Clinical Progression-free Survival Research Articles

Prostate-specific antigen response and clinical progression-free survival in Black and White men with chemotherapy-naïve metastatic castration-resistant prostate cancer treated with enzalutamide in a real-world setting

BackgroundIn the United States, Black men have a higher incidence of prostate cancer (PC)-related mortality than men of other races. Several real-world studies in advanced PC suggest, however, that Black men respond better to novel hormonal therapies than White men. Data on treatment responses to enzalutamide by race are limited. We assessed real-world prostate-specific antigen (PSA) response and clinical progression-free survival (cPFS) of Black vs. White men with chemotherapy-naïve PC treated with enzalutamide.MethodsThis retrospective cohort study included patients with PC who initiated enzalutamide treatment from 2014 to 2018 in the IntrinsiQ Specialty Solutions™ database, a collection of electronic medical records from community urology practices. Index date was the date of the first prescription for enzalutamide, used as a proxy for metastatic castration-resistant PC (mCRPC). Patients who had undergone chemotherapy and/or abiraterone therapy were excluded. Kaplan–Meier and Cox models adjusted for baseline characteristics were used to estimate PSA response and cPFS by race.ResultsThe study included 214 Black and 1332 White men with chemotherapy-naïve PC presumed to have mCRPC based on the enzalutamide indication during the study period. Black men were younger and had higher baseline median PSA levels than White men. Enzalutamide therapy duration, follow-up time, and number of post-index PSA tests were similar between races. In multivariable analyses, the risk of patients achieving a ≥ 50% PSA decline was similar, whereas a numerically higher trend of ≥90% PSA decline was observed in Black men (HR 1.23; 95% CI 0.93–1.62 [P = 0.14]). In the multivariable analysis, Black men had significantly better cPFS (HR 0.82; 95% CI 0.68–0.98 [P = 0.03]).ConclusionsBlack and White men with presumed chemotherapy-naïve mCRPC had similar PSA responses when treated with enzalutamide, but Black men had better cPFS than White men. Further research is warranted to validate these findings.

SPARKLE: a new spark in treating oligorecurrent prostate cancer: adding systemic treatment to stereotactic body radiotherapy or metastasectomy: key to long-lasting event-free survival?

BackgroundMetastasis-directed therapy (MDT) significantly delays the initiation of palliative androgen deprivation therapy (pADT) in patients with oligorecurrent prostate cancer (PCa) with a positive impact on patient’s quality of life. However, it remains unclear whether the addition of ADT improves polymetastatic free survival (PMFS) and metastatic castration refractory PCa-free survival (mCRPC-FS) and how long concomitant hormone therapy should be given. A significant overall survival (OS) benefit was shown when an androgen receptor targeted agent (ARTA) was added to pADT in patients with metastatic hormone sensitive PCa (HSPC). However, whether the addition of and ARTA to MDT in the treatment of oligorecurrent PCa results in better PMFS and mCRPC-FS has not been proven yet.Methods & designPatients diagnosed with oligorecurrent HSPC (defined as a maximum of 5 extracranial metastases on PSMA PET-CT) will be randomized in a 1:1:1 allocation ratio between arm A: MDT alone, arm B: MDT with 1 month ADT, or arm C: MDT with 6 months ADT together with ARTA (enzalutamide 4 × 40 mg daily) for 6 months. Patients will be stratified by PSA doubling time (≤ 3 vs. > 3 months), number of metastases (1 vs. > 1) and initial localization of metastases (M1a vs. M1b and/or M1c). The primary endpoint is PMFS, and the secondary endpoints include mCRPC-FS, biochemical relapse-free survival (bRFS), clinical progression free survival (cPFS), cancer specific survival (CSS), overall survival (OS), quality of life (QOL) and toxicity.DiscussionThis is the first prospective multicentre randomized phase III trial that investigates whether the addition of short-term ADT during 1 month or short-term ADT during 6 months together with an ARTA to MDT significantly prolongs PMFS and/or mCRPC-FS.Trial registrationClinicalTrials.gov Identifier: NCT05352178, registered April 28, 2022.

PP03 Presentation Time: 9:20 AM: Patterns of Failure for Salvage HDR Prostate Brachytherapy in the Prostate PET Imaging Era

<h3>Purpose</h3> Although some patients who undergo prostate re-irradiation achieve long-term biochemical control, the majority of patients ultimately experience a biochemical recurrence. Furthermore, a small, but significant percentage of patients may experience significant toxicities. Prostate positron emission tomography (PET) may improve the management of radiorecurrent prostate cancer, by better delineating the systemic extent of disease prior to treatment. Furthermore, PET may allow for a more precise understanding of the patterns of failure after treatment. The purpose of this study is to analyze oncologic outcomes including patterns-of-failure for a contemporary cohort of patients who underwent salvage high-dose rate (HDR) prostate brachytherapy in the prostate PET imaging era. <h3>Materials and Methods</h3> We conducted a retrospective analysis of all patients, who underwent salvage HDR brachytherapy from 2017 onwards. 18F-fluciclovine and 18F-DCFPyL became available in 2017 and 2021, respectively. We utilized the Kaplan-Meier method to measure oncologic endpoints including biochemical progression-free survival (bPFS), clinical progression free survival (cPFS), and metastasis-free survival (MFS). We also implemented Cox regression analysis to identify factors associated with the development of bPFS and MFS. <h3>Results</h3> The median follow-up was 16.6 months. Of the 50 patients included in this study, 48 patients had 18F-fluciclovine (Axumin) imaging and two had 18F-DCFPyL (PSMA) imaging prior to treatment initiation. Six patients (12%) had oligometastatic disease prior to treatment and were treated with SBRT to those sites. Six patients (12%) had castrate-resistant prostate cancer at the time of salvage brachytherapy. The median brachytherapy dose was 1150 cGy in two treatments, and the entire prostate was treated. 43 (86%) patients were concurrently treated with androgen deprivation therapy. Six patients (12%) patients experienced a biochemical recurrence, and four patients (8%) experienced a local-regional recurrence by post-salvage PSMA or Auxmin imaging. Two patients (4%) experienced distant metastatic progression. No initial covariates were statistically associated with bPFS survival (Figure 1). However, increasing time to recurrence trended towards negative association (HR 0.77| CI 0.56 - 1.04, p = 0.091). The bPFS was 100% (CI 100% - 100%), 94% (CI 87% - 100%), and 90% (CI 81% - 100%) at 6 months, 12 months, and 18 months, respectively. <h3>Conclusion</h3> Patients undergoing HDR prostate brachytherapy to salvage recurrent disease in the prostate PET imaging era have durable bPFS. In this cohort, HDR salvage was equally effective regardless of initial treatment covariates (i.e. initial risk group), status of disease immediately prior to salvage (i.e. castrate resistance or oligometastases), or use of androgen deprivation therapy (ADT) during salvage. Therefore, prostate PET may identify candidates for whom HDR salvage will be effective.

