Significant Improvement In OS Research Articles

The evolving treatment landscape of metastatic urothelial cancer.

Cisplatin-based chemotherapy is currently the first-line standard of care for patients with metastatic urothelial cancer (mUC); however, up to 50% of patients are ineligible for cisplatin, necessitating alternative treatment options. Immune checkpoint inhibitors have been shown to be effective in cisplatin-ineligible patients. However, despite advances in the first-line setting, the prognosis remains poor, and challenges persist in selecting optimal therapies, treatment sequences and combination regimens. Maintenance therapy with avelumab revealed improved overall (OS) and progression-free survival (PFS) compared with best supportive care alone in patients with platinum-responsive mUC. Antibody-drug conjugates and targeted therapy with fibroblast growth factor receptor (FGFR) inhibitors have shown promise in selected patients, particularly in patients with metastatic disease that has progressed despite platinum-based chemotherapy. At the European Society of Medical Oncology Congress in 2023, groundbreaking results were presented from two phase III trials, EV-302/KEYNOTE-A39 and CheckMate 901, focusing on previously untreated mUC. In the former, the combination of enfortumab vedotin and pembrolizumab showed significant improvements in OS, PFS and overall response rate compared with chemotherapy alone; the combination of nivolumab with gemcitabine-cisplatin chemotherapy demonstrated a significant extension in median OS, PFS and overall response rate compared with chemotherapy alone. Inaddition, erdafitinib therapy resulted in significantly longer OS than chemotherapy among patients with mUC and FGFR alterations after previous treatment with immune checkpoint inhibitors. This comprehensive summary of the current treatment landscape for mUC incorporates clinical trial evidence and discussion of agents that are currently under investigation to provide support for clinical decision making and understanding of future therapeutic approaches.

Abstract GS01-05: Pembrolizumab + Olaparib vs Pembrolizumab + Chemotherapy After Induction With Pembrolizumab + Chemotherapy for Locally Recurrent Inoperable or Metastatic TNBC: Randomized Open-Label Phase 2 KEYLYNK-009 Study

Abstract Background: Pembrolizumab (pembro) plus chemotherapy (chemo) showed statistically significant improvements in PFS and OS vs placebo + chemo in patients (pts) with previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer (TNBC) whose tumors expressed PD-L1 with a combined positive score (CPS) ≥10 in the phase 3 KEYNOTE-355 study. Tolerable and effective maintenance regimens after induction therapy are needed to sustain clinical benefit. The PARP inhibitor olaparib is an established maintenance therapy for multiple platinum-sensitive tumor types and prior data suggest that PARP inhibitors combined with PD-1/PD-L1 inhibitors could provide an improved therapeutic effect. KEYLYNK-009 (NCT04191135) is a randomized open-label phase 2 study to evaluate the efficacy and safety of maintenance pembro + olaparib vs pembro + chemo in pts with locally recurrent inoperable or metastatic TNBC who had clinical benefit from induction with 1L pembro + platinum-based chemo. Methods: Eligible pts with measurable, locally recurrent inoperable or metastatic TNBC that had not been previously treated with chemo in the metastatic setting received induction therapy for up to 6 cycles of pembro 200 mg + chemo (carboplatin AUC 2 + gemcitabine 1000 mg/m2 on days 1 and 8) every 3 wk (Q3W). Pts with complete response (CR), partial response (PR), or stable disease (SD) after 4-6 treatment cycles were randomized 1:1 to receive pembro 200 mg Q3W + olaparib 300 mg twice daily or pembro + chemo (continued induction regimen). Olaparib or chemo was continued until progression or unacceptable toxicity; pembro was continued for up to 35 cycles (including induction treatment), progression, or unacceptable toxicity. Pts were stratified by induction response (CR or PR vs SD, by RECIST v1.1), tumor PD-L1 status (CPS ≥1 vs CPS < 1), and tumor genomic status (tBRCAm vs tBRCAwt). Dual primary endpoints were PFS per RECIST v1.1 by BICR and OS from randomization in all pts. Secondary endpoints included PFS and OS from randomization in pts with PD-L1 CPS ≥10 tumors and in pts with tBRCAm, and safety. Results: Of the 460 pts who received induction therapy, 271 were randomly assigned to pembro + olaparib (n=135) or pembro + chemo (n=136). At the Dec 15, 2022 data cutoff, median follow-up was 17.2 mo. Maintenance pembro + olaparib did not significantly improve PFS or OS vs pembro + chemo after induction therapy (Table). Median PFS was longer with pembro + olaparib vs pembro + chemo in pts with tBRCAm, but not in pts with PD-L1 CPS ≥10 tumors; a similar trend was observed for OS (Table). In 268 treated pts, treatment-related AEs (TRAEs) occurred in 114 of 135 pts (84.4%) for pembro + olaparib and in 128 of 133 pts (96.2%) for pembro + chemo. Grade ≥3 TRAEs occurred in 44 pts (32.6%) for pembro + olaparib (0 deaths) and in 91 pts (68.4%) for pembro + chemo (2 [1.5%] deaths), with 12 (8.9%) vs 26 (19.5%) discontinuations for TRAEs, respectively. Conclusions: The primary endpoints of PFS and OS were not met in an unselected population of pts with advanced TNBC. However, directionally favorable improvements in PFS and OS were observed in pts with tBRCAm with pembro + olaparib vs pembro + chemo, representing a potential maintenance strategy. Further data are required to confirm this effect. No new safety signals were observed, and there were fewer TRAEs in the pembro + olaparib group vs the pembro + chemo group. PFS and OS were evaluated from the time of randomization. *Based on stratified Cox regression model with Efron’s method of tie-handling with treatment as a covariate. NR = not reached. Citation Format: Hope Rugo, Mark Robson, Seock-Ah Im, Florence Dalenc, Eduardo Yañez Ruiz, Young-Hyuck Im, Sergii Kulyk, Oleksandr Dudnichenko, Néstor Llinás-Quintero, Shigehira Saji, Yasuo Miyoshi, Nadia Harbeck, Li Fan, Jaime Mejia, Vassiliki Karantza, David Cescon. Pembrolizumab + Olaparib vs Pembrolizumab + Chemotherapy After Induction With Pembrolizumab + Chemotherapy for Locally Recurrent Inoperable or Metastatic TNBC: Randomized Open-Label Phase 2 KEYLYNK-009 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 GS01-05.

