Improvement In OS Research Articles

Activity of cabozantinib (CABO) plus durvalumab (DURVA) in patients (pts) with advanced urothelial carcinoma (UC) or non-UC variant histologies (VH) after platinum chemotherapy: Interim results from the phase 2 ARCADIA trial.

4578 Background: Combining multitargeted receptor tyrosine kinase inhibitor (TKI) with checkpoint inhibitors has shown synergistic effect in pts with UC due to the immunomodulatory propriety of VEGFR inhibitors. We investigated if the combination of CABO and DURVA in pts with advanced UC and non-UC histology (VHs) in a phase II study (NCT03824691). Herein the preliminary results of the interim analysis. Methods: Patients affected by UC and VHs recurred or progressed after failure of at least one line of platinum-based chemotherapy for metastatic disease have been treated with CABO 40 mg daily, orally, and are administered DURVA 1500 mg IV, q28 days, until disease progression (PD, by RECIST 1.1) or onset of unacceptable toxicity. Key inclusion criteria were ECOG-PS 0-1 and adequate organ function. Response was evaluated by RECIST criteria v.1.1 every 8 wks. The primary endpoint of the study was OS. Secondary endpoints included safety (CTCAE v.4.03), objective response-rate (ORR), duration of response (DoR), progression-free survival (PFS). The assumption was to detect an improvement in the median OS from ≤6 months (H0) to ≥9 months (H1). Results: Between September 2019 and February 10, 2023, the ARCADIA study enrolled 63 pts: this interim analysis was performed after obtaining at least one post-baseline tumor assessment data from 58 pts. The median follow-up was 23.5 mos (interquartile [IQ] range: 7.7-27.7mos): 27% were female, the median age was 64 yrs (range: 42-81), 20 pts (34%) had a pure/predominant non-UC VH: 9 (45%) a squamous differentiation/sarcomatoid tumor, 5 (25%) an adenocarcinoma, 4 (20%) a small-cell neuroendocrine tumor, 1 (5%) a clear-cell tumor, and 1 a nested VH (5%). Eleven pts (19%) had received ≥2 prior systemic anticancer therapies. In 58 response-evaluable pts, 12 (20%) complete responses (CR) and 11 partial responses (PR) were obtained, the ORR being 39.7% (95%CI: 27.1-53.4) and disease control rate was 69% (95%CI: 55.5-80.5). In the cohort of pts with VH, the ORR was 45% (95%CI: 23.1-68.5). Median PFS was 7.6 mos (95%CI: 4.6-13-6 mos) and median OS was 11.6 (95% CI 6.8-20.3 months). Median exposure of treatment was 4.8 mos; 35 pts (55.5%) of 63 pts had all-grade treatment-related adverse events (AE) and 4 pts (6.3%) reported grade 3 (treatment related) AE with no grade 3-5 events. Dose-reductions of CABO were needed in 25 pts (39%). No treatment-related deaths were reported. Conclusions: CABO in combination with DURVA showed promising preliminary activity with a manageable safety profile in pts with advanced UC and in non-UC VH after previous chemotherapy exposure, deserving further evaluation of the combination that is ongoing with ARCADIA and other clinical trials. More mature results with longer follow-up will be presented. Clinical trial information: NCT03824691 .

The changing landscape of small-cell lung cancer.

e20634 Background: Small-cell lung cancer (SCLC) is an aggressive histologic subtype of lung cancer with distinct biology and clinical course. The aim of this study is to investigate the trends in demographics and outcomes. Methods: We queried the Surveillance, Epidemiology, and End Results (SEER) database to assess the incidence, demographics, and survival for SCLC using SEER 8 (8 registries), which include data from 1975 to 2019. The pattern of metastases was evaluated using SEER 17 from 2010 to 2019. Jointpoint analysis was used to calculate the trends in annual percentage change according to year of diagnosis. Results: There were 530,198 patients with lung cancer, including 73,362 (13.8%) patients with SCLC in the SEER 8. The percentage of SCLC among all lung tumors progressively increased from 13.3% in 1975 to a peak of 17.5% in 1986, followed by steadily decrease since 1990, reaching 11.1% in 2019. The incidence per 100,000 population increased from 9.5 in 1975 to 15.3 in 1986 followed by a gradual decline to 6.5 in 2019. Among patients with SCLC included in SEER 8, demographic changes from 1975-1979 to 2015-2019 included increased median age at diagnosis from 63 years to 69 and increased percentage of women from 31.4% to 51.2%. The percentage of patients with stage IV increased from 56.9% to 63.8% from 1995-1999 to 2000-2004, and to 69.5% in 2010-2014 without further increase. Among the 55,035 patients with SCLC in SEER 17 from 2010 to 2019, the most common sites of metastasis at diagnosis were mediastinal lymph nodes (69.9%) liver (30.5%), bone (22.8%), and brain (15.8%). The median, 1-year, and 5-year overall survival increased from 6 months, 23%, and 3.6% respectively in 1975-1979 to 7 months, 30.8%, and 6.8% respectively in 2010-2019 (P < 001). Conclusions: The incidence of SCLC in the United States reached a peak in 1985 to 1989 followed by a gradual decline. Demographic changes included an increased median age at diagnosis and the percentage of women, which surpassed men in the last study period. There was also an increase in the percentage of stage IV. The improvement in 5-year OS has been statistically significant but clinically modest.

