Progression-free Survival Hazard Ratio Research Articles

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.

Abstract PO4-05-10: A Carryover Effect: Antibody Drug Conjugates Constantly Provide a Substantial Improvement in Overall Survival more than in Progression-free Survival

Abstract Background: In metastatic breast cancer (MBC), progression-free survival (PFS) improvement does not always translate into overall survival (OS) benefit. Multiple treatment options after progression resulted in a long post-progression survival in MBC patients, and these would make the dissociation of PFS benefit and OS benefit. We have reported the constant correlation of PFS improvement and OS improvement in anti-HER2 containing treatment (Breast 2021; 59:211-220). The relationship between PFS and OS improvement in antibody drug conjugate has not been thoroughly examined. Methods: “Metastatic breast cancer” and “antibody drug conjugate” (ADC) were used as keywords to search for randomized clinical trials that report both PFS and OS. Hazard ratios (HR) and median survival were analyzed. Increments in PFS (delta PFS) and increments in OS (delta OS) were compared between studies. Results: A total of 8 trials were identified and summarized in table 1. The target of ADC was HER2 (N=6) or Trop2 (N=2). In DESTINY-Breast 03 trial, the control arm was another ADC (T-DM1). The control arms in all the other 7 trials were chemotherapy. The HR of PFS (range 0.28-0.66) was smaller than HR of OS (range 0.48- 0.83) in all of the trials. The median OS was not reached (NR) in 1 of the trials (DB-03) and was thus removed from the analysis for delta PFS and delta OS. In the comparison of delta PFS, the increments of median PFS fell between 1.5 and 10.9 months(m). The increments of median OS were between 1.6 and 12.7 m. All the delta OS are greater than the delta PFS in the 7 trials with available PFS and OS data. Conclusion: In MBC, ADCs targeting HER2 and Trop2 both constantly provide improvement of OS greater than PFS. Further investigation on the potential mechanism is warranted. Table 1 Citation Format: I-Chun Chen, Ching-Hung Lin, Yen-Shen Lu. A Carryover Effect: Antibody Drug Conjugates Constantly Provide a Substantial Improvement in Overall Survival more than in Progression-free Survival [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 PO4-05-10.

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 RF01-03: PARSIFAL-LONG: Extended follow-up of hormone receptor-positive/HER2-negative advanced breast cancer patients treated with fulvestrant and palbociclib vs. letrozole and palbociclib in the PARSIFAL study

Abstract Background: The Phase 2 PARSIFAL study assessed whether fulvestrant (FUL) or letrozole (LET) was the optimal endocrine partner for the cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) palbociclib (PAL) in patients (pts) with untreated, endocrine-sensitive, hormone receptor-positive (HR+)/HER2-negative (HER2-) advanced breast cancer (ABC) in the first-line setting. This trial failed to demonstrate an improvement in progression-free survival (PFS) of PAL+FUL over PAL+LET (Llombart-Cussac et al. Jama Oncol 2021). Following progression on CDK4/6i-based regimens in the metastatic setting, the EMERALD study (Bardia et al, SABCS 2022 GS3-01) identified early progressions (< 12 months [mo]) as a strong predictor of resistance to subsequent endocrine therapies. Here, we report updated PFS and overall survival (OS) from PARSIFAL, exploring a PFS <12 mo threshold as a prognostic factor for poor outcomes. Methods: This was an observational, international, multicenter study that included pts from the prospective PARSIFAL study, in which pts were randomly assigned (1:1) to receive PAL (oral 125 mg/day, 28-day cycles; 3 weeks on, 1 week off) plus FUL or LET at conventional doses. The primary objective was to extend the assessment of OS of PARSIFAL study with a longer median follow-up. Secondary objectives included extended PFS, other post-progression efficacy data, and the identification of new prognostic and predictive markers. The design had a planned recruitment of at least 388 pts with 195 deaths. The 2-sided stratified log-rank test (α = 0.05) had a 70% power to detect a hazard ratio ≤0.70 in favor of FUL + PAL arm. Results: A total of 389 pts (80.5%) from the PARSIFAL study were included in this analysis, involving 32 of the 47 original sites. Pts signed a new informed consent form according to local regulations. Demographic and baseline disease characteristics were similar between the PARSIFAL-LONG and the overall PARISFAL intention-to-treat populations. At the time of analysis, after a median follow up of 5.0 years (range, 0.1-7.3), 241 and 213 events were reported for PFS and OS, respectively. No differences in efficacy were observed between treatment arms whether for PFS (hazard ratio, 1.0, p=0.985) or OS (hazard ratio, 0.94, p=0.635). In accordance with the protocol for PARSIFAL-LONG, both arms were combined for subsequent analysis. The median PFS (mPFS) for the first-line PAL-based regimen population was 33.2 mo (95%CI, 27.7-39.5), with a median OS (mOS) of 65.4 mo (95%CI, 57.8-72.0). A total of 86 pts (22.1% of the population) had a mPFS time <12 mo (early progressors). mOS and mPFS for this early progressor subgroup were 24.0 mo (95%CI, 17.3-30.1) and 7.0 mo (95%CI, 5.6-8.3), respectively, and only 11 pts (12.8%) were still alive at the time of analysis. The remaining 303 pts (77.9%) were progression-free on PAL-based regimens at 12 mo (PFS≥12). The number of events for PFS and OS at this time were 165 (54.5%) and 138 (45.5%), respectively. mOS from randomization for the PFS≥12 subgroup was 81.5 mo (95%CI, 70.2-not achieved) and the mPFS was 49.8 mo (95%CI, 40.9-59.8). Following progression on PAL-based regimens, the PFS≥12 criteria was a strong predictor for mOS, with 27.0 vs 18.0 mo (hazard ratio, 0.67, 95%CI, 0.51-0.90, p=0.007) for PFS≥12 and early progressors, respectively. These differences may increase in the future, as 54.5% of pts with PFS≥12 are still alive compared to 12.8% of pts with an early progression. Conclusions: Extended follow-up analysis from PARSIFAL study confirms no major differences between LET or FUL when combined with PAL. mPFS and mOS results are consistent with those reported in other first-line trials involving different CDK4/6i. Progression within the first year of first-line CDK4/6i-based regimen for HR+/HER2- ABC pts may be prognostic of less favorable outcomes. Citation Format: Antonio Llombart-Cussac, José Manuel Pérez-García, Meritxell Bellet- Ezquerra, Florence Dalenc, Miguel Gil-Gil, Manuel Ruíz - Borrego, Joaquín Gavilá, Peter Schmid, Pilar Zamora, Duncan Wheatley, Eduardo Martínez-de Dueñas, Kepa Amillano, Antonio Antón, Paul Cottu, Gemma Viñas, Thierry Petit, Petra Tesarová, Juan Cueva, Marco Colleoni, Maria Purificación Martínez del Prado, Raquel Andrés, Marta Díaz Cabo, Susana Victorino, Miguel Sampayo-Cordero, Javier Cortés. PARSIFAL-LONG: Extended follow-up of hormone receptor-positive/HER2-negative advanced breast cancer patients treated with fulvestrant and palbociclib vs. letrozole and palbociclib in the PARSIFAL study [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 RF01-03.

