12-month Overall Survival Research Articles

Impact of trial-eligibility as factor for clinical outcome of patients with renal cell carcinoma treated with first-line pazopanib: Subgroup analysis from the prospective, non-interventional study PAZOREAL.

e16511 Background: In a real-world setting, a substantial number of patients (pts) with metastatic renal cell carcinoma (mRCC) do not meet all eligibility criteria for a clinical trial. Thus, data on effectiveness and safety of 1st-line (1L) treatment with pazopanib (PAZO) as well as quality of life (QoL) is underrepresented for those pts and data on treatment sequences implementing PAZO as 1L are sparse. Methods: PAZOREAL is a prospective, multi-center, non-interventional study to evaluate effectiveness, safety and QoL in pts with mRCC treated with 1L PAZO, and nivolumab (NIVO) or everolimus in second and third line. In this subgroup analysis, the clinical outcome of trial-eligible (TE) and trial-ineligible (TIE) pts with mRCC was assessed by means of overall survival (OS), time on drug (ToD), treatment-emergent adverse events (TEAE) and QoL evaluated by EQ-5D-5L. Pts were rated TIE if they met at least one of the following three ‘TIE criteria’: (i) Karnofsky Performance Status < 70%, (ii) hemoglobin below the lower limit of normal, and (iii) non-clear cell carcinoma1. Results: Of 398 pts treated between December 2015 and February 2021, 376 pts received 1L treatment with PAZO. The median age was 69.7 years. 146 pts were categorized TE and 184 pts TIE, for 46 pts assessment was not applicable. Most of all pts were initially treated with PAZO 800 mg (TE: 71.9% vs TIE: 63.0%). Median ToD for PAZO was 7.7 months (95% CI 6.1-9.0) for TE and 6.0 months (95% CI 4.5-8.1) for TIE. A similar fraction of TE and TIE pts were treated with 2L NIVO (43.8% vs 44.0%). Median OS was 53.2 months (95% CI 38.9-NA) for TE and 26.0 months (95% CI 17.3-35.9) for TIE. The 12-month OS rate was 77.9% for TE and 67.1% for TIE. In patient reported outcome (PRO) measures, baseline QoL was estimated higher for TE than TIE, i.e., 63.2% TE vs 49.2% TIE pts had no limitations for mobility and 82.9% TE vs 61.7% TIE pts were independent in self-care. Frequency of related TEAEs grade 3/4 were comparable for TE and TIE (26.7% vs 25.0%), while TE tended to have less related serious TEAEs (13.0% vs 16.3%). Treatment was discontinued due to related TEAEs in 19.2% of TE and 13.0% of TIE pts. Conclusions: PAZOREAL provides real-world data for mRCC pts usually not represented in clinical trials during the study period. As it was to be expected, median OS and PRO were more favorable for TE than for the TIE pts, reflecting the difference in general condition between these groups. But more importantly, these data underline the tolerability of 1L PAZO treatment even for TIE pts, which is supported by comparable ToD for 1L PAZO and the comparable safety profile in both subgroups.1 Marschner, N. et al. Clin Genitourin Cancer 2017; 15(2):e209-215. doi:10.1016/j.clgc.2016.08.022.

A phase Ib/II study of the combination of lenvatinib (L) and eribulin (E) in advanced liposarcoma (LPS) and leiomyosarcoma (LMS) (LEADER): Efficacy updates.

11506 Background: There are limited treatment options for advanced LPS and LMS, the two most common histologies in soft tissue sarcoma. Patients (pts) treated with E had an improved overall survival (OS) compared to dacarbazine but with an unsatisfactory 4% objective response rate (ORR). Early studies of L, a multi-targeted anti-angiogenic inhibitor, had suggested efficacy in sarcoma pts. We hypothesized that the L+E could potentiate the treatment efficacy in advanced LMS and LPS. Methods: LEADER was a single-arm phase Ib/II study for advanced adult LMS and LPS pts who had received no more than 2 lines of systemic chemotherapy (NCT03526679). The phase Ib part (starting dose: L 18mg/day, E 1.1mg/m2) had been reported and the recommended phase 2 dose (RP2D) was determined at L 14mg/day and E 1.1mg/m2 D1, D8 every 21 days. The primary endpoint of the phase II part was ORR by RECIST 1.1, secondary endpoints included progression-free survival (PFS), 6-month PFS rate, and OS. Pts in phase Ib/II part were analyzed together for efficacy. Results: As of Nov 15 2021, 30 pts (F/M 20/10) had been treated with at least one cycle of L + E; 21 were LMS (9 uterine, 12 non-uterine) and 9 were LPS (5 dedifferentiated, 2 myxoid round cell, 2 pleomorphic). The median age was 59 (range 29-73); the median lines of treatment(s) received before enrollment was 1 (range 0-3). The ORR by RECIST 1.1 was 20 % (6/30) (95% CI 10-53%); the ORR for pts received L 18mg/day (2/6) and L 14mg/day (4/26) were not significantly different (p = 0.23). After a median FU time of 20.1 months, the median PFS and 6-month PFS rate was 8.56 mos (95% CI 4.40-not reached (NR)) and 59%, respectively. The median PFS for LMS (8.56 mos, 95% CI 4.17- NR) and LPS (11.36 mos, 95% CI 4.4-NR) were not significantly different (p = 0.73). The median OS and 12-month OS rate was 26.2 mos (95% CI 21.4-NR) and 89%, respectively, but LPS pts had significantly worse OS (HR 3.5, p = 0.04). Twenty pts experienced at-least one grade (gr) 3 or 4 adverse event (AE); gr 3 or 4 AEs occurred in > 1 pt included hypertension (n = 4); hand-foot-syndrome (HFS) (n = 5), proteinuria (n = 3), febrile neutropenia (n = 3), neutropenia (n = 11, without G-CSF support). Compared to L 18mg/day, pts treated with RP2D were associated with lower gr3/4 HFS and hypertension. There were no sustained grade 3/4 AEs for pts receiving long-term L+E. Conclusions: L + E had shown promising efficacy in advanced LMS and LPS. L at 14mg (vs 18mg) had a better AE profile without compromising activity. Future randomized study to confirm the efficacy of the combination is warranted. Clinical trial information: NCT03526679.

