Disease-free Survival Benefit Research Articles

Effectiveness of the Sanyin Formula Plus Chemotherapy on Survival in Women With Triple-Negative Breast Cancer: A Randomized Controlled Trial.

PurposeTo evaluate the efficacy of the Sanyin formula (SYF) plus conventional standard chemotherapy in operable triple-negative breast cancer (TNBC) patients, a randomized controlled trial was implemented at 5 hospitals and cancer centers in China between May 23, 2016, and October 31, 2019.Materials and MethodsFemale patients aged 18 to 80 years with operable TNBC after definitive surgery were screened and enrolled. The exclusion criteria included metastatic disease, other tumors, or locally advanced disease. Patients were randomly divided into groups SYF plus conventional standard chemotherapy and placebo plus conventional standard chemotherapy at a ratio of 1:1. The primary endpoint of the investigation was disease-free survival (DFS), and secondary endpoints included overall survival (OS) and toxicity.ResultsA total of 252 operable female TNBC patients were randomized to receive SYF plus conventional standard chemotherapy (N = 127) or a placebo plus conventional standard chemotherapy (N = 125). At a median follow-up of 51 months, 5-year DFS time was longer in those assigned to SYF plus conventional standard chemotherapy compared with placebo plus conventional standard chemotherapy (94.2%vs 85.5%, hazard ratio [HR] = 0.40; 95%CI, 0.17-0.97; P = 0.034). The absolute benefit for 5-year DFS was 8.7% in the SYF plus conventional standard chemotherapy group. No statistically significant difference was observed in OS between the two groups (P = 0.23). Patients with negative node status benefited more from SYF plus conventional standard chemotherapy treatment (HR = 0.21, P-interaction = 0.013) in accordance with the exploratory subgroup analyses of DFS.ConclusionsThe results of the present study suggest that the traditional Chinese medicine SYF plus conventional chemotherapy regimens is an effective alternative adjuvant chemotherapy strategy for female operable TNBC patients.Clinical Trial Registrationhttps://www.chictr.org.cn/searchproj.aspx, identifier ChiCTR-IPR-16008590.

Adjuvant chemotherapy after curative D2 gastrectomy in Latin American patients with gastric cancer.

BackgroundGastric cancer (GC) is the fourth most common cause of cancer deaths around the world and the first cause of cancer deaths in Peru; however, there are no prospective trials for adjuvant chemotherapy in GC after curative gastrectomy in this country. The objective of this study was to evaluate the effectiveness of adjuvant chemotherapy in stage II–III gastric cancer patients who underwent D2 gastrectomy.MethodsWe included patients with stage II–III gastric cancer who underwent radical gastrectomy and D2 dissection between 2014 and 2016 at our institution. Patients received 3-week cycles of capecitabine (1,000 mg/m2 twice daily on days 1–14) plus oxaliplatin (130 mg/m2 on day 1) for 6 months. Survival curves were estimated with the Kaplan–Meier method, and the Cox proportional hazards model was used to identify prognostic factors for survival.ResultsIn total, 173 patients were included: 100 (57.8%) patients received adjuvant chemotherapy and surgery (AChS) and 73 (42.2%) surgery alone (SA). Three-year disease-free survival (DFS) was higher in the AChS groups (69%) than in the SA group (52.6%) (p = 0.034). Regarding overall survival (OS), 31 patients (31%) died in the AChS group compared with 34 (46.6%) in the SA group (p = 0.027). In the multivariate analysis, adjuvant chemotherapy was an independent prognostic factor for DFS (HR = 0.60; 95% CI = 0.37–0.97; p = 0.036) and OS (HR = 0.58; 95% CI = 0.36–0.95; p = 0.029). ACh showed consistent benefit in DFS and OS for patients with albumin >3.5 g/dL, lymphovascular and perineural invasion, pT4, pN2–3, pathologic stage (PS) IIIA and IIIB and lymph node ratio (LNR) > 13.1.ConclusionThese data suggest that adjuvant capecitabine and oxaliplatin reduce the recurrence and mortality in patients with stage II–III gastric cancer who underwent D2 gastrectomy. PS IIIA and IIIB and LNR > 13.1 benefited more from receiving adjuvant chemotherapy and poorly cohesive gastric carcinoma did not significantly reduce the rates of survival.

PD10-01 DISEASE-FREE SURVIVAL WITH LONGER FOLLOW-UP FROM THE CHECKMATE 274 TRIAL OF ADJUVANT NIVOLUMAB IN PATIENTS AFTER SURGERY FOR HIGH-RISK MUSCLE-INVASIVE UROTHELIAL CARCINOMA

PD10-01 DISEASE-FREE SURVIVAL WITH LONGER FOLLOW-UP FROM THE CHECKMATE 274 TRIAL OF ADJUVANT NIVOLUMAB IN PATIENTS AFTER SURGERY FOR HIGH-RISK MUSCLE-INVASIVE UROTHELIAL CARCINOMA

Osimertinib: A Review in Completely Resected, Early-Stage, EGFR Mutation-Positive NSCLC.

Osimertinib (TAGRISSO®) is an orally administered, third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor that is approved for the adjuvant treatment of adults with completely resected, stage IB-IIIA, EGFR sensitizing mutation (exon 19 deletion or exon 21 [L858R] substitution)-positive non-small cell lung cancer (NSCLC). In the pivotal ADAURA trial in adults with completely resected, early-stage, EGFR mutation-positive (EGFRm+) NSCLC, osimertinib adjuvant therapy significantly prolonged disease-free survival (DFS) compared with placebo in the overall population of patients with stage IB-IIIA disease, as well as in the primary population of patients with stage II-IIIA disease. A DFS benefit of osimertinib was seen irrespective of whether or not patients received prior adjuvant chemotherapy. Overall survival (OS) data were very immature at the time of the analysis of DFS, and more mature OS data are awaited with interest. Osimertinib adjuvant therapy did not adversely affect health-related quality of life and was generally well tolerated, with a manageable safety profile and no new safety signals identified. Based on the available evidence, osimertinib is thus an appropriate targeted option for the adjuvant treatment of adults with completely resected, stage IB-IIIA, EGFRm+ NSCLC.

