Adverse Events In Pts Research Articles

Abstract CT218: Flat-dose nivolumab (NIVO) as second-line (2L) treatment (tx) for Asian patients (pts) with advanced non-small cell lung cancer (NSCLC): CheckMate 870

Abstract Introduction: Weight-based dosing of NIVO over 60 minutes is approved in China for 2L NSCLC tx; however, more convenient flat dosing over a shorter infusion time has yet to be fully assessed in Asian pts. In addition, the benefit of NIVO in Asian pts with NSCLC and EGFR or ALK mutations, or hepatitis B virus (HBV) infection, has yet to be evaluated. CheckMate 870 (NCT03195491) is a phase 3b trial assessing a flat dose of NIVO infused over 30 minutes for previously treated NSCLC in Asian pts. Methods: Eligible pts had stage IIIB/IV NSCLC with 1-2 prior systemic tx and ECOG PS 0-1. Pts with HBV had to have a viral titer < 500 IU/mL. Pts received NIVO 240 mg over a 30-minute infusion, Q2W, until progression, unacceptable toxicity, or for ≤ 2 years. The primary endpoint was high-grade (G; G3-5) tx-related select adverse events (AEs) in non-HBV infected pts. Results: Of 400 treated pts, 394 were from China; 34 pts had EGFR mutations, and 383 were non-HBV infected. Median (range) age was 61 (27-80) y and 78% were male. Clinical data cutoff was May 30, 2019, median duration of tx was 3 mo. The most common categories for G3-4 tx-related select AEs in non-HBV infected pts were hepatic (2%), skin (2%), pulmonary and endocrine (1% each). There were no G5 tx-related select AEs reported in non-HBV infected pts. No G3-5 tx-related select AEs were reported in HBV-infected pts (n = 17). There were 2 tx-related deaths, due to myocarditis (non-HBV infected pt) and lung infection (HBV-infected pt). G3-4 treatment-related AEs (TRAEs) were reported in 13% of all treated pts, and 2% had G3-4 TRAEs leading to discontinuation. Overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) are shown in the Table. Conclusions: Flat-dosing of NIVO 240 mg over 30 minutes was well tolerated and active in a predominantly Chinese pt population with previously treated NSCLC, including pts with EGFR mutations or HBV infection. These results are similar to pivotal trials of NIVO for previously treated NSCLC. No new safety signals were reported. Table.OS, PFS, and ORR among subgroups in CheckMate 870OSMedian PFSa,mo (95% CI)ORRaMedian,mo (95% CI)6-mo rates (%)n (%)All treated (N = 400)NR (11.7–NR)753.7 (3.1–3.9)62 (16)HBV statusbNo HBV (n = 383)NR (11.6–NR)753.7 (3.1–3.9)59 (15)With HBV (n = 17)NR (10.0–NR)822.0 (1.6–NR)3 (18)EGFR mutation statuscPositive (n = 34)NR (9.6–NR)851.9 (1.7–3.6)5 (15)Not detected (n = 261)NR (11.4–NR)743.6 (2.7–3.9)37 (14)Tumor histologyNon-squamous (n = 264)NR (11.5–NR)763.4 (2.1–3.8)37 (14)Squamous (n = 136)NR (10.5–NR)724.7 (3.1–5.6)25 (18)Tumor PD-L1 expressiond≥ 1% (n = 169)NR (11.7–NR)745.4 (3.7–5.6)42 (25)< 1% (n = 174)13.2 (10.9–NR)773.1 (2.0–3.8)15 (9)Minimum follow up was 10 mo.aPer investigator;bHBV status is a protocol pre-specified enrollment cohort; the number of pts with HBV entering the study was capped at 60 (15% of the total population);cThe number of pts entering the study with EGFR mutations was capped at 40;dOf all treated patients, 343 (86%) were evaluable for tumor PD-L1 expression level. NR, not reached. Citation Format: Shun Lu, Ying Cheng, Jianying Zhou, Mengzhao Wang, Jun Zhao, Gongyan Chen, Baocheng Wang, Jifeng Feng, Zhiyong Ma, Lin Wu, Changli Wang, Shucai Zhang, Kewei Ma, Jun Liang, Yong Song, Jie Wang, Yi-Long Wu, Ang Li, Ting Ma, Jianhua Chang. Flat-dose nivolumab (NIVO) as second-line (2L) treatment (tx) for Asian patients (pts) with advanced non-small cell lung cancer (NSCLC): CheckMate 870 [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT218.

A prospective pilot study of pharmacogenetic-based dosing of 5-fluouracil (5-FU) and irinotecan (IRI) in patients (pts) with gastrointestinal (GI) malignancies.

e16138 Background: 5-FU and IRI are core components of chemotherapies for GI malignancies. Previous studies have shown that mutations in DPYP and TYMS predispose the pts to 5-FU toxicities. Mutations in UGT1A1 predispose pts to increased IRI toxicities. Retrospective data suggest that these mutations may have implications in selecting dosage and/or schedule of 5-FU and IRI. We present here a prospective study of upfront pharmacogenetic testing with tailored dose of respective drugs in pts with these mutations. Methods: Pts with GI malignancies were tested for DPYD, TYMS and UGT1A1 mutations before initiating 5-FU and/or IRI. Mutation analyses were performed at Quest Diagnostics Nichols Institute. Pts were dosed at 50% if DPYD was abnormal and 25% dose reduction if indicated by TYMS or UGT1A1 * 28 (homozygous) abnormality. Adverse events (AEs) were graded according to CTCAE v.5.0. We compared AEs to our previously collected data in DPYD, TYMS deficient pts who underwent genetic testing due to toxicity to 5-FU. Results: Of 226 pts screened, 5 pts had DPYP mutations with genotypes (3: c.1905+1G/A; 1: c.2846A/T; 1: c.557A/G). TYMS mutations were identified in 24 pts. For 3'-UTR, distributions were: intermediate expression genotype 4: INS/DEL, low expression genotype 5: DEL/DEL. For 5'TSER, distributions were: low expression genotypes (6:2R/2R; 3:2R/3RC; 4: 3RC/3RC) and high expression genotypes (2: 2R/3RG, 2: 3RG/3RC, 1: 3RG/3RG). UGT1A1*28 mutation was identified in 53 pts – 19 homozygous and 34 heterozygous. No grade ≥3 neutropenia was observed with reduced dose of IRI in UGT1A 1 variant pts compared to 33% reported in pts not tested. For TYMS and DPYD variants, no grade ≥3 AEs were seen. Comparison of AEs in pts with post treatment genetic testing is listed in Table. Conclusions: Pharmacogenetic based dosing of 5-FU and IRI led to less frequent, less severe toxicities and no death related to AEs was observed in our pts. This can improve pts’ quality of life and lessen economic burden of managing severe AEs. Currently, there are no formal guidelines regarding testing for DPYD, TYMS and UGT1A1. Although non-randomized, this study advocates for systemic screening of pharmacogenetic testing in pts with GI malignancies. [Table: see text]

