Progression-free Survival Estimates Research Articles

Abstract PO2-14-09: Baseline genomic alterations and the activity of lasofoxifene (LAS) plus abemaciclib (Abema) in patients with ER+/HER2- metastatic breast cancer (mBC): the ELAINE 2 study

Abstract Introduction: Estrogen receptor-positive (ER+)/HER2-negative (HER2-) breast cancers commonly acquire constitutively active mutations in the ERα-encoding gene (ESR1), resulting in endocrine therapy (ET) resistance. In the phase 2, ELAINE 2 study (NCT04432454), LAS (a breast ER antagonist) combined with Abema provided a median progression-free survival (PFS) of ~13 months (mos) and clinical benefit rate (CBR) of 66% in patients with endocrine-resistant, ER+/HER2- mBC and ESR1 mutations (mESR1; Damodaran. J Clin Oncol 2023;41:suppl16;1057). Our objective was to describe baseline genomic alterations co-occuring with mESR1 and treatment responses to LAS plus Abema in patients with these concurrent genomic alterations. Methods: Women (age ≥18 yrs) with ER+/HER2- mBC that progressed after prior ET and CDK4/6 inhibitor (CDK4/6i) with an mESR1 detected in blood using the Sysmex-Inostics SafeSeq circulating tumor DNA (ctDNA) test were enrolled in ELAINE 2. Oral LAS 5 mg/day and Abema (provided by Eli Lilly and Co) 150 mg BID were taken until disease progression, death, unacceptable toxicity, or withdrawal. The Guardant360 CDx test was used to identify and describe baseline genomic alterations in ctDNA (including mESR1). Median PFS and CBR were assessed in patients with mESR1 and co-existing baseline genomic alterations. For patients who withdrew before disease progression, their last observation time was used as the progression time for PFS estimation. Data were summarized descriptively with no formal hypothesis testing. Results: Of the 29 patients (median age 60 yrs) enrolled, mutations in ESR1 were identified in 26 by Guardant360; all these 26 patients had received prior CDK4/6i, 21 (81%) prior fulvestrant, and 12 (46%) prior chemotherapy for mBC. Alterations in 39 genes were concurrently identified with mESR1, including TP53 mutations (n=11), PIK3CA mutations (n=8), CCND1 amplifications (n=6), and FGFR1 amplifications (n=5); co-amplification of CCND1 and FGFR1 was identified in 3 patients. LAS plus Abema treatment was associated with a CBR of 73% and a median PFS of 12.9 mos in the 26 patients with mESR1 (Table). CBRs were 63% in the co-occurring PIK3CA mutation subgroup and 64% in the TP53 mutation subgroup; median PFS times were 7.8 and 8.3 mos, respectively. All patients in the CCND1 and FGFR1 amplification subgroups achieved clinical benefit (CBR 100%) and the median PFS was 16.6 mos for both subgroups. In patients with mESR1 and co-alterations in ≥2 other genes of interest (PIK3CA, FGFR1, CCND1, TP53, ERBB2, CCNE1, or RB1), CBR was 83% and median PFS was 16.6 mos. Conclusion: Using Guardant360 ctDNA profiling from patients in ELAINE 2, we demonstrate that other baseline genomic alterations are frequently detected concurrently with mESR1 in the endocrine resistant setting, but without apparent compromise on the efficacy of LAS plus Abema. These results should be interpreted with caution considering the small numbers of patients and the exploratory nature of the analysis. The ELAINE 2 study suggests the potential of LAS plus Abema for treating ESR1-mutated, ER+/HER2- mBC in the post-CDK4/6i setting. This will be further evaluated in the larger, registrational, phase 3, ELAINE 3 study (NCT05696626) that compares LAS plus Abema with fulvestrant plus Abema. Table. Treatment response by genomic alterations concurrent with ESR1 mutations (n=26). aFor patients who withdrew before disease progression, the last observation time was used as the progression time for PFS estimation. bOther genes of interest include PIK3CA, FGFR1, CCND1, TP53, ERBB2, CCNE1, or RB1. CBR, clinical benefit rate; mPFS, median progression-free survival. Citation Format: Senthil Damodaran, Massimo Cristofanilli, Matthew Goetz, Ciara O'Sullivan, Gary Riordan, Hope Rugo, Daniel Stover, Seth Wander, Dominic Carroll, Paul V. Plourde, David J Portman, Einav Nili-Gal Yam. Baseline genomic alterations and the activity of lasofoxifene (LAS) plus abemaciclib (Abema) in patients with ER+/HER2- metastatic breast cancer (mBC): the ELAINE 2 study [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-14-09.

