Progression-free Survival HR Research Articles

Prognostic Value of Pre-treatment Albumin/Fibrinogen Ratio in Patients with Diffuse Large B-cell Lymphoma

To investigate the value of pre-treatment albumin/fibrinogen ratio (AFR) on the prognosis of patients with diffuse large B-cell lymphoma (DLBCL). The data of DLBCL patients in the Affiliated Hospital of North Sichuan Medical College from April 2014 to March 2021 were retrieved, and 111 newly diagnosed patients who completed at least 4 cycles of R-CHOP or R-CHOP-like chemotherapy with complete data were included in the study. The clinical, laboratory examination and follow-up data of the patients were collected, and the receiver operating characteristic curve (ROC) was drawn according to patients' AFR before treatment and the survival status at the end of the follow-up, which could be used to preliminarily evaluate the predictive value of AFR for disease progression and patients' survival outcome. Furthermore, the correlation of AFR with the clinical and laboratory characteristics, progression-free survival (PFS) and overall survival (OS) was analyzed, and finally, univariate and multivariate Cox proportional hazard regression models were used to analyze factors affecting PFS and OS of DLBCL patients. The ROC curve indicated that AFR level had a moderate predictive value for PFS and OS in DLBCL patients, with the area under the curve (AUC) of 0.616 (P =0.039) and 0.666 (P =0.004), respectively, and the optimal cut-off values were both 9.06 for PFS and OS. Compared with high-AFR (≥9.06) group, the low-AFR (<9.06) group had a higher proportion of patients with Lugano III-IV stage ( P <0.001), elevated lactate dehydrogenase (P =0.007) and B symptoms (P =0.038). The interim analysis of response showed that the overall response rate (ORR) in the high-AFR group was 89.7%, which was significantly higher than 62.8% in the low-AFR group (P =0.001). With a median follow-up of 18.5 (3-77) months, the median PFS of the high-AFR group was not reached, which was significantly superior to 17 months of the low-AFR group (P =0.009). Similarly, the median OS of high-AFR group was not reached, either, which was significantly superior to 48 months of the low-AFR group (P < 0.001). In multivariate Cox regression analysis, AFR <9.06 was an independent risk factor both for PFS and OS (HR PFS=2.047, P =0.039; HR OS=4.854, P =0.001). Pre-treatment AFR has a significant value for the prognosis evaluation in newly diagnosed DLBCL patients.

Evolution of systemic therapy for advanced HCC patients: Did we make progress in 2022?

Evolution of systemic therapy for advanced HCC patients: Did we make progress in 2022?

Expression molecular subtype as a predictor of outcomes of chemoradiotherapy for esophageal cancer.

4030 Background: The standard treatment for advanced esophageal cancer is preoperative chemoradiotherapy (CRT) followed by surgery or definitive CRT (NCCN Guideline 2022 ver5). CRT has the advantage of preserving organs and functions and the prognosis for patients achieved complete response by CRT is good. However, it is currently impossible to predict the outcomes of CRT before treatment. We have performed RNA expression analysis of pre-treatment biopsy specimens of esophageal cancer and identified several intrinsic molecular subtypes, as well as E-type (high expression of squamous markers) with good prognosis for CRT and M2-type (high expression of stromal markers) with poor prognosis for CRT (US patent No 10,969,390 B2). Herein, we performed an integrated analysis to confirm the relationship between intrinsic expression molecular subtype classification and prognosis in the pooled population from two prospective cohort studies (UMIN000043637). Methods: Two cohort studies were as follows; 1) single institute prospective cohort study conducted at National Cancer Center Hospital East (n=157, UMIN-C000000459), 2) multicenter prospective cohort study conducted at 10 institutions (n=226, UMIN000016141). A total 383 cases met inclusion criteria and the Affymetrix U331Plus 2 panel (47,104 transcripts, 38,572 genes) was used to identify E-type and M2-type. The clinical course and outcome were blinded for subtype classification. Treatment was performed as usual at each institution, and treatment details and outcomes were examined by subtype. Results: Among 383 patients, 181 and 164 patients were treated by CRT and surgery, respectively. Ninety-nine percent (n=342) were squamous cell carcinoma. Stage I/II/III/IV were 13/61/86/21 and 17/63/81/3 in CRT group and surgery group, respectively. Among them, 76 (22%), 100 (29%), 169 (49%) patients were classified as E, M2 and others, respectively. Among the patients treated by CRT, CR rate of E-type and M2-type were 62.8% (95% CI, 47.8-75.7) and 33.3% (95% CI, 21.9-47.1) (p=0.006). The 5-year progression free survival (PFS) and overall survival (OS) rates of CRT group was 50.5% (95% CI, 34.7-64.4) and 59.8% (95% CI, 42.6-73.3) for E-type vs. 23.0% (95% CI, 12.0-36.2) and 29.0% (95%CI, 16.8-42.4) for M2-type, with statistically significant difference (p=0.011, p=0.003). Cox regression analysis showed that crude HR for PFS and OS of E vs M2 were 0.50 (95% CI, 0.296-0.859, p=0.012) and 0.41 (95% CI, 0.226-0750, p=0.004), respectively. In contrast, E and M2-type did not show the survival difference in surgery group. Conclusions: For the first time in the world, we confirmed that expression molecular subtype of esophageal cancer has the potential to predict the outcomes of CRT. The results may provide precision medicine in the selection of treatment for esophageal cancer.

Impact of pathogenic germline BRCA1/2 and PALB2 mutations and tumor aneuploidy in patients with HR+/HER2- metastatic breast cancer treated with CDK4/6 inhibitors.

