Prolonged Progression-free Survival Research Articles

Efficacy and safety of immune checkpoint inhibitors in patients with advanced intrahepatic cholangiocarcinoma

BackgroundTo assess the efficacy and safety of PD-1 and PD-L1 immune checkpoint inhibitors (ICIs) in managing advanced intrahepatic cholangiocarcinoma (ICC).MethodsA retrospective analysis of treatment data for patients with advanced ICC who received ICIs at the Second Affiliated Hospital of Chongqing Medical University from the inception of the inpatient medical record database until 30 April 2024. The analysis concentrated on the safety and efficacy of the treatment. The primary endpoint was progression-free survival (PFS), while the secondary endpoints included overall survival (OS) and safety. The Kaplan-Meier method was employed to plot survival curves, and differences between groups were assessed using log-rank tests.Results96 patients diagnosed with ICC were included, comprising 60 males (62.50%) and 36 females (37.50%). 85 patients exhibited disease progression, 22 patients succumbed, and 38 patients were lost to follow-up finally. Those who initiated immunotherapy promptly following first-line antitumor treatment exhibited a notably prolonged PFS compared to those experiencing tumor progression (5.63 months (95%CI: 3.12~8.14) vs 2.50 months (95%CI: 1.83~3.17), P=0.002). However, no significant disparity in the PFS with immunotherapy in different lines therapy(P=0.406) and the OS was observed between the two groups(P=0.360). 18 patients (18.75%) experienced treatment-emergent adverse events (AEs), with 3 patients encountering AEs of grade ≥3. All patients returned to normal after symptomatic treatment.ConclusionsIn patients with advanced ICC, the timely initiation of ICIs as adjuvant therapy following first-line antitumor treatment can result in favorable efficacy and a good safety profile.

The Efficacy and Safety of Hepatic Artery Infusion Chemotherapy Combined with Lenvatinib and Programmed Death (PD)-1 Inhibitors for Unresectable Intrahepatic Cholangiocarcinoma: A Retrospective Study

Objectives: Although systemic chemotherapy (SC) is the mainstay for treating unresectable intrahepatic cholangiocarcinoma (ICC), its efficacy is limited and it causes severe systemic side effects. This study focuses on evaluating the effectiveness and safety of hepatic arterial infusion chemotherapy (HAIC) in combination with lenvatinib plus programmed death-1 (PD-1) inhibitors (HLP), compared to SC in combination with lenvatinib plus PD-1 inhibitors (SCLP) for unresectable ICC. Methods: We analyzed patients initially diagnosed with unresectable ICC at our center between March 2021 and December 2023, classifying them into HLP and SCLP groups according to treatment regimen. This study assessed and compared overall survival (OS), progression-free survival (PFS), tumor response, and safety outcomes across the two treatment groups. Results: This study enrolled 53 subjects in total; 25 were treated with HLP and 28 with SCLP. The two groups showed well-matched baseline characteristics. The HLP group reported an extended median OS (12.8 vs. 11.0 months, p = 0.310) and a prolonged median PFS (8.8 vs. 6.4 months, p = 0.043), compared to the SCLP group. The HLP group had a better objective response rate (ORR) (52% vs. 25%, p = 0.043) and disease control rate (DCR) (96% vs. 78.6%, p = 0.104). Based on OS (p = 0.019) and PFS (p = 0.032) results, those without extrahepatic metastasis seemed to benefit more significantly from the HLP regimen than from the SCLP regimen. The HLP group experienced fewer grade 3–4 adverse events (AEs) than the SCLP group. Conclusions: The HLP regimen for unresectable ICC is an effective and safe strategy and is potentially better suited for patients without extrahepatic metastases.

Role of 18F-PSMA-1007 PET/CT-derived quantitative volumetric tumor parameters in cytoreductive radical prostatectomy selection for patients with low-volume metastatic hormone-sensitive prostate cancer: a retrospective study

BackgroundCytoreductive radical prostatectomy (cRP) has emerged as a promising therapeutic approach for low-volume metastatic hormone-sensitive prostate cancer (mHSPC), but the best candidates for cRP are still unknown. This study aims to explore the potential value of 18F-PSMA-1007 PET/CT-derived quantitative volumetric tumor parameters in cRP treatment selection among patients with low-volume mHSPC.MethodsA total of 122 patients with primary low-volume mHSPC who underwent 18F-PSMA-1007 PET/CT followed by systemic therapy alone or plus cRP were included. The whole-body PSMA-derived tumor volume (PSMA-TV) was defined as the total volume of whole-body PSMA-avid tumor lesions, and prostate PSMA-TV was defined as the volume of prostate PSMA-avid tumor lesions. Spearman’s correlation was used to analyze the relationships between whole-body PSMA-TV and clinicopathological characteristics. The primary endpoint was progression-free survival (PFS), and Cox regression analyses were performed to explore the independent predictors for PFS.ResultsAmong 122 patients, 37 (30.32%) underwent systemic therapy plus cRP. The median and optimal cutoff values of the whole-body PSMA-TV were 71.68 cm3 (41.28–157.41 cm3) and 78.57 cm3, respectively. Whole-body PSMA-TV was positively correlated with prostate-specific antigen (PSA), and patients with nonregional lymph node (NRLN) metastases had a greater whole-body PSMA-TV (P = 0.001). Cox regression analyses revealed that cRP, lower whole-body PSMA-TV and the absence of NRLN metastases were associated with better PFS (all P < 0.05). Subgroup analyses revealed that patients with a low whole-body PSMA or no NRLN metastases had a significant improvement in PFS for cRP versus no cRP (HR: 8.26; 95% CI: 2.72–25.06, P = 0.001; HR: 2.71; 95% CI: 1.25–5.93, P = 0.018). Moreover, among patients with higher prostate PSMA-TV and prostate PSMA-TV/whole-body PSMA-TV, cRP also significantly prolonged PFS compared with those without cRP (HR: 3.49; 95% CI: 1.49–8.18, P = 0.004; HR: 8.54; 95% CI: 2.47–29.50, P = 0.013).ConclusionIn management of primary low-volume mHSPC, whole-body and prostate PSMA-TV evaluations based on 18F-PSMA-1007 PET/CT could be helpful to identify the most suitable candidates for cRP.Trial registrationRetrospectively registered.