The impact of ImmunoPrecision in small bowel adenocarcinoma.

e16333 Background: Although approaches to treating adenoCA of the small bowel (SBA) are extrapolated from those of the colon, SBA has distinct pathogenesis, clinical presentation and poorer prognosis. We examine the impact of SBA treatment by ImmunoPrecision, which combines Immunotherapy and Precision genomic targeting. Methods: SBA pts were identified retrospectively from Cedars-Sinai electronic health record (2000 – 2022) on an IRB-approved protocol. Microsatellite status and genomic testing were done in CLIA-certified, CAP-accredited labs. Pt characteristics, pathology, in-depth clinical history and genomics were summarized with descriptive statistics. Endpoint of median OS was estimated by Kaplan-Meier and calculated from pre-treatment imaging to last event. Treatment groups were compared using log-rank test. Results: Between Jan 2003 – Dec 2022, 137 stage 1 – 4 SBA pts (93 duodenal; 44 jejunal/ileal) were identified. Median age was 67 (range 22 – 95). Microsatellite status and genomic testing data were done or known for 72 pts (53%). In 35 pts who had metastases at initial presentation, 15 pts had NGS genomics, which identified actionable targets: 20% Her2amp/mut, 13% FGFR1amp/mut, 7% ALKfusion, 7% KRAS G12C, and 7% ATM R35*. 40% of 10 metastatic pts tested for microsatellite status were MSI/TMB-High, and only 1 pt received immunotherapy. In pts with metastases, median OS was 9.5 mo in duodenal adenoCA (51 pts) vs 13.0 mo in jejunal/ileum adenoCA (23 pts) (p = 0.46). There was a non-significant improvement in median OS to 20.5 mo in metastatic duodenal adenoCA pts who received targeted inhibition of actionable genomics or had MSI/TMB-High status (p = .51). Conclusions: Our real-world cohort of metastatic duodenal adenoCA shows a trend toward improved median OS from ImmunoPrecision targeting of frequent MSI/TMB-High status and actionable genomics. ImmunoPrecision clinical trial investigation is warranted in this rare SBA population. [Table: see text]

A randomized study of consolidation chemoradiation (CTRT) vs observation after first-line chemotherapy (CT) in advanced gall bladder cancers (GBC): RACE-GB Study.

4016 Background: CT (gemcitabine plus cisplatin) is the standard of care for patients presenting with unresectable advanced GBC but their prognosis remains poor. The value of CTRT after CT is uncertain. We therefore conducted a randomised trial evaluating consolidation CTRT versus Observation after four cycles of CT in those patients whose disease did not progress during CT (NCT05493956). Methods: Responders (partial response and stable disease) to 4 cycles of CT were randomised to CTRT vs observation (n=135). CTRT was delivered by 3D-Conformal Radiation Therapy along-with concurrent capecitabine @1250 mg/m2. The dose of RT was 45 Gy in 25 fractions to GBC and lymphatics followed by a boost of 9 Gy in 5 fractions to the GBC. The primary endpoint was overall survival which was calculated from the date of randomisation. The trial is designed to detect an improvement in 2-year OS from 8% in the control arm to 25% in study arm with 80.0% power at a 0.05 significance level. The required sample size was 130 (65 in each arm) over a duration of 4-5 years. CTRT was delivered by 3DCRT along-with concurrent capecitabine @1250 mg/m2. The dose of RT was 45Gy in 25 fractions to GBC and lymphatics followed by a boost of 9 Gy in 5 fractions to the GBC. Toxicities documented during CT and CTRT were recorded using the CTCAE version 3.0. and RTOG criteria respectively. Chi square test and Survival analysis was performed for the data analysis. Demographic data and CTRT Dose volume data were correlated with side effects and survival. Statistical analysis was performed with SPSS version-23. Results: 67 patients were randomized to observation and 68 to CTRT. Their demographic characteristics were well balanced. 63% were women, 58% had T4 tumours, 42% had N2, 27% needed stenting for obstructive jaundice. The median overall survival in the CTRT arm was 10 months versus 4 months in the observation arm (HR 0.47 [95% CI 0.33-0.68] p=0.001). Adverse events (grade 3 or higher) due to CTRT included the following: Nausea 3%, Anemia 9%, GI bleed 6%, hepatotoxicity 13%. Updated survival data and prognostic factors affecting overall survival will be presented in the meeting. Conclusions: CTRT after 4 cycles of CT significantly prolonged overall survival but was also associated with adverse events. Clinical trial information: NCT05493956 .

