Dual HER2 inhibition: Is two better than one?

Understanding the relationship between the Objective Response Rate (ORR) and survival outcomes, notably Progression-Free Survival (PFS) and Overall Survival (OS), is relevant for assessing the efficacy of regimens in oncology. We evaluate the relationship between ORR, PFS and OS in immuno-oncology (IO) trials. Data from 68 clinical trials submitted to the FDA were evaluated, examining immunotherapy regimens, notably immune checkpoint inhibitors such as anti-programmed death (ligand)-1 [anti-PD-(L)1], cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) inhibitors and combination therapies [e.g., IO + IO, anti-PD-L1 + chemotherapy, anti-PD-L1 + CTLA-4, anti-PD-L1 + TKI (tyrosine kinase inhibitors)]. Studies were included based on their reporting of ORR, PFS, and OS. Of the 68 clinical trials reviewed, 55 were included in the analysis. The correlation between ORR and PFS was moderate across most immunotherapy regimens, indicating that ORR can serve as a useful predictor of short-term disease control. However, the correlation between ORR and OS was weaker, especially in trials including combination therapies, indicating that ORR alone may not reliably predict long-term survival outcomes. ORR predicts PFS better in first-line treatment but declines in later lines and remains a weak OS predictor overall. Differing degrees of correlation between ORR and survival metrics, particularly across treatment lines and combinations, are observed. While ORR can serve as a surrogate marker for PFS in IO trials, its utility in predicting OS is restricted and the interpretation of the relationship between ORR and PFS or OS is a key limitation. Rather, a decline in PFS with increasing ORR may reflect trial differences rather than a direct relationship. Future analyses should adopt better methodologies to capture these dynamics and focus on improving surrogate endpoints for immunotherapy to improve clinical trial design and patient outcomes.

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 & 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&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&II Match (Phase 3 Formulation) 11 (7) 31% 29% 71% 2.7 7.23

