Significant Prolongation Of Progression-free Survival Research Articles

Anti-HDGF antibody targets EGFR tyrosine kinase inhibitor-tolerant cells in NSCLC patient-derived xenografts.

Constitutively active mutant epidermal growth factor receptor (EGFR) is one of the major oncogenic drivers in NSCLC. Targeted therapy using EGFR tyrosine kinase inhibitor (TKI) is a firstline option in patients that have metastatic or recurring disease. However, despite the high response rate to TKI, most patients have a partial response, and the disease eventually progresses in 10 to 19 months. It is believed that drug-tolerant cells that survive TKI exposure during the progression-free period facilitate the emergence of acquired resistance. Thus, targeting the drug-tolerant cells could improve the treatment of NSCLC with EGFR mutations. We demonstrated here that EGFR mutant patient-derived xenograft (PDX) tumors responded partially to osimertinib despite near complete inhibition of EGFR activation. Signaling in AKT/mTOR and MAPK pathways could be reactivated shortly after initial inhibition. As a result, many tumor cells escaped drug killing and regained growth following about 35 days of continuous osimertinib dosing. However, when an antibody to hepatoma-derived growth factor (HDGF) was given concurrently with osimertinib, tumors showed complete or near-complete responses.There was significant prolongation of progression-free survival (PFS) of tumor-bearing mice as well. Immunohistochemistry and western blot analysis of tumors collected in the early stages of treatment suggest that increased suppression of the AKT/mTOR and MAPK pathways could be a mechanism that results in enhanced efficacy of osimertinib when it is combined with anti-HDGF antibody.

Updated results on multiple antigens stimulating cellular therapy (MASCT-I) in metastatic urothelial carcinoma: A randomized, open-label, phase I trial.

2545 Background: The appropriate treatment for mUC remains unmet medical needs. MASCT-I, an adoptive transfer of dendritic cells (DCs) presenting 15 types of tumor-associated antigens (TAAs), showed valuable treatment in solid tumors. We previously reported the efficacy and safety of MASCT-I alone, or plus camrelizumab or chemotherapy in mUC (NCT03034304). The biomarker analysis and long-term follow-up to for this promising approach was unknown. Methods: All enrolled patients were divided into in five groups (G) as previous reported. Patients in G2 receiving maintenance therapy of MASCT-I after first-line platinum based-chemotherapy were allowed to enter enrolled in G3 and receiving MASCT-I plus camrelizumab when disease progressed. We updated the exploratory endpoint of the IFN-γ ELISPOT assay, which was used to measure activation of the cytotoxic T Lymphocyte (CTL) response in eligible patients. Long-term follow-up results for safety, progression-free survival (PFS) and overall survival (OS) were reported. Results: 39 patients were enrolled. By January 31st, 2024, median follow-up time was 31.1 months. No new safety signals were updated. As previously reported, the most common adverse events (AEs) associated with MASCT-I included grade 1 and 2 flushing, pruritus, rash, muscle cramp, fever, and arthralgia. No MASCT-I-related death occurred. Median PFS and OS for all patients were 2.3 months, and 16.9 months, respectively. Patients in G2 presented superior OS of 41.2 months and duration of response (DOR) of 6.4 months. Nine patients treated with MASCT-I and camrelizumab after progression on MASCT-I in G2 presented a 24-month PFS rate of 55.6% and a 48-month DOR rate of 71.8%. Five patients had prolonged PFS for more than 20 months while two of them had PFS of more than 43 months. To identify the potentially beneficial population, IFN-γ ELISPOT data analysis revealed that patients who had positive TAAs ELISPOT response had significant prolonged PFS and OS compared to the non-responders (median PFS: 10.1 months vs 4.8 months, HR=0.30, 95% CI: 0.14-0.61, P<0.005; median OS: not reached vs 13.6 months, HR=0.16, 95% CI: 0.05-0.57, P<0.005). The Cmax value of INF-γ-positive T cells after cell infusion was also higher in patients with better PFS. In addition, we observed a significant increase in INF-γ-positive T cell activities in patients who progressed from G2 and were subsequently treated with a combination of MASCT-I and camrelizumab (Cmax mean (SD): 72 spots per million bulk PBMCs at G2 to 186 spots per million bulk PBMCs after transfer to G3, P=0.002). Conclusions: MASCT-I alone or in combination with immunotherapy or chemotherapy are safe and well tolerated, with inspiring survival benefit. The combination of PD-1 inhibitors may enhance the antitumor activity of MASCT-I. IFN-γ ELISPOT might be able to predict potentially beneficial populations. Clinical trial information: NCT03034304 .

Efficacy of immune-checkpoint inhibitors combined with cytotoxic chemotherapy in advanced or recurrent endometrial cancer: A systematic review and meta-analysis

BackgroundThe combination of immune checkpoint inhibitors (ICIs) and platinum-based chemotherapy has emerged as a highly promising primary option for advanced or recurrent endometrial cancer (EC). The study aimed to evaluate treatment efficacy of ICIs with cytotoxic chemotherapy in EC. MethodsWe conducted a comprehensive review of randomized controlled trials up to November 11, 2023, focusing on immunotherapy combined with chemotherapy versus chemotherapy alone for EC. The primary endpoint was the pooled hazard ratio (HR), which was further analyzed across subgroups based on mismatch repair (MMR) status, race, histology, and programmed death-ligand 1 (PD-L1) status. The protocol was registered in PROSPERO (CRD42023475669). FindingsFour trials with 2335 patients were analyzed. ICIs with chemotherapy significantly prolonged progression-free survival (PFS) (HR, 0.70; 95% CI, 0.62–0.79) and overall survival (OS) (HR, 0.75; 95% CI, 0.63–0.89) compared to chemotherapy alone. Stratification by MMR status showed substantial benefits for dMMR (PFS; HR, 0.33; 95% CI, 0.26–0.43; OS; HR, 0.37; 95% CI, 0.22–0.91) over pMMR cohorts in both PFS and OS. In the subgroup analysis, there was significant PFS advantage in Caucasian (HR, 0.63; 95% CI, 0.54–0.72) over non-Caucasian, in endometrioid histology (HR, 0.66; 95% CI, 0.56–0.78) over non-endometrioid, and in PD-L1 positive (HR, 0.39; 95% CI, 0.19–0.81) over PD-L1 negative population. InterpretationICIs combined with platinum-based chemotherapy significantly prolonged PFS and OS in patients with advanced or recurrent EC. Patients with dMMR status, Caucasians, endometrioid histology, and positive PD-L1 status showed significant PFS benefits, emphasizing the need for personalized treatment approaches to improve outcomes.

