Disease-free Survival Benefit Research Articles

296P Osimertinib as adjuvant therapy in patients (pts) with resected EGFR-mutated (EGFRm) stage IB-IIIA non-small cell lung cancer (NSCLC): Updated results from ADAURA

Osimertinib is a third-generation EGFR-tyrosine kinase inhibitor (EGFR-TKI) that potently and selectively inhibits EGFR-TKI sensitising and EGFR T790M resistance mutations. It has efficacy in EGFRm NSCLC, including in central nervous system (CNS) metastases. In the Phase III ADAURA (NCT02511106) primary analysis adjuvant osimertinib showed a significant and clinically meaningful disease-free survival (DFS) benefit vs placebo (PBO) in pts with completely resected EGFRm (ex19del/L858R) NSCLC, ± adjuvant chemotherapy (CT): stage IIꟷIIIA DFS HR, 0.17; 99.06% CI, 0.11, 0.26; p<0.0001; stage IBꟷIIIA DFS HR, 0.20; 99.12% CI 0.14, 0.30; p<0.0001.

DKK1 as a robust predictor for adjuvant platinum chemotherapy benefit in resectable pStage II-III gastric cancer

BackgroundAdjuvant chemotherapy (ACT) with 5-FU alone or 5-FU plus platinum after curative surgery improves the prognosis of pStage II-III gastric cancer (GC). However, only a subset of patients benefits from adjuvant platinum. To avoid the side effects of platinum, it is significant to accurately screen the patients who would benefit maximally with this treatment. The present study aimed to assess the value of DKK1 in predicting the benefit of adjuvant platinum chemotherapy in patients with pStage II -III GC. MethodsPlatinum sensitivity-related genes were screened by bioinformatics. DKK1 expression in 380 GC specimens was detected by immunohistochemistry (IHC) staining, and the correlation with adjuvant platinum-specific benefits were analyzed. ResultsDKK1 was screened as the most significant platinum sensitivity-related gene. In patients with DKK1high GC, the estimated absolute 5-year overall survival (OS) benefits from adjuvant platinum for pStage II-III, II, IIIA, IIIB, and IIIC were 25.5%, 17.3%, 36.4%, 29.2% and 31.1%, respectively, and the estimated absolute 5-year disease-free survival (DFS) benefits in the corresponding stages were 27.4%, 17.5%, 36.7%, 29.7% and 31.5%, respectively. These benefits were significantly higher than those in the same TNM stage without adjusting for DKK1 status. The performance of DKK1 was independent of the TNM stage and other clinicopathological variables. Similar results were obtained in the TCGA and ACRG cohorts. Furthermore, nomograms were constructed to predict the survival benefits in DKK1 subgroups. ConclusionsThe stratification strategy based on DKK1 status is more precise than the TNM staging system for the selection of pStage II-III GC patients suitable for platinum-containing ACT.

304TiP Minimal residual disease (MRD)-guided adjuvant tislelizumab after adjuvant chemotherapy in resected stage IIA-IIIB non-small cell lung cancer (NSCLC): A single-arm phase II study (Seagull)

Emerging data have shown the potential for circulating tumor DNA(ctDNA)-based MRD status to predict clinical recurrence in patients(pts) with stage I-III NSCLC. Moreover, research have shown that detection of ctDNA preceded radiographic progression by a median of 5.2 months. IMpower010 have shown a disease-free survival(DFS) benefit with atezolizumab versus best supportive care after adjuvant chemotherapy in patients with resected stage II–IIIA NSCLC. Tislelizumab, an anti-PD-1 mAb, has shown improved efficacy in patients with advanced NSCLC with a tolerable safety profile.

Radiotherapy Dose Received by the Internal Mammary Chain Lymph Nodes in Cases with Relapse at this Site: A Case-Control Study