Abstract PO2-15-06: ctDNA-based DNADX in hormone receptor-positive and HER2-negative (HR+/HER2-) advanced breast cancer following endocrine therapy and CDK4/6 inhibition: a correlative analysis from the randomized phase 2 PARSIFAL trial

Abstract ctDNA-based DNADX in hormone receptor-positive and HER2-negative (HR+/HER2-) advanced breast cancer following endocrine therapy and CDK4/6 inhibition: a correlative analysis from the randomized phase 2 PARSIFAL trial Background: DNADX, a novel machine learning-based approach, utilizes DNA from tumor tissue or plasma ctDNA to identify clinically relevant phenotypic tumor features and classify breast cancer into 4 subtypes (Nat Comm 2023). Here, we evaluated DNADX's ability to predict prognosis and treatment benefit in HR+/HER2- advanced breast cancer following endocrine therapy and a CDK4/6 inhibitor. Methods: DNADX was evaluated centrally in available baseline plasma ctDNA samples from PARSIFAL trial (NCT02491983) which randomized 486 patients (pts) with HR+/HER2- advanced breast cancer to receive (1:1 ratio) first line palbociclib with either fulvestrant or letrozole. Shallow whole genome sequencing was performed on ctDNA, and the 4 DNA-based subtypes (Clusters-1, -2, -3, and -4) were identified if the ctDNA tumor fraction (TF)≥3%. The main objective was to evaluate the association of DNADX subtypes with progression-free survival (PFS) and overall survival (OS). Secondary objective was to identify the subgroup of pts who benefit more from each endocrine treatment. Uni- and multi-variable Cox regression models were used after adjusting for TF, menopausal status, ECOG status, de novo metastasis (vs. recurrence), visceral disease and number of metastatic sites. Results: DNADX was evaluated in plasma ctDNA samples from 122 pts (25.1%). Clinical variables and median PFS (27.6 months) were similar as the overall PARSIFAL population. DNADX identified 56.6% pts with TF of < 3%, 14.8% with Cluster-1, 19.7% with Cluster-2, 5.7% with Cluster-3 and 3.3% with Cluster-4. In terms of PFS, pts classified with TF< 3% had a lower risk of progression compared to Cluster-1, Cluster-2, Cluster-3, Cluster-4 subtypes (pairwise PFS hazard ratios [HRs] of 1.88, 2.02, 3.15, and 5.62, respectively, with a global log-rank test of p=0.010). Similar results were obtained after adjusting for other clinical-pathologic variables. A numerical benefit of fulvestrant in comparison with letrozole was observed in pts classified in Cluster-1 and Cluster-4 (HR=0.42, 95% CI 0.14-1.24) in contrast to the other groups (HR=1.21, 95% CI 0.68-2.18), and the interaction test was statistically significant after adjusting for clinical-pathologic variables (anova p-value=0.037). In terms of OS, pts classified with TF< 3% had a lower risk of death compared to Cluster-1, Cluster-2, Cluster-3, and Cluster-4 subtypes (pairwise OS HRs of 1.90, 4.23, 11.13, and 6.80, respectively, with a global log-rank test of p=0.003). In the multivariable analysis, results were consistent after adjusting for clinical-pathologic variables and TF. Conclusions: Liquid biopsy-based DNADX subtypes predict outcomes in pts with HR+/HER2- advanced breast cancer on endocrine therapy and CDK4/6 inhibitors, potentially identifying the most optimal endocrine treatment for each pt. Citation Format: Fara Brasó-Maristany, Javier Cortés, José Manuel Pérez-García, Rosario Vega-León, Laia Paré, Guillermo Villacampa, Judit Matito, Francisco Pardo, Marina Gomez-Rey, Mario Mancino, Elena Martínez-García, Carmen Mora Gallardo, Leonardo Mina, Florence Dalenc, Meritxell Bellet- Ezquerra, Manuel Ruíz - Borrego, Miguel Gil-Gil, Peter Schmid, Charles M. Perou, Joel S. Parker, Patricia Villagrasa, Ana Vivancos, Aleix Prat, Antonio Llombart-Cussac. ctDNA-based DNADX in hormone receptor-positive and HER2-negative (HR+/HER2-) advanced breast cancer following endocrine therapy and CDK4/6 inhibition: a correlative analysis from the randomized phase 2 PARSIFAL trial [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 PO2-15-06.

