Ratio For Progression-free Survival Research Articles

Phase I and Randomized Phase II Study of Ruxolitinib With Frontline Neoadjuvant Therapy in Advanced Ovarian Cancer: An NRG Oncology Group Study.

The interleukin-6/Janus kinase (JAK)/signal transducers and activators of transcription 3 axis is a reported driver of chemotherapy resistance. We hypothesized that adding the JAK1/2 inhibitor ruxolitinib to standard chemotherapy would be tolerable and improve progression-free survival (PFS) in patients with ovarian cancer in the upfront setting. Patients with ovarian/fallopian tube/primary peritoneal carcinoma recommended for neoadjuvant chemotherapy were eligible. In phase I, treatment was initiated with dose-dense paclitaxel (P) 70 mg/m2 once daily on days 1, 8, and 15; carboplatin AUC 5 intravenously day 1; and ruxolitinib 15 mg orally (PO) twice a day, every 21 days (dose level 1). Interval debulking surgery (IDS) was required after cycle 3. Patients then received three additional cycles of chemotherapy/ruxolitinib, followed by maintenance ruxolitinib. In the randomized phase II, patients were randomly assigned to paclitaxel/carboplatin with or without ruxolitinib at 15 mg PO twice a day for three cycles, IDS, followed by another three cycles of chemotherapy/ruxolitinib, without further maintenance ruxolitinib. The primary phase II end point was PFS. Seventeen patients were enrolled in phase I. The maximum tolerated dose and recommended phase II dose were established to be dose level 1. One hundred thirty patients were enrolled in phase II with a median follow-up of 24 months. The regimen was well tolerated, with a trend toward higher grade 3 to 4 anemia (64% v 27%), grade 3 to 4 neutropenia (53% v 37%), and thromboembolic events (12.6% v 2.4%) in the experimental arm. In the randomized phase II, the median PFS in the reference arm was 11.6 versus 14.6 in the experimental, hazard ratio (HR) for PFS was 0.702 (log-rank P = .059). The overall survival HR was 0.785 (P = .24). Ruxolitinib 15 mg PO twice a day was well tolerated with acceptable toxicity in combination with paclitaxel/carboplatin chemotherapy. The primary end point of prolongation of PFS was achieved in the experimental arm, warranting further investigation.

Studying Outcomes after Steroid-Sparing Immunosuppressive Agent vs. Steroid-Only Treatment for Immune-Related Adverse Events in Non-Small-Cell Lung Cancer (NSCLC) and Melanoma: A Retrospective Case-Control Study.

The effects of steroid-sparing immunosuppressive agents (SSIAs), used for the treatment of immune-related adverse events (irAEs), on immune checkpoint inhibitor (ICI) antitumor activity is not well known. We compared tumor outcomes of patients who received corticosteroid monotherapy (CS) versus a corticosteroid plus SSIA (CS-SSIA) for irAE treatment, using statistical methods to address immortal time bias. We conducted a retrospective case-control study on patients ≥ 18 years with melanoma or non-small-cell lung cancer (NSCLC) treated with ≥1 ICI at a quaternary care center between 1 January 2016 and 11 January 2021. Patients were divided into two cohorts: CS or CS-SSIA. We used propensity score nearest-neighbor matching to match on tumor type, stage, and prior lines of therapy. Primary outcomes were progression-free survival (PFS) and overall survival (OS). Secondary outcomes included the time from the start of the irAE treatment to the irAE resolution. Hazard ratios (HRs) for PFS and OS were calculated using the Cox proportional hazard regression method with both (1) the time to the steroid and SSIA as time-varying covariates and (2) a binary exposure classification not accounting for the time to the treatment. A total of 167 patients were included after matching (132 in the CS cohort and 35 in the CS-SSIA cohort). Sixty-six percent of all the patients had melanoma. The most common irAEs requiring treatment were gastroenterocolitis and hepatitis. In an adjusted analysis not accounting for immortal time bias, there were no significant differences in PFS (HR 0.75, 95% CI [0.46-1.23]) or OS (HR 0.82, 95% CI [0.46-1.47]). In analyses using a time-varying treatment indicator, there was a trend toward improved PFS in patients treated with SSIAs (HR 0.54, CI 0.26-1.10). There was no difference in OS (HR 1.11, CI 0.55-2.23). Patients with melanoma who specifically received infliximab had improved PFS compared to patients with CS only, after adjusting for immortal time bias (HR 0.32, CI 0.24-0.43). The use of SSIAs with CS did not have worse outcomes than CS monotherapy. In melanoma, our findings showed improved PFS for the use of infliximab versus steroid monotherapy for irAEs. Large, prospective, randomized controlled trials are needed to confirm these findings and guide the optimal treatment of irAEs.

Abstract PO5-21-09: Clinical outcomes by age subgroups in the phase 3 TROPiCS-02 study of sacituzumab govitecan vs treatment of physician’s choice in HR+/HER2‒ metastatic breast cancer

