Improvement In Progression-free Survival Research Articles

Final overall survival and biomarker analyses of CHOICE-01: A double-blind randomized phase 3 study of toripalimab versus placebo in combination chemotherapy for advanced NSCLC without EGFR/ALK mutations.

9003 Background: Toripalimab in combination with chemotherapy showed significant improvement over chemotherapy alone in progression-free survival (PFS) and overall survival (OS) as first-line treatment of advanced NSCLC at the final PFS analysis of the CHOICE-01 study (NCT03856411). Here we report the final OS analysis. Methods: Patients (n=465) with treatment-naïve, advanced NSCLC without EGFR/ALK mutations were randomized 2:1 to receive toripalimab 240 mg (n=309) or placebo (n=156) in combination with chemotherapy for 4-6 cycles, followed by maintenance toripalimab or placebo plus standard care until disease progression, intolerable toxicity, or completion of 2 years of treatment. Patients from the placebo arm were actively crossed-over to receive toripalimab upon disease progression. The primary endpoint was PFS. The secondary endpoints included OS and safety. Results: By the cutoff date of August 31, 2022, when 283 events triggered the final OS analysis, the median survival follow up was 19.4 months. A significant improvement in OS was observed for the toripalimab arm over the placebo arm: HR=0.73 (95% CI: 0.57-0.93), two-sided p=0.0108, median OS 23.8 vs 17.0 months. A consistent effect on OS, favoring the toripalimab arm, was observed all PD-L1 expression subgroups. The OS benefit is greater in non-squamous NSCLC, HR=0.50 (95% CI: 0.36-0.70), median OS 27.8 vs 15.9 months, whereas no significant difference was found in the squamous subgroup (mOS 19.6 vs 18.1 months) despite a significant PFS improvement. The squamous subgroup had a high 70% crossover rate. No new safety signal was identified since the interim report. The incidence of Grade ≥3 adverse events (AEs) (78.9% vs 82.1%) was similar between the two arms. AEs leading to discontinuation of toripalimab/placebo (14.3% vs 3.2%), fatal AEs (5.5% vs 2.6%), and immune-related (irAEs) (50.6% vs. 21.2%) were more frequent in the toripalimab arm. Whole exome sequencing results indicated patients with mutations in the FAK-PI3K-Akt pathway achieved significantly better OS from the toripalimab arm. Conclusions: The addition of toripalimab to chemotherapy in patients with advanced NSCLC provided significant OS benefit than chemotherapy alone with a manageable safety profile. These results support the use of toripalimab with chemotherapy as 1st line therapy for advanced NSCLC patients without EGFR/ALK mutations. Clinical trial information: NCT03856411 .

Clinical activity of camizestrant, a next-generation SERD, versus fulvestrant in patients with a detectable ESR1 mutation: Exploratory analysis of the SERENA-2 phase 2 trial.

1066 Background: Camizestrant, a next-generation oral selective estrogen receptor antagonist and degrader (ngSERD), was compared at two dose levels to fulvestrant 500 mg (F) in post-menopausal women with advanced ER+, HER2˗ breast cancer with disease recurrence or progression after ≤1 endocrine therapy in the advanced setting in the Phase 2 randomized SERENA-2 study (NCT04214288). Camizestrant demonstrated statistically significant and clinically meaningful benefit vs F in progression-free survival (PFS) in the overall study population (Oliveira M et al. SABCS 2022 Annual Meeting. Abstract GS3-02.). Methods: Baseline circulating tumour DNA was collected at screening and/or Cycle 1 Day 1 and analysed by next-generation sequencing. A post hoc exploratory analysis compared investigator assessed PFS with camizestrant (data from 75 and 150 mg combined) vs F in patients with detectable baseline ESR1 (the gene that encodes ERα) hotspot mutations ( ESR1m). Patients were divided into subgroups based on whether 1 or >1 ESR1m variants were detected, the specific ESR1m, and whether mutations were detected in BRCA1/2 or the MAPK pathway. The most prevalent mutations are presented. A Cox proportional hazards model was used to compare PFS. Results: 48/147 (32.7%) patients treated with camizestrant and 35/73 (47.9%) treated with F had a detectable ESR1m in at least 1 baseline sample. ESR1m were detected in 6/9 (67%) patients with a BRCA1/2 mutation and 5/26 (19%) with a MAPK pathway alteration; however, the numbers were too small to analyse efficacy in these subgroups. Conclusions: Camizestrant showed improved outcome vs F in patients with a detectable ESR1m at baseline and in the subgroups tested. The greatest median PFS improvement was seen in patients where a single ESR1m variant was detected, suggesting that early intervention upon detection of an ESR1m may provide the maximum patient benefit for camizestrant, a hypothesis that is being tested in the SERENA-6 clinical trial (NCT04964934). Clinical trial information: NCT04214288 . [Table: see text]

The multikinase inhibitor axitinib in the treatment of advanced hepatocellular carcinoma: the current clinical applications and the molecular mechanisms.