PD26-06 ADJUVANT CHEMOTHERAPY PLUS RADIOTHERAPY VERSUS CHEMOTHERAPY ALONE FOR LOCALLY ADVANCED BLADDER CANCER AFTER RADICAL CYSTECTOMY

You have accessJournal of UrologyCME1 May 2022PD26-06 ADJUVANT CHEMOTHERAPY PLUS RADIOTHERAPY VERSUS CHEMOTHERAPY ALONE FOR LOCALLY ADVANCED BLADDER CANCER AFTER RADICAL CYSTECTOMY John Ernandez, Sumedh Kaul, Aaron Fleishman, Ruslan Korets, Peter Chang, Andrew Wagner, Simon Kim, Joaquim Bellmunt, Irving Kaplan, Aria Olumi, and Boris Gershman John ErnandezJohn Ernandez More articles by this author , Sumedh KaulSumedh Kaul More articles by this author , Aaron FleishmanAaron Fleishman More articles by this author , Ruslan KoretsRuslan Korets More articles by this author , Peter ChangPeter Chang More articles by this author , Andrew WagnerAndrew Wagner More articles by this author , Simon KimSimon Kim More articles by this author , Joaquim BellmuntJoaquim Bellmunt More articles by this author , Irving KaplanIrving Kaplan More articles by this author , Aria OlumiAria Olumi More articles by this author , and Boris GershmanBoris Gershman More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002574.06AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Survival for patients with locally advanced bladder cancer following radical cystectomy (RC) remains poor. Although adjuvant chemotherapy (AC) is standard of care, one small randomized trial has suggested a potential disease-free survival benefit with the addition of post-operative radiotherapy (PORT). We therefore examined the association of PORT with overall survival (OS) in patients with locally advanced bladder cancer after RC. METHODS: Using a completed phase 2 trial to inform the design of the present study, we conducted observational analyses to emulate a hypothetical target trial of patients aged 18-79 years with pT3-4 Nany M0 or pTany N1-3 M0 urothelial carcinoma of the bladder following RC who were treated with AC (multiagent chemotherapy within 3 months of RC) with or without PORT (≥45 Gy to the pelvis) from 2006-2015 in the National Cancer Database. Patients who received preoperative chemotherapy or radiotherapy were excluded. The associations of treatment arm with OS were evaluated using multivariable Cox regression. RESULTS: A total of 1,684 patients were included, of whom 66 underwent PORT+AC and 1,618 AC alone. Compared to patients treated with AC alone, those treated with PORT+AC were more likely to have pT4 disease (52% vs 26%; p<0.01), have positive surgical margins (44% vs 17%; p<0.01), and be treated at a non-academic facility (75% vs 53%; p<0.01). Crude 3- and 5-year OS were 31% and 19% for PORT+AC versus 48% and 36% for AC alone (p=0.01). Adjusted 3- and 5-year OS were 44% and 33% for PORT+AC versus 48% and 36% for AC alone (p=0.49). After adjusting for baseline characteristics including pathologic features, PORT+AC was not associated with improved OS compared to AC alone (HR 1.11; 95% CI 0.82-1.51; Figure 1). CONCLUSIONS: Although infrequently utilized, the present analyses suggest that the addition of radiotherapy to AC is not associated with improved OS in locally advanced bladder cancer. These results highlight the need for prospective trials to better define the potential benefits from PORT with regard to symptomatic progression and oncologic outcomes. Source of Funding: None © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e489 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information John Ernandez More articles by this author Sumedh Kaul More articles by this author Aaron Fleishman More articles by this author Ruslan Korets More articles by this author Peter Chang More articles by this author Andrew Wagner More articles by this author Simon Kim More articles by this author Joaquim Bellmunt More articles by this author Irving Kaplan More articles by this author Aria Olumi More articles by this author Boris Gershman More articles by this author Expand All Advertisement PDF DownloadLoading ...

EGFR-Mutant Non-Small-Cell Lung Cancer at Surgical Stages: What Is the Place for Tyrosine Kinase Inhibitors?

Simple SummaryTyrosine kinase inhibitors are drugs targeting the epidermal growth factor receptor. In lung cancer, they are used to treat advanced EGFR-mutant diseases, and more recently, one has been approved for adjuvant therapy. Even though publications on the topic are numerous, conclusions are difficult to interpret and are sometimes contradictory. We therefore reviewed the literature in order to present an overview of up-to-date data regarding the adjuvant and neoadjuvant use of tyrosine kinase inhibitors, with particular attention given to their benefits, proven or expected, as well as what challenges could be faced when entering them as protocols in standard care.The ADAURA trial has been significant for the perception of EGFR tyrosine kinase inhibitors (TKIs) as a tool for early stage non-small-cell lung cancer (NSCLC). It produced such great insight that the main TKI, Osimertinib, was rapidly integrated into international guidelines for adjuvant use. However, EGFR-mutant NSCLC is a complex entity and has various targeting drugs, and the benefits for patients might not be as clear as they seem. We reviewed trials and meta-analyses considering TKI adjuvant and neoadjuvant use. We also explored the influence of mutation variability and financial evaluations. We found that TKIs often show disease-free survival (DFS) benefits, yet studies have struggled to improve the overall survival (OS); however, the results from the literature might be confusing because of variability in the stages and mutations. The safety profiles and adverse events are acceptable, but costs remain high and accessibility might not be optimal. TKIs are promising drugs that could allow for tailored treatment designs.