Efficacy and safety of crizotinib in the treatment of advanced non-small cell lung cancer with ROS1 gene fusion: a systematic literature review and meta-analysis of real-world evidence

BackgroundCrizotinib was approved to treat patients with advanced non-small cell lung cancer (aNSCLC) with ROS proto-oncogene 1 (ROS1) gene fusion in 2016. We conducted a systematic literature review to identify real-world evidence (RWE) studies and estimated the efficacy and safety of crizotinib using meta–analyses (MA) for objective response rate (ORR), real-world progression-free survival (PFS), and overall survival (OS). MethodsWe searched MEDLINE®, Embase, and Cochrane CENTRAL from January 2016 to March 2023 using Ovid® for published single-arm or comparative RWE studies evaluating patients (N ≥ 20) receiving crizotinib monotherapy for aNSCLC with ROS1 gene fusion. Pooled estimates for ORR and grade 3/4 adverse events (AEs) were derived using the metafor package in R while pooled estimates for median real-world PFS (rwPFS) and OS were derived using reconstructed individual patient data from published Kaplan-Meier curves. The primary analysis included all studies regardless of crizotinib line of therapy; a subgroup analysis (SA) was conducted using studies evaluating patients receiving first-line crizotinib. ResultsFourteen studies met the eligibility criteria and were considered feasible for MA. For the primary analysis, the pooled ORR (N = 9 studies) was 70.6 % (95 % confidence interval [CI]: 57.0, 81.3), median rwPFS was 14.5 months (N = 11 studies), and OS was 40.2 months (N = 9 studies). In the SA, the pooled ORR (N = 4 studies) was 81.1 % (95 % CI: 76.1, 85.2) and the median rwPFS (N = 4 studies) and OS (N = 2 studies) were 18.1 and 60 months, respectively. All MAs were associated with significant heterogeneity (I2 > 25 %). Grade 3/4 AEs occurred in 18.7 % of patients (pooled estimate). ConclusionThe results from this study are consistent with clinical trial data and, taken collectively, supports crizotinib as a safe and effective treatment across different lines of therapy in patients with ROS1 aNSCLC in the real-world setting.

Optimizing radiotherapy strategies for skull base chordoma: a comprehensive meta-analysis and systematic review of treatment modalities and outcomes.

In the treatment of skull base chordoma (SBC) surgery is considered the mainstay approach, and gross-total resection has an established relationship with progression-free survival (PFS) and overall survival (OS). However, the tumor's location often interferes with attempts at complete resection. In this case, surgery for maximal resection followed by high-dose radiotherapy has been demonstrated to be the standard treatment. In this context, various modalities are available, yet no consensus exists on the most effective. This systematic review and meta-analysis aimed to evaluate the efficacy and safety of different radiotherapy modalities for SBC. Following PRISMA guidelines, the authors systematically searched for the treatment of SBC with radiation modalities in the PubMed, Cochrane, Web of Science, and EMBASE databases. Outcomes assessed for each modality were as follows: OS, PFS, local control (LC), and complications. The random-effects model was adopted. A single-proportion analysis with 95% CI was used to measure the effects in single-arm analysis. For the comparative analysis, the OR with 95% CI was used to compare outcome treatment effects. Heterogeneity was assessed using I2 statistics, and statistical significance was defined as p < 0.05. A total of 32 studies comprising 3663 patients, with 2322 patients who were treated with radiotherapeutic modalities, were included. Regarding 5-year OS findings in each modality study, the findings were as follows: in photon fractionated radiotherapy, an estimated rate of 77% (69%-84%, 568 patients); in conventional fractionated radiotherapy, 76% (65%-87%, 517 cases); in proton-based + carbon ion-based radiotherapy, 85% (82%-88%, 622 cases); and in a comparative analysis of proton-based and carbon ion-based therapy, there was an OR of 1.2 (95% CI 0.59-2.43, 306 cases). Regarding the 5-year PFS estimate, the rates were as follows: 35% (26%-45%, 95 cases) for photon fractionated therapy; 35% (25%-45%, 85 cases) for stereotactic radiotherapy; 77% (50%-100%, 180 cases) for proton-based and carbon ion-based radiotherapy; and 74% (45%-100%, 102 cases) for proton-based radiotherapy. Regarding LC in periods of 3 and 5 years after proton- and carbon ion-based therapy, the overall estimated rates were 84% (78%-90%, 326 cases) and 75% (65%-85%, 448 cases), respectively. For proton-based radiotherapy and carbon ion-based therapy, the 5-year LC rates were 76% (67%-86%, 259 cases) and 75% (59%-91%, 189 cases), respectively. The analysis highlights the finding that particle-based modalities like proton beam radiotherapy and carbon ion radiotherapy are the most effective radiation therapies available for the treatment of SBC. Furthermore, it reinforces the idea that surgery followed by radiotherapy constitutes the standard treatment.

Upfront neck dissection for treatment selection and improvement in quality of life as a novel treatment paradigm for deintensification in HPV+ OPSCC.

Locoregionally advanced HPV+ oropharyngeal squamous cell carcinoma (OPSCC) has excellent cure rates, although current treatment regimens are accompanied by acute and long-term toxicities. We designed a phase II de-escalation trial for patients with HPV+OPSCC to evaluate the feasibility of an upfront neck dissection to individualize definitive treatment selection to improve quality of life without compromising survival. Patients with T1-3, N0-2 HPV+ OPSCC underwent an upfront neck dissection with primary tumor biopsy. Patients with a single lymph node less than six centimeters, with no extracapsular spread(ECS), and no primary site adverse features underwent transoral surgery (Arm A). Patients who had two or more positive lymph nodes with no ECS, or those with primary site adverse features were treated with radiation alone (Arm B). Patients who had ECS in any lymph node were treated with chemoradiation (Arm C). The primary endpoint was quality of life at 1 year compared to a matched historical control. Thirty-four patients were enrolled and underwent selective neck dissection. Based on pathologic characteristics, 14 patients were assigned to arm A, 10 patients to arm B, and 9 to arm C. A significant improvement was observed in HNQOL compared to historical controls (-2.6 vs -11.9, p=0.034). With a median follow-up of 37 months, the 3-year overall survival was 100% and estimated 3-year estimated progression free survival was 96% (95% CI: 76-99%). A neck dissection driven treatment paradigm warrants further research as a de-intensification strategy.