Background: Blockade of the immune checkpoints PD-1 and CTLA-4 each results in improved overall survival in patients (pts) with metastatic melanoma using monotherapy. In a phase 1 dose-escalation study, dual inhibition of these pathways by nivolumab (NIVO) and ipilimumab (IPI) demonstrated encouraging antitumor activity. Methods: Treatment-naïve pts with advanced melanoma were randomized (double-blind) 2:1 to IPI 3 mg/kg combined with either NIVO 1 mg/kg (NIVO+IPI combination group) or placebo (PBO; IPI alone group) every 3 weeks (Q3W) for 4 doses, followed by NIVO 3 mg/kg or PBO, respectively, Q2W until disease progression or unacceptable toxicity. Primary endpoint was investigator-assessed objective response rate (ORR) in BRAF wild-type (WT) pts. Secondary endpoints included progression-free survival (PFS), ORR in BRAF V600 mutation-positive (MT) pts, and safety. Results: In BRAF WT pts, ORR was 60% (43/72) in the NIVO+IPI group vs 11% (4/37) in the IPI group (P<0.0001); complete response reported in 12 (17%) and 0 pts, respectively. Median change in target lesions was 57% reduction for NIVO+IPI vs 4% increase for IPI alone. Median duration of response was not reached in either group. In BRAF WT pts, median PFS was 8.9 months for NIVO+IPI; 4.7 months for IPI (HR 0.40, 95% CI 0.22-0.71; P = 0.0012). Similar results for ORR and PFS favoring the combination were observed in BRAF MT pts (Table). A higher rate of drug-related grade 3-4 adverse events was observed in the NIVO+IPI group compared to IPI (Table), leading to more frequent discontinuation. Pts who discontinued NIVO+IPI due to study drug toxicity had a 67% response rate; most continue to respond. Immune-mediated AEs were manageable by standard treatment interventions, and the majority resolved with immune-modulating medication. Conclusion: NIVO+IPI significantly improved ORR and PFS compared to IPI alone in treatment-naïve pts with advanced melanoma, and had a manageable safety profile. Efficacy (evaluated in all randomized patients)BRAF WTBRAF WTBRAF MTNIVO+IPIIPINIVO+IPIIPIRandomized patients, N72372310ORR,% (95% CI)59.7 (47.5-71.1)a10.8 (3.0-25.4)a43.5 (23.2-65.5)0 (0-30.8)Best overall response, n (%)Complete response12 (16.7)04 (17.4)0Partial response31 (43.1)4 (10.8)6 (26.1)0Stable disease10 (13.9)12 (32.4)5 (21.7)2 (20.0)Progressive disease10 (13.9)16 (43.2)5 (21.7)7 (70.0)Median PFS, mo (95% CI)8.9 (7.0, NE)4.7 (2.8, 5.3)7.4 (2.8, NE)2.7 (0.99, 5.4)HR, (95% CI)0.40 (0.22-0.71) P = 0.00120.33 (0.1, 0.9)bSafety (evaluated in all treated patients)Patients reporting AE, n (%)NIVO+IPI (N = 94)IPI (N = 46)Any GradeGrade 3-4Any GradeGrade 3-4Treatment-related AEs86 (91.5)48 (51.1)42 (91.3)9 (19.6)aP<0.0001; estimated odds ratio for objective response 12.23 (95% CI, 3.69-51.40)bDue to the small sample size in the BRAF MT subgroup, no P-value is provided NE = not estimable Citation Format: F. Stephen Hodi, Michael A. Postow, Jason Chesney, Anna C. Pavlick, Caroline Robert, Kenneth Grossmann, David McDermott, Gerald Linette, Nicolas Meyer, Jeffrey Giguere, Sanjiv S. Agarwala, Montaser Shaheen, Marc S. Ernstoff, David R. Minor, April Salama, Matthew H. Taylor, Linda Rollin, Christine Horak, Paul Gagnier, Jedd D. Wolchok. Improved clinical response in patients with advanced melanoma treated with nivolumab combined with ipilimumab compared to ipilimumab alone. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2860. doi:10.1158/1538-7445.AM2015-2860

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.

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]

e21067 Background: Efficacy of BRCA1/2 inhibitor in non-small cell lung cancer (NSCLC) is under investigation in serval clinical trials. Meanwhile immune checkpoint inhibitor (ICI) has become one of the standard therapies for advanced NSCLC, while its efficacy in BRCA mutant NSCLC is not clear. This study assessed the efficacy of anti-PD-(L)1/CTLA-4 in advanced BRCA-mutant NSCLC. Methods: Data of cohort OAK, POPLAR and Rizvi et al.,2018 was downloaded. Efficacy including objective response rate (ORR), progression-free survival (PFS) and overall survival (OS) were reviewed for BRCA1/2 mutant and wild-type group. The impact of mutant gene ( BRCA1, BRCA2), histological types (adenocarcinoma, squamous) and tumor mutation burden ranges (TMB, > 10 SNVs/Mb, < 10 SNVs/Mb) was analyzed if information was available. Results: A total of 809 ICI-treated advanced NSCLC patients, including 53 (6.6%) with BRCA1/2 mutation, were identified. In OAK/POPLAR cohort (atezolizumab monotherapy, 2nd line or more), TMB in BRCA1/2 mutant group was significant higher (19.2 vs. 10.24, P=0.008) than group of wild-type. The ORR of mutant group was 21.9% (Table), median PFS was 2.5 months, median OS was 9.5 months. The ORR and PFS were comparable between mutant and wild-type groups, while OS of the mutant group was significantly shorter than that in wild-type group (mOS, 9.5 months vs. 14.1 months, P= 0.02). Within mutant group, no significant difference of ORR, PFS and OS were found between mutant gene ( BRCA1 vs. BRCA2), histological type (adenocarcinoma vs. squamous) and TMB range (>10 vs. <10). In Rizvi’s cohort (anti-PD-(L)1 /CTLA-4 mono- or combination therapy, 1st line or more), TMB in mutant group was also significant higher (22.2 vs. 9.1, P=0.04) than wild-type group. ORR, PFS for mutant and wild-type groups were 25.0% vs. 20.1%, 3.2 months vs. 3.4 months, without significant difference. Within mutant group, superior PFS was found in adenocarcinoma subgroup (mPFS, 5.5 months vs. 1.2 months (squamous subgroup), P = 0.008) and BRCA2-mutant subgroup tend to have superior PFS (mPFS 5.5 months vs. 1.8 months, P=0.08) than BRCA1-mutant subgroup. Conclusions: This retrospective multicohort analysis showed a trend of worse survival in BRAC-mutant NSCLC patients after ICI treatment compared to those in wild-type group, in spite of higher TMB level. Analysis with more samples are needed to provide more precise treatment reference. [Table: see text]