Efficacy and safety of combination of poly-ADP-ribose polymerase inhibitor (PARPi) and chemotherapy compared with chemotherapy alone in treatment of recurrent ovarian carcinoma: a systematic review.

Platinum-based chemotherapy after surgical cytoreduction is the universal treatment for advanced ovarian cancer (OC), however, about eighty percent of patients experienced relapse and progression-free survival remained poor. Patients who relapsed within one year of treatment eventually become resistant to second-line chemotherapy. Poly-ADP-ribose polymerase inhibitors are a novel class of targeted therapy that could overcome these challenges by augmenting the chemotherapeutic activity of other cytotoxic agents. Cumulative Index to Nursing and Allied Health Literature (CINHAL), Cochrane and PubMed databases were searched for potentially relevant primary publications from 2011 to 2022 reporting on efficacy and safety of combination of a PARP inhibitor and chemotherapy versus chemotherapy in recurrent OC and reviewed. The outcomes of interest assessed qualitatively were progression-free survival (PFS) and grade 3 or higher adverse events (AEs) as measures of efficacy and safety respectively. Eight randomized controlled trials (RCTs) were included in the systematic review comprising 3,021 patients evaluated efficacy and safety of PARP inhibitors: Olaparib, niraparib and veliparib with combinations of bevacizumab, carboplatin, cisplatin, cediranib, cyclophosphamide and paclitaxel. 824 patients had 33 BRCA mutation while 1,430 had wild-type BRCA, an allele that confers increased risk of cancer. Most patients had platinum-sensitive cancers. There was significant prolongation of PFS with PARP inhibitor and chemotherapy combination compared to chemotherapy in all included trials except one which combined veliparib with cyclophosphamide. The prolongation of PFS was more remarkable in patients with BRCA mutation and occasionally patients with wild-type BRCA. Niraparib and veliparib were notably associated with grade 3 or higher anaemia, neutropenia, and thrombocytopenia, olaparib caused fatigue and gastrointestinal disturbances while bevacizumab and cediranib caused hypertension. This review suggested combined PARP inhibitor and chemotherapy significantly prolonged progression-free survival especially in patients with BRCA mutation compared to chemotherapy and the combined therapy is safe.

Clinical pharmacology profile of the claudin 18.2 antibody zolbetuximab.

316 Background: Zolbetuximab is an investigational first-in-class chimeric (mouse/human) monoclonal antibody directed against the tight junction protein claudin 18.2 (CLDN18.2). Zolbetuximab is currently being developed as first-line treatment of patients with locally advanced unresectable or metastatic HER2– gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors are CLDN18.2 positive, in combination with fluoropyrimidine- and platinum-containing chemotherapy. Methods: The clinical pharmacology of zolbetuximab (pharmacokinetics [PK] and impact of covariates, potential for drug-drug interactions and QTc prolongation, exposure-response [E-R] for efficacy and safety, immunogenicity [antidrug antibodies; ADAs]) was characterized from 9 studies in adults with advanced CLDN18.2-positive adenocarcinoma of the stomach, esophagus, or GEJ. Results: Zolbetuximab exhibited dose-proportional PK at doses of 33 to 1000 mg/m2. Based on population PK modeling using data from 714 participants, zolbetuximab exposure (Table) was not meaningfully affected by sex, race/ethnicity, age, mild/moderate renal impairment, or mild hepatic impairment. Gastrectomy was predicted to increase Cave by 36%. Coadministration of zolbetuximab with chemotherapy did not show clinically meaningful changes in drug exposures of zolbetuximab or chemotherapy. At therapeutic doses, zolbetuximab had no clinically meaningful effect on QTc prolongation. In phase 3 studies, zolbetuximab (800 mg/m2 loading dose/600 mg/m2 Q3W) had a manageable safety profile and was associated with significant prolongation of progression-free survival (PFS) and overall survival (OS). E-R analyses suggested that higher zolbetuximab exposure may further prolong PFS and OS but with increased probability of gastrointestinal events and infusion-related reactions. E-R model simulations suggested comparable zolbetuximab efficacy and safety between the 800/600 mg/m2 Q3W regimen and an alternative 800/400 mg/m2 Q2W regimen for use in combination with chemotherapy. ADAs were detected in 4.4% of patients in phase 3 studies with no apparent impact on zolbetuximab PK, efficacy, or safety. Conclusions: The clinical pharmacology of zolbetuximab was well characterized using data from 9 clinical trials. The integrated data support the proposed 800/600 mg/m2 Q3W regimen as well as an 800/400 mg/m2 Q2W regimen in combination with chemotherapy. Clinical trial information: NCT00909025 , NCT01671774 , NCT03528629 , NCT04086758 , NCT01197885 , NCT01630083 , NCT03505320 , NCT03504397 , NCT03653507 . [Table: see text]

Chemotherapy response score no longer predicts survival outcomes in high-grade serous ovarian cancer patients with BRCA mutation and/or maintenance therapy.

We aimed to revalidate the chemotherapy response score (CRS) system as a prognostic factor for ovarian cancer patients with breast cancer gene (BRCA) mutations or those receiving frontline poly-ADP ribose polymerase (PARP) inhibitors or bevacizumab as maintenance therapy. A retrospective analysis was performed using medical records of patients with high-grade serous carcinoma who received neoadjuvant chemotherapy followed by interval debulking surgery between January 2007 and December 2021 at 5 tertiary medical institutions in South Korea. At each hospital, pathologists independently assessed each slide of omental tissues obtained from surgery using the CRS system. Progression-free survival (PFS) and overall survival (OS) values were obtained using Kaplan-Meier analysis to evaluate the effect of BRCA mutation, maintenance therapy, and CRS on survival time. Of 466 patients, BRCA mutations were detected in 156 (33.5%) and 131 (28.1%) were treated with maintenance therapy; 98 (21.0%) and 42 (9.0%) were treated with PARP inhibitors or bevacizumab, respectively. Patients with CRS3 had significantly longer PFS than those with CRS1 or 2 (24.7 vs. 16.8 months, p<0.001). However, there was no significant difference in PFS improvement between CRS3 patients and those with CRS1 or 2 with BRCA mutation (22.0 vs. 19.3 months, p=0.193). Moreover, no significant PFS prolongation was observed in CRS3 patients compared to CRS1 or 2 patients treated with PARP inhibitors or bevacizumab (24.3 vs. 22.4 months, p=0.851; 27.5 vs. 15.7 months, p=0.347, respectively). CRS may not be a prognostic factor in patients with BRCA mutations and those receiving frontline maintenance therapy.

