PFS Analysis Research Articles

VP10-2021: Cabozantinib (C) plus atezolizumab (A) versus sorafenib (S) as first-line systemic treatment for advanced hepatocellular carcinoma (aHCC): Results from the randomized phase III COSMIC-312 trial

The multikinase inhibitor C has shown promising clinical activity in combination with immune checkpoint inhibitors, including A, in multiple tumor types. COSMIC-312 (NCT03755791) is evaluating C+A vs S as first-line systemic treatment for aHCC. In this open-label, global, phase 3 trial, patients (pts) were randomized 2:1:1 to C 40 mg QD plus A 1200 mg Q3W or S 400 mg BID or C 60 mg QD stratified by etiology, geographic region, and presence of extrahepatic disease and/or macrovascular invasion (EHD/MVI). Eligible pts had HCC not amenable to curative treatment or locoregional therapy, Child-Pugh class A, ECOG PS ≤1, and no prior systemic therapy for HCC. The dual primary endpoints were PFS by blinded independent review committee per RECIST 1.1 for C+A vs S in the first 372 pts randomized to these 2 arms and OS for C+A vs S in all randomized pts. The secondary endpoint was PFS for C vs S. Prespecified interim analyses of OS for C+A vs S and PFS for C vs S were performed at the primary PFS analysis. 837 pts were randomized to C+A (N=432), S (N=217), or C (N=188). 30% of pts had HBV, 31% had HCV without HBV, and 39% had non-viral etiology; 29% enrolled in Asia; and 69% had EHD/MVI. The study met the primary PFS endpoint; C+A significantly improved PFS vs S (HR 0.63, 99% CI 0.44–0.91; p=0.0012; median PFS 6.8 vs 4.2 mo). The interim analysis of OS did not show a statistically significant benefit for C+A vs S (HR 0.90, 96% CI 0.69–1.18; p=0.438). Grade 3/4 treatment-related AEs (TRAEs) occurred for 54% of pts with C+A vs 32% with S; the most common events were PPE (7.9% vs 8.2%), hypertension (7.0% vs 6.3%), AST increased (6.5% vs 2.4%), and ALT increased (6.3% vs 1.9%). Grade 5 TRAEs were 1.9% vs 0.5%. TRAEs led to discontinuations of C and A in 6.1%, C and/or A in 14%, and S in 7.7% of pts. Interim results for PFS with C vs S will also be presented. C+A showed statistically significant and clinically meaningful improvement of PFS vs S in pts with aHCC not previously treated with systemic therapy. The safety profile of C+A was manageable and consistent with the known safety profile of each agent. Follow-up for the final OS analysis is ongoing.

NIMG-44. PROGNOSTIC VALUE OF PH- AND OXYGEN-SENSITIVE MRI IN GLIOMA PATIENTS

Abstract Hypoxia and tissue acidosis are two key features of the glioma microenvironment, both associated with a more aggressive phenotype through promotion of invasion, angiogenesis, and resistance to a vast number of therapies. In the current study, we demonstrate that higher levels of acidity and hypoxia in glioma are associated with worse prognosis by using simultaneous pH- and oxygen-sensitive amine chemical exchange saturation transfer spin-and-gradient echo echo-planar imaging (CEST-SAGE-EPI). A total of 159 histologically confirmed adult glioma patients (WHO grade II: N = 42; grade III: N = 38; grade IV, N = 79) were retrospectively evaluated. All patients were scanned with a custom amine CEST-SAGE-EPI MRI pulse sequence at 3T. Magnetization transfer ratio asymmetry (MTRasym) at 3ppm was used as a measure of relative acidity, R2’ was used as a surrogate of hypoxia, and their product MTRasym×R2' was used to quantify the degree of both acidity and hypoxia. Cox regression was performed to evaluate prognostic factors for OS and PFS. Univariate results suggested higher hypoxia, R2' (HR = 1.44, p = 0.0002), and higher combined measure of acidity and hypoxia, MTRasym×R2' (HR = 1.14, p = 0.0008), were associated with a shorter OS. When considering age, treatment status, and IDH mutation status as covariates, R2' and MTRasym×R2' remained significantly associated with patient OS (R2': HR = 1.27, p = 0.045; MTRasym×R2': HR = 1.17, p = 0.002). Within the treatment naïve patients, tumor acidity MTRasym, was also associated with OS (HR = 3.72, p = 0.003). R2' and MTRasym×R2' were significantly associated with PFS, both using univariate (R2': p < 0.0001; MTRasym×R2': p < 0.0001) and multivariate analyses including clinical factors (R2': p = 0.010; MTRasym×R2': p < 0.0001). In summary, tumor acidity and hypoxia measured using pH- and oxygen-sensitive metabolic MRI are significant prognostic factors in glioma.

TP53 Mutations Identify High-Risk Peripheral T-Cell Lymphoma Patients Treated with CHOP-Based Chemotherapy

TP53 Mutations Identify High-Risk Peripheral T-Cell Lymphoma Patients Treated with CHOP-Based Chemotherapy

Definition and Clinical Significance of the MGUS-like Phenotype: A Study in 5,114 Patients (Pts) with Monoclonal Gammopathies

Definition and Clinical Significance of the MGUS-like Phenotype: A Study in 5,114 Patients (Pts) with Monoclonal Gammopathies

Association of B Symptoms With Plasma EBV-DNA Copy Number and Cytokine Profiles in Patients With Nasal Type Extranodal Natural Killer/T-Cell Lymphoma (ENKTL): A Mechanism and Prognostic Study