<h3>Purpose/Objective(s)</h3> Studies of sentinel lymph node biopsy of internal mammary nodes (IMN) in breast cancer show a 15% positivity rate, if untreated these may serve as a reservoir for regional recurrence (RR) and/or distant metastases. Randomized clinical trials examining the benefit of IMN radiotherapy (RT) haven't demonstrated an overall survival or disease-free survival benefit. However, in one study an ad hoc sub-analysis of patients with inner/central tumors showed a 7-year breast cancer mortality of 10.2% without IMNRT and 4.9% with IMNRT (Kim Y. JAMA Oncol 2022;8(1):96-105). IMNs often get some incidental dose from tangent RT, but this dose isn't known and we hypothesize that it might diminish the apparent benefit of deliberate IMNRT. <h3>Materials/Methods</h3> Patients diagnosed with non-metastatic breast cancer between 2005 and 2014, who relapsed with IMN disease, were identified in a population-based database. They were matched 1:3 by age, diagnosis year, pathological features and treatment received. An IMN CTV was outlined on planning CT scans covering the internal mammary vessels in the first 3 intercostal spaces. The equivalent dose in 2 Gy fractions to the IMNs was calculated to account for different RT prescriptions. A two-sample t-test and Cox regression analysis were used to evaluate the effect of IMN dose as a continuous variable on RR and breast cancer-specific survival (BCSS). <h3>Results</h3> 70 patients with IMN relapse were identified and 210 cases without relapse were matched. Median follow up was 10.8 years and median age 59 years. The matching of relapse and non-relapse cases, respectively, gave well balanced cohorts: most were pT2 (47.1% and 47.6%), pN2 and pN3 comprised 25.7% and 20.5% and tumor location was inner/central in 35.3% and 35.2%. RT was delivered to 43 (61.4%) relapse patients and 130 (61.9%) matched patients with 11 (15.7%) and 52 (24.8%) receiving intentional IMN coverage. The mean IMN dose was 44.9 Gy (94.1%) for intentional coverage and 13.3 Gy (28.3%) for incidental coverage. The average minimum dose to the IMNs was 6.8 Gy (14.4%) for the relapse cases and 14.7 Gy (31.0%) for the matches (p = 0.008). The average mean dose to the IMNs was 18.4 Gy (38.7%) for the relapse cases and 26.9 Gy (56.7%) for the matches (p <0.001). For the whole cohort, Cox regression modelling showed that the mean IMN dose was not significantly associated with RR (HR 0.87, 95% CI 0.74-1.02, p=0.08) or BCSS (HR 0.94, 95% CI 0.82-1.09, p=0.4). Similar results were shown for an N2/N3 subset, RR (HR 0.80, 95% CI 0.62-1.03, p=0.08) and BCSS (HR 0.86, 95% CI 0.70-1.07, p=0.2), and for a subset with inner/central tumors, RR (HR 0.87, 95% CI 0.65-1.17, p=0.4) and BCSS (HR 0.99, 95% CI 0.78-1.25, p=1.0). <h3>Conclusion</h3> Patients with IMN relapse received significantly lower mean IMN doses than those without IMN relapse, however, our sample size did not show a difference in clinical outcomes. The impact on IMN relapse from incidental RT dose should be considered when planning future studies in this field.

Effect of Postmastectomy Radiotherapy in Breast Cancer Patients according to Pathologic Nodal Status and Molecular Subtype after Neoadjuvant Chemotherapy

<h3>Purpose/Objective(s)</h3> The role of post-mastectomy radiation therapy (PMRT) in breast cancer patients who have achieved ypN0 after neoadjuvant chemotherapy (NAC) has not yet been established. This study aimed to evaluate the benefit of PMRT according to pathologic node status and molecular subtype in breast cancer patients who were treated NAC. <h3>Materials/Methods</h3> We retrospectively reviewed 511 patients with clinical stage II-III breast cancer who underwent NAC and mastectomy at our institution from 2013 to 2017. After mastectomy, ypN+ and ypN0 were identified in 289 (56.6%) and 222 (43.4%), respectively. In this study, molecular subtypes were classified according to hormone receptor (HR) and HER2 receptors as follows: luminal (HR+/HER2-), luminal-HER2 (HR+/HER2+), HER2 enriched (HR-/HER2+), triple-negative (HR -/HER2-). All HER2-positive patients were treated with trastuzumab-containing NAC. Of the total patients, 448 (87.7%) received PMRT and 63 (12.3%) did not. In ypN+ patients, PMRT was performed in 265 (91.7%) and 24 (8.3%) did not. In ypN0 patients, PMRT was performed in 183 (82.4%) and 39 (17.6%) did not. The effect of PMRT on locoregional recurrence-free survival (LRRFS), disease-free survival (DFS), and overall survival (OS) was evaluated based on pathologic nodal status and molecular subtypes. <h3>Results</h3> The median follow-up duration was 58 months. The cumulative incidence of locoregional recurrence and distant metastasis were 11.8% and 31.5% in ypN+ patients, and 6.8% and 13.5% in ypN0 patients, respectively. In ypN+ patients, PMRT showed significant benefit for LRRFS, DFS, and OS in multivariate analysis (all P < 0.001). In ypN0 patients, triple-negative subtype and lymphovascular invasion were significant prognostic factors for LRRFS (all P < 0.001) and DFS (P = 0.002 and P < 0.001, respectively) by multivariate analysis. However, in ypN0 patients, PMRT was not significantly associated with LRRFS, DFS, and OS. In addition, PMRT showed no significant difference in LRRFS in all molecular subtypes of ypN0 patients. <h3>Conclusion</h3> PMRT should be performed in patients with residual lymph node following NAC and mastectomy. Although a limited number of patients, this study suggests that the role of PMRT in ypN0 patients regardless of subtype remains unclear.