Bevacizumab plus erlotinib versus erlotinib alone for advanced EGFR-mutant non-small cell lung cancer: a meta-analysis of randomized clinical trials

ObjectivePrevious studies showed that the combination of bevacizumab and erlotinib (combination therapy) significantly prolonged progression-free survival (PFS) but no overall survival (OS) compared to erlotinib alone (monotherapy) for advanced EGFR-mutant non-small cell lung cancer (NSCLC). Two phase III randomized controlled trials (RCTs) had reported the OS results in 2021. This meta-analysis aimed to include the results of the two RCTs to make a decision.Materials and methodsWe systematically searched relevant databases for RCTs on the use of bevacizumab plus erlotinib in advanced EGFR-mutant NSCLC. The main outcomes of interest were PFS, OS, and the reported hazard ratio (HR). Fixed-effect model was used to estimate pooled HR.ResultsTotal 5 RCTs with 935 patients were eligible for this meta-analysis. All studies reached their primary study endpoints including PFS and OS. Compared to monotherapy, combination therapy remarkably prolonged PFS (HR = 0.60, 95% confidence interval CI 0.51–0.70; p < 0.00001); however, OS was similar between the two groups (HR = 0.90, 95% CI 0.76–1.08; p = 0.26). Subgroup analysis demonstrated that in deletion within exon 19 (19del) mutation subgroup, the combination therapy could only prolong PFS (HR = 0.60, 95% CI 0.47–0.76; p < 0.0001) but not OS (HR = 1.00, 95% CI 0.73–1.37; p = 1.00), and also in leucine-to-arginine substitution in exon 21 (L858R) mutation subgroup (HR = 0.59, p < 0.0001 and HR = 0.80, p = 0.18, respectively). For patients with brain metastasis at baseline, the combination therapy achieved a significant better PFS than the monotherapy (HR = 0.60, 95% CI 0.39–0.90; p = 0.01), and a better OS with the difference marginally significant (HR = 0.69, 95% CI 0.46–1.02; p = 0.06).ConclusionsCombination of bevacizumab and erlotinib can prolong progression-free survival but not overall survival compared to erlotinib alone in advanced EGFR-mutant non-small cell lung cancer patients. The combination therapy not only can prolong progression-free survival but also has a tendency to prolong overall survival for patients with brain metastasis at baseline.

Interim survival analysis of the randomized phase III GEMSTONE-302 trial: sugemalimab or placebo plus chemotherapy as first-line treatment for metastatic NSCLC.

The randomized, double-blinded, multi-center, phase III GEMSTONE-302 ( NCT03789604 ) study evaluated the efficacy and safety of sugemalimab versus placebo in combination with chemotherapy as first-line treatment for metastatic non-small-cell lung cancer (NSCLC). In this study, 479 treatment-naive patients with stage IV squamous or non-squamous NSCLC without known EGFR sensitizing mutations, ALK, ROS1 or RET fusions were randomized (2:1) to receive 1,200 mg of sugemalimab (n = 320) or placebo (n = 159) every 3 weeks in combination with platinum-based chemotherapy for up to four cycles, followed by maintenance therapy with sugemalimab or placebo for squamous NSCLC and sugemalimab or placebo plus pemetrexed for non-squamous NSCLC. Placebo-treated patients could cross over to receive sugemalimab monotherapy on disease progression. The primary endpoint was investigator-assessed progression-free survival (PFS) and the secondary endpoints included overall survival (OS) and objective response rate. Sugemalimab plus chemotherapy has demonstrated significant PFS prolongation in the primary analysis as reported previously. As of 22 November 2021, the prespecified interim OS analysis showed significant improvement with the addition of sugemalimab to chemotherapy (median OS = 25.4 versus 16.9 months; hazard ratio = 0.65; 95% confidence interval = 0.50-0.84; P = 0.0008). Sugemalimab plus chemotherapy provided superior PFS and OS compared to placebo plus chemotherapy, supporting the use of sugemalimab as a first-line treatment option for metastatic NSCLC.

Open-label phase II study of everolimus plus endocrine therapy in postmenopausal women with ER+, HER2- metastatic breast cancer (Chloe trial).

e13052 Background: In the treatment of ER-positive metastatic breast cancer (MBC), the addition of molecularly targeted drugs overcoming resistance to aromatase inhibitors (AI) improves outcomes. It is not clear, however, whether this drug is necessary in the first line treatment for all cases. Whether it should be administered before acquiring resistance, especially for MBCs with sensitivity to AI, is debatable. In this study, we prospectively investigated whether early additional administration of mTOR inhibitor to an AI-sensitive MBC regimen can delay the acquisition of resistance and extend the duration of AI efficacy. Methods: This was a multicenter, open-label, randomized, phase II study comparing patients with ER-positive postmenopausal MBC responsive to first-line treatment with AI for six months, and randomized to either continue to receive AI (standard group; SG) or add the 10 mg/day of mTOR inhibitor (experimental group; EG). The primary endpoint was progression-free survival (PFS). Secondary endpoints were overall survival, response rate (RR), disease control rate (DCR), adverse events (AE), and time to treatment failure (TTF). The planned number of registrations was 130 (65 cases in each group) with a registration period of 2 years. Results: The total enrollment was 44, with 21 in the SG and 22 in the EG (one patient did not receive treatment). As to patient backgrounds, 9.5% (2 patients) in SG and 22.7% in EG (5 patients) were PgR negative. Late recurrence (DFS＞5 years after surgery) was observed in 10 (47.6%) SG patients and 12 (54.5%) EG patients. Three SG patients (14.3%) and two EG patients (9.1%) had a history of chemotherapy after recurrence. Treatment was discontinued in 14 (66.7%) SG patients and 12 EG (54.5%) patients during follow-up. Progressive disease was observed in 12 (57.1%) and 4 (18.2%) patients, respectively, while in the EG we noted discontinuation due to AE (4 patients (18.2%)) and discontinuation at the patient's request (4 patients (18.2%)). There was no significant difference in PFS between the two groups. There was no significant difference in the DCR in patients with target lesions (62.5% in SG and 78.6% in EG). The frequency of AE greater than G2 was low in SG: only 3 with hyperglycemia and 1 with leukopenia. In contrast, numerous toxicities were observed in multiple patients in EG (68.2%). Conclusions: Early addition of an mTOR inhibitor for AI-sensitive MBC did not achieve significant PFS prolongation. Although the addition of mTOR inhibitors may have suppressed the deterioration of patient status, several cases required discontinuation due to AE associated with the drug. Further study with a larger sample size may be required to determine a significant difference between the two groups. Clinical trial information: jRCTs061180075 .