Involved-site Radiation Therapy is Equally Effective and Less Toxic Than Involved-field Radiation Therapy in Patients Receiving Combined Modality Treatment for Early-stage Unfavorable Hodgkin Lymphoma—An Analysis of the Randomized Phase 3 HD17 Trial of the German Hodgkin Study Group

PurposeCombined modality treatment (CMT) with chemotherapy followed by consolidation radiotherapy (RT), provides excellent outcomes for patients with early-stage Hodgkin lymphoma (HL). The international standard of care for consolidation RT, involved-site/involved-node radiotherapy (ISRT/INRT), has never been evaluated in a randomized phase III trial against the former standard involved-field radiotherapy (IFRT). Methods and materialsIn the multicenter phase III AnonymizedStudyGroupXXX AnonymizedStudyYYY trial, patients with early stage unfavorable HL were randomized between the standard CMT group and a positron-emission tomography (PET) -guided group. In the standard group, patients received two cycles of escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (eBEACOPP) and two cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) followed by 30 Gray (Gy) IFRT. In the experimental group patients received no further therapy if post-chemotherapy PET was negative, and 30 Gy AnonymizedStudyGroupXXX -INRT, comparable and therefore termed here ISRT, if PET was positive. Here, we analyze the interim PET positive patients in a post hoc analysis, and therefore the randomized comparison of IFRT versus INRT/ISRT. Results1,100 patients were randomized, of which 311 had a positive PET after chemotherapy. Kaplan-Meier estimates of 4-year progression-free survival (PFS) were 96.8 % (95% CI: 91.6% – 98.8%) in the IFRT group and 95.4% (95% CI: 89.9% – 97.9%; HR: 1.40, 95% CI: 0.44 – 4.42) in the ISRT group. Pattern of recurrence analyses indicated that none of the cases of disease progression or recurrence in the ISRT group would have been prevented by the use of IFRT. Acute grade III/IV toxicities occurred in 8.5% of IFRT patients and 2.6% of ISRT patients (p=0.03). ConclusionsFor the first time, consolidation INRT/ISRT was randomly compared to IFRT in a phase III trial. Regarding PFS, no advantage for IFRT could be demonstrated. In summary, our data confirm the place of INRT/ISRT as the current standard of care.

A multicenter study of venetoclax-based treatment for patients with Richter transformation of chronic lymphocytic leukemia

AbstractPatients with chronic lymphocytic leukemia (CLL) who develop Richter transformation (RT) have a poor prognosis when treated with chemoimmunotherapy regimens used for de novo diffuse large B-cell lymphoma. Venetoclax, a BCL2 inhibitor, has single-agent efficacy in patients with RT and is potentially synergistic with chemoimmunotherapy. In this multicenter, retrospective study, we evaluated 62 patients with RT who received venetoclax-based treatment outside of a clinical trial, in combination with a Bruton tyrosine kinase inhibitor (BTKi; n=28), rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone (R-CHOP) (n=13), or intensive chemoimmunotherapy other than R-CHOP (n=21). The best overall and complete response rates were 36%/25%, 54%/46%, and 52%/38%, respectively. The median progression-free and overall survival estimates for the same treatment groups were 4.9/14.3 months, 14.9 months/not reached, and 3.3/9 months, respectively. CLL with del(17p) was associated with a lower complete response rate in the total cohort (odds ratio [OR] 0.15; 95% confidence interval [CI] 0.04-0.6; p=0.01) and venetoclax-naïve subgroup (OR 0.13; 95%CI 0.02-0.66; p=0.01). TP53 mutated CLL was associated with a lower complete response rate (OR 0.15; 95%CI 0.03-0.74; p=0.02) and shorter progression-free survival (hazard ratio 3.1; 95%CI 1.21-7.95; p=0.02) only in venetoclax-naïve subgroup. No other clinical or baseline characteristics, including prior venetoclax treatment for CLL, showed statistically significant association with outcomes. Grade 3-4 neutropenia and thrombocytopenia events were most frequent with intensive chemoimmunotherapy + venetoclax; grade 3-4 infection rates were similar across treatment groups. In this difficult-to-treat RT patient population, venetoclax-based combination regimens achieved high response rates, with durable remission and survival observed in a subset of patients.

