Significant Disease-free Survival Benefit Research Articles

The role of immune checkpoint inhibitors (ICI) as adjuvant treatment in renal cell carcinoma (RCC): A systematic review and meta-analysis.

Pembrolizumab, a PD-1 ICI is approved for the adjuvant treatment of postnephrectomy patients with clear cell RCC in some countries worldwide. However, recent negative data from randomized clinical trials (RCT) with another ICIs makes the benefit of this treatment uncertain. A systematic review and study-level meta-analysis was performed to evaluate the benefit of disease-free survival (DFS) with adjuvant ICI treatment for patients with localized and/or metastatic resected RCC. Using the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) statement, a systematic search was performed in PUBMED/MEDLINE, Scopus and EMBASE up to September 15, 2022. The statistical analysis was performed by ProMeta 3 software in intention-to-treat (ITT) population and in predetermined subgroups. Four RCT totalizing 3407 patients were included in this analysis. Systemic immunotherapy was pembrolizumab, atezolizumab, nivolumab, and ipilimumab plus nivolumab in 496, 390, 404, and 405 patients, respectively. In the ITT population there was a nonstatistically significant DFS benefit with adjuvant ICI (HR: 0.85, 95% CI: 0.69-1.04). Regarding the subgroups, there was a DFS benefit for PD-L1 positive (HR: 0.72; 95% CI: 0.55-0.94), intermediate-high risk patients (HR: 0.77; 95% CI: 0.63-0.94), and patients with sarcomatoid component (HR: 0.66; 95% CI: 0.43-0.99). This meta-analysis did not demonstrate a statistically significant DFS benefit in overall population, however considering the heterogeneity between the RCTs the use of adjuvant ICI should be individualized.

MP28-18 ADJUVANT IMMUNOTHERAPY IN RENAL CELL CARCINOMA: A SYSTEMATIC REVIEW AND META-ANALYSIS OF RANDOMIZED CLINICAL TRIALS

You have accessJournal of UrologyCME1 Apr 2023MP28-18 ADJUVANT IMMUNOTHERAPY IN RENAL CELL CARCINOMA: A SYSTEMATIC REVIEW AND META-ANALYSIS OF RANDOMIZED CLINICAL TRIALS Emily Huang, Carlos Riveros, Sanjana Ranganathan, Zachary Klaassen, Rini Brian, Christopher Wallis, and Raj Satkunasivam Emily HuangEmily Huang More articles by this author , Carlos RiverosCarlos Riveros More articles by this author , Sanjana RanganathanSanjana Ranganathan More articles by this author , Zachary KlaassenZachary Klaassen More articles by this author , Rini BrianRini Brian More articles by this author , Christopher WallisChristopher Wallis More articles by this author , and Raj SatkunasivamRaj Satkunasivam More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003256.18AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Despite surgical resection, many patients with high-risk renal cell carcinoma (RCC) experience recurrence. Following approvals in metastatic RCC, there has been interest in using immune checkpoint inhibition (ICI) in the adjuvant setting. The objective of this study is to synthesize available data regarding the disease-free survival (DFS) benefit of adjuvant ICIs for patients with RCC and evaluate the overall safety profile of ICIs in this setting. METHODS: PubMed, Embase, and relevant conference proceedings were searched from inception up to September 18, 2022. Phase III randomized controlled trials (RCTs) comparing adjuvant ICI versus placebo/observation were included. Study screening and selection, along with data extraction was performed in duplicate according to a predefined registered protocol. The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline and the Cochrane Collaboration’s tool for assessing risk of bias were used. All outcomes were analyzed using random-effects meta-analysis owing to interstudy heterogeneity. Sensitivity and subgroup analyses were performed to identify potential sources of heterogeneity. The primary outcome of interest was DFS. Variables for subgroup analyses were PD-L1 expression, sarcomatoid features, nephrectomy type, and disease-risk category. Secondary outcomes included grade ≥3 adverse events (AEs), immune-related AEs, and treatment discontinuation due to AEs. RESULTS: Among the four included studies, one demonstrated a significant DFS benefit. There was considerable clinical and statistical heterogeneity (I2=64%) due to differences in inclusion criteria and interventions. While pooled results across the four studies did not demonstrate a significant benefit in DFS overall (HR 0.85, 95% CI 0.69-1.04), there was significant benefit among patients with positive PD-L1 expression (HR 0.72, 95% CI 0.55-0.94) or sarcomatoid features (HR 0.59, 95% CI 0.38-0.91). CONCLUSIONS: The evidence base to date regarding ICI as adjuvant therapy in RCC is mixed – conclusions are limited by considerable heterogeneity between studies. However, pooled analyses suggest that patients with positive PD-L1 expression or sarcomatoid features are most likely to benefit from adjuvant immunotherapy. Source of Funding: None © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e378 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Emily Huang More articles by this author Carlos Riveros More articles by this author Sanjana Ranganathan More articles by this author Zachary Klaassen More articles by this author Rini Brian More articles by this author Christopher Wallis More articles by this author Raj Satkunasivam More articles by this author Expand All Advertisement PDF downloadLoading ...