Omission of adjuvant radiotherapy in low-risk elderly males with breast cancer

PurposeRandomized clinical trials demonstrate that lumpectomy + hormone therapy (HT) without radiation therapy (RT) yields equivalent survival and acceptable local–regional outcomes in elderly women with early-stage, node-negative, hormone-receptor positive (HR +) breast cancer. Whether these data apply to men with the same inclusion criteria remains unknown.MethodsThe National Cancer Database was queried for male patients ≥ 65 years with pathologic T1-2N0 (≤ 3 cm) HR + breast cancer treated with breast-conserving surgery with negative margins from 2004 to 2019. Adjuvant treatment was classified as HT alone, RT alone, or HT + RT. Male patients were matched with female patients for OS comparison. Survival analysis was performed using Cox regression and Kaplan − Meier method. Inverse probability of treatment weighting (IPTW) was applied to adjust for confounding.ResultsA total of 523 patients met the inclusion criteria, with 24.4% receiving HT, 16.3% receiving RT, and 59.2% receiving HT + RT. The median follow-up was 6.9 years (IQR: 5.0–9.4 years). IPTW-adjusted 5-yr OS rates in the HT, RT, and HT + RT cohorts were 84.0% (95% CI 77.1–91.5%), 81.1% (95% CI 71.1–92.5%), and 93.0% (95% CI 90.0–96.2%), respectively. On IPTW-adjusted MVA, relative to HT, receipt of HT + RT was associated with improvements in OS (HR: 0.641; p = 0.042). RT alone was not associated with improved OS (HR: 1.264; p = 0.420).ConclusionAmong men ≥ 65 years old with T1-2N0 HR + breast cancer, RT alone did not confer an OS benefit over HT alone. Combination of RT + HT demonstrated significant improvements in OS. De-escalation of treatment through omission of either RT or HT at this point should be done with caution.

Fruquintinib plus paclitaxel versus paclitaxel as second-line therapy for patients with advanced gastric or gastroesophageal junction adenocarcinoma (FRUTIGA): A randomized, multicenter, double-blind, placebo-controlled, phase 3 study.

438780 Background: Fruquintinib (F), a highly selective and potent oral inhibitor of VEGFRs 1, 2, and 3, significantly improved the OS in metastatic colorectal cancer ( Li J, et al, JAMA 2018; Dasari A, et al, LANCET 2023). FRUTIGA was a randomized, double-blind, placebo (PBO)-controlled, phase 3 study evaluating the efficacy and safety of F plus paclitaxel (PTX) vs PTX alone in patients (pts) with advanced gastric or gastroesophageal junction (G/GEJ) adenocarcinoma who experienced disease progression (PD) on fluoropyrimidine- or platinum-containing first-line chemotherapy. Methods: Eligible pts were randomized 1:1 to receive F (4 mg, once daily, 3 weeks on/1 week off) or matching PBO orally, plus PTX (80 mg/m2, intravenously, days 1/8/15 per cycle) in 4-week cycles until PD or intolerable toxicity; treatment of PTX was allowed for up to 6 cycles. PFS and OS were dual-primary endpoints with α split and recycle. The study was considered positive when at least one endpoint met statistical significance. Results: 703 pts were randomized (F+PTX 351 vs PBO+PTX 352), and 699 pts received at least 1 dose of study drug (350 vs 349). PFS was significantly improved with F+PTX vs PBO+PTX (median PFS [mPFS] 5.55m vs 2.73m; HR = 0.569; p < 0.0001). The overall response rate was significantly higher in F+PTX group (42.5% vs 22.4%, p < 0.0001). Median OS (mOS) was 9.63m with F+PTX and 8.41m with PBO+PTX (HR = 0.956; p = 0.6064). Given an imbalance of pts receiving subsequent antitumor therapies (F+PTX 52.7% vs PBO+PTX 72.2%), post-hoc analyses were performed using cox-proportional hazards model adjusting for subsequent antitumor therapies and baseline factors. Results showed a nominal statistically significant improvement in OS with F+PTX (HR range 0.793-0.828; p range 0.0105-0.0350 with different subsequent antitumor therapy factors). Furthermore, among pts with lymph node metastases and non-diffuse G/GEJ adenocarcinoma (190 vs 208), mPFS was even more prolonged (6.08m vs 2.69m; HR = 0.454; p < 0.0001) and OS also showed a nominal statistically significant improvement (mOS 9.56m vs 7.85m; HR = 0.767; p = 0.0233). The most common TEAEs of Grade ≥ 3 were neutropenia (60.0% vs 36.4%), leukopenia (42.9% vs 23.5%), and anemia (11.7% vs 10.6%). The safety profile was consistent with F and PTX. No new safety signals were identified. Conclusions: FRUTIGA (NCT03223376) was a positive study by reaching statistical significance for one primary endpoint, PFS, and demonstrated improvement in the other primary endpoint, OS, that was not statistically significant, possibly due to the imbalance of subsequent antitumor therapies. These data support F+PTX as a potential new second-line treatment option for pts with advanced G/GEJ adenocarcinoma. Clinical trial information: NCT03223376 .

Approved immune checkpoint inhibitors in hepatocellular carcinoma: a large-scale meta-analysis and systematic review

A meta-analysis was performed to assess the benefits and safety profile of approved immune checkpoint inhibitors in hepatocellular carcinoma patients. Eligible studies were searched from Cochrane, Embase, and PubMed databases based on a well-established strategy. Following the exclusion of ineligible studies, 12 studies were included in this meta-analysis. Compared with control group, immune checkpoint inhibitors were associated with improved ORR (OR 3.03, 95% CI 2.26–4.05, P < 0.00001), SD (OR 0.77, 95% CI 0.62–0.95, P = 0.02), OS (HR 0.75, 95% CI 0.68–0.83, P < 0.00001), and PFS (HR 0.74, 95% CI 0.63–0.87, P < 0.0003). However, no significant differences were observed in DCR (OR 1.33, 95% CI 0.97–1.81, P = 0.07), PD (OR 0.90, 95% CI 0.67–1.21, P = 0.48), and all caused any-grade adverse events (OR 1.22, 95% CI 0.62–2.39, P = 0. 57), all caused ≥ grade 3 adverse events (OR 1.10, 95% CI 0.97–1.25, P = 0.14), treatment-related any-grade adverse events (OR 1.13, 95% CI 0.55–2.32, P = 0.73), and treatment-related ≥ grade 3 events (OR 0.82, 95% CI 0.34–1.97, P = 0.65) between the two groups. After subgroup analysis conducted, patients in the immune checkpoint inhibitor group compared with targeted drug group showed significant improvements in OS (HR 0.74, 95% CI 0.66–0.84, P < 0.00001) and PFS (HR 0.75, 95% CI 0.61–0.91, P = 0.004). Immune checkpoint inhibitors have demonstrated peculiar benefits in the treatment of HCC with an acceptable safety profile. Compared to targeted drugs, immune checkpoint inhibitors still offer advantages in the treatment of hepatocellular carcinoma. However, there is still considerable room for further improvement.

Pembrolizumab plus lenvatinib (P+L) versus alternative therapies in first-line (1L) advanced renal cell carcinoma (aRCC) by IMDC risk status: A network meta-analysis (NMA).