Advanced hepatocellular carcinoma (HCC) is a formidable public health problem with limited curable treatment options. Axitinib, an oral tyrosine kinase inhibitor, is a potent and selective second-generation inhibitor of vascular endothelial growth factor receptor (VEGFR) 1, 2, and 3. This anti-angiogenic drug was found to have promising activity in various solid tumors, including advanced HCC. At present, however, there is no relevant review article that summarizes the exact roles of axitinib in advanced HCC. In this review, 24 eligible studies (seven studies in the ClinicalTrials, eight experimental studies, and nine clinical trials) were included for further evaluation. The included randomized or single-arm phase II trials indicated that axitinib could not prolong the overall survival compared to the placebo for the treatment of advanced HCC, but improvements in progression free survival and time to tumor progression were observed. Experimental studies showed that the biochemical effects of axitinib in HCC might be regulated by its associated genes and affected signaling cascades (e.g. VEGFR2/PAK1, CYP1A2, CaMKII/ERK, Akt/mTor, and miR-509-3p/PDGFRA). FDA approved sorafenib combined with nivolumab (an inhibitor of PD-1/PD-L1) as the first line regimen for the treatment of advanced HCC. Since both axitinib and sorafenib are tyrosine kinase inhibitors as well as the VEGFR inhibitors, axitinib combined with anti-PDL-1/PD-1 antibodies may also exhibit tremendous potential in anti-tumoral effects for advanced HCC. The present review highlights the current clinical applications and the molecular mechanisms of axitinib in advanced HCC. To move toward clinical applications by combining axitinib and other treatments in advanced HCC, more studies are still warranted in the near future.

Zolbetuximab + CAPOX Improves Survival in Advanced Gastric/GEJ Cancer

Zolbetuximab + CAPOX Improves Survival in Advanced Gastric/GEJ Cancer

Progression-free survival and safety at 3.5 years of follow-up: results from the randomised phase 3 PRIMA/ENGOT-OV26/GOG-3012 trial of niraparib maintenance treatment in patients with newly diagnosed ovarian cancer

PurposeTo report updated long-term efficacy and safety from the double-blind, placebo-controlled, phase 3 PRIMA/ENGOT-OV26/GOG-3012 study (NCT02655016). MethodsPatients with newly diagnosed advanced ovarian cancer with complete or partial response (CR or PR) to first-line platinum-based chemotherapy received niraparib or placebo once daily (2:1 ratio). Stratification factors were best response to first-line chemotherapy regimen (CR/PR), receipt of neoadjuvant chemotherapy (yes/no), and homologous recombination deficiency (HRD) status (deficient [HRd]/proficient [HRp] or not determined). Updated (ad hoc) progression-free survival (PFS) data (as of November 17, 2021) by investigator assessment (INV) are reported. ResultsIn 733 randomised patients (niraparib, 487; placebo, 246), median PFS follow-up was 3.5years. Median INV-PFS was 24.5 versus 11.2months (hazard ratio, 0.52; 95% confidence interval [CI], 0.40–0.68) in the HRd population and 13.8 versus 8.2months (hazard ratio, 0.66; 95% CI, 0.56–0.79) in the overall population for niraparib and placebo, respectively. In the HRp population, median INV-PFS was 8.4 versus 5.4months (hazard ratio, 0.65; 95% CI, 0.49–0.87), respectively. Results were concordant with the primary analysis. Niraparib-treated patients were more likely to be free of progression or death at 4years than placebo-treated patients (HRd, 38% versus 17%; overall, 24% versus 14%). The most common grade ≥ 3 treatment-emergent adverse events in niraparib patients were thrombocytopenia (39.7%), anaemia (31.6%), and neutropenia (21.3%). Myelodysplastic syndromes/acute myeloid leukaemia incidence rate (1.2%) was the same for niraparib- and placebo-treated patients. Overall survival remained immature. ConclusionsNiraparib maintained clinically significant improvements in PFS with 3.5years of follow-up in patients with newly diagnosed advanced ovarian cancer at high risk of progression irrespective of HRD status. No new safety signals were identified.

Impact of cytoreductive nephrectomy prior to combination therapy of ipilimumab plus nivolumab in metastatic renal cell carcinoma.

The efficacy of cytoreductive nephrectomy (CN) for metastatic renal cell carcinoma (mRCC) treated with immune checkpoint inhibitors (ICIs) has been suggested in the real-world setting. We retrospectively examined the efficacy of CN prior to nivolumab plus ipilimumab systemic therapy for synchronous mRCC. Synchronous mRCC patients who received nivolumab plus ipilimumab at Kobe University Hospital or five affiliated hospitals between October 2018 and December 2021 were included in this study. We compared the outcomes of objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and adverse events (AEs) between patients with CN prior to systemic therapy and without CN. In addition, patients were 1:1 matched by propensity scores accounting for factors associated with treatment assignment. Twenty-one patients received CN prior to nivolumab plus ipilimumab (Prior CN) and 33 received nivolumab plus ipilimumab alone (Without CN). PFS of the Prior CN group was 10.8 months (95%CI 5.5-NR) and 3.4 months (95%CI 2.0-5.9) for the Without CN group (p = 0.0158). OS of Prior CN was 38.4 months (95%CI NR-NR) and 12.6 months (95%CI 4.2-30.8) for Without CN (p = 0.0024). Univariate and multivariate analyses identified prior CN as a significant prognostic indicator for PFS and OS. Moreover, propensity score matching analysis showed significant improvements in PFS and OS in Prior CN. Patients who underwent CN prior to nivolumab plus ipilimumab systemic therapy for synchronous mRCC had a better prognosis than patients treated with nivolumab plus ipilimumab alone. These results suggest the efficacy of prior CN for synchronous mRCC with ICI combination therapy.