Multiple antigen stimulating cellular therapy (MASCT)-I for metastatic urothelial carcinoma (mUC): A multicenter, phase I study (MASCT-I-1001).

e16572 Background: Immune checkpoint inhibitors (ICIs) showed unsatisfactory efficacy in mUC. This study aimed to evaluate the role of MASCT-I alone, or plus camrelizumab or chemotherapy in patients (pts) with mUC. Methods: Eligible pts were enrolled in five groups (G): MASCT-I alone as salvage treatment in pts who failed standard treatment (G1), or as maintenance therapy following first-line platinum based-chemotherapy (G2); MASCT-I plus camrelizumab in pts who had progressed after first-line chemotherapy (G3) or ICI (G4), and MASCT-I plus platinum-based chemotherapy as first-line treatment (G5). Pts in G2 were allowed to be enrolled in G3 when disease progressed. The primary endpoint was safety. The secondary endpoints included progression-free survival (PFS) and overall survival (OS). Dynamic biomarker analysis of specific immune responses against 15 antigens was performed by enzyme-linked immunospot assays (ELISPOT) in peripheral blood mononuclear cells from pts. Results: Thirty-nine pts were included from February 16th, 2017 to March 3rd, 2022, with two, 18, nine, four and six pts in G1, 2, 3, 4 and 5, respectively. The pts were 37-72 years old, and 69.2% were male. The main MASCT-I-related adverse events (AEs) included grade 1/2 flushing, pruritus, rash, muscle cramp, fever, and arthralgia. Two pts experienced serious AEs related to both MASCT-I and camrelizumab, including grade 3 rash, adrenocortical insufficiency, and pleural effusion in one pt, and grade 3 elevated transaminases in another. No MASCT-I-related death occurred. No new safety signal related to chemotherapy or camrelizumab was reported. Thirty-six out of 39 pts had at least one response evaluation, with one complete response, six partial response and 13 stable diseases. The median PFS and OS for all pts was 2.3 months and 15.5 months, respectively. The median PFS and OS for pts in G2 was 3.0 months and 39.3 months, respectively. Pts in G2 presented significantly superior OS compared with pts in other groups ( P&lt; 0.001). In nine pts enrolled in G3 after progression in G2, the OS was significantly longer than other nine pts in G3 (median OS: not reached vs 15.4 months, hazard ratio [HR] = 0.14, 95% confidence interval [CI]: 0.03-0.61, P= 0.034). Among 24 pts with available ELISPOT analysis, six were defined as responders, which showed a significant prolonged PFS and OS compared with the non-responders (median PFS: 10.1 vs 4.5 months, HR = 0.33, 95% CI: 0.13-0.81, P&lt; 0.005; median OS: not reached vs 13.5 months, HR = 0.19, 95% CI: 0.05-0.70, P&lt; 0.005). Conclusions: Both MASCT-I alone or combined with immunotherapy or chemotherapy showed manageable safety profiles. Maintenance of MASCT-I after first-line chemotherapy presented inspiring survival benefit. Synergistic effects between MASCT-I and ICIs may exist. Potential candidates for MASCT-I treatment may be identified by ELISPOT analysis. Clinical trial information: NCT03034304 .

LRP1B mutation is associated with tumor immune microenvironment and progression-free survival in lung adenocarcinoma treated with immune checkpoint inhibitors.

Only a fraction of lung adenocarcinoma (LUAD) patients are eligible for immunotherapy. The identification of biomarkers for immunotherapy is crucial to improve patient outcomes. This study aims to systemically analyze LRP1B mutation and its association with the tumor immune microenvironment (TIME) and immunotherapy. A cohort of immune checkpoint inhibitors (ICIs)-treated LUAD patients was analyzed to assess the association of LRP1B mutation with immunotherapy prognosis. Another cohort of LUAD patients with genetic and transcriptomic data was also obtained from The Cancer Genome Atlas (TCGA). By investigating the ICIs and the TCGA-LUAD cohorts, we compared the differences in mutation profiles, immunogenicity, TIME, and DNA damage repair (DDR) mutations between the LRP1B-mutated and LRP1B wild-type groups. Additionally, we performed multiplex immunohistochemistry (mIHC) to validate the differences in the tumor microenvironment. Our results revealed that LRP1B mutation is associated with multiple immune-related pathways. Analysis of TIME indicated that LUAD patients with LRP1B mutation expressed significant levels of genes involved in antigen presentation, cytotoxicity, chemokines, and pro-inflammatory mediators, whereas a few immune checkpoint genes were highly expressed in the LRP1B-mutated group as well. Cell-type Identification by Estimating Relative Subsets of RNA Transcripts (CIBERSORT) analysis indicated that LRP1B-mutated LUAD patients had higher infiltration of active immune cells. Multiplex IHC analysis showed that LRP1B-mutated LUAD patients had elevated programmed death ligand-1 (PD-L1) expression and immune cell infiltration. Patients with LRP1B mutation had higher tumor mutation burden, neoantigens, as well as more mutated genes in the DDR-related pathways. Finally, LRP1B-mutated LUAD patients showed a significant prolongation of progression-free survival (PFS) in the ICIs cohort and could be effectively predicted by our constructed nomogram. Our study suggests that LRP1B mutation is associated with higher immune cell infiltration and elevated immune gene expression in TIME and potentially serves as a prognostic biomarker for LUAD patients treated with ICIs.