421 Background: The International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk criteria is a widely used prognostic model in advanced RCC. Pembrolizumab plus lenvatinib (P+L) demonstrated a significant improvement in ORR, PFS, and OS versus sunitinib in subjects with cc aRCC in the KEYNOTE-581/CLEAR trial. This NMA indirectly compared the efficacy of P+L to other therapies in 1L aRCC subjects within IMDC risk groups using data from randomized clinical trials (RCTs). Methods: A systematic literature review was conducted to identify systemic therapies in 1L aRCC. Trials reporting results for IMDC favorable risk and/or intermediate+poor risk groups were included. A Bayesian NMA with fixed-effect models was performed to indirectly compare P+L to alternate therapies using sunitinib as the common comparator. Hazard ratios (HRs) for OS and PFS were calculated with 95% credible intervals (CrIs). The NMAs assuming constant hazard ratios (HRs) for OS and PFS were performed for all IMDC risk group categories. 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: For the IMDC favorable risk subgroup, P+L demonstrated statistically significant increase in ORR compared to nivolumab + ipilimumab (N+I) (OR=5.35; 95% CrI: 2.59, 11.41) and nivolumab (OR=8.41; 95% CrI: 1.84, 43.77). For PFS, P+L resulted in a statistically significant improvement in PFS compared to N+I (HR=0.31, 95% CrI: 0.17-0.56). For OS, no significant differences were observed compared to other alternatives in the network. For the IMDC intermediate+poor risk subgroup, P+L demonstrated statistically significant increase in ORR compared to nivolumab + cabozantinib (N+C) (OR=1.77; 95% CrI: 1.02, 3.10), N+I (OR=3.15; 95% CrI: 1.94, 5.10), and nivolumab + ipilimumab + cabozantinib (N+I+C) (OR=2.34; 95% CrI: 1.34, 4.12), pembrolizumab + axitinib (P+A) (OR=2.65; 95% CrI: 1.57, 4.44) and nivolumab (OR=4.68; 95% CrI: 1.84, 12.02). For PFS, P+L resulted in a statistically significant improvement compared to N+I (HR=0.59; 95% CrI: 0.41, 0.84) (P+A) (HR=0.64; 95% CrI: 0.44, 0.93), and avelumab + axitinib (A+A) (HR=0.65; 95% CrI: 0.46, 0.93). For OS, no significant differences were observed compared to other alternatives in the network. Conclusions: PFS analysis favored P+L over all alternative therapies in the network in favorable or intermediate+poor IMDC risk groups. ORR analysis favored P+L over all alternative therapies in the network in intermediate+poor IMDC risk groups. No significant difference in OS was observed between P+L and other alternative therapies in the network.

Management of nausea and vomiting (N/V) following first-line (1L) zolbetuximab + chemotherapy treatment in claudin-18.2 (CLDN18.2)+, HER2−, locally advanced (LA) unresectable or metastatic gastric or gastroesophageal junction (mG/GEJ) adenocarcinoma: Analysis from the phase 3 SPOTLIGHT and GLOW studies.

372 Background: The phase 3 SPOTLIGHT (NCT03504397) and GLOW (NCT03653507) studies showed clinically meaningful, statistically significant improvement in PFS and OS using 1L zolbetuximab + chemotherapy vs placebo (PBO) + chemotherapy in patients (pts) with CLDN18.2+, HER2−, LA unresectable or mG/GEJ adenocarcinoma. N/V were the most common treatment-emergent adverse events (TEAEs) reported in the zolbetuximab arm of these studies. We report an analysis of the incidence and management of N/V in SPOTLIGHT and GLOW. Methods: In SPOTLIGHT, pts (N = 565) were randomized 1:1 to zolbetuximab + mFOLFOX6 vs PBO + mFOLFOX6. In GLOW, pts (N = 507) were randomized 1:1 to zolbetuximab + CAPOX vs PBO + CAPOX. In both studies, neurokinin-1 receptor blockers (NK-1), selective serotonin receptor blockers (5-HT3), and other prophylactic antiemetic regimens were recommended to prevent and mitigate N/V per institutional care and guidelines. Results: A total of 279 pts in SPOTLIGHT and 253 pts in GLOW received zolbetuximab + chemotherapy. In SPOTLIGHT and GLOW combined, nausea occurred in 58% vs 18% of pts, and vomiting occurred in 43% vs 15% of pts in the first vs second zolbetuximab infusions, respectively; lower incidences of N/V were observed thereafter. During the first zolbetuximab infusion, the first episode of N/V occurred within 1 hour (median time, 48.0 min in SPOTLIGHT and 56.5 min in GLOW). Antiemetic usage and associated N/V rates are presented in the Table. The 96 pts in SPOTLIGHT and 52 pts in GLOW who had infusion modifications in cycle 1 due to TEAEs had numerically higher infusion rates than pts without infusion modifications; 85% of these modifications in SPOTLIGHT and 79% in GLOW were due to N/V. Zolbetuximab was discontinued within the first 9 weeks in 11 and 7 pts in SPOTLIGHT and 6 and 4 pts in GLOW due to nausea or vomiting, respectively. Conclusions: In SPOTLIGHT and GLOW, slower infusion rate and use of antiemetic combinations may have helped to mitigate N/V. These strategies will be important to support continued treatment and allow pts to achieve maximum clinical benefit with zolbetuximab + chemotherapy. Clinical trial information: NCT03504397 and NCT03653507 . [Table: see text]

Network meta-analysis of global trials of 1L therapies in locally advanced (LA) unresectable or metastatic gastric or gastroesophageal junction (mG/GEJ) adenocarcinoma.

325 Background: The phase 3 SPOTLIGHT (NCT03504397) and GLOW (NCT03653507) studies reported statistically significant improvement in PFS and OS with 1L zolbetuximab (anti-claudin-18 isoform 2 [CLDN18.2]) + mFOLFOX6 or CAPOX in pts with CLDN18.2+, HER2−, LA unresectable or mG/GEJ adenocarcinoma. This network meta-analysis (NMA) indirectly compared the relative efficacy of 1L therapies. Methods: A systematic literature review of phase 2, 3, or unknown phase randomized, global trials of 1L therapies (capecitabine + cisplatin [CX]; capecitabine + oxaliplatin [CAPOX]; fluorouracil + cisplatin [CF]; oxaliplatin + folinic acid + fluorouracil [FOLFOX]; S-1 + cisplatin [SC]; nivolumab + CAPOX/FOLFOX; pembrolizumab + CF/CAPOX or CX; and zolbetuximab + CAPOX/FOLFOX) in adults with LA unresectable or mG/GEJ adenocarcinoma. To form a connected main network, FOLFOX and CAPOX were assumed equally efficacious and combined. In the latest publicly available data, hazard ratios (HRs) of PFS and OS for intent-to-treat (ITT) populations were extracted or reconstructed from Kaplan-Meier curves when not reported as inputs for Bayesian fixed-effects NMAs. Comparative effectiveness was reported using median HR and 95% credible intervals (CrIs). Results: Trials reporting ITT populations were included, resulting in 9 trials (6663 pts) for PFS analysis and 10 trials (6735 pts) for OS analysis representing 8 regimens. Pts were randomly assigned to an experimental arm vs FOLFOX/CAPOX. Pts on 1L zolbetuximab, nivolumab, or pembrolizumab in combination with CF/CAPOX or FOLFOX/CAPOX had significantly reduced risk of disease progression or death vs FOLFOX/CAPOX (Table). Zolbetuximab + FOLFOX/CAPOX had the highest probability of being ranked first in treatment efficacy for both PFS (probability =0.54) and OS (0.36); followed by pembrolizumab + CX (0.27) and pembrolizumab + CF/CAPOX (0.13) for PFS; and by pembrolizumab + CF/CAPOX (0.3) and nivolumab + FOLFOX/CAPOX (0.24) for OS. Conclusions: This NMA examined the relative benefit of different targeted therapies when combined with chemotherapy. Zolbetuximab + FOLFOX/CAPOX for CLDN18.2+, HER2−, LA unresectable or mG/GEJ adenocarcinoma confers a significant PFS and OS benefit, similar to that achieved with PD-1/PD-L1 inhibitors + CF/CAPOX or FOLFOX/CAPOX. [Table: see text]