Exploratory study of TAS-102 combined with intermittent administration of fruquintinib in the treatment of third-line metastatic colorectal cancer.

174 Background: Fruquintinib and TAS-102 are two globally recognized standard therapies for mCRC patients who have previously undergone standard chemotherapy. A phase II exploratory study suggested that the combination of TAS-102 and fruquintinib could prolong progression-free survival (PFS) and overall survival (OS) in these patients. However, the benefits are sometimes limited due to tolerability issues associated with continuous dosing. This study aimed to investigate the efficacy and safety of intermittent administration of TAS-102 combined with fruquintinib as a third-line treatment for mCRC patients. Methods: This open-label, single-arm, single-center, exploratory clinical trial enrolled mCRC patients who had failed at least two standard treatment regimens. Eligible patients received oral fruquintinib (3 mg, once daily, on days 1-5 and 8-12) and TAS-102 (35 mg/m², twice daily, on days 1-5) every two weeks until disease progression or unacceptable toxicity occurred. The primary endpoint was objective response rate (ORR). Secondary endpoints included OS, PFS , DCR, and safety. Results: From August 2023 to September 2024, 26 eligible patients were enrolled. The median age of the patients was 58 years (range: 19-77), with 61.5% being female. RAS mutations were present in 57.7% of patients, 57.7% had left-sided colon or rectal cancer, 57.7% had liver metastases, and 76.9% had multiple metastases. As of September 10, 2024, 22 patients had undergone at least one tumor assessment, and 12 patients were still on treatment. Among them, 18.2% (4/22) achieved partial response , and 50% (11/22) had stable disease as the best response. Median PFS (mPFS) was 135 days (95% CI: 60.52-209.48). mPFS in RAS-mutant and RAS wild-type patients was 161 days (95% CI: 63.37-258.63) and 135 days (95% CI: 60.20-209.80), respectively, with ORRs of 25% and 12.5%. mPFS in patients with liver metastases (LM) and non-LM was 135 days (95% CI: 45.42-224.58) and 161 days (95% CI: 87.84-234.16), respectively, with ORRs of 14.3% and 25%. mPFS in patients with multiple metastases was 135 days (95% CI: 71.86-198.14), with an ORR of 17.6%. Median OS was not yet mature. Treatment-related adverse events (TRAEs) were generally manageable and tolerable. The most common hematological TRAEs (any grade, grades 3-4) included leukopenia (76.9%, 11.5%), neutropenia (73.1%, 11.5%), and anemia (53.8%, 7.7%). Non-hematological TRAEs were mostly grades 1-2, including anorexia (46.2%) and fatigue (19.2%). One case of grade 3 hypertension was reported. No treatment-related deaths were observed. Conclusion s: These preliminary results suggest that intermittent administration of TAS-102 in combination with fruquinitinib as a third-line treatment for patients with mCRC reduces hematological toxicity and is well tolerated, with encouraging clinical results. Clinical studies are ongoing. Clinical trial information: ChiCTR2300078241 .

A phase 1 trial of folinic acid, fluorouracil, oxaliplatin, bevacizumab, botensilimab, balstilimab (FOLFOX-3B) in microsatellite stable metastatic colorectal cancer.

180 Background: Botensilimab (BOT) is a novel Fc fragment engineered CTLA4 inhibitor designed to boost innate and adaptive immune response. The combination of BOT and the PD-1 antibody balstilimab (BAL) has been associated with durable and deep responses in microsatellite stable (MSS) metastatic colorectal cancer (mCRC). Given the potential synergistic activity between checkpoint inhibitors and oxaliplatin and VEGF(R) inhibitors, we performed a phase 1 clinical trial of folinic acid, fluorouracil, oxaliplatin, bevacizumab, botensilimab, and balstilimab (FOLFOX-3B). Methods: We enrolled ECOG performance status 0-1 patients (pts) with measurable MSS mCRC, up to 2 prior lines of therapy, and without progression following prior oxaliplatin. FOLFOX was given at a fixed dose, every 2 weeks, across the study: folinic acid at 400 mg/m 2 x 2 hours (hr), oxaliplatin at 85 mg/m 2 x 2 hr, and fluorouracil at 2400 mg/m2 x 46 hrs. BOT was administered at 2 dose levels (DL) of 25 mg and 75 mg IV Q6 weeks x 2. BAL was administered at a fixed dose of 240 mg IV Q2 weeks. The study followed a 3 x 3 escalation design with up to 9 patients per DL. A dose level was deemed safe if &lt; 1 out of 6 pts or &lt; 2 out of 9 pts had a DLT (expansion to 9pts only if 2 DLTs encountered in the 1 st 6 pts). The DLT period consisted of 6 weeks. Pts should have received all intended BOT/BAL and FOLFOX doses in the 1 st 6 weeks to be deemed DLT-evaluable. Results: 14 pts were enrolled on study: 9/14 with liver metastatic disease, 5/14 RAS -mutated, all TMB low. 7 were treated on DL1 and 7 on DL2. 6/7 pts at DL1 had received 1-2 prior lines of therapy, 4 of whom included oxaliplatin. 6/7 of pts at DL2 had 1-2 prior systemic therapy, all of whom received prior oxaliplatin. No DLT were noted at DL1 or DL2. 1 pt at each DL was not DLT-evaluable as they were not able to receive all intended therapy due to treatment interruptions. Grade (G)2 and above immune related toxicities included: one pt at DL1 with transient G3 AST/ALT elevation and transient G2 colitis (resolved with steroids and infliximab), one pt at DL1 with G2 hypothyroidism and one patient at DL2 with G2 hyperthyroidism. At DL1, 4/7 had a partial response (PR) - including 2/4 with prior oxaliplatin exposure. At DL2, 6/7 pts had a PR – including 5/6 with prior oxaliplatin exposure. 3 patients proceeded to surgical resection or ablation and are currently followed with observation only. In the combined cohort of DL1 and DL2, the median progression free survival (PFS) is 8 months and remains unreached for DL2. Overall survival outcome has not matured at the time of this analysis. Conclusions: FOLFOX-3B with BOT at 75 mg IV Q6 weeks x 2 in combination with BAL 240 mg Q2 weeks is well-tolerated and is associated with promising clinical activity with 5/6 PR and prolonged PFS. The study was amended to explore additional DL that explore higher doses of BOT (150 mg) or longer duration of BOT 75mg (4 doses). Clinical trial information: NCT05627635 .