Abstract PO1-18-12: Trial in progress: Open-label, randomized, multicenter, phase 3, ELAINE 3 study of the efficacy and safety of lasofoxifene plus abemaciclib for treating locally advanced or ER+/HER2- metastatic breast cancer with an ESR1 mutation

Abstract Background: Patients with estrogen receptor-positive (ER+) metastatic breast cancer (BC) may develop resistance to endocrine therapy (ET), particularly following treatment with a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i), potentially driven by a mutation in the ERa-coding gene, ESR1. Lasofoxifene, an oral, next-generation ET and ER breast antagonist, had potent activity in mBC xenograft models expressing ESR1 mutations, either as a single agent or combined with a CDK4/6i. Subsequently, two phase 2 studies evaluated lasofoxifene in women with ER+/HER2- metastatic BC and an ESR1 mutation who had disease progression on previous ET and CDK4/6i. The ELAINE 1 trial showed numerically greater progression-free survival (PFS, median ~6 vs 4 months; P=0.138), objective response rate (ORR, 13% vs 3%; P=0.124), and clinical benefit rate (CBR, 37% vs 22%; P=0.117) with lasofoxifene monotherapy versus the ER degrader fulvestrant, with a favorable safety profile (Goetz MP, et al. Ann Oncol. 2022;33:S1387). The single-arm, ELAINE 2 trial demonstrated that lasofoxifene combined with abemaciclib was well tolerated with a median PFS of ~13 months, ORR of 56%, and CBR of 66% (Damodaran S, et al. J Clin Oncol. 2023;41:suppl 16; abstr 1057). Based on these data, the phase 3, registrational, ELAINE 3 trial was initiated. Methods: ELAINE 3 (NCT05696626) is an open-label, phase 3, multicenter study evaluating the efficacy, safety, and tolerability of lasofoxifene plus abemaciclib versus fulvestrant plus abemaciclib. Key inclusion criteria are pre- and postmenopausal women and men aged ≥18 years; ER+/HER2-, locally advanced and/or metastatic BC (measurable and/or non-measurable disease); ≥1 acquired ESR1 mutation; progression on an aromatase inhibitor plus palbociclib or ribociclib as their first hormonal treatment for advanced/metastatic BC; and ≤1 line of chemotherapy in the advanced/metastatic setting. Patients will be randomized 1:1 to receive lasofoxifene 5 mg/day plus abemaciclib 150 mg BID, or fulvestrant 500 mg IM on days 1, 15, and 29, then 4 weekly plus abemaciclib 150 mg BID. Treatment will continue until progression, death, unacceptable toxicity, or withdrawal from the study. The primary endpoint is PFS; key secondary endpoints are ORR, overall survival, CBR, duration of response, and time to response. Time to cytotoxic chemotherapy, quality of life, and safety will also be evaluated. Blood samples for circulating tumor DNA (ctDNA) will be collected at screening, at weeks 4 and 8 and every 8 weeks thereafter, and at the final visit for genomic analyses. Outcomes with lasofoxifene/abemaciclib and fulvestrant/abemaciclib will be compared using a stratified Cox proportional hazards model and stratified logrank test. Expected PFS is ≥10.3 months for lasofoxifene/abemaciclib and 7 months for fulvestrant/abemaciclib (PFS hazard ratio of 0.68 at final analysis). The target sample size is 400, to achieve 90% power with a one-sided type I error rate of 0.025 after 285 PFS events. Full recruitment is expected to occur over 18 months at 125 global sites. Citation Format: Matthew Goetz, Seth Wander, Thomas Bachelot, Gerald Batist, Javier Cortés, Massimo Cristofanilli, Giuseppe Curigliano, Alexandre de Nonneville, Einav Nili-Gal Yam, Komal Jhaveri, Cynthia Ma, Heather Parsons, Hope Rugo, Sarah Sammons, Daniel Stover, Chris Twelves, Aditya Bardia, Paul V. Plourde, David J Portman, Senthil Damodaran. Trial in progress: Open-label, randomized, multicenter, phase 3, ELAINE 3 study of the efficacy and safety of lasofoxifene plus abemaciclib for treating locally advanced or ER+/HER2- metastatic breast cancer with an ESR1 mutation [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 PO1-18-12.

First-line immunotherapy of metastatic renal cell carcinoma: an updated network meta-analysis including triplet therapy.