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 .

Comparison of atezolizumab monotherapy to docetaxel with and without ramucirumab in patients with advanced non-small-cell lung cancer who received prior immunotherapy.

e21157 Background: Atezolizumab is superior to docetaxel for patients with advanced non-small-cell lung cancer (NSCLC) who are pretreated with platinum-based chemotherapy based on the POPLAR and OAK trials. However, patients who received prior immunotherapy (IO) were excluded from these trials. The preferred subsequent therapy for these patients remains to be docetaxel +/- ramucirumab. The efficacy and safety of atezolizumab as a subsequent therapy in IO-pretreated patients are unknown. Methods: We conducted a retrospective study of all patients with locally advanced/metastatic NSCLC who were pretreated with IO at Mayo Clinic Florida/Rochester in 2016 - 2022. Patients who received subsequent therapy of atezolizumab alone (Atezo), docetaxel (Doce), or docetaxel + ramucirumab (Doce+Ram) were included. Kaplan-Meier method and log-rank test were used for survival analysis. Results: Among 169 patients included, 51.5% were female, 91.7% were Caucasian. The median age was 67 (35 – 92). The histology was predominantly adenocarcinoma (76.3%). The most common metastatic sites were bone (51.5%), followed by CNS (44.4%). The median number of prior therapies was 2 (1 – 8). Pembrolizumab was the most used prior IO (87%), followed by durvalumab (10.7%) and nivolumab (8.3%). 13.6% (n = 23), 49.1% (n = 83), and 37.2% (n = 63) patients received subsequent Atezo, Doce, and Doce+Ram, respectively. PFS was improved in the Atezo group compared with Doce group (median PFS 3.9 vs. 3.7 months, HR 0.57, 95% CI 0.37 – 0.87, p = 0.015*). Notably, a prominent percentage of patients in the Atezo group appear to have long-term PFS benefits, demonstrated by 1-year PFS rates of 26.1%, 3.6%, and 4.8% (p = 0.003**), and 2-year PFS rates of 17.4%, 0%, and 0% (p = 0.002**), in the Atezo, Doce, and Doce+Ram groups, respectively. The median OS (months) in the Atezo, Doce, and Doce+Ram groups were 17.5, 7.6, and 11.5, respectively; and were 29.5, 7.2, and 6.9, respectively in the PD-L1 > 50% subgroups. The Atezo group showed significantly greater OS improvement compared with the Doce group (HR 0.42, 95% CI 0.26 – 0.66, p = 0.001**). This benefit appears greater and remains statistically significant in the PD-L1 > 1% (HR 0.39, 95% CI 0.22 – 0.71, p = 0.005**) and PD-L1 > 50% (HR 0.37, 95% CI 0.15 – 0.91, p = 0.022*) subgroups. 5 of 23 (21.7%) patients in the Atezo group developed immune-related adverse events. 3 patients were grade 3 or 4. No grade 5 event. Conclusions: We observed statistically significant and clinically meaningful PFS and OS benefits of atezolizumab monotherapy compared with docetaxel in patients with advanced NSCLC who were pretreated with IO. The OS benefits of atezolizumab over docetaxel +/- ramucirumab was greater in PD-L1 > 1% and PD-L1 > 50% subgroups. Atezolizumab appears to be tolerable in IO-pretreated patients. These findings need to be verified in a prospective study.

Abstract CT008: Pembrolizumab (pembro) in combination with gemcitabine and cisplatin (gem/cis) for advanced biliary tract cancer (BTC): Phase 3 KEYNOTE-966 study