Association between physical activity and the time course of cancer recurrence in stage III colon cancer

ObjectiveWe determined if postoperative physical activity prevents or delays cancer recurrence in patients with stage III colon cancer.MethodsThis cohort study nested within a randomised trial enrolled 1696 patients with surgically...

Abstract PD9-07: Role of immunosuppressive JNK pathway in the tumor microenvironment among Triple Negative Breast Cancer subtypes in IBCSG Trial 22-00

Abstract BACKGROUND: Although the triple-negative breast cancer (TNBC) tumor microenvironment (TME) has been deeply characterized, much remains unknown about pathways attributing to an immunosuppressive TME in this disease. The phosphorylation of JNK (c-Jun N-terminal kinase) pathway has been associated with promoting an immunosuppressive phenotype, enhancing TNBC aggressiveness. Here, we aimed to explore the role of the JNK pathway in TNBC using a gene signature inferring the level of JNK phosphorylation. For this purpose, we used the TNBC cohort from the phase III adjuvant IBCSG 22-00 trial, which evaluated low-dose cyclophosphamide and methotrexate (CM) chemotherapy showing no clinical benefit in the overall population. METHODS: JNK gene signature was developed in TNBC samples by integrating RNA-seq gene expression data and phospho-JNK-targeted proteomic data in The Cancer Genome Atlas. Stochastic subsampling was performed to select the candidate markers. LASSO regression was performed to determine the final transcriptional signature to reflect JNK phosphorylation. The signature was then applied in a cohort composed of 498 TNBCs selected using stratified 1:3 relapse cases and non-relapse subcohort ratio from the IBCSG 22-00 trial. RNA-seq data from FFPE tumor samples were available for 347 patients. The JNK signature was calculated as the mean of the products between gene expression and signature coefficients, defining high and low levels using the median cut-off. Immune hot tumors were defined according to TNBC molecular subtypes or tumor-infiltrating lymphocytes (TILs) levels higher than 30%. Multivariable Cox models were used for disease-free survival (DFS) analysis. Wilcoxon test was used to evaluate the association between gene signatures and the levels of JNK. RESULTS: Tumors with either immunomodulatory (IM) phenotype or high TILs showed better DFS when presenting low levels of JNK compared to high levels (HR = 0.75, 95% CI, 0.57 to 0.99; P-value = 0.024 and HR = 0.62, 95% CI, 0.43 to 0.89, P-value = 0.0013). No significant differences in DFS were observed in other TNBC subtypes or tumors with low TILs, further highlighting the relevance of JNK signaling pathway in tumors presenting immune infiltration. Moreover, immune hot tumors with high levels of JNK were enriched for angiogenesis and eosinophils signatures and linked to immunosuppression. The immune targets B7-H3, CSF1R, GITR, and GARP were significantly associated with high levels of JNK. Of note, these genes are involved in the immune escape, activation of macrophages, and regulation of Tregs population. On the other hand, low levels of JNK were associated with higher levels of activated CD8+ T cells, pointing to an anti-tumor immune response, as well as with higher levels of the immune targets PDL-1, CTLA4, CD47, DCIR, and TIGIT. Of interest, a significant DFS benefit was found in IM tumors with high levels of JNK when treated with low-dose CM, compared to those who were not (HR = 0.52, 95% CI, 0.28 to 0.99; P interaction = 0.045). CONCLUSIONS: We developed a JNK gene signature to estimate the phosphorylation level of JNK from gene expression data in TNBC, and validated the associated biological and prognostic value in the IBCSG 22-00 trial. Our results are in line with the immunosuppressive effect described by the JNK gene signature and highlight the heterogeneity of immune response in immune hot TNBCs. Of note, high levels of JNK were associated with worse DFS, as well as with a benefit from low-dose CM potentially related to the immunomodulatory effect described for metronomic regimens. Overall, our findings suggest a potential role of the JNK signature in identifying TNBCs with an immunosuppressive TME and provide the rationale to explore its role as a biomarker for immunotherapy. Further validation of these findings is required. Citation Format: Andrea Joaquin Garcia, Takashi Semba, Mattia Rediti, Daniel J. McGrail, Xuemei Xie, Xiaoping Wang, Dileep R. Rampa, David Venet, Samira Majjaj, Roswitha Kammler, Marco Colleoni, Sherene Loi, Giuseppe Viale, Meredith Regan, Françoise Rothé, Christos Sotiriou, Naoto T. Ueno. Role of immunosuppressive JNK pathway in the tumor microenvironment among Triple Negative Breast Cancer subtypes in IBCSG Trial 22-00 [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD9-07.