Surrogate Endpoints for Overall Survival in Immune-Oncology Trials of Advanced Gastro-Esophageal Carcinoma.

BackgroundWe aimed to assess whether the Response Evaluation Criteria in Solid Tumors (RECIST)-based objective response rate (ORR), disease control rate (DCR) and progression-free survival (PFS) could serve as surrogate endpoints for overall survival (OS) in immune-oncology (IO) trials of advanced gastro-esophageal (GE) carcinoma.MethodsRandomized controlled trials (RCTs) of IO that reported RECIST-based endpoints and OS in advanced GE carcinoma were screened. Surrogacy of endpoints for OS was assessed based on the correlation between endpoints with OS (arm-level), and between treatment effects on endpoints (trial-level). The correlations were quantified by Pearson correlation coefficient (R). Leave-one-out cross-validation was used to assess the prediction accuracy of surrogate model.ResultsSeventeen RCTs (9,657 subjects) with 20 comparisons were included. The correlations between DCR and OS were not strong at arm- (R = 0.80) and trial-levels (R = 0.45), but strong correlations between ORR (R = 0.91), PFS (R = 0.89) and OS at arm-level were observed. Treatment effect on ORR and PFS (both R = 0.71) was moderately correlated with treatment effect on OS. Leave-one-out cross-validation approach further validated the surrogacy of PFS. Our analysis showed that 3-month PFS could reliably predict 6-month OS, 6-month PFS could reliably predict 12-month OS, and 12-month PFS could reliably predict 18-month OS. The conservative minimum threshold effect of HRPFS was 0.73.ConclusionsPFS may be the appropriate surrogate for OS in IO trials of GE carcinoma. A conservative minimum threshold effect of HRPFS ≤ 0.73 has the potential to predict a significant improvement in OS.

Interim analysis of the phase II AVETUXIRI trial: Avelumab combined with cetuximab and irinotecan for treatment of refractory microsatellite stable (MSS) metastatic colorectal cancer (mCRC).

3595 Background: Immune checkpoint inhibitors demonstrated poor efficacy in MSS mCRC. Cetuximab (anti-EGFR inhibitor) could initiate, independently from RAS mutation, an immunogenic tumor cell death and mediate antitumor immune response. In this trial, we aim to explore the clinical efficacy and safety of avelumab (anti-PDL1) combined with cetuximab and irinotecan for treatment refractory MSS mCRC and to understand its mechanisms of action through associated translational research. Methods: AVETUXIRI trial (NCT03608046) enrols MSS, chemorefractory (fluoropyrimidine, oxaliplatin, irinotecan and anti-EGFR treatment if RAS wt tumor) mCRC patients in 2 cohorts (A: RAS-wt, n = 10 – B: RAS-mut, n = 13). Primary endpoints are safety and tumor response rate ((i)RECIST1.1). Secondary endpoints include disease control rate (DCR), progression-free survival (PFS) and overall survival (OS). According to a Simon 2-stage design, 23 patients have been included in the first stage of the trial. Multiplex immunofluorescence and RNA sequencing were realized on metastasis biopsies performed before, during and after the treatment. Densities of CD3+ (T cells) and CD8+ (cytotoxic) were quantified and analyzed with to generate an immunoscore (IS). RNA-seq data was used to perform differential expression analysis (DESeq2), gene set enrichment analysis (GSEA), deconvolution analysis (ConsensusTME) and gene ontology analysis (GO). Results:: No unexpected safety signals were observed. 3/10 tumor responses were observed in cohort A, 0/13 in cohort B. DCR was 60.0% and 61.5% in cohort A and B, respectively. 6-months PFS and 12-months OS rates were respectively 40.0% and 50.0% (cohort A) and 38.5% and 46.2% (cohort B). Independently of RAS mutation, patients with a high IS (metastasis biopsy, baseline) had significantly higher tumor shrinkage (OR = 18.67 p = 0.019), median PFS (6.9 vs 3.4 months; HR = 0.16, p = 0.002) and median OS (13.7 vs 7.9 months, HR = 0.26, p = 0.009). Similarly, tumor shrinkage and survival outcome (PFS > 6 months, OS > 12 months) were associated with upregulation of an adaptive immune response signature (including Th1, chemokine, adhesion molecules, immune checkpoints and T-cell activation genes, p. adj = 0.009) and the GSEA hallmark of epithelial to mesenchymal transition (p. adj = 0.045). Few modifications of IS and gene expression profiles were observed on the different metastasis biopsies performed overtime in the included patients. Conclusions: AVETUXIRI met its preliminary primary efficacy endpoint for RAS-wt mCRC pts, justifying its current continuation. Encouraging survival data observed in RAS-mut cohort allow the opening of a new cohort (PFS as primary endpoint). IS and adaptive immune response signature evaluated on metastases biopsies were associated with treatment efficacy and survival. Clinical trial information: NCT03608046.

Updated efficacy and safety results from the phase 2 study of serplulimab, a novel anti-PD-1 antibody, in patients with previously treated unresectable or metastatic microsatellite instability-high or mismatch repair-deficient solid tumors.