LBA47 Osimertinib as adjuvant therapy in patients (pts) with resected EGFR-mutated (EGFRm) stage IB-IIIA non-small cell lung cancer (NSCLC): Updated results from ADAURA

Osimertinib is a third-generation EGFR-tyrosine kinase inhibitor (EGFR-TKI) that potently and selectively inhibits EGFR-TKI sensitising and EGFR T790M resistance mutations. It has efficacy in EGFRm NSCLC, including in central nervous system (CNS) metastases. In the Phase III ADAURA (NCT02511106) primary analysis adjuvant osimertinib showed a significant and clinically meaningful disease-free survival (DFS) benefit vs placebo (PBO) in pts with completely resected EGFRm (ex19del/L858R) NSCLC, ± adjuvant chemotherapy (CT): stage IIꟷIIIA DFS HR, 0.17; 99.06% CI, 0.11, 0.26; p<0.0001; stage IBꟷIIIA DFS HR, 0.20; 99.12% CI 0.14, 0.30; p<0.0001. We report updated exploratory analyses of DFS and recurrence patterns after 2 yrs added follow up. Eligible pts (aged ≥18 yrs [≥20 in Japan/Taiwan], WHO PS 0/1, completely resected EGFRm stage IBꟷIIIA [AJCC 7th edition] NSCLC; adjuvant CT allowed) were randomised 1:1 to osimertinib 80 mg once daily or PBO for up to 3 yrs. Primary endpoint: investigator-assessed DFS in stage IIꟷIIIA. Secondary endpoints: DFS in stage IBꟷIIIA, overall survival and safety. Patterns of recurrence and CNS DFS were pre-specified exploratory endpoints. Data cut-off: 11 April 2022. Globally, 682 pts were randomised; osimertinib n=339, PBO n=343. In this updated analysis, in pts with stage IIꟷIIIA disease DFS HR was 0.23 (95% CI 0.18, 0.30; 242/470 events; 51% maturity); 3-yr DFS rate was 84% with osimertinib vs 34% with PBO. In the overall population (stage IBꟷIIIA) DFS HR was 0.27 (95% CI 0.21, 0.34; 305/682 events); 3-yr DFS rate was 85% with osimertinib vs 44% with PBO. In the osimertinib arm, fewer pts experienced local/regional and distant recurrence vs PBO. CNS DFS HR was 0.24 (95% CI 0.14, 0.42; 63/470 events) in stage IIꟷIIIA. The long-term safety profile remains consistent with the known profile of osimertinib. With 2 yrs further follow-up, a continued DFS benefit was sustained with osimertinib vs PBO, consistent with the primary analysis. These mature data reinforce adjuvant osimertinib as standard of care for pts with EGFRm stage IB–‍IIIA NSCLC after complete tumour resection and adjuvant CT, when indicated.

PL03.09 IMpower010:Overall Survival Interim Analysis of a Phase III Study of Atezolizumab vs Best Supportive Care in Resected NSCLC

IMpower010 (NCT02486718) was the first Phase III immunotherapy study to show a statistically significant disease-free survival (DFS) benefit with adjuvant atezolizumab vs best supportive care (BSC) in resected NSCLC following platinum-based chemotherapy (Felip et al. Lancet 2021). Based on these findings, atezolizumab was approved as adjuvant treatment after resection and platinum-based chemotherapy in patients with programmed death-ligand 1 (PD-L1) tumour cell (TC) ≥1% stage II-IIIA NSCLC in the US, China, and other countries; and in PD-L1 TC ≥50% stage II-IIIA NSCLC in the EU and other countries The key secondary OS endpoint was not mature at the IMpower010 DFS interim analysis (IA) but is of considerable clinical interest in this curative setting.

P1.06-01 Adjuvant Osimertinib vs Placebo in Completely Resected Stage IA2-IA3 EGFR-mutated NSCLC: The ADAURA2 Phase III Study

Management of patients with stage IA epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) is currently restricted to observation following complete tumor resection. No widely approved systemic adjuvant therapy has demonstrated a disease-free survival (DFS) or overall survival (OS) benefit in this setting. Approximately 25ꟷ30% of patients with stage IA NSCLC will have recurrent disease within 5 years, often involving distant metastases. Osimertinib is a third-generation, central nervous system (CNS)-active EGFR-tyrosine kinase inhibitor (TKI) selective for EGFR-TKI sensitizing and EGFR T790M resistance mutations.