Adjuvant immunotherapy in renal cell carcinoma: asystematic review and meta-analysis.

To synthesise available data regarding the disease-free survival (DFS) benefit of adjuvant immune checkpoint inhibitors (ICIs) for patients with renal cell carcinoma (RCC) and evaluate the overall safety profile of ICIs in this setting. We utilised PubMed, Embase, and relevant conference proceedings to identify phase III randomised controlled trials comparing adjuvant ICIs vs placebo/observation for RCC. The primary outcome of interest was DFS. Variables for subgroup analyses were programmed death-ligand 1 (PD-L1) expression, sarcomatoid features, nephrectomy type, and disease-risk category. Secondary outcomes included Grade ≥3 adverse events (AEs), immune-related AEs, and treatment discontinuation due to AEs. All outcomes were analysed using random-effects models owing to inter-study heterogeneity. Among the four included studies, one demonstrated a significant DFS benefit. There was considerable clinical and statistical heterogeneity (I2 = 64%) due to differences in inclusion criteria and interventions. While pooled results across the four studies did not demonstrate a significant benefit in DFS overall (hazard ratio [HR] 0.85, 95% confidence interval [CI] 0.69-1.04) there was significant benefit among patients with positive PD-L1 expression (HR 0.72, 95% CI 0.55-0.94) and sarcomatoid features (HR 0.59, 95% CI 0.38-0.91). The evidence base to date regarding ICIs as adjuvant therapy in RCC is mixed - conclusions are limited by considerable heterogeneity between studies. However, pooled analyses suggest that patients with positive PD-L1 expression or sarcomatoid features are most likely to benefit from adjuvant immunotherapy.

Adjuvant immunotherapy in renal cell carcinoma: A systematic review and meta-analysis of randomized clinical trials.

671 Background: There has been interest in adjuvant immune checkpoint inhibition (ICI) following surgical resection in patients with high-risk renal cell carcinoma (RCC) given high recurrence rates and approvals of ICI in metastatic RCC. The primary objective of this analysis was to synthesize available data regarding the disease-free survival (DFS) benefit of adjuvant ICIs for patients with RCC. Methods: This systematic review was performed according to the PRISMA guidelines. The protocol was registered in PROSPERO (CRD42022361599). We searched PubMed, EMBASE, and relevant conference proceedings to identify phase III randomized controlled trials (RCTs) comparing adjuvant ICI versus placebo/observation. The primary outcome of interest was DFS. Results: Among the four included studies, one demonstrated a significant DFS benefit. There was considerable clinical and statistical heterogeneity (I2=64%) due to differences in inclusion criteria and interventions. While pooled results across the four studies did not demonstrate a significant benefit in DFS overall (HR 0.85, 95% CI 0.69-1.04), there was significant benefit among patients with positive PD-L1 expression (HR 0.72, 95% CI 0.55-0.94) or sarcomatoid features (HR 0.59, 95% CI 0.38-0.91). Conclusions: The evidence base to date regarding ICI as adjuvant therapy in RCC is mixed – conclusions are limited by considerable heterogeneity between studies. However, pooled analyses suggest that patients with positive PDL1 expression or sarcomatoid features are most likely to benefit from adjuvant immunotherapy.

Prevalence, clinical and molecular characteristics of early stage EGFR-mutated lung cancer in a real-life West-European cohort: Implications for adjuvant therapy

ObjectivesThe landmark ADAURA study recently demonstrated a significant disease-free survival benefit of adjuvant osimertinib in patients with resected EGFR-mutated lung adenocarcinoma. However, data on prevalence rates and stage distribution of EGFR mutations in non-small cell lung cancer in Western populations are limited since upfront EGFR testing in early stage lung adenocarcinoma is not common practice. Here, we present a unique, real-world, unselected cohort of lung adenocarcinoma to aid in providing a rationale for routine testing of early stage lung cancers for EGFR mutations in the West-European population. Material and methodsWe performed routine unbiased testing of all cases, regardless of TNM stage, with targeted next-generation sequencing on 486 lung adenocarcinoma cases between 01- January 2014 and 01 February 2020. Clinical and pathological data, including co-mutations and morphology, were collected. EGFR-mutated cases were compared to KRAS-mutated cases to investigate EGFR-specific characteristics. ResultsIn total, 53 of 486 lung adenocarcinomas (11%) harboured an EGFR mutation. In early stages (stage 0-IIIA), the prevalence was 13%, versus 9% in stage IIIB-IV. Nine out of 130 (7%) stage IB-IIIA patients fit the ADAURA criteria. Early stage cases harboured more L858R mutations (p = 0.02), fewer exon 20 insertions (p = 0.048), fewer TP53 co-mutations (p = 0.007), and were more frequently never smokers (p = 0.04) compared to late stage cases with EGFR mutations. The KRAS-mutated cases were distributed more evenly across TNM stages compared to the EGFR-mutated cases. ConclusionAs (neo-)adjuvant targeted therapy regimes enter the field of lung cancer treatment, molecular analysis of early stage non-small cell lung cancer becomes relevant. Testing for EGFR mutations in early stage lung adenocarcinoma holds a substantial yield in our population, as our number needed to test ratio for adjuvant osimertinib was 14.4. The observed differences between early and late stage disease warrant further analysis to work towards better prognostic stratification and more personalised treatment.