1075 Background: CDK4/6 inhibitors lack established predictors of efficacy in HR+/HER2- mBC. Pathogenic germline BRCA2 variants, somatic homologous recombination deficiency (HRD) and APOBEC signatures conferred worse survival in small series. Broader tumor DNA panels enable the detection of these and other parameters such as aneuploidy and tumor mutational burden. Methods: Clinical and molecular data from a single institution cohort of CDK4/6i-treated HR+/HER2- mBC pts were analyzed. ECOG PS was 0-1. Clinical variables were collected retrospectively. Primary endpoints were progression-free survival (PFS) and overall survival (OS). Tumor-only sequencing was performed on clinical samples with 161-gene OCAv3, 523-gene TSO500 or 555-gene lab-developed NGS panels. HRD was assessed with the Signature Multivariate Analysis (SigMA) tool using a likelihood-based measure to estimate single base substitution signature 3. Aneuploidy scores were defined as the fraction of covered arms harboring arm-level somatic copy number alterations as determined by ASCETS v.1.1. Results: 153 pts were available for analysis. Median age was 54 y (29–88). 74% were postmenopausal, 28% de novo metastatic and 67% had visceral disease. Palbociclib was used in 80%, ribociclib in 17% and abemaciclib in 3%, mostly as early lines (1L 65%, 2L 22%). Median follow up was 46 mo (7–84) and median time from sample collection to CDK4/6i was 0.6 y (-18.5–+2.6). 76% of samples have been sequenced. The median number of mutations (muts) was 3 (1–32), most commonly in PIK3CA (37%), GATA3 (26%) and TP53 (20%). ESR1, KRAS and ARID1A, but not RB1 muts were numerically enriched in post–CDK4/6i mets (n=8). TP53 (HR 1.85 CI 1.02–3.33) and GATA3 (HR 0.48, CI 0.28–0.83) muts were associated with PFS. Germline ( g) testing was available in 68 (44%) pts, with 21 pts carrying pathogenic variants including 11 BRCA2, 2 BRCA1 and 2 PALB2. Cox regression showed a strong negative impact of gBRCA1/2-PALB2 on PFS (HR 4.0 CI 2.0–7.9) and OS (HR 3.5 CI 1.6–7.7) adjusted for age, visceral disease and prior chemo. In 1L, mPFS/OS was 9.9/28.1 mo for gBRCA1/2-PALB2 carriers, 26.8/NR mo for non-carriers and 23.7/49.2 mo for untested (Cox HR PFS 5.1 CI 2.1-14.0; HR OS 4.0 CI 1.4-11.2). Pts with gATM/ CHEK2/ BRIP1 had a 1L PFS/OS&gt;15/45 mo. Among 36 pts assessed for HRD, 22 were HRDlow and 14 HRDhigh with no significant survival association. 3/4 known gBRCA1/2 carriers were HRDhigh and 7/8 gWT HRDlow. In these pts, higher aneuploidy was associated with shorter PFS and OS (Cox HR PFS 2.0 CI 0.9-4.3, p=0.07; HR OS 2.6 CI 1.0-7.1; p=0.05). Conclusions: Pathogenic gBRCA1/2- PALB2 and higher aneuploidy were associated with shorter survival. Profiling of aneuploidy, HRD, TMB and APOBEC in all pts is ongoing including 55 baseline ctDNA samples and 361 samples from the GENIE BPC cohort. Results will account for FDR, left truncation and optimal cutoffs.

BRAF V600E/RAS Mutations and Lynch Syndrome in Patients With MSI-H/dMMR Metastatic Colorectal Cancer Treated With Immune Checkpoint Inhibitors.

We pooled data from 2 cohorts of immune checkpoint inhibitors-treated microsatellite instability-high/mismatch repair-deficient (MSI/dMMR) metastatic colorectal cancer patients to evaluate the prognostic value of RAS/BRAFV600E mutations and Lynch syndrome (LS). Patients were defined as LS-linked if germline mutation was detected and as sporadic if loss of MLH1/PMS2 expression with BRAFV600E mutation and/or MLH1 promoter hypermethylation, or biallelic somatic MMR genes mutations were found. Progression-free survival (PFS) and overall survival (OS) were adjusted on prognostic modifiers selected on unadjusted analysis (P < .2) if limited number of events. Of 466 included patients, 305 (65.4%) and 161 (34.5%) received, respectively, anti-PD1 alone and anti-PD1+anti-CTLA4 in the total population, 111 (24.0%) were treated in first-line; 129 (28.8%) were BRAFV600E-mutated and 153 (32.8%) RAS-mutated. Median follow-up was 20.9 months. In adjusted analysis of the whole population (PFS/OS events = 186/133), no associations with PFS and OS were observed for BRAFV600E-mutated (PFS HR= 1.20, P = .372; OS HR = 1.06, P = .811) and RAS-mutated patients (PFS HR = 0.93, P = .712, OS HR = 0.75, P = .202). In adjusted analysis in the Lynch/sporadic status-assigned population (n = 242; PFS/OS events = 80/54), LS-liked patients had an improved PFS compared to sporadic cases (HR = 0.49, P = .036). The adjusted HR for OS was 0.56 with no significance (P = .143). No adjustment on BRAFV600E mutation was done due to collinearity. In this cohort, RAS/BRAFV600E mutations were not associated with survival while LS conferred an improved PFS.

Abstract 5705: Digital pathology based prognostic &amp; predictive biomarkers in metastatic non-small cell lung cancer

Abstract Background: In recent years, a relationship between the tumor microenvironment (TME) and patient response to targeted cancer immunotherapy has been suggested. We applied machine-learning algorithms on H&amp;E stained tissue to study the TME in metastatic non-small cell lung cancer (NSCLC) patients. Our goal was to identify digital pathology (DP) features associated with outcome under combination treatment or monotherapy with atezolizumab (atezo), an anti-PD-L1 therapy, and relate those features to other data modalities. We analyzed patient data from two phase 3 clinical trials, OAK (docetaxel versus atezo in 2L+ NSCLC) and IMpower150 (bevacizumab, carboplatin, and paclitaxel (BCP) versus BCP+atezo (ABCP) in advanced 1L non-squamous NSCLC). Methods: As part of our effort to build a DP-based tumor-immune microenvironment atlas, digitized H&amp;E images were registered onto the PathAI research platform. Over 200K annotations from 90 pathologists were used to train convolutional neural networks (CNNs) that classify slide-level human-interpretable features (HIFs) of cells and tissue structures from images and deployed on images from OAK and IMpower150. HIFs and PD-L1 status were associated with outcome in all samples in each arm in OAK and results were validated in IMpower150, using Cox proportional hazard models. Bulk RNAseq was run using samples extracted from the same area as the H&amp;E slide. Results: We identified a composite feature capturing the ratio of immune cells to fibroblasts in the stroma predictive of both overall survival (OS) (HR=0.74 p=0.0046) and progression-free survival (PFS) (HR=0.87 p=0.14). While patients primarily benefit from atezo if they are PD-L1 high, we found that even PD-L1 negative patients benefited from atezo when enriched for this feature (22C3 PD-L1 assay: OS HR=0.59 p=0.015, PFS HR=0.8 p=0.25; SP142 PD-L1 assay: OS HR=0.74 p=0.12, PFS HR=0.88 p=0.45). We thus recognized a DP feature that was predictive for positive outcome with atezo treatment, independent of PD-L1 levels. This association was then validated in IMpower150 comparing ABCP to BCP, both overall (OS HR=0.69 p=0.012) and in PD-L1 negative patients (SP263 assay OS HR=0.56 p=0.034). Integrating with RNAseq, patients enriched for this DP feature showed similar enrichment for B and T gene signatures and depletion in CAF-related gene signatures, thus showing the harmonization of TME between different data modalities. Conclusions: Using a deep learning-based assay for quantifying pathology features of the TME from H&amp;E images in two NSCLC trials, we identified a novel biomarker predictive of outcome to PD-L1 targeting therapy, even in PD-L1 low &amp; negative patients. Importantly, our work shows how different data modalities (DP, gene expression) can be integrated to further our understanding of the TME. Citation Format: Aditi Qamra, Minu K. Srivastava, Eloisa Fuentes, Ben Trotter, Raymond Biju, Guillaume Chhor, James Cowan, Steven Gendreau, Webster Lincoln, Lisa McGinnis, Luciana Molinero, Namrata S. Patil, Amber Schedlbauer, Katja Schulze, Adam Stanford-Moore, Laura Chambre, Ilan Wapinski, David S. Shames, Hartmut Koeppen, Stephanie Hennek, Jane Fridlyand, Jennifer M. Giltnane, Assaf Amitai. Digital pathology based prognostic &amp; predictive biomarkers in metastatic non-small cell lung cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5705.