To compare the differential efficacy of first-line immune checkpoint inhibitor (ICI)-based combined therapies among patients with intermediate- and poor-risk metastatic renal cell carcinoma (mRCC), as recently, the efficacy of triplet therapy comprising nivolumab plus ipilimumab plus cabozantinib has been published. Three databases were searched in December 2022 for randomised controlled trials (RCTs) analysing oncological outcomes in patients with mRCC treated with first-line ICI-based combined therapies. We performed network meta-analysis (NMA) to compare the outcomes, including progression-free survival (PFS) and objective response rates (ORRs), in patients with intermediate- and poor-risk mRCC; we also assessed treatment-related adverse events. Overall, seven RCTs were included in the meta-analyses and NMAs. Treatment ranking analysis revealed that pembrolizumab + lenvatinib (99%) had the highest likelihood of improved PFS, followed by nivolumab + cabozantinib (79%), and nivolumab + ipilimumab + cabozantinib (77%). Notably, compared to nivolumab + cabozantinib, adding ipilimumab to nivolumab + cabozantinib did not improve PFS (hazard ratio 1.02, 95% confidence interval 0.72-1.43). Regarding ORRs, treatment ranking analysis also revealed that pembrolizumab + lenvatinib had the highest likelihood of providing better ORRs (99.7%). The likelihoods of improved PFS and ORRs of pembrolizumab + lenvatinib were true in both International Metastatic RCC Database Consortium (IMDC) risk groups. Our analyses confirmed the robust efficacy of pembrolizumab + lenvatinib as first-line treatment for patients with intermediate or poor IMDC risk mRCC. Triplet therapy did not result in superior efficacy. Considering both toxicity and the lack of mature overall survival data, triplet therapy should only be considered in selected patients.

Efficacy and Safety of Anti–Programmed Cell Death Protein 1/Programmed Death-Ligand 1 Antibodies Plus Chemotherapy as First-Line Treatment for NSCLC in the People’s Republic of China: a Systematic Review and Meta-Analysis

IntroductionThe available approved anticancer drugs for Chinese patients are relatively limited because of China's low participation rate in international clinical trials. Therefore, a focus on approved anti–programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) drugs in China is needed. This study aims to assess the heterogeneity of anti–PD-1/PD-L1 antibodies manufactured in China (domestic PD-1/PD-L1) and overseas (imported PD-1/PD-L1) when combined with chemotherapy as the first-line treatment of NSCLC. MethodsA systematic search was performed using PubMed, EMBASE, and Cochrane Library of publications up to July 13, 2023. Meta-analysis was applied to compare the efficacy and safety profile between anti–PD-1/PD-L1 antibodies plus chemotherapy (PD-1/PD-L1+Chemo) and chemotherapy alone using STATA software. Pooled hazard ratios for progression-free survival and overall survival, odds ratios for objective response rate, and incidence rate of grade greater than or equal to three treatment-related adverse events with 95% confidence intervals were calculated in the domestic group and imported group by a random-effects model, and the heterogeneity between the two estimates was assessed. ResultsThere were 14 eligible clinical studies with a total of 3951 patients involved in this analysis, including eight studies of domestic PD-1/PD-L1+Chemo and six studies of imported PD-1/PD-L1+Chemo. The study revealed that there was no significant difference between domestic and imported PD-1/PD-L1+Chemo in overall survival (p = 0.80), progression-free survival (p = 0.53), and incidence rate of grade greater than or equal to three treatment-related adverse events (p = 0.10). Nevertheless, the objective response rate of imported PD-1/PD-L1+Chemo was significantly higher than that of domestic PD-1/PD-L1+Chemo (p = 0.03). ConclusionsDomestic anti–PD-1/PD-L1 antibodies plus chemotherapy were found to have comparable efficacy and safety to those combined with imported anti–PD-1/PD-L1 antibodies based on current evidence.

Association of overall survival benefit of radiotherapy with progression-free survival after chemotherapy for intermediate and high risk diffuse large B-cell lymphoma: A systematic review and meta-analysis

ObjectiveTo evaluate whether improved progression-free survival (PFS) from radiotherapy (RT) translates into an overall survival (OS) benefit for diffuse large B-cell lymphoma (DLBCL). MethodsA systematic literature search identified randomized controlled trials (RCTs) and retrospective studies that compared combined-modality therapy (CMT) with chemotherapy (CT) alone. Weighted regression analyses were used to estimate the correlation between OS and PFS benefits. Cohen's kappa statistic assessed the consistency between DLBCL risk-models and PFS patterns. Furthermore, the benefit trend of RT was analyzed by fitting a linear regression model to the pooled hazard ratio (HR) according to the PFS patterns. ResultsFor both 7 RCTs and 52 retrospective studies, correlations were found between PFS HR (HRPFS) and OS HR (HROS) at trial level (r = 0.639–0.876), and between PFS and OS rates at treatment-arm level, regardless of CT regimens (r = 0.882–0.964). Incorporating RT into CT increased about 18% of PFS, and revealed a different OS benefit profile. Patients were stratified into four CT-generated PFS patterns (>80%, >60–80%, >40–60%, and ≤40%), which was consistent with risk-stratified subgroups (kappa > 0.6). Absolute gain in OS from RT ranged from ≤5% at PFS >80% to about 21% at PFS ≤40%, with pooled HROS from 0.70 (95% CI, 0.51–0.97) to 0.48 (95% CI, 0.36–0.63) after rituximab-based CT. The OS benefit of RT was predominant in intermediate- and high-risk patients with PFS ≤ 80%. ConclusionWe demonstrated a varied OS benefit profile of RT to inform treatment decisions and clinical trial design.