Adjuvant Immunotherapy in Patients with Early-Stage Non-small Cell Lung Cancer and Future Directions.

While cisplatin-based adjuvant chemotherapy has been the standard of care for the past two decades, the recent introduction of immunotherapy has heralded an important milestone in the adjuvant landscape of early-stage non-small cell lung cancer (NSCLC). The landmark approval of adjuvant atezolizumab based on disease-free survival (DFS) benefit in IMpower010 was swiftly followed by the recent data for use of adjuvant pembrolizumab in PEARLS/KEYNOTE-091, and similar trials involving other immune checkpoint inhibitors are eagerly anticipated. Although both atezolizumab and pembrolizumab demonstrated a significant DFS benefit in the intention-to-treat population, key subgroup analyses have raised questions about the role of predictive biomarkers such as PD-L1 expression and EGFR-mutation status. In this review, we examine the data from the two important trials (IMpower010 and PEARLS/KEYNOTE-091), discuss the controversies surrounding adjuvant immunotherapy including appropriate endpoints, biomarker selection and highlight key considerations in oncogene-driven NSCLC. Finally, we propose future directions including the impact of neoadjuvant therapy on developments in the adjuvant immunotherapy paradigm and role of minimal residual disease (MRD).

2021 Updated European Association of Urology Guidelines on the Use of Adjuvant Pembrolizumab for Renal Cell Carcinoma

Adjuvant treatment of nonmetastatic high-risk renal cell carcinoma is an unmet medical need. In the past, several tyrosine kinase inhibitor trials have failed to demonstrate an improvement of disease-free survival (DFS) in this setting. Only one trial (S-TRAC) provided evidence for improved DFS with sunitinib but without an overall survival (OS) signal. Keynote-564 is the first trial of an immune checkpoint inhibitor that significantly improved DFS with adjuvant pembrolizumab, a programmed death receptor-1 antibody, in clear cell renal cell carcinoma with a high risk of relapse. The intention-to-treat population, which included a group of patients after metastasectomy and no evidence of disease (M1 NED), had a significant DFS benefit. The OS data are not mature as yet. The Renal Cell Carcinoma Guideline Panel issues a weak recommendation for the adjuvant use of pembrolizumab for high-risk clear cell renal carcinoma, as defined by the trial until final OS data are available. However, the trial reilluminates the discussion on when and in whom metastasectomy should be performed. Here, caution is necessary not to perform metastasectomy in patients with poor prognostic features and rapid progressive disease, which must be excluded by a confirmatory scan of disease status prior to planned metastasectomy. Patient summaryNew data from the adjuvant immune checkpoint inhibitor trial with pembrolizumab (a programmed death receptor-1 antibody) for the treatment of high-risk clear cell renal cell carcinoma (ccRCC) after surgery showed that the drug prolonged the period of being cancer free significantly, although whether it prolonged survival remained uncertain. Consequently, pembrolizumab is cautiously recommended as additional (ie, adjuvant) treatment in high-risk ccRCC after kidney cancer surgery.

IMpower010: Primary results of a phase III global study of atezolizumab versus best supportive care after adjuvant chemotherapy in resected stage IB-IIIA non-small cell lung cancer (NSCLC).