Abstract 5583: Pre-radiotherapy ctDNA risk-stratifies non-small cell lung cancer patients with oligometastatic disease

Abstract Background: Oligometastatic non-small cell lung cancer (NSCLC) patients may uniquely benefit from personalized therapies via liquid biopsy. Widespread metastatic disease is incurable, yet some patients with oligometastatic disease experience prolonged progression-free survival when treated with aggressive local stereotactic body radiotherapy (RT). Distinguishing patients who would benefit from aggressive RT from those who would benefit from systemic therapies remains a challenge. We hypothesized that pre-RT ctDNA can be used to risk-stratify those with oligometastatic NSCLC and enable earlier personalized approaches when considering systemic therapy versus aggressive local RT. Methods: A retrospective multi-institutional cohort of 1,487 patients (median age: 65 years, 53% female [n=784], 47% male [n=703]) who were diagnosed with oligometastatic NSCLC was selected. Each patient underwent liquid biopsy ctDNA analysis using the Tempus xF assay (v2) at least once, with a subset of patients undergoing serial sampling at 2-8 timepoints for a total of 1,880 ctDNA assays. 309 of the patients (20%) underwent RT after liquid biopsy was obtained and oligometastatic NSCLC was diagnosed. Outcomes for overall survival (OS) and progression-free survival (PFS) were defined with respect to the initiation time of RT (i.e., time from RT to death, time from RT to progressive disease). Results: Across all ctDNA assays, 3,520 pathogenic or likely pathogenic (P/LP) variants were identified (1.8 variants/sample, mean). Among patients with a liquid biopsy obtained prior to RT, 48% (n=151) experienced progressive disease and 11% (n=34) died during the study period. Focusing on patients with ctDNA obtained pre-RT, P/LP variants were detected in 74% (n=230) while 26% (n=79) had zero variants detected. Of those with detectable variants, 76% (n=175) had 1-3 variants, while 24% (n=55) had ≥4 P/LP variants detected in ctDNA. Both overall survival and progression-free survival were significantly worse in patients with detectable ctDNA from pre-RT liquid biopsy compared to those without (median OS 16.8 months vs. 25 months; p=0.027, HR=1.65; median PFS 5.4 months vs. 8.8 months; p=0.021, HR=1.57). Remarkably, survival correlated inversely with the number of detected variants from pre-RT liquid biopsies; when patients were stratified by variant quantity, both OS and PFS were significant (OS p=0.045, PFS p=0.003; stratified by 0, 1-3, and ≥4 variants). This finding was also significant in a multivariate Cox proportional hazards analysis (OS HR=1.15, CI 1.04-1.24; PFS HR=1.16, CI 1.06-1.25), but was not significant for parameters such as age at diagnosis or squamous histology. Conclusions: These data suggest that a ctDNA-informed approach may be a powerful pre-RT biomarker to help risk-stratify oligometastatic NSCLC patients and potentially enable personalized decision-making for RT versus systemic therapy. Citation Format: Nicholas P. Semenkovich, Yun E. Wang, Aadel A. Chaudhuri. Pre-radiotherapy ctDNA risk-stratifies non-small cell lung cancer patients with oligometastatic disease. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5583.

Abstract P3-05-26: Association of muscle mass and density with outcomes in patients with ER positive metastatic breast cancer: correlative analysis of ECOG-ACRIN 2112

Abstract Introduction: Observational data investigating the relationship between body habitus and survival or toxicity in breast cancer has been largely centered in the curative setting and focused on weight- based metrics, with variable and inconsistent results. Muscle is a large, active endocrine organ that affects physical function, drug metabolism, inflammation, and quality of life, but is not adequately measured by body weight alone. Very few studies have evaluated muscle measures in metastatic breast cancer (MBC) and have been focused on patients receiving cytotoxic chemotherapy. Here, we evaluate the impact of muscle mass and muscle density measured on CT scan on outcomes in patients with MBC receiving endocrine- based therapy. Methods: Baseline CT scans done at the time of study enrollment were centrally collected from participants in ECOG-ACRIN E2112, a randomized phase III study of exemestane with or without entinostat in MBC, which ultimately did not impact survival. A transverse cut at the L3 level was extracted and processed using semi-automated SliceOmatic software (Tomovision) by two independent investigators to obtain total body skeletal muscle mass and muscle attenuation. Low muscle mass was defined as skeletal muscle index (SMI, lean muscle area/height, cm2/m2) less than 41 and low skeletal muscle attenuation (SMA) was defined as average muscle density less than 41 HU, or less than 33 HU if the patient is overweight or obese by BMI. Chi-square tests were used to determine the association between SMI and SMA and other clinical characteristics, including body weight, race, and performance status. Multivariable Cox proportional hazard models were used to determine the association between low SMI or low SMA and overall survival (OS), progression free survival (PFS), and patient- reported outcomes. Results: Of the 608 patients randomized in E2112, 546 had analyzable CT scans and follow up data available. 45% (n=246) of participants had obesity by BMI (≥30); 39% (n=212) had low SMI and 56% (n=305) had low SMA. Obese patients were more likely to have higher SMI (p&amp;lt; 0.001); however, 9.5% (n=52) of the study population had both obesity and low SMI. Low SMA was associated with higher rate of obesity and worse performance status (p&amp;lt; 0.001), consistent with muscle quality being a predictor of functional status. Low SMI was not associated with survival outcomes (OS HR 1.04 95%CI 0.83-1.30, PFS HR 1.12 95% CI 0.92-1.36), nor was low SMA (OS HR 1.02 95%CI 0.81-1.28; PFS HR 1.02 95%CI 0.84-1.23). In addition, BMI was not related to survival outcomes. Conclusions: Low muscle mass and low muscle density are prevalent in estrogen receptor positive MBC patients. Muscle measures correlated with obesity and performance status; however, neither low SMI nor low SMA were associated with worse prognosis in this population. Further work is needed to refine body composition measurements and select optimal cutoffs and meaningful endpoints in specific breast cancer populations, particularly in those living with metastatic disease. Citation Format: Tarah J. Ballinger, Gloria Xue, Helga S. Marques, Constantine Gatsonis, Richard Hoffman, Kathy D. Miller, Fengmin Zhao, Joseph Sparano, Roisin Connolly. Association of muscle mass and density with outcomes in patients with ER positive metastatic breast cancer: correlative analysis of ECOG-ACRIN 2112 [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-05-26.

Impact of Lynch syndrome, BRAFV600E, and RAS mutations on outcomes in MSI/dMMR metastatic colorectal cancer (mCRC) treated with immune checkpoint inhibitors (ICI): Analysis of combined international cohorts.