Background The steroidal irreversible aromatase inhibitor (AI) exemestane (E), the non-steroidal reversible AI anastrozole (A) and tamoxifen (T) are approved for the first-line treatment of the postmenopausal women with hormone receptor (HR) positive advanced breast cancer (ABC) in Japan. Although there are some studies which compare the efficacy and safety of AIs and T in the first-line disease setting, the number of studies that compare efficacy and safety of AIs is limited. We conducted this multicenter, randomized, double-blinded non-inferiority study, to evaluate the time to progression (TTP) in HR positive ABC randomized to therapy with E or A. Methods Patients (pts) who were ≥20 years [yrs], postmenopausal, ECOG PS ≤1 and had HR positive ABC that recurred after the adjuvant therapy or metastatic disease settings were eligible and randomized (1:1) to 25 mg/day of E or to 1 mg/day of A. Data were evaluated for non-inferiority of E compared to A defined as the upper limit of a two-sided 95% confidence interval (CI) of the hazard ratio (HR) of TTP being less than or equal to 1.25. The primary endpoint was TTP assessed by the independent radiological images review committee (RIRC). Secondary endpoints included TTP by investigator, time to treatment failure, overall survival (OS), objective response rate (ORR), clinical benefit rate, and safety. Results A total of 298 pts from 58 sites were randomized to E (n=149; mean age: 63.4 yrs) or A (n=149; mean age: 64.0 yrs). The mean BMI for the E and A arms were 23.0 kg/m2 and 23.6 kg/m2, respectively. Six pts (2 pts in E arm, 4 pts in A arm) were excluded from the full analysis set due to lack of evaluation for anti-tumor response after study medication started. Median TTP (as per RIRC) was 13.8 months (M) vs. 11.1 M for E vs. A, respectively (HR 1.007; 95% CI: 0.771−1.317). Median TTP (Investigator) was 13.8 M vs. 13.7 M for E vs. A, respectively (HR 1.059; 95% CI: 0.816−1.374). The median OS for A treated pts was 60.1 M, OS for E was not reached (as of data cut-off: December 8, 2010). ORR for E was 43.9% (95% CI: 35.3−52.8) and 39.1% (95% CI: 30.6−18.1) for A. Other analyses, including sub-population analyses are ongoing. The incidence of treatment related adverse events (AEs) in E arm was 71.1% (n=106) and in A arm 59.7% (n=89); the AEs were mostly grade 1 and 2 in 61.7% (n=92) and 53.7% (n=80) of pts respectively. They were expected and manageable. Treatment related SAEs were similar in both groups: 6 (4.0%) in E arm and 5 (3.4%) in A arm. The most common AEs for E were hot flushes (22.1%), arthralgias (16.8%), musculoskeletal stiffness (11.4%) and γ-GTP increased (10.1%); in A arm, hot flushes (14.8%) and arthralgia (16.8%) were observed in >10% pts. Conclusions Although median TTP (RIRC) of E is slightly improved compared with that of A, the result of TTP did not meet the non-inferiority criteria. There were no significant differences found between E and A in ORR. Although AEs in E were numerically higher, the observed AE profiles were similar to those previously reported for E and A. This study shows that E is comparable to A in efficacy and safety. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-16-01.