8500 Background: Adjuvant platinum-based chemotherapy (chemo) provides only a modest 5-year survival benefit in fully resected, high-risk early-stage NSCLC. We report the primary disease-free survival (DFS) results from the pre-planned interim analysis of IMpower010, a randomized phase 3 open-label trial of adjuvant atezolizumab (atezo; anti–PD-L1) vs best supportive care (BSC) after adjuvant chemo in patients (pts) with early-stage resected NSCLC. Methods: Eligible pts had completely resected (4-12 weeks prior to enrollment) Stage IB (≥4 cm)-IIIA NSCLC (AJCC/UICC v7) and ECOG PS 0-1. A total of 1280 pts were enrolled, and 1269 pts received up to four 21-day cycles of cisplatin-based chemo (plus pemetrexed, docetaxel, gemcitabine or vinorelbine). Of these pts (n=1269), 1005 were subsequently randomized 1:1 to 16 cycles of atezo 1200 mg Q3W or BSC. The primary endpoint of investigator-assessed DFS and secondary endpoint of overall survival (OS) were tested hierarchically: first DFS in the PD-L1 TC ≥1% (SP263) subgroup with Stage II-IIIA disease, then DFS in all randomized pts with Stage II-IIIA disease, then DFS in the ITT population (Stage IB-IIIA) and finally OS in the ITT population. Efficacy assessments were based on randomized pts. Safety was assessed in the safety-evaluable population, defined as pts who received ≥1 dose of atezo or who had ≥1 post-baseline safety assessment if randomized to the BSC arm. Results: At data cutoff (January 21, 2021), median follow-up was 32.2 months in the ITT population. Baseline characteristics were generally balanced between arms. Atezo showed statistically significant DFS benefit vs BSC in the PD-L1 TC ≥1% Stage II-IIIA and all randomized Stage II-IIIA populations; the significance boundary was not crossed for DFS in the ITT population (Table). OS data were immature and not formally tested. Pts in the atezo arm received a median of 16 (range, 1-16) atezo doses. Any-grade AEs occurred in 92.7% (atezo) and 70.7% (BSC); events were Grade 3/4 in 21.8% and 11.5%, respectively. Grade 5 treatment-related AEs occurred in 0.8% of pts in the atezo arm. AEs leading to atezo discontinuation occurred in 18.2% of atezo-treated pts. Conclusions: IMpower010 met its primary endpoint, showing DFS benefit with adjuvant atezo vs BSC after adjuvant chemo in pts with resected Stage II-IIIA NSCLC, with pronounced benefit in the PD-L1 TC ≥1% subgroup. The safety profile of atezo was consistent with prior experience of atezo monotherapy across indications and lines of therapy. Funding: F. Hoffmann-La Roche Ltd. Clinical trial information: NCT02486718. [Table: see text]

Optimum adjuvant trastuzumab duration for human epidermal growth factor receptor-2 positive breast cancer: a network meta-analysis of randomized trials.

BackgroundAdjuvant trastuzumab treatment for 12 months is the standard-of-care for early HER2-positive breast cancer; however, the optimal duration is unclear. We performed a network meta-analysis (NMA) to determine the optimal treatment duration.MethodsWe identified 16 randomized controlled trials involving 29,837 patients that assessed trastuzumab treatment in HER2-positive early breast cancer. Our NMA compared six trastuzumab durations: observation, T-9 weeks, T-12 weeks, T-6 months, T-12 months, and T-24 months. We assessed overall survival (OS), disease-free survival (DFS), acceptability, and cardiotoxicities and grade 3–4 nonhematologic toxicities, and ranked the durations in terms of efficacy and safety by surface under the cumulative ranking (SUCRA).ResultsPairwise meta-analysis showed that while T-6 months was associated with a significant reduction in DFS compared to T-12 months. In our NMA, increasing or decreasing durations showed a significant benefit in DFS compared to observation; however, decreasing durations was not associated with a significant reduction in DFS compared with T-12 months, regardless of the lymph node and hormone receptor statuses. SUCRA ordered the optimum durations of trastuzumab treatment based on PFS as T-12 months (95.6%), T-24 months (69.6%), T-6 months (53.2%), T-9 weeks (41.2%), T-12 weeks (34.3%) and observation (6.1%).ConclusionsEscalating trastuzumab treatment beyond T-12 months confers no additional survival benefit but increased risk of cardiotoxicities. Furthermore, de-escalating treatment confers no improvement on OS compared to T-12 months. These data suggest that T-12 months is the most appropriate treatment schedule for HER2-positive early breast cancer.

Adjuvant Chemotherapy in High-Risk Prostate Cancer Patients after Primary Local Therapy: Recurrence, Metastasis, and Survival – A Meta-Analysis