Abstract 2391: Towards better prediction of treatment resistance: Directly modeling progression from multiple lesions

Abstract Late-stage cancers in the clinic present as a set of dispersed tumors, each with distinct growth kinetics. As most patients enrolled in trials of experimental anticancer therapeutics have late-stage malignancies, it is important to understand the impact of data analysis methodologies on the ability to detect treatment effect. In particular, we are interested in the potential risk posed by aggregating individual tumor measurements from multiple-lesion clinical data into a single tumor burden measurement, as this may cause a loss of information. In this work, we use quantitative modeling to assess how analyzing multiple lesions separately versus using an aggregated readout affects tumor response and detection of progression free survival and relapse. To assess the impact of data aggregation, we built a two-population clonal dynamics model consisting of sensitive and resistant tumor cells undergoing growth in the presence or absence of treatment. We performed parameter sweeps to assess the impact of individual model parameters on progression free survival and relapse. We then extended these sweeps to the multi-lesion situation, using nonlinear regression to compare parameter values of aggregated models and the parameter values of the individual models that comprised it. From our simulations, the most influential parameters in determining rebound are the growth rate of the resistant cells and the fraction of these cells, while growth rate of sensitive cells and growth rate inhibition affect effectiveness of treatment. In analyzing the multiple lesion model in different situations, we found that estimates for progression free survival were significantly more sensitive when the lesions were analyzed separately, rather than being aggregated. Our work suggests that aggregating the lesions into a single readout loses impact of individual lesion growth rate inhibitions, impairing early detection as the ability to detect fast growing, small, resistant lesions (despite overall tumor burden decreasing) is lost. Taken together, our findings suggest that data aggregation causes a loss of information. Relapse can be predicted at earlier times when using the multiple lesion model compared to an aggregated model. Citation Format: Samuel Protich, Madison Stoddard, Lin Yuan, Douglas White, Dean Bottino, Arijit Chakravarty. Towards better prediction of treatment resistance: Directly modeling progression from multiple lesions [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2391.

Abstract 6904: Model-derived progression-free survival (mPFS): A better metric for patient-derived xenograft studies

Abstract Patient-derived xenografts (PDX) are a powerful assay system for translational prediction of therapeutic potential for experimental therapeutics. The primary readout from PDX models is tumor shrinkage, measured by the ratio of treated/control tumor volume. This readout corresponds loosely to the Objective Response Rate (ORR) metric used in clinical trials, in that it is a readout of drug effect on the sensitive subclones within a tumor. In prior work, we have shown that there is a paradoxical relationship between short-term tumor response and progression-free survival (PFS). While ORR is the primary measure utilized in the Phase II to III transition in clinical development, approval hinges on survival metrics, and the disconnect between ORR and PFS creates a potential risk of late-stage failures for experimental anticancer therapeutics. Thus, it is of interest to understand whether there are alternative approaches to analyzing PDX data that can enable the assessment of therapeutic potential in terms of a projected PFS. In this simulation study, we will examine the accuracy of progression-free survival (PFS) estimates obtained directly from observation during a PDX study and compare their accuracy with the accuracy of PFS estimates derived using a mathematical model-based approach that relies on a kinetic model of tumor subclone growth (model-based PFS, or mPFS) fitted directly to PDX tumor growth and rebound kinetics under treatment. We generated our test dataset using a mathematical model of tumor kinetic growth to simulate xenograft data using fitted parameters derived from literature, adding in experimental error consistent with prior experimental measurement-derived variability. We used the simulated raw data to calculate an observed PFS as well as mPFS derived from fitting the tumor clonal kinetic model to the raw data in a blinded fashion. Our results show that the empirical PFS from PDX models is subject to overestimation, as a function of the observation time interval. On the other hand, mPFS is significantly less biased and more accurate, but is subject to some logistical constraints on sampling. Our work demonstrates the practical translational utility of a novel analysis method (mPFS) in deriving estimates of progression-free survival from PDX model data. Citation Format: Andrew Chen, Madison Stoddard, Lin Yuan, Debra Van Egeren, Arijit Chakravarty, Dean Bottino. Model-derived progression-free survival (mPFS): A better metric for patient-derived xenograft studies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6904.

Progression-free survival estimates are shaped by specific censoring rules: Implications for PFS as an endpoint in cancer randomized trials

Kaplan-Meier analysis hinges on the assumption that patients who are censored– lost to follow-up, or only recently enrolled on the study– are no different, on average, than patients who are followed. As such, censoring these patients– omitting their future information and taking the average of those who were followed– should not dramatically change the overall estimate. Yet, in a recent clinical trial, two sets of censoring rules– one favored by trialists and one favored by the US Food and Drug Administration– were applied to a progression-free survival (PFS) estimate. In response, the PFS estimate changed dramatically, increasing the median in the experimental arm from 32 to 43 months, while the control arm was essentially unchanged. In this commentary, we explore the reasons why PFS changed so dramatically. We provide a broad overview of censoring in oncology clinical trials, and suggestions to ensure that PFS is a more reliable endpoint.

Outcomes of Hepatic Artery-Based Therapies and Systemic Multiagent Chemotherapy in Unresectable Colorectal Liver Metastases: A Systematic Review and Meta-analysis.