2592 Background: Serplulimab is a novel humanized monoclonal antibody against PD-1. At ASCO 2021, we have presented the results from the phase 2 serplulimab study (NCT03941574) in patients with unresectable/metastatic microsatellite instability-high or mismatch repair-deficient (MSI-H/dMMR) solid tumors who have progressed on or been intolerant to standard therapies with a median follow-up of 7.7 months. Here, we report the updated efficacy and safety results together with the results from sensitivity analysis after another 6-month follow-up. Methods: In this single-arm, open-label, multicenter, phase 2 study, patients aged 18–75 years with histologically or cytologically confirmed unresectable or metastatic MSI-H/dMMR solid tumors were enrolled to receive 3 mg/kg of intravenous serplulimab every two weeks for up to two years. The primary endpoint was objective response rate (ORR) assessed by an independent radiological review committee (IRRC) per RECIST v1.1. Secondary endpoints included ORR assessed by the investigators, duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety. Results: As of July 10, 2021, 108 patients had received at least one dose of study treatment and were included in the safety set (SS). Among them, 68 patients with confirmed MSI-H (by local sites or central lab) were included in the main efficacy analysis population (MEAP); 58 patients with confirmed MSI-H (by central lab) and had no major protocol deviations were included in the sensitivity analysis population (SAP). The median follow-up duration was 13.5 months in the MEAP and 14.0 months in the SAP. IRRC-assessed ORR per RECIST v1.1 was 39.7% (95% CI 28.0–52.3; 3 complete response [CR]) in the MEAP and 43.1% (95% CI 30.2–56.8; 2 CR) in the SAP. Investigator-assessed ORRs were 38.2% (95% CI 26.7–50.8; 1 CR) and 41.4% (95% CI 28.6–55.1; 1 CR) in the MEAP and the SAP, respectively. Median DoR, PFS, and OS were not reached; 12-month OS rate was 74.5% (95% CI 62.2–83.3) in the MEAP and 82.4% (95% CI 69.7–90.1) in the SAP. In the SS, 57 (52.8%) patients had grade ≥3 treatment-emergent adverse events, most commonly anemia (9.3%). Thirteen (12.0%) patients had grade ≥3 immune-related adverse events. Three (2.8%) deaths (2 progressive disease and 1 intestinal obstruction) that might be related to serplulimab were reported. Conclusions: The encouraging antitumor activity and the manageable safety profile sustained after a longer duration of follow-up, supporting the further development of serplulimab as a potential tissue-agnostic antitumor treatment. Clinical trial information: NCT03941574.

Sintilimab plus anlotinib as second or further-line therapy for small cell lung cancer: An objective performance trial.

8516 Background: Small cell lung cancer (SCLC) tends to progress rapidly on first-line therapies, with limited subsequent-line treatment options. Methods: In this single-arm objective performance trial, adult patients with extensive-disease SCLC (ED-SCLC) received intravenous sintilimab 200 mg on day 1 and oral anlotinib 12 mg on days 1-14. Treatment lasted for 3 weeks per cycle and was continued until disease progression, unacceptable toxicities, or death. The primary endpoint was the superiority of progression-free survival (PFS) versus a PFS of 2.8 months with historical topotecan control. Results: Forty-two patients were enrolled, and 39 patients were evaluable for efficacy. Twenty-six patients (66.7%) had ED-SCLC, and 13 (33.3%) relapsed after concurrent chemoradiotherapy. The median follow-up was 11.9 months. The median PFS was 6.0 months (95%CI: 4.8-7.2). The 6- and 12-month PFS rate was 50.5% and 27.8%, respectively. Fourteen patients died by the data cut-off date, and overall survival (OS) was immature (16.1 months, 95%CI: 9.4-22.7). The 12- and 18-month OS rate was 56.7% and 42.5%, respectively. Three patients attained complete response and 16 achieved partial response, and 12 patients had stable disease; the objective response rate was 48.7% and the disease control rate was 79.5%. Forty patients (95.2%) had at least one treatment-related adverse event (TRAE). The most frequent TRAEs were hypothyroidism (45.2%), hypoproteinemia (40.5%) and elevated gamma-glutamyl transpeptidase (38.1%). Conclusions: Immunotherapy with sintilimab plus antiangiogenic drug anlotinib demonstrated promising antitumor activities as second or further-line therapy for ED-SCLC and had manageable toxicities. The findings support further development of this combination regimen for ED-SCLC. Clinical trial information: NCT04055792.

Alofanib in subsequent therapy for advanced gastric cancer: Final results from the phase Ib clinical trial.

e16077 Background: Alofanib (RPT835) is a first-in-class allosteric inhibitor that induces conformational changes in the extracellular domain of FGFR2. Here, we present the final results of the phase Ib clinical study (RPT835GC1B) of alofanib. Methods: Patients with metastatic gastric adenocarcinoma resistant to standard therapy with measurable disease were eligible. The dose finding part used a 3+3 design, starting with a dose level of 50 mg/m2, intravenously, 5 days on, 2 days off. Five dose levels were foreseen. Primary endpoint was maximum tolerated dose (MTD). Secondary endpoints included toxicity, PK, objective response rate (ORR), overall survival (OS), and progression-free survival (PFS). Results: 21 patients were enrolled. 4 (19.1%), 14 (66.7%), 9 (43%), 3 (14.3%), and 12 (57%) patients had ECOG PS 2, ≥2 metastatic sites, liver metastases, bone metastases, and 3-6 lines previous therapy, respectively. The MTD has not been reached and dose of 350 mg/m2 has been declared as recommended phase II dose. With median follow-up of 13.0 months 15 (71.4%) patients had any grade treatment related adverse events (TRAE). Grade 3-4 TRAE occurred in 6 (28.6%) patients. Two (9.5%) patients discontinued treatment due to grade 3 diarrhea and grade 4 reactions immediately after injections. There were no treatment-related deaths in the study. One partial response (5.26%) with a duration of 18.53 months was identified. Disease control rate (DCR) was 68.4% and median duration of stable disease was 4.91 months. Median PFS was 3.63 (95% CI 1.58–5.68) months. Median OS was 7.0 (3.82–10.18) months. 6-month OS rate was 57.1%. OS was almost 2 times better in patients with DCR (median 10.05 vs. 5.9 months) and without bone metastases (8.6 vs. 3.1). Only one patient (4.8%) had FGFR2 amplification (time to death was 7 months). PK parameters linearly changed depending on the dose level, but no correlation with efficacy was found. Table summarizes rate of TRAE and DCR in dose cohorts. Conclusions: Alofanib was feasible and showed early signals of efficacy in heavily-pretreated patients with metastatic gastric cancer. A phase 2 randomized trial is planned. Clinical trial information: NCT04071184. [Table: see text]