Abstract Background Sacituzumab govitecan (SG) is a Trop-2directed antibody-drug conjugate approved for second-line or later (2L+) treatment of metastatic triple-negative breast cancer in multiple countries and for 2L+ treatment of HR+/HER2‒ (IHC 0, 1+, or 2+/ISH) metastatic breast cancer (mBC) in the US. SG significantly improved progression-free survival (PFS) and overall survival (OS) vs treatment of physician’s choice (TPC) in patients (pts) with pretreated, endocrine-resistant HR+/HER2‒ mBC in the TROPiCS-02 study. The incidence of HR+/HER2‒ mBC increases with age, especially after 65, and older pts often have poorer prognosis due to comorbidities, increased toxicity, and reduced efficacy of chemotherapy. In TROPiCS-02, pts aged ≥ 65 years (yr) derived consistent PFS benefit and clinically meaningful improved OS with SG vs TPC. In this analysis, we present additional efficacy and safety outcomes by age subgroup. Methods Pts with HR+/HER2‒ mBC who had received at least 1 endocrine therapy, taxane, and CDK4/6 inhibitor, and 2 to 4 prior lines of chemotherapy for mBC, were randomized to either SG (10 mg/kg IV days 1 and 8, Q3W) or TPC. The primary end point was PFS, and secondary end points included OS, objective response rate (ORR), and safety. A post hoc analysis was conducted by age subgroups (< 65 vs ≥ 65, < 75 vs ≥ 75). Results In total, 543 pts were randomized to the SG (n = 272; 73 [27%] ≥ 65, 16 [6%] ≥ 75) and TPC (n = 271; 67 [25%] ≥ 65, 8 [3%] ≥ 75) groups. Baseline characteristics were generally similar across treatment arms in each age subgroup, but a higher proportion of pts had performance status 1 vs 0 in the ≥ 65 vs < 65 and ≥ 75 vs < 75 subgroups, respectively. The data cutoff date was July 1, 2022. SG demonstrated longer median PFS and OS vs TPC across age subgroups. Hazard ratios (HR) for PFS with SG vs TPC were 0.69, 0.59, 0.70, and 0.30 for the < 65, ≥ 65, < 75, and ≥ 75 subgroups, respectively (Table). The HR for OS were 0.81, 0.80, 0.82, and 0.56 in these subgroups, respectively (Table). Median duration of response (DoR) was also longer with SG vs TPC across age subgroups, although median DoR was not estimable in the ≥ 75 subgroup (Table). ORR was higher with SG vs TPC, except in the ≥ 75 subgroup (Table). Safety was generally similar with SG vs TPC across subgroups with the following differences. Grade ≥ 3 treatment-emergent adverse events were more common in the ≥ 75 subgroup than the other subgroups (SG, 81% in ≥ 75 vs 68%-73% for all others; TPC, 71% in ≥ 75 vs 60%-61% for all others). TEAEs leading to dose reduction were also more common in pts treated with SG in the ≥ 75 subgroup, but were consistent across other subgroups (Table). However, sample sizes in the ≥ 75 subgroup were small, which limits interpretation (Table). TEAEs leading to treatment discontinuation were more common in older pts, irrespective of treatment group (Table). Conclusions SG showed benefit in PFS and OS vs TPC in pts with HR+/HER2‒ mBC across age subgroups, consistent with the intent to treat population. SG was associated with a slight increase in toxicity for elderly pts, as expected. SG demonstrated a favorable benefit/risk profile, with efficacy benefit and acceptable toxicity, for elderly pts. Table. Citation Format: Aditya Bardia, Peter Schmid, Sara Tolaney, Frederik Marmé, Javier Cortés, Theresa Valdez, Hao Wang, Wendy Verret, Hope Rugo. Clinical outcomes by age subgroups in the phase 3 TROPiCS-02 study of sacituzumab govitecan vs treatment of physician’s choice in HR+/HER2‒ metastatic breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-21-09.

Abstract PO2-04-10: Effect of Alpelisib Dose Modification for AE Management on Progression-Free Survival and Treatment Duration in SOLAR-1 and BYLieve Clinical Trials

Abstract Background: Alpelisib (ALP) is an α-selective phosphatidylinositol 3-kinase (PI3K) inhibitor and degrader approved with fulvestrant (FUL) for patients (pts) with phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA)-mutated, hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2−) advanced breast cancer (ABC) following progression on/after endocrine therapy-based treatment (tx). Toxicity limited ALP exposure in some pts in the SOLAR-1 and BYLieve studies. On-target effects of PI3K inhibitors, including hyperglycemia, rash, and diarrhea, are among the most common adverse events (AEs) associated with ALP. During SOLAR-1, median onset times were 15 and 13 days for grade ≥3 hyperglycemia and rash and 46 days for grade 2/3 diarrhea. ALP dose modification can help manage AEs. We report efficacy of ALP + FUL as second-line (2L) tx in pts who underwent ALP dose reduction (DR). Methods: Pts with PIK3CA mutations from SOLAR-1 and BYLieve, treated with ALP + FUL in 2L, were included. Landmark (LM) analyses were performed at 1, 2, 3, 4, 5, and 6 mo after tx initiation to evaluate the association between DR status (yes, no) with progression-free survival (PFS) and duration of tx (DoT), respectively. Pts with PFS or exposure time less than each LM time point were excluded from each LM analysis; pts were then grouped by DR (yes, no) before each LM time point. Median PFS and DoT were obtained using a modified Kaplan-Meier method. Alternatively, Cox regression analysis was used to assess the effect of DR on PFS and DoT, where 2 time-dependent variables were included separately in the model as a covariate: 1) DR status, and 2) DR groups (300 to 250 mg [1 DR] vs no DR, 300 to 250 to 200 mg [2 DR] vs no DR). Association between AEs and DR was evaluated descriptively. A matched analysis of AEs will be presented. Results: In all, the analysis included 212 pts in 2L: 77 from SOLAR-1, and 95 and 40 from BYLieve Cohorts A and C, respectively. Of these pts, 92 (43.4%) had no DR and 120 (56.6%) had DRs: 70 (58.3%) had 1 DR, 43 (35.8%) had 2, and 7 (5.8%) had other types of DR. 25 of 92 pts (27.2%) with no DR and 40 of 120 pts (33.3%) with DR had ≥12-mo exposure to ALP. Hazard ratios (HRs) for PFS and DoT in DR status for the LM analysis are shown (Table). HRs (95% CI) for PFS from the time-dependent covariate analyses were 1.28 (0.94-1.74) with DR status as the covariate, and 1.24 (0.88-1.76) and 1.21 (0.79-1.84) with DR group (1 DR vs no DR, 2 DR vs no DR) as the covariate, respectively; for DoT, these were 1.34 (1.00-1.79) for DR status, and 1.30 (0.93-1.80) and 1.30 (0.87-1.93) for DR group, respectively. During the treatment period, the incidence rate for grade ≥3 AEs was the highest for pts with 2 DR and lowest for those with no DR. Similarly, incidence of AEs leading to DR or tx discontinuation was higher in pts with 2 DR than 1 DR. The post-DR incidence rate for grade ≥3 AE was similar for pts with 2 DR or 1 DR. A matched analysis will assess the relationship between DR group and AE. Conclusions: In this pooled analysis, regardless of if/when DR occurred, PFS was similar and DoT may be sustained with ALP + FUL. ALP DR can potentially reduce AEs, which may allow pts to remain on tx. Using DR as an AE management strategy may enable pts with PIK3CA-mutated, HR+, HER2− ABC to optimize tx duration and clinical benefit of ALP in the 2L. Landmark Analyses of PFS and Tx Duration by DR Group (Yes vs No; Pooled FAS) Citation Format: Hope Rugo, Alessandra Gennari, Stephen Chia, Dejan Juric, Neil Vasan, Sherko Küemmel, Patrick Neven, Florence Lerebours, Manuel Ruíz - Borrego, Pedram Razavi, Jyotika Singh, Yogesh Chattar, Murat Akdere, Eva Ciruelos. Effect of Alpelisib Dose Modification for AE Management on Progression-Free Survival and Treatment Duration in SOLAR-1 and BYLieve Clinical Trials [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-04-10.