Cost of adverse events (AEs) with second-line (2L) immuno-oncology agents (IO) and chemotherapy (CHEMO) in advanced non-small cell lung cancer (aNSCLC) in the real-world

Abstract Background Randomized clinical trials in aNSCLC demonstrated that 2L IO prolonged overall survival and lowered AE rates compared with 2L CHEMO. However, real-world (RW) evidence from clinical practice is limited, and the potential cost benefits of lower AE rates have not been examined. Here, we report average costs per patient (pt) associated with grade 3-4 AEs during 2L treatment with IO and CHEMO in aNSCLC from a US payer perspective. Methods AEs in pts treated with 2L IO or CHEMO for aNSCLC (Mar 2015-Dec 2017) were abstracted from US electronic health records in COTA’s database. Hospitalization costs for each ICD-10 code associated with the management of a grade 3-4 AE during treatment were estimated using the Healthcare Cost and Utilization Project (HCUP) National Inpatient Sample 2017 dataset. Results Of 596 pts in the analysis, 276 received IO (199 nivolumab) and 320 received CHEMO. The proportion of IO- vs CHEMO-treated pts was higher for pts aged Table . 74P Average cost of grade 3-4 AEs per patient (Pt) IO (n = 276) CHEMO (n = 320) n Average Cost per Pt n Average Cost per Pt 107 $6,877 114 $17,203 ≥65 y 169 $11,033 206 $14,832 Male 150 $4,417 150 $10,460 Female 126 $15,379 170 $20,279 White 176 $9,265 233 $17,547 Former/current smoker 255 $7,973 265 $17,292 History of brain metastasis 101 $9,760 117 $20,219 No history of brain metastasis 175 $9,226 203 $13,059 Squamous 43 $3,096 53 $18,749 Nonsquamous 233 $10,634 267 $15,181 Conclusion In this RW analysis in pts with aNSCLC, 2L IO was associated with lower costs for the management of grade 3-4 AEs than 2L CHEMO. Editorial acknowledgement Writing assistance was provided by Roland Tacke, PhD, of Evidence Scientific Solutions Inc, funded by Bristol-Myers Squibb. Legal entity responsible for the study Bristol-Myers Squibb. Funding Bristol-Myers Squibb. Disclosure C.K. Wang: Shareholder / Stockholder / Stock options, Full / Part-time employment: COTA. K. Gupte-Singh: Full / Part-time employment: Bristol-Myers Squibb. A.J. Belli: Shareholder / Stockholder / Stock options, Full / Part-time employment: COTA. D.C. Lane: Shareholder / Stockholder / Stock options, Was an employee at Bristol-Myers Squibb while this work was done and recently joined COTA: Bristol-Myers Squibb. A. Lakshmanan: Shareholder / Stockholder / Stock options, Full / Part-time employment: COTA. A.D. Norden: Shareholder / Stockholder / Stock options, Full / Part-time employment: COTA.

A Randomized Phase 2 Study Comparing Acalabrutinib with or without Obinutuzumab in the Treatment of Early Stage High Risk Patients with Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL)

A Randomized Phase 2 Study Comparing Acalabrutinib with or without Obinutuzumab in the Treatment of Early Stage High Risk Patients with Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL)

A Phase 1b/2 Study of Chidamide Combined with CHOP in Previously Untreated Patients with Peripheral T-Cell Lymphoma (PTCL)

