The Relationship Between Response Rate and Survival Benefits in Randomized Immunotherapy Studies.

489 Background: Limited studies have investigated the real-world effectiveness and safety of Lenvatinib (LEN) combined with everolimus (EVE) in metastatic renal cell carcinoma (mRCC), particularly after failure of immune checkpoint inhibitors (ICIs) and VEGFR tyrosine kinase inhibitors (TKIs). This study aimed to evaluate the efficacy and safety of LEN plus EVE in patients who had progressed after these prior therapies. Methods: This single-center retrospective study included mRCC patients at Asan Medical Center, Korea, who initiated LEN plus EVE as second-line or later therapy between September 2017 and June 2024. We reviewed electronic medical records for dosage, dose reductions, discontinuation, response, progression, and survival outcomes. The primary objectives were objective response rate (ORR) and progression-free survival (PFS), with secondary objectives including overall survival (OS), adverse events, and prognostic factors. Results: Eighty-two eligible patients were included, predominantly with clear cell type (n=74, 90.2%). ECOG performance status was 1 in 54 patients, and 2 in 26. At treatment initiation, the IMDC risk distribution was favorable (n=6, 7.3%), intermediate (n=48, 58.5%), and poor (n=28, 34.1%). The median number of prior therapies was four (range, 1-7), with 80.5% receiving LEN plus EVE as fourth-line or later therapy. All patients had prior anti-angiogenic TKI exposure, 86.6% had been treated with ICIs, and 37.8% had prior mTOR inhibitor therapy. The ORR was 39.0% (n=32/82), with a disease control rate (DCR) of 81.7% (n=67/82). The median follow-up duration was 21.8 months. The median time to progression (TTP) was 6.4 months (95% Confidence Interval [CI], 5.4-9.7), while the median PFS was 5.4 months (95% CI, 4.3-6.4), and the median OS was 7.7 months (95% CI, 6.2-12.1). Subgroup analyses indicated comparable ORR and PFS for patients treated beyond the fourth line (ORR 36.4%, PFS 5.3 months), those previously exposed to mTOR inhibitors (ORR 29.0%, PFS 5.5 months), and those who had progressed after both ICI and TKIs (ORR 38.0%, PFS 5.3 months). The median treatment duration was 6.8 months. Adverse events were significant: 54.9% required dose reductions of LEN, and 25.6% experienced treatment interruptions. For EVE, 17.1% required dose reductions, and 25.6% had interruptions due to toxicities. Notably, 31 patients (37.8%) developed proteinuria, with 18 experiencing grade 3 or higher. Conclusions: LEN plus EVE shows promising efficacy and disease control in heavily pretreated mRCC patients after failure of ICIs and VEGFR TKIs, even beyond the fourth line and in those previously treated with mTOR inhibitors. The safety profile aligns with known adverse effects, but the high incidence of proteinuria is notable. Further studies are warranted to optimize treatment protocols in this patient population.

Immune checkpoint inhibitors (ICIs) combined with chemotherapy have been applied as a first-line treatment for lung cancer, but consistent beneficial results have not been documented. Therefore, our meta-analysis aimed to evaluate the effectiveness and safety of combination therapy to promote its application. We searched electronic databases for studies that estimated the safety and efficacy of combined therapy. The objective response rate (ORR) and disease control response (DCR) parameters were evaluated with odds ratio (OR) values of the combination arm over the non-combination arm. Hazard ratios (HR) and its 95% confidence intervals (95% CI) were used to calculate progression-free survival (PFS) and overall survival (OS) in the combination and non-combination arms. All treatment-related adverse events (TRAEs) and 3 to 5 TRAEs were expressed as relative risk (RR) values of the combination arm over the non-combination arm. Ten eligible studies involving 4,887 patients were identified. The pooled ORs for ORR and DCR were 1.85 (95% CI: 1.30-2.63, P<0.01) and 1.14 (95% CI: 0.70-1.86, P<0.01), respectively. The pooled HRs for PFS and OS were 0.67 (95% CI: 0.58-0.79, P<0.001) and 0.76 (95% CI: 0.65-0.88, P<0.001), respectively. In subgroup analysis, ORR and DCR were significantly improved in the programmed cell death-1/L1 (PD-1/L1) blockade for non-small cell lung cancer (NSCLC) group (subgroup A), with a combined OR values of 2.36 (95% CI: 1.79-3.13, P<0.001) and 1.92 (95% CI: 1.10-3.35, P<0.001), respectively. However, no significant benefits were observed in the cytotoxic T lymphocyte antigen-4 (CTLA-4) blockade for small cell lung cancer (SCLC) (subgroup B) and CTLA-4 blockade for NSCLC groups (subgroup C). In addition, a significant improvement in PFS was observed in subgroup A, subgroup B and subgroup C, with pooled HR values of 0.58 (95% CI: 0.52-0.63, P<0.001), 0.86 (95% CI: 0.76-0.97, P<0.05) and 0.83 (95% CI: 0.68-1.00, P<0.05), respectively. Only subgroup A exhibited an OS benefit, with a combined HR value of 0.67 (95% CI: 0.55-0.81, P<0.001). Moreover, as the expression of PD-L1 increased, the PFS and OS benefits were more significantly. Furthermore, patients without central nervous system (CNS) metastasis who were treated with PD-1/L1 inhibitors had a longer OS than patients with CNS metastasis (HR: 0.67, 95% CI: 0.55-0.80, P<0.001). Finally, combined therapy was associated with 3 to 5 TRAEs (RR: 1.26, 95% CI: 1.08-1.47; P<0.01). Patients treated with immunotherapy and chemotherapy in combination exhibited superior in ORR, DCR, PFS and OS as well as slightly increased TRAE levels compared with those of patients treated with either monotherapy.