Chemoimmunotherapy plus radiotherapy in advanced esophageal squamous-cell carcinoma.

437 Background: Chemotherapy plus Immune checkpoint inhibitors (ICIs) have improved survival outcomes of patients with advanced or metastatic esophageal squamous-cell carcinoma in both first- and second-line settings. However, the benefit of additional radiotherapy for the residual esophageal lesion after chemo-immunotherapy remains unclear. Methods: We conducted a one-arm, three-center, open label study involving patients who were treatment naïve, radiological and histological confirmed advanced or metastatic squamous-cell esophageal carcinoma. Enrolled patients were expected the survival time was three months or longer; and ECOG performance status score was 0 or 1. In induction phase, patients received four cycles of TP regimen chemotherapy (docetaxel, 75/mg 2 , iv on day 1 and cisplatin, 75mg/m 2 , iv on day 1) combined with PD-1 inhibitor (sintilimab, 200mg intravenous infusion on day 1) every 21 days. Patients who finished four cycles of chemo-immunotherapy with stable disease (SD) or partial response (PR) were initiated 50Gy/25f irradiation for residual tumors. 3-4weeks after radiotherapy, maintenance sintilimab therapy was administered every 21 days for another 31 cycles or until disease progression or intolerable toxicity. Results: Total of 39 patients were enrolled in this study, 30 of them could be evaluated in efficiency and toxicities. All of them were male and were squamous-cell carcinoma in histology. 12/30 (40.0%) patients were in stage III, and 18/30 (60.0%) were in stage IV. 29/30 (96.7%) patients completed four cycles chemo-immunotherapy, the complete response (CR) rate was 6.7% (2/30), the partial response (PR) rate was 53.3% (16/30) and disease control rate (DCR) was 86.7% (26/30). The median depth of response (DpR) was 34.5% for chemoimmunotherapy and was 64.0% after radiotherapy. The progression-free survival (PFS) was 16.4 months and the overall survival (OS) was not reached. The most common grade 3 or worse adverse event was neutropenia and occurred in 3 (10.0%) patients. Conclusions: Four cycles sintilimab plus cisplatin and docetaxel followed by radiotherapy for residual tumors and maintained sintilimab had high response rate, prolonged PFS and tolerable toxicities as first line treatment in patients with advanced or metastatic esophageal squamous-cell carcinoma. Longer OS is promising and more patients enrolled in this study is needed in future. Clinical trial information: NCT06138028 . Clinicopathological features and patient factors. Factors No. of patients (n=30) (%) Gender Male 30 (100.0) Female 0 (0) Age (year) &lt; 65 27 (43.3) ≥ 65 17 (56.7) PD-L1 (CPS) &lt; 5 9 (30.0) ≥ 5 21 (70.0) Clinical Stage III 12 (40.0) IV 18 (60.0) Metastatic Pattern Regional lymph node 12 (40.0) Cervical &amp; Supraclavicular 4 (13.3) Abdomen 5 (16.7) Lung 6 (20.0)

Efficacy and safety of cabozantinib for advanced gastrointestinal (GI) neuroendocrine tumors (NET) after progression on prior therapy: Subgroup analysis of the phase 3 CABINET trial (Alliance A021602).