Background: CHOP is widely used for untreated PTCL patients (pts), although it has limited efficacy. Chidamide is an oral benzamide class of HDAC inhibitor with subtype specificity in inhibition of HDAC 1, 2, 3 and 10, approved in China for relapsed or refractory PTCL at 30 mg twice per week. A Phase 1b/2 study (NCT02809573) is evaluating the safety, pharmacokinetics and preliminary efficacy of chidamide in combination with CHOP (CHOP-chidamide) in the first-line treatment for PTCL pts. Results from the study are reported. Methods: This open-label, multicenter study enrolled pts (18~65 years) with previously untreated PTCL. Pts received one dose chidamide as the run-in treatment, and 4 days later the induction treatment of CHOP (6 cycles [each 21 days]) with chidamide on days 1, 4, 8 and 11. Pts who achieved a complete response or unconfirmed complete response (CR/CRu) at end of induction (EOI) received consolidation treatment with chidamide on days 1, 4, 8 and 11 every 21 days for 24 months maximum. A 3+3 design was employed in the chidamide dose-escalation stage with the starting dose at 20 mg. The first 21-day treatment cycle was a dose-limiting toxicities (DLTs) observation period (phase 1b; safety and pharmacokinetics), followed by a phase 2 cohort expansion stage. For pharmacokinetic (PK) evaluation, blood samples were collected at pre-dose and 1,2,4,8,12,24,48 and 72 h after the first dose of chidamide in the run-in period and in the first cycle of CHOP-chidamide. Primary endpoints were safety and tolerability of chidamide in combination with CHOP assessed by the incidence of adverse events (AEs) in both phase 1b and 2 and as DLTs during phase 1b. Secondary endpoint was efficacy as determined by the investigator. Results: Between Nov 15, 2016 and Aug 29, 2018, 30 pts were enrolled and received treatment. Pt demographics and disease characteristics are shown in Table 1. Fifteen pts were in the dose-escalation cohort and 15 in the expansion cohort (Table 2).One DLT with grade (Gr) 3 febrile neutropenia occurred in the first three enrolled pts in the 20 mg group, and 1 DLT with Gr 3 vascular access complication in the 35 mg group. Also, in the 35 mg group, 1 pt occurred Gr 2 neutropenia with sustained temperature >38℃, and the dose-escalation was stopped at this dose level. Serious AEs occurred in 7 (23.3%) of 30 pts during the combination treatment, including neutropenia (3 [10%]), leukopenia (2 [6.7%]), interstitial pneumonia (2 [6.7%]), thrombocytopenia (1 [3.3%]), febrile neutropenia (1 [3.3%]), pneumonia (1 [3.3%]), hyponatremia (1 [3.3%]), appendicitis (1 [3.3%]) and vascular access complication (1 [3.3%]). The most common (≥10%) Gr 3 or 4 treatment-related AEs were leukopenia (90%), neutropenia (83.3%), lymphocytopenia (40%), vomiting (13.3%), thrombocytopenia (10%) and febrile neutropenia (10%).No fatal AEs were reported. There were no apparently remarkable differences in frequency and intensity of AEs in pts between chidamide dose groups of 20 mg, 25 mg and 30 mg. Among 28 pts evaluable for response, 13 pts (46.4%) had a CR/CRu, 10 pts (35.7%) had a partial response, 1 pt (3.6%) had stable disease, and 4 pts (14.3%) had progressive disease (Table 3). Fifteen pts entered the consolidation phase (13 pts with CR/CRu, 1 pt with PR, 1 pt not evaluable), and the median treatment time was 189 days (35, 483). There was no AE leading to consolidation discontinuation. Progression-free survival (PFS) and overall survival (OS) at 12 months were 54.3% and 100%. At the data cutoff (Jan 8, 2019), median PFS was 14 months and median OS was not achieved. A total of 16 pts were evaluated in the PK analysis. Over the dose range from 20 to 35 mg, a linear and dose-dependent PK profile of chidamide was characterized in both monotherapy and combination treatment. In addition, co-administration of chidamide and CHOP did not significantly affect the plasma exposure of chidamide, with geometric mean ratio (combination vs monotherapy) values for Cmax and AUC were 97.6% (73.6%, 129.2%) and 97.9% (78.4%, 122.2%), respectively. Conclusions: The combination of 20mg to 30 mg chidamide to a standard 3-week cycle of CHOP chemotherapy showed a manageable safety profile and favourable antitumour activity in pts with previously untreated PTCL. This combination could be further explored in comparison to CHOP alone in a randomized trial. CHOP-chidamide did not significantly alter the chidamide pharmacokinetics. Disclosures No relevant conflicts of interest to declare. OffLabel Disclosure: Chidamideis an oral benzamide class of HDAC inhibitor with subtype specificity in inhibition of HDAC1, 2, 3 and 10, approved in China for relapsed or refractory PTCL at 30 mg twice per week. This Phase 1b/2 study (NCT02809573) is evaluating the safety, pharmacokinetics and preliminary efficacy of chidamide in previously untreated PTCL patients.

Cirmtuzumab, a ROR1 Targeted Mab, Reverses Cancer Stemness, and Its Combination with Ibrutinib Is Safe and Effective: Planned Analysis of the Cirll Phase 1/2 Trial for CLL and MCL

Cirmtuzumab (Cirm) is a novel humanized mAb specific for ROR1, which is expressed primarily during embryogenesis and in many cancers, including chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL), but generally not on normal post-partum tissues. A Phase I study involving patients (pts) with CLL showed Cirm was safe and effective in blocking ROR1-signaling and in reversing cancer-cell-stemness transcriptome signatures associated with aggressive malignancies (Choi et al., Cell Stem Cell, 2018; Malta et al., Cell, 2018). Cirm also was shown to block Wnt5a-ROR1 survival-signaling in CLL or MCL cells of pts taking ibrutinib (Ibr), and had synergistic anti-tumor activity with Ibr in animal models (Yu et al., Leukemia, 2016; Yu et al., Oncotarget, 2018), forming the rationale for testing Cirm+Ibr in pts with CLL or MCL in the CIRLL study (Cirmtuzumab plus Ibrutinib in Relapsed Leukemia and Lymphoma), a 3-part clinical trial: Part 1 (P1)evaluated increasing doses of Cirm with Ibr for safety and to determine the recommended dose regimen (RDR); Part 2(P2) evaluated pts treated with the RDR (Ibr plus Cirm at 600 mg IV on day 1, 14, 28 and then q28 days thereafter). For P1 and P2, we treated 34 pts with CLL (23 with relapsed/refractory (R/R) CLL) and 6 pts with R/R MCL who required therapy. Part 3(P3) will randomize patients to receive Cirm+Ibr versus Ibr alone based on the efficacy analysis of data collected in P1 and P2. We did not observe any serious adverse events in pts treated in P2, which had an overall safety profile consistent with that of ibr alone; no new adverse events were attributed to Cirm. Correlative studies showed that Cirm at the RDR suppressed expression of NF-kB-target genes induced by ROR1-signaling and reversed cancer-cell-stemness transcriptome signatures in the CLL cells of treated pts. Of 6 CLL pts treated at or below the RDR with ≥24 wks. of evaluable data, the overall response rate (ORR) was 100%, including 1 patient with a confirmed complete response (CR) with clearance of CLL in the marrow by histology. Another 15 CLL pts with ≥12 wks. of evaluable data had an ORR of 87%. No pt with CLL had progressive disease (PD) on therapy. Of the 6 heavily-pre-treated MCL pts with ≥12 wks. of evaluable data, 2 had a CR (one sustained for 9+ mos.), 2 had a partial response (PR), and 2 had PD. The 2 pts with PD had aggressive disease progression prior to therapy that subsided for 3 to 6 mos. on therapy. Taken together, these data demonstrate that Cirm+Ibr is biologically active, well tolerated, safe, and effective. Moreover, the data from the CLL pts in P1 and P2 of the study support initiation of P3 of the study, which will allow for comparison of the activity of Cirm+Ibr versus Ibr alone for patients with CLL. Disclosures Choi: Abbvie: Consultancy, Research Funding, Speakers Bureau; Oncternal: Research Funding; Gilead: Consultancy, Speakers Bureau; Rigel: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding, Speakers Bureau; Genentech: Consultancy, Speakers Bureau. Siddiqi:TG Therapeutics: Research Funding; Celgene: Research Funding; BeiGene: Research Funding; Seattle Genetics: Speakers Bureau; Juno Therapeutics: Consultancy, Other: travel support, Research Funding; PCYC: Consultancy, Research Funding, Speakers Bureau; AstraZeneca: Consultancy, Research Funding, Speakers Bureau; Janssen: Speakers Bureau; Kite, A Gilead Company: Research Funding. Wierda:Genentech: Research Funding; Pharmacyclics LLC: Research Funding; Acerta Pharma Inc: Research Funding; Xencor: Research Funding; Gilead Sciences: Research Funding; Loxo Oncology Inc.: Research Funding; Juno Therapeutics: Research Funding; Cyclcel: Research Funding; KITE pharma: Research Funding; Oncternal Therapeutics Inc.: Research Funding; Sunesis: Research Funding; Miragen: Research Funding; Janssen: Research Funding; AbbVie: Research Funding; GSK/Novartis: Research Funding. Barrientos:AbbVie: Consultancy, Research Funding; Bayer: Consultancy; Genentech: Consultancy; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; Sandoz: Consultancy; Oncternal Therapeutics: Research Funding; Janssen: Honoraria; AstraZeneca: Consultancy; Gilead: Consultancy. Lamanna:Celgene: Consultancy; Infinity/ Verastem: Research Funding; Ming: Research Funding; TG Therapeutics: Research Funding; Oncternal: Research Funding. Isufi:Celgene: Consultancy; Novartis: Consultancy; Astra Zeneca: Consultancy. Bieler:Oncternal Therapeutics: Employment. Ianopulos:Oncternal Therapeutics: Employment. Breitmeyer:Oncternal Therapeutics: Employment, Equity Ownership. Kipps:Verastem: Membership on an entity's Board of Directors or advisory committees; AstraZeneca, Inc.: Membership on an entity's Board of Directors or advisory committees; Velos-Bio: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding; Jannsen Pharmaceutical Companies of Johnson & Johnson: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Safety and Efficacy of Venetoclax in Combination with Navitoclax in Adult and Pediatric Relapsed/Refractory Acute Lymphoblastic Leukemia and Lymphoblastic Lymphoma