Prognostic and Predictive Performance of a 24-Gene Post-Operative Radiation Therapy Outcomes Score (PORTOS) in a Phase 3 Randomized Trial of Dose-Intensified Salvage Radiotherapy after Radical Prostatectomy (SAKK 09/10)

<h3>Purpose/Objective(s)</h3> The SAKK 09/10 phase 3 trial showed that dose-intensified salvage radiotherapy (SRT) was not superior to conventional dose SRT for biochemically recurrent prostate cancer (PCa) after radical prostatectomy (RP). We previously reported on the validation of the 22-gene genomic classifier as prognostic in this trial but did not observe an interaction with RT dose. Herein, we examine the PORTOS classifier, an expression signature of 24 DNA damage repair and immune pathway genes, previously shown to predict benefit from postoperative radiotherapy, to test its predictive ability to SRT dose. <h3>Materials/Methods</h3> The SAKK 09/10 trial (NCT01272050) was a multicenter, randomized phase 3 trial that included PCa patients with biochemical progression after RP (PSA > 0.1 to 2 ng/mL at randomization). Patients were randomized to 64Gy vs 70Gy to the prostate bed. No patients received concurrent androgen suppression or pelvic nodal radiotherapy. After central review, the highest-grade tumors were profiled using the Decipher whole-transcriptome assay (Veracyte, San Diego, CA) to generate PORTOS. The independent prognostic ability and interaction effects were examined for the biochemical progression, clinical progression-free survival (CPFS), receipt of salvage hormone therapy, and metastasis-free survival endpoints with Cox multivariable and interaction analyses (MVA). Categorical analyses used the published threshold for PORTOS radiotherapy response (high vs low). <h3>Results</h3> Of the 226 trial patients with transcriptome data, 16% had high PORTOS radiation response compared to 84% with lower PORTOS. Patients with high PORTOS were well balanced between the randomization arms. PORTOS was not prognostic for the endpoints in MVA with the trial stratification factors. A high PORTOS, however, was predictive for improved outcomes in patients receiving dose-intensified SRT. Patients with high PORTOS that received 70Gy dose had 5-year CPFS of 94% compared to 49% with the 64Gy dose (log-rank p=0.006). In interaction analysis, PORTOS had a statistically significant interaction with RT dose for multiple endpoints: freedom from biochemical progression (interaction p=0.04), clinical progression-free survival (interaction p=0.003) and metastasis-free survival (interaction p=0.037). <h3>Conclusion</h3> In a phase 3 trial testing SRT dose intensification after RP, patients with high PORTOS had significantly better outcomes with dose-intensified treatment, suggesting that higher doses should be considered in this subgroup. Further studies are warranted to validate PORTOS as the first predictive biomarker to help personalize dose prescription in the postoperative setting.

The association between PI3K, JAK/STAT pathways with the PDL-1 expression in prostate cancer.

Programmed cell death protein-1/programmed death-ligand-1 (PD-1/PDL-1) signalling pathway has gained attention in prostate cancer. The relationship between pSTAT-1, pSTAT-3 expressions and PTEN loss with PDL-1 expression was assessed and the effects of the pathways on prostate cancer prognosis were evaluated. Patients who underwent radical prostatectomy between 2011 and 2017 were included in our study. Prostatectomy materials were evaluated using immunohistochemical staining of pSTAT-1, pSTAT-3, PTEN, and PDL-1. The relationship between PDL-1 and pSTAT-1, pSTAT-3 expressions and PTEN loss was evaluated. Additionally, factors affecting biochemical recurrence-free survival and clinical progression-free survival were analysed. Within100 patients, 9 of 11 patients with PDL-1 expression also had intermediate-high pSTAT-1 staining intensity, and those with PDL-1 expression had higher pSTAT-1 staining intensity than those without (81.9% vs. 56.2%, p=0.014). In univariate analysis, pSTAT-1, pSTAT-3 and PDL-1 expressions had significant impact on biochemical recurrence-free and clinical progression-free survival. In multivariate analysis, pSTAT-1 staining intensity with radical prostatectomy ISUP grade in terms of biochemical recurrence-free survival and the pSTAT-1 H-score with radical prostatectomy ISUP grade in terms of clinical progression-free survival were independent risk factors. Moderate-high expression of pSTAT-1 was closely associated with PDL-1 expression, and pSTAT-1 was also a predictor of biochemical recurrence and clinical progression.