Context: Several randomized clinical trials (RCTs) have recently tested adjuvant chemotherapy to high-risk prostate cancer patients (PCA) after primary local therapy. Objective: The aim of the study was to perform a systematic review and meta-analysis of RCTs evaluating the adjuvant chemotherapy in high-risk prostate cancer patients after primary local therapy. The primary endpoint was overall survival (OS). The secondary endpoint was disease-free survival (DFS) and biochemical recurrence-free survival (BRFS). Methods: A systematic review of PubMed/Medline, Embase, and Cochrane databases was performed to identify relevant studies published in English up to March 2020. Six trials were selected for inclusion. Results: There were 7 studies included in the present study. The meta-analysis did not show a significant OS benefit from adjuvant chemotherapy in patients with high-risk prostate cancer after primary local therapy (hazard ratio [HR]: 0.87; 95% confidence interval [CI], 0.72–1.05; p = 0.15). But docetaxel in patients with high-risk prostate cancer after primary local therapy was associated with a slightly OS improvement (HR: 0.79; 95% CI, 0.63–0.98; p = 0.03). It also did not show a significant benefit in DFS and BRFS in patients with high-risk prostate cancer (HR: 0.89, 95% CI, 0.75–1.06, p = 0.18; HR: 0.85, 95% CI, 0.69–1.06, p = 0.16). Conclusions: This meta-analysis shows a slightly OS benefit from docetaxel in patients with high-risk prostate cancer after primary local therapy. It did not show a significant benefit in DFS and BRFS from adjuvant chemotherapy in patients with high-risk prostate cancer.

Nivolumab for the treatment of esophageal cancer

ABSTRACT Introduction: Esophageal cancer (EC) is the seventh most common cancer and the sixth leading cause of cancer death worldwide. The prognosis for advanced EC patients remains poor and there are few effective therapeutic agents available. Nivolumab is a fully human IgG4 monoclonal antibody that exerts antitumor activity by inhibiting the interaction of programmed cell death protein 1 on activated lymphocytes with its ligands. Nivolumab monotherapy showed significant benefit for overall survival of patients with advanced esophageal squamous cell carcinoma (ESCC) relative to taxane as a second-line treatment. Additionally, adjuvant nivolumab monotherapy showed significant disease-free survival benefit relative to placebo for resectable EC patients with residual pathologic disease who had received neoadjuvant chemoradiotherapy followed by surgery. Areas covered: Here, we provide an overview of checkpoint blockade with nivolumab and present the available clinical data related to its use in EC. Expert opinion: Nivolumab should be the standard second-line treatment for advanced ESCC patients and possibly adjuvant treatment of choice after neoadjuvant chemoradiotherapy followed by surgery. Trials assessing efficacy of a combination of cytotoxic agents and nivolumab as first-line treatment, nivolumab-containing chemoradiotherapy, and neoadjuvant chemotherapy are ongoing. These trials should result in improved protocols for better clinical outcomes in EC.

Sequential vs concurrent adjuvant chemotherapy of anthracycline and taxane for operable breast cancer

BackgroundWhether a sequential or concurrent regimen of anthracyclines and taxanes is superior for breast cancer is controversial. We compared the efficacy of two regimens in patients with operable breast cancer based on all relevant published data of phase III randomized controlled trials.MethodsA comprehensive literature search on PubMed, Web of Science, Embase, ScienceDirect, Google Scholar, and ClinicalTrials.gov databases was performed up to May 2020. Meta-analysis was performed to evaluate the different efficacy on disease-free survival (DFS) and overall survival (OS) for the two chemotherapy regimens. Subgroup analyses were further carried out in terms of node status and anthracycline selection.ResultsCompared to the concurrent regimen, the sequential regimen did not improve the DFS or OS in the population studied. Subgroup analysis showed that in node-positive patients, the sequential regimen had better DFS, but not OS, than the concurrent regimen. In sequential regimen, patients who received doxorubicin and taxanes had improved DFS and OS than patients who were administered epirubicin and taxanes. Furthermore, for patients who received doxorubicin and taxanes, compared to the sequential regimen, fewer cycles (4 cycles) of concurrent treatment resulted in a worse DFS and OS, which can be rescued by more cycles (6 cycles).ConclusionsThe sequential regimen of anthracyclines and taxanes for patients with operable breast cancer did not yield a significant benefit in DFS or OS over the concurrent regimen. The sequential regimen, however, provided a better DFS than concurrent regimen for node-positive patients. Interestingly, further subgroup analysis showed that for node-positive patients who were given doxorubicin and taxanes, more cycles (6 cycles) of the concurrent regimen may rescue the efficacy for fewer cycles (4 cycles).