Safety and Efficacy of Venetoclax in Combination with Navitoclax in Adult and Pediatric Relapsed/Refractory Acute Lymphoblastic Leukemia and Lymphoblastic Lymphoma

Safety, PK and preliminary efficacy of talazoparib in Japanese patients with advanced solid tumors; Phase 1 Study

Abstract Background Talazoparib is a potent, orally bioavailable, small molecule poly (adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitor. The recommended dose (RD) of single-agent talazoparib in non-Japanese patients (pts) was determined as 1 mg/day [QD]. This ongoing Phase 1 study evaluated the safety, preliminary efficacy, and PK profile of single-agent talazoparib in Japanese pts with advanced solid tumors. Methods Primary endpoint was first-cycle dose limiting toxicity (DLT). The single dose and multiple-dose PK and anti-tumor activity were evaluated as secondary endpoints. Two dose levels (0.75 mg and 1 mg QD) of talazoparib were studied using modified 3 + 3 dose escalation scheme. Talazoparib was administered continuously with the cycle length of 28 days. Results A total of 9 pts (3 pts in 0.75 mg and 6 pts in 1 mg QD) with a variety of tumor types were enrolled. No DLT was reported in either dose levels. The most common treatment-related (TR) adverse events (AEs) were neutrophil count decreased, platelet count decreased and stomatitis (22.2%, 2 pts each). No grade 3 or more TRAEs were reported. Based on the preliminary PK analysis, the median time to reach maximum plasma concentration (Tmax) was ranging from 1.0 to 2.0 hours. Talazoparib was eliminated with terminal phase half-life ranging from 49 to 133 hours after single dose. The distributions of maximum plasma concentration (Cmax) and area under concentration-time curve (AUC) after single and multiple dose were within the range of those in non-Japanese pts. RD in Japanese pts was determined to be 1 mg QD. Conclusions No DLT was reported in Japanese pts who received up to 1 mg QD. Hematological toxicity was common AEs in Japanese pts as well as non-Japanese pts. RD in Japanese pts was determined as 1 mg QD. The PK profile in Japanese pts was comparable with that in non-Japanese pts. Now the study is expanding to evaluate the efficacy in Japanese pts with germline BRCA mutated advanced breast cancer.

1542P - Safety of lorlatinib in subgroups of patients from a phase I/II trial

1542P - Safety of lorlatinib in subgroups of patients from a phase I/II trial

Abstract CT199: IMpower133: Primary efficacy and safety + CNS-related adverse events in a Ph1/3 study of first-line (1L) atezolizumab (atezo) + carboplatin + etoposide in extensive-stage SCLC (ES-SCLC)