Limited Benefit from the Addition of Immunotherapy to Chemotherapy in TKI-Refractory EGFR-Mutant Lung Adenocarcinoma.

Simple SummaryAlthough it is known that anti-PD1/L1 monotherapy does not render significant benefit in patients with EGFR-mutant lung adenocarcinoma, whether the addition of anti-PD1/L1 therapy to chemotherapy can enhance chemotherapy efficacy for TKI-refractory EGFR-mutant lung adenocarcinoma patients is not clear. To address this question, we retrospectively analyzed a cohort of 178 EGFR-mutant lung adenocarcinoma patients who had progressed on EGFR TKIs and received subsequent non-TKI systemic therapy to determine whether the addition of immunotherapy to chemotherapy truly improves clinical outcomes. We found that the addition of anti-PD1 immunotherapy did not add benefit to the platinum-based chemotherapy at the time of TKI progression for EGFR-mutant LUAD. Although underpowered, the anti-VEGF therapy demonstrated a trend towards adding benefit. As ongoing clinical trials with newer agents or combinations demonstrate preliminary efficacy in TKI-resistant EGFR-mutant LUAD patients, the ideal choice for post-TKI treatment is still being evaluated.Background: The benefit of chemotherapy combined with immunotherapy in EGFR-mutant lung adenocarcinoma (LUAD) patients whose tumor developed resistance to EGFR tyrosine kinase inhibitors (TKIs) is not thoroughly investigated. The goal of this retrospective cohort study is to assess the clinical efficiency of immunotherapy alone or in combination with chemotherapy in a real-world setting. Methods: This retrospective cohort study enrolled LUAD patients with EGFR sensitive mutations whose tumor had acquired resistance to EGFR TKIs and received systemic treatment with chemotherapy (chemo; n = 84), chemotherapy combined with immunotherapy (chemoIO; n = 30), chemotherapy plus bevacizumab with or without IO (withBev; n = 42), and IO monotherapy (IO-mono; n = 22). Clinical progression-free survival (PFS) and overall survival (OS) were evaluated. Associations of clinical characteristics with outcomes were assessed using univariable and multi-covariate Cox Proportional Hazards regression models. Results: A total of 178 patients (median age = 63.3; 57.9% females) with a median follow-up time of 42.0 (Interquartile range: 22.9–67.8) months were enrolled. There was no significant difference in PFS between chemoIO vs. chemo groups (5.3 vs. 4.8 months, p = 0.8). Compared to the chemo group, patients who received withBev therapy trended towards better PFS (6.1 months vs. 4.8; p = 0.3; HR 0.79; 95% CI: 0.52–1.20), while patients treated with IO-mono had inferior PFS (2.2 months; p = 0.001; HR 2.22; 95% CI: 1.37–3.59). Furthermore, PD-L1 level was not associated with PFS benefit in the chemoIO group. Patients with EGFR-mutant LUAD with high PD-L1 (≥50%) had shorter PFS (5.8 months) than non-EGFR/ALK LUAD patients who received chemoIO (12.8 months, p = 0.002; HR 0.22; 95% CI: 0.08–0.56) as first-line treatment. Chemotherapy-based therapy rendered similar benefit to patients with either EGFR exon19 deletion vs. L858R in the LUAD. Conclusions: This retrospective analysis revealed that immunotherapy provided limited additional benefit to chemotherapy in TKI-refractory EGFR-mutant LUAD. Chemotherapy alone or combined with bevacizumab remain good choices for patients with actionable EGFR mutations.

Outcome and Prognostic Factors in Cats Undergoing Resection of Intestinal Adenocarcinomas: 58 Cases (2008-2020).

The purpose of this multi-institutional retrospective study was to expand the available data pertaining to pre-operative clinical findings, progression-free and overall survival times, and potential prognostic factors for cats undergoing surgery for intestinal adenocarcinomas. Fifty-eight cats treated over a 12-year period were included in the study. Progression-free and overall survival times were estimated using Kaplan-Meier analyses. Potential prognostic variables were evaluated for associations with progression-free and overall survival using univariate Cox proportional hazards regression analyses. Prior to surgery, the intestinal mass was identified using ultrasonography in 89% of cats in which it was applied; however, imaging findings suggestive of intrathoracic metastases were observed in only 9% of cats. Among 22 cats undergoing ultrasound-guided fine needle aspiration cytology, the results agreed with the results of histopathology in only 10 cats. Discordant results were most commonly related to the presence of marked inflammation in cytology samples, which may have obscured the presence of neoplastic cells. Diffuse intestinal small cell lymphoma was identified as a comorbidity in 5 cats. Resection of the tumor with the objective of obtaining wide surgical margins was performed in each cat. On histopathology, 20 tumors were classified as mucinous adenocarcinoma and 28 were adenocarcinoma not otherwise specified. Intestinal transection site margins were complete in 94% of cats; however, complete mural margins were present in only 15% of cats. Local lymph node metastases were identified in 52% of cats and carcinomatosis was diagnosed in 81% of cats. Disease progression was documented in 32 of the 58 cats (55%). Of these 32 cats, 14 (43%) had local recurrence of the primary intestinal tumor. Median progression-free survival was 203 days (95% CI 130–299 days), and median overall survival time was 284 days (95% CI 200–363 days). Mitotic count was inversely associated with progression-free survival (HR 1.04; 95% CI 1.01–1.07, P = 0.005); however, none of the remaining potential prognostic factors, including administration of adjuvant chemotherapy, were significantly associated with progression-free or overall survival. Feline intestinal adenocarcinoma remains an aggressive and highly fatal disease. Large, randomized controlled clinical trials will be needed to improve the survival prospects for affected cats.

