Progression-free Survival HR Research Articles

Predictive Value of Skeletal Muscle Mass in Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma Patients Treated With Immune Checkpoint Inhibitors.

BackgroundReduced muscle mass has been associated with increased treatment complications in several tumor types. We evaluated the impact of skeletal muscle index (SMI) on prognosis and immune-related adverse events (IrAEs) in a cohort of recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) treated with immune checkpoints inhibitors (ICI).MethodsA single-institutional, retrospective study was performed including 61 consecutive patients of R/M HNSCC diagnosed between July 2015 and December 2018. SMI was quantified using a CT scan at L3 to evaluate body composition. Median baseline SMI was used to dichotomize patients in low and high SMI. Kaplan-Meier estimations were used to detect overall survival (OS) and progression-free survival (PFS). Toxicity was recorded using Common Terminology Criteria for Adverse Event v4.3.ResultsPatients were 52 men (85.2%) with mean of age 57.7 years (SD 9.62), mainly oral cavity (n = 21; 34.4%). Low SMI was an independent factor for OS in the univariate (HR, 2.06; 95% CI, 1.14–3.73, p = 0.017) and multivariate Cox analyses (HR, 2.99; 95% CI, 1.29–6.94; p = 0.011). PFS was also reduced in patients with low SMI (PFS HR, 1.84; 95% CI, 1.08–3.12; p = 0.025). IrAEs occurred in 29 (47.5%) patients. There was no association between low SMI and IrAEs at any grade (OR, 0.56; 95% CI, 0.20–1.54; p = 0.261). However, grades 3 to 4 IrAEs were developed in seven patients of whom three had low SMI.ConclusionsLow SMI before ICI treatment in R/M HNSCC patients had a negative impact on OS and PFS. Further prospective research is needed to confirm the role of body composition as a predictive biomarker in ICI treatment.

Evaluation of the Lung Immune Prognostic Index in Non-Small Cell Lung Cancer Patients Treated With Systemic Therapy: A Retrospective Study and Meta-Analysis

The lung immune prognostic index (LIPI) has been shown to be an important prognostic marker for various tumors. However, the prognostic value of LIPI among non-small cell lung cancer (NSCLC) patients treated with systemic therapy remains controversial. We aimed to evaluate survival status according to LIPI among NSCLC patients receiving different forms of systemic therapy at our institution. We also performed a meta-analysis of articles from PubMed and Embase to illustrate this question. For our cohort, we found that good LIPI was associated with better overall survival (OS) among 91 patients on immunotherapy, 329 patients on targeted therapy, and 570 patients on chemotherapy. For the meta-analysis, a total of eight studies with 8,721 patients were included. Pooled results showed that a higher LIPI (those with 1 or 2 factors) was associated with poor overall progression-free survival (PFS) (hazard ratio [HR], 1.57; 95% confidence interval [CI], 1.45−1.71) and OS (HR, 2.01; 95% CI, 1.75−2.31). Subgroup analyses showed that a higher LIPI was related to poor survival among patients prescribed different systemic therapies: immunotherapy (OS HR, 2.50; 95% CI, 1.99–3.13; PFS HR, 1.77; 95% CI, 1.56–2.01), chemotherapy (OS HR, 1.58; 95% CI, 1.34–1.86; PFS HR, 1.38; 95% CI, 1.23–1.55), and targeted therapy (OS HR; 2.15, 95% CI, 1.57–2.96; PFS HR, 1.60; 95% CI, 1.25–2.06). The study shows that the LIPI is a clinically significant prognostic factor for NSCLC patients receiving systemic therapy.Systematic Review Registrationhttps://www.crd.york.ac.uk/PROSPERO/, identifier CRD420209009.

Clinical Value of Consensus Molecular Subtypes in Colorectal Cancer: A Systematic Review and Meta-Analysis.

BackgroundThe consensus molecular subtypes (CMSs) of colorectal cancer (CRC) capture tumor heterogeneity at the gene-expression level. Currently, a restricted number of molecular features are used to guide treatment for CRC. We summarize the evidence on the clinical value of the CMSs.MethodsWe systematically identified studies in Medline and Embase that evaluated the prognostic and predictive value of CMSs in CRC patients. A random-effect meta-analysis was performed on prognostic data. Predictive data were summarized. ResultsIn local disease, CMS4 tumors were associated with worse overall survival (OS) compared with CMS1 (hazard ratio [HR] = 3.28, 95% confidence interval = 1.27 to 8.47) and CMS2 cancers (HR = 2.60, 95% confidence interval = 1.93 to 3.50). In metastatic disease, CMS1 consistently had worse survival than CMS2-4 (OS HR range = 0.33-0.55; progression-free survival HR range = 0.53-0.89). Adjuvant chemotherapy in stage II and III CRC was most beneficial for OS in CMS2 and CMS3 (HR range = 0.16-0.45) and not effective in CMS4 tumors. In metastatic CMS4 cancers, an irinotecan-based regimen improved outcome compared with oxaliplatin (HR range = 0.31-0.72). The addition of bevacizumab seemed beneficial in CMS1, and anti-epidermal growth factor receptor therapy improved outcome for KRAS wild-type CMS2 patients.ConclusionsThe CMS classification holds clear potential for clinical use in predicting both prognosis and response to systemic therapy, which seems to be independent of the classifier used. Prospective studies are warranted to support implementation of the CMS taxonomy in clinical practice.