A randomized phase III, double-blinded, placebo-controlled trial of aspirin as adjuvant therapy for breast cancer (A011502): The Aspirin after Breast Cancer (ABC) Trial

360922 Background: In-vitro and in-vivo evidence suggests that aspirin may have an anti-tumor effect. Multiple epidemiologic studies have reported improved breast cancer survival among regular aspirin users compared to non-users. Pooled data from randomized trials of aspirin for cardiovascular disease have also reported a decreased risk of metastatic cancer among aspirin users. Thus, we conducted a prospective randomized controlled trial to determine the true benefits and risks of adjuvant aspirin therapy for breast cancer survivors. Methods: The primary objective was to compare the effect of 300 mg aspirin daily versus placebo upon invasive disease-free survival (iDFS) in patients with high-risk, HER2-negative breast cancer. Secondary objectives included effects on overall survival, cardiovascular disease, toxicity, and adherence. Eligible participants included patients aged 18-70 diagnosed with a primary invasive HER2-negative breast cancer. If hormone receptor (HR)–positive, tumors needed to be node positive and diagnosed within the past 10 years. If HR negative, tumors could be node positive or T2-4N0 and diagnosed within the past 18 months. Participants were randomly selected (1:1) to aspirin 300 mg versus placebo daily for 5 years in a double-blinded fashion. Stratification factors include HR status (positive vs. negative), body mass index (&lt; or ≥ 30 kg/m2), and stage (II vs. III). Based upon an accrual goal of 2,936 patients to reach 381 iDFS events, the study was estimated to have 80% power to detect HR 0.75. Results: From January 2017 to December 2020, 3,021 participants were enrolled. Treatment arms were well balanced in terms of key characteristics. In November 2021, the Data Safety and Monitoring Board recommended that the trial be unblinded because the stratified hazard ratio had crossed a pre-specified futility boundary. After 191 iDFS events (aspirin: 107, placebo: 84) and median follow-up of 20 months, the stratified hazard ratio comparing aspirin to placebo was 1.27 (z-score: -1.64), which is greater than the pre-specified hazard ratio of futility 1.03 (z-score &lt; -0.192). There was no difference in the frequency of grade 3/4 adverse events by study arm. Compliance was high and similar across arms. Non-protocol use of aspirin/non-steroidal anti-inflammatory drugs was similar across arms and less than 14%, consistent with prior randomized aspirin trials. Updated results on iDFS events will be provided at presentation. Conclusions: In this double-blinded, placebo-controlled, randomized trial, there was no benefit in breast cancer invasive disease-free survival with the addition of 300 mg aspirin daily. Although inflammation may still play a role in cancer progression, aspirin is not recommended for prevention of breast cancer recurrence. Clinical trial information: NCT02927249.

Clinical efficacy of adjuvant treatments for patients with resected biliary tract cancer: a systematic review and network meta-analysis

ObjectiveThis study aimed to determine the benefits of adjuvant therapy in patients with resected biliary tract cancer (BTC) and identify the optimal adjuvant treatment scheme.DesignSystematic review and network meta-analysis.Data sourcesStudies...

Deconstructing ADAURA: It is Time to Forgo Adjuvant Platinum-Based Chemotherapy in Resected IB-IIIA EGFR+ NSCLC (Except with RB Alterations?) When Adopting Adjuvant Osimertinib.

Adjuvant cisplatin-based chemotherapy is considered the standard of care for resected stage IB (tumor ≥ 4m)–IIIA non-small cell lung cancer (NSCLC). The ADAURA trial is a randomized placebo-controlled Phase III trial that demonstrated statistically significant improved disease-free survival (DFS) with the use of 3-years of adjuvant osimertinib in resected stage IB–IIIA NSCLC harboring epidermal growth factor receptor (EGFR) del 19 or L858R mutations. Subgroup analysis revealed that the DFS improvement with adjuvant osimertinib is independent of adjuvant chemotherapy in the primary analysis. A recent follow-up report suggested that adjuvant cisplatin-based chemotherapy provided no additional 2-year DFS improvement on top of adjuvant osimertinib regardless of stage (IB, II, or IIIA) and minimal numerical DFS benefit in stage II or IIIA resected EGFR+ NSCLC for those patients who did not receive adjuvant osimertinib. Here, we argue that if clinicians adopt the use of 3 years of adjuvant osimertinib in resected early-stage EGFR+ NSCLC, there is no role for adjuvant platinum-based chemotherapy. The use of adjuvant chemotherapy was balanced between the osimertinib and the placebo arms by stage even though adjuvant chemotherapy was not one of the three stratification factors (del 19 vs L858R; Stage IA vs II vs III; Asians versus non-Asian) in ADAURA. There may be a potential role of adjuvant cisplatin/vinorelbine in a small subgroup of EGFR+ NSCLC patients whose tumor harbors retinoblastoma (RB) gene alterations but requires further investigation.

Six-year absolute invasive disease-free survival benefit of adding adjuvant pertuzumab to trastuzumab and chemotherapy for patients with early HER2-positive breast cancer: A Subpopulation Treatment Effect Pattern Plot (STEPP) analysis of the APHINITY (BIG 4-11) trial

AimThe APHINITY trial showed that adding adjuvant pertuzumab (P) to trastuzumab and chemotherapy, compared with adding placebo (Pla), significantly improved invasive disease-free survival (IDFS) for patients with HER2+ early breast cancer both overall and for the node-positive (N+) cohort. We explored whether adding P could benefit some N− subpopulations and whether to consider de-escalation for some N+ subpopulations. MethodsSubpopulation Treatment Effect Pattern Plot (STEPP) is an exploratory, graphical method that plots estimates of treatment effect for overlapping patient subpopulations defined by a covariate of interest. We used STEPP to estimate Kaplan–Meier differences in 6-year IDFS percentages (P minus Pla: Δ ± standard error [SE]), both overall and by nodal status, for overlapping subpopulations defined by (1) a clinical composite risk score, (2) tumour infiltrating lymphocytes (TILs) percentage, and (3) human epidermal growth factor receptor 2 (HER2) FISH copy number. Because of multiplicity, a Δ of at least three SE is required to warrant attention. ResultsThe average absolute gains in 6-year IDFS percentages were 2.8 ± 0.9 overall; 4.5 ± 1.2 for N+ and 0.1 ± 1.1 for N−. Largest gains were for patients with intermediate clinical composite risk (5.3 ± 1.9 overall; 6.9 ± 2.3 N+; 4.0 ± 3.0 N−), highest TILs percentage (6.3 ± 1.7 overall; 7.4 ± 2.4 N+; 3.2 ± 1.7 N−), and intermediate HER2 copy number (2.8 ± 1.9 overall; 7.4 ± 2.5 N+; −1.3 ± 1.9 N−), but clear evidence indicating a pattern of differential subpopulation treatment effects was lacking. ConclusionsSTEPP plots for N− did not identify subpopulations clearly benefiting from adding P, and those for N+ did not identify subpopulations warranting de-escalation. TILs percentage appeared to be more predictive of P treatment effect than clinical composite risk score. Trial registrationclinicaltrials.gov Identifier NCT01358877.