Cabazitaxel versus docetaxel for treatment of metastatic castrate refractory prostate cancer.

ObjectivesTo assess cabazitaxel versus docetaxel re‐challenge for the treatment of metastatic castrate refractory prostate cancer (CRPC) patients previously treated with docetaxel at inception of primary hormone therapy.Patients and MethodsThe CANTATA trial was a prospective, two‐arm, open‐label, phase II study conducted in eight UK centres. Patients over the age of 18, with histologically proven, metastatic prostate cancer who had been previously treated with up to 6 cycles of docetaxel as part of the STAMPEDE trial (or treated with the same drug outside of the trial at primary diagnosis) and had a performance status (PS) of 0–2, were eligible. Patients who progressed during primary treatment with docetaxel or had received prior systemic chemotherapy were excluded. Cabazitaxel (25 mg/m2) or docetaxel (75 mg/m2) was administered via intravenous infusion every 3 weeks with oral prednisolone (10 mg) for up to 10 cycles, until disease progression, death or unacceptable toxicity. The primary outcome was clinical progression‐free survival (PFS) as defined by either date of pain progression, date of a cancer‐related skeletal‐related event, or date of death from any cause. Analyses were by intention to treat. EudraCT number: 2012‐003835‐40ResultsBetween 7 March 2013 and 4 January 2016, 15 patients with a median age of 70 years (range 54–76) were recruited; seven received cabazitaxel, eight docetaxel. The study was halted due to slow accrual. The median clinical PFS time in the cabazitaxel group was 6.2 months compared with 8.4 for the docetaxel group (95% confidence intervals were not reached due to the small number of patients). A total of 13 serious adverse events were reported.ConclusionDue to the low number of patients recruited, meaningful comparisons could not be made. However, toxicity was in line with known outcomes for these agents, demonstrating it is feasible and safe to deliver chemotherapy to men relapsing with CRPC after upfront chemotherapy.

Abstract 1251: Low plasma Arginine level is associated with resistance to immune checkpoint blockers in patients with advanced cancer

Abstract Background: The discovery of immune checkpoint blockers (ICB) has revolutionized the systemic approach of the treatment of cancer. However, most patients receiving ICB do not derive benefit. Therefore, there is a crucial need to identify reliable predictive biomarkers of response to anti-PD-1/PD-L1 agents, both to develop precision medicine in cancer immunotherapy and to better understand mechanisms of sensitivity and resistance. One pathway that plays an important role in the regulation of immune cell reactivity is L-Arginine (Arg) metabolism, which is essential to T-cell activation. We therefore aimed at evaluating the association of baseline plasmatic level of Arg - serving as a surrogate of Arginase (Arg1) activity - and clinical benefit to ICB. Methods: Correlation with Arg levels and efficacy of ICB in the pre-clinical setting was assessed by using a syngeneic mouse model of colorectal cancer (MC38) known to be responsive to ICB. Correlation of Arg levels and clinical activity of ICB was assessed by analyzing the plasma samples obtained before treatment onset in two independent cohorts of patient with advanced cancer and included in two institutional molecular profiling programs (discovery cohort: BIP, NCT02534649, n=77; validation cohort: PREMIS, n=295, NCT03984318). In addition, using matched PBMCs-plasma samples, we analyzed the correlation between Arg level and features of PBMCs that were captured through multiplexed-flow cytometry analysis. Results: As expected, treatment of MC38-tumor bearing mice with anti-PD(L)1 antibodies demonstrated a strong anti-tumor effect with tumor rejection observed for app. 40% of mice (11 out of 28). The tumor rejection rate was significantly higher in mice with high baseline Arg level than in mice with low Arg level: 85.7% versus 23.8%, p=0.004. In both discovery and validation cohorts, low Arg level at baseline (42 &amp;lt;µmol/L) was significantly associated with worse clinical benefit rate, progression-free survival (PFS) and overall survival (OS). Multivariate analysis showed that low baseline Arg level isd an independent prognostic factor for both PFS and OS. Finally, PBMCs immunophenotyping showed that low Arg level was significantly associated with increased PDL1 expression in several immune cell subsets from the myeloid lineage. Conclusions: Altogether, our results demonstrate that baseline Arg levels are highly predictive of ICB efficacy. Increase in PDL1 expression in myeloid cells upon Arg deprivation could partly underly its suppressive activity. Plasmatic Arg quantification can therefore represent an attractive biomarker to tailor novel therapeutic regimens targeting the Arginase pathway in combination with ICB. Citation Format: Jean-Philippe Guegan, Florent Peyraud, Aurelien Marabelle, Nathalie Chaput, Dominique Bodet, Laure Fontan, Anthony Gaultier, Imane NAFIA, Francois-Xavier Danlos, David Planchard, Caroline Robert, Caroline Even, Mohamed Khettab, Lambros Tselikas, Luc Friboulet, Jean-Charles Soria, Fabrice Andre, Fabrice Barlesi, Alban Bessede, Antoine Italiano. Low plasma Arginine level is associated with resistance to immune checkpoint blockers in patients with advanced cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1251.

Longitudinal monitoring of disease burden and response using ctDNA from dried blood spots in xenograft models.