Clinical outcomes after incomplete cycles of R-CHOP for diffuse large B-cell lymphoma: 10 years’ real-world experience in a single institute

Although the current standard of care for diffuse large B-cell lymphoma (DLBCL) is six cycles of rituximab/cyclophosphamide/doxorubicin/vincristine/prednisolone combination chemotherapy (R-CHOP), a larger than expected number of patients cannot complete planned six cycles for various reasons in the real world. We aimed to evaluate the prognosis of patients with DLBCL after incomplete treatment by analyzing the chemotherapy response and survival according to the cause of discontinuation and the number of cycles. We analyzed a retrospective cohort of patients diagnosed with DLBCL who underwent incomplete cycles of R-CHOP at Seoul National University Hospital and Boramae Medical Center from January 2010 to April 2019. A total of 1183 patients were diagnosed with DLBCL, of which 260 (22%) did not complete six cycles of R-CHOP. The most common cause of discontinuation of chemotherapy was life-threatening infection, and the most common pathogen was Pneumocystis jirovecii. Overall survival (OS) and progression-free survival (PFS) were significantly better in patients who achieved complete response (CR) or partial response (PR) at the first response evaluation. Patients underwent three or more cycles of chemotherapy had a longer OS than those who did not. In patients with limited-stage disease, consolidative radiotherapy showed a significant improvement in OS and PFS. Advanced stage, high comorbidity score, and poor primary response to chemotherapy were poor prognostic factors in patients with unplanned treatment shortening. This study provides real-world outcomes for patients who could not complete the planned six cycles of R-CHOP.

Dual Biomarker Combining DNA Damage Repair Gene Mutations and PD-L1 Expression for Immune Checkpoint Inhibitors in Non-small Cell Lung Cancer.

Immune checkpoint inhibitors (ICIs) improve long-term survival in advanced non-small cell lung cancer (NSCLC) and require robust predictive biomarkers for the selection of responders. This study investigated the optimal implementation of DNA damage repair (DDR) gene mutations to predict response to ICIs in real-world NSCLC patients. We retrospectively reviewed 55 advanced NSCLC patients who had undergone targeted high-throughput sequencing and received ICIs. Patients with two or more DDR gene mutations were defined as DDR2 positive. The patients' median age was 68 (range=44-82) years, and 48 (87.3%) were men. Seventeen patients (30.9%) showed ≥50% high programmed death-ligand 1 (PD-L1) expression. Ten patients (18.2%) received an ICI-chemotherapy combination as first-line therapy, and 38 (69.1%) received ICI monotherapy as more than second-line therapy. Fourteen patients (25.5%) were DDR2-positive. The objective response rate of patients with DDR2-positive or PD-L1 ≥50% was 45.5%, and that of patients with DDR2-negative and PD-L1 <50% was 11.1% (p=0.007). In the PD-L1 low expression subgroup (<50%), patients with DDR2-positive had improved progression-free survival (PFS) and overall survival (OS) after ICIs compared to those with DDR2-negative (PFS: 5.8 vs. 1.9 months, p=0.026, OS: 14.4 vs. 7.2 months, p=0.078). DDR2-positive patients or those with PD-L1 ≥50% (24, 43.6%) had statistically significant improvement in PFS and OS after ICIs compared to DDR2-negative and those with PD-L1 <50% (PFS: 4.4 vs. 1.9 months, p=0.006, OS: 11.6 vs. 7.2 months, p=0.037). A dual biomarker combining DDR gene mutations and PD-L1 expression improves the prediction of response to ICIs in advanced NSCLC.

Molecular markers impacting survival in patients receiving concurrent chemoradiation and Tumor-Treating Fields (TTF) in patients with newly diagnosed glioblastoma: secondary analysis of SPARE trial (P13-13.003)