4088 Background: Regorafenib is the first oral targeted drug as a second-line agent in patients with unresectable hepatocellular carcinoma (HCC) who progressed on sorafenib treatment.There is a lack of data to validate the second-line therapy after progression of targeted-immune combination therapy. Our aim was to investigate the efficacy and safety of regorafenib alone or in combination with a programmed death-1 (PD-1) inhibitor in second-line treatment for patients who have failed tyrosine kinase inhibitor (TKI) in combination with PD-1 or TKI monotherapy, respectively. Methods: A total of 288 patients were enrolled in this multicenter, retrospective study. These patients received regorafenib with or without PD-1 inhibitor (Sintilimab/Camrelizumab/Pembrolizumab) as second-line therapy after failure of TKI (sorafenib/lenvatinib) or such TKIs combined with PD-1 inhibitor (Sintilimab/Camrelizumab/Pembrolizumab). The primary study endpoint was the evaluation of overall survival (OS), while secondary study endpoints were progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and treatment safety. Results: In the first line treatment, 126 patients received TKI and 162 patients received TKI plus PD-1. In the TKI cohort, the Reg-PD-1 group exhibited markedly higher ORR (29.69% vs 4.84%; p&lt;0.001) and DCR (89.06% vs 67.74%; p=0.004), as well as longer median PFS (10.5 vs 4.7 months; p&lt;0.001) and median OS (18.9 vs 14.0 months; p=0.03) compared to the Reg monotherapy group.There was no significant difference in PFS, OS, ORR, and DCR between the two groups in the TKI plus PD-1 cohort.The incidence of AEs was higher in the Reg-PD-1 group compared to the Reg group (81.25 % vs 58.06%; p=0.005) in the TKI cohort. And Reg-PD-1 group was comparable to Reg group (76.70% vs 66.10%; p=0.144) in the TKI Plus PD-1 cohort. Conclusions: Regorafenib plus PD-1 may enhance efficacy in uHCC patients who failed first-line TKI therapy. However, in patients who have progressed after first-line TKI plus PD-1 therapy, using regorafenib alone or in combination with PD-1 in second-line therapy does not show a significant difference in efficacy.These findings have significant implications for the selection of second-line treatment strategies for HCC patients, indicating that the combination of regorafenib and PD-1 might not provide additional benefits in certain patient subgroups. Outcomes in the two cohorts. Outcomes TKI TKI plus PD-1 Reg(n=62) Reg-PD-1 (n=64) P value Reg (n=59) Reg-PD-1 (n=103) P value CR 2 3 - 3 2 - PR 1 16 - 6 21 - SD 39 38 - 35 62 - PD 20 7 - 15 18 - ORR 4.84% 29.69% ＜0.001 15.25% 22.33% 0.276 DCR 67.74% 89.06% 0.004 74.58% 82.52% 0.227 PFS(m) 4.7 10.5 ＜0.001 6.3 9.2 0.062 OS(m) 14.0 18.9 0.03 13.2 16.2 0.13