Whole‐genome sequencing (WGS) of circulating tumour DNA (ctDNA) is now a clinically important biomarker for predicting therapy response, disease burden and disease progression. However, the translation of ctDNA monitoring into vital preclinical PDX models has not been possible owing to low circulating blood volumes in small rodents. Here, we describe the longitudinal detection and monitoring of ctDNA from minute volumes of blood in PDX mice. We developed a xenograft Tumour Fraction (xTF) metric using shallow WGS of dried blood spots (DBS), and demonstrate its application to quantify disease burden, monitor treatment response and predict disease outcome in a preclinical study of PDX mice. Further, we show how our DBS‐based ctDNA assay can be used to detect gene‐specific copy number changes and examine the copy number landscape over time. Use of sequential DBS ctDNA assays could transform future trial designs in both mice and patients by enabling increased sampling and molecular monitoring.

On-treatment plasma ctDNA fraction and treatment outcomes in metastatic castration-resistant prostate cancer.

5051 Background: Androgen receptor pathway inhibitors (ARPI) are standard of care for treatment-naive metastatic castration-resistant prostate cancer (mCRPC), but primary or rapidly acquired resistance is common. Early identification of resistant disease is critical for improving management strategies. We investigated whether on-treatment changes in plasma ctDNA fraction (ctDNA%; the proportion of cell-free DNA that is tumor-derived) associate with ARPI treatment outcomes. Methods: We collected serial plasma cell-free DNA from 81 patients with mCRPC: at baseline and following 4 weeks of treatment during two prospective multi-center observational studies (NCT02426333; NCT02471469). CtDNA% was calculated by integrating deep targeted and shallow whole-genome sequencing. Samples were dichotomized at above and below 1%, and designated as high or low ctDNA%, respectively. Outcome measurements were radiographic and/or clinical progression-free survival (rcPFS) and overall survival (OS). Non-durable responses were defined as rcPFS &lt; 6 months, excluding patients with PSA progression alone (n = 3) or treatment cessation for toxicity (n = 4). Results: Median follow-up was 27.4 months (IQR 17.7-34.9). CtDNA% was high in 47/81 (58%) patients at baseline and 29/81 (36%) patients at 4 weeks. The median ctDNA% for patients with high ctDNA was 15.0% (IQR 4.9-43.8%) at baseline and 5.0% (IQR 2.0-20.6%) at 4 weeks. High baseline ctDNA% was prognostic for rcPFS and OS (Table). RcPFS and OS was shortest for patients that retained high ctDNA% at 4 weeks. However, patients converting from high to low ctDNA% at 4 weeks did not experience different outcomes to patients with low ctDNA at both timepoints. ctDNA% associations with rcPFS and OS were independent of established clinical prognostic factors. 23/27 (85%) patients experiencing non-durable responses had high ctDNA% at baseline and 4 weeks. Only 3/47 patients (6%) experiencing durable responses had high ctDNA% at both timepoints. Sensitivity and specificity for predicting non-durable response was 85% and 94%, respectively. Conclusions: Early changes in ctDNA% are strongly linked to duration of first-line ARPI treatment benefit in mCRPC and may have utility for informing clinical trials testing early therapy switches in patients unlikely to experience durable disease responses. Clinical trial information: NCT02426333; NCT02471469. [Table: see text]

Limited benefit from the addition of immunotherapy to chemotherapy in TKI-refractory EGFR-mutant lung adenocarcinoma.

e21169 Background: The benefit of adding immunotherapy to chemotherapy in EGFR-mutant lung adenocarcinoma (LUAD) with acquired resistance to EGFR tyrosine kinase inhibitors (TKIs) is not fully investigated. This study aimed to explore the outcomes of immunotherapy combinations in such population in a real-world setting. Methods: This retrospective analysis included patients with EGFR-mutant LUAD who progressed on EGFR TKIs and received subsequent therapy with chemotherapy (chemo; n = 84), chemotherapy with immunotherapy (chemoIO; n = 30), chemotherapy plus bevacizumab with or without IO (withBev; n = 42), and IO monotherapy (IO-mono; n = 22). Clinical progression-free survival (cPFS) from the start of the therapy to discontinuation was assessed. Associations of clinical characteristics with cPFS were evaluated using univariable and adjusted Cox regression models. Results: A total of 178 patients (mean age = 62.6; 57.9% females) with a median cPFS (mcPFS) of 4.9 (95% CI: 4.4-5.4) months with 162 (91%) progression events. There was no difference in cPFS between chemoIO vs chemo groups (5.3 months vs 4.8, P = 0.8). Compared to the chemo group, patients who were treated withBev trended towards better PFS (6.1 months vs 4.8; P = 0.3; HR 0.79; 95% CI: 0.52-1.20;), while patients with IO-mono had inferior PFS (2.2 months; P = 0.001; HR 2.22; 95% CI: 1.37-3.59). Patients who were administered one-line of TKI prior to subsequent therapy acquired better PFS when compared to those with multiple prior TKIs (5.2 months vs 4.5; P = 0.011; HR 0.66; 95% CI: 0.48-0.91). The significance remained the same after adjusted by other clinicopathological variables including post-TKI treatment strategies and metastatic status (P = 0.005). Furthermore, among the chemoIO group, patients with PD-L1 expression had better PFS (n = 15, 7.7 months vs 4.5, P = 0.04; HR 0.36; 95% CI: 0.13-0.96) than those without PD-L1 expression (n = 6). However, PD-L1 was not associated with PFS among the patients treated with chemoIO plus bevacizumab. Brain or liver metastases were associated with worse PFS. Conclusions: Immunotherapy adds limited benefit when combined with chemotherapy in TKI-refractory EGFR-mutant LUAD. Chemotherapy +/- bevacizumab are reasonable treatment options for these patients.