Abstract Background Platinum chemotherapy (carboplatin or cisplatin) + etoposide is the current 1L standard of care treatment (tx) for ES-SCLC. Despite high response rates on this regimen, patient (pt) outcomes remain poor. IMpower133 is a Ph1/3, double-blind, randomized, placebo (PBO)-controlled trial that is evaluating the efficacy and safety of adding PD-L1-inhibitor atezo or PBO to 1L tx for ES-SCLC (NCT02763579). Methods IMpower133 enrolled pts without prior tx for ES-SCLC; PD-L1 testing was not required. Pts were randomized 1:1 to four 21-day cycles of carboplatin (AUC 5 mg/mL/min IV, Day 1) + etoposide (100 mg/m2 IV, Days 1-3) with either atezo (1200 mg IV, Day 1) or PBO, then maintenance atezo or PBO until PD, unacceptable toxicity or loss of clinical benefit. Maintenance prophylactic cranial irradiation (PCI) was allowed per protocol, while definitive thoracic radiation (TR) was not. Coprimary endpoints were OS and investigator-assessed PFS. A key exploratory endpoint was outcomes by blood tumor mutation burden (bTMB) analyzed at prespecified cutoffs (≥ 16 vs < 16 and ≥ 10 vs < 10 mutations/Mb). Results Adding atezo to carboplatin + etoposide demonstrated significant improvement in efficacy (OS and PFS) in 1L ES-SCLC (Table). Survival benefits were consistent across key subgroups and prespecified bTMB cutoffs. 44 pts (22 in each arm [per ITT]) received PCI, and 7 (3 in atezo arm, 4 in PBO arm) received TR. Gr 3-4 tx-related adverse events (AEs) occurred in 57% of atezo pts vs 56% of PBO pts; serious tx-related AEs occurred in 23% vs 19%. Occurrence of CNS-related AEs in pts who had PCI are shown in the Table. Conclusion Adding atezo to carboplatin + etoposide resulted in a significant improvement in survival in this 1L ES-SCLC all-comers population. There were no new safety signals, including in pts who received PCI or TR. Atezo + carboplatin + etoposide may represent a new standard regimen for untreated ES-SCLC. Atezo + carboplatin + etoposiden = 201PBO + carboplatin + etoposiden = 202Co-primary endpointsMedian OS, mo12.310.3HR 0.70 (95% CI: 0.54, 0.91); P = 0.0069Median PFS, mo5.24.3HR 0.77 (95% CI: 0.62, 0.96) P = 0.017Secondary efficacy endpointsInvestigator-assessed confirmed ORR, %60.264.4Median DoR, mo4.23.9CNS-related AEs in pts who had PCI, n (%)a,bn = 23n = 21Headache8 (34.8)4 (19.0)Asthenia5 (21.7)2 (9.5)Dizziness2 (8.7)0Insomnia2 (8.7)1 (4.8)Fall2 (8.7)1 (4.8)aSafety population; safety analyses conducted according to tx received (1 pt randomized to the control arm received a dose of atezo).bIncludes AEs occurring in ≥ 2 patients. Citation Format: Aaron S. Mansfield, Stephen V. Liu, Aleksandra Szczęsna, Libor Havel, Maciej Kzrakowski, Maximilian J. Hochmair, Florian Huemer, György Losonczy, Melissa L. Johnson, Makoto Nishio, Martin Reck, Tony S. Mok, Sivuonthanh Lam, David S. Shames, Juan Liu, Fairooz Kabbinavar, Alan Sandler, Leora Horn. IMpower133: Primary efficacy and safety + CNS-related adverse events in a Ph1/3 study of first-line (1L) atezolizumab (atezo) + carboplatin + etoposide in extensive-stage SCLC (ES-SCLC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT199.

Efficacy and safety of selinexor in recurrent glioblastoma.

2005 Background: New treatment modalities are needed for recurrent glioblastoma (rGBM). Selinexor (SEL) is a novel, oral selective inhibitor of nuclear export which forces nuclear retention of tumor suppressor proteins including p53 and p27, leading to apoptosis. We previously reported interim results showing tolerability, preliminary efficacy, and blood-brain barrier penetration in a surgical cohort (N = 8). We now report updated results following completion of accrual to non-surgical cohorts (N = 68). Methods: This is an open-label, multicenter, phase 2 study of SEL monotherapy. Patients (pts) not undergoing surgery for measurable rGBM (per RANO) were enrolled in one of 3 arms encompassing different dosing schedules. Treatment was continuous, although cycles were defined as 28 days and response was assessed every other cycle by MRI. Prior treatment with radiotherapy and temozolomide was required and prior bevacizumab was exclusionary. The primary endpoint was 6-month progression free survival (6mPFS) rate, calculated by the Kaplan Meier method. Results: A total of 76 pts were enrolled. Median age was 56 years (range 21-78). Median number of prior treatments was 2 (range 1-7). At the end of the 6 cycles, 30.2% patients on 80 mg QW were free from progression. The 6mPFS rate on 80 mg QW was 15.1%. Best RANO-defined responses (assessed locally) among 26 evaluable pts on 80 mg QW included 1 complete response, 2 partial responses, 7 stable disease, and 16 with progressive disease. Median duration of response was 10.8 months. The most common related adverse events in pts on ~85 mg BIW/60 mg BIW/80 mg QW were nausea (42%/64%/60%), leukopenia (38%/7%/43%), fatigue (71%/71%/43%), neutropenia (29%/14%/33%), decreased appetite (46%/71%/27%), and thrombocytopenia (67%/29%/23%). Conclusions: SEL demonstrated efficacy, with durable responses and disease stabilization in rGBM. Based on the favorable efficacy and safety profile, SEL at a dose of 80 mg QW is recommended for further development in rGBM. Clinical trial information: NCT01986348. [Table: see text]

Economic burden of select adverse events (AEs) in patients (Pts) with advanced urothelial cancer (aUC) treated with first-line (1L) systemic therapy.

363 Background: Limited information on costs related to incident AEs in pts with aUC in the real-world setting is available. Methods: Pts with aUC treated with 1L systemic therapy (94% chemotherapy, 6% immune checkpoint inhibitor) between 1/2012-9/2017 (first therapy administration defined the index date) were identified using IQVIA Real-World Data Adjudicated Claims – US database. Pts with continuous enrollment for ≥6 months pre- and ≥3 months post-index and ≥1 UC diagnosis code were included. Proportions of pts with febrile neutropenia (FN), dehydration, acute kidney injury (AKI), sepsis, colitis, hepatitis, adrenal insufficiency, and pneumonitis (select AEs), and per-pt-per month (PPPM) healthcare costs were assessed. Incident AEs during 1L therapy were identified using outpatient/inpatient claims and a subgroup of severe AEs (identified using only inpatient claims) was analyzed separately. Incremental costs of AEs were calculated as cost differences (CDs) between pts with and without AEs using multivariate linear regression to adjust for baseline differences. Results: Pts with (n = 666) and without (n = 569) select AEs had similar median age of 62 years; pts with select AE had more women (34.4% vs. 29.0%) and chemotherapy-treated pts than pts without select AEs (96.1% vs. 91.0%) (both p < 0.05). Baseline characteristics were similar in pts with (n = 290) and without (n = 1,290) severe AEs. FN (28.0%; severe 6.3%), dehydration (26.5%; severe 8.3%), AKI (11.3%; severe 8.8%), and sepsis (8.8%; severe 8.0%) occurred most frequently during 1L therapy (median duration: 15 weeks). Adjusted PPPM CDs between pts with and without AEs were $1,716 overall and $6,130 for severe AEs, with the greatest CDs observed for pneumonitis ($14,400; severe $20,242), sepsis ($8,581; severe $9,490) and AKI ($7,977; severe $8,843) (all p < 0.05). Inpatient costs had the largest impact on CDs. Conclusions: Costs of AEs, especially severe, during 1L treatment of aUC can cause substantial burden to healthcare system. Biomarker-based therapy selection, education/awareness early recognition and management of AEs may reduce hospitalizations and healthcare costs, and may impact care quality.