Venetoclax combined with FLAG-IDA induction and consolidation in newly diagnosed acute myeloid leukemia.

Multi-agent induction chemotherapy (IC) improves response rates in younger patients with acute myeloid leukemia (AML); however, relapse remains the principal cause of treatment failure. Improved induction regimens are needed. A prospective single-center phase Ib/II study evaluating fludarabine, cytarabine, G-CSF, and idarubicin combined with venetoclax (FLAG-IDA + VEN) in patients with newly diagnosed (ND) or relapsed/refractory AML. The primary efficacy endpoint was assessment of overall activity (overall response rate [ORR]: complete remission [CR] + CR with partial hematologic recovery [CRh] + CR with incomplete hematologic recovery [CRi] + morphologic leukemia free state + partial response). Secondary objectives included additional assessments of efficacy, overall survival (OS), and event-free survival (EFS). Results of the expanded ND cohort with additional follow-up are reported. Forty-five patients (median age: 44 years [range 20-65]) enrolled. ORR was 98% (N= 44/45; 95% credible interval 89.9%-99.7%). Eighty-nine percent (N= 40/45) of patients attained a composite CR (CRc + CRh + CRi) including 93% (N= 37/40) who were measurable residual disease (MRD) negative. Twenty-seven (60%) patients transitioned to allogeneic stem cell transplant (alloHSCT). Common non-hematologic adverse events included febrile neutropenia (44%; N= 20), pneumonia (22%, N= 10), bacteremia (18%, N= 8), and skin/soft tissue infections (44%, N= 20). After a median follow-up of 20 months, median EFS and OS were not reached. Estimated 24-month EFS and OS were 64% and 76%, respectively. FLAG-IDA + VEN is an active regimen in ND-AML capable of producing high MRD-negative remission rates and enabling transition to alloHSCT when appropriate in most patients. Toxicities were as expected with IC and were manageable. Estimated 24-month survival appears favorable compared to historical IC benchmarks.

Mebendazole plus lomustine or temozolomide in patients with recurrent glioblastoma: A randomised open-label phase II trial.

SummaryBackgroundRecurrent glioblastoma (GBM) has dismal outcomes and limited treatment options. Mebendazole (MBZ) has activity in glioma both in-vivo and in-vitro, and is well tolerated in combination with lomustine (CCNU) and temozolomide (TMZ). In this study, we sought to determine whether the addition of MBZ to CCNU or TMZ would improve overall survival (OS) in recurrent GBM.MethodsIn this phase II randomized open-label trial, adult patients with ECOG PS 0–3, with recurrent GBM who were not eligible for re-radiation, were randomized 1:1 to the CCNU-MBZ and TMZ-MBZ arms. CCNU was administered at 110 mg/m2 every 6 weeks with MBZ 800 mg thrice daily and TMZ was administered at 200 mg/m2 once daily on days 1–5 of a 28 days cycle with MBZ 1600 mg thrice daily. The primary endpoint was OS at 9 months. A 9-month OS of 55% or more in any arm was hypothesized to warrant further evaluation and a value below 35% was too low to warrant further investigation. OS was analyzed using intention to treat (ITT) and per-protocol (PP) analyses. Per-protocol analysis was used for safety analysis. Clinical Trials Registry-India number, CTRI/2018/01/011542.FindingsParticipants were recruited from 14th March 2019 to 18th June 2021, 44 patients were randomised on each arm. At 17.4 months, 68 events for OS analysis had occurred, 33 in the TMZ-MBZ and 35 in the CCNU-MBZ arm. The 9-month OS was 36.6% (95% CI 22.3–51.0) and 45% (95% CI 29.6–59.2) in the TMZ-MBZ and CCNU-MBZ arms respectively, in the ITT population. ECOG PS was the only independent prognostic factor impacting OS (HR-0.48, 95% CI 0.27–0.85; P = 0.012). Grade 3–5 adverse events were seen in 8 (18.6%; n = 43) and 4 (9.5%; n = 42) patients in the TMZ-MBZ and CCNU-MBZ arms respectively. There were no treatment related deaths.InterpretationThe addition of MBZ to TMZ or CCNU failed to achieve the pre-set benchmark of 55% 9-month OS. This was probably due to 28.6% of patients having poor PS of 2–3.FundingBrain Tumor Foundation (BTF) of India, Indian Cooperative Oncology Network (ICON), and India Cancer Research Consortium (ICRC) under ICMR (Indian Council of Medical Research).