Real-world effectiveness of immune checkpoint inhibitors alone or in combination with chemotherapy in metastatic non–small cell lung cancer.

9055 Background: The benefit of combination immune checkpoint inhibitor (ICI) with chemotherapy over ICI monotherapy in non-small cell lung cancer (NSCLC) remains underexplored. Methods: This retrospective cohort included patients with metastatic NSCLC from a single-institution database treated with ICI monotherapy or with chemotherapy between 1/2014-2/2020. Clinical progression-free survival (PFS) and overall survival (OS) were the primary outcomes. Propensity score adjustment for clinical and sociodemographic characteristics was used for analysis of first-line treatment outcomes. Results: A total of 1,139 patients (54% male; median age, 64.9) were included. Adenocarcinoma histology, smoking history, higher PD-L1 expression, and lower metastatic stage associated with improved PFS. However, PD-L1 expression and smoking associated with PFS only in adenocarcinoma (LUAD); squamous (LUSC) patients had shorter PFS independent of PD-L1 and smoking history (PD-L1 &gt; 50% vs 1-49%: LUAD P &lt; 0.001; LUSC P = 0.69; Former vs never smoker: LUAD P = 0.008; LUSC P = 0.89). In first-line patients (n = 680), treatment with ICI plus chemotherapy (ICI-chemo) associated with higher progression-free rates at 3 and 6 months compared with ICI-monotherapy (ICI-chemo vs ICI-mono: 3-month PFS, 85.2% vs 68.8%, P = 0.001; 6-month PFS, 66.4% vs 52.6%, P = 0.008). However, there was no difference overall in PFS or OS in either the full or propensity-matched cohort. Treatment with ICI and chemotherapy concurrently vs sequentially was associated with similar PFS (log-rank P = 0.12). Conclusions: In this real-world cohort, the addition of chemotherapy to ICIs may protect against early progression but does not influence long-term outcomes. Treatment with sequential vs concurrent ICI and chemotherapy produced similar outcomes. These findings suggest that combination therapy may maximally benefit patients at risk of early progression.

Interruption of imatinib in advanced gastrointestinal stromal tumor after prolonged imatinib maintenance in the absence of gross tumor lesions.

11539 Background: Although current guidelines recommend indefinite imatinib treatment in advanced gastrointestinal stromal tumor (GIST) patients, prolonged imatinib treatment is often challenging. Imatinib-refractory progression-free survival (PFS) and overall survival were reportedly not different between those who interrupted imatinib and those did not. Methods: Clinical outcomes of 77 consecutive patients with recurrent or metastatic GIST who interrupted imatinib treatment after maintaining around 5 years of imatinib treatment in the absence of gross tumor lesions were retrospectively analyzed. Association between clinical factors and progression-free survival (PFS) following imatinib interruption was analyzed. Results: Median time from the absence of gross tumor lesions to imatinib interruption was 61.5 months (range 41.4–122.7 months). Since imatinib interruption, median PFS was 19.6 months, and the PFS rate at 60 months was 26.3%. Among patients who had progressive disease following interruption, imatinib re-introduction led to 88.6% objective response rate and 100% disease control rate, with the median imatinib-refractory PFS since re-introduction of 112.4 months. Complete removal of initial gross tumor lesion(s) (hazard ratio [HR] 0.32, 95% confidence interval [CI] 0.12–0.81, P = 0.016) and complete removal of residual gross tumor lesion(s) (HR 0.45, 95% CI 0.21–0.94, P = 0.033) by local treatment (vs. no local treatment or residual lesions after local treatment) were independently associated with favorable PFS. Conclusions: Interruption of imatinib may be considered with close surveillance in selected patients who maintained years of imatinib treatment in the absence of gross tumor lesions, especially for those who had complete removal of gross tumor lesions by local treatment.

Phase 1/2 study of devimistat in combination with hydroxychloroquine (HCQ) in patients with relapsed or refractory (R/R) clear cell sarcoma (CCS).

TPS11595 Background: CCS of the soft tissues is a rare and aggressive subtype of sarcoma that often starts in the tendons of the arms or legs. It is molecularly characterized by t(12;22)(q13;q12) translocation, resulting in EWSR1-ATF1 or EWSR1-CREB1 gene fusion. Despite reports of occasional responses to systemic therapies, currently available therapies have shown limited efficacy in advanced CCS. Therefore, there is a significant unmet medical need for more active agents in CCS. Devimistat is a stable intermediate of a lipoate analog that inhibits pyruvate dehydrogenase and α-ketoglutarate dehydrogenase enzymes of the tricarboxylic acid (TCA) cycle preferentially within the mitochondria of cancer cells. Devimistat induces autophagy in cancer cells. In a metastatic mouse model of CCS, treatment with devimistat in combination with chloroquine significantly suppressed tumor growth (Egawa et al, 2018). Based on this data, we hypothesized that inhibition of autophagy with HCQ may sensitize cancer cells to devimistat with increased efficacy and acceptable toxicity. Given its expected synergy, we have initiated a single-arm phase I/II prospective, multicenter, open-label, non-randomized study to evaluate maximally tolerated dose (MTD), safety, and efficacy of devimistat in combination with HCQ in patients with R/R CCS. Methods: In the phase 1 portion of the study, patients with R/R CCS and other fusion-positive R/R sarcomas will be enrolled and a standard 3+3 design will be followed to evaluate toxicity, MTD, and recommended phase 2 dose. There will be two patient groups based on weight, and dose escalation will be conducted separately for each group. Starting dose of HCQ will be 5mg/kg PO BID for patients &lt; 45 kg and 200 mg PO BID for patients ≥45 kg on days 1 through 5 of every 28 days. The first dose of HCQ each day will be followed 2 hours later by 1,000 mg/m2 devimistat (for patients &lt; 45 kg) and 2,000 mg/m2 of devimistat (for patients ≥ 45 kg) administered over 2 hours. A maximum of 36 patients will be enrolled for the phase I portion, 18 for each patient group. In the phase 2 portion of the study, only relapsed or refractory CCS patients will be enrolled, and the response rate will be determined using RECIST 1.1. In phase 2, pharmacokinetics, duration of response, clinical benefit rate, progression-free survival, overall survival, safety, and patient-reported outcomes will also be assessed. This portion of the study will utilize Simon’s admissible two-stage design with 29 patients. This study started enrolling participants in November 2021 and has dosed six patients to date. The first two dose-escalation cohorts for patients ≥45 kg have been completed without DLT and the third dose level will be opening shortly. Clinical trial information: NCT04593758.

