bluuebunny/crossref_metadata_2025 huggingface dataset:
A health-related quality-of-life (HRQoL) analysis of pomalidomide + low-dose dexamethasone + daratumumab in relapsed refractory multiple myeloma (RRMM) after lenalidomide treatment.
Authors: Reece Donna Ellen , Bahlis Nizar J. , Samaras Christy Joy , Sebag Michael , Berdeja Jesus G. , Ganguly Siddartha , Matous Jeffrey , Song Kevin W. , Seet Christopher , Talamo Giampaolo , Acosta-Rivera Mirelis , Bar Michael , Quick Donald , Anz Bertrand Marquess , Fonseca Gustavo A. , Agarwal Amit , Chung Weiyuan , Zafar Faiza , Siegel David Samuel DiCapua
Published: March 2020

8025

Background: Treatment (Tx) of RRMM is complex and requires evaluation of disease and patient (pt) factors to maximize efficacy and minimize toxicity. HRQoL has become an important aspect of MM Tx, as survival has improved with therapeutic advances. Results of the ongoing phase 2 MM-014 trial (NCT01946477) have demonstrated that pomalidomide (POM) + low-dose dexamethasone (LoDEX) + daratumumab (DARA) is safe and effective in RRMM pts after first- or second-line lenalidomide (LEN)-based Tx failure. Here we report the impact of this regimen on HRQoL. Methods: RRMM pts with 1 to 2 prior Tx lines, LEN-based Tx as their most recent regimen, and progressive disease during or after their last Tx line received POM + LoDEX + DARA in 28-day cycles (MM-014 cohort B). HRQoL, an exploratory endpoint for cohort B, was assessed via EuroQol’s EQ-5D. Results: As of October 15, 2018, 108 pts were evaluable for HRQoL. Baseline characteristics were similar to those of the ITT population (N = 112). EQ-5D completion rates for each cycle (1-6) were ≥ 88%. Mean change from baseline in the EQ-5D index and VAS health score was stable through 6 Tx cycles. At cycle 6, 28.8% and 39.0% of pts achieved minimum clinically important improvement in the EQ-5D index (≥ 0.1) and VAS health score (≥ 6), respectively. EQ-5D index values were stable, with a trend toward improvement in usual activities, pain/discomfort, and anxiety/depression (Table). Conclusions: In RRMM pts with early-line LEN Tx failure, HRQoL was maintained or trended toward improvement with POM + LoDEX + DARA, despite the combination of 3 drugs with distinct toxicities. These findings further support the earlier use of POM-based Tx in RRMM immediately after LEN failure. Clinical trial information: NCT01946477. [Table: see text]
Minimal residual disease clinical monitoring and depth of response in multiple myeloma.
Authors: Martinez-Lopez Joaquin , Wong Sandy Wai Kuan , Shah Nina , Bahri Natasha , Zhou Kaili , Martin Thomas G. , Wolf Jeffrey Lee
Published: March 2020

8026

Background: MRD assessment is a known surrogate marker for survival in multiple myeloma (MM). Most data come from patients enrolled in clinical trials. We present a single institution’s experience assessing MRD in patients receiving frontline therapy and therapy for relapsed disease. We describe the impact of depth, duration, and direction of response on prognosis. Methods: 181 MM patients at University of California, San Francisco (UCSF) from 2008 to 2016. 126 were newly diagnosed and 55 in ≥ 2nd line. MRD was assessed in patients achieving VGPR or better by IMWG criteria. MRD assessment was performed by NGS (Adaptive Biotechnologies, Seattle, WA). PFS curves were plotted by the Kaplan-Meier method, and the log-rank test was used to estimate statistical significance. Results: 398 MRD samples were analyzed. MRD was available at 3 time points for 59 patients and 2 time points for 36 patients. Median follow up was 26m. Overall, 66 of 181 patients (36%)achieved MRD- ( < 10-6) on one or more samples. In the newly diagnosed group, 43 of 126 (34%), achieved MRD- at least once. These patients had a prolonged PFS versus patients who were persistently MRD+ (NR vs 49m, p = 0.006). Of the 55 patients who received therapy for relapsed disease, 21 achieved MRD- (38%) and PFS was also prolonged versus patients who remained MRD+ (53m vs 23m, p = 0.03). We analyzed the effects of depth of response. Patients who were MRD- or who were MRD+, at a very low level (between 10-5and 10-6), had a better prognosis than those with higher disease burdens ( > 10-5) (p = 0.001). Finally, we analyzed the effect of repeated MRD monitoring on PFS. Three categories were identified in newly diagnosed patients: (A) patients with ≥3 MRD- samples, (B) patients with continuously declining detectable clones, and (C) patients with a stable number of clones. Groups A and B had a more prolonged PFS than group C (NR vs 31m, p < 0.0001). Conclusions: MRD assessment in a real-world setting has the same predictive power as that seen in clinical trials. MRD dynamics can accurately predict disease evolution and drive clinical decision-making. This study lends support to the concept of MRD-driven decision-making and helps validate the relevance of MRD.
Carfilzomib (K) in relapsed and refractory multiple myeloma (RRMM): Frailty subgroup analysis from phase III ASPIRE and ENDEAVOR.
Authors: Facon Thierry , Niesvizky Ruben , Weisel Katja , Bringhen Sara , Ho P. Joy , Obreja Mihaela , Yang Zhao , Klippel Zandra Karina , Blaedel Julie , Mezzi Khalid , Siegel David Samuel DiCapua
Published: March 2020

8028

Background: K-based regimens improved progression-free survival (PFS) and overall survival (OS) in RRMM patients (pts) in ASPIRE (K [27 mg/m2]-lenalidomide-dexamethasone [KRd] vs Rd) and ENDEAVOR (K [56 mg/m2]-dexamethasone [Kd56] vs bortezomib-dexamethasone [Vd]), regardless of age. Frailty scores have been developed based on age, comorbidities, and functional status (Palumbo Blood 2015;125:2068–74; Facon Blood 2015;126:4239). We assessed post hoc pt outcomes by frailty status. Methods: PFS, OS, and safety were assessed by treatment arm and frailty score (based on age, medical history-derived Charlson Comorbidity Index, and ECOG performance status); frailty scores: 0 = fit, 1 = intermediate (int), and ≥2 = frail. Results: Pt frailty status was balanced between treatment arms in ASPIRE and ENDEAVOR. Median PFS and OS were longer with K-based regimens vs controls in ASPIRE and ENDEAVOR across frailty subgroups (Table). Rates of treatment-emergent adverse events are summarized in the Table. Conclusions: Kd56 and KRd consistently improved outcomes vs Vd and Rd, respectively, in all frailty subgroups as defined by the algorithm above. These findings support the favorable benefit-risk profile of KRd and Kd56 regardless of frailty score. Clinical trial information: NCT01080391 and NCT01568866. [Table: see text]
Effect of t(11;14) on outcomes of patients (pts) with newly diagnosed multiple myeloma (NDMM) in the connect MM registry.
Authors: Gasparetto Cristina , Jagannath Sundar , Rifkin Robert M. , Durie Brian G. , Narang Mohit , Terebelo Howard R. , Toomey Kathleen , Hardin James W. , Wagner Lynne I. , Ailawadhi Sikander , Omel James , Lee Hans Chulhee , Srinivasan Shankar , Dhalla Mazaher , Catamero Donna , Agarwal Amit , Abonour Rafat
Published: March 2020