A Phase 2 Clinical Trial of Combination Nivolumab, Ipilimumab, and Paclitaxel in Patients With Untreated Metastatic NSCLC: The OPTIMAL Trial

IntroductionMost patients with advanced NSCLC will experience disease progression and death within 2 years. Novel approaches are needed to improve outcomes. MethodsWe conducted an open-label, nonrandomized, phase 2 trial in patients with treatment-naive, advanced NSCLC to assess the safety and efficacy of nivolumab 360 mg every 3 weeks, ipilimumab 1 mg/kg every 6 weeks, and four to six cycles of paclitaxel 80 mg/m2 on days 1 and 8 of every 21-day treatment. The primary end point of the study was median progression-free survival (PFS), with secondary end points of safety, objective response rate, and median overall survival (OS). ResultsA total of 46 patients underwent consent and received treatment. The median age was 66 (range: 48–82) years, most had adenocarcinoma (63%), and 50% (23) had programmed death-ligand 1 greater than or equal to 1%. The median follow-up on the study as of October 2021 was 19 months. The primary end point of median PFS was 9.4 months (95% confidence interval [CI]: 5.9–16.6) in all patients regardless of programmed death-ligand 1 expression. The objective response rate for patients in the study was 47.8% (95% CI: 33.4–62.3). The 12-month OS rate was 69.5% (95% CI: 53%–81%), and median OS was not yet reached. Treatment-related grade greater than or equal to 3 adverse events was found in 54.3% of the patients. ConclusionsThe toxicity observed was consistent with other reported chemo-immunotherapeutic combinations and was manageable. The primary end point of exceeding median PFS of 9 months was achieved with nivolumab, ipilimumab, and weekly paclitaxel and should be evaluated further in a randomized trial.

Serum parameters as prognostic biomarkers in a real world cancer patient population treated with anti PD-1/PD-L1 therapy

Background Immune checkpoint inhibitors (ICI) are regarded as a standard of care in multiple malignancies. We hypothesized that serum parameters are of prognostic value in ICI treated patients suffering from solid tumours. Methods Data from 114 patients treated with ICIs for solid malignancies from 2015 to 2019 at the Medical University of Vienna were collected retrospectively. Data included baseline characteristics, cancer type, serum parameters such as lactate dehydrogenase (LDH), C-reactive protein (CRP), albumin (Alb) and lymphocyte counts as well as overall survival (OS) and progression free survival. Additionally, the Gustave Roussy Immune Score (GRIm score) and the Glasgow prognostic score (GPS) were calculated. Cox regression models including time-dependent effects and strata for tumour type were used. Prognostic factors were pre-selected using a relaxed LASSO approach. Results The majority of patients were male (64.9%). The most common cancer types were non-small cell lung cancer (30.7%) and renal cell carcinoma (21.9%). Increased LDH and CRP were associated with poor 6-month OS (Hazard ratios (HR)=1.16 and 1.06 per 20% LDH/CRP increase; 95% CI 1.07–1.26 and 95% CI 1.03–1.09, respectively; p < .001). Both GRIm Score and GPS had a significant influence on OS (GRIm: HR = 2.84, 95% CI 1.72–4.69; p < .001 for high vs. low; GPS HR 3.57, 95% CI 1.76–7.25; p < .001 for poor vs. good). The proportion of explained variation (PEV) of our full multivariable model was significantly higher compared to the GRIm and GPS (PEV = 29.5% vs. 14.8% and 14.65%). When grouped into quartiles according to the individual 8-weeks change, both increased LDH and CRP correlated with poor OS (LDH (p=.001) and CRP (p < .001)). Conclusion The results of this analysis suggest that serum parameters might have prognostic value for the outcome of cancer patients treated with ICI, regardless of the tumour type. Key messages In this retrospective analysis, 114 patients with solid tumours were included. The results of this analysis point out that pre-treatment LDH, CRP and albumin levels are strongly prognostic for a poor 6-month OS. In addition to that, a high GRIm-score and poor GPS were associated with a worse OS (GRIm: HR = 2.84, 95% CI 1.72–4.69; p < .001 for high vs. low; GPS HR = 3.57, 95% CI 1.76–7.25; p < .001 for poor vs. good). Pre-treatment serum parameters might have prognostic value for the outcome of cancer patients treated with ICI, regardless of the tumour type.

MP56-02 NEOADJUVANT PEMBROLIZUMAB MAY RESULT IN LONG-TERM OUTCOME IMPROVEMENT IN BIOMARKER-UNSELECTED PATIENTS WITH MUSCLE-INVASIVE BLADDER CANCER (MIBC): UPDATED RESULTS FROM PURE-01