Treatment of unresectable colorectal liver metastases (UCRLM) includes locoregional and systemic therapy. A comprehensive analysis capturing long-term outcomes of these treatment options has not been performed. A systematic review and meta-analysis was performed to calculate pooled outcomes of hepatic artery infusion with systemic chemotherapy (HAI-S), transarterial chemoembolization with systemic chemotherapy (TACE-S), transarterial radioembolization with systemic chemotherapy (TARE-S), doublet (FOLFOX, FOLFIRI), and triplet chemotherapy (FOLFOXIRI). Outcomes included overall survival (OS), progression-free survival (PFS), rate of conversion to resection (CTR), and response rate (RR). A total of 32, 7, 9, and 14 publications were included in the HAI-S, TACE-S, and TARE-S chemotherapy arms. The 6/12/24/36-month OS estimates for HAI-S, TACE-S, TARE-S, FOLFOX, FOLFIRI, and FOLFOXIRI were 97%/80%/54%/35%, 100%/83%/40%/14%, 82%/61%/34%/21%, 96%/83%/53%/36%, and 96%/93%/72%/55%. Similarly, the 6/12/24/36-month PFS estimates were 74%/44%/19%/14%, 66%/20%/9%/3%, 57%/23%/10%/3%, 69%/30%/12%/7%, and 88%/55%/18%/11%. The corresponding CTR and RR rates were 31, 20%, unmeasurable (TARE-S), 35, 53; and 49, 45, 45, 50, 80%, respectively. The majority of chemotherapy studies included first-line therapy and liver-only metastases, whereas most HAI-S studies were pretreated. On subgroup analysis in first-line setting with liver-only metastases, the HAI-S arm had comparable outcomes to FOLFOXIRI and outperformed doublet chemotherapy regimens. Although triplet chemotherapy appeared to outperform other arms, high toxicity and inclusion of potentially resectable patients must be considered while interpreting results. HAI-S and multiagent chemotherapy are effective therapies for UCRLM. To make definitive conclusions, a randomized trial with comparable patient characteristics and line of therapy will be required. The upcoming EA2222 PUMP trial may help to address this question.

Treosulfan compared to busulfan in allogeneic haematopoietic stem cell transplantation for myelofibrosis: a registry-based study from the Chronic Malignancies Working Party of the EBMT.

We aimed to compare outcomes following treosulfan (TREO) or busulfan (BU) conditioning in a large cohort of myelofibrosis (MF) patients from the EBMT registry. A total of 530 patients were included; 73 received TREO and 457 BU (BU ≤ 6.4 mg/kg in 134, considered RIC, BU > 6.4 mg/kg in 323 considered higher dose (HD)). Groups were compared using adjusted Cox models. Cumulative incidences of engraftment and acute GVHD were similar across the 3 groups. The TREO group had significantly better OS than BU-HD (HR:0.61, 95% CI: 0.39-0.93) and a trend towards better OS over BU-RIC (HR: 0.66, 95% CI: 0.41-1.05). Moreover, the TREO cohort had a significantly better Progression-Free-Survival (PFS) than both the BU-HD (HR: 0.57, 95% CI: 0.38-0.84) and BU-RIC (HR: 0.60, 95% CI: 0.39-0.91) cohorts, which had similar PFS estimates. Non-relapse mortality (NRM) was reduced in the TREO and BU-RIC cohorts (HR: 0.44, 95% CI: 0.24-0.80 TREO vs BU-HD; HR: 0.54, 95% CI: 0.28-1.04 TREO vs BU-RIC). Of note, relapse risk did not significantly differ across the three groups. In summary, within the limits of a registry-based study, TREO conditioning may improve PFS in MF HSCT and have lower NRM than BU-HD with a similar relapse risk to BU-RIC. Prospective studies are needed to confirm these findings.

Patterns of Failure in Patients With Borderline Resectable/Locally Advanced Pancreatic Cancer After Preoperative Chemotherapy and Stereotactic Body Radiation Therapy

The role of preoperative stereotactic body radiation therapy (SBRT) in pancreatic cancer is controversial, and questions regarding the optimal dose and radiation treatment field remain. To better inform future investigations of SBRT dose and radiation fields, we evaluated the patterns of failure in patients with borderline resectable/locally advanced pancreatic cancer (BR/LAPC) after preoperative chemotherapy and SBRT in patients who underwent surgical resection. We performed a single-institution retrospective review of consecutive patients treated from September 2017 to January 2022 with BR/LAPC. Patients who underwent preoperative chemotherapy and SBRT followed by surgical resection were reviewed. SBRT was delivered to a dose of 33 Gy in 5 fractions. Kaplan-Meier overall survival and progression-free survival estimates were calculated. In total, 18 patients (12 BRPC, 6 LAPC) were included. Median age was 69 years (range 41-84 years). Median follow-up was 30 months (range 13-59 months). Seventeen patients (94%) had a R0 resection and 13 (72%) underwent vascular reconstruction. Median overall survival and progression-free survival was 42 months (range 13-59 months) and 23 months (range 1-45 months), respectively. In total, 61% (11/18) patients experienced progression at any point during follow-up. Of the patients who experienced recurrence, 27% (3/11) experienced local progression as component of their first recurrence, whereas 100% (11/11) experienced distant progression as a component of their first recurrence. When examining all recurrences that occurred at any point in follow-up, 28% (5/18) of patients experienced local or locoregional recurrence and 61% (11/18) experienced distant progression. Local control and margin negative resection rates were excellent with preoperative chemotherapy and nondose-escalated SBRT in surgically resected patients with BR/LAPC. Distant recurrence was the predominant site of failure with lower incidences of isolated locoregional recurrences. Additional research is needed to determine the ideal treatment volume and patients who may benefit from dose escalation.

Clinico-Radiological Outcomes in WNT-Subgroup Medulloblastoma.