EP04.01-017 Cost-Effectiveness of Atezolizumab for Adjuvant Treatment of Patients with Stage II-IIIA PD-L1+ Non-small Cell Lung Cancer

Chemotherapy was the historical standard of care for adjuvant treatment of early-stage resectable NSCLC. Atezolizumab demonstrated a significant disease-free survival (DFS) benefit versus best supportive care (BSC) as adjuvant treatment following resection and platinum-based chemotherapy for adults with stage II-IIIA (AJCC 7th edition) NSCLC and PD-L1 expression on ≥1% of tumor cells (PD-L1+). This regimen was FDA-approved based on the randomized, open-label, phase 3 IMpower010 clinical trial (NCT02486718). Understanding the economic impact of therapeutic innovations is essential to prioritizing healthcare resources. This study evaluated the cost-effectiveness of atezolizumab vs BSC in this setting from a US commercial payer perspective.

Outcomes and prognostic factors of cytoreductive surgery and perioperative intraperitoneal chemotherapy in high-volume peritoneal carcinomatosis

Background and objectives The management of patients with extensive appendiceal mucinous neoplasms and mesothelioma is controversial. Our aims were to analyze overall survival (OS), disease-free survival (DFS) and independent prognostic factors associated with high peritoneal cancer index (PCI) status in patients who underwent cytoreductive surgery (CRS) and perioperative intraperitoneal chemotherapy (PIC). Methods A prospectively-maintained database for patients with appendiceal neoplasms and mesothelioma undergoing CRS/PIC from year 1996 to 2018 was retrospectively analyzed. Patients who achieved complete cytoreduction were stratified into limited (PCI < 30) and extensive (PCI ≥ 30) disease groups. Results 260 female and 235 male patients were identified. The 5-year survival for low-grade appendiceal mucinous neoplasms (LAMN) was significantly higher in the low PCI group (96.2% vs. 63.5%, p < 0.001). There was no difference in the OS across both groups in high-grade appendiceal mucinous neoplasms (HAMN) (63 vs. 69 months; p = 0.942) and mesothelioma (72 vs. 42 months; p = 0.058). Overall mortality was 2%. Grade III/IV complications were significantly higher in extensive disease (68% vs. 36.6%, p < 0.001). On multivariate analysis, use of EPIC and blood transfusion (>8 units) were independent positive and negative prognostic factors, respectively, associated with OS. Meanwhile, use of EPIC conferred benefit in DFS while increased blood transfusion (>8 units) and elevated preoperative CA125 were predictive of a poor DFS. Conclusion Long-term survivals following CRS/PIC are achievable with acceptable mortality and higher morbidity rates in extensive appendiceal mucinous neoplasms and mesothelioma. High PCI status does not preclude treatment with CRS/PIC.

Evaluation of the prognostic value of lymphadenectomy in low-grade serous ovarian cancer: A case-control multicenter retrospective study (177)

Objectives: To evaluate the effect of lymphadenectomy on clinical outcome in patients with low-grade serous ovarian cancer (LGSOC). Methods: The study mainly included patients with LGSOC whose initial treatment was surgery. Disease-free survival (DFS) and overall survival (OS) was selected as primary endpoints. Propensity score matching (PSM) algorithm was used to balance the basic characteristics of patients with lymphadenectomy or not, and the Kaplan-Meier analysis was used to evaluate the impact of clinical prognosis. Finally, univariate and multivariate Cox proportional hazards regression analyses were performed to analyze the high-risk factors associated with clinical prognosis. Results: A total of 147 women from four medical centers were enrolled. In the before matching cohort, 101 (68.7%) patients underwent lymphadenectomy. Fifty-two (35.4%) patients experienced recurrence, and 25 (17%) patients died. Kaplan-Meier analysis showed no significant difference in DFS (p=0.058) and OS (p=0.067) in the after-matching cohort. Cox proportional hazard regression analysis showed that age (p=0.012), FIGO stage (p=0.031), and effective cytoreductive surgery (p=0.044) were three high-risk factors associated with recurrence. Age (p=0.031) and effective cytoreductive surgery (p=0.009) were two high-risk factors associated with death. Conclusions: Lymphadenectomy seems not to provide a significant benefit in neither DFS nor OS in our study. Age, the FIGO stage, and effective cytoreductive surgery are high-risk factors associated with clinical prognosis in LGSOC patients. Objectives: To evaluate the effect of lymphadenectomy on clinical outcome in patients with low-grade serous ovarian cancer (LGSOC). Methods: The study mainly included patients with LGSOC whose initial treatment was surgery. Disease-free survival (DFS) and overall survival (OS) was selected as primary endpoints. Propensity score matching (PSM) algorithm was used to balance the basic characteristics of patients with lymphadenectomy or not, and the Kaplan-Meier analysis was used to evaluate the impact of clinical prognosis. Finally, univariate and multivariate Cox proportional hazards regression analyses were performed to analyze the high-risk factors associated with clinical prognosis. Results: A total of 147 women from four medical centers were enrolled. In the before matching cohort, 101 (68.7%) patients underwent lymphadenectomy. Fifty-two (35.4%) patients experienced recurrence, and 25 (17%) patients died. Kaplan-Meier analysis showed no significant difference in DFS (p=0.058) and OS (p=0.067) in the after-matching cohort. Cox proportional hazard regression analysis showed that age (p=0.012), FIGO stage (p=0.031), and effective cytoreductive surgery (p=0.044) were three high-risk factors associated with recurrence. Age (p=0.031) and effective cytoreductive surgery (p=0.009) were two high-risk factors associated with death. Conclusions: Lymphadenectomy seems not to provide a significant benefit in neither DFS nor OS in our study. Age, the FIGO stage, and effective cytoreductive surgery are high-risk factors associated with clinical prognosis in LGSOC patients.