Abstract P1-13-21: Loss of CDKN2B expression as a potential marker of resistance to CDK4/6 inhibitor in Luminal Breast Cancer cells

Abstract Background Cyclin-Dependent Kinase (CDK) 4/6 inhibitors have significantly improved progression-free survival of Hormone Receptor positive (HR+), Human Epidermal Growth Factor Receptor type 2 negative (HER2-) luminal breast cancers (LBC). Several studies demonstrated that the addition of CDK4/6 inhibitors to endocrine therapy results in a significant prolongation of progression-free survival in patients with endocrine-sensitive or endocrine-resistant LBCs. However, the percentage of patients unresponsive or refractory to these therapies is as high as 40%, and no reliable and reproducible biomarkers able to select a priori responder or resistant patients have been validated till now. The main cause of resistance is the selection of mutant clones in the target oncoprotein. Other mechanisms, like oncogene amplification/overexpression or mutations in other pathways, have been described in several models. Here, we focused on palbociclib, a selective inhibitor of CDK4/6. Methods: We generated and characterized human luminal breast cancer MCF-7 and T47D derived cell lines, able to survive and proliferate at different palbociclib concentrations, which also shows cross-resistance to abemaciclib. The resistant MCF7 cell line was characterized by RNA sequencing. Results: To confirm resistance, we performed cell viability assays in MCF-7 and T47D palbociclib sensitive cells (MCF-7pS and T47pS) versus MCF-7 and T47D palbociclib resistant cells (MCF-7pR5), showing a 10-fold increase of IC50 in MCF-7pR5 compared to parental MCF-7pS cells (16.7 vs 1.8 µM) and a 3-fold increase of IC50 in T47DpR5 vs parental T47DpS. We also confirmed a significant cross resistance using abemaciclib in MCF-7pR5 with an IC50 equal to 6.8 vs 0.35 µM and in T47DpR with an IC50 of 10.72 vs 0.5 µM. RNA sequencing, qRT-qPCR and Western blot results demonstrated a dramatic downregulation of the CDK4 inhibitor CDKN2B in both cell lines and we found upregulation of an miR-31, a putative regulator of CDKN2B. This finding was further validated in a biopsy from a patient progressing on CDK4/6 inhibitor therapy. Conclusions: This study provides new relevant information regarding the mechanism of resistance to CDK4/6 inhibitors and suggests potential new markers to follow up patients during the treatment. Citation Format: Nicoletta Cordani, Luca Mologni, Rocco Piazza, Viola Cogliati, Francesca Pepe, Serena Capici, Camillo Di Bella, Marta Jaconi, Maria Grazia Cerrito, Matteo Villa, Pietro Tettamanti, Guido Cavaletti, Marialuisa Lavitrano, Marina Elena Cazzaniga. Loss of CDKN2B expression as a potential marker of resistance to CDK4/6 inhibitor in Luminal Breast Cancer cells [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-13-21.

Abstract GS3-01: GS3-01 EMERALD phase 3 trial of elacestrant versus standard of care endocrine therapy in patients with ER+/HER2- metastatic breast cancer: Updated results by duration of prior CDK4/6i in metastatic setting

Abstract Background: In patients (pts) with ER+/HER2− metastatic breast cancer (MBC) following progression on prior endocrine and CDK4/6i therapy, the EMERALD trial demonstrated significantly prolonged progression-free survival (PFS) and a manageable safety profile for elacestrant versus standard of care endocrine therapy (SoC). Benefit was observed in all pts and in pts with ESR1 mutant MBC (ESR1-mut). EMERALD is the only oral SERD monotherapy pivotal trial where all pts were pretreated with CDK4/6 inhibitor (CDK 4/6i). Here, we examine the impact of duration of prior CDK4/6i on PFS. Methods: EMERALD (NCT03778931) is a randomized, open-label, phase 3 trial that enrolled pts with ER+/HER2- MBC who previously had 1-2 lines of endocrine therapy, mandatory CDK4/6i, and ≤1 chemotherapy; prior treatment with fulvestrant was allowed. Patients were randomized 1:1 to elacestrant (400 mg orally daily) or SoC (investigator’s choice of aromatase inhibitor or fulvestrant). If randomized to the control arm, patients who received prior fulvestrant were to receive an aromatase inhibitor, and vice versa. If two CDK4/6i were used in the metastatic setting (n=40), the cumulative duration was calculated. Results: A total of 478 pts were randomized (228 with ESR1-mut) between Feb 2019 – Oct 2020 (n=239, elacestrant; n=239, SoC). Overall survival was not yet mature, as of September 2nd 2022. Updated PFS results show statistically significant results in favor of elacestrant, both in all pts and in pts with ESR1-mut. The duration of prior CDK4/6i in the metastatic setting was positively associated with PFS, the longer the duration of prior CDK4/6i in the metastatic setting (n=465), the longer the PFS on elacestrant versus SoC (Table 1). Updated safety data were consistent with previously reported results. Most of the adverse events (AEs), including nausea, were grade 1 and 2, and only 3.4% and 0.9% of the pts discontinued trial therapy because of an AE on elacestrant and SoC, respectively. A low percentage of pts received an antiemetic; 8.0%, 3.7%, and 10.3%, on elacestrant, fulvestrant, and AI, respectively. No hematological safety signal was observed and none of the patients in either of the two treatment arms had sinus bradycardia. Conclusions: EMERALD is the first phase 3 trial to demonstrate a significant PFS improvement versus SoC in all pts and in the subgroup with ESR1 mutations in pts with ER-positive/HER2-negative MBC with 1-2 prior lines of endocrine treatment ± one line of chemotherapy. Elacestrant demonstrated longer PFS versus SOC that was positively associated with the duration of prior treatment with CDK4/6i, which was more pronounced in pts with ESR1-mut MBC. In this 2nd and 3rd line setting, elacestrant was well tolerated with significantly longer PFS versus SoC, highlighting its potential role as a therapeutic option for pts with ER+/HER2- MBC. Table 1: PFS estimates in the elacestrant and SoC arms based on different cut-off points for the duration of prior CDK4/6i. Citation Format: Aditya Bardia, Francois-Clement Bidard, Patrick Neven, Guillermo Streich, Alberto J. Montero, Frederic Forget, Marie-Ange Mouret-Reynier, Joo Hyuk Sohn, Donatienne Taylor, Kathleen K. Harnden, Hung Khong, Judit Kocsis, Florence Dalenc, Patrick Dillon, Sunil Babu, Simon Waters, Ines Deleu, Jose Angel García-Sáenz, Emilio Bria, Marina Elena Cazzaniga, Philippe Aftimos, Javier Cortés, Giulia Tonini, Tarek Sahmoud, Nassir Habboubi, Krzysztof Grzegorzewski, Virginia Kaklamani. GS3-01 EMERALD phase 3 trial of elacestrant versus standard of care endocrine therapy in patients with ER+/HER2- metastatic breast cancer: Updated results by duration of prior CDK4/6i in metastatic setting [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr GS3-01.