171 Background: ICI have demonstrated efficacy in patients (pts) with MSI/dMMR mCRC . Lynch (LS) vs sporadic (Sp) status, BRAFV600E and RAS mutations (mt) are known factors of clinical and molecular heterogeneity in this population. We aimed to evaluate the prognostic value of these parameters in ICI-treated MSI mCRC pts. Methods: Pts are drawn from international cohorts (France, Italy, Spain, and USA). Pts were considered to have cancer linked to LS only in case of determined germline mutation and Sp in case of loss of MLH1/PMS2 protein expression associated with BRAF V600E mutation and/or hypermethylation of MLH1 promoter, or in case of biallelic somatic mutations of MMR genes. Survival analyses: progression-free survival (PFS) per iRECIST criteria and overall survival (OS) were adjusted on prognostic modifiers, selected on unadjusted analysis (p &lt; 0.2) in case of limited number of events. Results: On the 466 pts included, 112 (24%) received ICI in first line, 305 (65%) received anti-PD1 alone, 161 (35%) anti-PD1 plus anti-CTLA4, 129 (29%) had BRAFV600Emt and 153 (34%) RASmt. Median follow-up was 24.0 months. In adjusted analysis of the whole population (n=466; 186 PFS events and 143 OS events), no association with PFS and OS was observed for BRAFV600E mt (PFS HR 1.20 [0.80 to 1.79], p=0.372; OS HR 1.06 [0.66 to 1.70], p= 0.811) and RASmt (PFS HR 0.93 [0.64 to 1.36], p= 0.712; OS HR 0.75 [0.48 to 1.17] p= 0.202). Adjusting factors were age, ECOG status, number of prior chemotherapies, treatment type (bi vs monotherapy), sidness (right vs left + rectum), primary tumor surgery. Concerning the population with determined Lynch status (n= 242; 83 PFS events and 54 OS events), PFS results are displayed. The analysis of impact of LS was not adjusted on BRAFV600E mutational status due to collinearity. In adjusted analysis, LS improved PFS compared with Sp (HR = 0.49, 95%CI (0.25 to 0.96), p = 0.036). Adjusted HR for OS was 0.56 without reaching significance 95%CI (0.25 to 1.22), p = 0.143. Conclusions: In this analysis of ICI-treated MSI/dMMR mCRC pts, RAS/BRAFV600E mutations are not associated with survival while Lynch syndrome pts demonstrated improved PFS. [Table: see text]

IMbrave151: A phase 2, randomized, double-blind, placebo-controlled study of atezolizumab with or without bevacizumab in combination with cisplatin plus gemcitabine in patients with untreated, advanced biliary tract cancer.

491 Background: VEGF blockade coupled with cytotoxic chemotherapy can promote an immune-permissive tumor microenvironment that can augment response to PD-L1 inhibition. IMbrave151 (NCT04677504) is a randomized, double-blind, global Phase II study evaluating the efficacy of atezolizumab (atezo), bevacizumab (bev) and cisplatin and gemcitabine (CisGem) as first-line treatment for patients with advanced biliary tract cancer (aBTC). Methods: Patients with previously untreated aBTC were randomized 1:1 to receive atezo (1200 mg every 3 weeks [q3w]) + bev (15 mg/kg q3w) or placebo + CisGem (cisplatin 25 mg/m2 and gemcitabine 1000 mg/m2 on Days 1 and 8 q3w) for up to 8 cycles, followed by atezo (1200 mg q3w) + bev (15 mg/kg q3w) or placebo until disease progression or unacceptable toxicity. Patients were stratified by disease status, geographic region and primary tumor location. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate (ORR), duration of response (DOR), disease control rate and safety. No formal hypothesis testing was performed. Results: In total, 162 patients were randomized to receive either atezo + bev + CisGem (n=79) or atezo + placebo + CisGem (n=83). Median age 63 years, Asia/Rest of World (43/57%), ECOG PS 0/1 (53/48%), intrahepatic/extrahepatic cholangiocarcinoma and gallbladder (54/19/27%), and metastatic/locally advanced stage (82/18%). The HR for PFS was 0.76 (95% CI: 0.51, 1.14). Median PFS was 8.4 months for atezo + bev + CisGem and 7.9 months for atezo + placebo + CisGem; the 6-month PFS rates were 78% and 63%, respectively. The confirmed ORR was 24% for atezo + bev + CisGem and 25% for atezo + placebo + CisGem. DOR ≥6 months was 89% for atezo + bev + CisGem vs 47% for atezo + placebo + CisGem. The incidence of Grade 3 or 4 adverse events was 73% and 74% with atezo + bev + CisGem and atezo + placebo + CisGem, respectively. Median OS is not reached. Conclusions: Both combinations of IMbrave151 showed a manageable safety profile. The aggregate of data suggests that combining atezo with bev and chemotherapy may provide clinical benefit in a subset of patients with aBTC. Follow-up is ongoing for OS. Clinical trial information: NCT04677504 .

Efficacy and tolerability of immune checkpoint inhibitors in elderly patients with MSI/dMMR gastrointestinal cancers and impact of toxicities on efficacy: The immunoMSI cohort.

795 Background: Immune checkpoint inhibitors (ICI) are the new standard of care for some MSI/dMMR advanced tumors in first-line setting or after progression under conventional chemotherapy. Frequency of MSI/dMMR increasing with age, the tolerability and efficacy of ICIs in elderly patients, appears as a crucial clinical issue. We aimed to evaluate the tolerability and efficacy of ICIs in ≥ 75 years patients with metastatic MSI/dMMR gastro-intestinal (GI) cancer. Methods: All pts with MSI/dMMR metastatic GI cancer treated by anti-PD1 ± anti-CTLA4 without concomitant chemotherapy at Saint-Antoine hospital and included in our prospective, monocenter cohort, were analyzed. Pts were divided into the elderly (≥75 years) and non-elderly (&lt;75 years) groups. The incidence and evolution of grade ≥ 3 immune-related adverse events (irAE) and grade ≥ 2 endocrine adverse events were evaluated. Secondary objectives were progression-free survival (PFS) and overall survival (OS) regarding age and the occurrence of irAEs. Results: Two hundred and one patients were included: 24 pts≥75 years (75 to 90 years) and 177 pts&lt; 75 years (22 to 74 years). 171 (79%) had mCRC. In the entire population, the incidence of irAEs was 40.5% with anti-PD1 plus anti-CTLA4 and 23% with anti-PD1 monotherapy (p= 0.011). Combination of anti-PD1 and anti-CTLA4 were administered to 29% of the elderly group and 40% of the non-elderly group. There was no statistical difference in the incidence of irAEs between the two populations (37.5% in the elderly group vs 29% in the non-elderly group; p=0.48) neither in their type (12% vs 7% of hepatic cytolysis, 13% vs 16% of endocrine irAEs) or management (17% vs 19% corticosteroid therapy, 21% and 16% of ICI discontinuation). No significant difference was observed between elderly/non elderly for PFS (HR 0.91, 95%CI 0.40-2.06; p=0.83) and OS (HR 1.6, 95%CI 0.65-3.96; p= 0.21). Pts experiencing irAEs had superior survival outcomes than those without irAEs (PFS HR 2.93, 95%CI 1.69-5.09; p=0.02 and OS HR 2.05, 95%CI 1.13-3.74; p=0.045) in the whole cohort (n=201). Conclusions: Tolerability and efficacy of ICIs for pts with MSI/dMMR GI cancers are similar for elderly compare as for non-elderly pts. Pts experiencing irAEs had superior survival outcomes. Further prospective studies with systematic geriatric assessment are required to evaluate the tolerability of ICIs especially for frail elderly pts.