<h3>Objective:</h3> The objective of this study was to evaluate the impact of molecular markers (PTEN, TP53, EGFR, and TERT) on overall survival (OS) and progression-free survival (PFS) of SPARE trial patients. <h3>Background:</h3> SPARE trial (Scalp-sparing radiation with concurrent temozolomide (TMZ) and tumor treating fields; NCT03477110) is a single-arm pilot study that demonstrated the safety and feasibility of concurrent TTF with chemoradiation for newly diagnosed glioblastomas (GBM). <h3>Design/Methods:</h3> This is a secondary analysis of the SPARE trial. Molecular markers of histologically-confirmed, IDH-wildtype GBM patients age ≥ 18 years old with a Karnofsky performance status (KPS) ≥ 60 who received concurrent chemoradiation and TTF followed by maintenance TMZ + TTF were evaluated. Molecular profile was evaluated with next-generation sequencing. Interaction of mutations in PTEN, TP53, EGFR, and TERT with TTF on OS and PFS was evaluated using a multivariable model. <h3>Results:</h3> A total of 30 patients were enrolled in the SPARE trial. 1 patient with IDH-mutant histology was excluded. The median age was 58 (range; 19–77). The median KPS was 90 (range; 70–100). 9 patients (31.0% ) had a methylated MGMT promotor. 14 patients (48.3%) were found to have PTEN mutation, 9 patients (31.0%) with EGFR alteration, 7 (24.1%) with TP53 mutation, and 23 patients (79.3%) with TERT mutated. MGMT methylation remained statistically significant for an increased OS (p=0.032; HR 7.18). TERT had a statistically significant OS benefit (p=0.012; HR 7.60). TERT also showed significant improvement in PFS. However, neither EGFR, TP53, nor PTEN showed any association of PFS or OS for patients who received concurrent TTF and chemoradiation treatment. <h3>Conclusions:</h3> In this secondary analysis, neither EGFR, TP53, nor PTEN mutation showed any association of PFS or OS. However, patients with TERT mutations showed improved OS. Due to the small sample size, further validation studies should be conducted. <b>Disclosure:</b> Ms. Kayne has nothing to disclose. Dr. Poiset has nothing to disclose. Dr. Ali has nothing to disclose. Dr. Miller has nothing to disclose. Dr. Niazi has nothing to disclose. Dr. Cappelli has nothing to disclose. The institution of Dr. Alnahhas has received research support from Novocure. Dr. Shi has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Novocure. Dr. Shi has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for zai lab. Dr. Shi has received personal compensation in the range of $500-$4,999 for serving as a Consultant for varian. Dr. Shi has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for novocure.

Abstract CT082: Next-generation sequencing (NGS) and cytokine assessment from a phase III study of copanlisib in combination with rituximab in patients with indolent non-Hodgkin lymphoma (iNHL) - associations with survival endpoints

Abstract Introduction: The PI3K inhibitor copanlisib (C) plus the anti-CD20 antibody rituximab (R) was superior to R plus placebo (P) in patients (pts) with relapsed iNHL (Matasar et al. Lancet Oncol 2021). We previously reported that C+R improved median progression-free survival (PFS) in the iNHL, follicular lymphoma (FL), and non-FL groups, with a statistically significant improvement in the PTEN-positive population (Shalini et al., AACR 2022). Here we conducted NGS analysis from pts treated with either C+R or P+R for possible impact on PFS outcomes. We also determined if there was an association between plasma cytokine levels at baseline with survival. Methods: Adult pts with relapsed B-cell iNHL were randomly assigned 2:1 to either C+R or P+R; standard dosing on a 28-day cycle applied. Either fresh or archival tumor tissues were collected for central pathology review and biomarker analysis. NGS was conducted using the TSO500 platform for 476 genes. Analyses included EZH2 and BCL2 mutation status in FL subset, and other genes for FL subsets and overall iNHL, as prognostic and predictive markers. The effect of mutations on PFS and overall survival (OS) outcomes was assessed. Cytokines from baseline plasma were assessed using the multiplex MSD platform (71-plex). Association between cytokine levels and PFS and OS were explored. Results: Baseline tumor samples were evaluable by NGS from 200 pts; 127 C+R and 73 P+R. Variant alleles with frequencies &amp;gt;10% were analyzed. One quarter (25.7%) of FL pts were determined to have EZH2 mutations. C+R treatment significantly improved PFS for FL pts with in mutant EZH2 (p=0.0066) compared to P+R. FL pts with mutant BCL2 had a statistically improved PFS compared to WT BCL2 when receiving C+R treatment. Plasma samples were available for 71-plex assessment in 373 pts; 246 C+R and 127 P+R. Pts were assigned as high or low baseline cytokine groups based on the median values. For majority of cytokines, the low cytokine group correlated with better PFS for all pts, FL and Other iNHL pts in the C+R arm. For OS, there were too few events at the time of primary data cutoff to make any associations. However, with longer follow up (2 years from primary completion) there was a significant improvement in OS in iNHL pts with low IL2 values at baseline receiving C+R compared to pts receiving P+R; HR 0.495 (95%CI: 0.270,0.908), p=0.0230. This association was only seen for pts with low (or undetected) levels of IL2 at baseline. Conclusions: Mutation status was associated with improvements in PFS in FL pts with mutant BCL2 or mutant EZH2 treated with C+R. iNHL pts with low plasma levels of IL2 levels treated with C+R showed a significant improvement in OS. Citation Format: Shalini Chaturvedi, Anke Weispfenning, David Bauer, Rong Du, Tine Descamps, Sara Bellinvia, Teresa Lunt, Lidia Mongay Soler, Barrett H. Childs, Pier Luigi Zinzani. Next-generation sequencing (NGS) and cytokine assessment from a phase III study of copanlisib in combination with rituximab in patients with indolent non-Hodgkin lymphoma (iNHL) - associations with survival endpoints [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT082.