The Benefits and Risks of Receiving Investigational Solid Tumor Drugs in Randomized Trials : A Systematic Review and Meta-analysis.

Many patients participate in cancer trials to access new therapies. The extent to which new treatments produce clinical benefit for trial participants is unclear. To estimate the progression-free survival (PFS) and overall survival (OS) advantage of assignment to experimental groups in randomized trials for 6 solid tumors. ClinicalTrials.gov was searched for trials of investigational drugs with results posted between 2017 and 2021. Investigational drugs were defined as those not yet having full approval from the U.S. Food and Drug Administration for the study indication. Trials were included if they were randomized and tested drugs or biologics. Data extraction was completed by 2 independent reviewers. Data were pooled using a random-effects model. The sample included 128 trials comprising 141 comparisons of a new drug and a comparator. These comparisons included 47 050 patients. The pooled hazard ratio for PFS was 0.80 (95% CI, 0.75 to 0.85), indicating statistically significant benefit for patients in experimental groups. This corresponded to a median PFS advantage of 1.25 months (CI, 0.80 to 1.68 months). The pooled hazard ratio for OS was 0.92 (CI, 0.88 to 0.95), corresponding to a survival gain of 1.18 months (CI, 0.72 to 1.71 months). The absolute risk for a serious adverse event for comparator group patients was 29.56% (CI, 26.64% to 32.65%), with an increase in risk of 7.40% (CI, 5.66% to 9.14%) for patients in experimental groups. Trials in this sample were heterogeneous. Comparator group interventions were assumed to reflect standard of care. Assignment to experimental groups produces statistically significant survival gains. However, the absolute survival gain is small, and toxicity is statistically significantly greater. The findings of this review provide reassuring evidence that patients are not meaningfully disadvantaged by assignment to comparator groups. Canadian Institutes of Health Research.

Abstract LB391: Deep learning AI predicts HRD and platinum response from histologic slides

Abstract Background: Cancers with homologous recombination deficiency (HRD) can benefit from platinum salts and PARP inhibitors. Standard diagnostic tests, including FDA-approved companion diagnostics, for detecting HRD require molecular profiling, which is not universally available with global testing rates lowest among minority, rural, and other underserved populations. Methods: We trained DeepHRD, a deep-learning platform for predicting HRD from hematoxylin and eosin (H&E)-stained histopathological slides, using primary breast (n=1,008) and ovarian (n=459) cancers from The Cancer Genome Atlas (TCGA). DeepHRD was compared to four standard HRD molecular tests using breast (n=349) and ovarian (n=141) cancers from multiple external and independent datasets, including clinical cohorts with platinum complete response, progression-free survival (PFS) and overall survival (OS) endpoints. Results: DeepHRD detected HRD from held-out H&E-stained breast cancer slides in TCGA with an AUC of 0.81 ([0.77-0.85]; 95% confidence interval). This performance was confirmed in two independent primary breast cancer cohorts (AUC=0.76; [0.71-0.82]). In an external platinum-treated metastatic breast cancer cohort, samples detected as HRD had a higher complete response (AUC=0.76; [0.54-0.93]) with 3.7-fold increase in median PFS (14.4 versus 3.9 months; p-value=0.0019) and hazard ratio (HR) of 0.45 (p=0.0047) after correcting for PAM50 molecular subtype and age at diagnosis. This deep-learning classifier outperformed four genomic HRD tests used in the clinic, including standard HRD score, BRCA1/2, 26-HR gene panel and single-base substitution signature 3 (SBS3). Multiresolution spatial mapping identified morphological features utilized by DeepHRD for detecting HRD, notably enriched for neoplastic and necrotic tissues, and a higher macrophage density. Through transfer learning to high-grade serous-ovarian cancer, DeepHRD-positive samples exhibited better overall survival after TCGA first-line (HR=0.46; p=0.030) and an external neoadjuvant (HR=0.49; p=0.015) platinum-treated cohorts. Conclusion: In summary, DeepHRD exhibits consistent hazard ratios ranging from 0.45 to 0.49 across the three clinical cohorts and captures 1.8- to 3.1-fold more HRD-positive breast and ovarian cancer patients. DeepHRD-positive breast cancer patients that received platinum exhibited better complete response and PFS. Similarly, DeepHRD-positive platinum-treated ovarian cancer patients had a better OS. DeepHRD’s ability to detect HRD from digital H&E slides provides an important precision oncology tool that can be utilized in resource-constrained and underserved areas where genomic testing is generally not existent. Citation Format: Erik N. Bergstrom, Ammal Abbasi, Marcos Diaz-Gay, Loïck Galland, Sylvain Ladoire, Scott M. Lippman, Ludmil B. Alexandrov. Deep learning AI predicts HRD and platinum response from histologic slides [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB391.