Abstract P6-18-12: EMBRACA: Efficacy and safety of talazoparib or physician's choice of therapy in patients with advanced breast cancer and a germline BRCA1/2 mutation: A regional analysis

Abstract Background: Talazoparib (TAL) prevents DNA damage repair by inhibiting poly (ADP-ribose) polymerase (PARP) enzymes and trapping PARP on DNA, resulting in cell death in BRCA1/2-mutated cells. Methods: EMBRACA is an open-label, randomized, 2-arm phase 3 trial in which efficacy and safety of TAL (1 mg/d) were compared with physician's choice of therapy (PCT; capecitabine, eribulin, gemcitabine, vinorelbine) in patients (pts) with locally advanced or metastatic breast cancer (ABC) and a germline BRCA mutation (gBRCAm). Outcomes were assessed by region of the world (North America [NA]; Europe [EU]; rest of world [ROW]). Progression-free survival (PFS), objective response rate (ORR), and clinical benefit rate (CBR) at 24 wks were assessed; safety was also assessed. Results: 431 pts were randomized 2:1. Pt characteristics were well balanced, although a higher percentage of pts in ROW had more severe disease (eg, triple-negative breast cancer [TNBC], Disease-free interval [DFI]<12 mo, more distant metastases, more disease sites) and were on average younger than pts in NA/EU. TAL provided improvement in PFS, ORR, and CBR in all regions vs PCT. The most common toxicities with TAL included anemia, neutropenia, thrombocytopenia, fatigue, and nausea for all regions. Alopecia was less frequent with TAL in EU/ROW. Serious adverse events for pts receiving TAL were more frequent in EU than NA/ROW. Incidences of adverse events associated with permanent treatment discontinuation in pts receiving TAL were low in all regions and generally lower than for PCT. Table 1CategoryNA* (N=156)EU* (N=190)ROW* (N=85)Mean age, years49.049.244.2Race, % White76.971.152.9Black5.8-3.5Asian5.8-42.4Not reported-27.4-TNBC, %424447BRCA1**, %414748BRCA2**, %595352DFI<12 mo, %313444Distant metastases, %949397≥3 disease sites, %474049PFS, (hazard ratio [HR]; [95% CI]); P value0.46 [0.29-0.74] P=.00090.52 [0.33-0.80]; P<.0030.57 [0.31-1.07] ;P=.08ORR (odds ratio [OR] [95% CI]); P value5.54 [2.4-16.1];P<.00013.75 [1.57-9.87]; P=.0016.7 [1.61-28.39]; P=.001CBR (OR [95% CI]); P value4.71 [2.20-10.57]; P<.00013.39 [1.56-7.36]; P=.00075.70 [1.70-17.13]; P=.002Hematologic AEs, % Anemia50.558.642.6Neutropenia31.332.346.3Thrombocytopenia28.322.635.2Nonhematologic AEs, % Fatigue59.643.650.0Nausea47.545.957.4Headache32.330.837.0Alopecia34.320.320.4Serious adverse events, %25.340.622.2Treatment discontinuation, n/N, (%) TAL7/99 (7.1)12/133 (9.0)3/54 (5.6)PCT7/43 (16.3)3/54 (5.6)2/29 (6.9)AE, adverse event; CI, confidence interval; *NA (United States); EU (Belgium, France, Germany, Ireland, Italy, Poland, Spain, United Kingdom, Russia, Ukraine, Israel); ROW (Brazil, Korea, Australia, Taiwan).**Central laboratory. Conclusions: In pts with gBRCAm ABC, TAL demonstrated significant improvements in clinical outcomes compared with PCT regardless of the region of the world in which they lived. However, slight differences among the regions in baseline characteristics were noted, possibly due to regional variation in diagnosis and detection of gBRCAm ABC as well as different treatment paradigms for metastatic breast cancer. Funding: Medivation LLC, acquired by Pfizer. Citation Format: Mina L, Lee K-H, Gonçalves A, Woodward N, Hurvitz SA, Diab S, Yerushalmi R, Goodwin A, Moreira Costa Zorzetto M, Kim S-B, Czibere A, Tudor IC, Gauthier E, Litton JK, Ettl J. EMBRACA: Efficacy and safety of talazoparib or physician's choice of therapy in patients with advanced breast cancer and a germline BRCA1/2 mutation: A regional analysis [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-18-12.

Characterization of the Long-Term Efficacy and Safety of Duvelisib Monotherapy in Patients with Relapsed/Refractory CLL/SLL on Treatment for > 2 Years across 4 Clinical Studies

Characterization of the Long-Term Efficacy and Safety of Duvelisib Monotherapy in Patients with Relapsed/Refractory CLL/SLL on Treatment for > 2 Years across 4 Clinical Studies

Phase 1 Results from a Phase 1/2 Study to Assess the Safety, Tolerability and Recommended Phase 2 Dose (RP2D) of Brentuximab Vedotin Plus Doxorubicin, Vinblastine and Dacarbazine (A+AVD) in Pediatric Patients (Pts) with Advanced Stage Newly Diagnosed Classical Hodgkin Lymphoma (cHL)

