective response rate (ORR, the proportion of patients with partial or complete response according to mRECIST and RECIST v1.1), surgical conversion rate (the proportion of patients who successfully underwent resection), progression-free survival (PFS), overall survival (OS), disease control rate (DCR), and safety. Results: A total of 27 patients were enrolled (median age 52 years [range, 29–74], 81% males, 85% with HBV infection, 41% with cirrhosis, 48% with AFP level ≥400 ng/mL, and 67% in BCLC C). All patients received donafenib and anti-PD-1 antibodies with hepatic arterial infusion chemotherapy (HAIC, n = 10), transarterial chemoembolization (TACE, n = 8), or both (n = 9). By the cutoff date of January 6, 2023, the median follow-up duration was 6.8 months (95% confidence interval [CI], 5.9–7.7), and 17 (63.0%) patients were still undergoing treatment. The ORR and DCR were 59.3% and 92.6% by mRECIST, and 18.5% and 88.9% by RECIST v1.1, respectively. The surgical conversion rate was 22.2%, and the median surgical conversion time was 3.4 months (range, 2.2–4.6). The median PFS was 8.3 months (95% CI, 6.8–9.8), and median OS was not reached. The 6-month PFS rate and 12-month OS rate were 74.7% and 72.9%, respectively. Grade 3 treatment-related adverse events (TRAEs) were observed in 5 patients (18.5%), the most common of which was increased total bilirubin (11.1%). No grade 4/5 TRAEs occurred. Conclusions: Donafenib combined with anti-PD-1 antibodies plus transarterial therapy shows promising efficacy and manageable toxicity in patients with initially uHCC. Clinical trial information: NCT05638438 .

Introducing yttrium-90 radioembolization to atezolizumab and bevacizumab regimen for intermediate and advanced stage hepatocellular carcinoma: A preliminary report of safety and effectiveness.

e16231 Background: The IMbrave150 Phase III trial demonstrated superiority of atezolizumab and bevacizumab (Atezo/Bev) over sorafenib in unresectable hepatocellular carcinoma (HCC). Combined radiotherapy and immune checkpoint inhibitors have been shown to induce synergistic effects in treatment of HCC and other solid tumors. Barcelona Clinic Liver Cancer 2022 updated guidelines recommend consideration of transarterial radioembolization (TARE) for early stage and very early stage HCC. The present study sims to evaluate the safety and effectiveness of combining TARE and the Atezo/Bev regimen for intermediate and advanced stage HCC. Methods: Retrospective review at a single institution was performed between May 2021 and December 2022. Patients who received TARE using yttrium-90 (Y90) with concomitant or sequential Atezo/Bev systemic treatment were included. The following outcomes were retrieved: overall survival (OS), radiologic tumor response, progression-free survival, technical adverse events related to TARE, and toxicity based on the National Cancer Institute–Common Terminology Criteria for Adverse Events version 5.0. Results: Ten consecutive patients (9 male, 1 female) with unresectable HCC received TARE and Atezo/Bev were included. A total 21 of doses of Y90 were administered with a median target dose of 156 Gy. Tumor control was achieved in all target lesions (100%) based on modified Response Evaluation Criteria in Solid Tumors criteria. Overall disease progression occurred in 4 patients after TARE with a 6- month PFS of 80% (95%CI: 40.9-95.6%) and 12-month PFS of 53.3% (17.3%-79.8%). Two patients died during follow-up, with 6-month and 12-month OS rates of 88.9% (95%CI: 43.3-98.4%) and 76.2% (95%CI: 33.2-93.5%), respectively. One patient developed grade 3 transaminitis and hypoglobulinemia. Atezo/Bev was switched to Lenvatinib in one patient due to myositis. Bevacizumab was held in one patient due to suspected transient ischemic attack. Conclusions: This small patient cohort demonstrated preliminary safety and effectiveness of TARE in combination with Atezo/Bev in treating intermediate and advanced stage HCC. Further prospective and comparative studies with large sample sizes are warranted.

OUTCOMES OF THE TREATMENT AFTER ANTI‐CD19 CAR‐T THERAPY FAILURE IN PATIENTS WITH AGGRESSIVE B‐CELL LYMPHOMA—ANALYSIS OF DATA FROM THE CZECH REPUBLIC