Abstract 2558: Molecularly matched targeted therapies benefit high risk pediatric cancer patients

Abstract Introduction: Genomic technologies have the potential to transform the paradigm for diagnosing and treating children with cancer. Although druggable alterations are identified in a large fraction of pediatric cancer patients, the extent to which point-of-care genomic testing directly impacts therapeutic outcomes of individual patients in real-world settings is less well-known. A review of patients sequenced through the Precision in Pediatric Sequencing (PIPseq) program at Columbia University Irving Medical Center (CUIMC) was conducted to describe outcomes of patients treated with a molecularly matched targeted therapy (MTT). Methods: Matched tumor-normal whole exome and tumor transcriptome sequencing was conducted in a CLIA-certified laboratory at CUIMC between January 2013 and March 2023 on samples from 373 high risk pediatric cancer patients including those with <50% survival, rare cancers lacking standard therapies, and relapsed/refractory disease. All cases were reviewed at a multi-disciplinary molecular tumor board and reports were transmitted to the electronic health record (EHR). EHR data were reviewed to identify patients who received a MTT. Tumor-specific response and progression-free survival (PFS) among the MTT cohort were investigated. Clinical benefit was further assessed using the Growth Modulation Index (GMI) whereby patients served as their own control. GMI is the ratio of PFS on the MTT therapy to the PFS on the most recent prior therapy. A ratio of >/=1.3 indicates meaningful clinical activity. Results: Thirty pediatric patients (solid tumors, n=5; CNS tumors, n=15; hematologic malignancies, n=10) received a MTT. Median age at sequencing was 11 years, range 10 months-23 years. Median time to MTT from sequencing was 4.5 months, range 7 days to 19.2 months. Best overall response included 7 complete responses (23%), 6 partial responses (20%), 5 with stable disease (17%), 10 with progressive disease (33%), and 2 indeterminate due to early death or lack of follow-up during therapy (7%). GMI was calculated for 19/30 patients (63%); median GMI=1.1. 11 patients were excluded due to lack of prior therapy, early death, insufficient follow-up, or lack of progression between prior and targeted therapies. GMI ratios indicated clinical benefit from MTT for 12/19 patients (63%), median GMI=1.5. Conclusions: Clinical comprehensive molecular profiling for pediatric patients with high risk cancers identified patients who are candidates for MTT. Overall, MTT led to stable disease, partial or complete response, for 60% of patients. Utilizing GMI ratios as an indicator of clinical benefit for select patients provided additional information beyond traditional endpoints. Twelve patients with GMI >/=1.3 experienced improved PFS compared to their most recent prior therapy. These results demonstrate real-world clinical benefit from MTT, supporting molecular profiling of pediatric high risk tumors. Citation Format: Alice Tao, Jovana Pavisic, Jennifer A. Oberg. Molecularly matched targeted therapies benefit high risk pediatric cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2558.

Selective Internal Radiation Therapy Using Y-90 Resin Microspheres for Metastatic Colorectal Cancer: An Updated Systematic Review and Network Meta-Analysis.

This literature review and exploratory network meta-analysis (NMA) aimed to compare the clinical effectiveness and tolerability of selective internal radiation therapy (SIRT) using yttrium-90 (Y-90) resin microspheres, regorafenib (REG), trifluridine-tipiracil (TFD/TPI), and best supportive care (BSC) in adult patients with chemotherapy-refractory or chemotherapy-intolerant metastatic colorectal cancer (mCRC). In light of recently published data, the literature was searched to complement and update a review published in 2018. Studies up to December 2022 comparing two or more of the treatments and reporting overall survival (OS), progression-free survival (PFS), or incidence of adverse events (AE) were included. The NMA compared hazard ratios (HRs) for OS and PFS using Markov chain Monte Carlo techniques. Fifteen studies were included, with eight studies added (none addressing SIRT). All active treatments improved OS in relation to BSC. SIRT had the longest OS among all treatments, although without statistically significant differences (HR [95% credible interval] for SIRT, 0.48 [0.27, 0.87]; TFD/TPI, 0.62 [0.46, 0.83]; REG, 0.78 [0.57, 1.05]) in a fixed effects model. Information regarding SIRT was insufficient for PFS analysis, and TFD/TPI was the best intervention (HR 2.26 [1.6, 3.18]). One SIRT study reported radioembolization-induced liver disease in > 10% of the sample; this was symptomatically managed. Non-haematological AEs (hand-foot skin reaction, fatigue, diarrhoea, hypertension, rash or desquamation) were more common with REG, while haematological events (neutropoenia, leukopenia, and anaemia) were more common with TFD/TPI. Current evidence supports SIRT treatment in patients with chemotherapy-refractory or chemotherapy-intolerant mCRC compared to newer oral agents, with comparable OS and low incidence of AEs.

Pembrolizumab plus lenvatinib (P+L) versus alternate therapies in first-line (1L) for advanced renal cell carcinoma (aRCC): A network meta-analysis (NMA).

422 Background: Patients with advanced renal cell carcinoma (aRCC) have poor prognosis resulting in significant burden. In the KEYNOTE-581/CLEAR trial, pembrolizumab plus lenvatinib (P+L) as 1L therapy showed statistically significant and clinically meaningful improvements in overall survival (OS), progression-free survival (PFS), and overall response rate (ORR) versus sunitinib in patients with aRCC. This NMA synthesized evidence from randomized clinical trials (RCTs) to indirectly compare the relative treatment effects of P+L vs alternate therapies in treatment-naïve aRCC. Methods: A systematic literature review was conducted to identify systemic therapies in 1L aRCC. A Bayesian NMA with fixed-effect models was performed to indirectly compare P+L to alternate therapies using sunitinib as the common comparator in 1L aRCC. Hazard ratios (HRs) for OS and PFS were calculated with 95% credible intervals (CrIs). NMAs assuming constant hazard ratios (HRs) and time-varying HRs were performed for OS and PFS. For the proportion of patients experiencing response, a binomial likelihood and logit link were used, and relative effects were expressed as odds ratios (OR). Results: A total of 33 unique RCTs met the inclusion criteria and were included in the analyses. The constant HR analysis resulted in no significant differences in OS between P+L and alternatives in network. Results showed statistically significant higher ORR for P+L compared to nivolumab + ipilimumab (N+I) (OR=3.19; 95% CrI: 2.14, 4.82) and pembrolizumab + axitinib (P+A) (OR=1.84; 95% CrI: 1.21, 2.80). The analysis also favored P+L over nivolumab + cabozantinib (N+C) (OR=1.35; 95% Crl: 0.86, 2.12) and avelumab + axitinib (A+A) (OR=1.46; 95% Crl: 0.96, 2.23), but was not statistically significant. The constant HR analysis showed that P+L resulted in a statistically significant improvement in PFS compared to N+I (HR=0.55; 95% CrI: 0.40, 0.75), A+A (HR=0.68; 95% Crl: 0.49, 0.96) and P+A (HR=0.69; 95% CrI: 0.51, 0.94). The analysis also favored P+L over N+C (HR=0.81; 95% Crl: 0.58, 1.14), but was not statistically significant. Conclusions: NMA indicates P+L has higher ORR and improved PFS compared to other regimens in 1L aRCC. No significant differences in OS were observed between P+L and competing interventions.