666 Background: In the phase 3 CABINET trial (NCT03375320), cabozantinib (CABO) significantly prolonged median progression-free survival (PFS) compared to placebo (PB) in patients with advanced, previously treated, progressive extrapancreatic NET (epNET) [HR 0.38 (95% CI, 0.25-0.59, P&lt;0.0001)] and pancreatic NET (pNET) [HR 0.23 (95% CI, 0.12-0.42, P&lt;0.0001)] (Chan et al., NEJM, 2024). In this analysis, we focus on outcomes of patients with epNET arising in the GI tract. Methods: Patients with locally advanced or metastatic epNET or pNET were randomized 2:1 in separate cohorts to receive CABO 60 mg daily vs PB. The epNET cohort included patients with tumors arising in the GI tract (not including pancreas), lung, unknown primary, and other rare primary sites. In this subgroup analysis of the epNET cohort, patients with GI NET were included. Eligibility included progression by RECIST within 12 months (mo) prior to registration, ≥ 1 prior systemic therapy. Primary endpoint: PFS by blinded independent central review (BICR). Secondary endpoints: objective response rate, overall survival, safety. Results: 116 of the 203 patients in the epNET cohort had GI NET (CABO, n=70; PB, n=46). Median age was 66 yrs; females: 46%; G1/G2/G3/unknown grade: 35%/57%/6%/2%. ECOG performance status: 0/1-2: 43%/57%. White race: 86%. The most common primary tumor locations were ileum/cecum (54%), small intestine with location not specified (20%); non-cecum colon or rectum (11%), stomach (4%); duodenum (3%); jejunum and nonspecified midgut site (3% each). Prior systemic therapies included somatostatin analogs (SSA) (100%), everolimus (59%); Lu-177 dotatate (77%); temozolomide +/- capecitabine (16%). In patients with GI NET, CABO was associated with improved PFS by BICR compared to PB (stratified HR, 0.50; 95% CI: 0.28-0.88, 1-sided stratified log-rank P=0.007). Median PFS with cabozantinib was 8.5 mo (95% CI, 6.0-16.7) compared to 5.6 mo (95% CI, 3.9-11.0) with PB. CABO demonstrated potential benefit in patients with midgut GI NET and across clinical factors including grade, functional status related to hormone secretion, concurrent SSA use, and prior therapy with Lu-177 dotatate or everolimus. The most frequent grade 3/4 adverse events attributed to therapy with CABO included hypertension (19%), diarrhea (13%), fatigue (10%). Conclusions: CABO is associated with improvement in PFS compared to PB in patients with advanced GI NET. Potential benefit was observed across clinical factors including grade, functional status, concurrent SSA, and prior treatment. The safety profile for CABO in patients with GI NET is consistent with that previously reported. Support: U10CA180821, U10CA180882; U10CA180820 (ECOG-ACRIN), U10CA180868 (NRG Oncology), U10CA180888 (SWOG); Exelixis; https://acknowledgments.alliancefound.org . Clinical trial information: NCT03375320 .

Artificial intelligence-based spatial analysis of tertiary lymphoid structures and clinical significance for endometrial cancer.

With the incorporation of immune checkpoint inhibitors into the treatment of endometrial cancer (EC), a deeper understanding of the tumor immune microenvironment is critical. Tertiary lymphoid structures (TLSs) are considered favorable prognostic factors for EC, but the significance of their spatial distribution remains unclear. B cell receptor repertoire analysis performed using six TLS samples located at various distances from the tumor showed that TLSs in distal areas had more shared B cell clones with tumor-infiltrating lymphocytes. To comprehensively investigate the distribution of TLSs, we developed an artificial intelligence model to detect TLSs and determine their spatial locations in whole-slide images. Our model effectively quantified TLSs, and TLSs were detected in 69% of the patients with EC. We identified them as proximal or distal to the tumor margin and demonstrated that patients with distal TLSs (dTLSs) had significantly prolonged overall survival and progression-free survival (PFS) across multiple cohorts [hazard ratio (HR), 0.56; 95% confidence interval (CI), 0.36-0.88; p = 0.01 for overall survival; HR, 0.58; 95% CI, 0.40-0.84; p = 0.004 for PFS]. When analyzed by molecular subtype, patients with dTLSs in the copy-number-high EC subtype had significantly longer PFS (HR, 0.51; 95% CI, 0.29-0.91; p = 0.02). Moreover, patients with dTLSs had a higher response rate to immune checkpoint inhibitors (87.5 vs. 41.7%) and a trend toward improved PFS. Our findings indicate that the functions and prognostic implications of TLSs may vary with their locations, and dTLSs may serve as prognostic factors and predictors of treatment efficacy. This may facilitate personalized therapy for patients with EC.

Lenvatinib plus hepatic arterial infusion chemotherapy of oxaliplatin, fluorouracil, and leucovorin versus lenvatinib alone for advanced hepatocellular carcinoma.

580 Background: Lenvatinib stands out as a first-line therapy for individuals with advanced hepatocellular carcinoma (HCC). Concurrently, hepatic arterial infusion chemotherapy comprising oxaliplatin, fluorouracil, and leucovorin (FOLFOX-HAIC) has emerged as a potential option for those with advanced HCC. It is necessary to investigate the efficacy and safety of lenvatinib plus FOLFOX-HAIC (lenvaHAIC) for advanced HCC in real-world situations. Methods: In this retrospective analysis, 127 consecutive patients underwent lenvaHAIC, while 184 patients received lenvatinib alone as first-line treatment at six Chinese academic centers between January 2019 and June 2022. Following 1:1 propensity-score matching, we established paired cohorts (113 patients in each group) for evaluating survival. Overall survival (OS), progression-free survival (PFS), objective response rate (ORR) evaluated by RECIST 1.1 and mRECIST criteria, and safety profiles were compared between the two groups. Results: The lenvaHAIC group exhibited significantly prolonged median PFS and OS than the lenvatinib group (PFS: 12.3 vs. 6.2 months; OS: 25.6 vs. 12.3 months; P &lt; .001 for each). In the propensity-score matched cohorts (113 pairs), both PFS and OS were notably extended in the lenvaHAIC group compared with those in the lenvatinib group (P &lt; .001). Multivariate analysis identified lenvaHAIC treatment as an independent factor for improved PFS (hazard ratio [HR] 0.45; P &lt; .001) and OS (HR 0.38; P &lt; .001). Grade 3-4 adverse events, including nausea, vomiting, diarrhea, thrombocytopenia, and neutropenia, were more prevalent in the lenvaHAIC group. Conclusions: LenvaHAIC may be a promising treatment in patients with advanced hepatocellular carcinoma, demonstrating enhanced OS, PFS, and ORR and an acceptable safety profile.