<h3>Purpose/Objective(s)</h3> Extranodal natural killer/T-cell lymphoma, nasal type (ENKTL) is characterized with Epstein-Barr virus (EBV) infection and often presence of B symptoms (including fever, night sweat, and weight loss), but the mechanisms of B symptoms remain unclear. We sought to identify the association of B symptoms with plasma EBV-DNA copy number and cytokine profiles in patients with ENKTL to provide some explanation as well as prognostic analyses. <h3>Materials/Methods</h3> We retrospectively analyzed data from 681 newly diagnosed patients with ENKTL at our institution from April 2007 to December 2019. Plasma EBV-DNA copy levels at presentation were divided into 4 groups: group A (EBV-DNA = 0 copies/ml), group B (0 < EBV-DNA < 10³ copies/ml), group C (10³ ≤ EBV-DNA < 10⁶ copies/ml), and group D (EBV-DNA ≥ 10⁶ copies/ml). In the subgroup of 167 patients with detailed data of cytokines (including IFN, IL-10 and IL-6), patients were divided into three tertiles based on individual cytokines. We explored the association between EBV-DNA levels, cytokines tertiles, and B symptoms via Cochran-Armitage trend test and Goodman-Kruskal Gamma test. Univariate and multivariate analysis for PFS and OS were performed. <h3>Results</h3> The median age of all the 681 patients was 44 years (range 9-83 years). There were 467 males, and 321 patients had B symptoms. The majority of patients were those aged ≤60 years (84.9%), presented with early-stage disease (Ann-Arbor I or II) (79.3%), and with tumor originating from the upper aerodigestive tract (UADT, 84.7%). There were 158 (23.2%), 143 (20.1%), 284 (41.7%), and 96 (14.1%) patients in EBV-DNA group A, B, C, and D, respectively. The Cochran-Armitage trend test demonstrated an upward trend in the incidence of B symptoms from 25.9%, 36.4%, 53.2%, to 80.2%, in EBV-DNA groups with increasing copy number (<i>P</i> < 0.0001). Among 321 patients with B symptoms, 82.6% had a fever with significance. Similarly, the incidence of fever also increased over the four EBV-DNA load groups, which were 15.8%, 31.5%, 45.4%, and 68.8%, respectively (<i>P</i><0.0001). Further analysis of 167 patients with cytokines data demonstrated IFN, IL-10, IL-6 were correlated with EBV-DNA load (<i>P</i> < 0.0001 for all). In addition, the tertiles level of IFN, IL-10 and IL-6 were significantly associated with the presence of B symptoms (<i>P</i> < 0.0001, <i>P</i> = 0.0001, <i>P</i> = 0.0001, respectively) and fever (<i>P</i> = 0.0002, <i>P</i> = 0.0003, <i>P</i> = 0.0005, respectively). In univariate analysis, EBV-DNA load and B symptoms were significant predictor of PFS (<i>P</i> < 0.0001 for both) and OS (<i>P</i> < 0.0001 for both). Multivariate Cox regression analysis showed B symptoms (<i>P</i> = 0.026), primary tumor location (<i>P</i> = 0.019), and Ann-Arbor stage (<i>P</i> = 0.032) as predictive factors of OS. <h3>Conclusion</h3> This exploratory study provided more evidence for a potential association and mechanism, that the massive replication of EBV in vivo could trigger cytokinemia, which may lead to B symptoms and poor prognosis in patients with ENKTL.

The Significance of PARP1 as a biomarker for Predicting the Response to PD-L1 Blockade in Patients with PBRM1-mutated Clear Cell Renal Cell Carcinoma

Immune checkpoint inhibitors (ICIs) have become key agents in the management of clear cell renal cell carcinoma (ccRCC), but their benefits are limited and responders remain unidentified. We investigated the significance of PARP1 in ccRCC using RNA sequencing data for 311 tumors from patients enrolled in prospective clinical trials of PD-1 blockade. Among patients treated with nivolumab (n = 181), overall survival (OS) was significantly higher in the PARP1-low group than in the PARP1-high group (p = 0.006), and PARP1 status was significantly associated with OS (hazard ratio [HR] 1.7; p = 0.007). By contrast, for patients treated with everolimus (n = 130) there was no significant difference by PARP1 status for progression-free survival (PFS; p = 0.9) or OS (p = 0.38). In subgroup analysis for PBRM1-mutated ccRCC, PFS (p = 0.016) and OS (p = 0.004) were significantly longer in the group with PARP1-low status and PBRM1 mutation in comparison to the other groups. In addition, PARP1 status was significantly associated with PFS (HR 2.6; p = 0.007) and OS (HR 3.5; p = 0.016) among patients with PBRM1-mutated ccRCC treated with nivolumab. Our study suggests that PARP1 can be used as a biomarker for predicting response to ICI treatment for patients with PBRM1-mutated ccRCC. Patient summaryImmune checkpoint inhibitors (ICIs) are key agents in the treatment of multiple cancers. We found that expression of the PARP1 protein was associated with survival after ICI treatment and with the response to ICI treatment in patients with clear cell kidney cancer who have a mutation of the PBRM1 gene.

Abstract 1364: Exposure-response (E-R) analysis of efficacy for avelumab in combination with axitinib in patients with advanced renal cell carcinoma (aRCC) in JAVELIN Renal 101