Introduction: In patients with aggressive B-cell lymphomas (BCL), the long-term progression-free survival (PFS) after anti-CD19 CAR-T therapy is around 30-40%. The prognosis of patients with progression/relapse after this therapy is poor. There are currently limited data on treatment approaches to improve the prognosis of this group of patients (p) and optimal management is not yet defined. Based on the published data, it seems that some of the new drugs being tested in clinical trials (polatuzumab vedotin, bispecific antibodies, lenalidomide, tafasitamab, selinexor, loncastuximab tesirine) could be used as a "bridge" to allogeneic transplantation, which remains a potentially curative treatment option for some of these patients. Methods: We analyzed patients with aggressive BCL (diffuse large B-cell lymphoma /DLBCL/ – 64p, transformed DLBCL – 19p, high-grade BCL – 12p and primary mediastinal large BCL – 11p) who were treated with anti-CD19 CAR-T cells (tisagenlecleucel 79p and axicabtagene ciloleucel 27p) between Dec 2019 and Dec 2022. This is a multicentre retrospective analysis from 5 university hematological centres, where the patients were referred for CAR-T therapy after ≥ 2 lines of treatment failure from the Czech Republic and Slovakia. We focused on the group of patients who did not respond to this treatment. Results: 106p were treated with anti-CD19 CAR-T therapy. The median follow-up (FU) was 16.4 months. The median PFS and overall survival (OS) were 4.3 and 26.4 months. The overall response rate (ORR) was observed in 63p (60%) with 52% complete response (CR). We further analyzed subsequent therapy in a subgroup of 60p who did not respond to CAR-T treatment (progression in 37p/stable disease in 6p) or had relapse (9p) or progression (8p) after initial response (CR/partial remission). The median FU for failed patients was 9.5 months. Overall, 42p in our cohort received therapy; 18p rapidly progressed and were not treated. 4p were treated with radiotherapy (2p achieved CR) and 38p with systemic therapy (glucocorticoids – 6p, lenalidomide+-rituximab – 6p, chemotherapy+-rituximab – 16p, polatuzumab+bendamustine and rituximab – 6p, CAR-T reinfusion – 2p, other 2p). The ORR after systemic therapy was observed in 17% of patients. Patients who were not treated had more likely massive involvement > 5cm at the time of apheresis (p = 0.02). Of the 60p with CAR-T treatment failure, 39p (65%) died. Median OS for CAR-T therapy failed patients (n=60) was 3.1 months from diagnosis of progression/relapse after CAR-T treatment (6-month and 1-year OS 34.9% and 26%). The median OS were 4.7 for treated and 0.2 months for untreated patients from diagnosis of progression/relapse after CAR-T. The research was funded by: This work was supported by grant AZV NU21-03-00411 from the Ministry of Health of the Czech Republic, by the Cooperatio Program, research area "Oncology and Haematology and by MH CZ – DRO (UHHK, 00179906) Keywords: Aggressive B-cell non-Hodgkin lymphoma, Cellular therapies Conflicts of interests pertinent to the abstract A. Sýkorová Consultant or advisory role GILEAD, NOVARTIS K. Polgárová Consultant or advisory role GILEAD SCIENCES, NOVARTIS Honoraria: NOVARTIS GILEAD SCIENCES Educational grants: GILEAD SCIENCES F. Folber Consultant or advisory role NOVARTIS, GILEAD SCIENCES K. Steinerová Educational grants: GILEAD SCIENCES D. Belada Honoraria: GILEAD SCIENCES, NOVARTIS Educational grants: GILEAD SCIENCES M. Trněný Consultant or advisory role GILEAD SCIENCES, NOVARTIS Honoraria: GILEAD SCIENCES, NOVARTIS Educational grants: GILEAD SCIENCES R. Pytlík Consultant or advisory role GILEAD SCIENCES, NOVARTIS Educational grants: GILEAD SCIENCES, NOVARTIS

17th International Conference on Malignant Lymphoma, Palazzo dei Congressi, Lugano, Switzerland, 13 - 17 June, 2023.

Introduction: Enteropathy associated T-cell lymphoma (EATL) is a rare peripheral T-cell lymphoma (PTCL) associated with celiac disease that has a poor prognosis. Treatment of EATL is challenging due to the lack of clinical trials. In PTCL, the preferred chemotherapeutic regimen is cyclophosphamide, doxorubicine, vincristine and prednisone (CHOP), either with or without etoposide (CHOEP) followed by consolidative autologous stem cell transplantation (ASCT). This nationwide Dutch study describes the incidence, treatment and outcome of all reported EATL cases. Methods: All patients diagnosed with EATL between 1989 and 2020 were identified in the Netherlands Cancer Registry with survival follow-up through February 1, 2022, thereby excluding post-mortem diagnoses. Baseline characteristics, treatment modality and survival outcomes were collected. Patients were categorized into three periods (1989–1999, 2000–2010, 2011–2020) and in limited (I/II) or advanced (III/IV) stage disease. For patients diagnosed as of 2014, detailed information on treatment regimens was available. Overall survival (OS) was defined as the time from diagnosis to all-cause-death. Multivariable analysis of OS was performed using Cox regression. Results: We included 338 patients (median age 67 years [range 37–90 years], 57% male) in our study. Limited stage disease was more common than advanced stage (51% versus 38%, 11% undetermined). Treatment consisted of surgery (18%), chemotherapy (CT; 33%), CT followed by ASCT (3%), surgery and CT (19%), surgery and CT followed by ASCT (3%), surgery and RT (1%) or no treatment (23%). Between 2014 and 2020, the most commonly used CT regimens were CHOP (54% in limited stage and 66% in advanced stage disease) and CHOEP (32% in all stages). Over time, the use of CT increased from 22% to 46%, whereas resection only and resection combined with CT became uncommon (decrease from 33% to 7%, and 23% to 5% respectively; Figure 1). Two-year OS improved from 19% in 1989–1999 to 26% in 2011–2020. The 6-month, 2-year and 5-year OS for limited stage were 51%, 24% and 15% (median OS 6.3 months) and for advanced stage 44%, 16% and 7% (median OS 5.1 months), respectively (Figure 2). In multivariable analysis, surgery only (hazard ratio [HR] 1.97; 95% confidence interval [CI] 1.41–2.74), no therapy (HR 3.66; 95% CI: 1.72–3.76) and advanced stage disease (HR 1.31; 95% CI: 1.02–1.70) were independent predictors of poor prognosis, whereas ASCT (HR 0.38; 95% CI: 0.17–0.81) was associated with improved OS. Keyword: aggressive T-cell non-Hodgkin lymphoma No conflicts of interests pertinent to the abstract.

Outcomes by complete response to first-line pembrolizumab or platinum-based chemotherapy in advanced urothelial carcinoma (UC) in KEYNOTE-361.