Albumin-Bilirubin Grade Analyses of Atezolizumab plus Bevacizumab versus Sorafenib in Patients with Unresectable Hepatocellular Carcinoma: A Post Hoc Analysis of the Phase III IMbrave150 Study

Introduction: Atezolizumab + bevacizumab showed survival benefit in patients with unresectable hepatocellular carcinoma (HCC) versus sorafenib in the Phase III IMbrave150 study. This exploratory analysis examined the prognostic impact of a baseline albumin-bilirubin (ALBI) score. Methods: Patients with treatment-naïve unresectable HCC, ≥1 measurable untreated lesion, and Child-Pugh class A liver function were randomized 2:1 to receive atezolizumab 1,200 mg + bevacizumab 15 mg/kg every 3 weeks or sorafenib 400 mg twice daily. Overall survival (OS) and progression-free survival (PFS) were assessed in the intention-to-treat population by ALBI/modified (m)ALBI grade. Time to deterioration (TTD; defined as time to 0.5-point increase from the baseline ALBI score over 2 visits or death) of liver function and safety were investigated. Results: Of 501 enrolled patients, 336 were randomized to receive atezolizumab + bevacizumab (ALBI grade [G] 1: n = 191; G2: n = 144 [mALBI G2a: n = 72, G2b: n = 72]; missing ALBI grade: n = 1) and 165 to sorafenib (ALBI G1: n = 87; G2: n = 78 [mALBI G2a: n = 37; G2b: n = 41]). Median follow-up was 15.6 months. OS and PFS improved with atezolizumab + bevacizumab versus sorafenib in patients with ALBI G1 (OS HR: 0.50 [95% CI: 0.35, 0.72]; PFS HR: 0.61 [95% CI: 0.45, 0.82]). In patients with ALBI G2 or mALBI G2a or G2b, PFS was numerically longer with atezolizumab + bevacizumab versus sorafenib, but no OS benefit was seen. Median TTD in the intention-to-treat population was 10.2 months (95% CI: 8.0, 11.0) with atezolizumab + bevacizumab versus 8.6 months (95% CI: 6.2, 11.8) with sorafenib (HR: 0.82 [95% CI: 0.65, 1.03]). Safety profiles of atezolizumab and bevacizumab were consistent with previous analyses, regardless of ALBI grade. Conclusion: ALBI grade appeared to be prognostic for outcomes with both atezolizumab + bevacizumab and sorafenib treatment in patients with HCC. Atezolizumab + bevacizumab preserved liver function for a numerically longer duration than sorafenib.

Exploratory Analysis of Patients With Gastric/Gastroesophageal Junction Adenocarcinoma With or Without Liver Metastasis From the Phase 3 RAINBOW Study.

Liver metastasis (LM) is reported in approximately 40% of patients with advanced/metastatic gastric/gastroesophageal junction adenocarcinoma (metastatic esophagogastric adenocarcinoma; mGEA) and is associated with a worse prognosis. This post-hoc analysis from the RAINBOW trial reported the efficacy, safety, and biomarker outcomes of ramucirumab and paclitaxel combination treatment (RAM+PAC) in patients with (LM+) and without (LM-) LM at baseline. Patients (n=665) were randomly assigned on a 1:1 basis to receive either RAM+PAC (LM+: 150, LM-: 180) or placebo and paclitaxel (PL+PAC) (LM+: 138, LM-: 197). The overall survival (OS) and progression-free survival (PFS) were evaluated using stratified Kaplan-Meier and Cox regression models. The correlation of dichotomized biomarkers (VEGF-C, D; VEGFR-1,2) with efficacy in the LM+ versus LM- subgroups was analyzed using the Cox regression model with reported interaction P-values. The presence of LM was associated with earlier progression than those without LM, particularly in patients receiving PL+PAC (hazard ratio [HR], 1.68). RAM+PAC treatment improved OS and PFS irrespective of LM status but showed greater improvement in LM+ than that in LM- (OS HR, 0.71 [LM+] vs. 0.88 [LM-]; PFS HR, 0.47 [LM+] vs. 0.76 [LM-]). Treatment-emergent adverse events were similar between patients with and without LM. No predictive relationship was observed between biomarker levels (VEGF-C, D; VEGFR-1,2) and efficacy outcome (OS, PFS) (all interaction P-values >0.05). RAM provided a significant benefit, irrespective of LM status; however, its effect was numerically stronger in patients with LM. Therefore, RAM+PAC is a clinically meaningful therapeutic option for patients with mGEA and LM. ClinicalTrials.gov Identifier: NCT01170663.

Training and Validation Cohorts for Predicting the Impact of High Molecular Risk Mutations after Allogeneic Stem Cell Transplantation in Myelofibrosis