ADAURA: The Splash of Osimertinib in Adjuvant EGFR-Mutant Non-small Cell Lung Cancer.

The introduction of tyrosine kinase inhibitors (TKI) for the treatment of metastatic non-small cell lung cancer (NSCLC) harbouring sensitizing epidermal growth factor receptor (EGFR) gene mutations revolutionized the diagnostic and treatment algorithm of this subset of patients almost two decades ago. Since then, a number of trials have evaluated the role of TKI therapy in early-stage disease, with encouraging disease-free survival (DFS) results but lack of a survival advantage. ADAURA, a phase III trial evaluating 3 years of adjuvant osimertinib versus placebo in patients harbouring EGFR mutations with completely resected stage IB–IIIA NSCLC, recently reported a profound DFS benefit (hazard ratio 0.21), favourable quality of life and reduction in the risk of brain metastases. These results led to osimertinib’s fast track approval by the US Food and Drug Administration, with this drug thus becoming the first EGFR-TKI approved for the treatment of early-stage disease. However, the key endpoint of overall survival remains immature and questions around indication (i.e. stage, need for adjuvant chemotherapy), optimal treatment duration, biomarkers of response and cost-effectiveness remain to be answered. In this article, we critically appraise the findings of ADAURA and discuss future challenges.

The effect of postoperative pathological findings related to the eligibility of adjuvant immunotherapy on oncologic outcomes in patients with locally advanced urothelial cancer.

254 Background: The CheckMate 274 trial demonstrated a benefit in disease-free survival (DFS) with adjuvant nivolumab therapy in patients at high risk of muscle-invasive UC and may become a standard of care in the future. In that study, postoperative pT3-4/ypT2-4 or pN+ was used as an inclusion criterion for the high-risk group, but the validity of this criterion in clinical practice remains unclear. Also, there is an urgent need for the proportion of patients who are eligible for adjuvant immunotherapy in clinical practice. We aimed to evaluate the effect of postoperative pathological findings related to the eligibility of adjuvant immunotherapy on oncologic outcomes in patients with localized and locally advanced muscle-invasive bladder carcinoma (MIBC) and upper tract urothelial carcinoma (UTUC). Methods: We retrospectively evaluated 1082 patients treated with radical cystectomy (n = 597) and nephroureterectomy (n = 485) between January 2000 and April 2021. Patients were divided into two groups: pT3-4 or pN+ without neoadjuvant chemotherapy and ypT2-4 or pN+ treated with neoadjuvant chemotherapy (trial-eligible group) or others (trial-ineligible group). The primary outcome was the effect of trial eligibility for adjuvant immunotherapy on disease-free survival (DFS) and overall survival (OS). Secondary outcomes included the additional effect of lymphovascular invasion (LVI) status to the clinical trial criteria on prognosis and a risk model development. Results: The median age of the patients was 69 and 72 years in the MIBC and UTUC groups, respectively. Fifty-two percent of patients met the trial inclusion criteria. Trial eligibility was significantly associated with poor DFS and OS among patients with MIBC and UTUC. LVI-positive status was significantly associated with poor prognosis among patients in the trial-eligible group. A very high risk (LVI+ or pN+ among the pT3-4 or ypT2-4) was significantly associated with poor prognosis. Conclusions: A total of 52% of patients were eligible for adjuvant immunotherapy. Trial eligibility was significantly associated with a poor prognosis. LVI+ and pN+ may play a key role in candidate selection for adjuvant immunotherapy.

Pembrolizumab as post nephrectomy adjuvant therapy for patients with renal cell carcinoma: Results from 30-month follow-up of KEYNOTE-564.

290 Background: The double-blind, multicenter, randomized KEYNOTE-564 study (NCT03142334) is the first positive phase 3 study of adjuvant immunotherapy for patients (pts) with renal cell carcinoma (RCC) at intermediate-high or high risk of recurrence after nephrectomy or nephrectomy and resection of metastatic lesions. Adjuvant pembrolizumab resulted in a statistically significant improvement in disease-free survival (DFS) vs placebo with 24 months of follow-up (HR 0.68, 95% CI 0.53−0.87; P = 0.0010 [one-sided]). We present updated efficacy and safety results from KEYNOTE-564 with 6 months of additional follow-up. Methods: Pts had histologically confirmed, clear cell RCC (pT2, grade 4 or sarcomatoid, N0 M0; pT3 or pT4, any grade, N0 M0; any pT, any grade, N+ M0; or M1 NED [no evidence of disease after primary tumor and soft tissue metastases completely resected ≤1 year from nephrectomy]) and had undergone surgery ≤12 weeks prior to randomization. The primary endpoint was DFS by investigator assessment in all randomized pts (ITT population). Overall survival (OS) was a key secondary endpoint. Safety/tolerability in all treated pts was a secondary endpoint. Results: 994 pts were randomized 1:1 to pembrolizumab (N = 496) or placebo (N = 498). As of data cutoff date of June 14, 2021, median (range) follow-up, defined as time from randomization to data cutoff, was 30.1 (20.8−47.5) months. In this updated analysis, DFS benefit with pembrolizumab was maintained (HR 0.63, 95% CI 0.50−0.80; nominal P &lt; 0.0001) and was consistent across subgroups, including pts with M0 disease with intermediate-high risk of recurrence (HR 0.68, 95% CI 0.52−0.89), M0 high risk of recurrence (HR 0.60, 95% CI 0.33−1.10), or M1 NED (HR 0.28, 95% CI 0.12−0.66). The estimated DFS rate at 24 months was 78.3% with pembrolizumab vs 67.3% with placebo. A total of 66 OS events were observed, 23 in the pembrolizumab arm and 43 in the placebo arm (HR 0.52, 95% CI 0.31−0.86; P = 0.0048); the p-value did not cross the statistical hypothesis testing boundary and additional follow-up is planned for this key secondary endpoint. The estimated OS rate at 24 months was 96.2% with pembrolizumab vs 93.8% with placebo. With additional follow-up, no increase in any-grade or grade 3-4 adverse events, or steroid use for immune-mediated adverse events was observed. No deaths related to pembrolizumab occurred. Conclusions: At 30 months of follow-up, adjuvant pembrolizumab continued to demonstrate a consistent and clinically meaningful improvement in DFS vs placebo in pts with RCC at high risk of recurrence. No new safety signals were observed with pembrolizumab in the adjuvant setting. Clinical trial information: NCT03142334.