Benefit of immune checkpoint inhibitors (ICI) for patients with advanced esophageal squamous cell carcinoma and low PD-L1 expression: A systematic review and meta-analysis.

346 Background: Immunotherapy has improved survival for patients with advanced esophageal squamous cell carcinoma (aESCC) and currently is the standard of care for patients with a positive PD-L1 status (CPS ≥10; TPS ≥1%) in the first-line setting. For PD-L1 negative/low, treatment options are limited, and chemotherapy is usually the first choice and associated with adverse events that may impair quality of life. Immunotherapy trials harbor conflicting results in this subgroup of patients, therefore, we performed a systematic review and meta-analysis to evaluate the potential benefit of ICI as single treatment for patients with aESCC and a PD-L1 expression negative/low. Methods: Studies that enrolled patients with aESCC treated with ICI versus chemotherapy in first and second-line settings and provided separate outcomes for patients with PD-L1 negative/low were identified by searching the EMBASE, PubMed and Cochrane databases. The outcomes evaluated were Overall Survival (OS), Progression Free-Survival (PFS) and Treatment-Emergent Adverse Events (TEAE). We pooled hazard ratio (HR) for PFS and OS endpoints and odds ratio (OR) with 95% confidence intervals (CI) for TEAE. Statistical analyses were performed using Revman 5.4 and a random-effects model. I² analysis was used to assess heterogeneity. This meta-analysis was recorded on Prospero ID CRD42023411251. Results: We included 6 randomized clinical trials with a total of 674 individuals in the final analysis. Most studies (5/6) included previously treated patients. ICI monotherapy in aESCC patients and PD-L1 expression negative/low was associated with a better OS (HR 0.86; 95% CI 0.76-0.97; p = 0.02; I² = 0%) and worse PFS (HR 1.37; 95% CI 1.10-1.71; p = 0.005; I² = 0%). Regarding the safety profile, it showed higher grade 3-5 toxicity rates (OR 1.8; 95% CI 1.17-2.78; p = 0.007; I² = 85%) for chemotherapy. Conclusions: ICI is effective for patients with aESCC and low/negative PD-L1 expression with an improvement in OS and a favorable safety profile.

Safety and efficacy of zolbetuximab for CLDN18.2-positive gastric or gastroesophageal junction adenocarcinoma: A systematic review and meta-analysis of randomized controlled trials.

370 Background: Monoclonal antibody (Nivolumab, Trastuzumab, Bemarituzumab) with chemotherapy has shown benefit for patients with metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma. Zolbetuximab, a new monoclonal antibody against Claudin (CDLN) 18.2 has demonstrated interesting results in clinical trials, however, there is still a need to find a safe and effective first-line treatment, especially for epidermal growth factor receptor (HER) 2-negative patients. Therefore, we aimed to perform a meta-analysis exploring the use of combined immunotherapy (Zolbetuximab) and standard chemotherapy versus chemotherapy alone. Methods: We searched PubMed, Embase and Cochrane Central for randomized controlled trials (RCTs) comparing Zolbetuximab to chemotherapy alone in patients with CLDN18.2-positive gastric or GEJ adenocarcinoma. The outcomes evaluated were Overall Survival (OS), Progression Free-Survival (PFS), Objective Response Rate (ORR) and Treatment-Emergent Adverse Events (TEAE). We pooled hazard ratio (HR) for PFS and OS endpoints and risk ratio (RR) for ORR and TEAE, with 95% confidence intervals (CI). Statistical analyses were performed using R software version 4.3.1 with a random-effects model. I² analysis was used to assess heterogeneity. Adverse Events (AE) were graded according to the National Cancer Institute Common Terminology Criteria for AE. Results: From sixty-six studies, three were included, with a total of 1349 patients. 671 (49.7%) were part of the intervention group, 769 (57.0%) were male, 360 (26.7%) underwent prior gastrectomy and 1304 (96.7%) had a more than 70% CLDN18.2 cellular staining rate. Age range was 21-83 years. Treatment with Zolbetuximab was associated with significantly higher PFS (HR 0.64; CI 0.49-0.84; p = 0.0011; I² = 59.6%) and OS (HR 0.70; CI 0.59-0.84; p<0.0001; I² = 40.0%). TEAEs grade ≥ 3 (RR 1.09; CI 1.03-1.16; p = 0.0051; I² =0.0%) were greater for the intervention group. ORR and serious TEAE had no difference when compared with the control group. Most frequent AEs were nausea (34.6%), vomiting (30.2%) and decreased appetite (18.6%). Conclusions: In summary, the use of Zolbetuximab alongside standard chemotherapy reduces mortality and disease progression, although it might increase the risk for grade ≥ 3 treatment-emergent AEs.

Bevacizumab, Irinotecan, or Topotecan Added to Temozolomide for Children With Relapsed and Refractory Neuroblastoma: Results of the ITCC-SIOPEN BEACON-Neuroblastoma Trial.