Abstract Introduction: BTC has a poor prognosis despite available treatment. KEYNOTE-966 is a randomized, double-blind, phase 3 trial of pembro versus placebo in combination with gem/cis as first-line therapy for unresectable locally advanced or metastatic BTC (NCT04003636). Methods: Eligible patients (pts) with histologically confirmed, RECIST v1.1-measurable disease with no prior systemic therapy in the unresectable or metastatic setting were randomized 1:1 to pembro 200 mg or placebo administered IV on day 1 Q3W for ≤35 cycles added to gemcitabine 1000 mg/m2 administered IV on days 1 and 8 Q3W until disease progression and cisplatin 25 mg/m2 administered IV on days 1 and 8 Q3W for ≤8 cycles. Randomization was stratified by region (Asia vs non-Asia), stage (metastatic vs locally advanced), and tumor origin (gallbladder vs intrahepatic vs extrahepatic). The primary end point was OS. Secondary end points were PFS, ORR, and DOR per RECIST v1.1 by blinded independent central review and safety. Per protocol, the final analysis of PFS and ORR was at the first interim analysis (IA1; data cutoff, December 15, 2021). All other data are from the protocol-specified final analysis (FA; data cutoff, December 15, 2022). One-sided P-value boundaries for significance were 0.0200 for OS, 0.0125 for PFS, and 0.0125 for ORR. Results: 1069 pts were randomized to pembro + gem/cis (n = 533) or placebo + gem/cis (n = 536). Baseline characteristics were generally balanced between arms; 45.5% of pts were from Asia, 88.2% had metastatic disease, and 59.2% had intrahepatic origin. Median study follow-up was 25.6 mo (range 18.3-38.4) at FA. At FA, median (95% CI) OS was 12.7 mo (11.5-13.6) for pembro + gem/cis vs 10.9 mo (9.9-11.6) for placebo + gem/cis (HR 0.83; 95% CI 0.72-0.95; P = 0.0034); 24-mo OS was 24.9% vs 18.1%. OS results were generally consistent across subgroups. At IA1, median (95% CI) PFS was 6.5 mo (5.7-6.9) for pembro + gem/cis vs 5.6 mo (5.1-6.6) for placebo + gem/cis (HR 0.86; 95% CI 0.75-1.00; P = 0.0225); 12-mo PFS was 25.4% vs 19.8%. At IA1, ORR (95% CI) was 28.7% (24.9-32.8) for pembro + gem/cis vs 28.5% (24.8-32.6) for placebo + gem/cis (difference 0.2; 95% CI -5.2 to 5.6; P = 0.4735); median (range) DOR was 9.7 mo (1.2+ to 22.7+) vs 6.9 mo (0.0+ to 19.2+). Grade 3-5 AEs occurred in 85.3% of 529 pts treated in the pembro + gem/cis arm vs 84.1% of 534 treated in the placebo + gem/cis arm (drug related, 71.3% vs 69.3%). Grade 5 AE incidence was 5.9% vs 9.2% (drug related, 1.5% vs 0.6%). Potentially immune-mediated AEs and infusion reactions occurred in 22.1% vs 12.9%. Conclusion: Pembro + gem/cis provided a statistically significant, clinically meaningful OS improvement versus placebo + gem/cis in pts with previously untreated metastatic or unresectable BTC. The safety profile of pembro + gem/cis was as expected and manageable. These data support pembro + gem/cis as a new first-line treatment option in this setting. Citation Format: Robin Kate Kelley, Changhoon Yoo, Richard S. Finn, Junji Furuse, Zhenggang Ren, Thomas Yau, Heinz-Josef Klümpen, Stephen Lam Chan, Arndt Vogel, Masato Ozaka, Chris Verslype, Mohamed Bouattour, Joon Oh Park, Olga Barajas, Uwe Pelzer, Juan W. Valle, Li Yu, Usha Malhotra, Abby B. Siegel, Julien Edeline, Makoto Ueno. Pembrolizumab (pembro) in combination with gemcitabine and cisplatin (gem/cis) for advanced biliary tract cancer (BTC): Phase 3 KEYNOTE-966 study [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 CT008.

Efficacy of adjuvant radiation in early-stage cancers of buccal mucosa: an institutional experience.

The purpose of this study is to determine if depth of infiltration is the only risk factor that will determine the outcomes in early-stage buccal mucosa patients or do the other minor risk factors have an impact too. It is a retrospective analysis of 226 patients with early-stage buccal mucosa cancer who were treated with curative intent from 2010 to 2020. These patients were grouped in two arms, surgery alone (n = 111) and surgery followed by adjuvant radiotherapy (n = 115). Patients were followed up and local and regional recurrences and distant metastasis were recorded. Our results show that addition of radiation to the standard surgery arm improves overall survival and disease-free survival, though the improvement in overall survival was not statistically significant. This improvement was more pronounced in the depth of infiltration > 5mm and in 5mm or less depth of infiltration this benefit was not statistically significant. Other factors like perineural invasion, lymphovascular invasion, tumour size, node positive, margin positive were considered for univariate analysis. Although there was a trend towards improvement of OS and DFS, it was not statistically significant as far as these factors are concerned. The role of adjuvant radiation in early-stage cancers of buccal mucosa is a crucial tool with definitive DFS benefit and requires more prospective trials to answer the OS benefit.

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.

Evidence of clinical benefit of WHO essential anticancer medicines for children, 2011-2021.