Abstract CT076: Randomized, global, phase 3 study of tislelizumab plus chemotherapy versus chemotherapy as first-line treatment for advanced or metastatic esophageal squamous cell carcinoma (RATIONALE-306): China subgroup analysis

Abstract Background: Tislelizumab, an anti-programmed cell death protein 1 (PD-1) antibody, + chemotherapy (chemo) demonstrated a statistically significant and clinically meaningful improvement in overall survival (OS) vs placebo + chemo, with a manageable safety profile, as a first line (1L) treatment for patients (pts) with advanced or metastatic esophageal squamous cell carcinoma (ESCC) at interim analysis of the phase 3 RATIONALE-306 study. We report data from the China subgroup analysis. Methods: In this randomized, double-blind, global study, adults with unresectable locally advanced or metastatic ESCC, with no prior systemic treatment for advanced disease were enrolled regardless of programmed death-ligand 1 (PD-L1) expression status. Pts were randomized (1:1); stratified by region, prior definitive therapy, and investigator-chosen chemo (platinum + fluoropyrimidine or platinum + paclitaxel). Pts received tislelizumab (T) 200 mg intravenously + chemo (C) (Arm T+C) or placebo (P) + chemo (Arm P+C) once every three weeks; treatment continued until disease progression by investigator per RECIST v1.1, intolerable toxicity, or withdrawal. The primary endpoint was OS in the intent-to-treat (ITT) population. Secondary endpoints included investigator-assessed progression-free survival (PFS) per RECIST v1.1, objective response rate (ORR), and duration of response (DoR), in addition to safety. Results: Of 649 pts in the overall population, 370 (57.0%) were enrolled from China. At data cutoff (Feb 28, 2022), the median study follow-up in the China subgroup (ITT population) was 15.8 months (mo) in Arm T+C (n=182) and 10.6 mo in Arm P+C (n=188). Longer OS (median OS 16.6 mo vs 11.2 mo; unstratified hazard ratio [HR] 0.69, 95% confidence interval [CI] 0.54, 0.89) and PFS (median PFS 8.3 mo vs 5.6 mo; unstratified HR 0.58, 95% CI 0.45, 0.75) indicate survival benefit in Arm T+C vs P+C, respectively. Arm T+C had higher response rates and more durable responses than Arm P+C; ORR was 64.8% vs 44.1% (odds ratio 2.33 [95% CI 1.53, 3.55]) respectively, and median DoR was 7.4 mo (95% CI 5.6, 9.5) vs 5.7 mo (95% CI 4.3, 7.5), respectively. Similar proportions of pts in Arm T+C vs P+C had ≥1 treatment-related adverse event (TRAE; 98.8% vs 98.9%) and ≥grade 3 TRAEs (72.9% vs 73.4%). Serious TRAEs occurred in 27.6% vs 21.2% of pts in Arm T+C vs P+C, and TRAEs leading to death occurred in 2.9% vs 1.6% of pts, respectively. Treatment-emergent adverse events leading to discontinuation occurred in 28.2% vs 17.4%, in Arm T+C vs P+C. Conclusions: In the China subgroup, 1L tislelizumab + chemo demonstrated clinically meaningful improvement in OS, PFS, ORR, and DoR vs placebo + chemo in pts with advanced or metastatic ESCC, with a manageable safety profile, consistent with published results in the overall population. Acknowledgments: This study was sponsored by BeiGene, Ltd. Medical writing support, under the direction of the authors, was provided by Emma Ashman, BSc, of Ashfield MedComms, an Inizio company, and was funded by BeiGene, Ltd. Citation Format: Yongqian Shu, Yueyin Pan, Ping Lu, Yi Jiang, Jingdong Zhang, Xiaohong Wu, Yuanhu Yao, Lin Shen, Yi Ba, Zhiyong He, Yuxian Bai, Jianhua Chen, Guohua Yu, Yanyan Peng, Hongqian Wu, Lei Wang, Liyun Li, Jianming Xu. Randomized, global, phase 3 study of tislelizumab plus chemotherapy versus chemotherapy as first-line treatment for advanced or metastatic esophageal squamous cell carcinoma (RATIONALE-306): China subgroup analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT076.

Pazopanib in Locally Advanced or Metastatic Renal Cell Carcinoma: Results of a Randomized Phase III Trial.