Analysis of disease-free survival in CheckMate 274 by PD-L1 combined positive score and tumor proportion score.

491 Background: CheckMate 274 demonstrated a significant improvement in disease-free survival (DFS) with nivolumab (NIVO) versus placebo (PBO) both in the intent-to-treat population (hazard ratio [HR], 0.70; 98.22% confidence interval [CI], 0.55–0.90; P &lt; 0.001) and in patients (pts) with tumor programmed death ligand 1 (PD-L1) expression ≥ 1% assessed by the tumor proportion score (TPS) (HR, 0.55; 98.72% CI, 0.35–0.85; P &lt; 0.001). An exploratory subgroup analysis showed a trend toward a DFS benefit with NIVO in pts with TPS &lt; 1% (0.82; 95% CI, 0.63–1.06). To further characterize the relationship between PD-L1 expression and NIVO efficacy, we report an analysis of DFS based on PD-L1 expression in both tumor and immune cells using the combined positive score (CPS). Methods: CheckMate 274 is a phase 3, randomized, double-blind, multicenter trial of NIVO versus PBO in pts with high-risk muscle-invasive urothelial carcinoma after radical surgery. Pts were randomized 1:1 to NIVO 240 mg or PBO every 2 weeks intravenously for 1 year of adjuvant treatment. The primary endpoints of the study are DFS in the intent-to-treat population and in pts with TPS ≥ 1%. The Dako PD-L1 IHC 28-8 pharmDx assay was used to evaluate TPS. CPS was determined retrospectively from previously stained immunohistochemistry slides using the CPS algorithm. CPS was calculated as the number of both PD-L1 positive tumor and immune cells divided by the number of viable tumor cells in the evaluable tumor area, multiplied by 100; TPS was similarly calculated with the number of PD-L1 positive tumor cells as the numerator. This analysis only included pts with both quantifiable CPS and TPS. Results: Of the 629 pts with quantifiable TPS and CPS, 249 (40%) had TPS ≥ 1% (NIVO, n = 124; PBO, n = 125), 380 (60%) had TPS &lt; 1% (NIVO, n = 191; PBO, n = 189), 557 (89%) had CPS ≥ 1 (NIVO, n = 281; PBO, n = 276), and 72 (11%) had CPS &lt; 1 (NIVO, n = 34; PBO, n = 38). Within TPS &lt; 1% pts, 81% (n = 309) had CPS ≥ 1. The number of pts and the DFS outcomes in pts with TPS ≥ 1% and CPS ≥ 1 are shown in the Table. In pts with TPS &lt; 1% who also had CPS ≥ 1, median DFS (95% CI) was 19.2 (15.6–33.4) months with NIVO versus 10.1 (8.2–19.4) months with PBO. The HR for NIVO versus PBO in these pts was 0.73 (95% CI, 0.54–0.99). Conclusions: This exploratory analysis of PD-L1 expression by CPS showed a higher proportion of pts with CPS ≥ 1 than TPS ≥ 1%, and that most pts with TPS &lt; 1% had CPS ≥ 1. In the CPS ≥ 1 subgroup, median DFS with NIVO was more than double that with placebo. These results support the conclusion that pts with TPS &lt; 1% also benefit from adjuvant NIVO. Clinical trial information: NCT02632409. [Table: see text]

Quantifying absolute benefit of adjuvant treatments in renal cell carcinoma: A systematic review and network-meta-analysis.

360 Background: Pembrolizumab has been established as an effective treatment option in adjuvant renal cell carcinoma after the publication of KEYNOTE-564. However, the magnitude of benefit based on different risk categories is not well defined. Methods: We included full-text publications of phase II/III randomized controlled trials (RCTs) evaluating immune checkpoint inhibitors or tyrosine kinase inhibitors (TKIs) in adjuvant renal cell carcinoma after a systematic search. The outcomes of interest included disease free survival (DFS), overall survival (OS), all grade or grade ≥3 treatment related, and all cause adverse events. Mixed treatment comparisons were computed through a fixed-effect multivariate meta-regression within the frequent framework. Relative treatment rankings were assessed using P-scores. We used stratified baseline risks of disease progression from observational data and at 5, 10, 15 years from the Leibovich risk stratification system (based on risk scores ranging from 0 to ≥15). Corresponding intervention risks (CIRs) were then approximated using relative effect estimates (from NMA) and baseline risks. The difference between CIRs and baseline risks were calculated to present absolute risk differences in each baseline category. Results: This NMA included six RCTs with a total of 7525 participants and five unique treatment options. Mixed treatment comparisons showed significant DFS and OS benefit with pembrolizumab (rank 1) when compared against sunitinib (DFS HR 0.74 [0.55-0.99]; OS HR 0.51 [0.27-0.94]). However, there were no significant differences with pembrolizumab compared to pazopanib (DFS HR 0.81 [0.60- 1.09]; OS HR 0.54[0.29-1.01]) and axitinib (DFS HR 0.78 [0.54-1.14]; OS HR 0.52 [0.24-1.16]). The safety profiles were comparable. Absolute benefit of TKIs in adjuvant setting was minimal whereas this benefit increased with higher T and N patients in patients treated with pembrolizumab (Table). Similarly, the treatment benefit increased with higher Leibovich’s risk scores at 5, 10 and 15 years of follow up. Conclusions: The current analysis suggests that a risk adapted approach may be useful when considering adjuvant pembrolizumab in RCC patients.[Table: see text]