Access to essential cancer medicines is a key determinant of childhood cancer survival. WHO published the Model List of Essential Medicine for Children (EMLc) and updated it every two years since 2007 to promote better access to medicines for children. This study aimed to assess whether the inclusion of essential anticancer medicines for respective indications for children was based on evidence of significant clinical benefit between 2011 and2021. We identified all anticancer medicine indications added to the WHO EMLc Section 8 since 2011 and extracted evidence of benefit documented in the corresponding technical reports. Evidence in children was defined as evidence that included participants under 12, and graded into five levels, according to the Oxford Centre for Evidence-Based Medicine Levels of Evidence. We analyzed whether each anticancer medicine indication was listed with documented OS benefit or improvements in surrogate measures based on the highest level of documented evidence in children. A total of 115 anticancer medicine indications were added to the EMLc from 2011 to 2021, of which 101 (87.8%) had some clinical evidence in children and 4 (3.5%) were added without any clinical evidence. Among the 101 medicine indications, none were added with level-1 evidence in children, and 43 (42.6%), 11 (10.9%), 41 (40.6%), and 6 (5.9%) were listed with level-2, level-3, level-4, and level-5 evidence in children, respectively. Only eight (7.9%) medicine indications were reported to have OS benefit, another 12 (11.9%) were reported to have improvements on surrogate measures, and 81 (80.2%) were listed in the EMLc without documented improvements in either OS or surrogate measures. Most anticancer medicine indications of the WHO EMLc were added based on limited evidence of statistically significant clinical benefit in children. Our results suggest that WHO should refine requirements for clinical benefit criteria and permissible forms, quality, and reporting of evidence of essential anticancer medicines for children, specify whether anticancer medicine indications have required evidence of clinical benefit in children, and provide further details in its technical reports that summarise the available evidence. Not applicable.

Anti-Claudin Treatments in Gastroesophageal Adenocarcinoma: Mainstream and Upcoming Strategies.

Claudins (CLDNs) are a multigene family of proteins and the principal components of tight junctions (TJs), which normally mediate cell-cell adhesion and selectively allow the paracellular flux of ions and small molecules between cells. Downregulation of claudin proteins increases the paracellular permeability of nutrients and growth stimuli to malignant cells, which aids the epithelial transition. Claudin 18.2 (CLDN18.2) was identified as a promising target for the treatment of advanced gastroesophageal adenocarcinoma (GEAC), with high levels found in almost 30% of metastatic cases. CLDN18.2 aberrations, enriched in the genomically stable subgroup of GEAC and the diffuse histological subtype, are ideal candidates for monoclonal antibodies and CAR-T cells. Zolbetuximab, a highly specific anti-CLDN18.2 monoclonal antibody, demonstrated efficacy in phase II studies and, more recently, in the phase III SPOTLIGHT trial, with improvements in both PFS and OS with respect to standard chemotherapy. Anti-CLDN18.2 chimeric antigen receptor (CAR)-T cells showed a safety profile with a prevalence of hematologic toxicity in early phase clinical trials. The aim of this review is to present new findings in the treatment of CLDN18.2-positive GEAC, with a particular focus on the monoclonal antibody zolbetuximab and on the use of engineered anti-CLDN18.2 CAR-T cells.

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]

Clinical benefit of granulocyte-colony stimulating factor (GCSF) use during chemoimmunotherapy treatment for metastatic pancreatic adenocarcinoma (mPDAC).

757 Background: GCSF is used for primary/secondary prophylaxis of chemotherapy(chemo)-associated neutropenia in patients (pts) with mPDAC. GCSF may also increase the populations of healthy, naïve immune cells in an otherwise immunologically dysregulated and cold environment, potentially augmenting therapy outcome with immunomodulatory (IO) agents. Here, we describe the impact of GCSF administration on OS, PFS, and time on treatment (TOT) in the setting of mPDAC for (1) a trial in which pts were administered chemo-IO combinations and (2) a synthetic control arm using retrospective real-world data from pts who received standard-of-care (SOC) chemo (PASCAL). Methods: PRINCE is a ph1b/2 study evaluating gemcitabine (gem) and nab-paclitaxel (NP) ± sotigalimab (sotiga; CD40 agonist) ± nivolumab (nivo; anti-PD1) for pts with mPDAC (NCT0324250), where prophylactic GCSF use was prohibited. PASCAL pts received SOC gem/NP and primary/secondary GCSF use was allowed. In this retrospective analysis, GCSF use was defined as receiving at least 1 dose of GCSF anytime during treatment. OS, PFS, and TOT and associated HRs and CIs were calculated using Kaplan-Meier and Cox methods. PFS data not available for PASCAL. Results: 32/123 (26%) and 16/68 (24%) pts received GCSF in PRINCE and PASCAL, with 84% and 88% of pts receiving at least 1 dose within the first 3 cycles, respectively. In PRINCE, GCSF use was associated with significant improvements in OS (HR [95% CI]: 0.62 [0.40-0.97]), PFS (0.71 [0.47-1.08]), and TOT (0.67 [0.45-1.01]). These improvements were most notable in the sotiga-containing arms (table). In the absence of IO treatment, however, no statistical significance was observed in PASCAL (HR [95% CI]: OS = 0.81 [0.44-1.51]; TOT = 0.90 [0.51-1.58]). Additional work is ongoing to understand the association of GCSF usage with known prognostic factors. Conclusions: These analyses suggest that GCSF use may enhance the clinical benefits of chemo-IO in mPDAC. These potential benefits of GCSF usage warrant further evaluation in other chemo-IO trials as well as prospective evaluation in pre-clinical and clinical settings. Clinical trial information: NCT03214250 . [Table: see text]