Medulloblastoma (MB) comprises four broad molecular subgroups, namely wingless (WNT), sonic hedgehog (SHH), Group 3, and Group 4, respectively, with subgroup-specific developmental origins, unique genetic profiles, distinct clinico-demographic characteristics, and diverse clinical outcomes. This is a retrospective audit of clinical outcomes in molecularly confirmed WNT-MB patients treated with maximal safe resection followed by postoperative standard-of-care risk-stratified adjuvant radio(chemo)therapy at a tertiary-care comprehensive cancer centre. Of the 74 WNT-MB patients registered in a neuro-oncology unit between 2004 to 2020, 7 patients accrued on a prospective clinical trial of treatment deintensification were excluded, leaving 67 patients that constitute the present study cohort. The median age at presentation was 12 years, with a male preponderance (2:1). The survival analysis was restricted to 61 patients and excluded 6 patients (1 postoperative mortality plus 5 without adequate details of treatment or outcomes). At a median follow-up of 72 months, Kaplan-Meier estimates of 5-year progression-free survival and overall survival were 87.7% and 91.2%, respectively. Traditional high-risk features, large residual tumour (≥1.5 cm2), and leptomeningeal metastases (M+) did not significantly impact upon survival in this molecularly characterized WNT-MB cohort treated with risk-stratified contemporary multimodality therapy. The lack of a prognostic impact of conventional high-risk features suggests the need for refined risk stratification and potential deintensification of therapy.

Prognostic value of artificial intelligence (AI) –driven tumor estimation of PSMA PET total tumor burden (TTB) in newly diagnosed high-volume metastatic hormone-sensitive prostate cancer (mHSPC).

47 Background: Prostate cancer represents a significant economic burden for health systems; the identification of risk factors that allows the identification of subgroups of patients that require closer follow-up or more intense therapeutic regimens has a direct impact on the prognosis and expenses for the patient, there is currently great interest in patients with high-volume mHSPC, this group is defined according to the number of lesions and their location, this could represent a challenge in decision making due to the variety of presentations regarding tumor burden, currently with the development of AI algorithms it is possible to estimate the PSMA TTB by identifying patients who are candidates for specific therapies without exposing them to comorbidities associated to aggressive regimens. Methods: Baseline PSMA PET scans of patients with histopathological corroborated diagnosis of prostate cancer and considered as high volume according to 68Ga PSMA PET/CT imaging in the period from October 2017 to June 2020 were retrospectively analyzed using an automated algorithm to estimate PSMA TTB, the median follow-up was of 44 +/- 9.7 months. These patients were divided into two groups according to the optimal cutoff values of PSMA TTB and estimate progression-free survival after initial therapy with Kaplan-Meier curves and correlation index between tumor burden and prostatic specific antigen. Results: 53 patients with a mean age of 71 years (+/- 5.1) were included, 17 with Gleason 7 (4+3/3+4), 18; G8 (4+4), 15; G9 (5+4/4+5) and 3; G10 (5+5), ISUP group 3 (n=17), group 4 (n=18) group 5 (n=18), the mean PSA value at diagnosis was 62.1 ng/dL (range 25.2- 201.5). PSMA TTB mean was 100.1cm3 (range 21cm3- 518.8 cm3). Log-rank test revealed that PSMA TTB lower than 45 cm3 (n=21) presented higher time of progression-free survival in comparison with patients with PSMA TTB higher than 45 cm3 (n=32) (31.1 mo vs 47.8 mo, p &lt;0.003). TTB and PSA demonstrated a significant correlation (Pearson r= 0.526, p&lt; 0.0001). There was no difference between groups of low and high PSMA TTB and ISUP groups or Gleason score. Sites of visceral disease were lung (n=11), (pleura=9) liver (n=9), adrenal, (n=5) brain, (n=2), and sites of extra spinal and pelvic disease were ribs (n=24) femur (n=16), skull (n=8), scapula (n=7), humerus (n=7). All patients had one or more lesions at previously described sites. Conclusions: PSMA TTB has great value in predicting progression-free survival of patients with newly diagnosed high-volume metastatic hormone-sensitive prostate cancer and has a strong correlation with PSA, strengthening the role of next-generation molecular imaging with PSMA PET as an invaluable tool in initial diagnosis and potentially in follow-up by providing information on the biological behavior of the disease in a systemic way.

A Network Meta-Analysis of the Systemic Therapies in Unresectable Head and Neck Squamous Cell Carcinoma.

We referenced randomized controlled trials (RCTs) from January 2000 to July 2023 by extensively reviewing PubMed, EMBASE, and Web of Science databases, adhering to the Cochrane methodology. Relevant data, including summary estimates of overall survival (OS) and progression-free survival (PFS), were extracted from these selected studies and recorded in a predefined database sheet. Subsequently, we conducted a random effects network meta-analysis using a Bayesian framework. Based on the Surface Under the Cumulative Ranking (SUCRA) values, the league table organizes the various treatments for OS in the following order: IC + RT&MTT, MTT-CRT, IC + CRT&MTT, CRT, IC + CRT, MTT-RT, IC + MTT-RT, and RT. In a similar order, the treatments rank as follows according to the league table: IC + CRT&MTT, MTT-CRT, IC + CRT, IC + RT&MTT, CRT, IC + MTT-RT, MTT-RT, and RT. Notably, none of these treatments showed significant advantages over concurrent chemoradiotherapy. Despite concurrent chemoradiotherapy being the prevailing treatment for LASCCHN, our findings suggest the potential for improved outcomes when concurrent chemoradiotherapy is combined with targeted therapy or induction chemotherapy.

A phase 1 study of fianlimab (anti-LAG-3) in combination with cemiplimab (anti-PD-1) in patients with advanced ccRCC.