4513 Background: In the randomized, open-label, phase 3 KEYNOTE-361 (NCT02853305) study, superior efficacy was not demonstrated with first-line pembrolizumab ± chemotherapy versus chemotherapy in patients with advanced UC. Although not formally tested, survival outcomes appeared similar with pembrolizumab monotherapy versus chemotherapy (hazard ratio [HR] 0.92; 95% CI, 0.77-1.11). This post hoc exploratory analysis examined efficacy outcomes in patients with complete response (CR) to pembrolizumab or chemotherapy in KEYNOTE-361. Methods: Patients with advanced UC were randomly assigned 1:1:1 to receive first-line pembrolizumab (200 mg IV every 3 weeks for up to 2 years) ± chemotherapy (1000 mg/m2 gemcitabine on day 1 and day 8 + cisplatin [70 mg/m2] or carboplatin [area under the concentration curve of 5 mg/ml/min] on day 1 of each 3-week cycle) or chemotherapy alone. Patients were stratified by PD-L1 combined positive score (≥10 vs <10) and investigator’s choice of platinum (cisplatin vs carboplatin). End points of this post hoc exploratory analysis were duration of response (DOR) and progression-free survival (PFS) by RECIST v1.1 by blinded independent central review and overall survival (OS) in patients who achieved a CR in the pembrolizumab monotherapy or chemotherapy arms. Results: Overall, 34 of 307 patients (11.1%) in the pembrolizumab arm and 43 of 352 patients (12.2%) in the chemotherapy arm had a CR. Median follow-up (time from randomization to the data cutoff date) for patients with CR was 30.7 months (range, 22.6-42.3). Median DOR was not reached (NR; range, 4.4+ to 36.1+ months) in the pembrolizumab arm and 12.8 months (range, 2.1+ to 36.3+) in the chemotherapy arm; 75.5% and 37.1% of patients, respectively, remained in CR for ≥24 months. Median PFS was NR (95% CI, 30.3-NR) with pembrolizumab and 15.1 months (95% CI, 8.8-NR) with chemotherapy (HR, 0.32 [95% CI, 0.15-0.70]). The estimated 24-month PFS rates were 75.5% and 42.2% in the pembrolizumab and chemotherapy arms, respectively. Median OS was NR (95% CI, NR-NR) with pembrolizumab and NR (95% CI, 25.1-NR) with chemotherapy (HR, 0.20 [95% CI, 0.06-0.70]). The estimated 24-month OS rates were 94.1% and 69.5% in the pembrolizumab and chemotherapy arms, respectively. Overall, 9 patients (26.5%) in the pembrolizumab arm and 21 patients (48.8%) in the chemotherapy arm experienced disease progression after an initial CR. Among patients who achieved CR, 2 patients (5.9%) in the pembrolizumab arm and 22 patients (51.2%) in the chemotherapy arm received subsequent therapy. Conclusions: This post hoc exploratory analysis suggests CRs with pembrolizumab were more durable than CRs with chemotherapy in patients with advanced UC, with corresponding longer PFS and OS. Further investigation into patient selection is needed to determine which patients could benefit most from first-line pembrolizumab. Clinical trial information: NCT02853305 .

Long-term survival outcomes and immune checkpoint inhibitor (ICI) retreatment in patients with advanced cervical cancer who received camrelizumab plus apatinib in the CLAP study.

e17513 Background: Camrelizumab (a programmed death 1 [PD-1] inhibitor) plus apatinib (a vascular endothelial growth factor receptor 2 [VEGFR2] inhibitor) showed promising efficacy and safety profiles in patient with advanced cervical cancer in the CLAP study (NCT03816553). Herein we present updated efficacy and safety data with more than 24 months of additional follow-up, and outcomes for patients retreated with ICIs following disease progression. Methods: In this single-arm phase 2 trial, 45 patients received camrelizumab (200 mg intravenously, q2w) and apatinib (250 mg orally, qd) on a 4-week cycle until disease progression, unacceptable toxicity, withdrawal of consent, or up to 2 years. For patients who completed 2 years treatment and were considered to benefit from continuing treatment, a one-year extension treatment would be provided if the patients agreed. Results: At the data cutoff (August 31, 2022), the median duration of follow-up was 11.9 (range, 1.0–43.9) months. Nine (20.0%) patients completed 2-year treatment (eight entered the one-year extension treatment, of which five completed and three discontinued due to disease progression) and 36 (80.0%) discontinued treatment (24 [53.3%] disease progression, 4 [8.9%] adverse events, 5 [11.1%] patient refusal, and 3 [6.7%] withdrawal of consent). The median duration of treatment was 6 (range, 0.9–37.4) months. The confirmed objective response rate was 55.6% (95% CI: 40.0, 70.4) that was unchanged from previous report, including two (4.4%) complete response (CR) and 23 (51.1%) partial response (PR). The median duration of response was 16.6 (95% CI, 5.6–29.9) months among 25 responders. Median progression-free survival (PFS) was 8.9 (95% CI, 5.6–18.1) months; the 12-month PFS rate was 40.7% (95% CI, 25.2–55.6). The median overall survival (OS) was 15.9 (95% CI, 9.3–36.9) months; the 24-month OS rate was 46.4% (95% CI, 30.1–61.1). Age > 50, programmed death-ligand 1 (PD-L1) combined positive score (CPS) ≥ 1, CPS ≥ 10, TMB-high, and PIK3CA mutation were associated with longer OS. Seven patients were retreated with the same or other ICIs after disease progression. All of them showed initial response (one CR and 6 PR) to study treatment, then had progressive disease (PD) and discontinued treatment. Of the seven patients, six achieved stable disease and one had PD following ICIs retreatment. Four patients died and three were alive at the data cutoff. Two patients received ICIs retreatment for more than 20 months, one of which was still on ICIs retreatment. No new safety signals were identified with additional 24-month follow-up. Conclusions: This long-term follow-up data demonstrate sustained and durable efficacy of camrelizumab plus apatinib, with no new safety signals, in patients with advanced cervical cancer who progressed after prior platinum-based chemotherapy. Clinical trial information: NCT03816553 .