Abstract BACKGROUND: Avelumab, a monoclonal antibody targeting PD-L1, is currently approved in the USA in combination with axitinib for the first-line treatment of patients with aRCC. This analysis evaluated the relationship between potential covariates, including avelumab exposure, and the efficacy endpoints progression-free survival (PFS; by blinded independent central review per Response Evaluation Criteria in Solid Tumors [RECIST] criteria) and objective response (OR; per RECIST) in patients with aRCC. METHODS: Exposure metrics for all patients in JAVELIN Renal 101 who received avelumab 10 mg/kg every 2 weeks (Q2W) in combination with axitinib were derived from a population pharmacokinetic model (N=434). E-R analysis for PFS was conducted using parametric time-to-event (TTE) methodology. The hazard distribution was tested using exponential, Weibull, log-normal, and log-logistic distributions. E-R analysis for OR was performed using generalized binomial logistic regression. For OR, the full model included the influence of all potential covariates, while the final model retained statistically significant covariates after stepwise backwards elimination (α=0.15). For PFS, covariates were included in the full model based on forward addition (α=0.05), and the final model was determined using backward elimination (α=0.01). Model evaluation included TTE-visual predictive checks, the likelihood ratio test, the Hosmer-Lemeshow test, and receiver operating characteristic curves. RESULTS: The best fit to the PFS data was the log-normal distribution. Avelumab exposure (cycle 1 day 15 trough concentration) was associated with probability of longer PFS in both univariate and multivariate regression models. In addition, the favorable-risk group, according to baseline Heng criteria, was associated with probability of longer PFS relative to patients with intermediate prognosis using Heng criteria. Similarly, increasing avelumab exposure was associated with a higher probability of achieving OR. However, several factors have confounded the interpretation of the causal relationship between exposure and PFS or OR, including the imbalance of Heng prognostic criteria across exposure quartiles, correlation among covariates, and that data were from a single-dose regimen. No relationship was found between incidence of ADA or baseline PD-L1 status and the efficacy endpoints PFS or OR. CONCLUSION: The E-R analyses were considered exploratory and no definite conclusions could be made on the impact of exposure on PFS or OR, as other variables confounded interpretation of the relationship. Overall, the exposure from avelumab 10 mg/kg IV Q2W in combination with axitinib was associated with a manageable and tolerable safety profile and demonstrated superior efficacy compared with sunitinib in terms of PFS in treatment-naive patients with aRCC. Citation Format: Carlo Bello, Satjit Brar, Joanna C. Masters, Akash Khandelwal, Ana M. Novakovic, Ana Ruiz-Garcia, Jennifer Hibma. Exposure-response (E-R) analysis of efficacy for avelumab in combination with axitinib in patients with advanced renal cell carcinoma (aRCC) in JAVELIN Renal 101 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1364.

Multiple Myeloma and Renal Impairment: Analysis of Induction Therapy Strategies and Outcome after Autologous Stem Cell Transplantation

Introduction: Multiple Myeloma (MM) is frequently accompanied by renal impairment (RI) at diagnosis. As MM-specific therapeutic strategies have evolved drastically within the past decades, we aimed at delivering a re-evaluation of applied treatments and outcomes according to renal function at diagnosis.Methods: In this multicenter, retrospective cohort analysis, we analyzed 366 patients who were diagnosed with MM between 1997-2016 and subsequently underwent autologous stem cell transplantation (ASCT). RI at diagnosis was defined as an estimated glomerular filtration rate (eGFR) <60 ml/min/1.73m2. We carried out statistical analysis of patient groups stratified by renal function with regard to induction therapy defined as conventional chemotherapy (CT) versus immuno-chemotherapy (ICT) including either a proteasome inhibitor and/or an immunomodulator. Further, overall and progression-free survival (OS, PFS) were analyzed in the defined subgroups.Results: Of 366 patients, 287 received ICT versus 79 who had CT alone. The choice of the applied treatment strategy was highly dependent on diagnosis date, as all patients diagnosed before the year 2000 received chemotherapy alone, while all but 4 patients diagnosed after 2006 received ICT. Patients with renal impairment were just as likely to receive ICT as those without (75.9 vs. 79.5%, p=0.259). On OS analysis in the patient groups A) normal renal function/ICT (n=202), B) normal renal function/CT (n=52), C) impaired renal function/ICT (n=85), D) impaired renal function/CT (n=27), a longer survival was observed in groups A and B; however without statistical significance (p=0.080; Figure 1). On analysis of PFS, no differences were observed (p=0.784; Figure 2).Conclusions: Impaired renal function confers only a slight and statistically insignificant OS disadvantage in newly diagnosed MM patients receiving ASCT. On analysis of treatment strategy, however, it is evident that ICT attains better OS outcomes compared to CT alone. Therefore, while renal impairment remains common in patients with MM, an interdisciplinary mode of action between hemato/oncologists and nephrologists concerning the optimal induction therapy prior to ASCT is of pivotal clinical importance. The application of an adequate immuno-chemotherapy should conquer the fear of the negative impact of renal failure on outcome in patients with MM. [Display omitted] DisclosuresGisslinger:Janssen Cilag: Honoraria; Shire: Honoraria; PharmaEssentia: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; AOP Orphan Pharmaceuticals AG: Consultancy, Honoraria; Takeda: Honoraria. Krauth:Takeda: Honoraria; Janssen Cilag: Honoraria; Novartis: Honoraria; Amgen: Honoraria; AOP Orphan Pharmaceuticals AG: Honoraria; Celgene: Honoraria; BMS: Honoraria.

Addition of Cyclophosphamide to Pomalidomide and Dexamethasone in Case of Suboptimal Response to Pomalidomide and Dexamethasone Alone in Relapsed and/or Refractory Multiple Myeloma: Results of the GMMG-Perspective Trial

Addition of Cyclophosphamide to Pomalidomide and Dexamethasone in Case of Suboptimal Response to Pomalidomide and Dexamethasone Alone in Relapsed and/or Refractory Multiple Myeloma: Results of the GMMG-Perspective Trial

A Phase 2, Randomized, Double-Blind, Placebo-Controlled, Multicenter Study of Siltuximab (Anti IL-6 Monoclonal Antibody) in Patients with High-Risk Smoldering Multiple Myeloma

A Phase 2, Randomized, Double-Blind, Placebo-Controlled, Multicenter Study of Siltuximab (Anti IL-6 Monoclonal Antibody) in Patients with High-Risk Smoldering Multiple Myeloma

The status of WIF1 methylation in cell-free DNA is associated with the insusceptibility for gefitinib in the treatment of lung cancer.