Association between body mass index, dosing strategy, and efficacy of immune checkpoint inhibitors

BackgroundIncreased body mass index (BMI) has been associated with improved response to immune checkpoint inhibitors (ICIs) in multiple cancer types. We evaluated associations between BMI, ICI dosing strategy, and clinical...

Differences in treatment effect size between progression-free survival and overall survival in anti-PD-1/PD-L1 inhibitors-based trials in advanced NSCLC: a systematic review and meta-analysis.

BackgroundTo investigate the differences in treatment effect sizes between progression-free survival (PFS) and overall survival (OS) in advanced non-small cell lung cancer (NSCLC) treated with programmed cell death 1 (PD-1) and its ligand (PD-L1) blockade-based treatments.MethodsThe differences in treatment effect sizes between PFS and OS were assessed by using a ratio of hazard ratio (rHR): the HR for PFS to that for OS. A random effects meta-analysis across trials was conducted to generate the combined rHR. We also evaluated the feasibility of adopting PFS as the surrogate of OS by using Spearman correlation coefficient (R) between logHRPFS and logHROS.ResultsA total of 27 randomized controlled trials (RCTs) with 15,590 patients were included. Treatment effect sizes were comparable, on average, for OS than for PFS (pooled rHR, 0.98; 95% CI, 0.91 to 1.08). Subgroup analysis revealed that treatment effect sizes were greater for OS than for PFS for trials with immunotherapy as second or above line treatment (rHR, 1.17; 95% CI, 1.06 to 1.29), while the differences were greater for PFS than for OS for trials with immunotherapy as first-line setting (rHR, 0.91; 95% CI, 0.84 to 0.99; Pinteraction<0.01). The coefficient of determination was 40% and R was 0.63 between logHRPFS and logHROS. Subgroup analysis showed that coefficient of determination and R were 62% and 0.79 in trials with immunotherapy as first-line setting, 22% and 0.47 in trials with immunotherapy as second or above line treatment, respectively.DiscussionTreatment effect sizes between PFS and OS were roughly consistent in trials with different anti-PD-(L)1 inhibitor-based therapies. PFS could be a potential alternative endpoint for OS in trials with immunotherapy as first-line setting, but PFS should be cautiously interpreted without OS data for trials with immunotherapy as second or above line treatment.

Gene expression signature to predict radiation response in lower-grade gliomas.

2019 Background: Standard of care for lower-grade glioma (LGG) is maximal safe resection and risk-adaptive adjuvant therapy. While patients who benefit the most from adjuvant chemotherapy have been elucidated in prospective randomized studies, comparable insights for adjuvant radiotherapy (RT) are lacking. We sought to identify and validate patterns of gene expression that are associated with differential outcomes among LGG patients treated by RT from two large genomics databases. Methods: Patients from The Cancer Genome Atlas (TCGA) with LGG (WHO grade II–III gliomas) treated by surgery and adjuvant RT were randomized 1:1 to a training set or an internal validation set. Using patients in the training set, association between gene expression from resected tumor and progression-free survival (PFS) as well as overall survival (OS) was evaluated with adjustment for clinicopathologic covariates. A genomic risk score (GRS) was then constructed from the expression levels of top genes also screened for involvement in glioma carcinogenesis. The prognostic value of GRS was subsequently validated in the internal validation set of TCGA and a second distinct database, compiled by the Chinese Glioma Genome Association (CGGA). Results: From TCGA, 289 patients with LGG received adjuvant RT alone (38 grade II, 30 grade III) or chemoradiotherapy (CRT) (51 grade II, 170 grade III) between 2009 and 2015. From CGGA, 178 patients with LGG received adjuvant RT alone (40 grade II, 13 grade III) or CRT (41 grade II, 84 grade III) between 2004 and 2016. The genes comprising GRS are MAP3K15, MAPK10, CCL3, CCL4, and ADAMTS1, involved in MAP kinase activity, T cell chemotaxis, and cell cycle transition. High GRS, defined as having a GRS in the top third, was significantly associated with worse outcomes independent of age, sex, glioma histology, WHO grade, IDH mutation, 1p/19q co-deletion, and chemotherapy status in the training set (OS HR 2.74, P &lt; 0.001; PFS HR 1.61, P = 0.014). These findings were further validated in the internal validation set (OS HR 1.84, P = 0.015; PFS HR 1.58, P = 0.027) and again in the CGGA external validation set (OS HR 1.72, P = 0.001). Association between GRS and outcomes was observed only among patients who received RT (RT alone or CRT), in both TCGA and CGGA. Conclusions: This study successfully identified an expression signature of five genes that stratified outcomes among LGG patients who received adjuvant RT, with two rounds of validation leveraging independent genomics databases. Expression levels of the highlighted genes were associated with survival only among patients whose treatments included RT, but not among those with omission of RT, suggesting that expression of these genes may be predictive of radiation treatment response. While additional prospective studies are warranted, interrogation of these genes to determine high/low GRS may be considered in the multidisciplinary management of LGGs.

Plasma thymidine kinase activity (TKa) as a novel prognostic biomarker in metastatic melanoma.