The SPEARHEAD-1 trial of afamitresgene autoleucel (afami-cel [formerly ADP-A2M4]): Analysis of overall survival in advanced synovial sarcoma.

11563 Background: Afami-cel is an autologous, T-cell receptor (TCR) T-cell therapy to treat human leukocyte antigen (HLA) A*02–eligible patients (pts) with advanced solid tumors positive for the cancer testis antigen melanoma-associated antigen A4 (MAGE-A4). The efficacy and safety of afami-cel in pretreated pts with advanced/metastatic synovial sarcoma or myxoid/round cell liposarcoma are being evaluated in the Phase 2, two-cohort, open-label, SPEARHEAD-1 (NCT04044768) trial. Here we report interim overall survival (OS) data in the pts with advanced synovial sarcoma in Cohort 1. Methods: Pts who were HLA-A*02 positive with advanced synovial sarcoma (with evidence of clinical/radiological progression) positive for MAGE-A4 received afami-cel after lymphodepleting chemotherapy containing fludarabine and cyclophosphamide. The primary endpoint was overall response rate per RECIST v1.1 by independent review. Secondary endpoints included OS and progression-free survival (PFS), estimated utilizing the Kaplan-Meier method. Results: As of August 29, 2022, 44 pts with synovial sarcoma received afami-cel (2.68–9.99×109 transduced T-cells) in Cohort 1. The median age was 41 years (range: 19–73 years), 50% of pts were female, 89% of pts were white, 96% of pts were typed as HLA-A*02:01P, and median tumor MAGE-A4 expression H-score was 257 (132–300). Pts were heavily pre-treated with a median of 3 prior lines of therapy (range: 1–12). The median follow-up time at the data cut-off was 20.8 months. Median PFS was 3.8 months (95% CI: 2.8, 5.8) and 4.1 months (95% CI: 2.8, 6.9) by independent and investigator review, respectively. Median OS by independent review was 15.4 months (95% CI: 10.9, not estimable) with 52% of pts censored at the data cut-off. The 12-month OS probability was 60% and 24-month OS probability was 40%. Twenty-one pts received additional therapy during long term follow up (systemic therapy, n = 20; radiation, n = 6; other, n = 4). In the 17 pts who had a RECIST response by independent review, the median OS was not reached, the 12-month OS probability was 90%, and 24-month OS probability was 60%. Conclusions: Pts with advanced synovial sarcoma treated with afami-cel in SPEARHEAD-1 had encouraging survival, especially those pts with a RECIST response. Clinical trial information: NCT04044768 .

Randomized phase 2 study of nab-paclitaxel and gemcitabine with or without tocilizumab as first-line treatment in patients with advanced pancreatic cancer (PACTO).

4147 Background: Pancreatic cancer (PC) presents one of the most aggressive malignancies for which currently available treatments are modestly effective. We report the findings of a randomized phase 2 trial (NCT02767557) to test the efficacy of gemcitabine/nab-paclitaxel (gem/nab) with or without tocilizumab (toc), as first-line treatment in patients with locally advanced or metastatic PC. Methods: Prior to randomization, a safety cohort of 6 participants received gem 1000 mg/m2, nab 125 mg/m2 (days 1, 8, and 15 of each 28-day cycle) and toc 8 mg/kg (day 1 of each cycle). Participants were then randomized 1:1 to receive gem/nab or gem/nab/toc. Patients had modified Glasgow Prognostic Score of 1 or 2 and were stratified by performance status (PS) and stage. The primary endpoint was the overall survival (OS) rate at 6 months (OS6). Secondary end points included median progression-free survival (PFS), median OS, overall response rate (ORR), and safety. Results: A total of 147 patients were treated; 141 were randomized to receive gem/nab/toc (n = 70), or gem/nab (n = 71). As of January 9, 2023, the median follow-up was 8.1 months (IQR 4.2–13.9). OS6 was 68.6 % (95% CI, 56.3-78.1) in gem/nab/toc group and 62.0% (95% CI, 49.6-72.1) in gem/nab group (p = 0.41). No significant differences in the median OS or PFS were observed between the gem/nab/toc group and the gem/nab group (OS, 8.4 versus 8.0 months; HR, 0.75; 95% CI, 0.54-1.05; p = 0.10), and (PFS, 5.6 versus 5.5 months; HR, 0.85; 95% CI, 0.61-1.20; p = 0.36). The 12, 18 and 24-month OS rates were 37.1% (95% CI, 26.0%-48.3%), 27.1% (17.4%-37.8%), 10% (4.4%-18.3%) for gem/nab/toc and 28.2% (18.3%-38.9%), 7.0% (2.6%-14.5%), 2.8% (0.5%-8.8%) for gem/nab, respectively. The ORR was 37.1% (95% CI, 25.9%-49.5%) in gem/nab/toc group and 35.2% (24.2%-47.5%) in gem/nab group. The incidence of grade 3 or higher treatment related adverse events was 88.2% in gem/nab/toc and 63.4% in gem/nab group (p < 0.001). Of those, neutropenia (55.3% versus 16.9%), and thrombocytopenia (40.8% versus 11.3%) were most common. Two and one treatment-related deaths, respectively, in gem/nab/toc and gem/nab group, occurred during the study. Conclusions: In patients with advanced PC, the addition of tocilizumab to gem/nab did not result in improved OS rate at 6 months. Although more patients were alive at 18 months in the gem/nab/toc, long-term survival rates exceeding 24 months were not different between groups. The biomarkers for selection of patients who might benefit from gem/nab combined with tocilizumab are to be identified. Clinical trial information: NCT02767557 .