Nivolumab (Anti-PD-1; BMS-936558, ONO-4538) Maintenance as Monotherapy or in Combination With Bevacizumab (BEV) for Non-Small Cell Lung Cancer (NSCLC) Previously Treated With Chemotherapy: Metastatic Non-Small Cell Lung Cancer

<div>Abstract<p>Patients with metastatic melanoma whose disease progresses on ipilimumab can clearly derive benefit from subsequent anti–programmed death-1 (PD-1). However, patients experience heterogeneous outcomes with ipilimumab, including rapid or delayed progression, and it is unclear whether patterns of ipilimumab progression influence subsequent clinical responses to anti–PD-1. We retrospectively reviewed data from 116 patients with metastatic melanoma who progressed on ipilimumab and were subsequently treated with pembrolizumab. The study objectives were to determine whether progression-free survival (PFS) with ipilimumab was associated with PFS, objective response rate (ORR), and clinical benefit rate (CBR; ORR + stable disease) with pembrolizumab. Patients with PFS ≥90 days after treatment with ipilimumab generally had superior outcomes with subsequent pembrolizumab treatment compared with patients with PFS <90 days (ORR, 49% vs. 35%, <i>P</i> = 0.12; CBR, 66% vs. 46%, <i>P</i> = 0.03). Patients with prolonged ipilimumab benefit (PFS ≥ 180 days) had excellent outcomes with pembrolizumab compared with rapid progressors (PFS < 45 days; ORR, 55% vs. 25%; CBR, 80% vs. 25%; median PFS, 249 vs. 50 days). Using logistic regression models, PFS with ipilimumab was independently correlated with response to pembrolizumab (odds ratio, 1.22; 95% CI, 1.02–1.51). This study shows that prolonged PFS with ipilimumab predicts excellent outcomes with subsequent pembrolizumab treatment, offering valuable prognostic information for clinicians. <i>Cancer Immunol Res; 4(7); 569–73. ©2016 AACR</i>.</p></div>

TPS489 Background: Tucatinib (TUC), a highly selective HER2-directed TKI approved in multiple regions for HER2+ metastatic breast cancer, is being investigated as a novel therapy for patients (pts) with metastatic colorectal cancer, gastric cancer, and other GI tumors. Preclinical and clinical data have shown HER2-targeted agents may improve clinical outcomes. In xenograft models of HER2+ and HER2-mutated tumors, dual targeting of HER2 with TUC + trastuzumab (Tras) showed superior activity to either agent alone (Kulukian 2020). Interim results from the MOUNTAINEER study have shown promising activity for TUC + Tras in HER2+ colorectal cancer. In 23 response-evaluable pts, an objective response rate (ORR) of 52% was observed with a median progression-free survival (PFS) of 8.1 months (mo) (Strickler 2019). The prognosis for pts with biliary tract cancers (BTCs) remain poor, and treatment options are limited. Given that approximately 12%-15% of BTC pts are HER2+, and 1%-8% have HER2 mutations, TUC + Tras warrants further evaluation in this patient population. The SGNTUC-019 basket study (NCT04579380) is evaluating TUC + Tras in pts with previously treated, locally advanced, unresectable or metastatic solid tumors including BTC that display HER2 overexpression/amplification or activating mutations. We describe the design of the BTC cohort. Methods: SGNTUC-019 is a multi-cohort, open-label, international Phase 2 study. Pts must be ≥18 years old; have an ECOG PS of ≤1; have adequate hepatic, hematological, renal, and cardiac functions; and have no previous exposure to HER2-directed therapy. BTC pts must have progressed on or after ≥1 previous line of treatment. The HER2+ BTC cohort will enroll 12 response-evaluable pts. If >2 responses are observed, the cohort will be expanded to 30 pts. HER2-mutated BTC patients may also be enrolled in a 30 pts cohort for other HER2-mutated solid tumors. The primary objective is antitumor activity with confirmed ORR as the primary endpoint. Secondary efficacy endpoints include disease control rate, duration of response, PFS, and OS. For eligibility, HER2 alterations can be demonstrated by HER2 overexpression/amplification in tumor tissue by prior IHC/ISH, or by HER2 amplification/mutation in a prior or on-study NGS assay of ctDNA or prior tissue NGS assay. Pts will receive TUC 300 mg orally twice a day and Tras 8 mg/kg intravenously on Cycle 1 Day 1 then 6 mg/kg every 21 days from Cycle 2 Day 1. Disease assessments per RECIST 1.1 are every 6 weeks for the first 24 weeks, then every 12 weeks. Quality of life will be evaluated every 2 cycles using EQ-5D-5L. Sites are currently enrolling within the US, EU and Asia-Pacific. Clinical trial information: NCT04579380.