Clinical characteristics and real-world progression-free survival (rwPFS) of patients with HER2-positive and hormone receptor (HR)-positive metastatic breast cancer (MBC) initiating endocrine therapy (ET) in combination with the first line of treatment: An analysis of electronic health records in the United States.

e13028 Background: Dual HER2 blockade with pertuzumab (P) + trastuzumab (H), combined with taxane induction therapy, is the standard of care for the first-line treatment of patients with HER2-positive MBC. In clinical practice, after achieving clinical benefit with approximately 4–6 cycles of PH + taxane induction, maintenance therapy is continued with PH only until disease progression or unmanageable toxicity. Approximately 50–60% of patients with HER2-positive MBC also have concurrent HR expression and may receive ET in combination with PH. This study investigated the clinical characteristics and outcomes of patients initiating ET combined with PH as maintenance therapy after completion of PH + taxane induction. Methods: We conducted a retrospective cohort study using a nationwide US electronic health record-derived de-identified database (Flatiron Health). Patients with HER2-positive and HR-positive MBC who initiated an ET between Jan 1, 2012 and Feb 28, 2021 with concomitant PH after receiving at least four cycles of first-line PH + taxane induction were included. The index date was the date of ET initiation. Progression data were abstracted from the medical charts. Mortality data were abstracted and combined with patient-level structured data (obituaries and Social Security Death Index). rwPFS was defined as the time from index date until first progression event &gt; 14 days after the index date, or date of death; otherwise, patients were censored on the date of last clinical note abstraction. Baseline characteristics were described using summary statistics, and rwPFS in the maintenance setting was described using a Kaplan–Meier estimator from the index date. Results: Of 24,690 patients diagnosed with MBC in the database, 252 (1%) met the eligibility criteria. All patients were female. The median age was 56.6 years; 149 patients (59%) were diagnosed with de novo MBC; 248 (98%), with estrogen receptor-positive disease; and 182 (72%), with progesterone receptor-positive disease. One hundred ninety-three patients (77%) received an aromatase inhibitor as ET. The median number of taxane cycles received prior to the index date was six. Median maintenance rwPFS was 21.4 months (95% confidence interval = 16.1, 25.3). Conclusions: Given the therapeutic opportunity presented by HER2/HR co-expression and the favorable maintenance rwPFS shown here with PH + ET following taxane induction, the investigation of more potent ETs combined with PH is justified in order to further improve outcomes in first-line HER2-positive/HR-positive MBC.

Results from plasmaMATCH trial cohort E: A phase II trial of olaparib and ceralasertib in patients with triple-negative advanced breast cancer (CRUK/15/010).

1024 Background: The plasmaMATCH trial was an open label platform trial, consisting of circulating tumour DNA (ctDNA) testing in ̃1000 patients with advanced breast cancer (ABC) linked to parallel treatment cohorts with therapies matched to mutations identified in ctDNA. Cohorts A-D have already reported (Turner N et al, Lancet Oncol 2020). Cohort E recruited patients with triple negative breast cancer (TNBC) without a targetable mutation identified at ctDNA screening, treating with olaparib (PARP inhibitor) plus ceralasertib (ATR inhibitor). Methods: Patients with TNBC who had received 1 or 2 lines of chemotherapy for advanced disease or relapsed within 12 months of (neo)adjuvant chemotherapy were eligible. Treatment was olaparib 300mg b.i.d continuously and ceralasertib 160mg qd on days 1–7 on a 28 day cycle, until disease progression. The primary endpoint was confirmed objective response rate by RECIST v1.1. Secondary endpoints included clinical benefit rate, progression-free survival (PFS) and safety. Biomarker analysis included response according to BRCA and somatic DNA repair gene status and ATM loss. Using a two-stage design with a target response rate of 25%, unacceptable response rate of 10%, alpha=2% and power=90%, ≥13 responses out of 69 evaluable stage 2 patients were required to infer efficacy (5/37 stage 1). Results: Between 17/09/18 and 5/10/20 75 patients enrolled in Cohort E of whom 70 were evaluable for response. The median age was 55.6 years. 42 (56%) patients had 1 and 13 (17.3%) had 2 prior line(s) of chemotherapy for metastatic disease. Efficacy is shown in Table. The most common grade ≥3 adverse events were: hypertension 12 (17%) and anaemia 9 (13%). Dose reductions and interruptions occurred in 19 (26.4%) and 34 (47.2%) patients respectively. Conclusions: The response rate to olaparib and ceralasertib did not meet pre-specified criteria for efficacy in the overall evaluable population. Responses were observed in patients without germline or somatic BRCA1/2 mutations. Translational analyses are underway to identify potential biomarkers of response in this population and will be presented at the meeting. Clinical trial information: ISRCTN16945804. [Table: see text]