e13124 Background: Bria-IMT, an allogeneic whole-cell cancer vaccine (SV-BR-1-GM), was administered w/ an anti PD1 checkpoint inhibitor (CPI) to evaluate its safety and efficacy in advanced/metastatic breast cancer (MBC). SV-BR-1-GM breast cancer cells were engineered to directly stimulate anti-tumor immunity through expression of tumor associated antigens and secretion of GM-CSF to enhance endogenous dendritic cell activation. Addition of a CPI potentiates SV-BR-1-GM action by overcoming the immune suppressive tumor microenvironment and may have a differential impact vs monotherapy SV-BR-1-GM. Methods: In this exploratory analysis of the Phase 1 + randomized Phase 2, HLA matching status was assessed to explore potential correlations w/ clinical outcomes. Pts were stratified by overall HLA match by Class I or II (0 vs ≥1 matches), formulation and MBC subtype to assess objective response rate (ORR), clinical benefit rate (CBR), progression free survival (PFS), and overall survival (OS). Partial HLA matching (≥1 Class I and ≥1 Class II allele) was also analyzed. Results: In the total pt population, the ORR was 10%, CBR 56%, PFS 3.2 months and OS 9.9 months. In those pts treated w/ the phase 3 formulation, ORR was 15%, CBR 63%, PFS 3.6 months and OS 13.4 months. Using available HLA data (n = 52), 25% had 0, 34.6% 1, 32.6% 2, and 8% ≥3 matches. While OS and PFS were greater (Undefined vs 8.5 mos ; p = .02) in pts without an HLA match compared w/ those w/ ≥1 match (see Table), ORR and CBR were similar. This was also the case for pts who had 0 HLA Class I matches vs those w/ ≥1 Class I match (15.6 vs 7.2 mos; p = .002). ORR, CBR, PFS and OS were generally similar for pts who had 0 Class II HLA matches vs those w/ ≥1 match. Pts who matched at least at 1 Class I and 1 Class II allele had a higher ORR and CBR than those who matched at a single Class I or a single Class II allele although PFS and OS were similar between the groups. Similar observations were seen for pts treated w/ the phase 3 formulation. Conclusions: Matching at Class I seemed to decrease PFS &amp; OS, but did not have a similar effect on ORR and CBR. Both matched and non matched pts demonstrated favorable OS and response rates. These findings support further investigation into specific mechanisms and the clinical significance of HLA matching in immunotherapy response. A randomized phase 3 trial is ongoing comparing Bria-IMT vs treatment of physician's choice (NCT06072612). Clinical trial information: NCT03328026 . n (Evaluable) % of Cohort Best ORR Best CBR PFS OS Full Cohort 52 (41) 10% 56% 3.2 9.9 No Match (Overall) 13 (10) 25% 20% 60% 4.2 Undefined Any Match (Overall) 39 (31) 75% 6% 55% 3 8.5 MHC Class I No Match / Any Match 27 (20) / 25 (21) 52% / 48% 10% /10% 55% /57% 3.5 / 2.7 15.6 / 7.23 MHC Class II Any Match 27 (19) 52% 11% 63% 3.2 11.4 MHC Class I&amp;II Match 13 (9) 25% 22% 77% 2.8 8.6 Phase 3 Formulation (N=35) 35 (27) 15% 63% 3.57 13.43 No Match (Phase 3 Formulation) 11 (9) 31% 22% 67% 5.6 Undefined MHC Class I&amp;II Match (Phase 3 Formulation) 11 (7) 31% 29% 71% 2.7 7.23