Burden of Hospitalization before and after a Disease Progression Following Triple-Class Exposure in Patients with Relapsed and Refractory Multiple Myeloma

Introduction: Multiple myeloma (MM) is a plasma cell malignancy with various clinical complications. Patients with relapsed and refractory multiple myeloma (RRMM) often suffer from disease progression and cycle through multiple treatments, including those from the same drug classes that they have failed before. Disease progression is usually associated with significant burden, including high health care resource utilization (HCRU) and costs. However, no current known literature quantifies HCRU and costs before and after disease progression in RRMM patients who have been exposed to multiple classes of therapies. This study aims to describe and compare hospitalization use and associated costs before and after disease progression in patients with RRMM who are triple-class exposed (TCE; defined as exposure to a proteosome inhibitor, an immunomodulatory agent, and an anti-CD38 antibody). Methods: This retrospective cohort study used the Optum Clinformatics® Data Mart database from 1/1/2012 to 12/31/2021. Adults with ≥2 diagnosis codes for MM (ICD-10-CM: C90.0x) ≥30 days apart and who received a subsequent line of therapy (LOT) after becoming TCE were included. The start of a subsequent LOT after TCE was used as a surrogate to define disease progression, and the initiation date of the latest of such LOTs was defined as the index date if multiple eligible LOTs were observed for the same patient. Patients were also required to have ≥6-month continuous enrollment (CE) in medical and pharmacy plans before and after index. Patient characteristics were described at index and during the 6-month baseline period. A 2-month pre-post analysis was performed to compare all-cause inpatient admissions, intensive care unit (ICU) stays, hospitalization length of stay, and direct inpatient costs. Categorical variables were compared using McNemar's test, and counts and costs were compared using paired generalized linear models. Subgroup analyses were performed in patients with commercial insurance or Medicare Advantage. Results: A total of 523 patients met the study criteria. The mean age was 70.2 years, 63.1% were White, 51.2% were female, 72.5% had Medicare Advantage, the mean Quan-Charlson comorbidity index was 4.2, and 34.8% had ≥4 prior LOTs within the CE period containing the index date. The proportion of patients who had an all-cause inpatient admission (20.1% vs 12.8%, P = 0.0008) and an ICU stay (6.5% vs 1.9%, P = 0.0004) were significantly higher during the 2-month post- versus pre-index period. During the 2-month post-index period, patients on average had significantly more all-cause inpatient admissions (0.29 vs 0.16, P <0.0001). The mean inpatient length of stay for the cohort was numerically higher during the 2-month post- versus pre-index period (1.67 vs 1.07 days, P = 0.0751). The mean per-month cost of all-cause hospitalization was significantly higher during the 2-month post- versus pre-index period ($3,590.81 vs $1,267.18, P = 0.0008). The majority of the all-cause hospitalization use and costs (>90%) were MM-related. Similar trends were observed among commercial and Medicare Advantage patients. Conclusions: This study found a pronounced increase in hospitalization and costs in the 2 months immediately following disease progression in RRMM patients who are TCE. The data may support economic assessment and value framework for innovative treatments with significant prolonged progression-free survival. In addition, there is a need to focus on multifaceted efforts to improve overall well-being and the total cost of care for patients with RRMM.

968TiP A phase II, multicenter study of lazertinib as consolidation therapy in patients with locally advanced, unresectable, EGFR mutation positive non-small cell lung cancer (stage III) who have not progressed following definitive, platinum-based, chemoradiation therapy (PLATINUM trial)

The PACIFIC trial has demonstrated that durable progression free survival (PFS) and sustained overall survival (OS) benefit with durvalumab as consolidation therapy after concurrent chemoradiation therapy (CCRT). In a subgroup analysis, the effect was not proven in patients with EGFR mutation positive. There is an unmet need for consolidative therapy after CCRT in patients with unresectable stage III EGFR mutation positive. A recent ADAURA trial showed that osimertinib had a significant prolongation of PFS in the postoperative adjuvant treatment in EGFR mutation positive patients.

Prolonged progression-free survival achieved by octreotide LAR plus transarterial embolization in low-to-intermediate grade neuroendocrine tumor liver metastases with high hepatic tumor burden.

ObjectiveTo evaluate the efficacy and outcome of transarterial embolization (TAE) plus octreotide long‐acting repeatable (LAR) on patients with low‐to‐intermediate neuroendocrine tumor liver metastases (NETLM).MethodsOne hundred and sixteen patients with G1/G2 NETLM treated with TAE plus octreotide LAR at the First Affiliated Hospital, Sun Yat‐sen University between January 12, 2016 and September 24, 2020 were reviewed. Radiological response was evaluated according to response evaluation criterion in solid tumor version 1.1. Overall progression‐free survival (PFS) was assessed. Intrahepatic and extrahepatic PFS were evaluated in the whole cohort and in patients with the extrahepatic disease (EHD), respectively. Factors affecting treatment response and overall PFS were analyzed using the logistic regression model and Cox proportional hazard model. Adverse events were recorded and evaluated according to Common Terminology Criteria for Adverse Events 5.0.ResultsThe median overall PFS of the whole cohort was 13.6 months. For the patients with EHD, the median intrahepatic PFS and extrahepatic PFS were 13.6 and 26.1 months, respectively. The median overall PFS of patients with hepatic tumor burden (HTB) <10%, 10%–25%, 25%–50%, and >50% were 25.2, 13.6, 11.2, and 12.3 months, respectively. Ki67 >10%, HTB >50%, and bone metastasis were independently associated with overall PFS. The objective response rate was 78.4%. In patients with HTB 25%–50% and >50%, responders (complete response or partial response) had significant prolonged PFS compared with nonresponders (stable disease or progression disease). Ki67 >10%, bone metastasis, and clear tumor margin were independently associated with response to TAE. The most frequent adverse events that occurred after TAE were postembolization syndrome, and no treatment‐associated death occurred during the perioperative period.ConclusionTransarterial embolization plus octreotide LAR can significantly prolong the PFS of neuroendocrine tumor liver metastases, especially with high HTB over 50%. Selected patients with HTB >25% (ki67 ≤10%, absence of bone metastasis, clear tumor margin) could derive prognostic advantage from the combined treatment.