Pazopanib is an oral angiogenesis inhibitor targeting vascular endothelial growth factor receptor, platelet-derived growth factor receptor, and c-Kit. This randomized, double-blind, placebo-controlled phase III study evaluated efficacy and safety of pazopanib monotherapy in treatment-naive and cytokine-pretreated patients with advanced renal cell carcinoma (RCC). Adult patients with measurable, locally advanced, and/or metastatic RCC were randomly assigned 2:1 to receive oral pazopanib or placebo. The primary end point was progression-free survival (PFS). Secondary end points included overall survival, tumor response rate (Response Evaluation Criteria in Solid Tumors), and safety. Radiographic assessments of tumors were independently reviewed. Of 435 patients enrolled, 233 were treatment naive (54%) and 202 were cytokine pretreated (46%). PFS was significantly prolonged with pazopanib compared with placebo in the overall study population (median, PFS 9.2 v 4.2 months; hazard ratio [HR], 0.46; 95% CI, 0.34 to 0.62; P < .0001), the treatment-naive subpopulation (median PFS 11.1 v 2.8 months; HR, 0.40; 95% CI, 0.27 to 0.60; P < .0001), and the cytokine-pretreated subpopulation (median PFS, 7.4 v 4.2 months; HR, 0.54; 95% CI, 0.35 to 0.84; P < .001). The objective response rate was 30% with pazopanib compared with 3% with placebo (P < .001). The median duration of response was longer than 1 year. The most common adverse events were diarrhea, hypertension, hair color changes, nausea, anorexia, and vomiting. There was no evidence of clinically important differences in quality of life for pazopanib versus placebo. Pazopanib demonstrated significant improvement in PFS and tumor response compared with placebo in treatment-naive and cytokine-pretreated patients with advanced and/or metastatic RCC.

Abstract 4527: CD8 T cell-melanoma cell interactions in response and resistance to ipilimumab plus nivolumab: Biopsy analysis of SWOG S1616

Abstract Background: In the randomized S1616 trial (NCT03033576), patients with metastatic melanoma refractory to anti-PD-1-based therapy had improved progression free survival (PFS, HR = 0.63, p = 0.037) and objective response to ipilimumab plus nivolumab (ipi/nivo, RR 28%) compared to ipilimumab alone (ipi, RR = 9%). We hypothesized that reversal of resistance to PD-1 blockade with CTLA-4 blockade would result in increased CD8 T-cell infiltration in patient biopsies. Methods: Multiplex ion beam imaging (MIBI) for 32 protein markers, spanning tumor, immune, and stromal cell types, was used to evaluate the tumor microenvironment in melanoma tumor biopsies collected at baseline (N=21 samples) and one month on-treatment (N=22; N=16 paired timepoints). Tumor-immune cell dynamics were determined by comparing baseline and on-treatment biopsies within clinical groups (ipi/nivo response, N=10; ipi/nivo no-response, N=9; ipi no-response, N=8). Results: Multiplex analysis in ipi/nivo responsive patients demonstrated increased proportions of CD8 (median 1.6X increase), CD4 (2.1X), regulatory T cells (1.6X), and monocytes (1.4X), with a paralleled 8.1X decrease in melanoma cells over the course of treatment. This was confirmed by histopathologic evidence of tumor regression, necrosis, and immune infiltrate in on-treatment, responding tumor biopsies, as determined by dermatopathologists. Melanoma cells had direct, cell-membrane interactions with CD8 T cells in ipi/nivo responsive patients, both at baseline (median 26%) and on-treatment (median 86%). The shared interface between melanoma and CD8 T-cells had polarized expression of CD3, CD8, and CD45RO. There was no change in T-cell infiltration nor tumor cell content over the course of treatment in ipi/nivo non-responders nor ipi non-responders; similar proportions of melanoma cells were interacting with CD8 T-cells at baseline (median 24%) and on-treatment (27%). Conclusion: Reversal of resistance to PD-1 blockade is associated with increased frequency of CD8 T-melanoma cell interactions and pathological response, reflective of different stages of antitumor immune responses. Response to ipi/nivo in the anti-PD-1 refractory setting was further associated with increased tumor-polarized and activated CD8 T cells interacting with melanoma cells, demonstrated by the colocalized expression of immune synapse proteins at tumor-CD8-T-cell membrane interfaces. Citation Format: Katie M. Campbell, Lawrence Kuklinski, Zaid Bustami, Jessica Maxey, Egmidio Medina, Sandra Santulli-Marotto, Cynthia R. Gonzalez, Nataly Naser Aldeen, Kari Kendra, Sapna Patel, Siwen Hu-Lieskovan, James Moon, Shay Bellasea, Christine N. Spencer, Marshall A. Thompson, Michael Wu, Ari Vanderwalde, Philip O. Scumpia, Antoni Ribas. CD8 T cell-melanoma cell interactions in response and resistance to ipilimumab plus nivolumab: Biopsy analysis of SWOG S1616. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4527.