Introduction Myelofibrosis (MF) is the most aggressive form of Philadelphia negative myeloproliferative neoplasm and allogeneic hematopoietic stem cell transplantation (HSTC) is the only curative approach, but non relapse mortality limits the indication for HSTC to high-risk patients. The prognostic evaluation of MF patients is evolving during time together with a better understanding of the mutational landscape of this disease. The presence of high molecular risk (HMR) mutations, specifically ASXL1, SRSF2, EZH2, IDH1, IDH2 and U2AF1Q157, harbors a detrimental effect on survival and leukemic transformation and has been incorporated in different prognostic scoring systems. In this multicenter study we aimed to determine the impact of HMR mutations on transplant outcome. Methods We studied two independent cohorts of patients: 44 patients (training, retrospective cohort) were part of a multicenter, randomized GITMO (Gruppo Italiano Trapianti di Midollo Osseo) clinical trial (Patriarca F, BBMT 2019) and 29 patients (validation, prospective cohort) were subsequently recruited at the Bergamo Bone Marrow Transplant Unit. Patients from the training cohort (median age 56, range 36-66) were conditioned with busulfan-fludarabine or thiotepa-fludarabin while patients in the validation cohort (median age 61, range 36-67) were conditioned with a reduced intensity thiotepa-busulfan-fludarabin regimen. The mutational profile obtained on the pre-transplant DNA was performed by sequencing 30 myeloid related genes by applying SOPHia GENETICS Myeloid Solution on Illumina MiniSeq platform. Results In the training retrospective cohort, driver mutations were detected in 40 (29 JAK2/8 CALR/3 MPL) patients, with 4 patients having a triple negative MF. At least one HMR mutation was detected in 43% of patients and an unfavorable karyotype was present in 18% of patients. According to the Mutation-Enhanced International Prognostic Scoring System 70 plus (MIPPS70+) scoring system, 77% of patients were allocated in the high/very high groups. With a median follow up of 4.2 years (range 0.02-9), the 5-years Overall Survival (OS) and Progression Free Survival (PFS) were 61% and 45% respectively. The 5-years Non-Relapse Mortality (NRM) and Cumulative Incidence of Relapse (CIR) were 25% and 30%. In the prospective validation cohort, a driver mutation was detected in all patients (15 JAK2/7 CALR/7MPL). At least one HMR mutation was detected in 48% of patients and an unfavorable karyotype was present in 24% of patients. Patients allocated to the MIPPS70+ high/very group were 52%. After a median follow up of 10.7 months (range 0-44), the 2-years OS and PFS were 61% and 49% respectively. The 2-years NRM and CIR were 33% and 18%. In the training cohort, a higher risk of death and progression was observed in patients with high/very high risk MIPPS70+ prognostic index [HR for OS 4.3 (95% CI 0.6-33.1), HR for PFS 4.1 (95% CI 0.9-16.9)]. Conversely, the presence of HMR mutations did not significantly affect OS, PFS (Figure 1), NRM or CIR. The prognostic significance of MIPSS70+ risk classification was confirmed in the validation cohort, with a higher risk of death and progression for high/very high MIPSS70+ group [OS HR 3.2 (95% CI 0.4-27.1), PFS HR 3.8 (95% CI 0.5-31.4)]. Similarly, in the validation cohort the presence of HMR mutations did not affect transplant outcome, with no impact on OS, PFS (Figure 2), NRM or CIR. In the whole group of 73 patients, the presence of JAK2V617F mutation showed an adverse prognostic impact on CIR [HR 3.4 (95% CI 1-11.8)], while MIPPS70+ confirmed its role on PFS. Conclusions In this study we prospectively confirmed that the presence of HMR mutations did not impact on transplant outcome. Allogeneic stem cell transplantation can lead to a significant cure rate of MF patients, regardless the presence of HMR mutations. Patients in the high/very high MIPSS70+ risk group had a higher risk of death and progression after transplant. Appropriate timing and selection of patients is crucial for transplant outcome in MF. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Initial Treatment Response Is Prognostic and Predictive of Relapse Patterns: Outcomes of >500 Patients Treated for Primary CNS Lymphoma

Introduction: Given concerns for neurotoxicity of standard dose (SD) whole brain radiotherapy (WBRT) after high-dose methotrexate (MTX), consolidation for primary CNS lymphoma (PCNSL) has evolved to either autologous hematopoietic cell transplantation (AHCT) or reduced dose (RD; ≤24Gy) WBRT with cytarabine. We sought to evaluate factors influencing consolidation approach and survival outcomes by consolidation strategy. For a disease that has historically been considered multifocal, we analyzed patterns of relapse in a large cohort of contemporarily treated patients. Methods: PCNSL patients treated at Memorial Sloan Kettering from 1983-2020 were analyzed. Initial site was determined by T1 post-contrast-enhancing MRI. Patients were categorized by response (complete/unconfirmed [CR/CRu], partial [PR], stable, progression [POD]) to induction and consolidation (AHCT, RD vs SD WBRT, cytarabine, other). Factors impacting consolidation strategy were assessed by multinomial logistic regression models. Site of initial progression was categorized as local (involving/adjacent to initial site) vs distant intraparenchymal, leptomeningeal (CSF and/or MRI), or other. Cumulative incidence of local failure was assessed with death as a competing risk. Progression-free survival (PFS) was assessed from consolidation start with Kaplan Meier and proportional hazards. Results: Of 645 patients, 559 were eligible for inclusion (diffuse large B-cell, sufficient data, ≥1 MRI response assessment). Median follow-up was 7.4 years. From diagnosis, median PFS was 2.2 years and median overall survival (OS) was 5.7 years. Median age was 63 years (IQR 54-72), and most (57%) were recursive partitioning analysis (RPA) class 2 (age≥50, KPS≥70). Most had supratentorial (420, 81%), multifocal (274, 53%), bilateral (224, 43%), and deep structure involvement (314, 56%). Nearly all received MTX-based induction (532, 95%); common regimens were rituximab, MTX, procarbazine, vincristine (R-MVP; 257, 46%) and MVP (144, 26%). Most (403, 72%) responded to induction (305 [76%] CR/CRu, 98 PR [25%]). 385 patients received consolidation: 116 (21%) WBRT, of which 55 (47%) had RD; 80 (15%) AHCT; 170 (31%) cytarabine; 19 (3%) other. Consolidation approaches evolved over time (SD WBRT 65% in 1980s-1990s vs 3% in 2000s-2020s, RD WBRT 0% in 1980s-1990s vs 18% in 2000s-2020s, AHCT 4% in 1980s-1990s vs 25% in 2000s-2020s; Fisher's exact test, p-value <0.001). RPA and induction response were significantly associated with consolidation approach, while baseline tumor size and leptomeningeal involvement were not. Patients with higher RPA were less likely to undergo AHCT than RD WBRT (RPA 3 vs 1, HR 0.15 [0.04, 0.53], p=0.003). Compared to patients with CR, those with PR were more likely to receive SD WBRT (HR 4.56 [1.70, 12.3] p=0.003) and less likely to receive AHCT (HR 0.34 [0.13, 0.93] p=0.036) than RD WBRT. Of the 385 patients consolidated, 352 (91%) achieved CR/CRu, of whom 145 (41%) later relapsed. Most relapses after CR to consolidation were multifocal, non-local (1- and 5-year cumulative incidences: 43% and 86%, respectively) as opposed to unifocal local (8% and 16% at 1- and 5-years) or unifocal non-local (31% and 70% at 1- and 5-years). Upon controlling for diagnosis year, induction regimen, RPA, consolidation approach, and the interaction between consolidation and RPA, there was no significant difference in PFS or OS by consolidation strategy (AHCT vs RD WBRT: PFS HR 1.25 [0.31, 5.05], p=0.755; OS HR 0.88 [0.36, 2.19], p=0.788; Figure). Among those who did not achieve CR to consolidation (POD n=16, PR n=14, stable n=4), patients who progressed had the worst prognosis (median OS: POD 1.04 years, PR 2.7 years, Stable 6.1 years; p=0.005) with 6 (38%) experiencing local only progression. Of the 81 patients with POD on induction, 46 (57%) had local only progression. Conclusion: In a large PCNSL cohort, modern consolidation (AHCT, RD WBRT) achieved similar survival outcomes upon controlling for clinical variables in patients who achieved CR to consolidation. Performance status, age, and response to induction influenced consolidation strategy and outcomes, suggesting a role for further personalization. While delayed relapses after achieving CR to consolidation were often multifocal and non-local, early progression patterns in refractory patients (with many remaining localized) may suggest a role for focal RT for residual disease. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