Background and clinical significance of biomarker-based patient enrichment in non-small-cell lung cancer drug development

Pharmaceutical companies have adopted biomarker-based enrichment (personalized) strategies to improve research and development productivity. We explored the background in which personalized strategies are adopted and examined whether their adoption is linked to improved efficacy of new drugs approved for non-small cell lung cancer (NSCLC) by US Food and Drug Administration (FDA). We extracted data from the first labels of drugs approved for NSCLC between May 2003 and February 2021, and performed a qualitative comparative analysis and meta-analysis. Personalized strategies were adopted in more than half of the trials (16/27) and were often used in trials aimed at obtaining first-line indications and in drugs that were not first-in-class. The meta-analysis showed that personalized trials had significantly improved progression-free survival (PFS) hazard ratio (HR) than trials without personalization but not for relative response rate ratio (RRR) or overall survival (OS) HR. Trials in which PFS HR was the primary endpoint tended to have improved PFS HR, and trials in which OS HR was the primary endpoint had worse PFS HR. The efficacy endpoints that are substantially affected by personalized strategies appear to differ, especially for new drugs with novel mechanism of action (MOA), because trial designs are employed to validate drug-specific advantages.

Abstract 6389: An exosome-based liquid biopsy powered by machine learning predicts progression-free and overall survival before commencing first-line EGFR inhibitors for metastatic colorectal cancer: The EXONERATE Study

Abstract Introduction: We developed a liquid biopsy assay based on exosomal and cell-free microRNA (exo- and cf-miRNA, respectively) for patients with chemotherapy-naïve, metastatic, unresectable, RAS and BRAF wild-type colorectal cancer (mCRC), to predict progression-free (PFS) and overall survival (OS) before the commencement of first-line treatment with EGFR inhibitors (EXONERATE). Methods: Patients with mCRC were consecutively enrolled in two open-label, nationwide clinical trials and received first-line cetuximab or panitumumab. Cf- and exo-miRNA expression was quantified using RT-qPCR in plasma samples obtained before exposure to EGFR inhibitors. The prespecified primary endpoint was 12-month PFS, hierarchically tested in left-sided mCRC, right-sided mCRC, and the entire cohort. As secondary endpoints, the EXONERATE status was correlated with PFS and OS hazard ratios (HR). Results: After excluding those with RAS/BRAF mutations and unavailable samples, the complete analysis dataset comprised 120 patients (94 with left-sided and 26 with right-sided mCRC; 87 received cetuximab and 33 panitumumab). As expected, right-sided mCRC patients showed inferior PFS and OS outcomes (HR 1.80 [CI95% = 1.13 - 2.80] and 1.80 [CI95% = 1.00 - 3.27], respectively). Genome-wide small RNA sequencing on 20 patient samples identified 12 cf- and 14 exo-miRNA candidates, then narrowed to 8 and 9 based on best performance. We employed machine learning algorithms to develop two liquid biopsy assays, one based on cf- and the other on exo-miRNAs, predicting 12mPFS with AUC values of 0.84 and 0.81, respectively. These were then combined to establish the EXONERATE assay for left-sided mCRC (AUC = 0.89), successfully validated in right-sided mCRC patients (AUC= 0.84). Among left-sided mCRC patients, 35% were EXONERATE-high, exhibiting shorter median PFS (mPFS = 9.5 vs. 18.5 months, p<.001) and a higher mortality rate (HR 0.21 [CI95% = 0.10 - 0.42]). In the right-sided mCRC cohort, the EXONERATE-high panel robustly identified patients with shorter mPFS (8.6 vs. 23.7 months, p=.0042) and predicted 12mPFS with high accuracy (sensitivity 100%, NPV 81%, PPV 100%). Although in univariate analysis both the EXONERATE panel and sidedness showed associations with PFS and OS, in multivariate analysis only the EXONERATE panel could fully account for the differences in PFS and OS (HR 0.22 and HR 0.19, respectively). Hence, we employed the EXONERATE panel agnostically of tumor sidedness and observed that EXONERATE-high patients demonstrated poorer survival outcomes in mPFS (8.9 vs. 19.6 months, HR 0.27 [CI95% = 0.17 - 0.41]) and mOS (22.6 vs. >60 months, HR 0.18 [CI95% = 0.09 - 0.37]). Conclusion: The EXONERATE panel robustly predicted PFS and OS outcomes in both right- and left-sided mCRC patients before receiving either EGFR inhibitor. Citation Format: Xu Caiming, Alessandro Mannucci, Roy Souvick, Esposito Francis, Oliveres Helena, Alonso-Orduña Vicente, Escudero Pilar, Fernández-Martos Carlos, Salud Antonieta, Gallego Javier, Rodriguez Jose Ramon, Martín-Richard Marta M. Marta, Fernández-Plana Julen, Manzano Hermini, Aparicio Jorge, Feliu Jaime, Maurel Joan, Ajay Goel. An exosome-based liquid biopsy powered by machine learning predicts progression-free and overall survival before commencing first-line EGFR inhibitors for metastatic colorectal cancer: The EXONERATE Study [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 6389.