Rationale 305: Phase 3 study of tislelizumab plus chemotherapy vs placebo plus chemotherapy as first-line treatment (1L) of advanced gastric or gastroesophageal junction adenocarcinoma (GC/GEJC).

286 Background: In a phase 2 study, tislelizumab (TIS), an anti-PD-1 monoclonal antibody, plus chemotherapy demonstrated durable antitumor activity as 1L in Chinese GC/GEJC patients (Xu et al, 2020). RATIONALE 305 (NCT03777657) was a global, double-blind, phase 3 study comparing 1L TIS plus investigator-chosen chemotherapy (TIS+ICC) vs placebo plus ICC (P+ICC) in GC/GEJC patients. Results from the interim analysis (IA) in the PD-L1+ population are presented; ITT population outcomes will be presented after final analysis. Methods: Adults with previously untreated, unresectable locally advanced or metastatic GC/GEJC, regardless of PD-L1 expression, were randomized (1:1) to receive TIS (200 mg IV Q3W) plus ICC (oxaliplatin [130 mg/m² IV Q3W] and oral capecitabine [1,000 mg/m² BID, Days 1-14 Q3W] or cisplatin [80 mg/m² IV Q3W] and 5-fluorouracil [800 mg/m²/day IV, Days 1-5 Q3W]) or P+ICC. Randomization was stratified by region, PD-L1 expression, peritoneal metastasis, and ICC. Patients with known HER2-positive status were excluded. RATIONALE 305 had dual primary endpoints of OS in the PD-L1+ and ITT analysis set; PD-L1+ was defined as PD-L1 TAP score ≥5% (VENTANA SP263 assay) assessed by blinded independent central laboratory. Secondary endpoints include PFS, ORR and DoR per RECIST 1.1, HRQoL, and safety profile. The prespecified IA was conducted after ~70% of total OS events had occurred. Results: Of 546 PD-L1+ patients enrolled from 13 counties/regions (73.8 % Asia; 26.2% Europe/ North America), 274 were randomized to receive TIS+ICC and 272 to receive P+ICC. As of 8 Oct 2021, median follow-up was 11.8 (TIS+ICC) and 11.7 mo (P+ICC). TIS+ICC showed statistically significant and clinically meaningful OS improvement vs P+ICC (HR 0.74 [95% CI: 0.59-0.94], mOS 17.2 vs 12.6 mo; 1-sided P= .0056). Compared with P+ICC, TIS+ICC also had longer PFS (mPFS 7.2 vs 5.9 mo; HR 0.67 [95% CI: 0.55-0.83]), higher ORR (50.4% vs 43.0%), and more durable response (mDoR 9.0 vs 7.1 mo). Patients treated with TIS+ICC reported better HRQoL than patients treated with P+ICC, as indicated by EORTC-QLQ-C30 global health status and physical functioning scores as well as the QLQST022 index score. No new safety signals were observed with TIS+ICC or P+ICC. While TEAEs leading to discontinuation of any treatment were higher with TIS+ICC than P+ICC (22.4% vs 12.1%), incidence rates of grade ≥3 TEAEs (64.7% vs 62.9%), serious TEAEs (42.3% vs 36.8%), and TEAEs leading to death (8.8% vs 7.7%) were comparable between both arms. Conclusions: In RATIONALE 305, TIS+ICC provided significant and clinically meaningful improvement in OS vs P+ICC with well acceptable safety as 1L in PD-L1+ patients with advanced GC/GEJC. These data suggest this combination is a new 1L option for this patient population. Clinical trial information: NCT03777657 .

Phase II trial of durvalumab (MEDI4736) with/without tremelimumab for advanced hepatocellular carcinoma after palliative hypofractionated radiotherapy.