Background:Pediatric pts with cHL have better responses to therapy compared with adult pts; however, the combination regimens and radiotherapy used in treatment can result in significant morbidity. Including brentuximab vedotin as a component of multi-agent chemotherapy for pediatric pts with newly diagnosed HL may provide clinical benefit by decreasing the need for radiotherapy following chemotherapy, and reducing the risks of late effects associated with radiotherapy, including secondary malignancies, cardiac toxicity and thyroid dysfunction. The phase 1 portion of the study assessed the safety, tolerability, and RP2D of brentuximab vedotin when combined with doxorubicin, vinblastine, and dacarbazine (AVD) for frontline treatment of advanced stage cHL in pediatric pts.Methods:Eligible pts were aged 5 to <18 years, with treatment-naïve stage III/IV cHL, a Lansky Play/Karnofsky Performance Status of ≥50, and bidimensional measurable disease by radiography. Pts received up to six 28-day cycles of 48 mg/m2 brentuximab vedotin with AVD on days 1 and 15 of each cycle. RP2D was confirmed according to a modified 3+3 design; at least three pts were monitored for dose limiting toxicities (DLTs) during the evaluation period (cycle 1+28 days; from the first dose through study day 56), if 0/1 DLTs were observed, at least 3 additional pts were enrolled and monitored for DLTs. Toxicity was evaluated according to the NCI CTCAE, v4.03. The primary endpoints were to determine the RP2D of brentuximab vedotin in combination with AVD, and to assess treatment-emergent adverse events (AEs) and serious AEs (SAEs) from the first dose of treatment through 30 days after the last dose; pharmacokinetics (PK) was a secondary endpoint. G-CSF use was not permitted in the DLT-evaluation period.Results:Eight pts were enrolled (50% male), age range 6-17 years, with advanced stage cHL (stage III, n=5; IV, n=3) one of whom had bone marrow involvement. Four pts (50%) had two extra-nodal sites of involvement and four pts (50%) had no extranodal involvement. Two pts were not DLT-evaluable due to the administration of G-CSF under the original protocol. Of the six DLT-evaluable pts, all completed the 56-day DLT evaluation period with no DLTs reported. The RP2D of brentuximab vedotin was confirmed as 48 mg/m2. All pts reported at least one treatment-emergent, treatment-related AE during the DLT-evaluation period. During the DLT-evaluation period, 10 grade 4 AEs were reported, all treatment-related: neutrophil count decrease or neutropenia (n=7) and white blood cell (WBC) count decrease (n=3). One pt reported a treatment-related SAE of grade 3 febrile neutropenia for a duration of 2 days. Fifteen additional grade 3 AEs included: vomiting (n=3), WBC decreased (n=4), neutrophil count decreased or neutropenia (n=7), mucositis (n=1), and headache (n=1, not treatment related). Treatment-related AEs in pts who were not DLT-evaluable included: grade 4 neutropenia (n=3), grade 3 neutrophil count decrease (n=4), and grade 3 WBC decreased (n=1); non treatment-related AEs (1 each; grade 3) were leukopenia, anemia, and aspartate aminotransferase increase. Dose delays during the DLT-evaluation period were due to neutrophil count decrease/neutropenia (n=6) and mucositis (n=1). Currently, 5 of the Phase 1 patients continue on treatment while 3 patients have completed all 6 cycles. Full Phase 1 AE data will be provided. PK concentrations were within target range and consistent with two prior brentuximab vedotin studies: Phase 3 ECHELON-1 study (C25003; NCT01712490) and C25002 pediatric study (NCT01492088).Conclusions:The safety, tolerability, and PK profile of brentuximab vedotin were consistent with its expected profile, and a dose of 48mg/m2 was confirmed as the RP2D. Phase 2 is currently open for enrollment in the USA, Italy, Singapore, Taiwan, Hong Kong, Japan, and Brazil. Clinicaltrials.gov NCT02979522. DisclosuresZecca:Chimerix: Honoraria. Song:Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Suri:Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Leonard:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment; Takeda Pharmaceutical Company Limited: Equity Ownership. Locatelli:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bellicum: Consultancy, Membership on an entity's Board of Directors or advisory committees; bluebird bio: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Miltenyi: Honoraria.

Initial dose of apatinib in Chinese patients with chemotherapy-refractory advanced or metastatic adenocarcinoma of stomach or gastroesophageal junction in third- or later-line setting: 500 mg or 850 mg?

35 Background: A fine balance between maintaining efficacy and reducing toxicity is necessary for drug therapies in many cancers. This study seeks to review the data from phase IV clinical trial of Ahead-G201 to help elucidate the optimal initial dose of apatinib in advanced gastric cancer. Methods: Pts data from the Ahead-G201 study at cut-off date of Jul 10, 2017 were extracted to explore the correlation of apatinib initial dose (500 mg vs 850 mg) with safety and clinical efficacy. Results: 864 of eligible pts received apatinib at an initial dose of 500 mg, and 58 pts received at 850 mg. Dose interruption occurred in 258 pts (33.1%) at 500 mg and in 27 pts (46.5%) at 850 mg. For safety, the most common adverse events (AEs) were proteinuria, hypertension and leukocyte decrease in both groups. Moreover, the incidence of all AEs and grade 3-4 AEs in pts at 500 mg was significantly lower than pts at 850 mg (Table). For efficacy, pts at 500 mg achieved an objective response rate (ORR) of 10.8% and a disease control rate (DCR) of 70.6%, at best response, which were 10.3% and 55.2% in pts at 850 mg. Pts at 500 mg got a significantly longer median progression-free survival (mPFS) and median overall survival (mOS) than pts at 850 mg (PFS, 4.6 mos vs 2.2 mos; OS, 6.8 mos vs 4.0 mos). Multivariate analysis indicated that apatinib treatment at an initial dose of 500 mg was significantly associated with longer mOS in advanced gastric cancer pts (6.8 mos vs 4.0 mos: hazard ratio, 0.5; 95%CI, 0.3 to 0.8), compared to initial dose of 850 mg. Conclusions: Compared to receiving apatinib at initial dose of 850mg, oral administration of apatinib starting from 500 mg seemed to bring more clinical benefit for patients with advanced gastric cancer, whilst with lower toxicities. Clinical trial information: NCT02426034. [Table: see text]

P2.07-047 Poor Performance Status and BRAF Mutation Predict Grade 3-5 Immune-Related Adverse Events in Pts with Advanced NSCLC

P2.07-047 Poor Performance Status and BRAF Mutation Predict Grade 3-5 Immune-Related Adverse Events in Pts with Advanced NSCLC

Effects of pazopanib (PAZ) and sunitinib (SUN) dose modification on safety and efficacy in patients with metastatic renal cell carcinoma (mRCC) from COMPARZ.