Targeted cancer therapy has shed light on the treatment of tumor, especially for patients with non-small cell lung cancer. However, only a limited portion of NSCLC patients carrying specific mutations showed an ideal drug response. In addition, DNA methylation status showed a great potential for cancer detection and prognosis prediction. Bisulfite sequencing was performed to analyze the DNA methylation of WIF1 promoter in cfDNA and tumor tissue samples collected from NSCLC patients. PFS and OS analyses were carried out to evaluate the prognosis of gefitinib treatment in patients with differential levels of WIF1 DNA methylation. Quantitative real-time PCR was used to analyze the expression of WIF1 mRNA, while immunohistochemistry was performed to assess the expression of WIF1 protein. Furthermore, ELISA was carried out to evaluate the WIF1 activity in plasma. The DNA methylation level of WIF1 promoter was lower in the cfDNA of NSCLC patients with a complete or partial response to gefitinib, and NSCLC patients with hypomethylated WIF1 showed better PFS and OS. The DNA methylation of WIF1 promoter in the resected tumor tissues was consistent with WIF1 DNA methylation in cfDNA, indicating that cfDNA was mainly derived from lung cancer tissues. As a result, the expression of WIF1 in tissue samples and the WIF1 activity in plasma was inhibited in patients with hypermethylated WIF1. Moreover, the cell viability of gefitinib-resistant cells was decreased by the suppressed WIF1 methylation in vitro. And the expression level of WIF1 mRNA was higher in gefitinib-resistant cells overexpressing ALKBH5, a known suppressor of WIF1 methylation. In summary, the findings of this study demonstrated that the level of WIF1 methylation in cfDNA was associated with the insusceptibility of gefitinib in the treatment of lung cancer.

Brentuximab vedotin with chemotherapy in adolescents and young adults (AYAs) with stage III or IV Hodgkin lymphoma: A subgroup analysis from the phase 3 Echelon-1 study.

7528 Background: Hodgkin lymphoma (HL) is a rare disease that commonly occurs in adolescents and young adults (AYAs) which is typically defined as 15 to 39 years. Given their young age at presentation, key factors in treatment selection include a high cure rate and limiting long-term toxicities. Brentuximab vedotin (Adcetris®; A) is a CD30-directed ADC approved in combination with doxorubicin, vinblastine, and dacarbazine chemotherapy (A+AVD) for adults with previously untreated stage III/IV cHL based on results from the phase 3 ECHELON-1 trial. Recent 5-year data demonstrated a significantly improved PFS per investigator (INV) vs doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) (HR, 0.69; 95% CI, 0.54–0.9; P = 0.003) (Straus 2020). Here we describe key efficacy and safety results for AYA pts enrolled in ECHELON-1. Methods: ECHELON-1 (N = 1334) is a global, open-label, multicenter, randomized trial of pts with previously untreated stage III/IV cHL. A total of 771 AYAs (57.8%) received either A+AVD (n = 396) or ABVD (n = 375) with a PET scan after cycle 2 (PET2). An analysis of PFS (time from randomization to progression or death from any cause) per INV was conducted. Results: After a median follow-up of 60.7 months (95% CI, 60.4-61.0), there was a 36% reduction in the risk of progression or death in AYAs receiving A+AVD vs ABVD (HR 0.64; 95% CI, 0.45-0.92; P = 0.013) with a 5-year PFS of 86.3% vs 79.4%, respectively, similar to the ITT population. The PFS benefit of A+AVD vs ABVD was independent of PET2 status; PET2 positivity (Deauville 4-5) was 6% and 8%, respectively. On the A+AVD arm, 81 AYAs (20%) had at least 1 subsequent anticancer therapy vs 96 AYAs (26%) on the ABVD arm; 26 AYAs (7%) received subsequent high dose chemotherapy and autologous stem cell transplant vs 32 AYAs (9%) on the A+AVD and ABVD arms, respectively. Resolution or improvement of peripheral neuropathy (PN) were similar in both arms; 224 AYAs (88%) on the A+AVD had resolution or improvement of PN vs 133 AYAs (89%) on the ABVD arm. Ongoing PN was predominantly Gr 1 (62%) and Gr 2 (26%), with 8 AYAs (13%) on the A+AVD arm and 1 AYA (5%) on the ABVD arm reporting ongoing Gr 3 PN. Finally, 7 AYAs (1.8%) and 5 AYAs (1.4%) on the A+AVD and ABVD arms, respectively, reported a secondary malignancy. Subsequent pregnancies were reported in female pts (44 A+AVD; 26 ABVD) and partners of male pts (31 A+AVD; 30 ABVD). No stillbirths were reported. All but 1 pt in each arm was &lt; 40. Conclusions: Consistent with the ITT population, AYAs treated with A+AVD compared to ABVD had a durable PFS benefit at this significant 5-year milestone. No impact on the rate of secondary malignancies and a numerically greater number of pregnancies were observed, outcomes of interest to AYAs. Additionally, the majority of PN events improved or resolved over time. A+AVD should be considered a treatment option for AYAs with stage III/IV cHL. Clinical trial information: NCT01712490.

Efficacy of olaparib therapy in metastatic pancreatic ductal adenocarcinoma (PDAC) with homologous recombination deficiency (HRD).

e16266 Background: Pancreatic cancer is one of the deadliest malignancies, with a 5 year OS of around 3%. Up to 3% of unselected patients (pts) with (PDAC) have the BRCA 1/2 mutation, while up to 15% possess HRD (ARID1A, ATM, BAP1, BARD1, BRIP1, CHEK1/2, FANCA, PALB2, RAD50, RAD51). PARP inhibitors, like olaparib, demonstrate clinical benefit in metastatic PDAC with BRCA mutations (mBRCA) and may have a role in those with HRD. The objective of this study is to determine the role of PARP inhibition in PDAC with HRD. Methods: This was a retrospective chart review of metastatic PDAC pts with germline (g) or somatic (s) mBRCA or HRD who received olaparib. An analysis of PFS and OS was performed for PDAC pts with mBRCA vs. HRD. Results: Forty-six pts with metastatic pancreatic cancer were identified to have mBRCA (n = 13) or HRD (n = 23) and received olaparib in our database. Median age was 73 years for mBRCA and 66 years for HRD. Five pts received olaparib as maintenance therapy after disease control with platinum: 2 mBRCA and 3 HRD pts. Six pts with mBRCA and 7 pts with HRD were platinum naïve prior to olaparib. Zero pts with mBRCA and 3 pts with HRD received olaparib after disease progression on platinum. The median (med)PFS for mBRCA vs. HRD was 6.1 months vs. 2.8 months (HR 0.5, 95% CI: 0.2-1.1, p = 0.07). The medOS for mBRCA vs. HRD was 7.7 vs. 5.3 months (HR 0.7, 95% CI: 0.2-1.9, p = 0.4). Of those with mBRCA who received olaparib, prior cisplatin exposure (n = 8) vs. cisplatin naïve (n = 5) led to medPFS of 6.1 vs. 7.8 months (HR 1.8, 95% CI 0.5-6.7, p = 0.3) and medOS of 6.8 months vs. 9.5 months (HR 1.5, 95% 0.3-6.4, p = 0.6). Six pts with HRD including gCHEK2 c.407T &gt; C, gCHEK2 c.1461+1 G &gt; A, gPALB2 gain (exon 11), sFANCI p.N1252S, sATM p.V2716A, sARID1A Q944fs*14 were noted to have disease control of at least 3 months on olaparib. Only one of these pts received olaparib as maintenance therapy after platinum. The medPFS was 6.1 months and medOS was not reached. One pt with HRD (sFANCI N1252S) had progressive disease on platinum prior to olaparib, but had stable disease &gt; 5 months with olaparib. Conclusions: Our study suggests olaparib may have anticancer activity in PDAC with certain HRD. In addition, olaparib may have a role outside maintenance therapy in PDAC with mBRCA. Prospective studies are needed to confirm these findings.