Multi-institutional study of osimertinib dose-optimization in non-small cell lung cancer patients with EGFR activating mutation aged 70years or older ('MONEY' trial).

Osimertinib is the standard of care for patients with epidermal growth factor receptor-activating mutation-positive non-small cell lung cancer. Dose-toxicity has been previously reported, but no dose-response data within the range of 20-240mg daily (mg/d). Thus, the current 80mg/d dosing might be too high for elderly Japanese patients with an average body weight of only 50kg, resulting in excessive toxicity and cost. We therefore initiated a study to investigate whether osimertinib at 40mg/d is non-inferior to 80mg/d in patients with advanced or recurrent epidermal growth factor receptor-activating mutation-positive non-small cell lung cancer aged ≥70years, using a regression discontinuity design. Osimertinib is administered at 40mg/d for body weight ≤50kg, and 80mg/d for body weight >50kg. The primary endpoint is progression-free survival. Sample size is 550 patients, based on a non-inferiority margin of the progression-free survival hazard ratio 1.333, 0.10 one-sided type I error and 80% power.

Immunotherapy time of infusion impacts survival in head and neck cancer: A propensity score matched analysis

The adaptive immune response is physiologically regulated by the circadian rhythm. Data in lung and melanoma malignancies suggests immunotherapy infusions earlier in the day may be associated with improved response; however, the optimal time of administration for patients with head and neck squamous cell carcinoma (HNSCC) is not known. We aimed to evaluate the association of immunotherapy infusion time with overall survival (OS) and progression free survival (PFS) in patients with HNSCC in an Institutional Review Board-approved, retrospective cohort study. 113 patients met study inclusion criteria and 98 patients were included in a propensity score-matched cohort. In the full unmatched cohort (N = 113), each additional 20 % of infusions received after 1500 h conferred an OS hazard ratio (HR) of 1.35 (95 % C.I.1.2–1.6; p-value = 0.0003) and a PFS HR of 1.34 (95 % C.I.1.2–1.6; p-value < 0.0001). A propensity score-matched analysis of patients who did or did not receive ≥20 % of infusions after 1500 h showed that those who were administered ≥20 % of infusions after 1500 h trended towards a shorter OS (HR = 1.35; p-value = 0.26) and a shorter PFS (HR = 1.57, 95 % C.I. 1.02–2.42, p-value = 0.04). Each additional 20 % of infusions received after 1500 h remained robust in the matched cohort multivariable analysis and was associated with shorter OS (adjusted HR = 1.4 (95 % C.I.1.2–1.8), p-value < 0.001). Patients with advanced HNSCC who received more of their infusions in the afternoon were associated with shorter OS and PFS and scheduling immunotherapy infusions earlier in the day may be warranted.

Adjusted Indirect Treatment Comparison of Progression-Free Survival with D-Rd and VRd Based on MAIA and SWOG S0777 Individual Patient-Level Data.

Daratumumab plus lenalidomide and dexamethasone (D-Rd) and bortezomib plus lenalidomide and dexamethasone (VRd) are commonly used treatment combinations for transplant-ineligible (TIE) patients with newly diagnosed multiple myeloma (NDMM). D-Rd and VRd demonstrated superior efficacy relative to lenalidomide and dexamethasone (Rd) in the MAIA and SWOG S0777 trials, respectively, but have not been compared directly in a head-to-head trial. Naïve comparisons of efficacy across the two trials may be biased because MAIA enrolled only TIE patients (median age 73years), whereas SWOG S0777 enrolled both TIE patients and transplant-eligible patients who chose to defer/refuse frontline stem cell transplantation (median age 63years). The present study compared progression-free survival (PFS) in TIE patients with NDMM treated with D-Rd versus VRd based on an adjusted indirect treatment comparison (ITC) that leveraged individual patient-level data from MAIA and SWOG S0777. Harmonized inclusion/exclusion criteria (including age ≥ 65years as a proxy for transplant ineligibility) and propensity-score weighting were used to balance the trial populations on measured baseline characteristics. After differences in trial populations were adjusted for, an anchored ITC was performed wherein within-trial PFS hazard ratios (HRs) for D-Rd versus Rd and VRd versus Rd were estimated and used to make indirect inference about PFS for D-Rd versus VRd. PFS HRs were 0.52 (95% confidence interval [CI] 0.41-0.67) for D-Rd versus Rd based on MAIA data, 0.88 (95%CI 0.63-1.23) for VRd versus Rd based on SWOG S0777 data, and 0.59 (95%CI 0.39-0.90) for the Rd-anchored ITC of D-Rd versus VRd. Sensitivity and subgroup analyses produced results consistent with the primary results. This anchored ITC demonstrated a greater PFS benefit for D-Rd versus VRd in TIE patients with NDMM. In the absence of head-to-head trials comparing D-Rd and VRd, the present trial may help inform treatment selection in this patient population.