Avelumab as second-line or later (2L+) treatment in patients (pts) with metastatic Merkel cell carcinoma (mMCC): Analysis of real-world outcomes in France using the CARADERM registry and the French national healthcare database.

9537 Background: Avelumab, an anti–PD-L1 antibody, has been approved in multiple countries for the treatment of mMCC based on the results of the pivotal phase 2 JAVELIN Merkel 200 trial (NCT02155647). In pts who received avelumab as 2L+ treatment in the trial (part A), median overall survival (OS) was 12.6 months and median progression-free survival (PFS) was 2.7 months. The French health technology assessment agency requested the collection of real-world data from pts with mMCC from a comprehensive registry; data are reported here. Methods: This retrospective, noninterventional, real-world study evaluated all pts with mMCC in France using combined data from 2 databases: CARADERM (French national database of rare dermatological cancers) and Système National des Données de Santé (SNDS; national healthcare database). For this analysis, eligible pts were diagnosed with mMCC and initiated 2L+ avelumab outside of a clinical trial between August 2016 and December 2019. Pts were followed for 24 months after initiation of avelumab. Probabilistic linkage was performed to identify pts registered in both databases. OS and PFS were analyzed using Kaplan-Meier methodology. Safety data were not collected. Results: A total of 180 pts who received 2L+ avelumab were identified, data were obtained for 112 pts from the CARADERM database and for 68 additional pts after SNDS linkage. Median age at diagnosis was 74.0 years, 66.7% were male, and 98.3% received chemotherapy as first-line treatment. Median follow-up was 13.1 months. 79.5% of CARADERM database pts had discontinued avelumab; the most common reasons specified were progressive disease (36.4%), complete response (17.0%), and death (13.6%). Median OS was 14.6 months (95% CI, 9.9-21.3 months) overall; in CARADERM database pts, median OS was 15.9 months (95% CI, 8.6-28.3 months) vs 13.3 months (95% CI, 6.7-19.1 months) in non-CARADERM database pts. 12- and 24-month OS rates in the overall population were 53.8% (95% CI, 46.2%-60.8%) and 40.5% (95% CI, 33.2%-47.6%), respectively. In CARADERM database pts (data not available in non-CARADERM database pts), median PFS was 3.6 months (95% CI, 2.7-7.5 months), and the objective response rate was 55.3% (95% CI, 45.3%-65.4%), including complete response in 31.9%. Median duration of response was 39.3 months (95% CI, 24.3 months-not estimable). Conclusions: In this real-world study of national data from France, outcomes with avelumab as 2L+ treatment for mMCC were similar to those observed in part A of the JAVELIN Merkel 200 trial. These findings confirm the effectiveness of avelumab in pts with mMCC that have progressed following first-line systemic treatment in routine clinical practice.

Durvalumab outcomes for patients with PD-L1 positive and negative stage III unresectable non-small cell lung cancer treated at veterans health administration facilities.

e18793 Background: Clinical trials and real-world studies have documented the benefit of durvalumab consolidation therapy in patients with stage III unresectable non-small cell lung cancer (UR-NSCLC) following chemoradiotherapy (CRT). Methods: Patients with stage III UR-NSCLC on durvalumab following CRT, at any Veterans Health Administration (VHA) facility from 1/1/17 to 6/30/20, were included. Patients were followed from their durvalumab initiation date through the earliest of their last VHA visit, loss to follow up, death, or end of study. Electronic health record and chart review data were retrospectively collected to determine baseline characteristics, number of durvalumab doses, length of follow-up, and overall survival (OS). Chi-square and Wilcoxon rank sum tests were used to compare baseline characteristics for patients with PD-L1 negative (<1%) and positive (1% or greater) tumors. Kaplan-Meier curves were constructed for OS. Cox proportional hazards regression, with controls for divergent baseline characteristics, were used to compare OS between the two groups. Results: Of 935 available patients, 340 had PD-L1 results: 221 had PD-L1 positive (65%) and 119 had PD-L1 negative (35%) tumors. The two groups of patients were largely similar with respect to baseline characteristics, including age, sex at birth, White race, smoking status, marital status, Charlson Comorbidity Index, ECOG status, histology, stage, EGFR, and RAS mutations (Table). Patients with PD-L1 positive and negative tumors had a similar median (interquartile range [IQR]) number of durvalumab doses (15 [6-24] vs 12 [5-23], p=0.38) and length of follow-up (31.5 [12.1-43.5] vs 28.7 [12.2-40.6] months, p=0.43). Kaplan-Meier survival curves were similar for patients with PD-L1 positive and negative tumors: estimated 12-month OS rates (95% CI) of 84% (78%-88%) vs 89% (81%-93%) and 24-month OS rates of 72% (65%-78%) vs 76% (67%-84%); median OS was not reached in patients with PD-L1 positive tumors and was 47.0 months for the PD-L1 negative group. Cox Proportional Hazards regression analysis also demonstrated similar OS for both groups (p=0.64). Conclusions: In this real-world study of a subpopulation of VHA patients with stage III UR-NSCLC and known PD-L1 levels, survival benefits with durvalumab were consistent with those reported in the PACIFIC trial, despite having worse baseline prognostic factors. Patients with PD-L1 positive and negative tumors experienced similar overall survival, including 12- and 24-month OS rates.[Table: see text]