BackgroundLung cancer remains the leading cause of cancer incidence and mortality worldwide. Non-small cell lung cancer (NSCLC) accounts for approximately 80%–85% of cases, and the majority of patients are diagnosed at an advanced stage with poor prognosis. Immune checkpoint inhibitors (ICIs) combined with chemotherapy have become the standard first-line treatment for advanced NSCLC, significantly improving survival outcomes. However, considerable inter-individual variability in treatment response persists, underscoring the urgent need for novel predictive biomarkers. Systemic inflammation and immune status are closely associated with immunotherapy efficacy. Lymphocytes play a critical role as effector cells in antitumor immunity, while high-density lipoprotein (HDL), beyond its role in lipid metabolism, also exerts anti-inflammatory and immunomodulatory functions. The lymphocyte-to-HDL ratio (LHR), a composite indicator integrating immune and metabolic status, has demonstrated prognostic value in several malignancies. Nevertheless, its predictive significance in advanced NSCLC patients receiving chemo-immunotherapy remains unclear. This study aims to evaluate the prognostic value of LHR for long-term outcomes in this population, thereby providing insights for individualized treatment strategies.AimTo investigate the predictive value of the lymphocyte-to-high-density lipoprotein ratio (LHR) for long-term outcomes in patients with advanced non-small cell lung cancer (NSCLC) receiving chemo-immunotherapy, and to evaluate its potential as a convenient and cost-effective biomarker for guiding individualized clinical treatment.MethodsThis single-center retrospective study included 287 patients with advanced non-small cell lung cancer (NSCLC) who received first-line treatment with immune checkpoint inhibitors (ICIs) combined with platinum-based chemotherapy. Pretreatment lymphocyte-to-high-density lipoprotein ratio (LHR) levels were calculated, and the optimal cutoff value was determined using receiver operating characteristic (ROC) curve analysis. Univariate and multivariate Cox proportional hazards regression analyses were performed to identify independent prognostic factors associated with progression-free survival (PFS) and overall survival (OS). Based on these factors, a nomogram prediction model was developed. Variable selection was guided by clinical relevance, routine applicability, and data availability. Model performance was evaluated using the concordance index (C-index), area under the ROC curve (AUC), and calibration plots.ResultsBased on the optimal cutoff value determined by ROC curve analysis, 287 patients with advanced NSCLC were stratified into a low LHR group (<35.3) and a high LHR group (≥35.3). The median progression-free survival (PFS) was significantly longer in the low LHR group compared with the high LHR group (17.00 [14.00–22.00] vs. 11.80 [9.80–14.50] months; p = 0.028). Similarly, the median overall survival (OS) was 24.00 (21.00–29.00) months in the low LHR group and 18.00 (16.00–20.00) months in the high LHR group (p < 0.001). The objective response rate (ORR) and disease control rate (DCR) were also higher in the low LHR group than in the high LHR group (ORR: 48.92% vs. 35.81%, p = 0.025; DCR: 87.77% vs. 78.38%, p = 0.035). Multivariate Cox regression analysis identified LHR, PD-L1 expression, distant metastasis, and carcinoembryonic antigen (CEA) as independent prognostic factors for both PFS and OS (all p < 0.05). A nomogram prediction model for PFS and OS was subsequently developed based on these factors. In the training cohort, the C-index of the PFS model was 0.73 (95% CI: 0.69–0.78), with an internal validation C-index of 0.78 (95% CI: 0.71–0.85), indicating good discriminative ability. The AUCs for 6- and 12-month PFS prediction were 0.82 (95% CI: 0.76–0.89) and 0.86 (95% CI: 0.75–0.96) in the training cohort, and 0.87 (95% CI: 0.80–0.93) and 0.89 (95% CI: 0.81–0.97) in the validation cohort, respectively. For OS prediction, the C-index values were 0.80 (95% CI: 0.76–0.84) in the training cohort and 0.82 (95% CI: 0.77–0.86) in the validation cohort. The model demonstrated high accuracy in predicting OS at 12, 18, and 24 months: training cohort AUCs of 0.81 (95% CI: 0.74–0.89), 0.85 (95% CI: 0.74–0.91), and 0.94 (95% CI: 0.90–0.98), and validation cohort AUCs of 0.89 (95% CI: 0.80–0.98), 0.88 (95% CI: 0.80–0.96), and 0.82 (95% CI: 0.71–0.93), respectively. Calibration plots showed strong agreement between predicted and observed outcomes, confirming the model’s robustness and clinical applicability.ConclusionThis study demonstrated that the lymphocyte-to-high-density lipoprotein ratio (LHR) is an independent predictor of long-term outcomes in patients with advanced NSCLC receiving chemo-immunotherapy. A low LHR was associated with improved progression-free survival, overall survival, and higher objective response and disease control rates. The nomogram model incorporating LHR showed favorable predictive accuracy and clinical applicability.

4094 Background: In recent years, the first-line treatment options for advanced HCC has been increasingly abundant, including transarterial therapies, combination of the immune checkpoint inhibitors (ICIs) and the anti-vascular endothelial growth factor (VEGF) inhibitor, ICIs combined with ICIs, and tyrosine kinase inhibitors. However, it remains to be confusing which treatment pattern would benefit people most, especially for different subgroups. Methods: A systematic literature search was conducted on PubMed, Embase, Cochrane Central Register of Controlled Trials, and American Society of Clinical Oncology and European Society of Medical Oncology meeting proceedings for III phase randomized clinical trials (RCTs) investigating first-line treatments for HCC compared with sorafenib. The survival outcomes and toxic effects of RCTs should be reported, including overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and adverse events (AEs) of grade 3 or higher. This systematic review was performed in line with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Guidelines. The random-effects model was used to calculate the summary hazard ratios (HRs) of OS and PFS. The likelihood of ORR, and AEs of grade 3 or higher was performed by odds ratios (ORs) using a random-effects model. Results: A total of 13 phase III RCTs involving 8505 patients were included in this study. Hepatic arterial infusion of oxaliplatin combined with fluorouracil (FOHAIC-1) showed OS, PFS, and ORR benefit over all other first-line therapies, except for the regimen of sorafenib plus HAIC of FOLFOX (OS: HR, 0.88; 95% CI, 0.37-2.09; ORR: OR, 1.53; 95% CI, 0.29-8.13). More importantly, we found that sorafenib combined with FOLFOX was superior to other regimens in patients with HBV infection regarding OS except FOHAIC-1 (HR, 0.57; 95%CI, 0.21-1.52) and tremelimumab-durvalumab (HR, 0.42; 95%CI, 0.16-1.11). While in HCV-infected subgroup, ICIs combined with anti-VEGF inhibitor improved OS benefit compared with tremelimumab-durvalumab (HR, 0.31; 95% CI, 0.11-0.84) and sorafenib (HR, 0.38; 95% CI, 0.16-0.88). HAIC-FO also showed significant OS benefits to other therapies in patients with portal invasion or extrahepatic metastasis. The probability of adverse events of grade 3 or higher was significantly lower with HAIC-FO than with others except for nivolumab (RR, 0.96; 95%CI, 0.51-1.82) and tislelizumab (RR, 0.57; 95%CI, 0.30-1.08). Conclusions: This network meta-analysis supports arterial infusion as the first-line treatment for patients with HCC. In portal invasion and extrahepatic metastasis subgroups, HAIC-FO may be a preferred option, with sorafenib combined with FOLFOX as an additional option in those with HBV infection. Besides, novel combination therapy should be focused on in patients with certain subgroups.