A phase III study of combination therapy with everolimus plus lanreotide versus everolimus monotherapy for unresectable or recurrent gastroenteropancreatic neuroendocrine tumor (JCOG1901, STARTER-NET).

652 Background: There is limited evidence regarding the benefit of adding somatostatin analogs to molecular targeted agents for well-differentiated gastroenteropancreatic neuroendocrine tumors (GEP-NETs). This phase III trial was conducted to compare everolimus plus lanreotide (EVE/LAN) with everolimus monotherapy (EVE) in patients with unresectable or recurrent GEP-NETs in the first-line setting. Methods: Patients with grade 1 or grade 2, nonfunctioning GEP-NETs with poor prognostic factors (Ki-67 labeling index (LI) 5-20% or diffuse liver metastases) were randomly assigned (1:1) to EVE (10 mg/day) or EVE/LAN (EVE + LAN 120 mg every 28 days). The primary endpoint was progression-free survival (PFS). The key secondary endpoint was overall survival (OS), and other secondary endpoints were objective response rate (ORR), disease control rate (DCR), and safety. The study was based on the hypothesis of an assumed median PFS of 11.0 months for EVE, expecting a 4-month improvement by EVE/LAN (HR: 0.73). The planned sample size was 250, requiring 195 events overall with a one-sided alpha level of 5%, a power of 70%, an accrual period of 5 years, and a follow-up period of 1.5 years. Results: Between April 2020 and June 2024, a total of 178 patients were enrolled, and the planned interim analysis was conducted in 145 patients (72 in the EVE and 73 in the EVE/LAN) in June 2024 with a data cut-off date of Nov 2023. The median PFS was 11.5 months in the EVE arm and 29.7 months in the EVE/LAN arm (HR 0.38 [99.91% CI 0.15–0.96], P = 0.00017 &lt; the prespecified significance level of 0.00046, by the stratified log-rank test). The HR for OS was 0.97 (95% CI: 0.24-3.90). The ORR and DCR were 8.7% (6/69) and 87.0% (60/69) in the EVE arm and 26.8% (19/71) and 91.5% (65/71) in the EVE/LAN arm, respectively. Both hematologic and non-hematologic toxicities tended to be more frequent in the EVE/LAN arm than in the EVE arm. No treatment-related deaths were observed in either arm. Based on the efficacy results, the Data and Safety Monitoring Committee recommended early termination of the study. Conclusions: The EVE/LAN provides statistically significant prolongation of PFS compared with EVE monotherapy, and the safety profile of EVE/LAN was manageable. The EVE/LAN might be a new standard treatment in the first-line setting for well-differentiated grade 1/2 GEP-NETs with poor prognostic factors. Clinical trial information: jRCT1031200023.

Results of a multicenter retrospective cohort study evaluating the safety and efficacy of FTD/TPI plus ramucirumab in advanced gastric cancer (HGCSG2302).

351 Background: In advanced gastric cancer, trifluridine/tipiracil (FTD/TPI) is one of the standard treatments for later-line chemotherapy. Ramucirumab (RAM), an anti-VEGFR-2 monoclonal antibody, has shown promising efficacy in combination with FTD/TPI in phase II studies conducted in Japan, suggesting that this combination could improve treatment outcomes. However, there remains a paucity of real-world clinical data comparing the efficacy and safety of FTD/TPI monotherapy and FTD/TPI plus RAM combination therapy in general clinical practice. Methods: This retrospective analysis to evaluate safety and efficacy included patients with gastric cancer who were received FTD/TPI plus RAM combination therapy or FTD/TPI monotherapy between August 2019 and March 2023 at 21 institutions. Results: 164 patients were analyzed, 38 patients in the RAM combination group and 126 in the FTD/TPI monotherapy group. The distribution of treatment lines (third/fourth/fifth) was 10/13/15 in the RAM group and 26/54/46 in the monotherapy group, respectively. RAM had been previously administered to 34 patients (89.5%) in the RAM group. Objective response rate and disease control rate were 11.1% / 55.6% (OR 2.0, 95% C.I. 0.84-4.77, p=0.126) in the RAM group and 5.5% /38.5% (OR 2.0, 95% C.I. 0.84-4.77, p=0.126) in the monotherapy group, respectively. Median progression-free survival (PFS) was 3.5 months in the RAM group and 2.1 months in the monotherapy group (HR 0.69, 95% C.I. 0.49-1.02, p=0.06), respectively. Median overall survival (OS) was 8.4 months in the RAM group and 5.8 months in the monotherapy group (HR 0.82, 95% C.I. 0.54-1.25, p=0.350), respectively. Grade 3 neutropenia was reported in 48.6%/52.4% (p=0.707), and there were no significant differences in other adverse event profiles between the two groups. Additionally, in the RAM group, a comparison between patients receiving standard dosing (2 weeks on/2 weeks off; n=7) and those on biweekly dosing (1 week on/1 week off; n=24) showed no notable differences in efficacy or safety. Conclusions: FTD/TPI plus RAM combination therapy showed a trend toward prolonged PFS compared to FTD/TPI monotherapy, but no significant difference in OS.