Outcomes for children with relapsed and refractory high-risk neuroblastoma (RR-HRNB) remain dismal. The BEACON Neuroblastoma trial (EudraCT 2012-000072-42) evaluated three backbone chemotherapy regimens and the addition of the antiangiogenic agent bevacizumab (B). Patients age 1-21 years with RR-HRNB with adequate organ function and performance status were randomly assigned in a 3 × 2 factorial design to temozolomide (T), irinotecan-temozolomide (IT), or topotecan-temozolomide (TTo) with or without B. The primary end point was best overall response (complete or partial) rate (ORR) during the first six courses, by RECIST or International Neuroblastoma Response Criteria for patients with measurable or evaluable disease, respectively. Safety, progression-free survival (PFS), and overall survival (OS) time were secondary end points. One hundred sixty patients with RR-HRNB were included. For B random assignment (n = 160), the ORR was 26% (95% CI, 17 to 37) with B and 18% (95% CI, 10 to 28) without B (risk ratio [RR], 1.52 [95% CI, 0.83 to 2.77]; P = .17). Adjusted hazard ratio for PFS and OS were 0.89 (95% CI, 0.63 to 1.27) and 1.01 (95% CI, 0.70 to 1.45), respectively. For irinotecan ([I]; n = 121) and topotecan (n = 60) random assignments, RRs for ORR were 0.94 and 1.22, respectively. A potential interaction between I and B was identified. For patients in the bevacizumab-irinotecan-temozolomide (BIT) arm, the ORR was 23% (95% CI, 10 to 42), and the 1-year PFS estimate was 0.67 (95% CI, 0.47 to 0.80). The addition of B met protocol-defined success criteria for ORR and appeared to improve PFS. Within this phase II trial, BIT showed signals of antitumor activity with acceptable tolerability. Future trials will confirm these results in the chemoimmunotherapy era.

Immune checkpoint inhibitors plus chemotherapy in first-line endometrial cancer treatment: Still the era of microsatellites?

The combination of immune checkpoint inhibitors (ICIs) plus chemotherapy is currently being tested as the first-line treatment of advanced endometrial. We aimed to evaluate the efficacy and safety of this combination. We performed a meta-analysis of randomized clinical trials. Patients with advanced endometrial carcinoma receiving ICIs plus chemotherapy in the experimental arm, compared with chemotherapy plus placebo in the control arm, were included. We evaluated the progression-free survival (PFS) as an efficacy outcome and the number and grades of adverse events (AEs) for safety. Hazard ratios (HR) for PFS and risk ratios (RR) for AEs, with 95% confidence intervals (CI), were calculated. 1303 patients were treated in the included studies. Adding ICIs to chemotherapy significantly improved PFS in mismatch repair deficient (dMMR-HR 0.29; 95% CI, 0.20-0.42; p < 0.00001) and in mismatch repair proficient (pMMR-HR 0.64; 95% CI, 0.46-0.90; p = 0.01) patients. No difference emerged for all-grades AEs (RR 1.00; p = 0.98), but the risk of ≥G3 AEs was increased in the ICIs + chemotherapy group (RR 1.22; 95% CI, 1.11-1.34; p < 0.0001). Adding ICIs to chemotherapy significantly improves PFS in first-line endometrial cancer, regardless of MMR status.

The value of oral selective estrogen receptor degraders in patients with HR-positive, HER2-negative advanced breast cancer after progression on ≥ 1 line of endocrine therapy: systematic review and meta-analysis

BackgroundCurrently, the value of oral selective estrogen receptor degraders (SERDs) for hormone receptor-positive (HR+) and human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (aBC) after progression on ≥ 1 line of endocrine therapy (ET) remains controversial. We conducted a meta-analysis to evaluate progression-free survival (PFS) and safety benefits in several clinical trials.Materials and methodsCochrane Library, Embase, PubMed, and conference proceedings (SABCS, ASCO, ESMO, and ESMO Breast) were searched systematically and comprehensively. Random effects models or fixed effects models were used to assess pooled hazard ratios (HRs) and 95% confidence intervals (CIs) for treatment with oral SERDs versus standard of care.ResultsA total of four studies involving 1,290 patients were included in our analysis. The hazard ratio (HR) of PFS showed that the oral SERD regimen was better than standard of care in patients with HR+/HER2- aBC after progression on ≥ 1 line of ET (HR: 0.75, 95% CI: 0.62-0.91, p = 0.004). In patients with ESR1 mutations, the oral SERD regimen provided better PFS than standard of care (HR: 0.58, 95% CI: 0.47-0.71, p < 0.00001). Regarding patients with disease progression following previous use of CDK4/6 inhibitors, PFS benefit was observed in oral SERD-treatment arms compared to standard of care (HR: 0.75, 95% CI: 0.64-0.87, p = 0.0002).ConclusionsThe oral SERD regimen provides a significant PFS benefit compared to standard-of-care ET in patients with HR+/HER2- aBC after progression on ≥ 1 line of ET. In particular, we recommend oral SERDs as a preferred choice for those patients with ESR1m, and it could be a potential replacement for fulvestrant. The oral SERD regimen is also beneficial after progression on CDK4/6 inhibitors combined with endocrine therapy.

Prediction of 5-year overall survival of diffuse large B-cell lymphoma on the pola-R-CHP regimen based on 2-year event-free survival and progression-free survival.

This study aimed to predict the 5-year overall survival (OS) benefit of pola-R-CHP versus R-CHOP in the POLARIX trial based on the 2-year event-free survival (EFS) and progression-free survival (PFS) rates in diffuse large B-cell lymphoma (DLBCL). We identified randomized controlled trials (RCT) published before 31 May 2023. The correlation between the logarithmic (log) hazard ratio (HR) for EFS (HREFS ) or PFS (HRPFS ) and the HR for OS (HROS ) was estimated at the trial-level. Correlation analysis was performed between 2-year PFS or EFS and 5-year OS rates at the treatment arm-level. Linear regression models were used to calculate the 5-year OS of pola-R-CHP and R-CHOP. In the included 20 RCTs, a linear correlation between HREFS (r = 0.765) or HRPFS (r = 0.534) and HROS was observed at the trial- level. Two-year EFS (r = 0.918) or 2-year PFS (r = 0.865) correlated linearly with 5-year OS. Linear regression analysis between 2-year EFS/PFS and 5-year OS gave estimated 5-year OS rates between pola-R-CHP and R-CHOP of 6.4% and 6.3%, respectively. Two-year EFS and PFS are feasible early endpoints in patients with DLBCL treated primarily with immunochemotherapy. The pola-R-CHP regimen is expected to improve 5-year OS.