You have accessJournal of UrologyCME1 May 2022MP56-02 NEOADJUVANT PEMBROLIZUMAB MAY RESULT IN LONG-TERM OUTCOME IMPROVEMENT IN BIOMARKER-UNSELECTED PATIENTS WITH MUSCLE-INVASIVE BLADDER CANCER (MIBC): UPDATED RESULTS FROM PURE-01 Luigi Nocera, Marco Moschini, Daniele Raggi, Laura Marandino, Maurizio Colecchia, Roberta Lucianò, Ewan Gibb, Jeffrey Ross, Antonella Messina, Giuseppina Calareso, Andrea Gallina, Federico Dehò, Alberto Briganti, Francesco Montorsi, and Andrea Necchi Luigi NoceraLuigi Nocera More articles by this author , Marco MoschiniMarco Moschini More articles by this author , Daniele RaggiDaniele Raggi More articles by this author , Laura MarandinoLaura Marandino More articles by this author , Maurizio ColecchiaMaurizio Colecchia More articles by this author , Roberta LucianòRoberta Lucianò More articles by this author , Ewan GibbEwan Gibb More articles by this author , Jeffrey RossJeffrey Ross More articles by this author , Antonella MessinaAntonella Messina More articles by this author , Giuseppina CalaresoGiuseppina Calareso More articles by this author , Andrea GallinaAndrea Gallina More articles by this author , Federico DehòFederico Dehò More articles by this author , Alberto BrigantiAlberto Briganti More articles by this author , Francesco MontorsiFrancesco Montorsi More articles by this author , and Andrea NecchiAndrea Necchi More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002639.02AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: PURE-01 trial provided several activity signals mainly represented by pathological response endpoints. We aimed to report updated results on recurrence-free survival (RFS) and overall survival (OS) at longer follow-up. METHODS: From 02/2017 to 06/2020, 136 patients were treated. RFS was defined as the time from first pembrolizumab dose to either: i) radiological progression, ii) local or distant recurrence, iii) death from any cause. Statistical analyses consisted of Kaplan-Meier analyses and Cox regression models. RESULTS: Of all 136 patients, 120 (88%) were males and median age was 68 years (IQR 62-74), while 76 patients (56%) exhibited a PD-L1 CPS≥10% on the TURB specimen pre-therapy. At radical cystectomy pathology, 57 (42%), 25 (18%), 34 (25%) and 20 (15%) patients harbored respectively ypT0N0, ypT1/a/isN0, ypT2-4N0 and ypTanyN+ disease. Finally, 9 patients (7%) received also adjuvant chemotherapy: 3 ypT2-4N0 and 6 ypTanyN+ patients. After a median follow-up of 27 months (IQR 21-38), 22 patients (16%) experienced a recurrence, while 14 patients (10%) died. At Kaplan-Meier curves (Figure 1), patients treated with neoadjuvant pembrolizumab exhibited a 36-month OS of 95%, 86%, 93% and 56% for respectively ypT0N0, ypT1/a/isN0, ypT2-4N0 and ypTanyN+ stages. Similarly, they exhibited a 36-month RFS of 94%, 96%, 67% and 44% for respectively ypT0N0, ypT1/a/isN0, ypT2-4N0 and ypTanyN+ stages. In ITT population, 36-month RFS and OS for CPS≥10% vs CPS>10 cohorts were respectively 88% vs 72% and 91% vs 79%. At multivariable Cox regression analyses, only age (HR 1.1, p=0.02) and ypTanyN+ stage (HR 9.0, p=0.02) represented independent predictors of overall mortality, after adjustment for stage, CPS ≥10% and adjuvant chemotherapy. Similarly, when recurrence represented the outcome, only ypT2-4N0 (HR 8.6, p=0.007) and ypTanyN+ (HR 15.9, p=0.001) stages represented independent predictors. CONCLUSIONS: Pembrolizumab followed by radical cystectomy confirms to be an effective treatment for patients with MIBC, unselected for biomarkers and for cisplatin eligibility. This data should be tested towards the data emerging in adjuvant setting and in light of the ongoing randomized perioperative phase 3 trials. Source of Funding: NA © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e971 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Luigi Nocera More articles by this author Marco Moschini More articles by this author Daniele Raggi More articles by this author Laura Marandino More articles by this author Maurizio Colecchia More articles by this author Roberta Lucianò More articles by this author Ewan Gibb More articles by this author Jeffrey Ross More articles by this author Antonella Messina More articles by this author Giuseppina Calareso More articles by this author Andrea Gallina More articles by this author Federico Dehò More articles by this author Alberto Briganti More articles by this author Francesco Montorsi More articles by this author Andrea Necchi More articles by this author Expand All Advertisement PDF DownloadLoading ...

Short-Term Outcomes and Clinical Efficacy of Stereotactic Body Radiation Therapy (SBRT) for Oligometastases of Prostate Cancer in China.

ObjectiveTo assess the efficacy and safety of stereotactic body radiation therapy (SBRT) in managing oligometastases of prostate cancer. Moreover, it is the largest-to-date study in China to report the safety and efficacy of SBRT by CyberKnife for oligometastases of prostate cancer.MethodsIn this retrospective study, 75 patients with 108 oligometastases were treated by SBRT from May 2012 to February 2021. Among these patients, 43 patients were treated with the intention to control all known metastatic lesions and 32 were treated for palliative care. Patients received regular follow-up evaluations every 3 months. Efficacy was assessed based on local control (LC) rates, biochemical progression-free survival (bPFS), progression-free survival (PFS), and overall survival (OS). Safety was assessed based on clinical adverse events.ResultsMedian follow-up time was 23.2 months (1.2-106.9 months). The complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD) rates were 63.0%, 10.2%, 21.3% and 5.6%, respectively. The 6-month, 1-, and 2-year LC rates were 100%, 97.5%, and 96.0% respectively while the 6-month, 1-, and 2-year bPFS rates were 74.6%, 53.3%, and 47.9%, respectively. Additionally, 6-month, 1-, and 2-year PFS rates were 77.5%, 50.8%, and 47.2%, respectively. The 6-month, 1-, and 2-year OS rates were 97.0%, 88.8%, and 87.0%, respectively. For the 15 metastatic castration-resistant prostate cancer (mCRPC) patients with 23 lesions, the 2-year LC rates were 93.8%, while for 60 metastatic hormone-sensitive prostate cancer (mHSPC) patients with 85 lesions, the 2-year LC rates were 96.7%. No predictors of LC were found after univariate analysis. In those not on androgen deprivation therapy (ADT; n = 27), the 2-year freedom from ADT was 44.0%. All of the 24 patients with oligmetastase-induced complications experienced varying degrees of alleviation after SBRT. The treatment was well tolerated. No grade 3 or higher toxicity was observed.ConclusionSBRT is a safe and effective treatment modality in the management of oligometastases of mHSPC and mCRPC with high LC rates and acceptable toxicity. SBRT could provide a treatment choice for mCRPC, as well as an alternative to delay the start of ADT for mHSPC.

Efficacy and safety of sintilimab plus docetaxel in patients with previously treated advanced non-small cell lung cancer: a prospective, single-arm, phase II study in China.