Abstract 3432: Ataxia-telangiectasia mutated loss of function displays variant and tissue specific differences across tumor types

Abstract Introduction: ATM loss of function (LOF) in cancer may serve as a predictive biomarker of response for antitumor therapies. However, clinical studies of targeted treatments in ATM-aberrant patients have yielded mixed results; thus, identifying the optimal strategy for selecting patients with ATM LOF tumors remains a critical area of unmet need. Methods: In order to investigate the heterogeneity observed in ATM aberrant tumors, we conducted a pan-cancer genomic and proteomic profiling of ATM LOF, and also performed retrospective review of clinical outcomes for a subset of patients with ATM LOF treated with platinum or ATR inhibition. Results: We identified 10,609 ATM variants in 8,587 patients with cancer. The prevalence of deleterious (Tier 1) versus variants of unknown significance (VUS)/benign (Tier 2) variants differed by cancer tissue type, as did selective pressure for loss of heterozygosity (LOH). Analysis of ATM protein staining in 471 patient tumors showed tumors with null, inactivating variants were significantly (p&amp;lt;0.005) more likely to display ATM loss of protein (LOP) than tumors with missense or wildtype, but 19% (N=27/140) and 9% (N=13/149) of tumors with ATM-VUS and wildtype showed loss of protein. In addition, concordance between inactivating mutations and loss of protein also differed based on tumor tissue context, with ovarian and breast cancer showing stronger concordance (greater than 80%) than melanoma and lung cancer ( less than 20%). Patients treated with platinum chemotherapy with select tumor types with deleterious variants in ATM and ATM LOP display improved progression free survival (PFS) (HR 0.50, P=0.03). Lastly, patients with tumor types that have stronger ATM variant-to-protein loss concordance display increased benefit from ATR inhibition (HR 0.40, P=0.04). Conclusions: Our data highlight that there is heterogeneity in ATM LOF in patients due to multiple variables, including notable tissue-specific differences in the type of variants seen and the relationship between ATM variant status and ATM protein. This genomic heterogeneity and tissue-specificity has implications for predictive biomarker development and clinical trial designs. Citation Format: Patrick G. Pilie, Daniel Mcgrail, Wei-Lien Wang, Natalie Ngoi, Keith Kyewalabye, Khalida Wani, Hung Le, Erick Campbell, Vijaykumar Holla, Kenna R. Shaw, Funda Meric-Bernstam, Alexander J. Lazar, Virginia Giuliani, Timothy Heffernan, Timothy A. Yap. Ataxia-telangiectasia mutated loss of function displays variant and tissue specific differences across tumor types [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3432.

MP08-03 PROGRESSION-FREE SURVIVAL AS SURROGATE ENDPOINT IN HIGH-RISK NON-MUSCLE INVASIVE BLADDER CANCER STUDIES: RESULTS FROM A MACHINE LEARNING-BASED ANALYSIS OF A LARGE MULTI-INSTITUTIONAL DATABASE

MP08-03 PROGRESSION-FREE SURVIVAL AS SURROGATE ENDPOINT IN HIGH-RISK NON-MUSCLE INVASIVE BLADDER CANCER STUDIES: RESULTS FROM A MACHINE LEARNING-BASED ANALYSIS OF A LARGE MULTI-INSTITUTIONAL DATABASE

Outcomes associated with treatment to all sites of disease in patients with stage IVB cancer of the cervix

ObjectiveThe use of chemoradiation in patients with stage IVB cancer of the cervix was evaluated to determine if definitive treatment offers benefit.MethodsA database of 546 patients with cancer of the...

Treatment With Liposomal Irinotecan Plus Fluorouracil and Leucovorin for Patients With Previously Treated Metastatic Biliary Tract Cancer

The NIFTY trial demonstrated the benefit of treatment with second-line liposomal irinotecan (nal-IRI) plus fluorouracil (FU) and leucovorin (LV) for patients with advanced biliary tract cancer (BTC). To report the updated efficacy outcomes from the NIFTY trial with extended follow-up of 1.3 years with reperformed masked independent central review (MICR) with 3 newly invited radiologists. The NIFTY trial was a randomized, multicenter, open-label, phase 2b clinical trial conducted between September 5, 2018, and December 31, 2021, at 5 tertiary referral centers in South Korea. Patients with advanced BTC whose disease progressed while receiving first-line gemcitabine plus cisplatin with at least 1 measurable lesion per Response Evaluation Criteria in Solid Tumors, version 1.1, were eligible. Data analysis was completed on May 9, 2022. Patients were randomized 1:1 to receive LV, 400 mg/m2, bolus and FU, 2400 mg/m2, for a 46-hour infusion intravenously every 2 weeks with or without nal-IRI, 70 mg/m2, before LV intravenously. Patients were treated until disease progression or unacceptable toxic effects. Primary end point was progression-free survival (PFS) as assessed by MICR. Secondary end points were PFS as assessed by the investigator, overall survival, and objective response rate. A total of 178 patients (75 women [42.1%]; median [IQR] age, 64 [38-84] years) were randomly assigned, and 174 patients were included in the full analysis set (88 patients [50.6%] in the nal-IRI plus FU/LV group vs 86 patients [49.4%] in the FU/LV alone group). In this updated analysis, the median MICR-assessed PFS was 4.2 months (95% CI, 2.8-5.3) for the nal-IRI plus FU/LV group and 1.7 months (95% CI, 1.4-2.6) for the FU/LV alone group (hazard ratio, 0.61; 95% CI, 0.44-0.86; P = .004), in contrast to the 7.1 and 1.4 months reported in the previous study, respectively. The discordance rate for tumor progression date between the MICR and investigators was 17.8% (vs 30% in the previous study). The NIFTY randomized clinical trial demonstrated significant improvement in PFS with treatment with nal-IRI plus FU/LV compared with FU/LV alone for patients with advanced BTC after progression to gemcitabine plus cisplatin. The combination of nal-IRI plus FU/LV could be considered as a second-line treatment option for patients with previously treated advanced BTC. clinicaltrials.gov Identifier: NCT03524508.