Dexamethasone and overall survival and progression free survival in patients with newly diagnosed glioblastoma: a meta-analysis.

Glioblastomas, the most common primary malignant brain tumors in adults, still hold poor prognosis. Corticosteroids, such as dexamethasone, are usually prescribed to reduce peritumoral edema and limit neurological symptoms, although potential detrimental effects of these drugs have been described. The present meta-analysis aimed to explore the association of dexamethasone with overall survival (OS) and progression free survival (PFS) in patients with newly diagnosed glioblastoma. PubMed, Cochrane Library, Embase, and ClinicalTrials.gov were searched for pertinent studies following the Preferred Reporting Items of Systematic Review and Meta-Analysis checklist. Pooled multivariable-adjusted hazard ratios (HR) for OS and PFS and their associated 95% confidence intervals (CIs) were calculated using the random-effects model and the heterogeneity among studies was assessed using I2. The quality of evidence was assessed using the GRADE criteria. Seven studies were included, pooling data of 1,257 patients, with age varying from 11 to 81 years. Glioblastoma patients on pre- or peri-operative dexamethasone were associated with a significantly poorer overall survival (HR: 1.33, 95% CI: 1.15, 1.55; 7 studies; I2: 59.9%) and progression free survival (HR: 1.77, 95% CI: 1.05, 2.97; 3 studies; I2: 71.1%) compared to patients not on dexamethasone. The quality of evidence was moderate for overall survival and low for progression free survival. Dexamethasone appeared to be associated with poor survival outcomes of glioblastoma patients.

Antibiotic use reduces the efficacy of immune checkpoint inhibitors in patients with urothelial carcinoma: A systematic review and meta-analysis

ContextAntibiotics have been suggested to diminish the efficacy of immune checkpoint inhibitors (ICIs) by alterations of the gut microbiota. ObjectiveTo perform a meta-analysis summarizing the effect of antibiotics on the overall survival (OS) and progression-free survival (PFS) of urothelial cancer (UC) patients receiving ICI. Evidence acquisitionPubMed, EMBASE (Ovid), and the Cochrane Library were searched to identify studies published up to July 14, 2023. Studies reporting the associations between antibiotics use and OS and PFS in UC patients treated with ICI were included in this systematic review and meta-analysis. The random-effect model was used to pool the Hazard Ratios (HRs) for OS and PFS with 95% confidence interval (95%CI). The ROBINS-I was used to assess the risk of bias in the included studies, while the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) framework was used to inform the quality of evidence. Evidence synthesisThirteen nonrandomized studies involving a total of 5,095 ICI-treated UC patients were included in this review, of which 1434 (28%) received antibiotics. Overall, compared to patients who did not receive antibiotics, the pooled HRs for OS and PFS in those who received antibiotics were 1.45 [95% CI 1.25–1.68] and 1.40 [95% CI 1.05–1.87], respectively. Subgroup analysis revealed that the types of ICI and timing of antibiotic initiation did not influence the effect of antibiotics on OS and PFS in UC patients (P > 0.05). ConclusionsAntibiotic use significantly reduced OS and PFS in UC patients receiving ICI. While antibiotics remain crucial for the treatment of infections in UC patients, antibiotics should be prescribed cautiously in UC patients receiving ICI. Patient summaryAntibiotic use is associated with worsened survival in UC patients receiving immune checkpoint inhibitors.

Comparison of efficacy and safety between PD-1 inhibitors and PD-L1 inhibitors plus platinum-etoposide as first-line treatment for extensive-stage small-cell lung cancer: a multicenter, real-world analysis

BackgroundImmunotherapy in combination with platinum-etoposide (EP) chemotherapy has been approved as a first-line treatment for extensive-stage small cell lung cancer (ES-SCLC). However, real-world (RW) data regarding the use of immune checkpoint inhibitors (ICIs) in ES-SCLC are lacking. We aimed to assess the differences between programmed death protein 1 (PD-1) inhibitors and programmed death ligand 1 (PD-L1) inhibitors, both in conjunction with EP chemotherapy, as first-line treatment for ES SCLC.MethodsWe conducted a real-world, multicenter, retrospective cohort, controlled study to compare the prognosis, efficacy, and safety of PD-1 and PD-L1 inhibitors in ES-SCLC patients when used along with chemotherapy. Each patient received up to six cycles of etoposide, carboplatin, or cisplatin combined with ICI drugs, including PD-1 and PD-L1 inhibitors. The primary endpoints were investigator-assessed progression-free survival (PFS) and overall survival (OS). The secondary endpoints were the investigator-assessed objective response rate (ORR) and disease control rate (DCR) according to the Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1).ResultsBetween January 2017 and December 2021, 194 patients with ES-SCLC from three clinical centers in a PLA general hospital were included in our study, including 93 patients in the PD-1 group and 101 patients in the PD-L1 group. At the time of data cutoff, progression-free survival in the PD-1 group (median PFS, 6.8 months; 95% CI, 5.3–8.1) was similar to that in the PD-L1 group (median PFS, 6.4 months; 95% CI, 5.5–7.5); the stratified hazard ratio for PFS was 1.12 (95% CI, 0.83–1.53; P = 0.452). The median OS was similar in the PD-1 and PD-L1 groups (15.8 m vs. 17.7 m, P = 0.566); the hazard ratio was 0.90 (95% CI, 0.62–1.30, P = 0.566). The two groups had comparable investigator-assessed confirmed objective response rates (ORR) (76.3% vs. 76.2%). Adverse effect (AE)-related discontinuation occurred in 4 (4.3%) patients in the PD-1 group and 2 (2.0%) patients in the PD-L1 group. Deaths due to AEs of any cause occurred in 2 (2.2%) patients in the PD-1 inhibitor group and 1 (1.0%) patient in the PD-L1 inhibitor group.ConclusionsOur research revealed that there were no significant differences in efficacy or prognosis between PD-1 inhibitor + EP chemotherapy and PD-L1 inhibitor + EP chemotherapy. The two groups seemed to have comparable safety profiles, but the number of discontinuation or death events was too small to draw a firm conclusion.