8032

Background: The impact of t(11;14) (16%–24% of MM pts) on prognosis is not fully understood. Consensus is lacking on the effects of induction treatment (tx) on outcomes with t(11;14). The Connect MM Registry (NCT01081028) is a large, US, multicenter, prospective observational cohort study of pts with NDMM designed to examine real-world diagnostic patterns, treatment (tx) patterns, clinical outcomes, and HRQoL pt-reported outcomes in pts with NDMM. The impact of t(11;14) on tx outcomes are reported. Methods: Analysis included data from pts from 250 community, academic, and government sites in cohort (C) 1 (9/2009–12/2011) and C2 (12/2012–4/2016), who completed first-line (1L; induction) tx and were tested for t(11;14) by FISH or cytogenetics. Primary end points (progression-free survival [PFS] and overall survival [OS]) were measured from start of 1L tx to earliest event (PFS, death or progression; OS, death), loss to follow-up, or data cutoff, adjusted for baseline (BL) risk factors. A sensitivity analysis excluding pts with concomitant cytogenetic abnormalities [del 17p, t(4;14), t(14;16), 1q+] was also performed. Results: By 1/2018, 3011 pts were enrolled; 2938 were treated. Of 1574 enrolled pts tested for t(11;14), 378 were t(11;14)+ and 1196 were t(11;14)−. More pts in C2 vs C1 were t(11;14)+ (60% vs 40%). BL characteristics were similar between groups. t(11;14) status did not affect PFS ( P= NS) or OS ( P= NS; Table). Pts in C1 and C2 received similar 1L txs (IMiD agent + proteasome inhibitor [PI], 30% vs 42%; PI only, 42% vs 43%; IMiD agent only, 17% vs 11%). Results were similar when pts with concomitant abnormalities were excluded. Conclusions: Results of this analysis suggest that t(11;14) does not affect PFS and OS outcomes in NDMM pts. Clinical trial information: NCT01081028. [Table: see text]
Efficacy and safety of daratumumab, bortezomib, and dexamethasone (D-Vd) in relapsed or refractory multiple myeloma (RRMM) based on cytogenetic risk: Updated subgroup analysis of CASTOR.
Authors: Weisel Katja , Spencer Andrew , Lentzsch Suzanne , Avet-Loiseau Herve , Mark Tomer M. , Spicka Ivan , Bosi Alberto , Hungria Vania TM , Cavo Michele , Lee Je-Jung , Nooka Ajay K. , Quach Hang , Munder Markus , Beksac Meral , Sonneveld Pieter , Soong David , Ukropec Jon , Qi Ming , Mateos Maria-Victoria
Published: March 2020

8040

Background: MM patients (pts) with high cytogenetic risk have poor outcomes. In CASTOR, D-Vd prolonged progression-free survival (PFS) vs bortezomib and dexamethasone (Vd) alone, and exhibited tolerability in RRMM pts. We conducted a subgroup analysis of D-Vd vs Vd in CASTOR, based on cytogenetic risk. Methods: Pts received ≥1 prior line of therapy. Cytogenetic risk was based on a combined analysis of next-generation sequencing (NGS) and fluorescence in situ hybridization/karyotype testing. High-risk pts had t(4;14), t(14;16), or del17p abnormalities. Standard (std)-risk pts were confirmed negative for all 3 abnormalities. Minimal residual disease (MRD; 10–5) was assessed via NGS using clonoSEQ assay V2.0. Results: In CASTOR (D-Vd, n = 251; Vd, n = 247), high-risk was confirmed in 26.7% and 25.9% of pts in the D-Vd and Vd groups, respectively. At a median follow up of 40.0 months (mo), D-Vd prolonged PFS vs Vd in pts with high- (median 13.4 vs 7.2 mo; HR, 0.40 [95% CI, 0.24-0.65]; P = 0.0002) or std-risk (median 18.4 vs 6.8 mo; HR, 0.28 [95% CI, 0.20-0.37]; P < 0.0001). Higher rates of ORR, MRD negativity, and sustained MRD negativity were seen with D-Vd vs Vd (Table). D-Vd prolonged PFS in first relapse pts (high risk: median 20.1 vs 8.4 mo; HR, 0.30 [95% CI, 0.14-0.64]; P = 0.0012; std risk: median 32.6 vs 7.9 mo; HR, 0.18 [95% CI, 0.11-0.29]; P < 0.0001) and PFS2 vs Vd (high risk: median 27.9 vs 18.6 mo; HR, 0.59 [95% CI, 0.37-0.94]; P = 0.0258; std risk: median 40.1 vs 21.6 mo; HR, 0.43 [95% CI, 0.32-0.59]; P < 0.0001) regardless of risk. Additional data will be presented. Conclusions: Adding daratumumab to Vd demonstrates significant efficacy in high-risk RRMM. Among high-risk pts, MRD negativity was only achieved with D-Vd. These findings support use of D-Vd for high-risk RRMM. Clinical trial information: NCT02136134. [Table: see text]
Adjuvant chemotherapy for pathological stage I non-small cell lung cancer with high-risk factors for recurrence: A multicenter study.
Authors: Tsutani Yasuhiro , Imai Kentaro , Ito Hiroyuki , Mimae Takahiro , Miyata Yoshihiro , Ikeda Norihiko , Nakayama Haruhiko , Okada Morihito
Published: March 2020