Background: We previously presented data of this multicentric, phase II study showing that everolimus plus octreotide long-acting repeatable (LAR) for advanced neuroendocrine neoplasms (NENs), in the first line setting, is an active and safe treatment. We now present updated data at 5 years. Methods: Patients with advanced well-differentiated, previously untreated neuroendocrine tumors of the gastroenteropancreatic tract and of the lung received octreotide LAR 30 mg plus everolimus 10 mg/day. The primary endpoint was the objective response rate (ORR). We performed an analysis of “long responder” patients and of time to progression (TTP) and overall survival (OS) at 5 years. Results: Fifty patients were enrolled; the primary tumor site was: pancreas (14 patients), lung (11 patients), ileum (9 patients), jejunum/duodenum (2 patients), and unknown (14 patients). Seventeen (34%) of these patients have received treatment for more than 2 years. The median exposure to study drugs was 519.5 days (range 48-2,024). Currently 3 patients are still in treatment. The ORR (partial response + complete response) was 18% (95% confidence interval [CI] 7.4-28.6): complete response 1 patient (2%), partial response 8 patients (16%), stable disease 37 patients (74%). The median TTP was 33.6 months (95% CI 18.7-41.2) and the median OS was 61.0 months (95% CI 49.8-not reached). Conclusion: In this update of clinical outcome at 5-year follow-up, everolimus plus octreotide has been shown to be active in advanced NENs. The current analysis showed a further prolongation of TTP and a long exposure to the study drug without major side effects in the long term.

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.