Abstract A175: A comparative meta-analysis of survival outcomes in Non-Small Cell Lung Cancer: Influence of tumor mutational burden and KEAP1, KRAS, STK11 mutations on the efficacy of immunotherapy combined with chemotherapy versus chemotherapy alone

Abstract Background: The management of non-small cell lung cancer (NSCLC) has been revolutionized by the identification of critical genetic markers such as Tumor Mutational Burden (TMB), KEAP1, KRAS, PD-L1 expression levels, and STK11 mutations, which have shown the potential to impact patient survival outcomes. This study aimed to assess the impact of these markers on the survival of NSCLC patients treated with immunotherapy combined with chemotherapy versus chemotherapy alone. Methods: A comprehensive search of PubMed, Embase, and Cochrane Library databases until March 2023 included randomized controlled trials (RCTs) assessing Progression-Free Survival (PFS) and Overall Survival (OS) in NSCLC patients treated with either combined immunotherapy and chemotherapy or chemotherapy alone and considering specific genetic and cellular factors. Using R software (version 4.0.3) with metafor and meta packages, data were analyzed through a random-effects model, using hazard ratios (HRs) for PFS and OS and relative risks (RRs) for response rate and major adverse events. Results: Our analysis included 17 studies, totaling 9520 patients; 5247 patients received combined immunotherapy and chemotherapy, while 4273 patients were treated with chemotherapy alone. For OS, patients with high TMB demonstrated a significant improvement, with a HR of 0.72 (95% Confidence Interval (CI) 0.56-0.91, P&amp;lt;0.01, I^2=0%). Similarly, patients with KRAS mutations showed a significant increase in OS, with a HR of 0.67 (95% CI 0.53-0.85, P&amp;lt;0.01, I^2=14%). Patients expressing PD-L1 in more than 1% and more than 50% also revealed significant improvement in OS, with HRs of 0.71 (95% CI 0.64-0.78, P&amp;lt;0.01, I^2=0%) and 0.67 (95% CI 0.57-0.79, P&amp;lt;0.01, I^2=0%) respectively. Furthermore, patients without STK11 mutations exhibited a significant improvement in OS with a HR of 0.77 (95% CI 0.62-0.96, P=0.02, I^2=38%). Turning to PFS, patients with low TMB showed significant improvement with a HR of 0.66 (95% CI 0.55-0.81, P&amp;lt;0.01, I^2=35%). This was also the case for patients with high TMB, with a HR of 0.43 (95% CI 0.33-0.57, P&amp;lt;0.01, I^2=47%), and for patients with KRAS mutations (HR=0.54, 95% CI 0.36-0.82, P&amp;lt;0.01, I^2=63%). Patients with PD-L1 expression levels of less than 1%, more than 1%, and more than 50% also demonstrated significant improvements in PFS, with HRs of 0.64 (95% CI 0.56-0.72, P&amp;lt;0.01, I^2=62%), 0.51 (95% CI 0.44-0.59, P&amp;lt;0.01, I^2=66%), and 0.42 (95% CI 0.37-0.48, P&amp;lt;0.01, I^2=0%) respectively. The response rate demonstrated a significant increase in the combined treatment group (RR=1.54, 95% CI 1.38-1.72, P&amp;lt;0.01, I^2=65%), while the major adverse events showed no significant difference between treatment groups (RR=0.98, 95% CI 0.87-1.13, P=0.87, I^2=89%). Conclusions: High TMB, KRAS mutations, and elevated PD-L1 expression in NSCLC patients may be associated with better outcomes with combined therapy. However, the roles of KEAP1 and STK11 mutations in survival require further study. These findings highlight these genetic markers' prognostic and therapeutic implications in NSCLC. Citation Format: Muhammed Khaled Elfaituri, Ala Khaled. A comparative meta-analysis of survival outcomes in Non-Small Cell Lung Cancer: Influence of tumor mutational burden and KEAP1, KRAS, STK11 mutations on the efficacy of immunotherapy combined with chemotherapy versus chemotherapy alone [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A175.

Pirtobrutinib versus venetoclax in covalent Bruton tyrosine kinase inhibitor-pretreated chronic lymphocytic leukemia: a matching-adjusted indirect comparison.

Venetoclax is a standard treatment for patients with CLL following covalent BTK inhibitor (cBTKi) therapy, despite relatively limited prospective data in this setting. Pirtobrutinib is a highly selective, non-covalent (reversible) BTKi that was designed to overcome the pharmacologic limitations of cBTKi and re-establish BTK inhibition. An unanchored matching-adjusted indirect comparison (MAIC) was conducted to estimate the treatment effect of pirtobrutinib versus venetoclax monotherapy in patients with cBTKi pre-treated CLL. Data from patients with CLL who were venetoclax-naïve and pre-treated with cBTKi received pirtobrutinib (n=146) in the phase 1/2 BRUIN study were compared with the only identified trial of patients with CLL receiving venetoclax after a cBTKi (n=91), as administered as monotherapy until progression. Outcomes included progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and treatment-emergent adverse events (TEAEs). Both unweighted and weighted analyses were conducted. PFS and OS of pirtobrutinib and venetoclax were comparable in both unweighted and weighted analyses (weighted hazard ratios for PFS: 1.01, 95% CI: 0.58-1.73, p=0.98 and OS: 0.64, 95% CI: 0.25-1.67, p=0.34). ORR was significantly higher for pirtobrutinib (80.2% vs 64.8%, p=0.01). Grade ≥3 TEAEs were lower in weighted analyses for pirtobrutinib vs venetoclax (all p.