Immunotherapy or Chemoimmunotherapy in Older Adults With Advanced Non–Small Cell Lung Cancer

Immune checkpoint inhibitor (ICI) plus chemotherapy combination treatment (ICI-chemotherapy) is now a standard treatment for non-small cell lung cancer (NSCLC) without targetable oncogene alterations, but there are few data on ICI-chemotherapy for patients 75 years and older. To inform the choice of first-line drugs in clinical practice and assess the safety and efficacy of ICI-chemotherapy combination treatment in older adult patients with previously untreated advanced NSCLC. This retrospective cohort study included 58 centers in Japan. The cohort consisted of patients 75 years and older with clinical stage IIIB, IIIC, IV, postoperative or radiotherapy recurrent NSCLC. Patients started first-line systemic therapy between December 2018 and March 2021. Those receiving first-line molecular targeted drugs were excluded. The data were analyzed from February 2022 to October 2022. Systemic therapy. The main outcomes were overall survival (OS), progression-free survival (PFS), and safety. A total of 1245 patients (median [range] age, 78 [75-95] years; 967 [78%] male) with NSCLC were included in the cohort. Programmed death ligand-1 (PD-L1) expression of less than 1% occurred in 268 tumors (22%); 1% to 49% in 387 tumors (31%); 50% and higher in 410 tumors (33%), and unknown expression in 180 tumors (14%). Median OS was 20.0 (95% CI, 17.1-23.6) months for the 354 patients receiving ICI-chemotherapy (28%); 19.8 (95% CI, 16.5-23.8) months for the 425 patients receiving ICI alone (34%); 12.8 (95% CI, 10.7-15.6) months for the 311 patients receiving platinum-doublet chemotherapy (25%); and 9.5 (95% CI, 7.4-13.4) months for the 155 patients receiving single-agent chemotherapy (12%). After propensity score matching, no differences in OS and PFS were found between the patients receiving ICI-chemotherapy vs ICI alone. Each group consisted of 118 patients. For PD-L1 expression of 1% and higher the OS hazard ratio (HR) was 0.98 (95% CI, 0.67-1.42; P = .90), and the PFS HR was 0.92 (95% CI, 0.67-1.25; P = .59). Significance was also not reached when separately analyzed for lower or higher PD-L1 expression (1%-49% or ≥50%). However, grade 3 or higher immune-related adverse events occurred in 86 patients (24.3%) treated with ICI-chemotherapy and 76 (17.9%) with ICI alone (P = .03). In this study, ICI-chemotherapy combination treatment did not improve survival and increased the incidence of grade 3 and higher immune-related adverse events compared with ICI alone in patients 75 years and older. Based on these results, ICI alone may be recommended for older adult patients with PD-L1-positive NSCLC.

Significance of PD-L1 in Metastatic Urothelial Carcinoma Treated With Immune Checkpoint Inhibitors

Immune checkpoint inhibitors (ICIs) have broadened the metastatic urothelial carcinoma (mUC) therapeutic scenario. The association of programmed death ligand 1 (PD-L1) with response and survival in patients treated with ICIs is still controversial. To evaluate the association of PD-L1 with response rate and overall survival among patients with mUC treated with ICIs. PubMed, Embase, American Society of Clinical Oncology and European Society for Medical Oncology Meeting Libraries, and Web of Science were searched up to December 10, 2023. Two authors independently screened the studies. Included studies were randomized and nonrandomized clinical trials enrolling patients with mUC receiving ICIs with available overall survival (OS), progression-free survival (PFS), or overall response rate (ORR) data, separated between patients with PD-L1-positive and -negative tumors. The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline was followed. Two reviewers independently extracted data. Fixed- or random-effects models were used depending on the heterogeneity among the studies. Primary outcomes were odds ratios (ORs) for ORR and hazard ratios (HRs) for OS, comparing patients with PD-L1-positive tumors and patients with PD-L1-negative tumors. Secondary outcomes were the PFS HR between patients with PD-L1-positive and -negative tumors and OS HR between ICI arms and non-ICI arms of only randomized clinical trials. A total of 14 studies were selected, comprising 5271 patients treated with ICIs (2625 patients had PD-L1-positive tumors). The ORR was 13.8% to 78.6% in patients with PD-L1-positive tumors and 5.1% to 63.2% in patients with PD-L1-negative tumors, with an association between PD-L1 status and ORR favoring patients with PD-L1-positive tumors (OR, 1.94; 95% CI, 1.47-2.56; P < .001). Median OS ranged from 8.4 to 24.1 months in patients with PD-L1-positive tumors and from 6.0 to 19.1 months in patients with PD-L1-negative tumors. The pooled HR showed a significant reduction for patients with PD-L1-positive tumors compared with those with PD-L1-negative tumors in the risk of death (HR, 0.71; 95% CI, 0.57-0.89; P = .003) and risk of progression (HR, 0.55; 95% CI, 0.44-0.69; P < .001) when ICIs were administered. PD-L1 is not likely to be a predictive biomarker of ICI response. This systematic review and meta-analysis suggests that PD-L1 expression is associated with improved ORR, OS, and PFS for patients with mUC who receive ICIs, but it is unlikely to be useful as a predictive biomarker. Developing predictive biomarkers is essential to select patients most likely to benefit from ICIs and avoid toxic effects and financial burden with these agents.