Educational Review: Neoadjuvant Approaches to Melanoma.

With the development of novel systemic therapies, the treatment of patients with melanoma has changed drastically over the past few years, especially with regard to neoadjuvant treatments. Standard of care for patients with resectable stage III/IV melanoma traditionally consisted of surgery, with possible adjuvant treatment. However, there have been promising improvements in patient outcomes with neoadjuvant treatment compared to upfront surgery, specifically with targeted and immune therapies. A review of clinical trials in the neoadjuvant treatment of stage III/IV melanoma was performed. Multiple phase I-II clinical trials have investigated the utility of interferon, targeted therapies (i.e., BRAF and/or MEK inhibitors) and immune checkpoint inhibitors (i.e., PD-1 or CTLA-4 inhibitors) in the treatment of resectable clinical stage III/IV melanoma. Large strides have been made with regards to optimal treatment strategy and dosing, to maximize clinical and pathologic response rates while minimizing toxicities. Additionally, complete pathologic response to neoadjuvant therapies translates to a disease-free survival benefit. Current and future directions include individualizing surgical and adjuvant therapy based on patient response to neoadjuvant treatments. The current evidence, represented by small phase I-II trials, demonstrates advantages to neoadjuvant treatment with targeted or immune therapy for patients with resectable stage III/IV melanoma. Future research is needed to determine the advantages of neoadjuvant compared to adjuvant treatment, and to further refine treatment strategies based on patient response.

Evolving Role of Adjuvant Systemic Therapy for Kidney and Urothelial Cancers.

The role of adjuvant therapy in renal cell carcinoma and urothelial carcinoma is rapidly evolving. To date, the U.S. Food and Drug Administration has approved sunitinib and pembrolizumab in the adjuvant setting for renal cell carcinoma and nivolumab for urothelial carcinoma based on disease-free survival benefit. The U.S. Food and Drug Administration held a joint workshop with the National Cancer Institute and the Society of Urologic Oncology in 2017 to harmonize design elements, including eligibility and radiologic assessments across adjuvant trials in renal cell carcinoma and urothelial carcinoma. Considerations from the discussion at these workshops led the U.S. Food and Drug Administration to draft guidances to help inform subsequent adjuvant trial design for renal cell carcinoma and urothelial carcinoma. Patient-centered decision-making is crucial when determining therapeutic choices in the adjuvant setting; utility functions can be used to help quantify each patient's goals, values, and risk/benefit trade-offs to ensure that the decision regarding adjuvant therapy is informed by their preferences and the evolving outcomes data.

PS1-5 IMpower010: results from Asian patients in a phase 3 study of adjuvant atezolizumab in resected stage IB-IIIA NSCLC

The Ph 3 IMpower010 study (NCT02486718) met its primary endpoint, showing significant disease-free survival (DFS) benefit with atezo vs best supportive care (BSC) after adjuvant chemo in patients (pts) with completely resected stage II-IIIA NSCLC (HR 0.79 95% CI 0.64, 0.96), with pronounced benefit in PD-L1 TC≥1% stage II-IIIA pts (HR 0.66 95% CI 0.50, 0.88). We report data from the Asian population (pts recruited from Japan, mainland China, Taiwan, Korea and Hong Kong).