TPS630 Background: Hepatocellular Carcinoma (HCC) is among the most common types and leading causes of cancer death globally, and the incidence is on the rise. For patients with advanced hepatocellular carcinoma (HCC), immune checkpoint inhibitors (ICI) in combination with anti-angiogenic agents or other ICI improve survival compared with tyrosine kinase inhibition. Though ICI-based regimens can achieve prolonged responses in some patients and prolong overall survival, only a subset of patients achieve durable responses. There is an urgent need for strategies to overcome primary and acquired resistance. Many of these patients have symptomatic sites of disease which could benefit from local palliative radiotherapy. Radiotherapy also has the potential to elicit an abscopal immune response when combined with ICI. We hypothesize that combining Radiation Treatment (RT) with Durvalumab or the combination of Durvalumab + Tremelimumab (combination D+T in STRIDE regimen showed OS improvement in HIMALAYA trial in 1st line HCC) will achieve a meaningful response rate in advanced HCC patients after progression on other ICI-based therapies. Methods: This is an open label, single center, two-arm, non-comparative phase II trial. Key eligibility criteria are; histologically-diagnosed HCC with progression during or after prior PD-(L)1 checkpoint inhibitor immunotherapy and at least 1 RECIST 1.1-measurable tumor present which has not received RT or other local therapy prior to enrollment, ECOG 0-1, and Child Pugh score of A, B7, or B8. Patients are assigned sequentially to either single-agent durvalumab initiated starting 3 to 10 days after completing RT (25 Gy in 5 fractions to 1-5 sites of disease), at fixed dose of 1500 mg IV every 28 days, or a single fixed dose of tremelimumab of 300 mg IV administered on Day 1, initiated within 3-10 days of completing RT, in combination with durvalumab at fixed dose of 1500 mg IV every 28 days; for up to 24 months or until confirmed radiographic progression. The primary end point is overall response rate (ORR) and secondary endpoints include proportion of participants with adverse events, overall survival, progression free survival and duration of response. Exploratory endpoints include profiling of peripheral blood mononuclear cell immune cells and plasma biomarkers. We plan to accrue 30 patients to this study, 15 to each Arm, to evaluate ORR which would allow us to detect at least a 20% ORR, which would be a clinically meaningful improvement in efficacy in this population with otherwise poor treatment options assuming a statistical power of 87% and a directional 5% statistical significance level based upon an exact binomial test. The trial is open and enrolling. Clinical trial information: NCT04430452 .

Effectiveness of Hyperthermic Intraperitoneal Chemotherapy Associated with Cytoreductive Surgery in the Treatment of Advanced Ovarian Cancer: Systematic Review and Meta-Analysis.

The use of hyperthermic intraperitoneal chemotherapy (HIPEC) as a treatment for epithelial ovarian cancer remains controversial. Our study aims to analyze the overall survival and disease-free survival for the use of HIPEC as a treatment for advanced epithelial ovarian cancer after neoadjuvant chemotherapy. A systematic review and meta-analysis was carried out using PubMed, Cochrane, Web of Science, and ClinicalTrials.gov. A total of six studies were used, comprising a total of 674 patients. The results of our meta-analysis of all studies analyzed together (observational and randomized controlled trials (RCT)) did not achieve significant results. Contrary to the OS (HR = 0.56, 95% IC = 0.33-0.95, p = 0.03) and DFS (HR = 0.61, 95% IC = 0.43-0.86, p < 0.01) of the RCT analyzed separately, a clear impact on survival was suggested. The subgroup analysis showed that studies making use of higher temperatures (≥42 °C) for a shorter period of time (≤60 min) achieved better results for both OS and DFS, as well as the use of cisplatin as the form of chemotherapy in HIPEC. Moreover, the use of HIPEC did not increase high-grade complications. The addition of HIPEC to cytoreductive surgery demonstrates an improvement in OS and DFS for patients with epithelial ovarian cancer in advanced stages, without an increase in the number of complications. The use of cisplatin as chemotherapy in HIPEC obtained better results.

HRAS Mutations Define a Distinct Subgroup in Head and Neck Squamous Cell Carcinoma