Clinical evaluation of a low-coverage whole-genome test for detecting homologous recombination deficiency in ovarian cancer

BackgroundThe PAOLA-1/ENGOT-ov25 trial showed that maintenance olaparib plus bevacizumab increases survival of advanced ovarian cancer patients with homologous recombination deficiency (HRD). However, decentralized solutions to test for HRD in clinical routine are scarce. The goal of this study was to retrospectively validate on tumor samples from the PAOLA-1 trial, the decentralized SeqOne assay, which relies on shallow Whole Genome Sequencing (sWGS) to capture genomic instability and targeted sequencing to determine BRCA status. MethodsThe study comprised 368 patients from the PAOLA-1 trial. The SeqOne assay was compared to the Myriad MyChoice HRD test (Myriad Genetics), and results were analyzed with respect to Progression-Free Survival (PFS). ResultsWe found a 95% concordance between the HRD status of the two tests (95% Confidence Interval (CI); 92%−97%). The Positive Percentage Agreement (PPA) of the sWGS test was 95% (95% CI; 91%−97%) like its Negative Percentage Agreement (NPA) (95% CI; 89%−98%). In patients with HRD-positive tumors treated with olaparib plus bevacizumab, the PFS Hazard Ratio (HR) was 0.38 (95% CI; 0.26–0.54) with SeqOne assay and 0.32 (95% CI; 0.22–0.45) with the Myriad assay. In patients with HRD-negative tumors, HR was 0.99 (95% CI; 0.68–1.42) and 1.05 (95% CI; 0.70–1.57) with SeqOne and Myriad assays. Among patients with BRCA-wildtype tumors, those with HRD-positive tumors, benefited from olaparib plus bevacizumab maintenance, with HR of 0.48 (95% CI: 0.29–0.79) and of 0.38 (95% CI: 0.23 to 0.63) with the SeqOne and Myriad assay. ConclusionThe SeqOne assay offers a clinically validated approach to detect HRD.

Additional local therapy before disease progression for EGFR-mutated advanced lung cancer: a systematic review and meta-analysis.

International guidelines recommend the use of local therapy (LT) to limited progression in patients with epidermal growth factor receptor (EGFR)-mutated advanced non-small cell lung cancer (NSCLC). However, the use of LT before disease progression has not been extensively analyzed. This meta-analysis evaluates the efficacy and safety of administering additional LT in conjunction with first-line EGFR-tyrosine kinase inhibitors (TKIs) before disease progression in patients with EGFR-mutated advanced NSCLC. We systematically searched PubMed, Embase, and the Cochrane Library for studies published up until May 31, 2023. The LT group consisted of patients who received first-line EGFR-TKIs in conjunction with additional LT, while the TKI group comprised participants treated with first-line EGFR-TKIs alone. Studies comparing the survival outcomes of the LT and TKI groups were included in this analysis. The primary outcomes were progression-free survival (PFS) and overall survival (OS). This review was registered on PROSPERO (registration number CRD42023439913). Among the 11 investigated studies covering 1,313 patients, the LT modalities included radiotherapy, surgery, and ablation therapy, which accounted for 91%, 27%, and 27% of the studies, respectively. The pooled hazard ratios of median PFS and OS were 0.34 [95% confidence interval (CI): 0.22-0.53; P<0.001] and 0.42 (95% CI: 0.36-0.48; P<0.001), respectively, which indicated significant benefits for the LT group compared to the TKI group. There was no significant difference between the LT and TKI groups (P=0.473) regarding the incidence of grade 3 or higher adverse events. This study suggests that the strategic use of additional LT before disease progression is a promising approach for the treatment of EGFR-mutated advanced NSCLC.

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.

Surrogacy of one-year survival for overall survival in advanced hepatocellular carcinoma

BackgroundThe increasing number of sequential treatments complicates the evaluation of overall survival (OS) in clinical trials for hepatocellular carcinoma (HCC), therefore, reliable surrogate endpoints (SEs) are required. This study aimed to evaluate the surrogacy of progression-free survival (PFS) and one-year (1-yr) milestone survival for OS in HCC trials.MethodsWe systematically searched databases for randomized clinical trials that evaluated systemic treatments for advanced HCC. Individual patient data were reconstructed to calculate the 1-yr survival rate. We adopted a two-stage meta-analytic validation model to evaluate the correlation between SEs and OS, and the correlation between treatment effects on SEs and OS. The hazard ratio (HR) was calculated to assess the treatment effects on PFS and OS, and the 1-yr survival ratio was calculated to evaluate the treatment effects on the 1-yr milestone survival.ResultsThirty-two HCC trials involving 13,808 patients were included. A weak correlation was detected between the median PFS and median OS (R2 = 0.32), whereas the correlation improved between PFS HR and OS HR (R2 = 0.58). We identified strong correlations between the 1-yr survival rate and median OS and between the 1-yr survival ratio and OS HR (R2 = 0.74 and 0.65, respectively). In subgroup analyses, PFS HR strongly correlated with OS HR in trials relevant to immune checkpoint inhibitors (ICIs). Although the correlation remained weak between PFS and OS even in trials with PFS HR ≤ 0.6, the 1-yr survival rate and 1-yr survival ratio were strong surrogates for median OS and OS HR, respectively (R2 = 0.77 and 0.75).ConclusionsOne-year milestone survival outperformed PFS as a SE for OS in HCC, indicating the application of 1-yr survival as a secondary endpoint. In particular, PFS HR was a potential SE for OS HR in the ICI trials.