Effect of radiotherapy sequence on long-term outcome in patients with node-positive breast cancer: a retrospective study

The optimal sequence of chemotherapy (CT) and radiotherapy (RT) after surgery in breast cancer patients is unclear. There is a lack of literature on RT given between anthracycline and taxane administration. We evaluated the effect of RT sequence on long-term outcome in breast cancer. Two hundred patients who underwent surgery between January 2009 and December 2012 for node-positive breast cancers were evaluated retrospectively. All patients were treated with doxorubicin and cyclophosphamide (AC) followed by taxane. Sandwich RT group that received RT between AC and taxane was compared to the group that received RT after CT. The mean follow-up period was 105.4 months. The locoregional recurrence (LRR) rate was lower in sandwich RT group (P = 0.012) and there was no significant difference in distant metastasis between the two groups. The RT sequence was an important predictor for LRR in multivariable analysis (P = 0.017). For luminal A subtype, disease-free survival (DFS) was better in sandwich RT group than in CT followed by RT group (P = 0.001). The overall survival did not correlated with RT sequence regardless of subtype. Sandwich RT can offer DFS benefit in luminal A subtype breast cancer. A tailored approach of sequencing chemotherapy and radiotherapy would be needed considering the factors that can influence outcome.

Results for patients with muscle-invasive bladder cancer (MIBC) in the CheckMate 274 trial.

4585 Background: In the CheckMate 274 trial, disease-free survival (DFS) was significantly improved with nivolumab (NIVO) vs placebo (PBO) both in intent-to-treat (ITT) patients (pts) (hazard ratio [HR], 0.70; 98.22% confidence interval [CI], 0.55–0.90; P &lt; 0.001) and in pts with tumor programmed death ligand 1 (PD-L1) expression ≥ 1% (HR, 0.55; 98.72% CI, 0.35–0.85; P &lt; 0.001). We report results for the subgroup of pts with bladder cancer, the most predominant type of urothelial carcinoma. Methods: CheckMate 274 is a phase 3, randomized, double-blind trial of adjuvant NIVO vs PBO in high-risk muscle-invasive urothelial carcinoma (bladder, ureter, renal pelvis) after radical resection. Pts were randomized 1:1 to NIVO 240 mg intravenously every 2 weeks or PBO for ≤ 1 year of adjuvant treatment and stratified by nodal status, prior neoadjuvant cisplatin, and tumor PD-L1 expression. Pts had radical resection ± neoadjuvant chemotherapy and were at high risk of recurrence on final pathologic staging. Primary endpoints were DFS in ITT pts and in pts with PD-L1 ≥ 1%. Non–urothelial tract recurrence-free survival (NUTRFS) was a secondary endpoint, and distant metastasis-free survival (DMFS) was an exploratory endpoint. This exploratory analysis focused on the subgroup of pts with muscle-invasive bladder cancer (MIBC) after radical resection. Results: Of 709 randomized pts in the trial, 560 had MIBC (NIVO, n = 279; PBO, n = 281). With a minimum follow-up of 11.0 months, a DFS benefit was observed with NIVO vs PBO in these pts, regardless of tumor PD-L1 expression (Table). DFS probability at 12 months in all MIBC pts was 66% with NIVO and 45% with PBO. DFS was improved with NIVO vs PBO across subgroups according to age, sex, ECOG performance status, nodal status, and PD-L1 expression status. Improvement in NUTRFS and DMFS with NIVO vs PBO was also observed (Table). Grade 3–4 treatment-related adverse events occurred in 17% and 6% of pts in the NIVO and PBO arms, respectively. Conclusions: Improvement in DFS was observed with NIVO over PBO in pts with MIBC after radical resection regardless of tumor PD-L1 expression. The DFS benefit was observed in all prespecified subgroups. These results further support adjuvant NIVO as a standard-of-care treatment for pts with high-risk MIBC after radical resection ± neoadjuvant cisplatin-based chemotherapy. Clinical trial information: NCT02632409. [Table: see text]

Bio-miR: A prognostic microRNA-based signature for localized clear cell renal cell carcinoma.