Background Tucatinib (TUC) is a highly selective oral tyrosine kinase inhibitor of HER2 with minimal inhibition of EGFR. It was recently approved by the FDA for patients (pts) with HER2+ metastatic breast cancer (MBC), including pts with brain metastases (BM) whose cancers have progressed on at least 1 prior anti-HER2 regimen in the metastatic setting. In the HER2CLIMB (NCT02614794) pivotal trial, pts with HER2+ MBC previously treated with trastuzumab (T), pertuzumab, and trastuzumab emtansine (T-DM1) were randomized to receive TUC or placebo in combination with T and capecitabine (C). The addition of TUC resulted in clinically meaningful and statistically significant improvements in overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) in HER2+ MBC pts. Primary methods and outcomes have been reported previously (Murthy, NEJM 2019). Here we present an exploratory analysis describing the outcomes in the HER2CLIMB trial based on hormone receptor (HR) status. Methods Pts were randomized 2:1 to receive TUC or placebo in combination with T and C. All pts had a baseline brain MRI and randomization was stratified by presence of BM, ECOG status, and geographic region. All pts with HER2+ MBC who were positive for either or both estrogen receptor and progesterone receptor (&amp;gt; 1%) were assigned to the HR “positive” subgroup. Pts not meeting the above criteria were assigned to the HR “negative” subgroup. For the exploratory HR+/HR- efficacy analysis presented here, PFS per RECIST 1.1 by blinded independent central review was evaluated in the first 480 pts enrolled. OS, PFS in pts with baseline BM, and confirmed ORR in pts with measurable disease were evaluated in the total study population. P values presented for PFS are nominal. Results Overall, 612 pts were enrolled to HER2CLIMB; 370 pts (60%) had HR+ and 242 (40%) had HR- tumors. Baseline demographics and disease characteristics in HR+/HR- subgroups were generally balanced between treatment arms. In the HR+ group, there was a 42% reduction in the risk of progression or death in the TUC arm (hazard ratio: 0.58; 95% CI: 0.42, 0.80; P=0.0008); median (95% CI) PFS was 7.6 mo (7.4, 9.5) in the TUC arm vs 5.6 mo (4.3, 7.4) in the control arm. In the HR- group, there was a 46% reduction in the risk of progression or death in the TUC arm (hazard ratio: 0.54; 95% CI: 0.34, 0.86; P=0.008); median (95% CI) PFS was 8.1 mo (7.0, 11.6) in the TUC arm vs 4.2 mo (3.1, 8.6) in the control arm. In the total population, median OS was 21.7 mo vs 18.2 mo in HR+ in the TUC arm vs control arm, respectively; median OS in HR- was 31.1 mo in the TUC arm vs 14.1 mo in the control arm. In pts with BM in the HR+ group (n=166 [45%]), there was a 52% reduction in the risk of progression or death (hazard ratio: 0.48; 95% CI: 0.31, 0.75; P=0.0008); median (95% CI) PFS was 7.5 mo (5.6, 9.5) in the TUC arm vs 5.1 mo (4.1, 5.7) in the control arm, and median OS was 18.1 mo vs 12.8 mo, respectively. In pts with BM in the HR- group (n=125 [52%]), there was a 50% reduction in the risk of progression or death (hazard ratio: 0.50; 95% CI: 0.27, 0.95; P=0.03); median (95% CI) PFS was 7.8 mo (6.1, 11.6) in the TUC arm vs 5.4 mo (2.9, 8.6) in the control arm, and median OS was 18.5 mo vs 11.5 mo, respectively. In the total population, ORR was numerically higher in the TUC arm vs the control arm regardless of HR status (HR+: 37.4% [95% CI: 30.8, 44.5] vs 27.1% [95% CI: 19.0, 36.6], respectively and HR-: 45.3% [95% CI: 36.7, 54.0] vs 15.6% [95% CI: 7.8, 26.9], respectively). Conclusions Among pts with HER2+ MBC previously treated with T, pertuzumab, and T-DM1, the addition of TUC to T and C showed clinically meaningful improvements of PFS, OS, and ORR independent of HR status. Furthermore, pts with HR+ and HR- MBC with BM derived similar benefit from the addition of TUC to T and C. Citation Format: Erika Hamilton, Mattea Reinisch, Sherene Loi, Alicia Okines, Paula R. Pohlmann, Eva Harder Brix, Hugues Bourgeois, Belinda Yeo, Cheryl Aylesworth, Melody Cobleigh, Anthony Goncalves, Rebecca Moroose, Katherine H.R. Tkaczuk, Michaela Tsai, Christine Simmons, Michael Andersson, Hatem Soliman, Michelina Cairo, Lisa A. Carey, David Cameron, Jorge Ramos, Wentao Feng, Mafalda Oliveira. Tucatinib vs placebo in combination with trastuzumab and capecitabine for patients with locally advanced unresectable or HER2-positive metastatic breast cancer (HER2CLIMB): Outcomes by hormone receptor status [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD3-08.

Ibrutinib Induces Durable Remissions in Treatment-Naïve CLL Patients with 17p Deletion/TP53 Mutations: Five Year Follow-up from a Phase 2 Study

LBA61 - A randomized phase II/III study to assess the efficacy of trametinib in patients with recurrent or progressive low-grade serous ovarian or peritoneal cancer