Efficacy and safety of first-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) combined with chemotherapy or antiangiogenic therapy as first-line treatment in patients with EGFR-mutant non-small cell lung cancer: A systematic review and meta-analysis.

6085 Background: Many studies have confirmed that the combination with anti-vascular drugs can significantly improve the efficacy of anti-PD-1/PD-L1 inhibitor in a variety of tumors. Camrelizumab is a humanized anti-programmed cell death receptor 1 (PD-1) antibody. Famitinib is a tyrosine kinase inhibitor which exhibits anti-angiogenesis and antiproliferative effects via targeting VEGFR-2, c-Kit and PDGFR-β. Herein, we aimed to evaluate the efficacy and safety of camrelizumab plus famitinib in the treatment of advanced or metastatic thyroid cancer. Methods: A single-arm, open-label phase II study was conducted, patients (pts) with advanced or metastatic thyroid cancer were recruited, including radioiodine-refractory differentiated thyroid cancer (group 1), differentiated thyroid cancer ineligible for 131I treatment (group 2), medullary thyroid cancer (group 3) and anaplastic thyroid cancer (group 4). Pts received camrelizumab 200mg i.v. on day 1 of each 21-day cycle and oral famitinib 20mg po qd in 21-day cycles until progressive disease or drug intolerance. The primary endpoint was objective response rate (ORR). The secondary endpoints were safety, adverse events (AEs), duration of response (DoR), disease control rate (DCR), progression-free survival (PFS) and overall survival (OS). Results: Between Jan 14, 2020 and Feb 9, 2022, 74 pts were enrolled. There were 12/26/5/31 pts in group 1/2/3/4 respectively. Median follow-up time was 11.4 months. In group 1, of 12 evaluable pts, confirmed ORR, ORR and DCR accounted for 33.3%, 41.7% and 100.0%, respectively. In group 2, of 25 evaluable pts, the confirmed ORR and DCR were 44.0% and 96.0%, respectively. In group 3, of 5 evaluable pts, the confirmed ORR and DCR were 40.0% and 100.0%, respectively. In group 4, of 24 evaluable pts, the confirmed ORR, ORR and DCR were 62.5%, 75% and 95.8%, respectively. PFS and OS were not yet mature for group 1-3, and in group 4, of all enrolled pts, estimated median PFS was 8.4 months and estimated median OS was 13.6 months. 73 pts were included in safety set. The most common treatment related AEs were diarrhea (37.0%), palmoplantiplanar swelling syndrome (34.2%), hypertension (31.5%) and fatigue (31.5%). Conclusions: Camrelizumab plus famitinib demonstrated promising anti-tumor efficacy with acceptable toxicity in pts with advcanced or metastatic thyroid cancer. Clinical trial information: NCT04521348.

BackgroundThe role and sequencing of combination immuno-oncology (IO) therapy following progression on or after first-line IO therapy has not been well-established. The Fast Real-time Assessment of Combination Therapies in Immuno-ONcology...