Association between Environmental Temperature and Survival in Gastroesophageal Cancers: A Population Based Study.

Cold stress suppresses antitumor response in animal models, leading to tumor growth. Recent studies have also shown a negative correlation between the average annual temperature (AAT) and cancer incidence. We hypothesized that esophageal cancer (EC) and gastric cancer (GC) patients living in warmer climates have improved survival outcomes than those living in colder climates. We conducted a retrospective analysis using the Surveillance, Epidemiology, and End Results (SEER) database from 1996 to 2015. We retrieved the National Centers for Environmental Information data to calculate the county-level AAT. Cox multivariate regression models were performed to measure the association between temperature (measured continuously at diagnosis and in 5-degree increments) and OS/DSS, adjusting for variables. All associations were compared at a significance level of 0.05. The OS and DSS were summarized using Kaplan-Meier methods. All statistics were performed using SAS version 9.4 (SAS Institute Inc., Cary, NC, USA). A total of 17,408 EC patients were analyzed. The average age of the cohort was 65 years, 79% of which were males and 21% were females. Of them, 61.6% had adenocarcinoma, and 37.6% were squamous. After adjusting for covariates, patients in regions with an AAT > 53.5 °F had an 11% improvement in OS [HR 0.89 (95% CI 0.86-0.92), p < 0.0001] and 13% in DSS [HR 0.87 (95% CI 0.84-0.90), p < 0.0001]. When the temperature was analyzed in 5 °F increments, with each increment, there was a 3% improvement in OS [HR 0.97 (95% CI 0.96-0.98), p < 0.0001] and 4% in DSS [HR 0.96 (95% CI 0.95-0.97), p < 0.0001]. Subgroup analysis of squamous and adenocarcinoma showed similar results. These findings were validated in 20,553 GC patients. After adjusting for covariates, patients in regions with an AAT > 53.5 had a 13% improvement in OS [HR 0.87 (95% CI 0.85-0.90), p < 0.0001] and 14% in DSS [HR 0.86 (95% CI 0.83-0.89), p < 0.0001]. When analyzed in 5 °F increments, with each increment, there was a 4% improvement in OS [HR 0.96 (95% CI 0.952-0.971), p < 0.0001] and 4% in DSS [HR 0.96 (95% CI 0.945-0.965), p < 0.0001]. We showed for the first time that higher environmental temperatures are associated with significant improvements in OS and DSS in patients with gastro-esophageal cancers, notwithstanding the limitations of a retrospective database analysis. Further confirmatory and mechanistic studies are required to implement specific interventional strategies.

Recent Advancements in Acute Myeloid Leukemia Have Led to Incremental Improvement in Overall Survival

Background: Treatment approaches in acute myeloid leukemia are rapidly evolving due to a dynamic treatment landscape, routine molecular profiling, and the detection of measurable residual disease. Recently, there has been a surge in FDA approvals for novel therapies (e.g., midostaurin, gilteritinib, CPX-351, enasidenib, ivosidenib, and venetoclax), as well as a departure from a “one-size-fits-all” treatment approach. It is unclear, however, what effect these changes have had on overall survival over time. Since 2017, we have witnessed a significant introduction of novel therapeutics. We hypothesized that patients diagnosed after 2017 may have improved survival due to recent therapeutic advances. Methods: We retrospectively analyzed 627 consecutive patients in the Project ERIS database aged &amp;gt; 18 years with AML treated at VCU Massey Comprehensive Cancer Center from 2015 to 2022. We limited the analysis to January 1, 2015 to December 31, 2019 to avoid confounding from the COVID-19 pandemic. We obtained cytogenetic and molecular characteristics, induction regimens, allogeneic stem cell transplant status, and survival data. The median overall survival (mOS) was compared across calendar years using the Kaplan-Meier method. Categorical variables were analyzed using Fisher's exact test. Results: The median age at AML diagnosis was 62.9 years (range, 19.6-93.0), and the median ECOG performance status was 1 (range, 0-4). The median Charlson Comorbidity Index score was 5 (range, 0-14). There were 139 (22.2%) patients with ELN 2022 favorable-risk disease, 199 (31.7%) with intermediate risk, and 260 (41.5%) with adverse risk. The median OS of all patients diagnosed with AML in 2015 was 8.8 months. In 2016, the mOS was 14.5 months. There was a statistically significant improvement in mOS in 2016 compared to 2015 (HR 0.62 [95% CI 0.40-0.95], p = 0.027). The mOS in 2017, 2018, and 2019 was 12.9 months, 11.1 months, and 19.7 months, respectively. A significant improvement in OS was noted between 2015 and 2019 (HR 0.55 [95% CI 0.36-0.85], p = 0.003) in the entire cohort (Figure 1). When stratified by ELN 2022 genetic risk, clinically relevant improvement in OS was noted across all risk categories from 2015 to 2019, which reached statistical significance in the adverse risk group - favorable risk mOS: 16.4 months vs not reached (p = 0.141); intermediate risk: 13 months vs 18.7 months (p = 0.064); adverse risk: 7.2 months vs 13 months (p = 0.02). We observed expected changes in front-line treatment in this timeframe with decreased single-agent hypomethylating agent (HMA) usage in favor of HMA + venetoclax and increased intensive induction therapies outside of 7+3 (Figure 2). Strikingly, increased procession to allogeneic stem cell transplantation (HCT) was noted in the same timeframe (18.9% in 2015 vs 35.1% in 2019, p = 0.049). Conclusions : Our data demonstrate an emerging trend of clinically significant improvement in overall survival in patients with AML. The introduction of a multitude of therapeutic options may be associated with significantly improved survival over time. In addition to the advent of novel therapeutics leading to improved outcomes, the refinement of SCT conditioning regimens has likely led to the improved accessibility of HCT. In summary, we present an encouraging and significant trend of improved survival and access to HCT, particularly for patients with adverse-risk disease.