Abstract P3-18-03: Long-term outcomes for breast conservation plus radiotherapy versus mastectomy in early breast cancer after neoadjuvant systemic therapy: Results from the Swedish national breast cancer register (NKBC)

Abstract Background: Population-based studies have consistently shown improved long-term outcomes with breast conserving surgery (BCS) plus radiotherapy (RT) vs. mastectomy in primarily operated breast cancer (BC) patients. However, the survival impact of type of local therapy following modern neoadjuvant systemic therapy (NST) is unclear. Methods: The population-based Swedish National Breast Cancer Register (NKBC), a prospectively collected population-based cohort, was used to identify female BC patients who were diagnosed from January, 2007 until December, 2017 and received NST in the Stockholm region. Patients were divided into BCS+RT and mastectomy groups, and the prognostic factors reflecting the response to NST like pathologic complete response (pCR) and Neo-bioscore calculated by pre/postoperative TNM stage, nuclear grade, and receptors status, were used for stratification. Disease-free survival (DFS), locoregional recurrence-free survival (LRFS), distant metastasis-free survival (DMFS) and overall survival (OS) were evaluated using inverse probability of treatment weighted (IPTW) Cox proportional hazards model, which enables covariates like age, St Gallen subtypes, cTNM and ypTNM stages to be balanced between the two groups. Results: Among 1,409 eligible women, 456 (32.4%) were treated with BCS+RT, and 953 (67.6%) with mastectomy. Overall, 87 (6.2%) local recurrences, 256 (18.2%) distant metastases, and 282 (20.0%) deaths occurred over a median follow-up of 61 months. Patients diagnosed during later years, younger patients, patients with earlier stage and higher-grade tumors were more likely to receive BCS+RT. After adjusting for age at diagnosis, Neo-bioscore, adjuvant chemotherapy and radiotherapy, significant improvements for BCS+RT compared with mastectomy were observed in DFS (weighted-multivariate hazard ratio (HR), 0.51; 95%CI, 0.28-0.93; median 5-year DFS: 79.1% vs 73.6%) and DMFS (HR, 0.44; 95%CI, 0.23-0.82; median 5-year DMFS: 83.7% vs 74.8%), but no difference was identified in LRFS (HR, 0.94; 95%CI, 0.29-3.07; median 5-year LRFS: 89.9% vs 92.0%) or OS (HR, 0.7; 95%CI, 0.34-1.45; median 5-year OS: 88.4% vs 81.2%). The DFS benefit was observed regardless of pCR status, but varied by Neo-bioscore. Patients with Neo-bioscore 4-7 treated with BCS+RT had better DFS (HR, 0.31; 95%CI, 0.12-0.81) compared with those undergoing mastectomy, whereas low-risk patients with Neo-bioscore 0-3 had similar DFS between the two groups. Both triple negative (N=252; HR for DFS, 0.26; 95%CI, 0.07-0.97) and HER2-positive (N=533; HR for DFS, 0.24, 95%CI, 0.09-0.68) BC patients benefited from BCS+RT, but not patients with luminal tumors (N=589; HR for DFS, 0.82, 95%CI, 0.31-2.18). Similarly, superior DFS with BCS+RT was also seen in patients with neoadjuvant anti-HER2 targeted therapy (N=505; HR, 0.19; 95%CI, 0.05-0.75) or neoadjuvant chemotherapy alone (N=594; HR, 0.47; 95%CI, 0.21-1.06), but not among those receiving neoadjuvant endocrine therapy (N=162; HR, 0.53; 95%CI, 0. 1-2.85). Conclusion: After adjusting for response to NST and other confounders, BCS+RT was associated with reduced risks of tumor recurrence or metastasis compared with mastectomy. This benefit was more pronounced in patients with high Neo-bioscore, indicating that Neo-bioscore rather than pCR status has the potential to tailor breast surgery after NST. Further studies with larger sample size or prospective randomized clinical trials are warranted to confirm our findings. Citation Format: Kang Wang, Aafke Duinmeijer, Alexios Matikas, Renske Altena, Hemming Johansson, Hanna Fredholm, Theodoros Foukakis. Long-term outcomes for breast conservation plus radiotherapy versus mastectomy in early breast cancer after neoadjuvant systemic therapy: Results from the Swedish national breast cancer register (NKBC) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-18-03.