8500

Background: The role of adjuvant chemotherapy for pathological stage I non-small cell lung cancer (NSCLC) is controversial. The purpose of this study was to investigate the effect of adjuvant chemotherapy for pathological stage I NSCLC with high-risk factors for recurrence. Methods: Prospectively collected data from 1,278 patients with pathological stage I (8th edition) NSCLC undergoing lobectomy were retrospectively analyzed. High-risk factors for recurrence were determined by multivariable Cox proportional hazards model for recurrence-free survival (RFS). RFS, overall survival (OS), and cancer-specific survival (CSS) were compared between patients who received adjuvant chemotherapy and those who did not. Results: In multivariable analysis, age (≥70 y; hazard ratio [HR], 2.14), invasive component size ( > 2 cm; HR, 1.60), visceral pleural invasion (HR, 1.81), lymphatic permeation (HR, 1.67), and vascular invasion (HR, 2.78) were identified as independent factors for RFS. In patients with high-risk factors for recurrence such as invasive component size of > 2 cm, visceral pleural invasion, lymphatic permeation, or vascular invasion (high-risk group; n = 641), RFS was significantly different between patients who received adjuvant chemotherapy (n = 222; 5-y RFS, 81.4%) and those who did not (n = 418; 5-y RFS, 73.8%; P = 0.023). OS and CSS were also significantly better in patients who received adjuvant chemotherapy (5-y OS, 92.7%; 5-y CSS, 95.0%) than in those who did not (5-y OS, 81.7%; P < 0.0001; 5-y CSS, 89.5%; P = 0.012). In patients without any high-risk factors for recurrence (low-risk group; n = 637), RFS was not significantly different between patients who received adjuvant chemotherapy (n = 83; 5-y RFS, 98.1%) and those who did not (n = 554; 5-y RFS, 95.7%; P = 0.30). OS and CSS were also not significantly different between patients who received adjuvant chemotherapy (5-y OS, 98.0%; 5-y CSS, 100%) and those who did not (5-y OS, 95.6%; P = 0.35; 5-y CSS, 99.4%; P = 0.52). Conclusions: Adjuvant chemotherapy may improve survival in patients with pathological stage I NSCLC who have high-risk factors for recurrence such as invasive component size of > 2 cm, visceral pleural invasion, lymphatic permeation, or vascular invasion.
The role of EGFR inhibitors as adjuvant therapy for EGFR mutation positive non-small cell lung cancer.
Authors: Xie Peng , Tang Wenjie , Li Xiaolin , Sun Xindong , Yu Jinming
Published: March 2020

8508

Background: Cisplatin-based chemotherapy as adjuvant therapy for resected NSCLC has reached its plateau, and was limited by high risk of recurrence and significant toxicities. The clinical value of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in resected non-small cell lung cancer (NSCLC) harboring EGFR mutations remains controversial. In this study, we performed a meta-analysis to evaluate the role of EGFR inhibitors as adjuvant therapy for targeted patients. Methods: Studies were identified via an electronic search on Pubmed, EMBASE, ISI Web of Science, ScienceDirect, SpringerLink, The Cochrane library and so on. Pooled odds ratio (OR) for disease-free survival (DFS) and overall survival (OS) were calculated for meta-analysis. Registration number: PROSPERO (CRD42018093144). Results: There were 11 trials (1,152 resected NSCLC patients with EGFR sensitive mutations) in this meta-analysis. Results showed that adjuvant treatment with EGFR-TKIs can prolong both OS and DFS when compared to treatment without TKIs as adjuvant therapy (OS: OR, 0.63; 95% CI, 0.46 to 0.87, P = 0.004; heterogeneity I2= 61%, P = 0.008; DFS: OR, 0.56; 95% CI, 0.43 to 0.72, P < 0.00001; heterogeneity I2= 37%, P = 0.1). Results of predefined subgroup analyses in this meta-analysis suggested a greater DFS with EGFR-TKI mono compared with chemotherapy, whereas the OS benefit failed to show a similar difference between the two arms (p = 0.3). And we also find that treatment with EGFR-TKI plus chemotherapy was associated with significantly longer DFS as well as OS than chemotherapy mono in patients with completely resected EGFR-mutant NSCLC (DFS: OR, 0.48; 95%CI, 0.34-0.68; P < 0.00001; heterogeneity I2= 15%, P = 0.29; OS: OR, 0.50; 95% CI, 0.31-0.78; P = 0.003; heterogeneity I2 = 57%, P = 0.05). And less grade 3 or higher AEs were observed in the TKIs group (OR, 0.22; 95% CI, 0.14 to 0.37, P < 0.00001; heterogeneity I2= 22%, P = 0.28). Conclusions: Adjuvant EGFR-TKIs may be a potential treatment option compared to adjuvant chemotherapy in completed resected patients with EGFR mutation-positive NSCLC. This project was supported by the National Natural Science Foundation of China (Grant No. 81502667), Key Research and Development Plan of Shandong, China (Grant No. 2016GSF201167).
A randomized phase II study of tremelimumab and durvalumab with or without radiation for patients with relapsed small cell lung cancer (SCLC).
Authors: Owonikoko Taofeek Kunle , Higgins Kristin Ann , Chen Zhengjia , Zhang Chao , Pillai Rathi Narayana , Steuer Conor Ernst , Saba Nabil F. , Pakkala Suchita , Shin Dong Moon , Zhang Guojing , Wang Shuhua , Hossain Mohammed S , Beardslee Tyler , Engelhart Anne , Revenig Janine , Khuri Fadlo , Curran Walter John , Lonial Sagar , Waller Edmund K. , Ramalingam Suresh S.
Published: March 2020