4574 Background: COMPARZ was a randomized, controlled, open-label, phase 3 trial that demonstrated comparable efficacy of first-line PAZ and SUN, but favorable safety and quality of life profiles for PAZ in patients (pts) with mRCC (NEJM 2013;369:722). We evaluated the relationship between dosing, safety, and efficacy in PAZ- and SUN-treated pts who did or did not undergo dose reduction or interruption resulting from adverse events (AEs) and other reasons. Methods: The AEs and median progression-free survival (mPFS) of PAZ and SUN were evaluated for pts with no, any, 1, and ≥2 dose reductions or dose interruptions lasting ≥7 days. Results: Similar percentages of pts in the PAZ and SUN groups had a dose interruption (44% vs 49%, respectively) or reduction (44% and 51%, respectively). The incidence of AEs in pts from the PAZ and SUN groups with dose modifications was higher compared to those with no dose modifications. Longer mPFS was observed in pts with dose modification (Table). Pts treated with PAZ or SUN with no dose reductions had mPFS of 7.3 months (mos) and 5.5 mos, respectively, whereas pts with any dose reduction had mPFS of 12.5 mos and 13.8 mos, respectively. Similarly, pts treated with PAZ or SUN with no dose interruptions lasting ≥7 days had mPFS of 8.2 mos and 5.6 mos, respectively, whereas those with any dose interruption lasting ≥7 days had mPFS of 12.6 mos and 13.8 mos, respectively. Pts with 2 or more dose interruptions or reductions had mPFS &gt; 16 mos with both SUN and PAZ. Conclusions: Consistent with previous data for SUN, the current analyses showed longer mPFS with PAZ and SUN when dose modification is required to manage toxicity, suggesting that pts are not disadvantaged by such dose reductions or interruptions. Pts not requiring dose modification may have sub-optimal therapeutic drug exposure. Clinical trial information: NCT00720941. [Table: see text]

Time to grade ≥3 adverse events in pts receiving trifluridine/tipiracil (TAS-102).

788 Background: The phase 3 RECOURSE showed that treatment with trifluridine/tipiracil in patients (pts) with refractory metastatic colorectal cancer was associated with significantly improved survival versus placebo (7.1 versus 5.3 months, respectively; HR for death 0.68, 95% CI 0.58–0.81, p &lt; 0.001), with few serious adverse events. Trifluridine/tipiracil is administered in 4-week cycles comprising 2 weeks with 5 days at 35 mg/m2 bid followed by 2 rest days, and then a 2-week rest period. Exploration of timing for AEs, particularly within the first cycle of treatment, is important for pt monitoring in the outpatient setting. Methods: We performed a post hoc analysis of the RECOURSE safety population (533 trifluridine/tipiracil; 265 placebo) to explore timing of hematological and nonhematological AEs. Results: Grade ≥ 3 adverse events (AEs) were more frequent with trifluridine/tipiracil than placebo for both hematological AEs (38% vs 0% neutropenia; 4% vs 0% febrile neutropenia; 18% vs 3% anemia; and 5% vs &lt; 1% thrombocytopenia) and nonhematological AEs (2% vs 1% nausea; 2% vs &lt; 1% vomiting; and 3% vs &lt; 1% diarrhea). The median time to nadir in cycle 1 for hematological events was 28 days (17–31) for grade ≥ 3 neutropenia, 22 days (9–39) for grade ≥ 3 anemia, and 18 days (9–33) for grade ≥ 3 thrombocytopenia; similar values were obtained in subsequent cycles. The median times to nadir and values at nadir over the whole treatment duration (all cycles) are presented in the table for hematological and nonhematological AEs. Conclusions: Hematological and nonhematological AEs with trifluridine/tipiracil appear to be most intense towards the end of treatment cycles, which is reassuring for its use in the outpatient setting. Clinical trial information: NCT01607957. [Table: see text]

Investigational NEDD8-activating enzyme inhibitor pevonedistat (Pev) plus chemotherapy in patients (Pts) with solid tumors (Phase 1b study): Antitumor activity of pev plus carboplatin (Carbo)/paclitaxel (Pac).

2580 Background: This is an open-label, multi-arm, dose-escalation study (NCT01862328) of pev (TAK-924/MLN4924) plus chemotherapy in pts with solid tumors. Safety and preliminary efficacy results have been reported (Lockhart et al, AACR-NCI-EORTC 2015); common adverse events in pts treated with pev + carbo/pac were fatigue (50%), nausea (38%), and G3 elevated AST/ALT (19%). We present previously unreported antitumor activity in pts treated with this combination. Methods: Twenty-six pts received pev IV 15, 20, or 25 mg/m2 on d 1, 3, and 5 with carbo AUC5 + pac 175 mg/m2 on d 1 (lead-in cohort, n = 6: pev 15 mg/m2 + carbo AUC6) every 21 d. The combination appeared tolerable; MTD pev 20 mg/m2 + carbo AUC5 + pac 175 mg/m2. Response was assessed per RECIST v1.1; sparse PK sampling was carried out during C1. ERCC1 expression was assessed by IHC. Results: Nine responses were observed in 32 pts (28%) including those resistant to prior platinum/taxane therapy. Two pts (1 endometrial carcinoma, 1 bladder cancer) achieved a complete response (CR), and remain on study ( > 12 cycles). Seven pts (3 head and neck, 1 cholangiocarcinoma, 1 NSCLC, 1 sarcoma, 1 breast cancer) achieved a partial response (PR). The 9 responders received 4–18 cycles and had a median of 4 (range 1–8) prior therapies, including 4 with prior taxane (best response: 1 CR, 1 PR, 1 stable disease [SD], 1 unknown) and 8 with prior platinum (best response: 1 PR, 6 SD, 1 unknown). The majority had response within 2 cycles. Prolonged SD was seen in 3 pts (1 sarcoma, 1 endometrial cancer, 1 ovarian cancer), all 3 discontinued chemotherapy due to toxicity but continued to benefit from single-agent pev (SD duration 4.9–14.7 mos). Pev PK was unaffected in the presence of carbo/pac. Archival tumor sections from 23/30 pts were evaluable for ERCC1 staining. Conclusions: Pev+ carbo/pac showed broad-based antitumor activity in heavily pre-treated pts with solid tumors. Consistent with preclinical synergy between agents, lengthy treatment durations and improved responses in pts resistant to prior platinum/taxane therapy suggest the potential reversal of resistance by the addition of pev. Clinical trial information: NCT01862328.