Enhanced Potential of Durvalumab in the Initial Treatment of Advanced Biliary Tract Cancer.

The prognosis of biliary tract cancer is extremely poor, with a 5-year survival rate of 20%. Surgery is the only treatment that can be expected to cure biliary tract cancer, but because many cases are unresectable or recurrent, chemotherapy has become the standard treatment. The effects of first-line administration of durvalumab have not been explored. This study examined whether durvalumab has an additive effect in the first line. Twenty-three patients who were diagnosed with recurrent or non-resected biliary tract cancer requiring anticancer chemotherapy were recruited. Three of these cases were excluded because they had only received one course of durvalumab. We retrospectively collected clinical and laboratory data. Progression-free survival (PFS) and overall survival (OS) were compared between patients who received durvalumab as first-line therapy (first group, FG) and those who received it as second-line or later therapy (second group, SG). PFS and OS were also compared in durvalumab-treated patients aged 75 years and older (older group) and in younger patients. Immune-related adverse events (irAEs) were graded using the Common Terminology Criteria for Adverse Events (CTCAE v5) based on the clinical notation available in the patient charts. Kaplan-Meier curves showed that SG was significantly associated with worse PFS (p=0.018), and the FG group also showed significantly prolonged OS (p=0.030). In addition, PFS from the start of durvalumab treatment was significantly longer in the older group compared to the younger group. However, no significant difference in OS was observed between the two groups. Durvalumab appears to contribute to prolonged PFS and OS when administered as an initial treatment. It may also contribute to improved outcomes in older patients with biliary tract cancer.

Updated Bayesian network meta-analysis on the efficacy and safety of PD−1 versus PD−L1 inhibitors in first−line treatment with chemotherapy for extensive−stage small-cell lung cancer

ObjectiveTo compare the efficacy and safety of programmed cell death 1 inhibitors plus chemotherapy (PD-1 + Chemo) and programmed cell death ligand 1 inhibitors plus chemotherapy (PD-L1 + Chemo) for the treatment of extensive-stage small-cell lung cancer (ES-SCLC).MethodsWe performed a meta-analysis of relevant data using R software, considering overall survival (OS), progression-free survival (PFS), and grade ≥ 3 treatment-related adverse events (TRAES).ResultsPD-1 + Chemo (OS: hazard ratio [HR] 0.71; PFS: HR 0.59) and PD-L1 + Chemo (OS: HR 0.72; PFS: HR 0.73) significantly prolonged survival and did not increase the incidence of grade ≥3 TRAEs compared with chemotherapy. Indirect comparisons showed no significant difference in clinical efficacy (OS: HR 0.99, 95% CI: 0.86–1.1; PFS: HR 0.80, 95% CI: 0.61–1.0) or safety (HR 1.0, 95% CI: 0.93–1.1) between PD-1 + Chemo and PD-L1 + Chemo. Non-cumulative probability ranking plot ranking results showed that PD-1 + Chemo ranked first in OS and PFS. Patients with PD-L1 expression levels &amp;lt; 1%, PD-1 + Chemo showed a trend of disadvantage (OS: HR 1.3; PFS: HR 1.2), whereas for patients with PD-L1 expression levels ≥ 1%, PD-1 + Chemo showed a trend of advantage (OS: HR 0.85; PFS: HR 0.85).ConclusionsPD-1 + Chemo and PD-L1 + Chemo significantly prolonged OS and PFS in patients with ES-SCLC and did not significantly increase the incidence of grade ≥ 3 TRAES. The efficacy and safety profiles of PD-1 + Chemo and PD-L1 + Chemo appear to be similar.

Prognostication of Brain-Metastasized Patients Receiving Subsequent Systemic Therapy: A Single-Center Long-Term Follow-Up

Background. Survival of patients with brain metastases (BMs) is poor. It has become clear that targeted therapy has an effect on BMs and patient’ prognosis. The question remains which patients benefit from additional systemic therapy. This assumption was evaluated in a large single-center cohort. Methods. Patients consecutively planned to undergo local radiotherapy for their BMs in 2006–2017 were selected (n = 200). Prognosis, using CERENAL, disease-specific graded prognostic assessment (DS-GPA), and Radiation Therapy Oncology Group recursive partitioning analysis (RTOG RPA), was evaluated. Results. Ninety-three (46.5%) patients received at least one additional line of systemic therapy subsequent to the diagnosis of their BMs. The median overall survival (OS) was 6.3 months. Having received subsequent systemic therapy resulted in a more favorable OS (10.4 versus 3.9 months). Interestingly, using dichotomized scores, CERENAL showed prognostic properties in all patients for disease-specific survival on multivariate analysis, whereas RTOG RPA and DS-GPA were not withheld in the model. Lastly, only having a favorable DS-GPA resulted in prolonged progression-free survival for first systemic therapy following BM diagnosis. Conclusions. Receiving subsequent systemic therapy has a profound influence on outcome in patients with BMs, indicating the effect of systemic therapy on BMs. Use of the CERENAL brain prognostic score shows potential for further prognostication of patients with more favorable outcomes.