393 Background: S-1 is an oral anticancer agent combining tegafur, a prodrug of 5-fluorouracil (5-FU), with 5-chloro-2,4-dihydroxypyridine and potassium oxonate. S-1 has shown efficacy for cytokine and/or tyrosine-kinase inhibitor (TKI) refractory metastatic renal-cell carcinoma (mRCC). We report the final results of a phase II study and evaluate 5-FU-related enzymes as a predictor of the response to S-1. Methods: 45 patients received S-1 at a dose of 40 mg/m2 twice daily for 28 days, followed by 14 days of rest. The primary endpoint was the objective response rate (ORR). The secondary endpoints of progression-free survival (PFS) and overall survival (OS) were estimated by the Kaplan-Meier method. Formalin-fixed, paraffin-embedded specimens obtained by radical nephrectomy were used for mRNA expression assay, performed by reverse-transcriptase polymerase chain reaction. Results: 45 patients including 6 were progressed after TKI were enrolled from April 2006. 24 patients received more than 5 cycles, and 2 continued to receive S-1 as of October 2011. Two (4.4%) of the 45 patients had complete responses to S-1, 9 (20.0%) had partial responses, and 28 (62.8%) had stable disease. The final PFS and OS were 9.2 and 42.8 months, respectively, and the PFS of TKI refractory patients was approximately two times of final PFS (18.0 months). The most common grade 3-4 adverse events according to CTCAE v.3.0 were similar to the previous report except for hemoglobin decreased and fatigue. On mRNA expression analysis, the expression level of thymidylate synthase correlated with ORR and PFS. On the other hand, OS did not differ significantly between patients with low expression and those with high expression of 5-FU-related enzymes. Conclusions: S-1 is effective and well tolerated in patients with cytokine and/or TKI refractory mRCC. Moreover, long-term treatment with S-1 is safe in mRCC patients enabling long-term disease control, especially in TKI refractory patients. Clinical trial with large number of TKI refractory patients is warranted to determine the efficacy of S-1.

3559 Background: XELAVIRI compared initial vs sequential irinotecan (iri) in combination with fluoropyrimidine (FP) plus bevacizumab (bev) in patients (pts) with mCRC, trial identification: NCT01249638. In the full analysis set of the study, non-inferiority of time to failure of strategy (TFS) was not shown (primary endpoint). Pts with RAS/BRAF wildtype (wt) tumors benefitted from initial iri. Methods: The study endpoints objective response rate (ORR), progression-free survival (PFS), time to failure of strategy (TFS) as well as overall survival (OS) were evaluated in female vs. male pts as well as molecular subgroups (i.e. RAS mutational status). Interaction of treatment and gender was tested by likelihood ratio tests. Results: Of 421 patients, 281/140 were male/female. In male patients, ORR was 33.6% without and 58.3% with initial iri (P &lt; 0.001). PFS (HR: 0.54 (95%CI 0.42-0.69) P &lt; 0.001) and OS (HR: 0.63 (95%CI 0.47-0.85), P = 0.002), were also significantly better with initial iri. In the subgroup analysis, this effect was especially pronounced in pts with RAS/BRAF wt tumors. In female pts, ORR was 43% in both arms, PFS was similar (HR: 1.09 (95%CI 0.76-1.55), P = 0.65) without and with initial iri. In OS, a strong trend for inferior outcome with initial iri was seen (HR: 1.46 (95%CI 0.95-2.24), P = 0.08) that reached significance in the multivariate analysis (HR: 1.73 (95%CI 1.04-2.86, P = 0.034). Female patients with RAS/BRAF wt tumors did not benefit from initial iri (HR 1.05 (95% CI 0.46-2.41), P = 0.903 for OS). Formal interaction of treatment and gender was seen for ORR (P = 0.018), PFS (P = 0.002) and OS (P = 0.001). There were some trends for more pronounced toxicities in female pts treated with Irinotecan. Conclusions: This unplanned exploratory analysis suggests that gender might interact with efficacy of initial iri when used in the context of FP and bev. While especially male RAS wild-type patients derived a significant and clinically meaningful benefit from initial use of iri, this was not observed in female patients with RAS wt tumors. Clinical trial information: NCT01249638.