Second-line (2L) pembrolizumab (pembro) in Chinese patients (pts) with advanced melanoma: Three-year follow up (FU) of the phase 1 KEYNOTE-151 study.

e21511 Background: Pembro as 2L therapy was well tolerated and had clinically meaningful antitumor activity in Chinese pts with advanced melanoma at first analysis of the phase 1b KEYNOTE-151 study. At median FU of 7.9 mo, ORR was 16.7% (1 complete response [CR]; 16 partial response [PR]), DCR was 38.2%, median DOR was 8.4 mo, median PFS was 2.8 mo, and median OS was 12.1 mo. Any grade and grade 3/4 treatment-related adverse events (TRAEs) occurred in 84.5% and 8.7% of pts, respectively. However, long-term efficacy and safety of 2L pembro in Chinese pts with advanced melanoma are unknown. Results from 3 y of FU are presented. Methods: Eligible pts were ≥18 y, of Chinese descent, had histologically confirmed locally advanced or metastatic melanoma, and had disease progression on or after first line therapy. Pts received pembro 2 mg/kg IV Q3W for ≤35 cycles. Eligible pts who discontinued pembro with stable disease or better could receive ≤17 additional cycles of pembro (second course) upon disease progression. Primary endpoints were safety and ORR per RECIST 1.1 by blinded independent central review (BICR). Secondary endpoints included DOR and PFS per RECIST 1.1 by BICR; ORR, DOR, and PFS per irRECIST by BICR; and OS. ORR was based on the exact binomial method; DOR, PFS, and OS analyses used the Kaplan-Meier method. The full analysis set (FAS) comprised all allocated pts who received ≥1 pembro dose and had baseline data for relevant analyses. Results: Of 103 enrolled pts, 43% were male, 51% had PD-L1 positive tumors, and 80% had BRAF wild-type tumors; median age was 52 y (range, 22-77). The FAS had 102 pts. Median time from first dose to database cutoff was 44.6 mo (IQR, 39.1-46.2). At database cutoff (July 13, 2020), 14 pts (13.5%) had completed treatment, 89 pts (86.4%) had discontinued. Any grade TRAEs occurred in 88 pts (85.4%); most commonly hypothyroidism (n = 27; 26.2%), increased ALT (n = 24; 23.3%), and hypertriglyceridemia (n = 23; 22.3%), all grade 1/2. Grade 3-5 TRAEs occurred in 13 pts (12.6%). Immune-mediated AEs and infusion reactions occurred in 35 pts (34.0%); most commonly grade 1/2 hypothyroidism (n = 27; 26.2%). 3 pts discontinued pembro because of a TRAE; none died because of a TRAE. ORR per RECIST 1.1 was 17.6% (95% CI 10.8-26.4; 1 CR/17 PR); DCR was 38.2% (95% CI 28.8-48.4). Median DOR per RECIST 1.1 was 13.8 mo (range, 2.7-37.4+); 1 pt had response duration ≥36 mo. Median PFS per RECIST 1.1 was 2.8 mo (95% CI 2.7-3.5); 36-mo PFS rate was 5.0%. ORR, DOR, and PFS were similar per RECIST 1.1 and irRECIST. Median OS was 13.2 mo (95% CI 10.4-16.5); 36-mo OS rate, 22.3%.1 pt completed the first and second courses of pembro and had investigator-confirmed CR. Conclusions: 2L pembro was well tolerated and continued to provide durable responses and clinically meaningful antitumor activity in Chinese pts with advanced melanoma. These results further support use of 2L pembro in Chinese pts with advanced melanoma. Clinical trial information: NCT02821000.

Correlation of HRD status with clinical and survival outcomes in patients with advanced-stage ovarian cancer.