8515

Background: The combination of PD-1 and CTLA-4 inhibition has demonstrated activity in the second line therapy setting for SCLC. Radiotherapy enhanced the effectiveness of immunotherapy in NSCLC. We conducted this signal finding study to assess the efficacy of combined ICI with or without radiation in relapsed SCLC. Methods: Patients with relapsed SCLC who have received not more than 2 lines of therapy were enrolled and randomized to either Arm A: [Tremelimumab (T) 1500mg/durvalumab (D) 75mg i.v. every 4 weeks without SBRT] or Arm B: T/D with immune sensitizing SBRT to one selected tumor site (9 Gy x 3 fractions). Treatment continued until progression or maximum of 2 years. Paired tumor biopsies and serial samples of peripheral blood were employed for correlative endpoints (changes in intratumoral and circulating lymphocyte repertoire and immune cytokines). The study was designed to show a promising efficacy signal in either Arm with a hypothesized median PFS of 7 months (10 patients give 87% power at 1-sided alpha of 0.1). Results: Study randomized 17 patients to Arm A (8 patients) or B (9 patients); median age of 70 yrs; females 41.2%; White, 70%, Black 17.6%. Best response in 14 overall evaluable patients was PD in 9 (64.3%), PR in 2 (14%) and SD in 3 (21.4%); median PFS of 2.76 months and OS of 4.47 months. There was no significant difference in efficacy between Arms A and B but a trend of improved PFS and OS with T/D plus SBRT (see table): Median PFS of 2.1 vs. 3.3 months [HR: 2.44 (0.75-7.93); p = 0.122] and median OS of 2.6 vs. 5.7 months [HR: 1.50 (0.45-4.99); p = 0.5068]. Observed grade ≥ 3 adverse events were: Cytopenia (4), Dyspnea (1), and endocrine disorders (3) in Arm A; diarrhea (3) and cytopenias (1) in Arm B. There was an increase in circulating CD8(+) lymphocytes on treatment versus baseline in patients with objective tumor response. Conclusions: The study did not show sufficient signal of efficacy for ICI with or without SBRT in relapsed SCLC. Detailed result of the biomarker analysis will be available at the meeting. Clinical trial information: NCT02701400. [Table: see text]
Ph1/2 study of Rova-T in combination with nivolumab (Nivo) ± ipilimumab (Ipi) for patients (pts) with 2L+ extensive-stage (ED) SCLC.
Authors: Malhotra Jyoti , Nikolinakos Petros , Leal Ticiana , Lehman Jonathan , Morgensztern Daniel , Patel Jyoti D. , Wrangle John M. , Curigliano Giuseppe , Dansin Eric , Greillier Laurent , Johnson Melissa Lynne , Ready Neal , Robinet Gilles , Lally Satwant , Wong Shekman , Avsar Emin , Valenzuela Ricardo , Scripture Charity D. , Selvaggi Giovanni , Besse Benjamin
Published: March 2020

8516

Background: Rovalpituzumab tesirine (Rova-T™) is an antibody-drug conjugate targeting DLL3, a Notch ligand expressed in SCLC but not normal tissue. Nivo ± Ipi has activity in 2L+ SCLC. Preliminary data suggest Rova-T may result in immunogenic cell death, complementing effects of Nivo ± Ipi. Methods: Eligibility: DLL3 expression (DLT phase only), progression after ≥1 line of therapy including a platinum-based regimen; ECOG 0-1; no prior immunotherapy. All pts received 0.3 mg/kg Rova-T IV on Day 1 of two 6-wk cycles. Cohort 1 (C1) also received two 3-wk cycles of 360 mg Nivo beginning on wk 4. Cohort 2 (C2) received four 3-wk cycles of 1 mg/kg Nivo and 1 mg/kg Ipi beginning on wk 4. Both cohorts then received 480 mg Nivo q4wks until PD. Primary objective: safety. Secondary: antitumor activity by RECISTv1.1, OS. Exploratory: PK. Results: As of Sep 7, 2018, 30 pts were dosed in C1 and 12 in C2. 55% were DLL3 high (≥75% DLL3 expression). 28 (67%) completed 2 planned cycles of Rova-T. 4 pts (1 in C1, 3 in C2) experienced DLTs including rash (3), pneumonitis (1) and colitis (1). C1 completed recruitment, and C2 enrollment was stopped after DLT evaluation phase. Preliminary PK showed Nivo±Ipi had no substantial effect on Rova-T exposure. Clinical trial information: NCT03026166. Conclusions: Despite activity in 2L+ ED-SCLC, Rova-T with Nivo/Ipi is not appropriate due to DLTs. Rova-T/Nivo demonstrated some durable responses; however, the safety data suggest that optimization of dose and schedule is warranted. NCT03026166.[Table: see text]
Randomized phase 2 study of maintenance pemetrexed (Pem) versus observation (Obs) for patients (pts) with malignant pleural mesothelioma (MPM) without progression after first-line chemotherapy: Cancer and Leukemia Group B (CALGB) 30901 (Alliance).
Authors: Dudek Arkadiusz Z. , Wang Xiaofei F. , Gu Lin , Stinchcombe Tom , Kratzke Robert Arthur , Vokes Everett E. , Kindler Hedy L.
Published: March 2020

8517

Background: Standard front-line chemotherapy for advanced MPM is (Pem and a platinum; optimal treatment duration is unknown. We performed a randomized phase 2 trial (NCT01085630) to determine if continuation of single-agent Pem after 4-6 cycles of Pem-platinum would improve progression-free survival (PFS). Methods: Eligible pts had histologically confirmed unresectable MPM, and performance status (PS) 0-1. Pts with at least stable disease following 4-6 cycles of Pem-platinum were stratified by first-line regimen (cis- or carboplatin) and histology (epithelioid versus other) and randomized 1:1 to Obs or continuation of Pem until progression. The primary endpoint was PFS. We assumed that Obs produced a median (m) PFS of 3 months (mo) and Pem would yield a 100% improvement in mPFS to 6 mo; 60 eligible pts (30 per arm) were to be randomized. Results: 72 pts from 30 sites registered 12/10-6/16. The study closed early due to slow accrual once 53 pts were randomized; 49 eligible pts (22 Obs, 27 Pem) are included in the efficacy analysis. Pt characteristics (Obs/Pem): age: median (range) 70 (39-85)/70 (52-87); male 68%/78%; PS 0 27%/33%; epithelioid histology 77%/70%; first-line cisplatin 27%/26%. A median of 4 cycles of Pem (range 1-33) was delivered; 22% of pts required dose modification. mPFS was 3 mo on Obs and 3.4 mo on Pem (hazard ratio (HR) 0.99; 95% CI: 0.51-1.90; p=0.9733). Median overall survival (mOS) was 11.8 mo for Obs, and 16.3 mo for Pem (HR 0.86; 95% CI 0.44-1.71; p=0.6737). Toxicities ≥ grade 3 on Pem included anemia 8%, lymphopenia 8%, neutropenia 4%, and fatigue 4%; there were no grade 5 toxicities. A higher baseline level of serum mesothelin related peptide (SMRP) was associated with worse PFS (HR 1.861, p=0.049). Baseline osteopontin did not significantly affect PFS (p=0.3630). Conclusions: Although it was well tolerated, maintenance Pem following initial Pem/platinum doublet chemotherapy does not improve PFS in MPM patients. High baseline SMRP was associated with shorter PFS. Support: U10CA180821, U10CA180882; https://acknowledgments.alliancefound.org . Clinical trial information: NCT01085630.
Clonal tumor evolution under induction chemotherapy and concurrent radiochemotherapy (RCHT) in patients with resectable stage IIIA (N2) and selected IIIb non-small cell lung cancer (NSCLC): Molecular analysis of the ESPATUE randomized phase III trial.
Authors: Hasheminasab Sayedmohammad , Knoll Maximilian , Schwager Christian , Nowrouzi Ali , Pfarr Nicole , Weichert Wilko , Rieken Stefan , Pöttgen Christoph , Gauler Thomas Christoph , Eberhardt Wilfried , Schuler Martin H. , Theegarten Dirk , Aigner Clemens , Debus Juergen , Stuschke Martin , Abdollahi Amir
Published: March 2020