9556 Background: In the recent decade, new effective immunotherapies and targeted therapies have emerged for the treatment of disseminated melanoma. However, a considerable fraction of patients does not respond or get lasting effects and the treatments also have significant side effects. Biomarkers can contribute with more knowledge on prognosis and the efficacy of these therapies in different patients. In other cancer types, the plasma activity of the enzyme thymidine kinase (TKa), has been demonstrated as a marker of tumor stage and prognosis. The TK enzyme is part of a reaction chain to introduce thymidine into the DNA strand. TK thereby has a key function in DNA-synthesis, -repair and cell division. Dividing cells release TK during mitotic exit and TK can thus be detected in the blood. This study is the first to investigate plasma TKa as a potential biomarker in melanoma patients. Methods: Plasma samples were collected within five days prior to treatment start in patients with unresectable metastatic cutaneous melanoma, treated with immunotherapy (anti-CTLA-4 and/or anti-PD-1) or targeted therapy (BRAF±MEK inhibitors). Plasma TKa levels were determined using the DiviTum TKa ELISA assay (Biovica, Sweden). TKa levels were correlated with the patients’ baseline criteria, response rate (RR), progression free survival (PFS) and overall survival (OS). Results: Among the 124 study patients, the median TKa was 50 Du/L (range &lt; 20-3491 Du/L). Significantly higher plasma TKa levels were found in patients with ECOG performance status ≥1 vs. 0-1 ( P&lt; 0.001), M1c-d vs. M1a-b disease ( P&lt; 0.001), ≥3 vs. 1-2 affected organs ( P= 0.002) or elevated vs. non-elevated LDH ( P&lt; 0.001). In the patients treated with immunotherapy (n = 86) the RR was 63.2% vs. 37.9% in those with low ( &lt; 60 Du/L) vs. high TKa ( P= 0.024). The median PFS and OS was 19.9 and &gt; 60 months in those with low TKa vs. 12.6 and 18.5 months in those with high TKa (HR for PFS: 1.73 (95% CI, 1.01-2.97), P= 0.044 and HR for OS: 2.16 (95% CI, 1.17-3.98), P= 0.011). In the patients treated with BRAF±MEK inhibitor (n = 38) a similar trend was observed, with shorter PFS and OS in those with high TKa, but the differences were not statistically significant. Conclusions: In this first study on plasma TKa in melanoma patients, high pretreatment TKa was significantly associated with poor baseline factors and poor response and survival in immunotherapy treated patients. Currently, plasma LDH is the only non-clinical factor that is routinely used as a prognostic marker in melanoma. Several other candidate markers have been described, such as PD-L1 tumor immunohistochemistry, tumor mutational burden, gut microbiome and circulating tumor DNA. Compared to these assays, TKa measured with DiviTum is a simpler, ELISA based test for a single plasma marker. TKa is hence a novel and interesting marker in melanoma and should be further studied to define its role as a prognostic and predictive marker in this disease.

Progression-free survival (PFS) and second PFS (PFS2) by disease stage in patients (pts) with homologous recombination deficiency (HRD)-positive newly diagnosed advanced ovarian cancer receiving bevacizumab (bev) with olaparib/placebo maintenance in the phase III PAOLA-1/ENGOT-ov25 trial.

5514 Background: In the Phase III PAOLA-1/ENGOT-ov25 trial (NCT02477644), the addition of maintenance olaparib to bev in pts with newly diagnosed advanced high-grade ovarian cancer (HGOC) resulted in a significant PFS benefit, particularly in HRD-positive (HRD+) pts (hazard ratio [HR] 0.33; 95% CI 0.25–0.45) (Ray-Coquard et al. NEJM 2019). We explored efficacy in HRD+ pts by disease stage. Methods: Pts with newly diagnosed, FIGO stage III–IV HGOC in response after platinum-based chemotherapy + bev received bev (15 mg/kg q3w for 15 months [mo]) + either olaparib (300 mg bid for 24 mo) or placebo (pbo). This exploratory analysis evaluated PFS (data cut-off [DCO]: Mar 22 2019) and PFS2 (DCO: Mar 22 2020) in HRD+ pts (tumor BRCA1/ BRCA2 mutation [tBRCAm] or genomic instability score [Myriad myChoice HRD Plus] ≥42) by FIGO stage. Results: 387/806 randomized pts (48%) were HRD+; 272/387 (70%) had stage III disease and 115/387 (30%) had stage IV disease. 153 (56%) HRD+ stage III pts and 61 (53%) HRD+ stage IV pts had a tBRCAm. Among HRD+ stage III pts, 172 (63%) had upfront surgery (51/172 [30%] had residual disease) and 90 (33%) had interval surgery (19/90 [21%] had residual disease); 52 (45%) HRD+ stage IV pts had upfront surgery (34/52 [65%] had residual disease) and 55 (48%) had interval surgery (18/55 [33%] had residual disease). Median follow-up for PFS and PFS2 was respectively 24.8 and 37.2 mo in HRD+ stage III pts and 24.0 and 37.0 mo in HRD+ stage IV pts. Median PFS, PFS2 and HRs are in the Table. Among HRD+ stage III pts, 36-mo PFS2 (olaparib + bev vs pbo + bev) was 74% vs 60%; among HRD+ stage IV pts, 53% vs 30%. Among HRD+ stage III pts with no residual disease after upfront surgery, HR (95% CI) for PFS was 0.15 (0.07–0.30) and for PFS2 was 0.22 (0.06–0.67). Among HRD+ stage III pts with residual disease after upfront surgery or who received neoadjuvant chemotherapy, or HRD+ stage IV pts, HR (95% CI) for PFS was 0.38 (0.27–0.53) and PFS2 was 0.68 (0.46–1.03). Conclusions: In the PAOLA-1 study, maintenance olaparib + bev provided a PFS and PFS2 benefit over pbo + bev in HRD+ pts, irrespective of FIGO stage and residual disease after upfront surgery. Clinical trial information: NCT02477644. [Table: see text]

Molecular results and potential biomarkers identified from MILO/ENGOT-ov11 phase 3 study of binimetinib versus physicians choice of chemotherapy (PCC) in recurrent low-grade serous ovarian cancer (LGSOC).