The Promising Third-Generation TKI Olverembatinib in Adult BCR::ABL1-Positive Acute Lymphoblastic Leukemia with T315I Mutation and Relapsed/Refractory Disease

Background Olverembatinib (HQP1351) is a novel third-generation tyrosine kinase inhibitor (TKI) that has shown remarkable efficacy and safety in chronic myeloid leukemia (CML). Still, few reports are available on BCR::ABL1-positive acute lymphoblastic leukemia (BCR::ABL1+ ALL). We first reported the early encouraging outcome of olverembatinib in BCR::ABL1+ ALL patients (pts) with T315I mutation or disease progression last year. Here, we enlarged the sample size and included a case of CML in lymphoid blast phase (CML-LBP) who also benefited from olverembatinib to a certain extent. Methods In this observational study, we retrospectively enrolled BCR::ABL1+ ALL or CML-LBP pts with T315I mutation, disease progression, or intolerant to previous TKIs in our institution from Dec. 2021 to May 2023. All pts received olverembatinib monotherapy (40mg qod) or combination therapy. Efficacy was assessed by CR rate, MRD negative (MRD &amp;lt;10 -4) rate by multiparameter flow cytometry (MFC), CMR (BCR-ABL1 transcript&amp;lt;10 -5) rate by RT-qPCR, as well as the survival data. PFS and OS were both calculated from the start of olverembatinib. Adverse events (AEs) were assessed and graded according to CTCAE v5.0. Results Totally, 30 pts with BCR::ABL1+ ALL (n=29) or CML-LBP (n=1) were analyzed. Among 29 BCR::ABL1+ ALL pts (median age of 60 years [range, 23-76]), 14 were in CR with molecular R/R disease, including 1 with MRD only detected by RT-qPCR. While the other 15 had hematological R/R disease, including 4 with central nervous system leukemia. T315I mutation was detected in 23 pts, including 8 with additional mutations. The baseline characteristics are detailed in Table 1. As for the 23-year-old female pt with CML-LBP, dasatinib was switched to olverembatinib when T315I, E255K, and E255V mutations were detected. T315I and E255V were eliminated rapidly after 1-month treatment of olverembatinib, while E255K still existed. At present, the patient maintained in CR, and blinatumomab will be used for MRD clearance before allo-HSCT. She was only included in the safety analysis. Among 14 pts with molecular R/R disease, 61.5% and 50% achieved MRD flow negativity and CMR with a median time of 1.3 months (range, 0.8-4.4) and 1.2 months (range, 0.9-4.4), respectively. Among 15 pts with hematological R/R disease, 80%, 53.3%, and 46.7% achieved CR/CRi, MRD flow negativity, and CMR, with a median time of 1 month (range, 0.2-2.5), 1 month (range, 0.2-3.3) and 2.1 months (range, 0.7-4.6), respectively. Totally, 8 pts underwent allo-HSCT with a median age of 48.5 years (range, 23-60), of which 6 pts achieved CMR before allo-HSCT, and all attained persistent CMR after allo-HSCT. By June 15, 2023, with a median follow-up time of 9.1 months (range, 1.7-16) in BCR::ABL1+ ALL pts, the median PFS was 7.8 months, and the median OS was not reached. For molecular R/R pts, the median PFS and OS were not reached, and for hematological R/R pts, the median PFS and OS were 6.5 and 8.6 months. MRD flow negativity or CMR responders had significantly better PFS and OS (PFS: p&amp;lt;0.001, p&amp;lt;0.001; OS: p&amp;lt;0.001, p&amp;lt;0.001), and bridging allo-HSCT after olverembatinib-based therapy showed a significant survival superiority (PFS: p=0.001; OS: p=0.017). Among the 23 pts with T315I mutation, the MRD flow negativity rate in pts with T315I single mutation was significantly higher than those with additional mutations (p=0.008), and the CMR rate tended to be better (p=0.089). Meanwhile, pts with T315I single mutation showed significant improvements in PFS and OS (Figure 1). As for safety analysis, the olverembatinib-based therapy was well-tolerated. Most non-hematological AEs were G1-2, and most G3-4 AEs were hematological, possibly related to chemotherapy. The incidence of G3-4 cardiovascular AEs was 6.7%. Five elderly pts (median age of 72 years [range, 63-76]) had temporary treatment suspension or dose reduction. No permanent discontinuation or death related to olverembatinib was observed. Conclusion This study further confirmed the efficacy of olverembatinib-based therapy in Chinese adults BCR::ABL1+ ALL pts with T315I mutation or R/R disease, especially in those with T315I single mutation. In addition, bridging allo-HSCT after deeper molecular remission could further improve survival. The safety profiles were manageable, but there is still a need to explore the optimal dose in elderly pts.

Survival of Hodgkin Lymphoma Patients Treated with Novel Immunotherapies after Autologous Stem Cell Transplantation Failure: A Retrospective Analysis of the Italian Lymphoma Foundation (FIL)

Background: Classical Hodgkin lymphoma (HL) is considered a highly curable disease and nearly 80-90% of patients (pts) may achieve complete remission (CR) with standard chemotherapy (Engert et. al. NEJM 2010).However up to 30% of HL pts experience primary refractory disease or eventually relapse after first-line treatment (Barrington et. al. Blood 2016, Press O et al. Clin Oncol 2016). High-dose chemotherapy followed by autologous hemopoietic stem cell transplantation (autoHSCT) has been showed to be an active salvage treatment in approximately 50% pts with chemosensitive relapse. Before the advent of novel immunotherapies, the median survival duration for pts failing autoHSCT was only 10 months (Vose et. al. Blood 1992). In this setting the introduction of Brentuximab Vedotin (BV) (Younes et. al. JCO 2012) and of the checkpoint inhibitors (CPI) Nivolumab (nivo) (Herrera et. al. Blood 2018) or Pembrolizumab (Chen et.al. Blood 2019) have shown to significant therapeutic active. Aims: To assess the therapeutic effects of BV and CPI in prolonging PFS and OS in patients with HL r/r post autoHSCT. Methods: This is an observational, retrospective, multicentric study from 15 centers of the Fondazione Italiana Linfomi (FIL). Adult patients who received salvage treatment with BV or CPI for post autoHSCT r/r HL from January 2015 to June 2018 were included in the analysis; the times of observation was censored in December 2020. Patients that had received pre-autoHSCT BV or CPI, were excluded from the analysis. Results: 40 pts, 25 treated with BV and 15 with nivo were included into the study. Patients' main characteristics at diagnosis are summarize in Table 1. Overall response was achieved in 23 (56%) pts treated with BV and in 9 (60%) with nivo, respectively. 14 (35%) out of 40 responsive to BV (10 pts) or nivo (4 pts) received allogeneic hemopoietic stem cell transplantation (alloHSCT) consolidation. The median follow-up time from the time of autoHSCT failure of the entire cohort was 36 months (range 2-70). At last follow-up, 32 (80%) pts were in CR, 1 (2%) in PR, while 2 (5%) and 5 (13%) were in SD and PD, respectively. 34 (85%) pts were alive and 6 (15%) have died. In the entire cohort, the median PFS and OS from the time of autoHSCT failure was 36 months and not reached, respectively; the 36-months projected PFS and OS of 50% and 86%, respectively. The median PFS and the 36-months projected OS of pts who received or not received alloHSCT were superimposable (Figure 1). Conclusion: In this retrospective analysis of pts with HL failing autoHSCT, BV or nivo resulted very active therapeutic salvage therapies. The comparison with historical results of the pre BV/CPI era suggests a major significant improvement both in PFS and OS. A significant proportion of pts received post BV or nivo alloHSCT but the effect of this treatment in prolonging PFS and OS should be further evaluated.