434 Background: Concurrent blockade of lymphocyte-activation gene 3 (LAG-3) may enhance efficacy of anti–programmed cell death protein 1 (PD-1) therapies. We present safety and clinical activity data from a Phase 1 study in patients with clear cell renal cell carcinoma (ccRCC) treated with anti–LAG-3 (fianlimab) + anti–PD-1 (cemiplimab). Methods: Patients with advanced or metastatic ccRCC who had received no more than 2 previous regimens of anti-angiogenic therapy who were anti–PD-1/PD-L1-naïve (cohort 3) or anti–PD-1/L1-experienced with most recent dose within 3 months prior to screening (cohort 4) were eligible. All patients were to receive fianlimab 1600 mg + cemiplimab 350 mg intravenously every 3 weeks for up to 24 months. Tumor measurements were performed by RECIST 1.1 every 6 weeks for 24 weeks, then every 9 weeks. Results: 15 patients (median age: 64 years) each in cohort 3 and 4 (total N=30) were enrolled and treated with fianlimab + cemiplimab as of 01 Nov 2022 data cutoff.For cohorts 3 and 4 respectively, 80% and 87% of patients were male, and 40% and 87% were White. All patients had prior cancer-related systemic therapy. 60% (9/15) and 93% (14/15) of patients in cohorts 3 and 4 had ≥2 lines of prior therapies, respectively. For cohorts 3 and 4, median treatment duration was 27 weeks and 18 weeks, and median follow-up was 13 months and 24 months, respectively. Grade ≥3 treatment-emergent adverse events (TEAEs) occurred in 53% and 33% of patients in cohorts 3 and 4, respectively. Serious TEAEs occurred in 33% and 13% of patients in cohorts 3 and 4, respectively. Treatment-related TEAEs (TRAEs) were reported in 80% of patients in cohorts 3 and 60% of patients in cohort 4. The most common TRAEs (any grade) were rash (27%) and infusion related reaction (grade 1 and 2) (27%) in cohort 3 and fatigue (20%) in cohort 4. Grade ≥3 TRAEs occurred in 27% of patients in cohorts 3. Treatment was discontinued due to any TEAE in 3 patients in cohort 3 and 1 patient in cohort 4. In cohort 3, there was one death. The patient was a 79-year-old woman with a history of antiphospholipid syndrome who died from complications of biopsy-proven ischemic colitis attributed to study treatment. RECIST 1.1-based investigator-assessed objective response rate (ORR) was 20% (3 partial responses [PRs]) in cohort 3 and 7% (1 PR) in cohort 4. The disease control rate (DCR) was 60% and 73% in cohorts 3 and 4, respectively. Kaplan–Meier estimation of median progression-free survival was 4 months (95% confidence interval [CI], 1–10) in cohort 3 and 4 months (95% CI, 1–7) in cohort 4 patients. Duration of responses were 4, 7, and 26 months in 3 responders in cohort 3; and 6 months in one responder in cohort 4. Conclusions: Fianlimab + cemiplimab demonstrated promising signs of clinical activity with durable responses among patients with anti–PD-1/PD-L1-naïve (cohort 3) and anti–PD-1/L1-experienced (cohort 4), with an acceptable safety profile. Clinical trial information: NCT03005782 .

Radiotherapy for Advanced Hodgkin Lymphoma with Initial Bulk: A Combined Analysis of Two Randomized Trials

PurposeThe role of consolidative radiotherapy (RT) in patients with advanced Hodgkin lymphoma (HL) with initial bulk is unclear. GITIL/FIL HD0607 and FIL HD0801, two randomized controlled trials with similar design and methodologies, did not identify a benefit to consolidative RT after a metabolic complete response (CR) to 6 cycles of ABVD. However, their limited sample sizes reduced statistical power to detect a small but clinically meaningful benefit to RT. Materials and MethodsIn a secondary analysis of these two phase 3 trials, reconstructed patient data were used to compare outcomes for early and complete responders randomized to no RT or RT to the site(s) of initial bulk. Estimates of progression-free survival (PFS) in the intent-to-treat (ITT) and per-protocol (PP) analyses were generated using the combined data and compared between groups using the log-rank test. ResultsA total of 412 patients were included in the ITT analysis and 373 patients were included in the PP analysis. Median age was 30-32, 42% of patients were stage IIB, and 73% of bulky sites were located in the mediastinum. For the no RT versus RT groups, 5-year ITT PFS estimates were 90.1% versus 90.1% (p=0.81). Five-year PP PFS rates were 90.9% versus 92.9% (p=0.31), respectively. There was no observed difference between no RT and RT groups in subgroups according to size of bulky disease: 5-7 cm (p=0.78), 7-10 cm (p=0.25), and >10 cm (p=0.69). ConclusionIn this combined analysis of two randomized phase 3 clinical trials, consolidative RT to initial sites of bulky nodal involvement was not associated with a PFS benefit in patients with advanced HL in metabolic CR after 2 and 6 cycles of ABVD.

Bevacizumab, Irinotecan, or Topotecan Added to Temozolomide for Children With Relapsed and Refractory Neuroblastoma: Results of the ITCC-SIOPEN BEACON-Neuroblastoma Trial.