5568 Background: Nearly 50% of patients with high grade ovarian cancer (HGOC) harbor a germline or somatic mutation in BRCA1/BRCA2 or have tumors characterized by homologous recombination deficiency (HRD). HRD is associated with response to poly(ADP-ribose) polymerase inhibitors (PARPi) in HGOC. Although PARPi show great promise, there is interest in investigating how HRD status affects outcomes and can be used to objectively tailor other treatment strategies. We aimed to compare clinical and survival outcomes in HGOC stratified by HRD status. Methods: We performed a retrospective analysis of all advanced HGOC from April 2013 to June 2019. Patients were included if germline BRCA and HRD status was known. Clinical outcomes were analyzed and stratified by (1) germline BRCA+ (2) germline BRCA - and somatic BRCA/HRD+, or (3) BRCA-/HRD-. Progression free (PFS) and overall survival (OS) were estimated using Kaplan-Meier methods stratified by HRD status and modeled via Cox proportional hazards regression. Results: 1271 patients with advanced HGOC presented during the study period of which 187 met inclusion criteria. 106 patients had germline BRCA mutation, 26 somatic BRCA/HRD+, and 55 BRCA/HRD-. Patients who had HRD- tumor had older median age at diagnosis (63 vs. 54 and 60 years, p&lt;0.001), white race (89% vs. 74% and 68%), non-serous histology (20% vs. 6% and 0%, p=0.04), required more NACT chemotherapy cycles (4 vs. 3 and 3 cycles, p=0.03), and less complete gross resection (R0) at tumor reductive surgery (TRS) (60% vs. 83% and 77%, p=0.02). Patients who had BRCA/HRD- tumor had worse PFS (14.9 months) compared to germline BRCA+ (23.5 months) or somatic BRCA/HRD+ (20.2 months, p&lt;0.001). Patients with BRCA/HRD- disease also had worse OS (42.3 months) compared to germline BRCA+ (68.8 months) or somatic BRCA/HRD+ (69.2 months). Multivariate analysis for PFS revealed that age (HR 1.02, 95% CI 1.00-1.04), p=0.01), stage (HR 5.7, 95% CI 1.39-23.4, p=0.02), R0 resection at TRS (HR 0.41, 95% CI 0.21-0.83, p=0.01), and BRCA/HRD- status (HR 1.63, 95% CI 1.07-2.48, p=0.02) were significant factors impacting PFS. Multivariate analysis for OS revealed that age (HR 1.07, 95% CI 1.03-1.10, p&lt;0.001) and R0 resection at TRS (HR 0.19, 95% CI 0.08-0.44, p&lt;0.001) were significant factors impacting OS. Conclusions: Germline BRCA-mutant, somatic BRCA/HRD+ HGOC was associated with improved PFS and OS regardless of primary TRS or NACT. BRCA-/HRD- was a negative prognostic factor for survival in HGOC.

Cabozantinib (C) exposure-response (ER) analysis for the phase 3 CheckMate 9ER (CM 9ER) trial of nivolumab plus cabozantinib (N+C) versus sunitinib (S) in first-line advanced renal cell carcinoma (1L aRCC).

4561 Background: In the phase 3 CM 9ER trial (NCT03141177), N+C significantly improved progression-free survival (PFS; HR 0.51, 95% CI 0.41–0.64; p &lt; 0.0001), overall survival (OS; HR 0.60, 98.89% CI 0.40–0.89; p = 0.0010), and objective response rate (p &lt; 0.0001) vs S in 1L aRCC (Choueiri, 2020). N+C was generally well tolerated with low rates of treatment-related discontinuations, indicating successful adverse event (AE) management with dose modification to maintain tolerability. Here the impact of C exposure on efficacy and safety outcomes in CM 9ER was evaluated using ER analysis. Methods: Patients (pts, N = 320) with previously untreated aRCC received C 40 mg QD in combination with N 240 mg Q2W; dose reductions of C to 20 mg QD or 20 mg Q2D were allowed to manage AEs. Time-to-event Cox proportional hazard ER models were developed to characterize the relationship between predicted C exposure or apparent clearance (CL/F) and specified endpoints, including PFS, dose modification, and select AEs (palmar-plantar erythrodysesthesia [PPE; Gr ≥1], diarrhea [Gr ≥3], hypertension [Gr ≥3], fatigue/asthenia [Gr ≥3], and ALT/AST elevation [Gr ≥3]). C exposure was defined as the overall average concentration from time zero to the time of event or censoring (CAVG) and estimated by population pharmacokinetic modeling for a typical patient. ER analysis for OS was not done due to the low number of events at the database lock date (March 30, 2020). Results: In the ER analysis of PFS, predicted C exposure at 40-mg and 20-mg QD doses was not significantly associated with the rate of progression or death (HR 1.00, 95% CI 0.78–1.27, for 20-mg vs 40-mg dose). In the ER analysis of AEs, lower predicted C exposure was significantly associated with lower rates of PPE (HR 0.63, 95% CI 0.50–0.78, for 20-mg vs 40-mg dose) and diarrhea (HR 0.48, 95% CI 0.29–0.80) but was not significantly associated with the rates of hypertension, fatigue/asthenia, or ALT/AST elevation. Higher predicted C CL/F was associated with a lower rate of C dose modification; however, this association was not statistically significant (HR 0.80, 95% CI 0.57–1.12, for CL/F 3.2 vs 1.2 L/hr). Conclusions: In ER models of pts with 1L aRCC treated with the combination of N+C, C exposure was not significantly associated with PFS; however, higher C exposure was associated with higher rates of PPE and diarrhea. ER modeling predicts that a starting dose of 40 mg QD C in combination with N with appropriate dose modifications to manage C AEs will not adversely affect the efficacy of the combination in 1L aRCC. Clinical trial information: NCT03141177.

Presence of CTCs and its prognostic potential compared to AR-V7 expression in mCRPC undergoing androgen-deprivation therapy.