TUMOUR TREATING FIELDS (TTFIELDS) THERAPY IN NEWLY DIAGNOSED GLIOBLASTOMA: A META-ANALYSIS AND SYSTEMATIC REVIEW OF REAL-WORLD SURVIVAL DATA

Abstract AIMS Tumour Treating Fields (TTFields) are electric fields that disrupt processes required for cancer cell viability and tumour progression. TTFields therapy gained FDA approval and CE accreditation for newly diagnosed glioblastoma (ndGBM) following the EF-14 study (NCT00916409). We aimed to determine the real-world survival benefit of TTFields therapy. METHOD Survival data from clinical studies in TTFields therapy-treated patients with ndGBM were identified using a literature search and analysed. The Cochran Q test and Higgins I2 statistic were used to assess and quantify inter-study heterogeneity. Survival curves were pooled using a distribution-free random-effects method. RESULTS Among studies evaluating the clinical effcacy of TTFields therapy in ndGBM, six studies were identified which compared the addition of TTFields therapy to standard of care (SOC) vs SOC alone. The meta-analysis showed a significant improvement in OS for TTFields therapy-treated patients vs SOC alone (P &amp;lt; 0.001). The pooled effect was robust and independent of any individual study. In post-approval studies, the pooled median OS was 22.2 months (95% CI, 17.3–42.6) and 17.3 months (95% CI, 13.6–22.0) for TTFields therapy-treated patients and SOC, respectively. Rates of gross total resection were generally higher in the real-world setting, irrespective of TTFields therapy use. Average device usage of ≥75% was associated with prolonged survival vs &amp;lt;75% usage (pooled HR: 0.63; 95% CI, 0.48–0.83; P = 0.001). CONCLUSIONS Data suggest a significant survival benefit when TTFields therapy is added to SOC for patients with ndGBM. Usage of ≥75% may be meaningful in the real-world setting.

Beyond PACIFIC: Real-World Outcomes of Adjuvant Durvalumab According to Treatment Received and PD-L1 Expression.

Adjuvant durvalumab after chemoradiotherapy (CRT) is the standard of care for unresectable stage III non-small cell lung cancer (NSCLC). A post hoc exploratory analysis of PACIFIC revealed no OS benefit in the PD-L1 < 1% subgroup. This retrospective analysis assesses the real-world impact of durvalumab on OS according to PD-L1 tumor proportion score (TPS). Patients with stage III, unresectable NSCLC treated by CRT, with available PD-L1 TPS, from 1 March 2018 to 31 December 2020, at BC Cancer, British Columbia, Canada were included. Patients were divided into two groups, CRT + durvalumab and CRT alone. OS and PFS were analyzed in the PD-L1 ≥ 1% and <1% subgroups. A total of 134 patients were included in the CRT + durvalumab group and 117, in the CRT alone group. Median OS was 35.9 months in the CRT + durvalumab group and 27.4 months in the CRT alone group [HR 0.59 (95% CI 0.42-0.83), p = 0.003]. Durvalumab improved OS in the PD-L1 ≥ 1% [HR 0.53 (95% CI 0.34-0.81), p = 0.003, n = 175], but not in the <1% subgroup [HR 0.79 (95% CI 0.44-1.42), p = 0.4, n = 76]. This retrospective study demonstrates a statistically significant improvement in OS associated with durvalumab after CRT in PD-L1 ≥ 1%, but not PD-L1 < 1% NSCLC. Variables not accounted for may have biased the survival analysis. A prospective study would bring more insight.

Impact of Adherence to Operative Standards and Stage-Specific Guideline-Recommended Therapy in Nonmetastatic Pancreatic Adenocarcinoma.

Achieving optimal surgical outcomes in pancreatic adenocarcinoma requires a combination of both curative-intent resection to oncologic standards and stage-specific neoadjuvant or adjuvant therapy. This investigation sought to examine factors associated with receipt of standard-adherent surgery (SAS) and guideline-recommended therapy (GRT) and determine the impact of compliance on patient survival. From the 2006-2016 National Cancer Database, 21,304 patients underwent resection for nonmetastatic pancreatic adenocarcinoma. SAS was defined as pancreatic resection with negative margins and ≥15 lymph nodes examined. Stage-specific GRT was defined by current National Comprehensive Cancer Network guidelines. Multivariable models were used to determine predictors of adherence to SAS and GRT and prognostic impact on overall survival. Overall, SAS was achieved in 39% and GRT in 65% of patients, but only 30% received both SAS and GRT. Increasing age, minority race, uninsured status, and greater comorbidities were associated with a decreased odds of receiving both SAS and GRT (all p<0.05). SAS (HR 0.79; CI 0.76-0.81; p<0.001) and GRT (HR 0.67; CI 0.65-0.69; p<0.001) were each independently associated with a survival advantage. Receipt of both SAS and GRT was associated with significant improvement in median OS compared with receiving neither (2.2years vs 1.1 years; p<0.001) which was independently associated with a 78% increased risk of death (HR 1.78; CI 1.70-1.86; p<0.001). Despite survival benefits associated with adherence to operative standards and receipt of guideline-recommended therapy, compliance remains poor. Future efforts must be directed toward improved education and implementation efforts around both operative standards and therapy guidelines.

Subgroup analyses of safety and efficacy by number and types of prior lines of treatment in FRESCO-2, a global phase III study of fruquintinib in patients with refractory metastatic colorectal cancer.