5519 Background: Lower responses to chemotherapy and the unique molecular profile of LGSO led to the adoption of MEK-inhibitors for this disease. Updated analysis from the MILO/ENGOT-ov11 phase III study of binimetinib vs PCC in recurrent LGSOC showed response rate of 24% in those treated with binimetinib (JCO, 2020; NCT01849874). Here we present results of the post-hoc tumor tissue biomarker analysis performed with MILO/ENGOT-ov11. Methods: Mutational/copy number analysis was performed via Foundation Medicine on archival tissue obtained prior to randomization. Unbiased univariate analysis was used to test association between mutation status and outcomes in binimetinib and PCC treated patients. Outcomes examined were progression free survival (PFS), binary response by local RECIST 1.1 (complete or partial response [CR/PR] vs. stable [SD] or progressive disease [PD]), and ordinal response. Kaplan-Meier was used to estimate PFS. Cox regression, binary logistic regression, and ordinal logistic regression were used to examine relationship between mutation status and outcomes. Results: MILO/ENGOT-OV11 enrolled 341 patients from June, 2013 to April, 2016. Patients were randomized 2:1 to binimetinib or PCC. Based on January 1, 2020 data cut-off the data is as-is, amongst those patients treated with binimetinib with molecular results available, PFS data is available for 144 and response rate (RR) data for 135. There were 47 mutations detected in ≥5% of patients, most commonly KRAS (33%). Patients harboring a KRAS mutation had 3.4 times the odds of responding to treatment with binimetinib as patients without KRAS mutation (95% CI 1.57,7.67; p-value 0.002). There was no difference in effect of KRAS G12V mutation vs other KRAS mutation on PFS (PFS HR 1.06; 95% CI:0.53, 2.12; p value 0.9). In the 135 patients with binimetinib RR data, other MAPK mutations were identified as follows; NRAS in 11(8.1%), BRAFV600E in 8(5.9%), RAF1 in 2 (1.5%), NF1 in 7 (5.2%). In patients with MAPK mutation (as defined above) the RR was 41% vs 13% in those without MAPK mutation. PFS was significantly better in patients treated with binimetinib harboring MAPK mutation vs those without (HR 0.5; 95% CI 0.31, 0.79; p = 0.003). In patients treated with PCC there was a nonsignificant trend towards improved PFS in those with MAPK mutation vs those without (HR 0.82; 95% CI 0.43,1.59; p = 0.6). A test for interaction between treatment and MAPK pathway was not significant by Cox regression model (p = 0.32). Conclusions: While this hypothesis generating analysis is limited by multiple testing, higher response rates and longer PFS were seen in those patients with LGSOC treated with binimetinib who harbored MAPK mutations, most commonly in KRAS. Somatic tumor testing should be routinely performed in patients with recurrent LGSOC to aid in clinical decision making. Clinical trial information: NCT01849874.

Daratumumab (DARA) maintenance or observation (OBS) after treatment with bortezomib, thalidomide and dexamethasone (VTd) with or without DARA and autologous stem cell transplant (ASCT) in patients (pts) with newly diagnosed multiple myeloma (NDMM): CASSIOPEIA Part 2.