Granular analysis of individual immune-related gene expression in a randomized phase I/II study of the oncolytic adenovirus, ONCOS-102, in combination with pemetrexed/cisplatin (P/C) in patients (pts) with unresectable malignant pleural mesothelioma (MPM).

e20536 Background: ONCOS-102 is an oncolytic adenovirus expressing granulocyte-macrophage colony stimulating factor (GM-CSF; Ad5/3-D24-GMCSF) that stimulates immune responses and modulates the tumor microenvironment, both as a monotherapy and in combination with programmed cell death protein 1 (PD-1) blockade. We present granular analyses of individual immune-related gene expression in response to ONCOS-102 in a randomized phase I/II study in MPM. Methods: Following a safety run-in (n = 6), 25 pts were randomized to receive ONCOS-102 (3 x 1011 virus particles in 2.5 mL) intratumorally under CT or US guidance on Days 1, 4, 8, 36, 78 and 120, plus six cycles of P/C starting on Day 22 (ONCOS+P/C), or six cycles of P/C only (control). Both treatment-naïve (1L) and previously treated patients were enrolled. Survival was followed up to 30 months. Tumor biopsies were collected at baseline and Day 36, and immunofluorescence for immune cell subsets, RNASeq and qPCR were performed. Results: In the pooled population (n = 31), median overall survival (OS) was 16.6 vs 18.3 months for ONCOS-102 + P/C vs control arms ( P> 0.05). In 1L patients (n = 17) median OS was 20.3 vs 13.5 months ( P> 0.05), and 30-month OS rate was 34.1% vs 0. A significant increase in tumour-infiltrating immune cells was observed (baseline to Day 36) with ONCOS-102 + P/C (n = 20) but not control (n = 11) using immunofluorescence and transcriptome analysis. CD8+, GranzymeB+ CD8+ cells, and CD8+:regulatory T-cell and M1:M2 macrophage ratios increased in ONCOS-102-treated pts (P≤0.016). A difference in tumor immune-infiltration was observed in ONCOS-102 + P/C pts stratified by survival at Month 18: while deregulation of complement pathways and inflammatory response was seen at baseline, at Day 36 adaptive immune response and T-cell activation were observed in pts who were alive but not in those deceased. Additionally, GM-CSF protein, likely derived from ONCOS-102, was transiently present in higher concentration at Days 4 and 8 in 18-month survivors vs deceased pts. Based on a previously described predictive inflammatory gene signature for treatment with checkpoint inhibitors in mesothelioma, a binomial model assessing baseline transcriptome levels demonstrated 89% accuracy in predicting 18-month survival. Conclusions: ONCOS-102 caused increased T-cell infiltration and upregulated immune response-related gene expression in tumor lesions. A trend for prolonged OS was observed in the 1L setting, only. Consistent with observations in PD-1 resistant melanoma, ONCOS-102-induced immune response in the tumor is hallmarked by a high prevalence of cytotoxic T-cells and depolarization of macrophages, which may support addition of checkpoint inhibitors to the combination of ONCOS-102 plus P/C in MPM. Clinical trial information: NCT02879669 .

Real-world outcomes of first-line maintenance with niraparib or bevacizumab in advanced ovarian cancer.

e17598 Background: Niraparib and bevacizumab are the only FDA-approved first-line maintenance (1LM) therapies for advanced ovarian cancer (AOC) without a biomarker requirement. However, little information exists regarding the effectiveness of these treatments in the real world. Methods: We identified 89 AOC patients from the US-based deidentified Integra PrecisionQ database who received 1LM bevacizumab (n=31) or niraparib (n=58) following induction chemotherapy (CT) ± bevacizumab initiated between July 1, 2019, and March 31, 2021, and followed them until the data cut-off of March 31, 2022. Using the start of maintenance therapy as the index date, we examined patient characteristics, time to next treatment or death (TTNT; often used as a real-world proxy for progression-free survival), and overall survival (OS) for these treatment groups. Results: For patients who received 1LM bevacizumab, the median age was 69 years, 65% had Stage III cancer at index date, 84% had Eastern Cooperative Oncology Group (ECOG) performance status 0–1, and 87% received CT + bevacizumab as first-line therapy. For patients who received 1LM niraparib, the median age was 68.5 years, 66% had Stage III cancer at index date, 88% had an ECOG performance status of 0–1, and 79% received chemotherapy alone as first-line therapy. Only 1 bevacizumab (BRCAm) and 11 niraparib (4 BRCAm, 7 BRCAwt HRd) patients had known homologous recombination deficiency (HRd)-positive tumors. Patients treated with bevacizumab had a median TTNT of 4.5 months (mo) and a 12-month OS mark of 83.6%; for patients treated with niraparib, the corresponding values were 9.9 mo and 96.3%. Conclusions: Our study provides real-world outcomes data for newly diagnosed AOC patients receiving maintenance niraparib or bevacizumab following CT +/- bevacizumab. HRd testing results were only available for 19% of bevacizumab- and 40% of niraparib-treated patients, highlighting a need for greater testing in the real world. Future studies should examine which patient characteristics are associated with long-term survival for these and other treatment options to aid in the decision-making process. Funding: GSK215281. [Table: see text]

Tp53 as a potential therapeutic biomarker in patients with recurrent high-grade glioma treated with anlotinib and temozolomide.