Long-term outcomes of concomitant cisplatin plus radiotherapy versus radiotherapy alone in patients with stage IIIB squamous cervical cancer: A randomized controlled trial

ObjectiveThe present analysis determined the disease free survival (DFS) and overall survival (OS) at up to 14 years of follow-up in women who participated in our previous phase 3 randomized controlled clinical trial, in which women with stage IIIB squamous cervical cancer received either cisplatin plus RT or RT alone for treatment. The first study showed that the addition of cisplatin to RT offered a significant benefit in DFS, but not in OS. MethodsThe present analysis examined DFS and OS in 146 women from the original cohort (72 patients in the CRT arm and 74 patients in the RT-only arm) with follow-up of up to 14 years. ResultsLonger term follow-up showed that treatment with CRT offers a significant benefit in DFS and OS compared with treatment with RT only. Patients who received RT alone had significantly worse OS (HR, 1.88; 95% CI, 1.09–3.24) and DFS (HR, 1.82; 95% CI, 1.07–3.08) compared with patients who received CRT. The multivariate analyses also showed that the patients with baseline Karnofsky performance status (KPS) <90% showed significantly worse OS (HR, 3.11; 95% CI, 1.78–5.43), as did those with hemoglobin <10 mg/dL (HR, 4.32; 95% CI, 2.23–8.36). Patients with baseline KPS < 90% showed significantly worse DFS (HR, 2.83; 95% CI, 1.60–5.01), as did those with hemoglobin <10 mg/dL (HR, 4.16; 95% CI, 2.17–7.95). ConclusionsFor stage IIIB cervical cancer, treatment with CRT offers a significant benefit in DFS and OS compared with treatment with RT only.

Quality of life-adjusted survival analysis of high-dose therapy with autologous bone marrow transplantation versus sequential chemotherapy for patients with aggressive lymphoma in first complete remission

AbstractEvaluating high-dose therapy (HDT) with autologous stem cell transplantation (ASCT) in term of both duration and quality of life (QOL) presents major interests for patients with non-Hodgkin lymphoma. The quality-adjusted time without symptom and toxicity (Q-TWiST) methodology was applied to the LNH87-2 trial comparing HDT with ASCT versus sequential chemotherapy in 541 patients in first complete remission (CR). Overall survival (OS) and disease-free survival (DFS) curves were used to estimate duration of 4 health states: acute short-term toxicity (Tox1), secondary toxicity (Tox2), time without symptom and toxicity (TWiST), and relapse (Rel). Areas under survival curves (AUC) were retrospectively weighted according to QOL coefficients. HDT increased, but not significantly, TWiST (+2.4 months in AUC, P = .17) and decreased Rel (−3 months,P < .01). Survival estimates did not differ between the 2 treatments (AUC 47.7 months for OS, 39.7 months for DFS). High-risk patients treated by HDT versus chemotherapy had a significant benefit in DFS (AUC 28.8 versus 24.9 months, P < .01) but not in OS (AUC 37.3 versus 36 months, P = .27). Sensitivity analysis, performed by varying QOL coefficients, demonstrated significant quality-adjusted survival gain in high-risk patients treated by HDT. In low-risk patients, a diagram provided an aid to clinical decision-making. This analysis supports the use of HDT in these patients with adverse prognostic factors in the first CR, even after adjusting for QOL using the Q-TWiST method.

Surgical versus clinical staging prior to primary chemoradiation in patients with cervical cancer FIGO stages IIB–IVA: oncologic results of a prospective randomized international multicenter (Uterus-11) intergroup study

ObjectiveRevised staging of patients with locally advanced cervical cancer is based on clinical examination, imaging, and potential surgical findings. A known limitation of imaging techniques is an appreciable rate of...

358P Adjuvant tyrosine kinase inhibitors in non-squamous non-small cell lung cancer with EGFR driver mutations: An updated meta-analysis of randomized trials

Current treatment guidelines state that resectable early stage NSCLC may be treated with adjuvant therapy in the form of chemotherapy and radiotherapy. For Nonsquamous Non-Small Cell Lung Cancer (NS NSCLC), Epidermal Growth Factor Receptor (EGFR) mutations may be present in up to 60% of cases. In the locally advanced and metastatic settings, EGFR tyrosine kinase inhibitors (TKI) have shown remarkable efficacy. With the basis of EGFR as a driver mutation for carcinogenesis, EGFR TKI treatment has been explored in several studies. However, the role of EGFR TKI in the adjuvant setting remains controversial due to lack of conclusive evidence. The latest treatment guidelines do not favor adjuvant EGFR TKI for EGFR-mutant resected early stage NS-NSCLC. Therefore, this meta-analysis evaluated existing randomized controlled trials (RCTs) for a more precise estimate of the efficacy of adjuvant EGFR TKI and associated lung cancer survival. A systematic search of Pubmed, Embase, Cochrane, and clinical trials databases as well as hand search were utilized to identify RCTs investigating adjuvant EGFR TKI treatment in resected NS-NSCLC. Seven RCTs were included (N=2095), all contain disease free survival (DFS) data. Four trials gave EGFR TKI treatment for 24 months, while one trial provided EGFR TKI treatment for 36 months. Erlotinib, gefitinib, icotinib, and osimertinib were the EGFR TKI used in the RCTs. Treatment with adjuvant EGFR TKI showed statistically significant DFS benefit (HR 0.64, 95% CI[0.50-0.82)], P=0.0005) although with substantial heterogeneity (I2=98%, P<0.00001). This heterogeneity was attributed to trial phase and EGFR TKI generation used. Subgroup analyses were done for trial phase, treatment duration, disease stage, type of EGFR TKI, and toxicity. It was found that use of EGFR TKI gefinitib has statistically significant survival (DFS) advantage (HR 0.56, 95% CI(0.47-0.66), P<0.00001; I2=0%). Results of this meta-analysis provide preliminary but strong evidence recommending EGFR TKI in the adjuvant setting among EGFR-mutant resected early NS NSCLC by improving DFS.