e16519 Background: Prognosis of localized clear cell renal cell carcinoma (ccRCC) patients is estimated by nomograms based on clinico-pathological factors. However, clinical guidelines do not recommend their use. Recently, pembrolizumab has demonstrated benefit in disease-free survival (DFS) in medium-high risk localized ccRCC, increasing the need for better patient stratification tools. In this study, we have defined and validated a molecular signature, Bio-miR, based on the expression of nine microRNAs, with prognostic value in ccRCC. Methods: The discovery and two validation cohorts (Leeds-UK and Spain) consisted of patients with resected localized (stage Ib-III) ccRCC and no adjuvant therapy. miRNA expression was analyzed using microarrays and validated using qPCR in FFPE nephrectomy tissues. Cox regression was used to define the best microRNAs combination to predict risk of relapse. Results: In the discovery cohort (n = 71), DFS at 5 years was 93.9% amongst Bio-miR-defined low-risk patients and 61.6% in high-risk patients (HR = 6.9 (3.4-42.9), p &lt; 0.001). Cancer-specific survival at 5 years was 95.7% and 86.4% in low- and high-risk patients, respectively (HR = 7.7 (1.7-35.1), p &lt; 0.01). Bio-miR compared favorably with different histopathological factors and UISS and Karakiewicz´s nomograms. In the Leeds validation cohort (n = 75/95 passing qPCR quality control), patients defined as low-risk had a 5-year DFS rate of 94% versus 62% in high-risk defined disease. In this cohort Bio-miR was able to divide the Leibovich intermediate-risk population into two groups with divergent five-year DFS rates (100% vs 71%). In the Spanish validation cohort (n = 180), DFS rates at 5 years were 82.9% in the low-risk group and 58.7% in the high-risk group (HR = 2.4 (1.4-4.4); p &lt; 0.005). Applying the inclusion criteria from the phase III KEYNOTE-564 trial, Bio-miR identifies a small low-risk population who could be spared adjuvant treatment. Conversely, amongst patients excluded from the study due to low-risk features, Bio-miR defines a high-risk population (DFS at five years of 50%) who should be prioritized for adjuvant therapy. Conclusions: We define and validate a nine-microRNA based signature capable of dichotomizing patients with localized ccRCC into low- and high-risk groups based on risk of relapse. Importantly, Bio-miR acts independently of tumor stage and grade and could, therefore, help refine the selection of patients for adjuvant therapy as well as inform the design of future adjuvant ccRCC trials.

PD-L1 score as a prognostic biomarker in Asian patients with early-stage, EGFR-mutated lung cancer.

8527 Background: Adjuvant Atezolizumab was recently approved in stage II-IIIA non-small cell lung cancer (NSCLC) with PD-L1 ≥1%. However, disease-free survival (DFS) benefit was mainly driven by PD-L1 ≥50% and among EGFR-mutated subgroup, atezolizumab did not demonstrate DFS benefit when PD-L1 0% patients were included. We sought to determine the prognostic value of PD-L1 score in early-stage EGFR-mutated NSCLC. Methods: Consecutive patients with Stage IA-IIIA NSCLC diagnosed 1/1/2010 – 31/12/2019 who underwent curative surgery at National Cancer Centre Singapore with evaluable EGFR and PD-L1 status were included. Co-primary endpoints were 2-year DFS and 5-year overall survival (OS) by Kaplan-Meier method. Results: 455 patients were included (267 EGFR-mutant; 188 EGFR-wildtype). Median age at diagnosis was 65 years, 52.3% (238/455) were males and 62.9% (286/455) were never-smokers. Adenocarcinomas comprised 92.1% (419/455) and 92.5% (421/455) had R0 resection. Stage IA comprised 42.4% (193/455), Stage IB 23.1% (105/455), Stage II 15.8% (72/455) and Stage IIIA 18.7% (85/455). Among EGFR-mutant, 45.3% (121/267) were Ex19del and 41.9% (112/267) were L858R. PD-L1 ≥1% among EGFR-mutant and EGFR-wildtype was 55.8% (149/267) and 60.1% (113/188) respectively (p = 0.361). PDL1 ≥50% was significantly associated with higher stage at diagnosis among EGFR-mutant (p &lt; 0.001) but not EGFR-wildtype (p = 0.319). At median follow up of 47 months, 178 patients had relapsed. Among EGFR-mutant, 2-year DFS comparing PD-L1 0% and PD-L1 ≥1% was 79.0% and 68.9% (p = 0.006) while 5-year OS was 87.6% and 70.6% (p = 0.006) respectively. 2-year DFS and 5-year OS by PD-L1 tertile (as shown in table) revealed that higher PD-L1 score was prognostically worse for both DFS and OS among EGFR-mutant. A similar trend was observed among EGFR-wildtype but did not reach statistical significance, apart from PD-L1 ≥50% which had significantly inferior DFS. Conclusions: Higher PD-L1 score was significantly associated with worse DFS and OS among early-stage EGFR-mutated NSCLC, possibly due to higher stage at diagnosis among PDL1 ≥50%. Our study highlights the poor prognosis of PDL1 ≥50% EGFR-mutated NSCLC in a pre-osimertinib era and underscores the importance of personalised risk-stratified adjuvant strategies. [Table: see text]

Patients' preferences for adjuvant osimertinib in non–small cell lung cancer (NSCLC) after complete surgical resection: What makes it worth it to patients? (PATT)—The Roswell Park (RP) Comprehensive Cancer Center experience.