Apatinib combined with pegylated liposomal doxorubicin (PLD) versus PLD for platinum-resistant recurrent ovarian cancer (APPROVE): a multicenter, randomized, controlled, open-label, phase II trial

Objectives: Anti-angiogenic therapy combined with chemotherapy could improve survival in patients with platinum-resistant ovarian cancer (OC). APPROVE was conducted to evaluate the efficacy and safety of apatinib, an oral tyrosine kinase inhibitor that selectively inhibits VEGFR-2, in combination with pegylated liposomal doxorubicin (PLD) in patients with platinum-resistant or refractory recurrent OC. Methods: Eligible patients were histologically confirmed non-mucinous ovarian, primary peritoneal cancer, or fallopian-tube cancer who had experienced disease progression during, or within 6 months of discontinuing, any prior line of platinum-based chemotherapy. Patients with at least 1 lesion (measurable and/or nonmeasurable) that could be accurately assessed at baseline by computed tomography/magnetic resonance imaging. Patients were randomly assigned (1:1) to receive PLD alone (Arm PLD, 40mg/m2 IV every 4 weeks for up to 6 cycles) or with apatinib 250mg orally once daily (Arm A-PLD) until disease progression, unacceptable toxicity, or consent withdrawal. Patients were stratified according to prior platinum-sensitive relapsed (yes vs no) and platinum-free interval (less than 3 vs 3 to 6 months from last platinum therapy to subsequent progression). The primary endpoint was progression-free survival (PFS) by RECIST 1.1 in the intent-to-treat population (ITT population). Secondary endpoints included overall survival (OS), objective response rate (ORR), disease control rate (DCR) and safety. Results: Between Mar 22, 2018, and Nov 16, 2020, 152 patients were enrolled and randomly assigned to receive A-PLD (n=78) or PLD (n=74). Median follow-up was 8.1months (IQR 3.7-12.8). Median PFS was 5.8 months with A-PLD therapy versus 3.3 months with PLD alone (HR 0.41, 95% CI 0.26-0.64, P=0.0001). In patients with evaluable disease (Arm A-PLD, n=61; Arm PLD, n=63), the ORR was 37.7% (23/61) versus 9.5% (6/63) for A-PLD and PLD, respectively (P=0.0002). The DCR of A-PLD and PLD arms were 82.0% (50/61) and 58.7% (37/63), respectively (P=0.0050). Overall survival data are immature. Hypertension and hand-foot syndrome were more common with apatinib. No adverse events beyond expectation were reported. Conclusions: Apatinib in combination with PLD statistically significant prolonged PFS in patients with platinum-resistant or refractory recurrent ovarian cancer. ORR and DCR were also significantly improved. Adverse events were consistent with the established safety profiles of apatinib and PLD. Anti-angiogenic therapy combined with chemotherapy could improve survival in patients with platinum-resistant ovarian cancer (OC). APPROVE was conducted to evaluate the efficacy and safety of apatinib, an oral tyrosine kinase inhibitor that selectively inhibits VEGFR-2, in combination with pegylated liposomal doxorubicin (PLD) in patients with platinum-resistant or refractory recurrent OC. Eligible patients were histologically confirmed non-mucinous ovarian, primary peritoneal cancer, or fallopian-tube cancer who had experienced disease progression during, or within 6 months of discontinuing, any prior line of platinum-based chemotherapy. Patients with at least 1 lesion (measurable and/or nonmeasurable) that could be accurately assessed at baseline by computed tomography/magnetic resonance imaging. Patients were randomly assigned (1:1) to receive PLD alone (Arm PLD, 40mg/m2 IV every 4 weeks for up to 6 cycles) or with apatinib 250mg orally once daily (Arm A-PLD) until disease progression, unacceptable toxicity, or consent withdrawal. Patients were stratified according to prior platinum-sensitive relapsed (yes vs no) and platinum-free interval (less than 3 vs 3 to 6 months from last platinum therapy to subsequent progression). The primary endpoint was progression-free survival (PFS) by RECIST 1.1 in the intent-to-treat population (ITT population). Secondary endpoints included overall survival (OS), objective response rate (ORR), disease control rate (DCR) and safety. Between Mar 22, 2018, and Nov 16, 2020, 152 patients were enrolled and randomly assigned to receive A-PLD (n=78) or PLD (n=74). Median follow-up was 8.1months (IQR 3.7-12.8). Median PFS was 5.8 months with A-PLD therapy versus 3.3 months with PLD alone (HR 0.41, 95% CI 0.26-0.64, P=0.0001). In patients with evaluable disease (Arm A-PLD, n=61; Arm PLD, n=63), the ORR was 37.7% (23/61) versus 9.5% (6/63) for A-PLD and PLD, respectively (P=0.0002). The DCR of A-PLD and PLD arms were 82.0% (50/61) and 58.7% (37/63), respectively (P=0.0050). Overall survival data are immature. Hypertension and hand-foot syndrome were more common with apatinib. No adverse events beyond expectation were reported. Apatinib in combination with PLD statistically significant prolonged PFS in patients with platinum-resistant or refractory recurrent ovarian cancer. ORR and DCR were also significantly improved. Adverse events were consistent with the established safety profiles of apatinib and PLD.