PurposeAlthough immune checkpoint inhibitor monotherapy has been used as a second-line treatment in advanced non-small cell lung cancer (NSCLC), the improvement in progression-free survival (PFS) remains unsatisfactory. We investigated the feasibility of sintilimab plus chemotherapy as a second-line treatment in advanced NSCLC.MethodsThis was a phase II, single-arm, prospective study in advanced NSCLC patients who had failed standard platinum-based chemotherapy (ChiCTR1900027634, Registered 22 November 2019). Eligible patients received docetaxel 75 mg/m2 (day 1) plus sintilimab 200 mg (day 3) Q3W. Those did not progress after 4–6 cycles received sintilimab 200 mg Q3W as maintenance treatment. The primary endpoint was PFS.ResultsForty patients were enrolled between October 2019 and October 2020. With a median follow-up of 12.2 months, the median PFS was 5.8 months, and the PFS rates at 6 and 12 months were 48% and 30%, respectively. The median overall survival (OS) was 12.6 months, with a 12-month OS rate of 62.0%. The overall response rate was 32.4%, and the disease control rate was 89.2%. The incidence of all and ≥ grade 3 treatment-related adverse events (TRAEs) were 65% (26/40) and 17.5% (7/40), respectively. No TRAEs-related permanent treatment discontinuation or death occurred. bTMB reduction at 6 weeks was associated with a longer PFS (NR vs 3.0 months, P < 0.0001).ConclusionThis prospective phase II study in China suggested that sintilimab plus docetaxel might improve PFS and tumor response with good tolerability for Chinese patients with previously treated advanced NSCLC. bTMB reduction at 6 weeks could serve as a potential predictive biomarker for this regimen.Supplementary InformationThe online version contains supplementary material available at 10.1007/s00432-022-04023-z.

Study of PD-1 Inhibitors in Combination with Chemoradiotherapy/Chemotherapy in Patients with Esophageal Squamous Carcinoma.

In this study, we aimed to evaluate the efficacy of PD-1 inhibitors in combination with concurrent CRT/CT for patients with inoperable ESCC in the real world and to find predictors for the efficacy of PD-1 inhibitors. Patients with unresectable ESCC were evaluated at baseline. The clinical data of patients with ESCC who received CRT/CT with or without PD-1 inhibitor were collected and retrospectively reviewed. The objective response rate (ORR), overall survival (OS), and progression-free survival (PFS) were analyzed statistically. A total of 96 patients with ESCC were included. As compared with a control group (n = 48), the PFS (6.0 months vs. 5.0 months, p = 0.025) and 6-month OS (70.8% vs. 47.9%, p < 0.001) were significantly longer in the ICIs group (n = 48). There were no significant differences in ORR and 12-month OS between the two groups. In addition, we found that body mass index (BMI) was associated with PFS (HR 0.85, 95% CI 0.76–0.95, and p = 0.004) and OS (HR 0.82, 95% CI 0.69–0.98, and p = 0.033) in the ICIs group. PD-1 inhibitors combined with CRT/CT is safe with acceptable complications and improved survival for patients with inoperable ESCC. CRT plus PD-1 inhibitor has superior antitumor efficacy. BMI was positively correlated with the efficacy of PD-1 inhibitors.

Olaparib Combined With Dacomitinib in Osimertinib-Resistant Brain and Leptomeningeal Metastases From Non-Small Cell Lung Cancer: A Case Report and Systematic Review

Lung cancer patients with brain and leptomeningeal metastases usually have poor prognosis. For those patients with EGFR mutations, osimertinib, a third-generation tyrosine kinase inhibitor (TKI), is the first choice of treatment. However, drug resistance to osimertinib frequently occurs; and to date, the available follow-up treatment strategies have limited efficacy. In this case study, we report that treatments with olaparib, a Poly (ADP-ribose) polymerase (PARP) inhibitor, combined with dacomitinib, a second-generation EGFR TKI, benefited a lung cancer patient with osimertinib-resistant brain and leptomeningeal metastases. This 55-year-old male patient was found to have a pL858R mutation on EGFR exon 21 combined with TP53 and ERBB2 mutations after developing drug resistance to osimertinib treatment. Based on the genetic testing results, he was treated with olaparib and dacomitinib, and obtained 6 months of progression-free survival (PFS) and 13 months of overall survival (OS) after the diagnosis of leptomeningeal metastasis. This case report represents the first study applying PARP inhibitor in combination with dacomitinib in the treatment of leptomeningeal metastases after osimertinib resistance.

High dose melphalan is an adequate preparative regimen for autologous hematopoietic stem cell transplantation in relapsed/refractory lymphoma

ABSTRACT Introduction High-dose melphalan (HD-Mel) has been successfully employed in autografting patients with multiple myeloma. An advantage of this regimen is that the total dose of Mel can be delivered in a single day, being particularly useful when non-frozen hematopoietic stem cells are employed in the autograft. Material and Methods All consecutive patients with R/R lymphomas, both HL and NHL studied and treated at two different centers were prospectively included in a study of ASCT employing a single dose of HD-Mel (200 mg/m2). A group of R/R HL or NHL autografted employing BEAM-like preparative regimens was constructed matched by diagnosis and age. The primary endpoint of the study was overall survival (OS), the secondary endpoint was event-free survival (EFS). Results Twenty-five R/R HL/NHL patients were prospectively accrued in the study. There were 8 (32%) females, 13 (52%) patients had at least 1 adverse effect: 7 (28%) developed mucositis, 5 (20%) neutropenic fever, and 6 (24%) grade IV nausea. In the HD-Mel group, median overall survival (OS) was not achieved and OS at 36 months was 71%, the transplant-related mortality being 0%. In the control group, median OS was not achieved and the 36-month OS was 76%, results not statistically significant (p 0.5). The EFS was also similar in both groups (p 0.5). Conclusion HD-Mel alone is non-inferior to a BEAM-like regimen as a preparative regimen for autografting patients with R/R HL and NHL. The regimen is adequate to graft persons with non-frozen stem cells.