e14000 Background: Patients with recurrent high-grade glioma (rHGG) had a dismal prognosis. Previous studies have found that anlotinib is effective in treating rHGG, but there are no predictive biomarkers to select potential beneficiaries. Methods: The clinical and pathological data of patients with rHGG treated with anlotinib and temozolomide (TMZ) in our hospital were collected and analyzed. Treatment response was assessed according to Response Assessment in Neuro-Oncology criteria. Survival was estimated using the Kaplan-Meier curve with the log-rank test. Tumor protein 53 ( TP53), O-6-methylguanine-DNA methyltransferase, and pre-treatment peripheral blood index were evaluated for potential therapeutic biomarkers. Results: From August 2017 to February 2022, 23 eligible patients with rHGG were included in this study. The objective response rate was 52.2% (95% confidence intervals [CI]: 30.6-73.2%), and the disease control rate was 91.3% (95% CI: 72.0-98.9%). The median progress-free survival (PFS) for all patients was 5.3 months (95% CI: 4.9-5.7 months), with a 6-month PFS rate of 30.4% (95% CI: 13.2-52.9%). The median overall survival (OS) and the 12-month OS rate were 11.0 months (95% CI: 9.7-12.3) and 39.1% (95% CI: 19.7-61.5%), respectively. Patients with TP53 wild-type had significantly higher OS than those with TP53 mutant-type (13.0 months [95% CI: 10.5-15.5 months] vs. 9.0 months [95% CI: 7.4-10.6 months], p= 0.009). Multivariate cox proportional hazards analysis showed that TP53 was an independent prognostic biomarker for OS. Conclusions: The present study showed that anlotinib combined with TMZ had a promising efficacy in treating rHGG and TP53 was a potential biomarker to predict prognosis.

Pretreatment clinical parameters associated with intracranial progression burden following an initial stereotactic radiosurgery course in a multi-institutional brain metastases cohort.

2013 Background: While brain metastasis (BM) velocity is a valuable prognostic metric at time of intracranial progression (ICP), pre-SRS risk factors for post-SRS high-burden intracranial progression (ICP) remain poorly characterized. We hypothesized that pre-SRS clinical parameters are associated with subsequent high-burden (ICP), defined as either ≥5 (ICP5) or new/progressive ≥11 BMs (ICP11). Methods: All patients completing an initial SRS course for BMs at two institutions from 1/2015-12/2020 were retrospectively identified. Patients with prior whole brain radiation therapy (WBRT) and/or BM resection were eligible. Demographic and clinical parameters were collected. ICP was defined as any radiographic concern for distant and/or in-field progression per multidisciplinary consensus. Overall survival (OS) and freedom from ICP were estimated via the Kaplan Meier method. Cox models assessed association between parameters and freedom from ICP5 and ICP11. Results: We identified 1383 patients completed SRS, with a median follow up of 8.7 months. Patients were 54.8% female, 45.6% with KPS ≥90, and a median of 63.4 years old. Primary tumor types included non-small cell lung (48.7%), breast (14.7%), and melanoma (8.5%). 46.9% had oligometastatic disease (≤5 metastatic foci: including BMs) at SRS, and 53.4% underwent SRS for > 1 BM. 10.3% of patients had undergone prior WBRT and 26.1% surgical resection. 555 patients (40.1%) experienced ICP following SRS, of whom 72.6% had 1-4, 11.5% had 5-10, and 15.9% had ≥11 new/progressive BMs. Among patients with ICP, 6-month freedom from ICP was 35.5% (95% CI: 31.1-40.5%) for those with 1-4 BMs at time of ICP, 29.7% (95% CI: 20.4-43.3%) for 5-10 BMs, and 20.5% (95% CI: 13.5-30.1%) for ≥11 BMs (p = 0.016). Respective 12-month OS rates were 56.8% (95% CI: 52.1-61.9%), 46.0% (95% CI: 35.1-60.1%), and 38.7% (95% CI: 29.4-50.9%; p < 0.001). Neurologic symptoms at time of ICP were observed in 21.1% of patients with 1-4 BMs, 28.1% with 5-10 BMs, and 50.0% with new/progressive ≥11 BMs (p < 0.001). On multivariable analysis, superior freedom from high-burden ICP was associated with the following pre-SRS parameters: oligometastatic burden (ICP5: HR 0.68, 95% CI: 0.47-0.99; ICP11: 0.59; 95% CI: 0.36-0.97), no prior immunotherapy (ICP11: HR 0.57, 95% CI: 0.34-0.57), and a single BM at time of initial SRS (1 vs 2 BM, ICP 5: HR 0.51, 95% CI: 0.31-0.82; ICP11: HR 0.45, 95% CI: 0.24-0.84), while primary tumor type was not associated with ICP5 or ICP11. Conclusions: Pre-SRS parameters including polymetastatic burden, prior receipt of immunotherapy, and > 1 BM were associated with post-SRS high-burden ICP. High burden ICP developed earlier following SRS completion and was associated with higher rates of neurologic decline and inferior OS.

Efficacy and safety of IBI110 in combination with sintilimab in first-line advanced HER2-negative gastric cancer or gastroesophageal junction cancer: Updated results from a phase Ib study.