8004 Background: D-VTd plus ASCT was approved for transplant-eligible (TE) NDMM based on part 1 of CASSIOPEIA. We report a prespecified interim analysis of CASSIOPEIA part 2: DARA maintenance vs OBS in pts with ≥partial response (PR) in part 1, regardless of induction/consolidation (ind/cons) treatment. Methods: CASSIOPEIA is a 2-part, randomized, open-label, phase 3 study in TE NDMM. Pts received 4 cycles ind and 2 cycles cons with D-VTd or VTd. 886 pts who achieved ≥PR were rerandomized to DARA 16 mg/kg IV Q8W for up to 2 yr (n = 442) or OBS (n = 444) until progressive disease per IMWG. Pts were stratified by ind (D-VTd vs VTd) and depth of response (minimum residual disease [MRD] status and post cons response ≥PR). Primary endpoint was progression-free survival (PFS) after second randomization. This interim analysis assessed efficacy and safety after 281 PFS events. A preplanned hierarchical procedure tested key secondary endpoints: time to progression (TTP), ≥complete response (CR), MRD negativity rates by NGS and overall survival (OS). Results: At median follow-up of 35.4 mo, median PFS was not reached (NR) with DARA and 46.7 mo with OBS (HR 0.53; 95% CI 0.42–0.68; P &lt;0.0001). PFS advantage for DARA was consistent across most subgroups. However, a prespecified analysis showed significant interaction with ind/cons treatment arm ( P&lt; 0.0001). PFS HR for DARA vs OBS was 0.32 (95% CI 0.23–0.46) in the VTd arm and 1.02 (0.71–1.47) in the D-VTd arm. Median TTP was NR for DARA vs 46.7 mo for OBS (HR 0.49; 95% CI 0.38–0.62; P &lt;0.0001). More pts in the DARA vs OBS arm achieved ≥CR (72.9% vs 60.8%; OR 2.17; 95% CI 1.54–3.07; P &lt;0.0001). MRD negativity (in ≥CR pts at 10-5) was 58.6% with DARA vs 47.1% with OBS (OR 1.80; 95% CI 1.33–2.43; P= 0.0001). Median OS was NR in either arm. Most common (≥2.5%) grade 3/4 adverse events (AEs) with DARA vs OBS were pneumonia (2.5% vs 1.4%), lymphopenia (3.6% vs 1.8%), and hypertension (3.0% vs 1.6%). Serious AEs occurred in 22.7% (DARA) vs 18.9% (OBS) of pts; the most common (≥2.5%) was pneumonia (2.5% vs 1.6%). 13 (3.0%) pts discontinued DARA due to an AE. The rate of infusion-related reactions was 54.5% (DARA-naïve pts) and 2.2% (prior DARA pts); 90% were grade 1/2.Second primary malignancies occurred in 5.5% (DARA) vs 2.7% (OBS) of pts. Conclusions: CASSIOPEIA part 2 demonstrated a clinical benefit of DARA maintenance in TE NDMM pts, with significantly longer PFS for DARA vs OBS. With current follow-up, maintenance PFS benefit appeared only in pts treated with VTd as ind/cons. Pts who received D-VTd ind/cons with or without DARA maintenance achieved similar PFS; longer follow-up is needed for PFS2 and OS. DARA significantly increased deeper response and MRD negativity rates vs OBS, and was well tolerated with no new safety signals. Clinical trial information: NCT02541383.

Randomized phase III trial of aumolertinib (HS-10296, Au) versus gefitinib (G) as first-line treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) and EGFR exon 19 del or L858R mutations (EGFRm).

9013 Background: Au is a novel, irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) with favorable pharmacologic properties that selectively inhibits both EGFR sensitizing and resistance mutations. Au has been approved in China for treatment of patients (pts) with EGFR mutant NSCLC with EGFR T790M upon progression of disease on previous EGFR TKIs (Proc. AACR 2020, Abstract CT190). This Phase III trial assessed the efficacy and safety of Au versus G as initial treatment of patients with advanced NSCLC with EGFRm. Methods: Pts with previously untreated metastatic or locally advanced NSCLC and EGFR exon 19 deletion or L858R were randomly assigned in a 1:1 ratio to receive either Au (110 mg once daily) or G (250 mg once daily). The primary endpoint was progression-free survival (PFS) by RECIST v1.1 per investigator assessment. At 262 PFS events, the study had 90% power to detect a PFS HR = 0.67. Secondary endpoints included overall survival (OS), objective response rate (ORR), duration of response (DoR) and safety. Results: Between Nov 30, 2018 and Sept 6, 2019, 429 patients across 53 sites in China were enrolled and randomized. Pt. characteristics were well-balanced. At the planned final event-driven PFS analysis, Au significantly prolonged PFS (median 19.3 vs 9.9 months, HR 0.46, p-value &lt;0.0001). DoR was also significantly prolonged with Au. Median OS has not been reached. Efficacy and relevant safety results are summarized in Table. Despite a significantly longer duration of treatment (median 463 vs 254 days), Au was associated with a lower incidence of rash, diarrhea, AST/ALT increase, and treatment related serious adverse events (SAEs) (4.2% vs 11.2%). Au was associated with more frequent events of CPK increased, platelet count decreased, and neutrophil count decreased, which were predominantly low grade. Conclusions: Au significantly prolonged PFS and DoR compared to G as first-line therapy in pts with advanced NSCLC with EGFRm. Au demonstrated a favorable safety profile, especially regarding toxicities mediated by wild-type EGFR. These results establish Au as a promising option for advanced NSCLC with EGFRm. Clinical trial information: NCT03849768. [Table: see text]

Nivolumab plus cabozantinib (N+C) versus sunitinib (S) for advanced renal cell carcinoma (aRCC): Outcomes by baseline disease characteristics in the phase 3 CheckMate 9ER trial.

4553 Background: First-line N+C significantly improved progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) vs S in aRCC patients (pts) in the phase 3 CheckMate 9ER trial, leading to FDA approval of N+C in this setting. A deeper understanding of how baseline disease characteristics may impact clinical outcomes with N+C vs S may inform clinical decision making. Methods: Pts with clear cell aRCC were randomized to N 240 mg IV Q2W + C 40 mg PO QD vs S 50 mg PO QD (4 weeks of 6-week cycles). In this post hoc exploratory analysis, PFS, OS, and ORR were evaluated across pt subgroups defined by baseline IMDC risk status, organ sites of metastases (mets), number of organs with any lesions, or target lesion size. Consistent with primary/secondary efficacy endpoints in ITT pts, PFS and ORR were evaluated per RECIST v1.1 by blinded independent central review in subgroups. Results: Median follow-up in ITT pts was 23.5 months. PFS, OS, and ORR (including complete response [CR]) outcomes are summarized in the table across subgroups: IMDC risk (favorable [FAV], intermediate [I], poor [P]); number of organs with ≥ 1 target/nontarget lesion (T/NT; 1 and ≥ 2); sum of diameters of target lesions (sDTL; &lt; and ≥ median [72.1 mm]), and in pts with liver, bone, or lung mets. The PFS HR favored N+C vs S and median (m) PFS was longer with N+C vs S across all subgroups. The OS HR also favored N+C vs S across most subgroups. ORR ranged from 38%–66% (N+C) vs 10%–44% (S) across subgroups, and CR benefits were seen with N+C in most subgroups. Additional outcomes including landmark OS and response details in subgroups will be reported. Conclusions: Consistent with outcomes in ITT pts, efficacy benefits with N+C vs S were observed regardless of IMDC risk status, organ site of mets, or extent of tumor burden at baseline. These results support N+C as a new first-line treatment option for pts with aRCC. Clinical trial information: NCT03141177. [Table: see text]