3604 Background: Effective treatment options are limited for patients (pts) with refractory metastatic colorectal cancer (mCRC). Fruquintinib (F), a highly selective, potent, oral tyrosine kinase inhibitor of VEGFR-1, -2, and -3, was evaluated in the global phase III FRESCO-2 study (NCT04322539) and demonstrated a clinically meaningful and statistically significant improvement in OS and PFS with a favorable safety profile. Here we report subgroup analyses of efficacy and safety by prior lines (PL) and types of anti-cancer treatment (Tx) for metastatic disease (MD). Methods: FRESCO-2 was conducted in the US, Europe, Japan &amp; Australia, comparing F + best supportive care (BSC) with Placebo (P) + BSC. Pts were given 5 mg PO, QD, 3 wks on, 1 wk off, in a 28-day cycle. Eligible pts received prior chemotherapy, anti-VEGF, and if RAS wild type, anti-EGFR therapies; if BRAFV600E mutant or MSI-H, and appropriate targeted regimen; and had progressed on, or were intolerant to, trifluridine/tipiracil (TAS-102) and/or regorafenib (R). Subgroup (sbgrps) analyses for efficacy and safety were performed according to number of prior lines of tx (LOT) and by types of therapy. Results: A total of 691 pts were randomized; F:461 vs P:230. The median number of prior lines of anti-cancer tx for metastatic disease F vs P was 4 (2, 16) vs 4 (2, 12). F improved OS and PFS compared to P for all sbgrps and prior tx for MD, consistent with those of the ITT population (pop). (Table: OS reported by sbgrps and prior tx for MD). Occurrence of adverse events (AEs) and serious adverse events were generally balanced between F vs P and consistent across all subgroups. The most common ≥ G3 AEs in ≥5% of pts on F within majority of sbgrps were hypertension, asthenia and palmar plantar erythrodysesthesia and were consistent with the overall safety population. Additional analyses based on duration of prior anti-VEGF and last therapy prior to F will be presented at the conference. Conclusions: F demonstrated clinically meaningful improvement in OS, PFS with an acceptable safety profile across all sbgrps. These results were consistent with the effect observed in the overall population; irrespective of previous tx with anti-VEGF, anti-EGFR, TAS-102 and R further supporting F as a potential new tx option for pts with refractory mCRC. Clinical trial information: NCT04322539 . [Table: see text]

Global prevalence of CLDN18.2 in patients with locally advanced (LA) unresectable or metastatic gastric or gastroesophageal junction (mG/GEJ) adenocarcinoma: Biomarker analysis of two zolbetuximab phase 3 studies (SPOTLIGHT and GLOW).

4035 Background: There is an unmet need for additional therapies to treat patients (pts) with locally advanced (LA) unresectable or metastatic gastric or gastroesophageal junction (mG/GEJ) adenocarcinoma. Claudin-18.2 (CLDN18.2), a new validated target in these pts, is expressed in normal gastric mucosa cells and often retained in G/GEJ tumor cells. There are limited data on the global prevalence of CLDN18.2 in tumors of pts with LA unresectable or mG/GEJ adenocarcinoma. The SPOTLIGHT (NCT03504397) and GLOW (NCT03653507) phase 3 studies demonstrated clinically meaningful and statistically significant improvement in PFS and OS with the CLDN18.2-targeted antibody zolbetuximab + chemotherapy (mFOLFOX6 or CAPOX, respectively) vs placebo + chemotherapy as 1L therapy in pts with CLDN18.2+/HER2− disease. We report the biomarker analysis of these studies. Methods: Pts with LA unresectable or mG/GEJ adenocarcinoma were screened for CLDN18.2 status by IHC before enrollment. Tumors were defined as CLDN18.2+ if they had ≥75% of tumor cells with moderate-to-strong membranous CLDN18 staining per the investigational VENTANA CLDN18 (43-14A) RxDx Assay. HER2 status was evaluated per central or local assessment. Ad hoc PD-L1 IHC was performed via the Dako PD-L1 IHC 28-8 pharmDx assay for a subgroup of enrolled pts. Results exclude pts from mainland China and pts missing data for disease type, Lauren classification, or tumor collection site. Results: Across SPOTLIGHT and GLOW, 3576 pts had valid CLDN18 IHC results; 1399 (39.1%) had CLDN18.2+ tumors. CLDN18.2 prevalence was 43.7% (513/1175) in female pts and 36.9% (886/2401) in male pts. CLDN18.2 prevalence was 44.0% (671/1524) in pts in Europe/Middle East, 37.7% (183/485) in pts in N. America, and 36.5% (479/1314) in pts in Asia Pacific. CLDN18.2 prevalence was 41.0% (1056/2576) in pts with gastric adenocarcinoma and 37.3% (302/809) in pts with GEJ adenocarcinoma. CLDN18.2 prevalence trended higher in pts with diffuse (48.9%, 479/980) vs intestinal (38.9%, 265/682) disease. CLDN18.2 prevalence was 41.1% (175/426) in tumors collected from metastatic sites and 38.6% (1195/3094) in tumors collected from primary sites. CLDN18.2 prevalence was similar across other clinical and histopathological characteristics. Of 2908 HER2− pts with valid CLDN18 IHC results, 1264 (43.5%) had CLDN18.2+ tumors. Of 599 enrolled pts tested for PD-L1 expression, 104 (17.4%) had a PD-L1 CPS ≥5. Conclusions: The SPOTLIGHT and GLOW phase 3 studies are the largest data sources to date for determining global CLDN18.2 prevalence. CLDN18.2 is a high prevalence biomarker, with high tumor expression in ~35–40% of pts with LA unresectable or mG/GEJ adenocarcinoma, for whom zolbetuximab + chemotherapy represents a potential 1L therapy. Clinical trial information: NCT03504397 , NCT03653507 .

Perineural invasion affects prognosis of patients undergoing colorectal cancer surgery: a propensity score matching analysis

BackgroundTumour perineural invasion (PNI) is a predictor of poor prognosis, but its effect on the prognosis of patients with colorectal cancer (CRC) has not yet been elucidated.MethodsThis retrospective study used propensity score matching (PSM). The clinical case data of 1470 patients with surgically treated stage I–IV CRC at Wuhan Union Hospital were collected. PSM was used to analyse and compare the clinicopathological characteristics, perioperative outcomes, and long-term prognostic outcomes of the PNI(+) and PNI(-) groups. The factors influencing prognosis were screened using Cox univariate and multivariate analyses.ResultsAfter PSM, 548 patients were included in the study (n = 274 in each group). Multifactorial analysis showed that neurological invasion was an independent prognostic factor affecting patients’ OS and DFS (hazard ratio [HR], 1.881; 95% confidence interval [CI], 1.35–2.62; P = 0.0001; HR, 1.809; 95% CI, 1.353–2.419; P < 0.001). Compared to PNI(+) patients without chemotherapy, those who received chemotherapy had a significant improvement in OS (P < 0.01). The AUROC curve of OS in the PNI(+) subgroup (0.802) was higher than that after PSM (0.743), while that of DFS in the PNI(+) subgroup (0.746) was higher than that after PSM (0.706). The independent predictors of PNI(+) could better predict the prognosis and survival of patients with PNI(+).ConclusionsPNI significantly affects the long-term survival and prognosis of patients with CRC undergoing surgery and is an independent risk factor for OS and DFS in patients with CRC undergoing surgery. Postoperative chemotherapy significantly improved the OS of PNI(+) patients.