Recent Developments in HER2-Directed Therapy in Breast Cancer

This review will discuss recent important trials for the treatment of HER2-positive breast cancer, emphasize ongoing areas of development, and highlight areas of unmet need. Advances for early-stage treatment have been driven by key clinical trials with pertuzumab, neratinib, and TDM-1. In the adjuvant setting, dual HER2 targeting with trastuzumab and pertuzumab has demonstrated modest improvement in disease-free survival. Neratinib also showed modest benefit in the extended adjuvant setting after prior trastuzumab. Finally, for patients who did not achieve pathologic complete response to neoadjuvant therapy, adjuvant therapy with TDM-1 showed significant disease-free survival benefit over trastuzumab. In advanced disease, neratinib appears to have activity beyond standard second line treatment. Promising compounds with early-phase data reviewed are tucatinib, margetuximab, and antibody-drug complexes. Immunotherapy in HER2-positive disease also has early-phase data. Endocrine therapy in combination with CDK4/6 inhibition and HER2-targeted therapy is in evaluation. Two areas of unmet need include CNS disease and disease treatment in the elderly population. In the wake of recent practice changing clinical trials, HER2-directed therapy is rapidly evolving. Future advances in therapy are anticipated with ongoing studies.

Disease-Free Survival Benefit of Radiotherapy Following Narrow-Margin Hepatectomy in Patients with Hepatocellular Carcinoma

To evaluate the effect of postoperative radiotherapy on the prognosis and recurrent patterns of hepatocellular carcinoma (HCC) patients with narrow-margin hepatectomy. From July 2007 to October 2016, a total of 234 patients with narrow-margin (<1.0 cm) hepatectomy were recruited in this study. Of which, 76 patients (Group A) eligible for inclusion in Phase II study were received postoperative radiotherapy, and the rest 158 patients were assigned to Group B. Kaplan-Meier survival analysis was performed to identify the association between postoperative radiotherapy and clinical outcomes of HCC patients with narrow-margin hepatectomy. Propensity score-matched (PSM) analysis was used to balance the differences in the basic clinical characteristics between Groups. Before PSM, the overall survival (OS) between Group A and Group B was not significantly different (P=0.2062), and the 1-year, 3-year and 5-year OS rate for the Group A and Group B were 98.6%, 89.0% and 72.6% versus 92.5%, 80.5% and 72.7%, respectively. While the disease-free survival (DFS) was significantly higher in Group A than in Group B (P=0.0337), and the 1-year, 3-year and 5-year DFS rate for the Group A and Group B were 88.0%, 71.3% and 60.2% versus 77.9%, 62.3% and 48.8%, respectively. After PSM, the OS between Group A and Group B were marginally different (P=0.0739), and the 1-year, 3-year and 5-year OS rate were 98.6%, 89.0% and 72.6% versus 88.0%, 76.8% and 66.9%, respectively. The DFS values were still significantly higher in Group A than in Group B (P=0.0076), and the 1-year, 3-year and 5-year DFS rate were 88.0%, 71.3% and 60.2% versus 73.4%, 55.6% and 43.2%, respectively. Before PSM, the surgical margin recurrence, single recurrence beyond the margin, and diffuse recurrence rates in Group A were 0% (0), 23.4% (18) and 5.3% (4) versus 5.1% (8), 12% (19), 13.9% (22) in Group B (P=0.009), respectively. There were no significant difference in extrahepatic recurrence rates (P=0.826), the early recurrence (less than 18 months after surgery) and late recurrence (more than 18 months after surgery) rates (P=0.104)．After PSM, regarding the patterns of margin recurrence, single recurrence beyond the margin or diffuse recurrence, the patients who had undergone postoperative IMRT still showed a significantly lower intrahepatic recurrence than those who did not undergo treatment (P=0.009). Postoperative radiotherapy has a significant DFS benefit for patients with narrow-margin hepatectomy. Long-term follow up and prospective studies with larger patient cohorts are needed to confirm OS benefit.