In head and neck squamous cell carcinoma (HNSCC), HRAS mutation is a new actionable oncogene driver. We aimed to evaluate HRAS mutational variants, comutation profile, and survival outcomes of this molecularly defined population. We leveraged four deidentified patient data sets with HRAS-mutant HNSCC, MD Anderson Cancer Center, Kura Oncology, Inc trial, Foundation Medicine, and American Association for Cancer Research GENIE v.12. Patient demographic information and clinical courses were extracted, when available, in addition to HRAS mutation type and co-occurring mutations. Survival outcomes were analyzed (Kaplan-Meier method). Two hundred forty-nine patients with HRAS-mutant HNSCC were identified from the four data sets. Median age ranged from 55 to 65 years, with a higher frequency in male patients (64%); the majority of HRAS-mutant HNSCC occurred in human papillomavirus-negative HNSCC. HRAS mutation patterns were similar across data sets; G12S was the most common (29%). Treatment responses to tipifarnib were not codon-specific. Compared with wild-type, significantly co-occurring mutations with HRAS were Casp8 (Fisher's exact test, P < .00013), TERT (P < .0085), and NOTCH1 (P < .00013). Analysis of clinical courses from the MD Anderson Cancer Center and Kura Oncology, Inc data sets demonstrated poor clinical outcomes with a high rate of recurrence following primary definitive treatment (50%-67% relapse < 6 months) and short disease-free survival (4.0 months; 95% CI, 1.0 to 36.0) and overall survival (OS; 15.0 months; 95% CI, 6.0 to 52.0). Use of tipifarnib in this data set demonstrated improved OS (25.5 months; 95% CI, 18.0 to 48.0). Oncogenic mutations in HRAS occur in 3%-4% of HNSCC, with G12S being the most frequent. Without targeted therapy, patients with HRAS-mutant HNSCC had poor clinic outcomes; observable trend toward improvement in OS has been noted in cohorts receiving treatments such as tipifarnib. The comutation pattern of HRAS-mutant in HNSCC is distinct, which may provide insight to future therapeutic combination strategies.

Treating accelerated and blast phase myeloproliferative neoplasms: progress and challenges.

Myeloproliferative neoplasms (MPNs) are a group of clonal hematologic malignancies that include polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis (MF). MPNs are characterized by activating mutations in the JAK/STAT pathway and an increased risk of transformation to an aggressive form of acute leukemia, termed MPN-blast phase (MPN-BP). MPN-BP is characterized by the presence of ⩾20% blasts in the blood or bone marrow and is almost always preceded by an accelerated phase (MPN-AP) defined as ⩾10-19% blasts in the blood or bone marrow. These advanced forms of disease are associated with poor prognosis with a median overall survival (mOS) of 3-5 months in MPN-BP and 13 months in MPN-AP. MPN-AP/BP has a unique molecular landscape characterized by increased intratumoral complexity. Standard therapies used in de novo acute myeloid leukemia (AML) have not demonstrated improvement in OS. Allogeneic hematopoietic stem cell transplant (HSCT) remains the only curative therapy but is associated with significant morbidity and mortality and infrequently utilized in clinical practice. Therefore, an urgent unmet need persists for effective therapies in this advanced phase patient population. Here, we review the current management and future directions of therapy in MPN-AP/BP.

Dual immune checkpoint inhibitors or combined with anti-VEGF agents in advanced, unresectable hepatocellular carcinoma

BackgroundImmune checkpoint inhibitor monotherapy did not show superiority of survival over standard therapy in advanced hepatocellular carcinoma. The combination immunotherapy including dual immune checkpoint inhibitors or combined with anti-VEGF agents have become a trend, but not fully evaluated. This study aimed to evaluate and compare distinct combination immunotherapy on efficacy in advanced hepatocellular carcinoma. MethodsPubMed, Embase, Web of Science and Cochrane databases were systematically searched from inception to January 31, 2022. The primary endpoints were overall objective response rate (ORR), disease control rate (DCR), six-month progression-free survival rate (PFSR6m) and one-year overall survival rate (OSR1y). Results11 studies with 16 independent cohorts and 3342 patients were included in the meta-analysis. Compared with first-line sorafenib, combination immunotherapy resulted in a significant improvement in ORR (RR, 2.74; 95%CI, 1.55–4.85; p = 0.0006), PFS (HR, 0.57; 95%CI, 0.49–0.65; p<0.0001) and OS (HR, 0.65; 95%CI, 0.52–0.82; p = 0.0002). Based on RECIST 1.1, the pooled ORR, PFSR6m and OSR1y for combination immunotherapy were 24.6% (95%CI: 20.3%-29.6%), 42.0% (95%CI: 34.2%-50.3%) and 61.8% (95%CI: 57.7%-65.7%), respectively. In distinct combination regimens, PD-1/L1 inhibitors plus anti-VEGF agents showed a significant superiority of clinical benefit than PD-1/L1 inhibitors plus CTLA-4 inhibitors (ORR: 25.2% vs 23.4%, p = 0.033; PFSR6m: 47.4% vs 23.2%, p<0.001; OSR1y: 65.1% vs 55.0%, p = 0.001). ConclusionsThis study was the first meta-analysis to demonstrate the better survival benefit and tolerable toxicity of combination immunotherapy than standard therapy in advanced hepatocellular carcinoma. Compared with PD-1/L1 inhibitors plus CTLA-4 inhibitors, the regimens of PD-1/L1 inhibitors plus anti-VEGF agents may be associated with a significantly better clinical benefit. The difference in long-term survival and response population between two distinct combination regimens required further exploration.