e17032 Background: Biomarkers predicting response to mCRPC treatment are rare. CTCs and AR-V7 status have been discussed as potential prognosticators. Methods: We evaluated 64 patients (pts.) treated with abiraterone (n=47) or enzalutamide (n=17), determined CTCs and analyzed AR-V7 status in correlation with survival using Kaplan-Meier-estimates and Cox-regression-models. Results: For PSA response, CTC- vs. CTC+ were not different (p=0.25) whereas AR-V7 status was predictive (68.2% AR-V7- and 33.3% AR-V7+ pts. (p=0.01)). Median PSA PFS was 17 mo. (CI 9.5-24.5) for CTC- and 6 (CI 5.2-6.9) for CTC+ pts. (p&lt;0.01) with 9 mo. (CI 4.2-13.8) for CTC+/AR-V7- and 5 (CI 3.0–7.0) for CTC+/AR-V7+ pts. (p=0.04). In univariate cox regression analysis (UV), prior abiraterone or enzalutamide (A/E) (p=0.01), bone metastases (p=0.03), CTC+ (p=0.01), AR-V7+ (p=0.01), Hb ≤12 g/dl (p=0.01) and PSA decline ≥50% (p&lt;0.01) were significant prognosticators. Within the CTC+ subgroup, AR-V7+ (p=0.02) and PSA decline ≥50% (p=0.03) showed a relevant difference. In multivariate analysis (MV), for CTC+ pts, AR-V7+ (p=0.02), PSA decline ≥50% (p=0.02) and visceral metastases (p=0.02) remained independent prognosticators. The analysis for PFS resulted in 22 mo. (CI NA) for CTC- compared to 9 (CI 7.7-10.3) for CTC+ (p=0.01) and 10 mo. (CI 8.2-11.8) for CTC+/AR-V7- vs. 6 (CI 1.9-10.1) for CTC+/AR-V7+ (p=0.07). Performing UV, prior A/E (p&lt;0.01), CTC+ (p=0.01), AR-V7+ (p=0.01), Hb ≤12 (p&lt;0.01), PSA decline ≥50% (p&lt;0.01) and ALP elevated at baseline (p=0.03) showed statistically significant differences. Within the CTC+ subgroup, prior A/E (p=0.01), visceral metastases (p=0.02), Hb ≤12 (p=0.01) and PSA decline ≥50% (p=0.03) were significant prognosticators, whereas AR-V7+ was not. In MV of CTC+ pts, visceral metastases (p=0.02), PSA decline ≥50% (p=0.02) and Hb ≤12 (p=0.05) remained independent prognosticators. Median OS was not reached for CTC- and 17 mo. (CI 9.8–24.2) for CTC+ (p&lt;0.01) with 27 (CI 10.6-43.4) vs. 14 (CI 10.4-17.7) mo. for AR-V7- and AR-V7+, respectively (p=0.06). UV resulted in statistically relevant differences for prior docetaxel (p=0.01), prior A/E (p&lt;0.01), visceral metastases (p=0.02), CTC+ (p=0.01), AR-V7+ (p&lt;0.01) and Hb ≤12 (p&lt; 0.01). Within CTC+, prior docetaxel (p&lt;0.01), prior A/E (p=0.01), visceral metastases (p&lt;0.01) and Hb ≤12 (p&lt;0.01) were statistically relevant parameters. UV for AR-V7 status did not result in a significant difference for OS either. In MV, CTC status as well as Hb ≤12 remained independent prognosticators (p=0.04 and p&lt;0.01, respectively). For MV of CTC+, visceral metastases (p=0.01), Hb ≤12 (p&lt;0.01) and prior docetaxel (p=0.01) were independent prognosticators of OS. Conclusions: Presence of CTCs seems to prognosticate PFS and OS in mCRPC patients undergoing Androgen-deprivation while presence of AR-V7 does not despite its predictive potential.

Neutrophil-lymphocyte radio (NLR) as a possible predictive factor in patients with advanced NSCLC WHO received immunotherapy.

e21042 Background: There exists a strong relationship between cancer and inflammation. For this reason, attempts have been made to identify different biomarkers of inflammation in recent years. The neutrophil - lymphocyte ratio (NLR) a marker of systemic inflammation, and the infiltranting lymphocytes of the tumor stroma (TILs) have been studied by our research team in different tumors, such as melanoma, breast cancer, colon cancer and NSCLC in patient who had recieved tratment with chemotherapy. We could observe that there was a significant relationship beteween DFS and a high NLR on the one hand, and DSF an intense TILs on the other. Our main objective is to evaluate the relationship between the objective response rate (ORR) and the pretreatment NLR in patients with advanced NSCLC who recieved immunotherapy. Our secondary objective is to analyzed the associated between PFS and RNL in patients with advanced NSCLC undergoing immunotherapy. Methods: Patients with diagnosis of advanced-stage NSCLC who recieved only immunotherapy, immunotherapy with another immunomodulator or in combination with platinum-based chemotherapy werw included. All patients had a follow-up of at least 6 months. The cutoff value &gt; or &lt; 3 for the NLR was use to reference. The laboratory control prior to the beginning of treatment was taken, and the ORR was determined using the Response Evaluation Criteria In Solid Tumors (RECIST) criteria. Statistical analysis was performed using dispersion and position measurements, T-Test and Chi Square test. For PFS analysis Kaplan-Meyer was used. The level of significance for the variables was p &lt; 0.05. Results: 41 patients with advanced NSCLC were analyzed. 43.9% (18 pts) recieved immunotherapy alone with nivolumab. 34.14% (14 pts) received a combined treatment (nivo / ipi) and 21.95% (9 pts.), immuno / QT combination (based on platinum). Regarding the histological presentation, 80.48% were adenocarcinoma. 54% (22 pts) had an NLR &gt; 3 and 46% (19 pts) an NLR &lt; 3. The ORR in the general population was 24%. in pts with an NLR &lt; 3, the ORR that was observed was 42% vs. ORR of 9% in pts with NLR &gt; 3 (p: 0.02). These differences were statistically significant. The median PFS was 11.27 months in the general population. As regards RNL, the median PFS were 20.74 vs 5.52 months in favor of pts with an NLR &lt; 3 (p: 0.04). Conclusions: We could conclude that patients with NSCLC and pretreatment NLR &lt; 3, who undergo immunotherapy, had better ORR compared to those with NLR &gt; 3. These differences was statistically significant. Also, we could observe better PFS in patient with NLR &lt; 3. These difference was estatically significant. We will keep working to obtain a greater number of patients. Then we could have a better analysis and statistical power. It is possible that NLR will be a highly useful and easy-to-acces predictive factor, and it could be used in patients with immunotherapy in our daily practice.

ESCORT-1st: A randomized, double-blind, placebo-controlled, phase 3 trial of camrelizumab plus chemotherapy versus chemotherapy in patients with untreated advanced or metastatic esophageal squamous cell carcinoma (ESCC).