2576 Background: Sintilimab plus oxaliplatin and capecitabine (XELOX) has become the standard of care in patients (pts) with untreated advanced, recurrent, or metastatic gastric or gastroesophageal junction adenocarcinoma (G/GEJ AC) in China. Dual inhibition of PD-1 and lymphocyte-activation gene 3 (LAG-3) may further improve anti-tumor effect. The preliminary safety and efficacy data of IBI110 plus sintilimab and XELOX in pts with first-line G/GEJ AC were previously presented (Chenyu Mao et al. ASCO 2022). Here, we presented updated safety and efficacy results of this study. Methods: This phase Ib study enrolled patients with previously untreated, unresectable, locally advanced or recurrent/metastatic HER2-negative GC/GEJ AC. Pts received IBI110 200mg IV Q3W and sintilimab 200mg IV Q3W plus XELOX (oxaliplatin 130 mg/m2 Q3W and capecitabine 1000mg mg/m2/time twice daily [BID]) until disease progression, unacceptable toxicity or death. The primary objectives were to evaluate the safety, tolerability, and efficacy of the combination therapy per RECIST v1.1. Results: As of data cutoff January 9th 2023, 17 pts were assessed as evaluable (median age: 61 years; ECOG PS=1: 14 pts; all gastric cancer). All pts (17/17, 100%) experienced treatment-related adverse events (TRAEs) of any grade, and the most commonly TRAEs were neutrophil count decreased (64.7%), white blood cell count decreased (52.9%), platelet count decreased (52.9%). Grade ≥ 3 TRAEs occurred in 11 pts (64.7%), the most frequent grade ≥ 3 TRAEs were consistent with TRAEs of any grade. Investigator-assessed immune-mediated adverse events (irAEs) occurred in 10 pts (58.8%). Grade ≥ 3 irAEs occurred in 3 pts (17.6%), all led to discontinuation. No treatment-related death occurred. As data cutoff, among 17 efficacy-evaluable pts, the unconfirmed and confirmed objective response rate (ORR) were 88.2% (95% CI, 63.6-98.5) and 64.7% (95% CI, 38.3-85.8), respectively. The disease control rate (DCR) was 94.1% (95% CI, 71.3-99.9). With a median follow up of 13.1 months (95% CI, 7.1-NC), the median duration of response (DoR) and progression-free survival (PFS) were 11.6 months (95% CI, 2.5-14.4) and 12.9 months (95% CI, 3.8-15.8), respectively. The median overall survival (OS) was not reached, and the 12-months OS rate was 70.6% (95% CI, 43.1-86.6). Conclusions: IBI110 in combination with sintilimab and XELOX demonstrated manageable safety and encouraging efficacy results in patients with first-line gastric adenocarcinoma. This is the first positive trial to show clinical benefits of a LAG3 plus PD-1 inhibitor combined with chemotherapy for this population. Clinical trial information: NCT04085185 .

Interim analysis of a phase II study of nivolumab/ipilimumab plus cabozantinib in patients with unresectable advanced melanoma.

9563 Background: Nivolumab/ipilimumab (Nivo/Ipi) is a standard therapy in patients with unresectable stage III/IV melanoma, demonstrating an objective response rate (ORR) of 58% and 12-month progression free survival (PFS) rate of 49% [Wolchok J, NEJM 2017]. c-MET/VEGFR2 inhibition with cabozantinib (Cabo) has modest clinical activity in melanoma and can augment antitumor immunity by increasing CD8+ Tcell and macrophage tumor infiltration, decreasing intratumoral regulatory Tcell levels, and increasing tumor cell MHC antigen presentation. Nivo/Ipi plus Cabo showed clinical activity and acceptable toxicity profile in GU malignancies [Apolo AB, JCO 2020]. We performed a study of Nivo/Ipi plus Cabo in advanced melanoma patients aimed at improving efficacy. Methods: We conducted a multicenter phase II study of induction Nivo 3mg/kg IV and Ipi 1mg/kg IV and Cabo 40mg PO daily every 3 weeks for 4 cycles, followed by Nivo 480mg IV plus Cabo 40mg PO daily every 4 weeks for up to 2 years, until disease progression or unacceptable toxicity/patient withdrawal. Patients with unresectable stage III/IV melanoma and no prior anti-PD-1 or CTLA-4 exposure (unless in adjuvant setting > 6 months since last dose) were included. Uveal melanoma excluded. Primary endpoint was 12-month PFS rate. Secondary endpoints included ORR, overall survival (OS), and adverse events (AEs). Interim analysis was preplanned after first 14 subjects were evaluated in a Simon 2 stage design (goal >8 subjects 12-month progression free). Results: As of 1/2023, 14 subjects were enrolled across three cancer centers within the Georgetown-Lombardi Comprehensive Cancer Center Consortium. Median age 66.5 years, all stage IV disease, 10 with cutaneous primary site, 5 with elevated LDH, and 6 with BRAF V600 mutant tumor. Median follow up was 10.6 mos. 12-month PFS rate was 30% (3/10 evaluable subjects); 3 subjects pending PFS evaluation; median PFS 10.3 mos. ORR was 46% (6/13 evaluable subjects) with 2 CR, 4 PR, and 1 SD. Responders had cutaneous (5) or unknown (1) primary sites. 9 patients were alive at last follow up. 12-month OS rate was 67% (6/9 evaluable subjects). Reasons for treatment discontinuation included AEs (4), patient withdrawal (1), and disease progression (6). 3 subjects remain on study drug(s). Treatment related AEs (TRAEs) were observed in 13 subjects; 9 experienced a grade 3-4 TRAE (most frequent were elevated AST/ALT 29% and hypokalemia 14%). Most frequent grade 2 TRAEs were diarrhea (35%) and palmar-planter-erythrodysesthesia (29%). No treatment related deaths occurred. Conclusions: Clinical activity was observed with Nivo/Ipi plus Cabo in advanced melanoma but did not meet the predefined threshold to advance to the second stage of enrollment. TRAE profile was similar to prior reports. Biomarker analyses are planned to identify patient profiles associated with particular benefit from this regimen. Clinical trial information: NCT04091750 .