Genomic profiling of advanced cervical cancer to predict response to programmed death-1 inhibitor combination therapy: a secondary analysis of the CLAP trial

BackgroundThe Camrelizumab Plus Apatinib in Patients with Advanced Cervical Cancer trial was a single-arm, phase II study that showed promising activity of the programmed death-1 (PD-1) inhibitor camrelizumab plus the...

MMSE is an independent prognostic factor for survival in primary central nervous system lymphoma

IntroductionTo assess the value of the Mini-Mental State Examination (MMSE)-score at baseline in predicting survival in adult primary central nervous system lymphoma (PCNSL) patients.MethodsIn the HOVON 105/ ALLG NHL 24 phase III study patients with newly-diagnosed PCNSL were randomized between high-dose methotrexate-based chemotherapy with or without rituximab. Data on potential (MMSE-score), and known baseline prognostic factors (age, performance status, serum LDH, cerebrospinal fluid total protein, involvement of deep brain structures, multiple cerebral lesions, and the IELSG-score) were collected prospectively. Multivariable stepwise Cox regression analyses were used to assess the prognostic value of all factors on progression-free survival (PFS) and overall survival (OS) among patients with available MMSE score at baseline. Age was analyzed as continuous variable, the MMSE-score both as a continuous and as a categorical variable.ResultsIn univariable analysis, age, MMSE-score and whether the patient received rituximab were statistically significantly prognostic factors for PFS. Age and MMSE-score were statistically significantly associated with OS. In a multivariable analysis of the univariately significant factors only MMSE-score was independently associated with the survival endpoints, as a continuous variable (HR for PFS 1.04, 95% CI 1.01–1.08; OS 1.06 (95% CI 1.02–1.10) and as categorical variable HR (< 27 versus ≥ 27 for PFS 1.55 (1.02–2.35); OS 1.68 (1.05–2.70). In our population, performance status, serum LDH, and CSF protein level were not of prognostic value.ConclusionNeurocognitive disturbances, measured with the MMSE at baseline, are an unfavorable prognostic factor for both PFS and OS in adult PCNSL patients up to 70 years-old.

Abstract PD14-05: Genomic profiling and clinical outcomes with first-line atezolizumab and nab-paclitaxel in triple-negative breast cancer: An exploratory analysis from the phase 3 IMpassion130 trial

Abstract Background: The clinical implications of genomic alterations in metastatic triple-negative breast cancer (mTNBC) have not been clearly addressed. In IMpassion130, atezolizumab (A) + nab-paclitaxel (nP) showed improved progression-free survival (PFS) and clinically meaningful overall survival (OS) benefit vs placebo (P) + nP in PD-L1+ mTNBC (Schmid, NEJM 2018). The goal of this exploratory study was to evaluate the prevalence of genomic alterations and their relationship with PD-L1 status and to determine whether a prognostic or predictive role for these factors exists for A + nP in a randomized dataset. Methods: Primary or metastatic tumor samples from patients in the IMpassion130 biomarker-evaluable population (BEP) were centrally evaluated for short variants (SV), copy number alteration (CNA) and rearrangements by using a targeted next-generation sequencing (NGS) panel (FoundationOne). PD-L1 status was evaluated using the VENTANA SP142 assay, with PD-L1 positivity defined by PD-L1-expressing immune cells on ≥1% of tumor area. Prognostic effects of genomic alterations were evaluated in the pooled population from both treatment arms. PFS and OS (co-primary endpoints) were analyzed by Cox proportional hazards models. ClinicalTrials.gov identifier: NCT02425891. Results: The BEP comprised 614 patients (68% of intent-to-treat population), 605 of whom received treatment. The most common pathogenic alterations were found in the following genes: TP53 (SV, 85%), MYC (CNA, 21%), PIK3CA (SV, 18%), PTEN (SV/CNA, 18%), RB1 (SV, 7%) and BRCA1 (SV, 9%). Primary tumors (n = 419), compared with metastatic tumors (n = 195), were more likely to bear alterations in BRCA1 (11.9% vs 5.6%) and less likely to have PIK3R1 alterations (4.8% vs 9.2%). TP53 loss-of-function mutations were associated with PD-L1+ status, whereas amplifications in VEGFA and CCND3 genes were significantly less associated; none of these alterations were linked with clinical outcomes favoring A + nP. Loss of RB1 (frequency 5%) was linked with reduced PFS and OS prognosis independent of treatment (hazard ratio [HR], 2.09 [95% CI: 1.42, 3.07] and HR, 1.98 [1.26, 3.11]), respectively), and CNA in CDKN2A (12%) and CDKN2B (11%) were associated with improved PFS and OS clinical activity in the A + nP arm vs the P + nP arm (HR PFS, 0.43-0.44 and HR OS, 0.47, respectively). Three of 584 microsatellite-evaluable samples (0.5%) had MSI-H status, which was not associated with PD-L1 status; all 3 MSI-H patients were from the P + nP arm. A total of 220 of 514 evaluable samples (42.8%) had PIK3CA/AKT1/PTEN-altered status, which was not significantly associated with PD-L1 status or A + nP clinical outcome. Conclusions: In this exploratory analysis using a targeted NGS panel, we show that tumors from patients with previously untreated mTNBC had similar genomic profiles at baseline as those published for early TNBC tumors. The few alterations that were linked to PD-L1 status were not linked to clinical outcome. CNA in cell cycle genes (e.g., RB1) had potential prognostic value, whereas CDKN2A and CDKN2B were potentially predictive of A + nP clinical benefit favoring A + nP. These data are hypothesis generating and require validation in an independent data set. Citation Format: Leisha Emens, Luciana Molinero, Sylvia Adams, Hope S. Rugo, Andreas Schneeweiss, Véronique Diéras, Hiroji Iwata, Carlos Barrios, Eric P. Winer, Ching-Wei Chang, Stephen Y. Chui, Peter Schmid, Sherene Loi. Genomic profiling and clinical outcomes with first-line atezolizumab and nab-paclitaxel in triple-negative breast cancer: An exploratory analysis from the phase 3 IMpassion130 trial [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD14-05.