Background: Breast cancer (BC) is the most frequent malignant tumor worldwide. The most frequent immunophenotype is luminal. 8-13% are diagnosed in metastatic stages and it is estimated that up to 20-40% of patients in local and locally advanced stages will recur. The first line of treatment in this scenario is cyclin-dependent kinase inhibitors 4 and 6 (ICDK4/6). However, in our setting real world evidence is poor. Methods: We conducted an observational, retrospective, descriptive, cohort study in which women &amp;gt;18 years with histological confirmation of breast cancer with hormone receptors (HR+) and HER-2 negative (-) in metastatic stage were evaluated at the ABC medical center. The primary objective was to evaluate clinical and pathological factors associated with progression-free survival (PFS). Results: 70 patients were treated with ICDK4/6, 54 (77%) presented recurrence while 16 (23%) presented de novo metastases, the median age was 58 years, 52 (74%) women were postmenopausal. The functional status they presented was ECOG 0 (7%), ECOG 1 (50%) and ECOG 2 (43%). Forty-five (64%) received ICDK4/6 in first, 13 (19%) in second, 9 (13%) in third and 3 (4%) in fourth or more lines of treatment. Forty (57%) had HER-2 low. The predominant number of metastatic sites was 2 in 25 (36%). Fifty (86%) used Palbociclib, 6 (9%) Ribociclib and 6 (5%) Abemaciclib. Factors that were associated with greater PFS were: using ICDK4/6 first line 23 vs 15, 20 or 4 months; HR=0.023 [95% CI; 0.004-0.136], p=&amp;lt;0.001; objective response rate (ORR) of 24 vs 6 months, p=0.001; absence of HER-2 low of 25 vs 17 months (p=0.011). Factors associated with longer overall survival (OS) were ORR p=&amp;lt;0.001, ECOG (p=0.019), INL &amp;lt; 4 (p=0.031), lung metastases (p=0.011), liver metastases (p=0.015), other metastatic sites (p=&amp;lt;0.001) and fatigue (p=0.036). HER-2 low status had a trend to lower OS (p=0.059). Adverse events (AE's) G3-4 occurred in 70%, with no differences between ICDK4/6 types, dose adjustments were required in 30%, treatment was discontinued in 19%, The most frequent toxicity with Palbociclib and Ribociclib was neutropenia (72% and 100% respectively), no grade 3-4 toxicities occurred with Abemaciclib. Conclusions: We present a Mexican study with real-world data in luminal breast cancer patients treated with ICDK4/6. PFS, OS, ORR and toxicity are similar to previous reported in clinical trials. Factors associated with higher PFS were the line in which ICDK4/6 was received and ORR. There was no difference between ICDK4/6 types. HER-2 low status appears to be a predictive factor in this setting. Citation Format: Juan Manuel Tovar Cabrera, Alejandro Noguez Ramos, Paula Anel Cabrera Galeana, Raquer Gerson C wilich. Clinical and pathologic factors associated with progression-free survival in patients with metastatic hormonal breast cancer treated with ICDK4/6 [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P5-01-10.

406 Background: Despite anatomical and biological differences, upper and lower tract UC (UTUC; LTUC) are usually managed similarly. Modern era clinical trial data comparing their outcomes with ICI are conflicting. We hypothesized that response and outcomes would be similar in patients (pts) with advanced UTUC and LTUC. Methods: We performed a retrospective cohort study collecting demographic, clinicopathologic, treatment, and outcome data for pts with advanced UC receiving ICI (2013-2020) across 24 centers (US; Europe). We compared objective response rate (ORR), overall survival (OS), and progression-free survival (PFS) between pts with UTUC and LTUC. Uni- / multi- variable logistic and Cox regression were used to assess the effect of UTUC on ORR, OS, and PFS. Stratified subgroup analyses were performed according to histology (pure, mixed) and line of treatment (first-line, subsequent). Results: A total of 984 pts were identified, and 707, 717, and 738 were included in ORR, OS, and PFS analyses, respectively. After exclusions, the UTUC group comprised of 130 pts (vs. 616 in LTUC) with median age 71 (40-92) (vs. 70 [32-93]), 62% men (vs. 76%), 41% never smokers (vs. 29%), 62% with history of prior radical surgery for primary tumor (vs. 52%), and 29% with liver metastases (vs. 18%). Table shows results of ORR, OS, and PFS analyses. In the overall population, pts with UTUC and LTUC receiving ICI had comparable ORR, OS, and PFS. Pts with mixed-histology UTUC had significantly lower ORR (adjusted OR 0.20, 95%CI 0.05-0.91) and shorter PFS (adjusted HR 1.66, 95%CI: 1.06-2.59) vs. mixed-histology LTUC. Conclusions: Pts with advanced UTUC and LTUC receiving ICI have similar response and outcomes, except for pts with mixed-histology UTUC vs LTUC. Subset analysis of primary tumor location in ongoing clinical trials can validate our data, while biomarker work is ongoing. [Table: see text]