Outcomes for children with relapsed and refractory high-risk neuroblastoma (RR-HRNB) remain dismal. The BEACON Neuroblastoma trial (EudraCT 2012-000072-42) evaluated three backbone chemotherapy regimens and the addition of the antiangiogenic agent bevacizumab (B). Patients age 1-21 years with RR-HRNB with adequate organ function and performance status were randomly assigned in a 3 × 2 factorial design to temozolomide (T), irinotecan-temozolomide (IT), or topotecan-temozolomide (TTo) with or without B. The primary end point was best overall response (complete or partial) rate (ORR) during the first six courses, by RECIST or International Neuroblastoma Response Criteria for patients with measurable or evaluable disease, respectively. Safety, progression-free survival (PFS), and overall survival (OS) time were secondary end points. One hundred sixty patients with RR-HRNB were included. For B random assignment (n = 160), the ORR was 26% (95% CI, 17 to 37) with B and 18% (95% CI, 10 to 28) without B (risk ratio [RR], 1.52 [95% CI, 0.83 to 2.77]; P = .17). Adjusted hazard ratio for PFS and OS were 0.89 (95% CI, 0.63 to 1.27) and 1.01 (95% CI, 0.70 to 1.45), respectively. For irinotecan ([I]; n = 121) and topotecan (n = 60) random assignments, RRs for ORR were 0.94 and 1.22, respectively. A potential interaction between I and B was identified. For patients in the bevacizumab-irinotecan-temozolomide (BIT) arm, the ORR was 23% (95% CI, 10 to 42), and the 1-year PFS estimate was 0.67 (95% CI, 0.47 to 0.80). The addition of B met protocol-defined success criteria for ORR and appeared to improve PFS. Within this phase II trial, BIT showed signals of antitumor activity with acceptable tolerability. Future trials will confirm these results in the chemoimmunotherapy era.

Effect of tumor type on response to adjuvant platinum-based chemotherapy and prognosis in patients with stage II-IV epithelial ovarian carcinoma.

To evaluate the effect of histological subtype on oncological outcome and adjuvant platinum-based chemotherapy response in patients with epithelial ovarian cancer (EOC). The study group was created with stage II-IV EOC patients. Progression-free survival (PFS) and disease-specific survival (DSS) estimates were determined by using the Kaplan-Meier method. The log-rank test and cox proportional hazards model were performed. A total 396 patients were included the study. Tumor type was serous in 332 (83.8%). Two hundred and thirty-one patients (58.3%) had maximal cytoreduction. Three hundred and twenty-seven (82.6%) patients received complete clinical response. Refractory disease was present in 69 (17.4%) patients. In patients with complete clinical response, 183 (56%) patients recurred. Five-year PFS was 32% in serous group and 31% in non-serous group (p = 0.755). Five-year DSS was 78% in serous group and 87% in non-serous group (p = 0.084). On multivariate analysis, recurrence rates 1.959 times (95% CI: 1.224-3.085; p = 0.004), death rates 2.624 times (95% CI: 1.328-5.185; p = 0.005) higher in patients with optimal cytoreduction than patients with maximal cytoreduction, respectively. Although the rate of maximal cytoreduction was higher in patients with non-serous tumor type, the rate of refractory disease was higher after adjuvant chemotherapy. However, the recurrence rate was higher in serous tumor type. Survival rates were similar in serous and non-serous tumor types. Maximal cytoreduction was an independent predictor factor for survival. Maximal cytoreduction should be the main target in EOC.

Postchemotherapy Retroperitoneal Lumpectomy in Patients with Nonseminoma Testicular Cancer: A Nationwide Study

Background and objectiveOptimal treatment outcomes in patients with metastatic nonseminoma testicular cancer are achieved with chemotherapy and subsequent surgery in cases with residual tumor. In Denmark, postchemotherapy retroperitoneal lumpectomy (RPLP) is performed in patients with residual tumors >1 cm. There is a need to clarify whether this surgical method provides acceptable treatment results. Our objective was to describe morbidity and oncological outcomes of postchemotherapy RPLP. MethodsThis was a retrospective population-based multicenter study including patients with nonseminoma testicular cancer and postchemotherapy RPLP performed in Denmark between 1990 and 2015. A total of 219 patients were eligible, with median follow-up of 19 yr. Postoperative complications were evaluated according to the Clavien-Dindo classification. The cumulative incidence of recurrence inside or outside the borders of a bilateral surgical template, progression-free survival (PFS), and overall survival estimates were calculated using the Kaplan-Meier method. Key findings and limitationsAfter median follow-up of 19 yr, 31/219 patients (14%) experienced a surgical complication, of which 5% were Clavien-Dindo grade ≥III. In total, 37 patients experienced a recurrence. The 5-yr, 10-yr, and 20-yr cumulative risk of recurrence inside a bilateral template was 4.3%, 5.9%, and 5.9%, respectively. The 10-yr PFS rate was 83% and the 10-yr overall survival rate was 96%. The main limitation of the study is the retrospective design. Conclusions and clinical implicationsWith few patients experiencing a major postoperative complication and a 10-yr cumulative rate of 5.9% for recurrence inside a bilateral surgical template, postchemotherapy RPLP appears to be a safe alternative to template surgery for disseminated nonseminoma. Patient summaryWe looked at minimal surgery to remove tumor tissue remaining after chemotherapy in patients with testicular cancer. We found a low frequency of complications, tumor recurrence, and death.