Investigating the relationship between secreted protein acidic and rich in cysteine expression level and therapeutic efficacy of nab-paclitaxel: a meta-analysis.

BackgroundSecreted protein acidic and rich in cysteine (SPARC) is always considered as a marker of poor prognosis. However, it helps to transport nab-paclitaxel and may lead better therapeutic ending. This meta-analysis was aimed to assess the relationship between SPARC expression level and clinical efficacy of nab-paclitaxel.MethodsThe PubMed and Embase databases were searched from inception to April 2020, and search terms included nanoparticle albumin-bound paclitaxel, nab-paclitaxel, nab-PTX, Abraxane, ABI-007, secreted protein acidic and rich in cysteine, SPARC, osteonectin, and BM-40. In addition, funnel plots were used to indicate the existence of publication bias.ResultsAfter further screening the full text, 5 studies that involved 336 patients were finally included in the study, of which, 3 studies concentrated on non-small cell lung cancer (NSCLC) and the other 2 on breast cancer and pancreatic cancer. SPARC status in tumor cells and stromal cells was taken into account. The HR for progression-free survival (PFS) between SPARC high and low groups was 1.25 (95% CI: 0.72–2.14, stromal cell) and 1.51 (95% CI: 0.93–2.46, tumor cell). The HR for OS between SPARC high and low groups was 1.07 (95% CI: 0.57–2.03, stromal cell) and 1.34 (95% CI: 0.74–2.43, tumor cell). It was revealed that SPARC expression level in tumor cells or stromal cells was not significantly correlated with the patient’s survival outcomes. No significant publication bias was found in each analysis.ConclusionsSPARC expression level detected by immunohistochemistry (IHC) cannot predict the efficacy of nab-paclitaxel, while further large-scale clinical trials are required to confirm our findings.

Body weight loss (BWL) as a prognostic/predictive factor in previously treated patients (pts) with metastatic gastric or gastroesophageal junction cancer (mGC/GEJC): Post-hoc analyses of the phase III tags trial.

476 Background: Nutritional status is closely linked to cancer mortality, and BWL has been shown to be prognostic for survival in curative, first-, and second-line settings in mGC/GEJC. In the phase III TAGS trial, trifluridine/tipiracil (FTD/TPI) showed clinical benefit versus placebo (PBO) and manageable safety in pts with mGC/GEJC who had received ≥2 prior chemotherapy regimens. The association of early BWL with survival outcomes in TAGS was examined in retrospective analyses. Methods: The TAGS intent-to-treat (ITT) population was categorized into pts who experienced &lt;3% or ≥3% BWL from the start of treatment until day 1 of cycle 2 (each cycle: 28 days). Overall survival (OS), and progression-free survival (PFS) were compared between subgroups within each treatment arm due to significant imbalances of early BWL between treatment arms. The effect of early BWL on OS was assessed by a univariate Cox proportional hazards (PH) model as well as a multivariate Cox PH model that adjusted for baseline prognostic factors identified in the original ITT analysis. Results: Body weight data were available for 451 of 507 (89%) pts in the study (n=304, FTD/TPI; n=147, PBO). In the FTD/TPI and PBO arms, respectively, 74% (224/304 pts) and 65% (95/147) experienced &lt;3% BWL, whereas 26% (80/304) and 35% (52/147) experienced ≥3% BWL at the end of cycle 1. Pts with &lt;3% BWL had longer OS than those with ≥3% BWL in both FTD/TPI (median [m] OS: 6.5 vs 4.9 months [mo]; hazard ratio [HR], 0.75; 95% CI, 0.55–1.02) and PBO arms (mOS: 6.0 vs 2.5 mo; HR, 0.32; 95% CI, 0.21–0.49). The PFS HR for pts with &lt;3% BWL vs ≥3% BWL was 0.95 (95% CI, 0.71–1.25; mPFS, 2.1 vs 1.9 mo) in the FTD/TPI group and 0.49 (95% CI, 0.34–0.72; mPFS, 1.9 vs 1.7 mo) in the PBO group. In the pooled ITT population, the unadjusted HR for the &lt;3% vs ≥3% BWL group calculated using a univariate Cox model was 0.58 (95% CI, 0.46–0.73), indicating a strong prognostic effect of early BWL. Results of multivariate analyses were consistent with univariate analyses and suggested that early BWL was both a prognostic ( P&lt;0.0001) and predictive (interaction P=0.0003) factor for OS in pts with mGC/GEJC. Grade ≥3 adverse events (AEs) of any cause were reported in 77% and 82% of FTD/TPI-treated pts in the &lt;3% and ≥3% BWL subgroups, respectively, and in 45% and 67% of placebo-treated pts in the &lt;3% and ≥3% BWL subgroups. Conclusions: To our knowledge, this is the first analysis to show that BWL is negatively associated with survival in pts with mGC/GEJC receiving third- or later-line treatment. In TAGS, early BWL (≥3% BWL at the end of cycle 1) was a strong negative prognostic factor for OS regardless of FTD/TPI or PBO treatment. Grade ≥3 AE frequencies were similar in FTD/TPI-treated pts with &lt;3% or ≥3% BWL. The relationship of BWL to other prognostic factors will be explored further. Clinical trial information: NCT02500043.