High-Plex Imaging and Cellular Neighborhood Spatial Analysis Reveals Multiple Immune Escape and Suppression Patterns in DLBCL

Background: DLBCL is a heterogeneous disease of malignant B cells and tumor microenvironment (TME). As a malignancy arising from the immune system, DLBCL tumor cells are known to deploy immune escape and/or suppression strategies to evade immunosurveillance. A deep understanding of the interactions between tumor and its TME is critical to any enduring treatment outcome. Here, we systematically characterize the spatial patterns of major tumor infiltrating immune cells in DLBCL using high-plex imaging data, and characterize them in known high-risk patient groups such as EFS24 failures, ABC subtype, double-hit, and a high risk transcriptional subtype A7 (Stokes submitted). Methods: We generated multiplexed ion beam imaging (MIBI) data for two cohorts (cohort 1 and cohort 2) of newly-diagnosed DLBCL cases (N=55 and N=30) with 17 and 33 markers, respectively. Both cohorts had associated RNAseq and FISH data, enabling determination of molecular high-risk patients. The first cohort also contained MIBI imaging for N=5 normal lymph node (NLN) samples, while the second cohort had associated progression-free survival (PFS) data with R-CHOP treatment. The imaging analysis identified major immune cell phenotypes and their relative abundances. Largely following the methods of Bhate 2022, we calculated cellular neighborhoods (CNs) consisting of each cell and its 20 nearest neighbors for all 532,755 and 643,114 cells in the two cohorts, respectively. We clustered the cellular composition of the CNs to identify characteristic CN clusters for each cohort, and investigated the spatial arrangement, or context (SC) of these CNs, and the CN cluster-specific expression of certain markers and their association with ABC subtype, DHIT, and A7. For cohort 2, we also performed univariate Cox proportional hazard modeling with PFS data. Results: Seven unique CN clusters were identified, each enriched with different types of infiltrating immune cells, which we named with ascending tumor content as: CD4-rich (6.3% tumor), CD8-rich (21%), M1/DC-rich (33%), Tumor/DC mix (46%), M2-rich (56%), Tumor/T mix (59%), and Tumor-rich (87%). These clusters, initially identified in cohort 1, were largely replicated in cohort 2. When contrasting ABC vs. GCB subtypes, we find that ABC has fewer Tumor-rich (p = 0.01) but higher abundance of M2-rich CNs (p=0.043). These M2-rich CNs, which are enriched with immune suppressive CD163+ macrophages, are present only in DLBCL and not in NLN samples, indicating a role of suppressive macrophages in ABC that is previously under-appreciated. CD163+ macrophages are associated with poor outcome in the 2ndcohort (HR=4.4 +/- 0.61, p = 0.015), confirming similar findings in literature (Bohn 2012, Nam 2014, Reiss 2019). As expected, tumor-rich CNs are associated with PFS24 failures (p = 0.026), and in DHIT (p = 0.0023), and A7 (p < 0.001) samples, in both cohorts. A7 samples lacked the two T-cell rich CNs, consistent with its low immune infiltration characteristic (Stokes submitted). Interestingly, the abundance of tumor/DC-mix CNs is also associated with A7 high-risk patients in both cohorts (p < 0.01). The two T cell-rich CNs were least enriched for tumor cells, indicating a structure of T cell exclusion from tumor-rich regions in DLBCL. We identified a SC motif of "T-cell islands" where CD4-rich CNs are enclosed by CD8-rich CNs, which are adjacent to a layer of tumor/T mix CNs and/or M2-rich CNs, followed by tumor-rich CNs (example in Figure 1B). We believe that this layered structure serves as an immune escape strategy, whereby CD4+ T helper cells are excluded from direct contact with tumor cells, which may reduce their antigen presentation capacity; while CD8-rich CN adjacency with M2-rich CNs could result in immunosuppression of cytotoxic CD8+ T cells. Among our other findings in cohort 2, infiltrating CXCR5+ CD8+ T cells are prognostic (PFS HR=0.23; p=0.021), and are highly enriched among the three highest tumor-rich CNs (p < 10-6). Conclusions: Using high-plex imaging and cellular neighborhood spatial analysis we have uncovered multiple spatial patterns between DLBCL tumor cells and their immune cell neighbors, which indicate that tumors exploit multiple mechanisms of immune escape or suppression. Detailed understanding of these mechanisms may provide new insights into tumor-TME interactions that will be useful for improving immune-oncology and combination strategies in DLBCL. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Time to Event Surrogate Endpoints in Multiple Myeloma Randomized Trials from 2005-2019: A Surrogacy Analysis

INTRODUCTIONThe use of surrogate endpoints such as progression-free survival (PFS) and other time-to-event (TTE) endpoints is common in multiple myeloma (MM) clinical trials. However, the validity of these alternative endpoints as surrogates for overall survival is not consistently proven in most malignancies, including MM, and requires further investigation. Furthermore, relapses in MM may occur clinically (with the appearance of new lytic lesions or extramedullary disease) or biochemically, with a rise of a monoclonal protein. As clinical progression may be more prognostically relevant than asymptomatic biochemical progression, it is important for clinical trials to include the nature of progression as part of their results. For all randomized trials that used a primary or co-primary time-to-event endpoint such as PFS, event-free survival (EFS) and time-to-progression (TTP), we assessed whether progression was reported as a biochemical progression or a clinical progression and whether a benefit in PFS translated to an OS benefit upon extended follow-up. We also performed a surrogacy analysis of PFS for OS in these trials to evaluate the strength of surrogacy. METHODS Three databases were searched (MEDLINE/PubMed, Embase, and Cochrane Registry of Controlled Trials) for all RCTs in MM from 2005 to 2019. The primary objectives of this study were twofold, to evaluate the proportion of RCTs using time-to-event endpoints that reported whether progression was biochemical and/or clinical, and to evaluate the strength of surrogacy of PFS to OS for all RCT's that used PFS as a primary or co-primary endpoint. We used an unadjusted linear regression to evaluate the association between OS HR and PFS HR for studies reporting time-concurrent numbers, or for studies reporting OS at a later follow up, and to calculate the coefficient of determination (R2). We also calculated Pearson's correlation coefficients and 95% confidence intervals for the correlation coefficients. We classified the strength of association as weak (r ≤ 0.7), medium (r > 0.7 to r < 0.85), and strong (r ≥ 0.85). RESULTS The initial search strategy yielded 1171 results. After searching conference proceedings and excluding duplicates or studies not meeting inclusion criteria, 151 discrete RCTs were included. When substratified for only those trials that were primarily evaluating time-to-event endpoints, a total of 88 studies were identified, of which 67 had PFS as either a primary or co-primary endpoint. A total of 45 studies included HR for both PFS and OS, allowing for regression analysis. Table 1 lists characteristics of included studies. We found only one study that described whether progression events were biochemical or clinical. Two additional studies reported time to first skeletal event and renal impairment reversal respectively but did not clearly differentiate between biochemical and clinical progression. Amongst the 45 studies where correlation could be assessed, the R2 from the regression model suggested that among the variance in OS, 45% was explained by PFS (Figure 1). The correlation between PFS and OS was 0.67 (95% CI 0.47-0.81), indicating a weak association of PFS with OS. For newly diagnosed (n=21) studies, 39% of the variance in OS was due to changes in PFS. The correlation between PFS and OS was 0.63 (95% CI 0.27-0.83) indicating a weak association of PFS with OS. For studies of relapsed/refractory MM (n=20), 60% of the variance in OS was due to changes in PFS. The correlation between PFS and OS was 0.77 (95% CI 0.49-0.91), indicating a medium association of PFS with OS. CONCLUSION We demonstrate that PFS is characterized poorly in MM trials, with almost no trials identifying whether progression events are biochemical or clinical. Our results show that PFS is a poor surrogate for OS in MM, especially for newly diagnosed disease. This review highlights the need for more comprehensive reporting of progression characteristics in order to establish the magnitude of clinical benefit to our patients. While acknowledging the tremendous improvements in outcomes in patients with MM with the current framework of trials, we highlight that differences in PFS do not reliably predict differences in OS, and we urge caution in attempts to establish surrogacy of other outcomes such as measurable residual disease with PFS. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Lenvatinib as First-Line Treatment for Unresectable Hepatocellular Carcinoma: A Systematic Review and Meta-Analysis.