8543

Background: A better understanding of molecular mechanisms governing clonal tumor evolution under RCHT is of utmost importance for development of novel biomarker and targeted therapies. We report here the first attempt to decipher RCHT induced cellular and molecular perturbation in NSCLC on an integrative multiscale level. Methods: Patients with stage III disease received induction chemotherapy with cisplatin and paclitaxel followed by concurrent RCHT with 45 Gy (1.5 Gy twice daily) and cisplatin/vinorelbine according to the ESPATUE protocol. Tumor tissue was sampled from tumor enriched areas marked by pathologists at diagnosis (biopsies, n= 23) and post RCHT during surgical resection (n=22, ESPATUE-Arm B) corresponding to 16 paired samples (PS). Transcriptome analysis (n=45, 16PS), methylome analysis (n=35, 12PS), deep whole exome sequencing (WES) including copy number variation (CNV) analysis by low-pass whole genome sequencing (WGS, n=34, 13PS) were performed. A confirmatory targeted ultra-deep NGS for 41 genes was conducted (n=20PS). Results: Similarity plots of delta transcriptome data identified three distinct clusters of tumor evolution under RCHT. Cluster 1 was highly enriched for STS (5 out of 7 Pat.) compared to cluster 3 enriched for LTS (4 out of 6), p<0.02. 146 transcripts were differentially expressed as the function of RCHT (FDR <0.05). Among them, 61 genes were upregulated and enriched for ECM and tissue remodeling (COL6A3/4, Col14A1, LAMA2, PAI1, MMP2), p53 signaling (p21, GADD45B) and stress response (FOSB, EGR1) pathways, p<0.01. 39 downregulated genes were enriched for genes attributed to cell cycle- and DDR signaling (FANCI, SLX1A) p<0.05. 4221 CpG were differentially methylated (FDR<0.05). Seven inversely regulated genes were found with SLIT3 and TBX5 being among upregulated and hypomethylated genes. WES analysis revealed patterns of tumor evolution with a range of clonal diversity. In 5/13 pairs the clonal composition remained unchanged after RCHT. Approximately 500 post RCHT exclusive mutations were found. Conclusions: Clonal, transcriptional and methylome dynamic of tumor evolution towards RCHT selection pressure is unrevealed in patients with locally advanced NSCLC. This multi-scale dynamic approach provides novel means for development of biomarker and therapeutic targets. Clinical trial information: ESPATUE.
Immune landscape of the tumor microenvironment to predict prognosis and DNA mutations in patients with lung adenocarcinoma.
Authors: Lee Sunyoung S. , Elkhanany Ahmed , Baird Andrew , Dolan Jillian , Lee Dong Chan , Park Shinyoung , Baird Stuart
Published: March 2020

8544

Background: The tumor microenvironment (TME) influences prognosis and response to therapy. The correlation between immune profiles in the TME and cancer DNA mutations is not well established. Methods: Clinical outcomes data, mRNA-seq, and DNA mutation of 480 patients (pts) with lung adenocarcinoma (LAD) were obtained from TCGA. Pts were clustered into 4 groups using unsupervised machine learning, based on mRNA expression of genes related to antigen presentation (AP) and cytolytic activity (CA): group (G) 1 with high AP and CA (52 pts); G2, high AP, low CA (82); G3, low AP, high CA (66); G4, low AP and CA (280). Analysis of the immune landscape was performed using mRNA-seq of 191 genes enriched in cellular and structural elements of TME. DNA mutations were analyzed using the R package ggpubr and correlated in G1-G4. Results: Pts in G1 have high expression of genes related to immune activation (IA) and decreased expression of immune suppression (IS) and have the best prognosis. Pts in G2 have intermediate prognosis with decreased IA genes and intermediate expression of genes related to IS and immune checkpoints. Pts in G3 have the worst prognosis with very high expression of genes related to immune checkpoints, desmoplasia, T cell co-inhibition, and IS. They also have low CD39 expression implying low cancer antigen-driven T cells. Pts in G4 have intermediate prognosis with highly depressed IA genes. Out of 70,199 non-synonymous mutations, the top 50 mutated genes in each pt group were identified: 36, 26, 31, and 17 DNA mutations were only found in G1, G2, G3, and G4 (refer to presentation). EGFR mutation was only found in G2; KRAS in G2/4; TP53 in G2/3/4. Conclusions: Our correlation analysis of mRNA-seq and DNA mutation shows that the immune landscape of TME can predict DNA mutations and prognosis. It further demonstrates a close connection between DNA mutations and changes in TME mRNA expressivity which appear to have valuable prognostication potential in the clinical setting with now widely available genomic testing.
Benefit of combining local treatment and systemic therapy for stage IV NSCLC: Results from the National Cancer Database.
Authors: Dendy Case Meaghan , Uhlig Johannes , Blasberg Justin , Boffa Daniel J. , Chiang Anne C. , Gettinger Scott N. , Kim Hyun S.
Published: March 2020