Abstract ES6-2: CDK4/6 for ER+

Abstract Hormone receptor positive (HR+) breast cancer is the most common subtype of breast cancer. A reasonable proportion of HR+ tumors recur during or following adjuvant endocrine therapy, and late recurrences (beyond 10 years from diagnosis) are not uncommon. The CDK4/6 inhibitors palbociclib, ribociclib and abemaciclib were approved in combination with endocrine therapy for the treatment of first and second-line metastatic HR+ breast cancer, based on impressive improvements in progression-free survival and overall survival. Therefore, transitioning these drugs to the adjuvant setting in high-risk patients made sense, to further prevent short and long-term metastatic recurrence of HR+ breast cancer. To date, 3 of the 4 phase III clinical trials with CDK4/6 inhibitors in the adjuvant setting have been reported, with mixed results. Penelope-B and PALLAS, both exploring the use of palbociclib for 1 and 2 years, respectively, along with endocrine therapy in patients with high-risk clinical characteristics failed to demonstrate a benefit in 4-years and 2-years disease-free survival (DFS), despite an early signal of benefit in the Penelope-B trial at 2-years. The Monarch-E trial, using abemaciclib for 2 years along with endocrine therapy for patients with very high anatomical and biologic recurrence risk, has shown a 3% higher 2-years DFS than endocrine therapy alone, but follow-up is quite short (19 months), and it is unclear if it will be maintained over time. The NATALEE trial, using ribociclib for 3 years with endocrine therapy is expected to yield results in 2025. These data highlight several questions that remained unanswered. Are the CDK4/6 inhibitors different from each other despite an identical mechanism of action? Does duration of treatment matter? Does disease biology matter? Discontinuation rates, albeit different between these trials, seems to be an unlikely answer for the discrepant results. Fortunately, all these adjuvant trials have collected a rich biorepository of tissue and blood, which allows the investigators to better ellucidate unique biomarkers that may predict individual benefit for each of the approved CDK4/6 inhibitors, that will hopefully guide optimal patient selection and treatment combinations. Till then, longer follow-up on the Monarch-E and NATALEE trials are necessary to explore if CDK4/6 inhibitors should or not be incorporated to endocrine therapy in the adjuvant setting for patients at high-risk of metastatic recurrence. Citation Format: IA Mayer. CDK4/6 for ER+ [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr ES6-2.

Abstract GS4-09: Quality of life results from OlympiA: A phase III, multicenter, randomized, placebo-controlled trial of adjuvant olaparib after (neo)-adjuvant chemotherapy in patients with germline BRCA1/2 mutations and high-risk HER-2 negative early breast cancer

Abstract Background: The primary results from the OlympiA trial were recently reported (NEJM, 2021) after an interim analysis demonstrated statistically significant invasive disease-free survival (DFS) benefit from 1 year of olaparib (OL) vs. placebo (PL) after 2.5 yrs median follow-up. Although there were fewer deaths with OL than PL, overall survival (OS) did not reach the statistical significance threshold prespecified for interim analysis. The initial publication also reported on the adverse event profile, which was similar to that previously reported, as well as Global Health Status/Quality of Life (GHQ), a secondary endpoint for the Patient-Reported Outcome (PRO) sub-study. The full protocol-specified PRO analyses are presented here. Methods: The OlympiA randomized phase III trial (NCT02032823, BIG 6-13, NSABP B-55) tested the role of 1 year of adjuvant OL after completion of (neo)adjuvant chemotherapy and definitive local therapy on invasive DFS, distant DFS and OS, and sought to collect PRO data from all eligible patients (pts) prior to randomization, on treatment (trt) (6 and 12 months [mos]), and after trt (18 and 24 mos) using validated questionnaires available in multiple languages. Fatigue, the primary PRO endpoint, was measured with the FACIT-Fatigue Scale in which a clinically meaningful (CM) difference is ≥3 points. Secondary PRO endpoints included gastrointestinal (GI) symptoms (nausea and vomiting [NV], diarrhea) and multiple quality of life (QOL) domains assessed with the EORTC QLQ-C-30 questionnaire (CM differences: small 5-10 points, moderate 10-20 points [Osoba, 1998]). The primary protocol-specified PRO hypothesis was that during trt pts treated with OL may experience greater fatigue severity at 6 and 12 mos. Secondary PRO hypotheses included: a) pts receiving OL may experience greater severity of GI symptoms at 6 and 12 mos with no difference by 24 mos; b) no difference in fatigue severity post-trt at 18 and 24 mos; and c) no difference in QOL over duration of the PRO sub-study between OL and PL as measured by the GHQ score and other EORTC QLQ-C30 subscales. A mixed model for repeated measures analysis compared the primary and secondary endpoints scores. Separate analyses were performed for neoadjuvant (NAC) and adjuvant (AC) chemotherapy subgroups due to differences in interval from NAC and AC to randomization. Two-sided p-values &amp;lt;0.05 were considered statistically significant. Results: Of 1,836 randomized pts, 1,751 (NAC: 875 [OL:440, PL: 435], AC: 876 [OL:436, PL:440]) were included in the PRO sub-study. Baseline QOL and symptom scores did not differ between OL and PL. Fatigue severity was statistically significantly greater in pts treated with OL than with PL at 6 mos (diff OL vs. PL: NAC -1.3 [95%CI -2.4, -0.2], p=0.024; AC -1.3 [-2.3,-0.2], p=0.017) and 12 mos (NAC -1.5 [-2.8,-0.2] p=0.025; AC -1.3 [-2.4,-0.1] p=0.027); however, the differences did not meet the pre-specified criterion for CM with the FACIT-Fatigue Scale. There were no meaningful differences in fatigue severity at 18 and 24 mos. NV symptom severity was worse in pts treated with OL than with PL with small differences at 6 mos (NAC: 6.0 [4.0, 8.0], p&amp;lt;0.001, AC: 5.3 [3.4,7.2], p&amp;lt;0.001) and 12 mos (NAC: 6.3 [4.4, 8.2], p&amp;lt;0.001, AC: 4.5 [2.8,6.2], p&amp;lt;0.001), and no differences at 18 and 24 mos. In general, there were no CM differences between OL and PL in terms of other symptoms and QOL subscales with improvements in functioning over time. Conclusions: Increased trt-emergent symptoms with OL were small and resolved after trt. QOL scores were similar and slowly improved during the 24 mos after (neo) adjuvant chemotherapy. Support: U10CA180868, -180822, UG1CA189867, AstraZeneca, Merck and Co, Inc. NCT02032823 Citation Format: Patricia A Ganz, Hanna Bandos, Tanja Spanic, Sue Friedman, Volkmar Müller, Sherko Kümmel, Suzette Delaloge, Etienne Brain, Masakazu Toi, Hideko Yamauchi, Eduardo-Martínez de Dueñas, Anne Armstrong, Seock-Ah Im, Chuangui Song, Hong Zheng, Tomasz Sarosiek, Priyanka Sharma, Giovanna Rossi, Priya Rastogi, Anitra Fielding, Richard D Gelber, Christine Campbell, Judy E Garber, Charles E Geyer, Jr, Andrew NJ Tutt, On behalf of the OlympiA Trial Steering Committeeand Investigators. Quality of life results from OlympiA: A phase III, multicenter, randomized, placebo-controlled trial of adjuvant olaparib after (neo)-adjuvant chemotherapy in patients with germline BRCA1/2 mutations and high-risk HER-2 negative early breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr GS4-09.