4000 Background: The current standard first-line therapy for advanced or metastatic ESCC is doublet chemotherapy, and prognosis remains poor. Camrelizumab, a humanized anti-PD-1 monoclonal antibody, has shown promising antitumor activity in previously treated advanced or metastatic ESCC (Huang et al. Lancet Oncol 2019). Immunotherapy may work synergistically with chemotherapy, but lacking clinical evidences in ESCC. Here, we report the findings of the phase 3 ESCORT-1st study which evaluated the efficacy and safety of camrelizumab plus chemotherapy vs chemotherapy in patients with untreated advanced or metastatic ESCC. Methods: Eligible patients were randomized 1:1 to receive camrelizumab 200 mg or placebo, both combined with up to 6 cycles of paclitaxel (175 mg/m2) and cisplatin (75 mg/m2). All were given intravenously Q3W. Tumor response was assessed every 6 weeks according to RECIST v1.1. Co-primary endpoints were OS and independent review committee (IRC)-assessed PFS. Efficacy was assessed in all randomized patients and safety was assessed in all treated patients. Data cutoff date for the prespecified interim OS and final PFS analysis was Oct 30, 2020. Results: From Dec 3, 2018 to May 12, 2020, 596 patients were randomized. 298 patients were treated with camrelizumb-chemotherapy and 297 patients with placebo-chemotherapy. With a median follow-up of 10.8 months, camrelizumab plus chemotherapy significantly improved OS compared with placebo plus chemotherapy (median, 15.3 month [95% CI 12.8-17.3] vs 12.0 months [11.0-13.3]; HR, 0.70 [95% CI, 0.56-0.88]; one-sided P = 0.0010). Camrelizumab plus chemotherapy was also superior for PFS (per IRC) vs placebo plus chemotherapy (median, 6.9 months [95% CI, 5.8-7.4] vs 5.6 months [95% CI, 5.5-5.7]; HR, 0.56 [95% CI, 0.46-0.68]; one-sided P &lt; 0.0001). ORR per investigator was 72.1% in camrelizumab-chemotherapy group vs 62.1% in placebo-chemotherapy group, and median DoR was 7.0 vs 4.6 months. Incidences of grade ≥3 treatment-related AEs were comparable between the two groups (63.4% vs 67.7%), with decreased neutrophil count (39.9% vs 43.4%) as the most common one. Serious treatment-related AEs occurred in 30.2% vs 23.2% of patients, and treatment-related deaths occurred in 3.0% vs 3.7% of patients, respectively. Conclusions: Addition of camrelizumab to chemotherapy provided superior OS and PFS vs placebo plus chemotherapy, with a manageable safety profile. Camrelizumab in combination with paclitaxel and cisplatin has the potential to become a new standard first-line therapy in patients with advanced or metastatic ESCC. Based on this trial, we are submitting NDA to seek the approval from China National Medical Products Administration for camrelizumab plus chemotherapy in the treatment of untreated advanced or metastatic ESCC. Clinical trial information: NCT03691090.

Post hoc analysis in patients (pts) with unresectable hepatocellular carcinoma (uHCC) who progressed to Child-Pugh B (CPB) liver function in the phase III REFLECT study of lenvatinib (LEN).

298 Background: The treatment landscape for pts with uHCC has recently expanded. However, there is an unmet need for effective treatment options in CPB pts. LEN is approved first-line in uHCC based on the REFLECT study (Child-Pugh A [CPA] pts were allowed, per inclusion criteria). In a prior analysis of REFLECT, pts treated with LEN benefited irrespective of baseline liver function (ALBI grade 1 or 2; Child-Pugh score 5 or 6). To determine outcomes in pts with reduced liver function, we report a post hoc analysis of key efficacy and safety results in LEN-treated pts from REFLECT who progressed to CPB and those who did not within the first 8 weeks of treatment. Methods: In REFLECT, pts with uHCC were randomized 1:1 to LEN (per bodyweight: 12 mg/day for ≥60 kg; 8 mg/day for &lt; 60 kg) or sorafenib (400 mg twice daily) in 28-day cycles. This analysis assessed ORR. Landmark analyses (starting at week 8) of PFS, time-to-progression (TTP), and OS in CPB pts and in pts who remained CPA at 8 weeks post-randomization were also conducted. Tumors were assessed by mRECIST by independent imaging review. Safety was also assessed from baseline. Results: This subgroup analysis included LEN-treated pts (n = 60) who progressed to CPB within the first 8 weeks of treatment (CPB pts) and 413 pts who did not (CPA pts). At baseline, 26.7% and 73.1% of pts had an ALBI grade of 1 and 73.3% and 26.9% of pts had an ALBI grade of 2 in CPB and CPA pts, respectively. ORR was 28.3% (95% CI 16.9–39.7) for CPB pts and 42.9% (95% CI 38.1–47.6) for CPA pts. A landmark analysis showed a median PFS of 3.7 mos (95% CI 1.8–7.4) for CPB pts and 6.5 mos (95% CI 5.6–7.4) for CPA pts from the week 8 timepoint. Landmark analyses at week 8 also showed that the median TTP was 5.6 mos (95% CI 3.5–9.3) for CPB pts and 7.3 mos (95% CI 5.6–7.4) for CPA pts; the median OS was 6.8 mos (95% CI 2.6–10.3) for CPB pts and 13.3 mos (95% CI 11.6–16.1) for CPA pts per week 8 landmark analyses. As expected, efficacy appeared to be greater in CPA pts versus CPB pts; however, OS of 6.8 months in CPB pts after the week 8 landmark is notable. Moreover, median duration of treatment was 3.2 mos for CPB pts and 6.9 mos for CPA pts, thereby suggesting CPB pts can remain on LEN. The incidence of grade ≥3 treatment-related AEs (TRAEs) was 71.7% in CPB pts and 54.7% in CPA pts. TRAEs leading to discontinuation occurred in 18.3% of CPB pts and 7.5% of CPA pts. Conclusions: In this post hoc analysis of pts in REFLECT, we examine the key efficacy and safety results for LEN-treated pts who progressed to CPB by week 8. This post hoc analysis is limited by its descriptive nature; however, the results indicate that further study of LEN in CPB pts with uHCC is warranted. Clinical trial information: NCT01761266.