8545

Background: To determine the potential benefit of combining local and systemic therapy in stage IV non-small cell lung cancer (NSCLC). Methods: Data from stage IV NSCLC patients receiving systemic therapy alone, surgical resection and systemic therapy, or external beam radiation therapy/thermal ablation (EBRT/TA) and systemic therapy were acquired from the 2010-2015 National Cancer Database (NCDB). EBRT and TA patients were combined to enhance the power of the study. Overall survival (OS) was evaluated via multivariable Cox proportional hazards models. Comparison was made between EBRT/TA and systemic therapy alone utilizing 1:1 propensity matching analysis. A multivariable logistic regression model was used to determine variables predictive of lung cancer treatment. Significant variables (p < 0.05) were used to calculate the propensity score, and patients receiving EBRT/TA and systemic therapy were 1:1 matched using a greedy (nearest-neighbor) approach. Results: 46,964 patients from the NCDB database fulfilled inclusion criteria (surgical resection n = 1,235; EBRT/TA n = 12,456; systemic therapy alone n = 33,273.) Treatment differed across patient demographics and disease characteristics. Surgical resection demonstrated superior OS compared to EBRT/TA and systemic therapy alone, even after multivariable adjustment (compared to systemic therapy alone HR = 0.54, 95% CI: 0.50-0.58, p < 0.001; compared to EBRT/TA HR = 0.56, 95% CI: 0.52-0.60, p < 0.001). EBRT/TA treatment demonstrated superior survival compared to systemic therapy alone after accounting for confounders via propensity score matching (HR = 0.95, 95% CI: 0.93-0.98, p = 0.002). Interaction analyses indicated heterogeneous effectiveness of EBRT/TA according to patient demographics and cancer factors: the survival benefit of EBRT/TA over systemic therapy alone was especially pronounced in stage IV squamous cell carcinoma patients with limited nodal and metastatic disease (HR = 0.78, 95% CI: 0.71-0.85, p < 0.001 compared to systemic therapy alone; OS rates at 1-year = 50.9% vs. 42.4%; 2-years = 26.6% vs. 19.8%; 3-years = 17.2% vs. 10.1%). Conclusions: Stage IV NSCLC patients who received EBRT/TA or surgical resection in addition to systemic therapy demonstrated prolonged survival. EBRT/TA in combination with systemic therapy should be preferred in selected patients that are ineligible surgical candidates.
Malignant pleural mesothelioma (MPM) genomic profile in the randomized phase II RAMES Study.
Authors: Pagano Maria , Gnoni Roberta , Bonelli Candida , Zanelli Francesca , Garassino Marina Chiara , Ceresoli Giovanni Luca , Pasello Giulia , Tiseo Marcello , Soto Parra Hector J. , Grosso Federica , Zucali Paolo Andrea , Torricelli Federica , Pinto Carmine
Published: March 2020

8547

Background: Since MPM is an uncommon neoplasia, its rarity has limited available data on molecular drivers. Methods: RAMES study evaluated the second-line efficacy of gemcitabine/ramucirumab treatment vs. gemcitabine/placebo. From December 2016 to July 2018 (end of enrolment), 164 patients (pts) were admitted to this study, which involved the collection of tumor samples - with diagnosis - to evaluate 34 genes by NGS (ACTB, ACTG1, ACTG2, ACTR1A, BAP1,CDH8, CDK4, CDKN2A, CDKN2B, COL3A1, COL5A2, CUL1, DHFR, GOT1, KDR, KIT, MXRA5, NF2, NFRKB, NKX6,-2, NOD2, PCBD2, PDZK1IP1, PIK3CA, PIK3CB, PSMD13, RAPGEF6, RDX, SETDB1, TAOK1, TP53,TXNRD1, UQCRC1, XRCC6). We reported the results of the first 87 pts (54%): hystotype was epithelioid in 70 pts (80%), biphasic in 14 pts (16%) and sarcomatoid in 3 pts (4%). Median age was 63 years (range 45-81). 70 pts were male (80%) and 17 pts were female (20%). In the present analysis, we included 55 pts in stage III (63%), 26 pts in stage IV (30%) and 6 pts whose stage was unknown. Median first-line PFS platinum/pemetrexed therapy was for 5.75 months (I.C. 95% 4.75-6.76). PFS was ≤6 months for 40 pts (49%), and 6 months for 41 pts (51%). Results: 187 functional somatic mutations were identified. Genomic alterations/patient were 1 gene in 29 pts (33%), 3 genes in 18 pts (21%) and ≥5 genes in 2 pts (2%). The most frequent somatic mutations were RDX in 35 pts (40%), MXRA5 in 20 pts (23%), BAP1 in 13 pts (15%) and ACTG 1 in 9 pts (11%). When patients were collated by stage, the most frequent mutations were: MXRA5 in 16 pts in stage III (29%), BAP1 in 5 pts in stage IV (19%) and RDX in 16 pts in stage IV (62%). The percentage of somatic mutations in patients with PFS as first-line chemotherapy for ≤6 and >6 months was 2.2 and 1.6 (p=0.032), respectively. The most frequent mutations/patient for ≤6 and >6 months PFS were: RDX in 14 pts (35%) with PFS < 6, RDX in 19 pts (46%) with PFS >6 and MXRA5 in 11 pts (27%) with PFS >6. Conclusions: This preliminary data suggests a possible role that a genetic signature may play in distinguishing MPM with different clinical-pathological features. The results are expected to be clarified further in the second step of the study, which is ongoing. Clinical trial information: 2016-001132-36.
Outcome of neo-adjuvant chemotherapy in 225 surgical candidates with malignant pleural mesothelioma.
Authors: Kondo Nobuyuki , Nakamichi Toru , Nakamura Akifumi , Kuroda Ayumi , Hashimoto Masaki , Takuwa Teruhisa , Matsumoto Seiji , Okumura Yoshitomo , Kuribayashi Kozo , Kijima Takashi , Tsujimura Tohru , Hasegawa Seiki
Published: March 2020

8548

Background: Since any surgery for malignant pleural mesothelioma (MPM) are cytoreductive, effective chemotherapy is a prerequisite for surgery. In this context, we give neo-adjuvant chemotherapy (NAC) to all surgical candidates. Methods: Hyogo College of Medicine MPM Surgery Program mandates all surgical candidates to receive NAC, and only patients with stable disease (SD) or better response proceeds to surgery. The program comprised NAC followed by extrapleural pneumonectomy (EPP) and hemithoracic radiation until 2012, and NAC followed by pleurectomy/decortication (P/D) and postoperative chemotherapy thereafter. Eligibility criteria are histologically confirmed non-sarcomatoid MPM, clinically resectable stage (T1-3N0-1M0), performance status 0–1, and no major comorbidity. Results: From December 2006 to December 2018, 225 patients were enrolled. Of 225, 24 patients (10.7%, Group A) did not proceed to surgery because of progressive disease (n=23) or serious adverse events (n=2). Of the remaining 201 patients with partial response (n=38, 16.9%) or stable disease (n=163, 72.4%), 19 refused surgery (Group B), 16 received exploratory thoracotomy (Group C), and 165 completed surgery (Group D, EPP58, P/D107). Surgical mortality rates at 30 and 90 days were 1.1% (n=2) and 2.8% (n=5), and surgical morbidity (≧grade 3) was 26.0% (n=47). Median survival time and survival rates of each group were shown in the table. Briefly, 2-yr survival competed among Group B,C and D, whereas 5-yr survival rapidly dropped in Group B and C. Conclusions: Approximately 90% of MPM patients with surgical intent successfully underwent either of EPP or P/D after effective chemotherapy with acceptable surgical mortality and morbidity. Comparison of patients who refused or accepted surgery suggested that surgery contributed to long-term survival. [Table: see text]
Phase 2 study of tremelimumab plus durvalumab for previously-treated malignant pleural mesothelioma (MPM).
Authors: Venkatraman Deepti , Anderson Adrienne , Digumarthy Subba , Lizotte Patrick H. , Awad Mark M.
Published: March 2020