Abstract CT080: Tremelimumab (T) + durvalumab (D) + chemotherapy (CT) in 1L metastatic NSCLC: Outcomes by blood tumor mutational burden (bTMB) in POSEIDON

Abstract Background: In the Phase 3 POSEIDON study (NCT03164616), 1L T plus D and platinum-based CT demonstrated statistically significant improvements in both PFS (HR, 0.72; 95% CI, 0.60-0.86; p=0.0003; data cutoff [DCO] July 24, 2019) and OS (HR, 0.77; 95% CI, 0.65-0.92; p=0.0030; DCO March 12, 2021) vs CT in patients (pts) with EGFR/ALK wild-type metastatic (m) NSCLC. On the basis of these results, T+D+CT was approved by the FDA in November 2022 for use in this setting. Here we report outcomes in POSEIDON pt subgroups defined by a range of bTMB values, including a pre-specified cutoff of 20 mutations/megabase (mut/Mb). Methods: Pts were randomized 1:1:1 to 1L T+D+CT (platinum-based), D+CT or CT, with stratification by tumor cell (TC) PD-L1 expression (TC ≥50% vs &amp;lt;50%; VENTANA PD-L1 [SP263] assay), disease stage (IVA vs IVB) and histology (squamous vs non-squamous). bTMB was assessed using the GuardantOMNI platform. OS, PFS and ORR with T+D+CT vs CT were determined for pts with bTMB ≥ vs &amp;lt;20 mut/Mb. Outcomes across additional bTMB cutoffs (10, 12 and 16 mut/Mb) were also explored. Results: Plasma samples were available for 958/1013 pts from the intention-to-treat (ITT) population. Of those with available plasma samples, 81.8% (784/958) were evaluable for bTMB, including 277 in the T+D+CT arm and 241 in the CT arm. Similar demographic characteristics and OS were observed in the bTMB evaluable vs ITT populations. Consistent with previous reports, the proportion of never smokers was higher in the bTMB &amp;lt;20 mut/Mb subgroup than in the bTMB ≥20 mut/Mb subgroup. Across all bTMB cutoffs analyzed, OS and PFS benefit for T+D+CT vs CT were generally consistent with the ITT population in both bTMB high and bTMB low subgroups. However, at each bTMB cutoff, OS and PFS benefit appeared more prominent among pts in the bTMB high subgroups. Median OS (mOS) was longer with T+D+CT vs CT in both the bTMB ≥20 mut/Mb and &amp;lt;20 mut/Mb subgroups and HRs suggested more pronounced benefit in the bTMB high group. mOS was 13.5 months with T+D+CT vs 10.3 months with CT (unstratified HR, 0.61; 95% CI, 0.42-0.88) for pts with bTMB ≥20 mut/Mb and 12.6 months vs 10.9 months (unstratified HR, 0.79; 95% CI, 0.63-0.99) for pts with bTMB &amp;lt;20 mut/Mb. PFS and ORR showed similar trends to OS (data will be presented). In both subgroups with PD-L1 TC ≥1% or &amp;lt;1%, HRs suggested more pronounced OS/PFS benefit in pts with bTMB ≥20 (vs &amp;lt;20) mut/Mb (data will be presented). Conclusions: In pts with mNSCLC, treatment with a limited course of T plus D (until progression) and four cycles of CT consistently improved clinical outcomes vs CT alone in both bTMB high and low subgroups, supporting the use of this regimen as a 1L treatment option for pts with mNSCLC. The clinical benefit vs CT appeared to be greater in pts with higher bTMB over a range of cutoffs, consistent with expectations based on mechanistic biology and previous clinical data. Citation Format: Solange Peters, Hisani Madison, Kelly Oliner, Anne L’Hernault, Marianne Ratcliffe, Karen Barrett, Xiaojin Shi, Edward B. Garon, Tony Mok, Melissa L. Johnson. Tremelimumab (T) + durvalumab (D) + chemotherapy (CT) in 1L metastatic NSCLC: Outcomes by blood tumor mutational burden (bTMB) in POSEIDON [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT080.

Effect of temperature on gastro-esophageal cancer outcomes: A SEER study.

467 Background: Cold stress suppresses antitumor response in animal models, leading to tumor growth . Recent studies have also shown a negative correlation between the average annual temperature (AAT) and cancer incidence. We hypothesized that esophageal cancer (EC) and gastric cancer (GC) patients living in warmer climates have improved overall (OS) and disease-specific survival (DSS) than those living in colder climates. Methods: A retrospective analysis was conducted using the Surveillance, Epidemiology, and End Results (SEER) database from 1996 to 2015. AAT at the county level was calculated based on the National Centers for Environmental Information. Cox multivariate regression models were performed to measure the association between temperature (measured continuously at diagnosis and in 5-degree increments) and OS/DSS, adjusting for variables. All associations were compared at a significance level of 0.05. The OS and DSS were summarized using Kaplan-Meier methods. All statistics were performed using SAS version 9.4 (SAS Institute Inc., Cary, NC). Results: A total of 17,408 EC patients were analyzed. The average age of the cohort was 65 years, 79% of which were male and 21% were female. Of them, 61.6% had adenocarcinoma, and 37.6% were squamous. After adjusting for covariates, patients in regions with AAT &gt;53.5°F had an 11% improvement in OS [HR 0.89 (95% CI 0.86-0.92), p&lt;0.0001] and 12% in DSS [HR 0.88 (95% CI 0.85-0.91), p&lt;0.0001]. When the temperature was analyzed in 5°F increments, with each increment, there was a 3% improvement in OS [HR 0.97 (95% CI 0.96-0.98), p&lt;0.0001] and 4% in DSS [HR 0.96 (95% CI 0.95-0.97), p&lt;0.0001]. Subgroup analysis of squamous and adenocarcinoma showed similar results. These findings were validated in 20,553 GC patients. After adjusting for covariates, patients in regions with AAT &gt;53.5 had a 12% improvement in OS [HR 0.88 (95% CI 0.85-0.90), p&lt;0.0001] and 14% in DSS [HR 0.86 (95% CI 0.83-0.89), p&lt;0.0001]. When analyzed in 5°F increments, with each increment, there was a 4% improvement in OS [HR 0.96 (95% CI 0.95-0.97), p&lt;0.0001] and 4% in DSS [HR 0.96 (95% CI 0.95 - 0.97), p&lt;.0001]. Conclusions: We showed for the first time that higher environmental temperatures are associated with significant improvements in OS and DSS in patients with gastro-esophageal cancer. Further confirmatory and mechanistic studies are required to implement specific interventional strategies.[Table: see text]