Lenvatinib was approved in 2018 as a first-line treatment for patients with unresectable hepatocellular carcinoma (HCC). This systematic review and meta-analysis aimed to provide the most updated evidence about the efficacy and safety of lenvatinib as a first-line treatment for unresectable HCC. An electronic search of the PubMed database, Web of Science, Embase, and Cochrane Library was undertaken to identify all relevant studies up to May 2022. The pooled effect sizes were calculated based on the random-effects model. One phase III randomized controlled trial and 23 retrospective studies of 2438 patients were eligible for analysis. For patients treated with lenvatinib as first-line treatment, the pooled median overall survival (OS), median progression-free survival (PFS), 1-year OS rate, 1-year PFS rate, objective response rate (ORR), and disease control rate (DCR) were 11.36 months, 6.68 months, 56.0%, 27.0%, 36.0% and 75.0%, respectively. Lenvatinib showed a significantly superior efficacy compared with sorafenib (HR for OS, 0.85 and HR for PFS, 0.72; OR for ORR, 4.25 and OR for DCR, 2.23). The current study demonstrates that lenvatinib can provide better tumor responses and survival benefits than sorafenib as a first-line treatment for unresectable HCC, with a comparable incidence of adverse events.

P011: IPS-7 or IPS-3 to identify very-high risk patients in advanced Classical Hodgkin’s Lymphoma: Which score to choose

Figure 1: PFS and OS for both IPS-3 and IPS-7 scores Introduction: The survival of patients (pts) with classic Hodgkin Lymphoma (cHL) has been significantly increased due to refinement of therapeutic strategies. International Prognostic Score (IPS-7) is the most used risk stratification tool for patients with advanced-stage cHL but it may have decreased prognostic value in cHL pts treated in the contemporary era. A novel scoring system, IPS-3, comprising three of the seven IPS-7 indicators (age ≥45, stage IV, haemoglobin <105 g/L), was recently proposed to identify high-risk patients but require further validation. Aim: To validate IPS-3 and evaluate its discriminatory power in advanced stages cHL. Methods: Single centre retrospective analysis of adult pts with cHL diagnosed between 1990 and 2017 treated with ABVD, ABVD hybrid protocols or escalated BEACOPP. Advanced stage was defined according to the German Hodgkin Study Group classification system. Stratified models for IPS-3 and IPS-7 were compared using Akaike’s information criteria (AIC) and Harrell’s concordance index (C-index). Results: We included 227 pts, with similar gender proportion; median age was 32.3 (18–80). Nodular sclerosis was the most common histologic subtype (n=176 pts; 77.5%); 90 pts (39.6%) presented stage IV; 13 pts (5.7%) had IPS-3 high risk, 12 pts (5.3%) IPS-7 high risk and 8 pts (3.5%) had both. After a median follow-up of 123 months (m), the median overall survival (OS) was not reached. IPS-7 (HR 2.13 [95%IC 1.49–3.05]; p<0.001) and IPS-3 (HR 3.05 [95%IC 1.98–4.69]; p<0.001) identify different prognosis groups for OS, with IPS-3 (AIC 633; C-index 0.6547) providing best fit for data compared with IPS-7 (AIC 643; C-index 0.6403). Median progression free survival (PFS) was 295.6m. IPS-7 (HR 1.43 [95%IC 1.05–1.96]; p=0.025) and IPS-3 (HR 1.72 [95%IC 1.20–2.46]; p=0.003) identified different prognostic groups for PFS, with IPS-3 (AIC 917; C-index 0.5717) providing best fit for data compared with IPS-7 (AIC 921; C-index 0.5570). IPS-3 remained predictive for OS (HR 3.05; p<0.001) and PFS (HR 1.72; p=0.003) after adjustment for treatment protocol and had a good performance discriminating high vs intermediate/low risk for OS and PFS (HR 2.40; p=0.002 and PFS HR 3.03; p=0.001, respectively). Conclusion: IPS-3 had better performance predicting OS and PFS compared with IPS-7, allowing a better segregation of patients with worse prognosis, which suggests its value to identify patients that will benefit more aggressive treatment protocol.

PD-L1 assessment in cytology samples predicts treatment response to checkpoint inhibitors in NSCLC

BackgroundTesting for tumor programmed death ligand-1 (PD-L1) expression was initially developed with histology specimens in non-small cell lung cancer (NSCLC). However, cytology specimens are widely used for primary diagnosis and biomarker studies in clinical practice. Limited clinical data exist on the predictiveness of cytology-derived PD-L1 scores for response to immune checkpoint inhibitor (ICI) therapy. MethodsWe reviewed all NSCLC specimens clinically tested at the University Health Network (UHN) for PD-L1 with 22C3pharmDx, from 01/2013 to 04/2021. Treatment outcomes in patients treated with single agent ICI therapy were reviewed and compared according to cytology- and histology-derived PD-L1 scores. ResultsWe identified 494 and 1942 unique patients with cytology- and histology-derived tumor proportion scores, respectively, during the study period. Informative testing rates were 95 % vs 98 % for cytology and histology, respectively. Clinical data were available for 152 patients treated with single agent ICI: 61 cytology and 91 histology. Overall response rates (ORR) were similar for cytology and histology (36 % vs 34 %; p = 0.23), as well as median progression free survival (PFS) (4.9 vs 4.2 months; p = 0.99) and overall survival (23.4 vs 19.7 months; p = 0.99). The results remained similar even after adjusting for PD-L1 expression levels and line of ICI treatment (PFS HR 1.15; 95 %CI 0.78–1.70; p = 0.47). ConclusionsTreatment outcomes to single agent ICI based on cytology-derived PD-L1 scores were comparable to histology controls. Our results support PD-L1 biomarker testing on both cytology and histology specimens.