e19535 Background: PBR and TafaL are two recently regulatory approved regimens that offer treatment options for R/R DLBCL patients who are ASCT ineligible or choose not to undergo ASCT. PBR is administered over 6 cycles, whereas TafaL is sustained until disease progression or death. We report here on an independent, naïve comparative, pharmacoeconomic evaluation of both regimens. Methods: Cost effectiveness and cost utility analyses were performed using a Markov model with 3 health states (progression free survival (PFS), post progression survival (PPS), death) parametrically extrapolated over a 5-year (y) time horizon (US payer perspective; 2020 USD). Cost inputs included main treatment, premedication, drug administration, adverse event management, and physician and laboratory fees. Incremental cost effectiveness ratios (ICER) and cost-utility ratios (ICUR) estimated the incremental costs to gain 1 unadjusted (LY) or quality adjusted life years (QALY), respectively. A novel metric of the incremental cost per 1% gain in probability of achieving objective response (OR), PFS and overall survival (OS) at trial follow up (̃2y) and PFS and OS at 5y with TafaL over PBR were estimated. Deterministic (DSA) and probabilistic (PSA) sensitivity analyses complemented base case analyses (BCA). Willingness to pay (WTP) thresholds were estimated. Results: At trial follow up (̃2y), PFS and OS rates were 38% and 63% for TafaL vs rates of 18% and 27.5% for PBR. The corresponding 5y PFS and OS rates were 13% and 32.7% for TafaL vs 5.2% and 11.3% for PBR. In BCAs, 5y TafaL costs ($470,949) exceeded PBR’s ($251,615) by $219,334 for incremental gains of 0.71 LY and 0.32 QALY. This yielded BCA ICER of $307,840/LYg and ICUR of $689,314/QALYg attenuated in PSA estimates of ICER of $280,042/LYg and ICUR of $589,215/QALYg. In DSAs, TafaL PFS utility value and PBR treatment costs were the most influential parameters. In PSAs, TafaL had a 50% probability of being cost effective at WTPs of $278,050/LYg and $560,360/QALYg. The incremental cost per 1% gain in probability to achieve OR, PFS and OS at follow up were $7,714, $5,785 and $3,259; and $28,120 and $10,249 for PFS and OS at 5 years. Conclusions: Considering that economic evaluations are intended to inform (but not set) policy, this independent analysis demonstrated that sustained TafaL treatment is associated with better survival outcomes than PBR though at greater cost. The incremental costs to gain a 1% improvement in 2y and 5y survival outcomes with TafaL over PBR were modest, underscoring the longer-term benefit of TafaL over PBR in pts ineligible for or opting out of ASCT.

e21552 Background: Immune checkpoint inhibitors (ICIs) and targeted therapies have significantly improved clinical outcomes in advanced melanoma. However, resistance to ICIs lead to relapse in a substantial proportion of patients, creating a critical need for effective treatment strategies after ICI failure. Tumor-infiltrating lymphocyte (TIL) therapy and oncolytic virus therapies like Talimogenelaherparepvec (TVEC), have emerged as promising approaches alongside other systemic therapies. This study systematically evaluates the efficacy and safety of systemic therapies after ICI failure to guide sequencing new treatment modalities in relapsed advanced melanoma. Methods: A systematic search of PubMed, Cochrane, and Ovid databases from January 2012 to December 2024 was conducted to identify studies on systemic therapies for advanced melanoma following ICI failure. Data were extracted on study design, treatment sequences, progression-free survival (PFS), overall survival (OS), and response rates (RR), including complete response (CR) and partial response (PR) rates that collectively contribute to the objective response rate (ORR). The data were summarized descriptively to capture treatment efficacy and safety outcomes across different therapeutic approaches. Results: From 145 studies identified, 31 (n = 3,462) met inclusion criteria. OS data were available on 2,407 patients, and PFS for 2,342 patients. For ICI/PD-1 retreatment (anti-CTLA-4 with nivolumab or pembrolizumab), the ORR ranged from 11% to 34%, with a median PFS of 2.5 to 8.5 months and OS of 14.3 months. In BRAF positive patients, MEK/BRAF inhibitors post-ICI therapy showed similar results (ORR 32%, PFS 7.5 months, OS 12.8 months). Sequential anti-CTLA-4/anti-PD-1 or anti-PD-1/anti-LAG-3 therapies yielded lower ORRs (8% to 14%) and shorter PFS (2.8 months). TIL/HD IL2 therapy achieved the highest efficacy, with an ORR of 37.5% and OS not reached among responders. TVEC therapy showed promising results (ORR 55%, PFS 37 months). Chemotherapy exhibited the lowest efficacy (ORR 11%, PFS 2.5 months). Grade 3-4 immune-mediated adverse events were noted in 5-57% of patients, with cytopenia affecting up to 100% of TIL therapy recipients. Conclusions: Therapeutic options for advanced melanoma after PD-1 failure are expanding, with TIL therapy, anti-LAG-3 inhibitors, TVEC, and targeted agents. Heterogeneity of study designs, response rates, and toxicity profiles complicate direct comparisons. Given the high efficacy, TIL therapy and TVEC should be considered as second line treatment options. Further research to establish optimal treatment algorithms and combination strategies with acceptable toxicity profile is warranted in relapsed melanoma.