8549

Background: Treatment options are limited for patients (pts) with MPM who experience disease progression after first-line pemetrexed-based chemotherapy. This study was designed to explore the activity of combined CTLA-4 + PD-L1 immune checkpoint inhibition using tremelimumab plus durvalumab in previously-treated MPM. Methods: We conducted a phase 2 study of tremelimumab 75 mg plus durvalumab 1500 mg administered intravenously every 4 weeks for four cycles followed by durvalumab maintenance every 4 weeks. Eligible pts had previously received pemetrexed-based platinum doublet chemotherapy and had measurable disease using modified RECIST criteria for mesothelioma. The primary endpoint was overall response rate (ORR) and secondary endpoints were progression-free survival (PFS), overall survival (OS), and duration of response (DoR) as well as safety and tolerability of this combination. A Simon two-stage design was employed to enroll up to 40 patients if 4 or more responses were observed among the first 19 study patients. Pre-treatment, on-treatment, and optional post-progression biopsies underwent flow cytometric immunoprofiling for correlative studies. Results: Among 19 pts enrolled in this study, the best objective response was a confirmed partial response in one patient (5%), stable disease in 9 pts (47%), progressive disease in 8 pts (42%), and not evaluable in one patient. At a median follow-up of 7.1 months, the median PFS was 2.8 months (95% CI 2.04-5.72), and the median OS was 7.8 months (95% CI 6.24-not reached). Of 17 PD-L1 evaluable cases, 10 (59%) were PD-L1 negative, and 7 (41%) had a PD-L1 tumor proportion score of ≥1%. Treatment was generally well-tolerated and there were no treatment-related study discontinuations or deaths. Flow cytometric immunologic changes over the course of treatment associated with disease control will be presented. Conclusions: Tremelimumab + durvalumab was well-tolerated in unselected pts with previously-treated MPM. This study did not meet its primary endpoint. Additional strategies are necessary to develop novel immunotherapeutics and biomarkers of response in MPM. Clinical trial information: NCT03075527.
Impact of large-scale nationwide genomic screening project for small cell lung cancer (LC-SCRUM-Japan).
Authors: Furuya Naoki , Umemura Shigeki , Udagawa Hibiki , Shimokawaji Tadasuke , Seto Takashi , Daga Haruko , Tsuruno Kosuke , Shingyoji Masato , Hara Satoshi , Murakami Haruyasu , Yokouchi Hiroshi , Matsumoto Shingo , Goto Koichi
Published: March 2020

8559

Background: A variety of genetic analyses have been performed in small cell lung cancer (SCLC), however the clinical relevance of them remains unclear. We prospectively analyzed clinical samples of small-cell lung cancer using a nationwide genomic screening project (LC-SCRUM-Japan). Methods: Submitted tumor samples were subjected to a next-generation sequencing (NGS) system, Oncomine™ Comprehensive Assay, enabling the simultaneous analysis of 143 (ver.1) or 161 (ver.3) cancer-related genes. Results: From July 2015 to January 2019, 707 SCLC patients had been enrolled. The median age was 68 years. 77% were male and 94% were smokers. Among 588 samples completed analysis, we identified high prevalence of inactivating TP53/RB1 mutations in 426 (72%) /194 (33%) of cases, respectively. MYC/MYCL1/MYCN amplifications were detected in 21 (4%) /30 (5%) /9 (2%) of cases, respectively. This NGS analysis also showed that 32 (5%) of cases had well-known genetic alterations in receptor tyrosine kinase genes: 9 EGFR mutations, 9 KRAS mutations and 14 FGFR1 copy number gains. Mutations in the PI3K pathway were detected in 44 (7%) of the tumors. Among them, 8 cases enrolled in the investigator-initiated phase II study of gedatolisib (UMIN 000020585). Survival data was available in 463 patients receiving platinum-based chemotherapy. Multivariate analysis revealed that the presence of PIK3CA mutation (HR; 2.56; 95% CI 1.19 – 5.52; p = 0.016) and MYCN amplification (HR; 4.36; 95% CI 1.91 – 9.97; p < 0.001) were significantly associated with unfavorable survival. The frequency of amplifications in MYC family genes was higher in the samples obtained ≥ 90 days after the first-line platinum-based chemotherapy (18.1%) than in those < 90 days (8.1%, p = 0.01), suggesting MYC family amplification as one of the resistance mechanisms. Conclusions: This large-scale nationwide screening system is helpful for identifying therapeutically relevant genetic alterations, prognostic prediction, and exploring resistance mechanism in SCLC. Updated screening results will be presented at the 2019 ASCO Annual Meeting. Clinical trial information: UMIN000018656.
RELAY: A multinational, double-blind, randomized Phase 3 study of erlotinib (ERL) in combination with ramucirumab (RAM) or placebo (PL) in previously untreated patients with epidermal growth factor receptor mutation-positive (EGFRm) metastatic non-small cell lung cancer (NSCLC).
Authors: Nakagawa Kazuhiko , Garon Edward B. , Seto Takashi , Nishio Makoto , Ponce Aix Santiago , Chiu Chao-Hua , Park Keunchil , Novello Silvia , Nadal Ernest , Imamura Fumio , Yoh Kiyotaka , Shih Jin-Yuan , Au Kwok Hung , Moro-Sibilot Denis , Enatsu Sotaro , Zimmermann Annamaria H. , Frimodt-Moller Bente , Visseren Grul Carla M. , Reck Martin
Published: March 2020