Pembrolizumab plus chemotherapy in Japanese patients with triple-negative breast cancer: Results from KEYNOTE-355.

Pembrolizumab plus chemotherapy improved progression-free survival (PFS) and overall survival (OS) compared with placebo plus chemotherapy in patients with previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer with tumor programmed cell death ligand 1 (PD-L1) combined positive score (CPS) ≥10 in the global, phase 3, randomized controlled trial KEYNOTE-355. We report results for patients enrolled in Japan. Patients were randomized 2:1 to pembrolizumab 200 mg or placebo Q3W for 35 cycles plus chemotherapy (nab-paclitaxel, paclitaxel, or gemcitabine-carboplatin). Primary endpoints were PFS per RECIST version 1.1 by blinded independent central review and OS in patients with PD-L1 CPS ≥10, PD-L1 CPS ≥1, and the intention-to-treat (ITT) population. No alpha was assigned to this exploratory analysis. Eighty-seven patients were randomized in Japan (pembrolizumab plus chemotherapy, n=61; placebo plus chemotherapy, n=26), 66 (76%) had PD-L1 CPS ≥1, and 28 (32%) had PD-L1 CPS ≥10. Median time from randomization to data cutoff (June 15, 2021) was 44.7 (range, 37.2-52.9) months in the ITT population. Hazard ratios (HRs; 95% CI) for OS were 0.36 (0.14-0.89), 0.52 (0.30-0.91), and 0.46 (0.28-0.77) in the PD-L1 CPS ≥10, PD-L1 CPS ≥1, and ITT populations, respectively. HRs (95% CI) for PFS were 0.52 (0.20-1.34), 0.61 (0.35-1.06), and 0.64 (0.39-1.05). Grade 3 or 4 treatment-related adverse events occurred in 85% of patients in each group (no grade 5 events). Consistent with the global population, pembrolizumab plus chemotherapy tended to show improvements in OS and PFS with manageable toxicity versus placebo plus chemotherapy in Japanese patients and supports this combination in this setting.

A review of treatments targeting DNA-repair gene defects in metastatic castration resistant prostate cancer.

Prostate cancer is the most common cancer in men. About 6% of those diagnosed will develop metastatic disease. Unfortunately, metastatic prostate cancer is fatal. Prostate cancer can be castration sensitive or castration resistant. Many treatments have been shown to improve progression free survival and overall survival in metastatic castration resistant prostate cancer (mCRPC). In recent years, studies have been exploring targeting mutations in the DNA Damage Repair (DDR) response that may amplify oncogenes. In this paper, we aim to discuss DDR, new approved targeted therapies, and the most recent clinical trials in the setting of metastatic CRPC.

Addition of metformin for non-small cell lung cancer patients receiving antineoplastic agents.

Background and purpose: Previous studies have found that metformin can inhibit tumor growth and improve outcomes for cancer patients. However, the association between the addition of metformin to the treatment regimen and survival in non-small cell lung cancer (NSCLC) patients receiving antineoplastic agents such as chemotherapy drugs, epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), and immune checkpoint inhibitors (ICIs) remains unclear. This study aimed to evaluate the effect of metformin in NSCLC patients who received the aforementioned antineoplastic therapies. Methods: Several electronic databases were searched for relevant studies published by 10 September 2022. The primary and secondary outcomes were overall survival (OS) and progression-free survival (PFS); eligible studies were those comparing patients with and without the addition of metformin. Hazard ratios (HRs) and 95% confidence intervals (CIs) were combined, with all statistical analyses performed using STATA 15.0. Results: A total of 19 studies involving 6,419 participants were included, of which six were randomized controlled trials. The overall pooled results indicate that the addition of metformin improved OS (HR = 0.84, 95% CI: 0.71-0.98, p = 0.029) and PFS (HR = 0.85, 95% CI: 0.74-0.99, p = 0.039). However, subgroup analysis based on treatment type and comorbidity of diabetes mellitus demonstrated that improvements in OS and PFS were observed only in diabetic and EGFR-TKI-treated patients (OS: HR = 0.64, 95% CI: 0.45-0.90, p = 0.011; PFS: HR = 0.59, 95% CI: 0.34-1.03, p = 0.061). Conclusion: Overall, this meta-analysis found that metformin use could improve outcomes for diabetic patients receiving EGFR-TKIs. However, no significant association between the addition of metformin and the survival of non-diabetic NSCLC patients receiving chemotherapy or ICI therapy was identified based on the current evidence.