Multicenter phase II trial of Camrelizumab combined with Apatinib and Eribulin in heavily pretreated patients with advanced triple-negative breast cancer

In the later-line setting or for patients with PD-L1-negative tumors, immunotherapy-based regimens remain ineffective against advanced triple-negative breast cancer (TNBC). In this multicentered phase II trial (NCT04303741), 46 patients with pretreated advanced TNBC were enrolled to receive camrelizumab 200 mg (day 1), and apatinib 250 mg daily, plus eribulin 1.4 mg/m2 (day 1 and 8) on a 21-day cycle until progression, or unacceptable toxicity. Primary endpoint was objective response rate (ORR) according to RECIST 1.1. Secondary endpoints included toxicities, disease control rate (DCR), clinical benefit rate, progression-free survival (PFS), and 1-year overall survival. With a median of 3 lines of prior chemotherapy in the advanced setting, 17.4% had received PD-1/PD-L1 blockade plus chemotherapy for advanced disease. The ORR was 37.0% (17/46, 95% CI 23.2–52.5). The DCR was 87.0% (40/46, 95% CI 73.7–95.1). Median PFS was 8.1 (95% CI 4.6–10.3) months. Tertiary lymphoid structure was associated with higher ORR. Patients with lower tumor PML or PLOD3 expression had favorable ORR and PFS. PD-L1 status was not associated with ORR/PFS. Grade 3/4 treatment-related adverse events occurred in 19 (41.3%) of 46 patients. Camrelizumab plus apatinib and eribulin shows promising efficacy with a measurable safety profile in patients with heavily pretreated advanced TNBC.

Efficacy of Camrelizumab in Advanced Non-Small-Cell Lung Cancer and Prognostic Analysis of Different PET/CT Features.

Objective To evaluate the efficacy of the PD-1 inhibitor camrelizumab plus chemotherapy in the first-line treatment of advanced non-small-cell lung cancer (NSCLC) and the prognostic differences of patients with different PET/CT features. Methods Between December 2018 and October 2020, 100 patients with NSCLC assessed for eligibility treated in our institution were recruited and randomly assigned (1 : 1) to receive either the TC regimen chemotherapy (control group) or the TC regimen chemotherapy plus camrelizumab (study group). The primary endpoints were clinical efficacy, progression-free survival (PFS), and overall survival (OS). A decrease of max standard uptake value (SUVmax) of >30% in primary lung cancer was considered as metabolic remission. The prognostic differences of the eligible patients with different PET/CT features were assessed. Survival data were analyzed using the Kaplan-Meier method to obtain the survival rate and calculate the median survival time. Results The metabolic remission rate and objective remission rate were significantly higher with chemotherapy plus camrelizumab versus chemotherapy alone. The study group had significantly higher CD3+ and CD4+ T-cell ratios and CD4+/CD8+ ratio and significantly lower CD8+ T-cell ratio than the control group after treatment. PFS (10 months versus 4 months) and OS (HR = 37.094, P ≤ 0.001) were better with camrelizumab plus chemotherapy versus stand-alone chemotherapy. The incidence of adverse events (AE) was similar between the two groups. The patients in the study group were stratified into metabolic remission and metabolic nonremission based on PET/CT results. Intersubgroup analysis showed significantly better PFS and OS in the metabolic remission group than in the nonmetabolic remission group. Conclusion The camrelizumab plus chemotherapy as a first-line treatment option for NSCLC significantly increases the survival benefit. Metabolic status shown by PET/CT correlates with long-term prognosis and demonstrates a great potential for early assessment of efficacy to support the choice of treatment regimens.

Prostate-specific antigen (PSA) outcomes in black (B) and white (W) chemotherapy-naïve (CN) prostate cancer (PC) patients (pts) treated with enzalutamide (ENZA).

20 Background: Population-level data suggest that B men are more likely to be diagnosed and die from PC. In juxtaposition, across multiple treatments for advanced PC, studies suggest B men have better survival than W men, including with novel hormone therapies (NHTs) such as ENZA. Whether improved survival is driven by better clinical response is unknown as data on racial differences in treatment response for ENZA are limited. This study assessed real-world PSA outcomes (response and progression) of ENZA-treated B vs W CN PC pts in the US. Methods: This retrospective cohort study included PC pts who initiated ENZA in the IntrinsiQ Specialty Solutions urology electronic medical records database from Sept 1, 2014 to Feb 28, 2018. The index date was the first prescription for ENZA. Patients with evidence of prior chemotherapy and/or abiraterone were excluded. Baseline characteristics, PSA response (PSA decline ≥50% or ≥90%), and clinical progression-free survival (cPFS) were assessed by race. Kaplan-Meier and Cox models adjusting for baseline characteristics were used to estimate PSA response and cPFS. Results: The study included 214 B and 1,332 W CN PC pts. Black pts were younger and had a higher baseline median PSA than W pts. Charlson Comorbidity Index (CCI), median duration of therapy, follow-up time, and number of post-index PSA tests were similar between races. In adjusted analyses, the chances of pts achieving ≥50% PSA decline was similar, whereas a numerically higher trend was observed for ≥90% PSA decline in B pts (Table). In addition, B men had significantly better cPFS (hazard ratio [HR] 0.82; 95% confidence interval [CI] 0.68, 0.98; p=0.03) [Table]. Conclusions: This real-world study found similar PSA response in B and W CN PC pts treated with ENZA but suggests that B pts may have better cPFS than W pts. Further research is warranted to validate these findings.[Table: see text]