9000

Background: Dual blockade of EGFR and VEGFR pathways in EGFRm NSCLC augments anti-tumor efficacy versus (v) EGFR inhibition alone. RELAY (NCT02411448) evaluated efficacy and safety of ERL, an EGFR TKI standard-of-care, plus RAM, a human IgG1 VEGFR2 antagonist, or PL in 1L EGFRm metastatic NSCLC. Methods: Eligibility included untreated metastatic NSCLC pts with Exon 19 deletion (del) or L858R and no CNS metastasis. Randomized (1:1) pts received ERL (150 mg/day) + RAM (10 mg/kg q2w) or ERL + PL, stratified by gender, geographic region (East Asia v other), EGFRm type (Ex19del v L858R) and EGFR testing method (Therascreen/Cobas v other). The primary endpoint was Investigator assessed progression free survival (PFS). Other objectives included ORR, DoR, PFS2, OS, safety, and plasma T790M mutation (Guardant NGS). Results: 449 pts were randomized characteristics were balanced between treatment arms: Asian 77%, Females 63%, Ex19del 54%. RAM + ERL significantly prolonged PFS, DoR, and PFS2 (Table). Grade >=3 TEAEs were greater with RAM (72%) v PL (54%), largely driven by hypertension (24 v 5%, no Gr4); with 1 treatment related on study death (hemothorax) in RAM v 0 PL. EGFR T790M+ rates at progression are forthcoming. Conclusion: RAM + ERL led to superior PFS in 1L EGFRm metastatic NSCLC. Safety was consistent with the established safety profiles of the individual compounds. Clinical trial information: NCT02411448. [Table: see text]
Capmatinib (INC280) in METΔex14-mutated advanced non-small cell lung cancer (NSCLC): Efficacy data from the phase II GEOMETRY mono-1 study.
Authors: Wolf Juergen , Seto Takashi , Han Ji-Youn , Reguart Noemi , Garon Edward B. , Groen Harry J.M. , Tan Daniel Shao-Weng , Hida Toyoaki , De Jonge Maja J. , Orlov Sergey V. , Smit Egbert F. , Souquet Pierre Jean , Vansteenkiste Johan F. , Giovannini Monica , Le Mouhaer Sylvie , Robeva Anna , Waldron-Lynch Maeve , Heist Rebecca Suk
Published: March 2020

9004

Background: Capmatinib is a highly potent and selective MET inhibitor. Previous data of GEOMETRY mono-1 study showed a clinically meaningful overall response rate (ORR) and manageable toxicity profile in patients (pts) with METΔex14–mutated NSCLC who received 1–2 prior lines of treatment (tx) (Cohort 4) and in particular a high ORR in tx-naïve pts (Cohort 5b). Here we report the results in METΔex14–mutated NSCLC for duration of response (DOR) and progression-free survival (PFS) as well as the updated results for ORR. Methods: GEOMETRY mono-1 is a phase 2, multi-cohort, multicenter study evaluating capmatinib in pts with METΔex14-mutated or MET-amplified advanced NSCLC across 6 cohorts. Pts (≥18 yrs) with ECOG PS 0–1, ALK and EGFR wt, and stage IIIB/IV NSCLC were eligible. Pts with METΔex14 mutation (centrally confirmed) were assigned (regardless of MET amplification status/gene copy number) to Cohorts 4 and 5b and received capmatinib tablets 400 mg BID. Primary endpoint was ORR by Blinded Independent Review Committee (BIRC) per RECIST v1.1. Key secondary endpoint was DOR by BIRC. Results: As of Nov 08, 2018, 97 pts with METΔex14-mutated NSCLC (Cohort 4: 69 pts; Cohort 5b: 28 pts) were evaluable for efficacy. ORR (95% CI) by BIRC was 39.1% (27.6-51.6) in Cohort 4 and 71.4% (51.3-86.8) in Cohort 5b. While still immature at the time of this analysis, data on durability are promising: median DOR (95% CI) by BIRC was 9.72 (4.27-11.14) and 8.41 (5.55-NE) mo for Cohorts 4 and 5b, respectively; median PFS (95% CI) by BIRC was 5.42 (4.17-6.97) and 9.13 (5.52-13.86) mo for Cohorts 4 and 5b, respectively. Safety profile remains favourable and unchanged. Most common AEs (≥25% all grades) across all cohorts (n = 315), were peripheral edema (49.2%), nausea (43.2%), and vomiting (28.3%); majority of the AEs were grade 1/2. Final efficacy analysis (12-mo f-u on DOR) including biomarker data will be presented during meeting. Conclusions: These data confirm capmatinib to be a promising new treatment option for pts with METΔex14-mutated advanced NSCLC regardless of the line of therapy with deep and durable responses and manageable toxicity profile. Clinical trial information: NCT02414139.
Blood tumor mutational burden (bTMB) and tumor PD-L1 as predictive biomarkers of survival in MYSTIC: First-line durvalumab (D) ± tremelimumab (T) versus chemotherapy (CT) in metastatic (m) NSCLC.
Authors: Rizvi Naiyer A. , Cho Byoung Chul , Reinmuth Niels , Lee Ki Hyeong , Luft Alexander , Ahn Myung-Ju , van den Heuvel Michel , Dols Manuel Cobo , Vicente David , Smolin Alexey , Moiseyenko Vladimir , Antonia Scott Joseph , Nakagawa Kazuhiko , Goldberg Sarah B. , Kim Edward S. , Walker Jill , Raja Rajiv , Liu Feng , Scheuring Urban J. , Peters Solange
Published: March 2020

9016

Background: MYSTIC, an open-label, Ph3 trial of first-line D (anti-PD-L1) ± T (anti-CTLA-4) vs platinum-based CT, showed an improvement in OS with D vs CT in pts with tumor cell PD-L1 expression ≥25% (PD-L1 TC ≥25%; HR 0.76 [97.54% CI 0.56–1.02], p = 0.036). Exploratory analyses showed bTMB was a predictive biomarker for OS with D±T vs CT. We report further exploratory analyses of OS according to PD-L1 and bTMB. Methods: Immunotherapy/CT-naïve pts with mNSCLC were randomized (1:1:1) to D, D+T or CT. bTMB levels (mut/Mb) were evaluated with the GuardantOMNI platform (Guardant Health), and PD-L1 TC expression with the VENTANA PD-L1 (SP263) IHC assay. Results: D improved OS vs CT in pts with PD-L1 TC ≥25% across bTMB levels (PD-L1 TC ≥25%/bTMB≥20 HR 0.79 [95% CI 0.45, 1.39]; PD-L1 TC ≥25%/bTMB < 20 HR 0.64 [95% CI 0.45, 0.90]). In contrast, D+T improved OS vs CT in pts with bTMB≥20 across different PD-L1 TC expression levels (Table; PD-L1 TC ≥25%/bTMB≥20 HR 0.44 [95% CI 0.23, 0.84]; PD-L1 TC < 1%/bTMB≥20 HR 0.42 [95% CI 0.17, 0.97]). Additional cutoffs and outcomes in subgroups defined by both biomarkers will be presented. Conclusions: These exploratory analyses from MYSTIC support PD-L1 TC expression as an appropriate predictive biomarker for OS with D vs CT, while suggesting bTMB as a predictive biomarker for OS with D+T in mNSCLC. These biomarkers appear to be independent and both may be important for mNSCLC treatment decisions. Interpretation of these data may be limited by small sample sizes; further investigations are warranted. Clinical trial information: NCT02453282. [Table: see text]