Pre-Therapeutic VEGF Level in Plasma Is a Prognostic Bio-Marker in Head and Neck Squamous Cell Carcinoma (HNSCC)

Simple SummaryIn the context of a growing variety in treatment strategies for patients with cancer, especially approaches based on antiangiogenetic pathways, we aimed to identify a useful biomarker for patients with head and neck squamous cell carcinoma (HNSCC). Our experimental results detected vascular endothelial growth factor (VEGF) in patients’ pre-therapeutic plasma, and not serum, which serves as a suitable biomarker for outcome prognostication. Results were validated in an independent cohort, confirming VEGF as an independent predictor (Pi) of outcomes in HNSCC patients. Therefore, pre-therapeutic VEGF in plasma may be an attractive biomarker in future HNSCC studies.Vascular endothelial growth factor (VEGF) is centrally involved in cancer angiogenesis. We hypothesized that pre-therapeutic VEGF levels in serum and plasma differ in their potential as biomarkers for outcomes in head and neck squamous cell carcinoma (HNSCC) patients. As prospectively defined in the study protocols of TRANSCAN-DietINT and NICEI-CIH, we measured VEGF in pretreatment serum and plasma of 75 HNSCC test cohort (TC) patients. We analyzed the prognostic value of VEGF concentrations in serum (VEGFSerum) and plasma (VEGFPlasma) for event-free survival (EFS) utilizing receiver-operating characteristics (ROC). Mean VEGF concentrations in plasma (34.6, 95% CI 26.0–43.3 ng/L) were significantly lower (p = 3.35 × 10−18) than in serum (214.8, 95% CI 179.6–250.0 ng/L) but, based on ROC (area under the curve, AUCPlasma = 0.707, 95% CI 0.573–0.840; p = 0.006 versus AUCSerum = 0.665, 95% CI 0.528–0.801; p = 0.030), superiorly correlated with event-free survival (EFS) of TC patients. Youden indices revealed optimum binary classification with VEGFPlasma 26 ng/L and VEGFSerum 264 ng/L. Kaplan–Meier plots demonstrated superiority of VEGFPlasma in discriminating patients regarding outcome. Patients with VEGFPlasma < 26 ng/L had superior nodal (NC), local (LC) and loco-regional control (LRC) leading to significant prolonged progression-free survival (PFS) and EFS. We successfully validated VEGFPlasma according the cut-off <26 ng/L as predictive for superior outcome in an independent validation cohort (iVC) of 104 HNSCC patients from the studies DeLOS-II and LIFE and found better outcomes including prolonged tumor-specific (TSS) and overall survival (OS). Outcomes in TC and iVC combined again was related to VEGFPlasma, and multivariate Cox regression revealed that VEGFPlasma was an independent outcome predictor. In HNSCC, pre-therapeutic VEGFPlasma is prognostic for outcomes.

Molecular follow-up of first-line treatment by osimertinib in lung cancer: Importance of using appropriate tools for detecting EGFR resistance mutation C797S

The C797S mutation encoded by EGFR exon 20 is classically observed as a tertiary event in EGFR-mutant non-small-cell lung carcinoma (NSCLC) primarily treated by first generation tyrosine kinase inhibitors (TKI) and secondarily treated by third-generation TKI, such as osimertinib, if the EGFR-T790M resistance mutation is detected. Recently, significant prolonged progression free survival has been observed following first-line osimertinib, in EGFR-mutant NSLC. While mechanisms of molecular resistance to first-generation TKI have been well studied, little is known about resistance induced by primary third-generation TKI treatments. We report the case of a 65 year-old female treated by first-line osimertinib for a multimetastatic exon 19-EGFR-mutant NSCLC. EGFR-C797S resistance mutation and PIK3CA mutation were detected together with the remaining EGFR-exon 19 deletion. This observation provides insights of acquired resistance to first line-osimertinib. It also highlights the importance of making molecular platforms which perform routine EGFR testing in lung cancer aware of the kind of therapeutic protocols given to the patient. Indeed, for rapid results or low-costs procedures, some targeted methods specifically targeting T790M may be used at relapse and may overlook alterations such as C797S or PIK3CA mutations. Targeted next generation sequencing is therefore a recommended option.

Results of biomarker analysis from phase II trial of nivolumab in refractory biliary tract cancer.

338 Background: Our previous phase II study demonstrated that nivolumab provides modest but durable clinical efficacy in patients (pts) with refractory biliary tract cancer (BTC), suggesting the significant clinical benefit of nivolumab in selected pts and identification of potential predictive biomarkers. Here, we report outcomes from the biomarker analysis. Methods: Pre-treatment tumor samples were obtained and assessed for immunohistochemistry (IHC) with PD-1 and PDL-1 antibodies, mRNA sequencing (RNAseq), and whole exome sequencing (WES). Clinical efficacy was correlated with the molecular analysis. Prior cisplatin exposure was reviewed to evaluate the impact of cisplatin on the tumor mutational burden (TMB) and clinical outcome. Results: Among 46 pts who had tumor response evaluation, 31 pts received cisplatin prior to nivolumab, and 15 were cisplatin-naive. Pre-treatment tumor samples were assessed for IHC (n = 42), RNAseq (n = 11), and WES (n = 11) based on tissue availability. There was no statistically significant correlation between prior cisplatin exposure and clinical outcome. Among 42 available tumor samples, 18 (43%) expressed PD-L1 positivity ( &gt; 1%), which was associated with a statistically significant prolonged progression free survival (PFS). Median PFS was 10.4 months for PD-L1 positive vs 2.4 months for PD-L1 negative (HR 0.23, 95% CI 0.10-0.51; P &lt; 0.001), while there was no statistically significant correlation between PD-1 expressing tumor infiltrating lymphocytes and clinical outcome. There was also no statistically significant difference in TMB of cisplatin-exposed (n = 8) vs. cisplatin-naïve tumor samples (n = 3) (9162, SD = 150 vs. 8898, SD = 806, p = 0.62). In comparing the group with prolonged disease control of at least 16 weeks (n = 4) to those with rapid disease progression (n = 7) who had mRNA sequencing performed, levels of AC005609.1, FAT3, TMEM151A, ADARB2, FAM153A were all significantly upregulated (p &lt; 0.01), while levels of CLCA1, MUC2, IGHV3-43, SWORA6, and CRISP3 were all significantly downregulated (p &lt; 0.01). Conclusions: Prior cisplatin exposure did not lead to statistically significant differences in clinical outcome or TMB in advanced BTC pts treated with nivolumab. However, PD-L1 expression &gt; 1% correlated with improved PFS, and variations in level of certain mRNA sequences were noted when comparing pts who had rapid disease progression vs. prolonged disease control with nivolumab. This suggests that BTC pts with positive PD-L1 expression and a particular mRNA profile may have a favorable response to nivolumab. Further studies are needed to confirm these findings. Clinical trial information: NCT02829918.