Incorporating radiomic feature of pretreatment 18F-FDG PET improves survival stratification in patients with EGFR-mutated lung adenocarcinoma.

BackgroundTo investigate the survival prognostic value of the radiomic features of 18F-FDG PET in patients who had EGFR (epidermal growth factor receptor) mutated lung adenocarcinoma and received targeted TKI (tyrosine kinase inhibitor) treatment.MethodsFifty-one patients with stage III-IV lung adenocarcinoma and actionable EGFR mutation who received first-line TKI were retrospectively analyzed. All patients underwent pretreatment 18F-FDG PET/CT, and we calculated the PET-derived radiomic features. Cox proportional hazard model was used to examine the association between the radiomic features and the survival outcomes, including progression-free survival (PFS) and overall survival (OS). A score model was established according to the independent prognostic predictors and we compared this model to the TNM staging system using Harrell's concordance index (c-index).ResultsForty-eight patients (94.1%) experienced disease progression and 41 patients (80.4%) died. Primary tumor SUV entropy > 5.36, and presence of pleural effusion were independently associated with worse OS (both p < 0.001) and PFS (p = 0.001, and 0.003, respectively). We used these two survival predictors to devise a scoring system (score 0–2). Patients with a score of 1 or 2 had a worse survival than those with a score of 0 (HR for OS: 3.6, p = 0.006 for score 1, and HR: 21.8, p < 0.001 for score 2; HR for PFS: 2.2, p = 0.027 for score 1 and HR: 8.8, p < 0.001 for score 2). Our scoring system surpassed the TNM staging system (c-index = 0.691 versus 0.574, p = 0.013 for OS, and c-index = 0.649 versus 0.517, p = 0.004 for PFS).ConclusionsIn this preliminary study, combining PET radiomics with clinical risk factors may improve survival stratification in stage III-IV lung adenocarcinoma with actionable EFGR mutation. Our proposed scoring system may assist with optimization of individualized treatment strategies in these patients.

Quantitative expression of Ikaros, IRF4, and PSMD10 proteins predicts survival in VRD-treated patients with multiple myeloma

AbstractThe search for biomarkers based on the mechanism of drug action has not been thoroughly addressed in the therapeutic approaches to multiple myeloma (MM), mainly because of the difficulty in analyzing proteins obtained from purified plasma cells. Here, we investigated the prognostic impact of the expression of 12 proteins involved in the mechanism of action of bortezomib, lenalidomide, and dexamethasone (VRD), quantified by capillary nanoimmunoassay, in CD138-purified samples from 174 patients with newly diagnosed MM treated according to the PETHEMA/GEM2012 study. A high level of expression of 3 out of 5 proteasome components tested (PSMD1, PSMD4, and PSMD10) negatively influenced survival. The 5 analyzed proteins involved in lenalidomide's mode of action were associated with time to progression (TTP); low levels of cereblon and IRF4 protein and high levels of Ikaros, AGO2, and Aiolos were significantly associated with shorter TTP. Although the glucocorticoid receptor (GCR) level by itself had no significant impact on MM prognosis, a high XPO1 (exportin 1)/GCR ratio was associated with shorter TTP and progression-free survival (PFS). The multivariate Cox model identified high levels of PSMD10 (hazard ratio [HR] TTP, 3.49; P = .036; HR PFS, 5.33; P = .004) and Ikaros (HR TTP, 3.01, P = .014; HR PFS, 2.57; P = .028), and low levels of IRF4 protein expression (HR TTP, 0.33; P = .004; HR PFS, 0.35; P = .004) along with high-risk cytogenetics (HR TTP, 3.13; P < .001; HR PFS, 2.69; P = .002), as independently associated with shorter TTP and PFS. These results highlight the value of assessing proteins related to the mechanism of action of drugs used in MM for predicting treatment outcome.

EPHA mutation as a predictor of immunotherapeutic efficacy in lung adenocarcinoma

BackgroundEphrin type-A receptors (EPHA) are members of family of receptor tyrosine kinases and are related to tumor immunogenicity and immune microenvironment, however, the association between EPHA mutation (EPHAmut) and efficacy...