Epigenetics-Associated Risk Reduction of Hematologic Neoplasms in a Nationwide Cohort Study: The Chemopreventive and Therapeutic Efficacy of Hydralazine.

BackgroundAlthough several epigenetic drugs have been reported to have therapeutic efficacy for some hematologic neoplasms (HNs) in clinical trials, few achieved disease-free survival benefit. The traditional drug discovery pathway is costly and time-consuming, and thus, more effective strategies are required. We attempted to facilitate epigenetic drug repositioning for therapy of HNs by screening the Human Epigenetic Drug Database (HEDD) in the web, conducting a bench-work cytotoxicity test and a retrospective nationwide cohort study prior to a clinical trial.MethodsFour FDA-approved epigenetic drugs with antitumor properties and completion of clinical phase II trials were selected from HEDD. Hydralazine (HDZ) and valproate (VAL) among the four were selected with higher cytotoxicity to HN cells, no matter whether carrying the JAK2V617F mutation or not. Both of them were chosen for a cohort study using the Longitudinal Health Insurance Database (LHID) 2000–2015 (N = 1,936,512), a subset of the National Health Insurance Research Database (NHIRD, N= 25.68 millions) in Taiwan.ResultsIn the initial cohort, HDZ or VAL exposure subjects (11,049) and matching reference subjects (44,196) were enrolled according to maximal daily consumption (300/2,100 mg per day of HDZ/VAL). The HN incidence in HDZ and VAL exposure groups reduced from 4.97% to 3.90% (p <.001) and 4.45% (p = .075), respectively. A further cohort study on HDZ at a lower range of the WHO defined daily dose (<34 mg per day) and HN incidence of HDZ exposure subjects (75,612) reduced from 5.01% to 4.16% (p = 1.725 × 10 -18) compared to the reference subjects (302,448).ConclusionsAn association of a chronically prescribed HDZ, even prescribed low dose, with reduction of overall incidence rate and in most subgroups of HN was observed in our study. Repositioning HDZ for HN management may be feasible. This is the first nationwide cohort study of the epigenetics-associated risk evaluation of overall HN in the existing literature, showing an effective method with a wider scope to inform contemporary clinical trials of epigenetic drugs in the future.

Diffusion-Weighted Magnetic Resonance Imaging-Guided Dose Painting in Patients With Locoregionally Advanced Nasopharyngeal Carcinoma Treated With Induction Chemotherapy Plus Concurrent Chemoradiotherapy: A Randomized, Controlled Clinical Trial

We hypothesized that diffusion-weighted magnetic resonance imaging (DWI)-guided dose-painting intensity modulated radiation therapy (DP-IMRT) is associated with improved local tumor control and survival in locoregionally advanced nasopharyngeal carcinoma (NPC). The purpose of this randomized study was to compare the efficacy and toxicity of DWI-guided DP-IMRT to conventional magnetic resonance imaging (MRI)-based IMRT in locoregional advanced NPC. A total of 260 patients with stage III-IVa NPC disease were randomly assigned in a 1:1 ratio to receive induction chemotherapy followed by chemoradiotherapy by DWI-guided DP-IMRT (group A, n=130) or conventional MRI-based IMRT (group B, n=130) in this prospective clinical trial. In group A, subvolume GTVnx-DWI (gross tumor volume of nasopharynx in DWI) was defined as the areas within the GTVnx (gross tumor volume of nasopharynx) with an apparent diffusion coefficient (ADC) below the mean ADC (ADC < mean) according to MRI before induction chemotherapy. The dose to GTVnx-DWI was escalated to 75.2 Gy/32 fx in patients with T1-2 disease and to 77.55 Gy/33 fx in those with T3-4 disease in 2.35 Gy per fraction. In group B, planning gross tumor volumeof nasopharynx was irradiated at 70.4 to 72.6 Gy/32 to 33 fx in 2.2 Gy per fraction. This trial is registered with chictr.org.cn (ChiCTR1800015779). A total of 260 patients were included in the trial (130 patients in group A and 130 in group B). Complete response rates after chemoradiotherapy were 99.2% (129 of 130) and 93.8% (122 of 130) in groups A and B, respectively (P=.042). At a median follow-up of 25 months, DWI-guided DP-IMRT was associated with improved 2-year disease-free survival (DFS; 93.6% [95% confidence interval {CI}, 88.1%-99.1%] vs 87.5% [95% CI, 81.4%-93.6%], P=.015), local recurrence-free survival (100% [95% CI, not applicable {NA}] vs 91.3% [95% CI, 85.4%-97.2%]), locoregional recurrence-free survival (LRRFS; 95.8% [95% CI, NA] vs 91.3% [95% CI, 85.4%-97.2%]), distant metastasis-free survival (DMFS; 97.8% [95% CI, NA] vs 90.9% [95% CI, 85.8%-96.0%]), and overall survival (100% [95% CI, NA] vs 94.5% [95% CI, 89.2%-99.8%]). Zero and 3 patients had local-only recurrences in group A and B, respectively. The most common site of first failure in each arm was distant organ failure. No statistically significant differences in acute and late toxic effects were observed. Multivariate analyses showed that DP (DWI-guided DP-IMRT vs conventional MRI-based IMRT without DP) was associated with DFS, local recurrence-free survival, LRRFS, and distant metastasis-free survival. Epstein-Barr virus DNA level was associated with DFS and LRRFS. DWI-guided DP-IMRT plus chemotherapy is associated with a disease-free survival benefit compared with conventional MRI-based IMRT among patients with locoregionally advanced NPC without increasing acute toxic effects.