Results of a Prospective Non-Interventional Post-Authorization Safety Study of Idelalisib in Germany

BackgroundIn pivotal studies, idelalisib demonstrated remarkable efficacy and manageable tolerability in patients with chronic lymphocytic leukemia (CLL) and follicular lymphoma (FL). This prospective, multicenter, non-interventional post-authorization study assessed the characteristics, clinical management, and outcome of CLL and FL patients receiving idelalisib in routine clinical practice in Germany. PatientsObservational study in CLL and FL patients treated with idelalisib between September 2015 and December 2020. ResultsA total of 147 patients with CLL and FL were included with a median age of 75 and 71 years, respectively. More than 80% of patients presented with comorbidity and many CLL patients with documented high-risk genetic features, including del(17p)/TP53 mutation or unmutated IGHV. The median progression-free survival (PFS) and overall survival (OS) were not reached in the CLL cohort irrespective of del(17p)/TP53 or unmutated IGHV. The estimated 6-month PFS and OS rates in CLL were 82% and 92%. The estimated 6-month PFS and OS rates for FL were 32.2% and 77.2%. Overall response rates in the CLL and FL cohorts were 70.4% and 36.4%, with the presence of high-risk genetics having no negative impact. No unexpected adverse events were observed. Most frequently reported adverse drug reactions (ADRs) were diarrhea, nausea, pneumonia, rash, and fatigue. ConclusionThis real-world study shows that idelalisib is an effective therapy for CLL and FL, regardless of age and high-risk genetic features, consistent with results from previous clinical trials. Collected safety data and the pattern of ADRs reflect those from previous studies.

Construction, Validation, and Visualization of Two Web-Based Nomograms for Predicting Overall Survival and Cancer-Specific Survival in Elderly Patients with Primary Osseous Spinal Neoplasms.

Background Primary osseous spinal neoplasms (POSNs) are the rarest tumor type in the spine. Very few studies have presented data on elderly patients with POSNs specifically. The present study was aimed at exploring the prognostic factors and developing two web-based nomograms to predict overall survival (OS) and cancer-specific survival (CSS) for this population. Method The data of elderly patients with POSNs was extracted from the Surveillance, Epidemiology, and End Results (SEER) database between 2004 and 2015. Cox regression analyses were performed to determine independent prognostic factors for OS and CSS, these prognostic factors were incorporated to establish nomograms. The discrimination of the nomograms was evaluated by the receiver operating characteristic (ROC) curve and the value of area under the curve (AUC). Calibration curve was plotted to assess the predictive accuracy of model. Decision curve analysis (DCA) was conducted to determine the net clinical benefit. Furthermore, two web-based survival rate calculators were developed. Result A total of 430 patients were finally selected into this study and were randomly assigned to the training set (302 cases) and validation set (128 cases). Of these, 289 patients were further considered for the analysis of CSS and were randomized into training set (205 cases) and validation set (84 cases). Based on the results of univariate and multivariate Cox analyses, variables that significantly correlated with survival outcomes were used to establish nomograms for OS and CSS prediction. Two established nomograms demonstrated good predictive performance. In the training set, the AUCs of the nomogram for predicting 12-, 24-, and 36-month OS were 0.849, 0.903, and 0.889, respectively, and those for predicting 12-, 24-, and 36-month CSS were 0.890, 0.880, and 0.881, respectively. Two web-based survival rate calculators were developed to estimate OS (https://research1.shinyapps.io/DynNomappOS/) and CSS (https://research1.shinyapps.io/DynNomappCSS/). Conclusion Novel nomograms based on identified clinicopathological factors were developed and can be used as a tool for clinicians to predict OS and CSS in elderly patients with POSNs. These models could help facilitate a personalized survival evaluation for this population.

Clinical utility of 18F-FDG PET/CT imaging in patients with pulmonary artery sarcoma

BackgroundPulmonary artery sarcoma (PAS) is a rare and fatal malignancy. Due to the lack of specific clinical and radiological features, PAS is always misdiagnosed as pulmonary thromboembolism (PTE). This study aimed to investigate 18F-FDG PET/CT in distinguishing PAS from PTE, and analyze its correlation with clinical and radiological findings and outcome of PAS.MethodsClinical, contrast-enhanced CT, and 18F-FDG PET/CT characteristics of 14 patients with PAS and 33 patients with PTE were retrospectively reviewed. The correlation between PET/CT metabolic parameters vs. clinical and CT findings was investigated in patients with PAS. The overall survival (OS) was analyzed in PAS patients.ResultsThe SUVmax of PAS (median: 8.0, range 3.0–17.2) was significantly higher than PTE (1.8[0.8–3.7]) (P < 0.001), and at a cutoff value of 2.9, the sensitivity and specificity were 100.0% and 93.9%, respectively. Compared with PTE, PAS more frequently occurred in younger population (P = 0.011), involved pulmonary trunk (P < 0.001), and displayed higher enhanced CT (P < 0.001) and ΔCT (enhanced CT compared to non-enhanced CT) (P < 0.001) values. SUVmax of PAS was associated with tumor staging (P = 0.022) and enhanced CT (P = 0.013) and ΔCT (P = 0.005) values. The median OS of PAS patients was 10.5 months, and 12-month and 24-month OS rates were 58.0% and 12.0%, respectively. Only D-dimer level (P = 0.038) and tumor staging (P = 0.019) were associated with OS.ConclusionsMost PAS displayed high glucometabolism, and SUVmax of 18F-FDG PET/CT was useful in distinguishing PAS from PTE.