8520 Background: There are clinical controversies surrounding the US FDA approval of Osimertinib in December 2020 as adjuvant therapy, based on disease-free survival (DFS) improvement in patients (pts) with surgically resected stage IB-IIIA EGFRm NSCLC. We initiated a survey study to investigate our hypothesis that DFS benefit alone even without significant OS maybe deemed a valuable endpoint to pts after considering trade-offs. Methods: Participants were recruited from pts seen at the RP Thoracic Clinic from 01/21 to 12/21. Eligible pts who were being evaluated for adjuvant systemic therapy following surgical resection were given a self-administered survey based on the validated questionnaire by Blinman et al, which was modified to provide explanation of the differences between OS and DFS and the ADAURA trial results. Survey responses were collected in an online repository. Associations between survey responses and demographics were assessed using Fisher’s exact test. Changes in preference responses were assessed using McNemar’s test. Results: A total of 524 pts with NSCLC were screened, of which 101 pts were eligible to receive the survey. 51 pts (50%) responded to the survey. Median age of respondents was 69yrs (37-83), majority were female (69%, n = 35,), married (61%, n = 31), retired ( 63%, n = 32), had at least some college or higher education level(54%, n = 28), with history of smoking (84%, n = 43) and with stage IIIA (43%, n = 22) adenocarcinoma (80%, n = 41). To evaluate toxicity-related tradeoffs (Q1), a ≥12 mo. improvement in OS benefit was needed for 66% of pts to consider adjuvant Osi. However, an increase of ≥ 6 mo. of DFS was enough for 66% of pts to justify taking a daily medication (Q2). One mo. increase in DFS or OS was not enough for 60% and 78% of pts respectively to justify taking the medication. A threshold 1% increase in 5-year OS was sufficient to persuade patients to take Osi for three years, even with respect to toxicity side effects (p = 0.023). (Q3). Finally, in the hypothetical cost-based scenario (Q4), there was no indication that pts were willing to pay more for each incremental increase in OS. There appears to be some association between employment status (p =.033) or educational degree (p =.049) for tolerance of side effects if there is at least 1 additional year of DFS or OS. Conclusions: We observed that the value patients ascribe to adjuvant Osimertinib is influenced by factors besides efficacy. Knowing pts' preferences for cancer treatments can better inform regulatory bodies in formulating cost-sharing structure for cancer therapies. Our study highlights the importance of shared decision making based on individual pts' preferences.

Utility of adjuvant chemotherapy in early-stage, estrogen receptor-positive breast cancer patients under 50 years with a 21-gene recurrence-score of 16-25: A retrospective analysis using the National Cancer Database.

e12501 Background: The TAILORx trial showed that addition of adjuvant chemotherapy (AC) to endocrine therapy (ET) had no advantage in estrogen receptor (ER)+, HER2-, node negative (N0) breast cancer (BC) patients with an intermediate (11-25) 21-gene recurrence-score (RS). However, a subgroup analysis revealed that in women ≤ 50 years, AC had a lower rate of distant recurrence if the RS was 16-25. Using a large national database, we studied the utilization of AC in the aforementioned subset. Methods: The 2004-2018 National Cancer Database BC cohort was used to include female patients of 18-50 years. Inclusion criteria were N0, M0 patients with any T stage, RS 16-25, ER+/PR± and HER2-. Patients who received neoadjuvant chemotherapy were excluded. Logistic regression was used to evaluate AC utility trends. Kaplan-Meier (KM) and multivariate (MV) propensity score (PS) weighted Cox model were used to compare survival between patients without and with AC use. Results: Of the 15,792 patients, 4808 (30.45%) received AC. Median RS was 18 and 21 in patients without and with AC. Factors associated with AC use were higher T stage, poor and moderately differentiated tumors, age &lt;40, care at an academic center, Caucasian race, patients undergoing mastectomy, regional lymph node (RLN) surgery, ET and Radiation Therapy (RT). KM survival at 10 years was better with AC [96.2% vs 91.6%]. Patients without AC had worse survival [Hazard Ratio (HR)=1.683, 95% Confidence Interval (CI): 1.392-2.036, p&lt;0.0001] (Table). Conclusions: In this analysis,AC use had a 5% improvement in 10 year overall survival, in contrast to TAILORx trial which only showed a disease free survival benefit. Whether the benefit was due to direct cytotoxicity or ovarian function suppression effect of AC remains to be seen. In clinical practice, AC use is determined based on patient and tumor characteristics. Limitations of our study include non-population-based data and the possibility of cofounding despite the use of PS matching. [Table: see text]