Abstract B031: Proteomic profiling of oligometastatic castration-sensitive prostate cancer treated with stereotactic ablative radiotherapy

Abstract Background: The trajectory of metastatic castration-sensitive prostate cancer varies based on disease presentation and biology. While proteomic profiling studies of primary prostate tissue have linked protein expression with metastatic progression and prognosis, few studies have explored biological changes after treatment and their associations with response. Therefore, we conducted proteomic profiling of patients with oligometastatic castration-sensitive prostate cancer (omCSPC) treated with stereotactic ablative radiotherapy (SABR) or observation in the ORIOLE phase 2 randomized clinical trial (RCT). Methods Plasma from omCSPC patients in the ORIOLE trial was collected at baseline (day 1), day 90, and day 180. Protein abundance was quantified using the Olink Explore Assay. Differential expression from baseline to day 90 or 180 in each treatment arm was analyzed using a 2-sided t-test with Benjamini-Hochberg correction. Changes in protein expression at day 90 and 180 were compared with a Pearson correlation. Pathway enrichment was performed via gene set enrichment analysis (GSEA) using Reactome, KEGG, and Hallmark gene sets. Associations with progression-free survival (PFS) were analyzed using Kaplan-Meier and log-rank tests. Results In total, 1,472 proteins were assayed across 130 samples from 46 patients over 3 time points. Significant changes in expression post-SABR were noted at day 90 and 180 compared to baseline (using adjusted p-value cutoff of 0.05). At day 90, four proteins (FCRL1, CD22, TCL1A, FCER2) were downregulated; at day 180, only FCRL1, a Fc receptor-like gene family preferentially expressed in B cells, remained downregulated. No significant expression changes were found in the observation arm. Differential expression of proteins during follow-up were associated with PFS. In particular, LTO1, a maturation factor of ABCE1 important for ribosomal biogenesis and translation, was overexpressed at both day 90 and 180 post-SABR, and overexpression was associated with improved PFS at day 90 (median 24.5 mo vs 6 mo; p=0.017) and day 180 (median 33 mo vs 6 mo; p=0.043). These associations were absent in the observation arm. For proteins differentially expressed in the SABR arm at day 90, several signaling pathways were significantly enriched for patients with prolonged PFS, including positive enrichment of unfolded protein response (UPR) (p=0.008) and IL-4/IL-13 (p=0.009). At 180 days, several pathways were enriched for patients with prolonged PFS including negative enrichment of CTLA4 inhibitory signaling (p=0.005) and CD28 co-stimulation (p=0.008). Conclusion Proteomic analysis in omCSPC patients from the ORIOLE trial reveals significant expression changes at days 90 and 180 after SABR. B-cell signaling proteins were selectively downregulated in the SABR arm, and pathways associated with protein translation and immune response were enriched post-SABR for patients with prolonged PFS. Further research will explore connections to genomic and transcriptomic changes, with additional validation needed. Citation Format: Jarey H. Wang, Amol Shetty, Yang Song, Noura Radwan, Soha Bazyar, Xiaolei Shi, Theodore L. DeWeese, Daniel Y. Song, Ryan M. Phillips, Matthew P. Deek, Philip Sutera, Ana P. Kiess, Phuoc T. Tran. Proteomic profiling of oligometastatic castration-sensitive prostate cancer treated with stereotactic ablative radiotherapy. [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Targeted Therapies in Combination with Radiotherapy; 2025 Jan 26-29; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(2_Suppl):Abstract nr B031.

Dual anti-CTLA-4 and anti-PD-1 blockade in metastatic basal cell carcinoma

We report the basal cell cancer (BCC) cohort of the SWOG/NCI 1609 Dual Anti-CTLA-4 & Anti-PD-1 blockade in Rare Tumors (DART), a phase II prospective, multicenter basket trial of nivolumab and ipilimumab. The primary endpoint was objective response rate (ORR) (RECIST v1.1). Overall survival (OS), progression-free survival (PFS), and toxicity were secondary endpoints. Sixteen patients with advanced/metastatic BCC were evaluable. The ORR was 31% (95% CI, 19–50%), and the 12-month OS, 75% (95% CI, 57–100%). Median PFS was 9.3 months (95% CI, 3.3–NA). Of 15 patients evaluable for clinical benefit, five partial responses (PRs) and five stable disease >6 months (total = 10/15 (66.7%)) were seen. The most common toxicities included fatigue (37.5%), pruritis (31.3%), and diarrhea (25%). In patients with advanced/metastatic BCC, ipilimumab and nivolumab produced an ORR of 31% and prolonged (>6 months) PFS in 73% of patients, with seven PFS/iPFS of >1 year, including one with prior anti-PD-1. ClinicalTrials.gov ID: NCT02834013 (Registered 7/15/2016; https://clinicaltrials.gov/ct2/show/NCT02834013).

Comprehensive Genome Profiling for Treatment Decisions in Patients with Metastatic Tumors: Real-World Evidence Meta-Analysis and Registry Data Implementation.

Although precision oncology has rapidly been developed in recent years, its real-world impact and challenges in healthcare implementation remain underexplored. Through a meta-analysis of real-world evidence (RWE), we aimed at investigating the applicability and clinical impact of comprehensive cancer genome profiling (CGP) in cancer patients with metastatic solid tumors. We systematically searched Medline, Embase, and Web of Science for RWE studies on CGP and matched therapies in metastatic solid tumors (publication period: 2012-2023). Pooled proportions of actionable genomic alterations, patients treated with matched targeted therapies, treatment, and survival outcomes were calculated. Data from Swedish cancer registries were used as a case-study for nationwide CGP implementation. Out of the 7218 identified studies, 144 were included in our analysis. 59.8% of CGP-tested patients had actionable genomic alterations, with 15.6% (95% Confidence Interval (CI) 13.4-18.2%) of them having received targeted therapy. Objective response was seen in 23.9% (95% CI 20.8-27.3%). Overall, CGP-guided treatment was correlated with prolonged progression-free survival (pooled Hazard Ratio (HR) = 0.63; 95% CI, 0.56-0.70; 18 studies) and overall survival (pooled HR = 0.60; 95% CI, 0.51-0.70; 21 studies) when compared to conventional treatment. Meta-regression time projections analyses showed that these rates will steadily increase by 2030. Pooled analyses of RWE studies indicate that approximately one-fourth of the patients receiving CGP-matched treatment have an objective response. By utilizing meta-regression projections, our nationwide cancer registry case-study offers insights into the potential of precision oncology for patients with metastatic cancer and to inform future healthcare strategies.

Exploring the Prognostic Role of Trop-2, CD47, and CD163 Expression Levels on Survival Outcomes in Patients with Triple-Negative Breast Cancer.

Background: This study evaluated the prognostic impact of Trop-2, CD47, and CD163 expression on clinical outcomes in triple-negative breast cancer (TNBC) and investigated their interactions with tumor progression. Methods: A retrospective cohort of 92 patients with TNBC was analyzed. The expression scores for Trop-2, CD47, and CD163 were categorized as negative/low (0-3 points) or high (4-6 points). The primary endpoint was overall survival (OS). Results: The median age of the cohort was 50 years old. High Trop-2 expression was observed in 55.4% of the patients and was significantly associated with advanced disease stage (p < 0.001). High CD47 expression (44.6%) was correlated with advanced stage (p = 0.044), whereas high CD163 expression (45.7%) was associated with advanced stage (p = 0.021), absence of comorbidities (p = 0.022), and lower pT stage (p = 0.023). Moderate positive correlations were found between Trop-2 and CD47 (p = 0.022), Trop-2 and CD163 (p = 0.037), and CD47 and CD163 (p < 0.001), respectively. Kaplan-Meier survival analysis revealed that patients with low Trop-2 expression exhibited significantly prolonged OS (p = 0.021) and progression-free survival (PFS) (p = 0.026) compared to those with high Trop-2 expression. Univariate and multivariate analyses revealed significant associations between OS and PFS for Trop-2, lymphovascular invasion, and BRCA status. Conclusions: Trop-2 expression is a significant prognostic factor for TNBC and is correlated with worse outcomes. Although CD47 and CD163 showed trends for poorer prognosis, their significance was not confirmed. These findings offer promising prospects for future studies on combined antibody-drug conjugates (ADCs), as they may present opportunities to address multiple resistance mechanisms in the management of TNBC and enhance clinical outcomes.

Bruton’s tyrosine kinase inhibitor zanubrutinib-based regimens in relapsed/refractory primary diffuse large B-cell lymphoma of the central nervous system

Patients with relapsed/refractory primary central nervous system lymphoma (R/R PCNSL) usually have a poor prognosis and limited treatment options. We respectively reviewed 38 patients with R/R PCNSL treated with zanubrutinib-based regimens in our center. The overall response rate, complete response rate and disease control rate were 76.3%, 47.4% and 92.1%, respectively. The median progression-free survival (PFS) was 31.0 months, the median overall survival (OS) was not reached. Unitivariate analysis by Cox’s proportional hazards model revealed that overall response (vs. no response, HR = 0.18, 95%CI:0.07,0.48, p = 0.001), long duration of zanubrutinib (≥6months vs 2-5 months, HR = 0.20, 95%CI:0.06,0.63, p = 0.006) were independent factors for prolonged PFS. The log-rank analysis indicated a prolongation of PFS among patients exhibiting a higher Tumor mutational burden (TMB, ≥14.75muts/Mb) following zanubrutinib-based treatment (p = 0.016). Our data showed promising efficacy with tolerable safety of zanubrutinib-based therapies in patients with R/R PCNSL. Long duration of zanubrutinib may be associated with prolonged PFS.

Elacestrant in women with estrogen receptor-positive and HER2-negative early breast cancer: results from the preoperative window-of-opportunity ELIPSE trial.

Elacestrant has shown significantly prolonged progression-free survival compared to standard-of-care endocrine therapy in estrogen receptor-positive (ER-positive), HER2-negative metastatic breast cancer (BC), while potential benefit in early-stage disease requires further exploration. The SOLTI-ELIPSE window-of-opportunity trial investigated the biological changes induced by a short course of preoperative elacestrant in postmenopausal women with early BC. Eligible patients with untreated T1c (≥1.5 cm)-T3, N0, ER-positive/HER2-negative BC with locally assessed Ki67≥10% received elacestrant at a daily dose of 345mg for 4 weeks. The primary efficacy endpoint was complete cell cycle arrest (CCCA), defined as Ki67≤2.7%, at day 28. Overall, 22 patients were evaluable for the primary endpoint. Elacestrant was associated with a CCCA rate of 27.3% and a statistically significant geometric mean change of -52.9% (p=0.007; 95%CI, -67.4 to -32.1). The treatment with elacestrant led to a shift toward a more endocrine-sensitive and less proliferative tumor phenotype based on PAM50-based gene signatures. Elacestrant increased the expression of immune-response genes (GZMB, CD4, CD8A) and suppressed proliferation and estrogen-signaling (MKI67, ESR1, and AR). These biological changes were independent of the levels of Ki67 suppression at day 28. Most common adverse events were grade 1: anemia (21.7%), hot flushes, constipation and abdominal pain (8.7%, each). One patient experienced a grade 3 cutaneous rash leading to treatment discontinuation. No other serious adverse events were reported. Preoperative treatment with elacestrant in early BC demonstrated relevant biological and molecular responses and exhibited a manageable safety profile. These findings support further investigation of elacestrant in the early setting.