Second-line Therapy In Pts Research Articles

Mutational heterogeneity of imatinib resistance and efficacy of ripretinib vs sunitinib in patients with gastrointestinal stromal tumor: ctDNA analysis from INTRIGUE.

397784 Background: Ripretinib, a switch-control tyrosine kinase inhibitor (TKI), is indicated for patients (pts) with gastrointestinal stromal tumor (GIST) who received prior treatment with ≥3 TKIs, including imatinib. Sunitinib is approved for advanced GIST after imatinib failure. Circulating tumor DNA (ctDNA) analysis may provide insight into the efficacy of these agents in second-line advanced GIST. Here, we present exploratory baseline ctDNA results from INTRIGUE. Methods: INTRIGUE is an open-label, phase 3 study that enrolled adult pts with advanced GIST who progressed on or had intolerance to imatinib (NCT03673501). Randomization was 1:1 to ripretinib 150 mg once daily (QD) or sunitinib 50 mg QD (4 wks on/2 wks off). Baseline peripheral whole blood was analyzed by Guardant360, a 74-gene ctDNA next-generation sequencing (NGS)-based assay. Only KIT mutations are reported here. Results: Of 453 pts in the overall intent-to-treat (ITT) population, 362 (80%) samples were analyzed. ctDNA was detected in 280/362 (77%), with KIT mutations detected in 213/280 (76%). Common resistance mutations were in the KIT activation loop (AL; exons 17/18; 89/213, 42%) and ATP-binding pocket (ATP-BP; exons 13/14; 81/213, 38%). Efficacy in pts with detectable ctDNA in the KIT exon 11 and overall ITT populations was consistent with the primary analysis based on tumor data used for randomization. Pts with KIT exon 11 + 17/18 (−9/13/14) mutations had superior progression-free survival (PFS), objective response rate (ORR), and overall survival (OS) with ripretinib vs sunitinib, whereas pts with exon 11 + 13/14 (−9/17/18) mutations had better PFS, ORR, and OS with sunitinib vs ripretinib (Table). Subgroup safety profiles were consistent with the primary analysis. Conclusions: While KIT ATP-BP mutations predicted clinical benefit from sunitinib vs ripretinib, pts harboring resistance mutations in the KIT AL derived meaningful clinical benefit from ripretinib but not sunitinib. This study demonstrates the value of ctDNA NGS-based sequencing of the complex landscape of KIT mutations to predict the clinical benefit of ripretinib or sunitinib as second-line therapy in pts with advanced GIST. Clinical trial information: NCT03673501 . [Table: see text]

A multicenter phase Ib/II study of liposomal-irinotecan, 5-fluorouracil (5-FU), and leucovorin (LV) with nivolumab as second-line therapy for patients with advanced biliary tract cancer (BilT-03).

438 Background: Patients (pts) with advanced biliary tract cancers (BTC) have poor prognosis despite systemic chemotherapy and treatment beyond first-line platinum doublet remains largely investigational. The immunomodulatory properties of conventional cytotoxic therapy, particularly in regard to the upregulation of PD-L1 expression rendering tumor cells less sensitive to T cell-mediated lysis, rapid emergence of chemotherapy resistance, and known modest efficacy of single agent anti-PD-1 antibody in BTC provide a rationale for combination chemoimmunotherapy. We conducted a multi-center, phase Ib/II, single-arm study to investigate the role of liposomal-irinotecan, 5FU and LV in combination with nivolumab as second-line therapy in pts with advanced BTC. Methods: Key eligibility criteria include histologically confirmed unresectable or metastatic BTC after progression or intolerance of first-line systemic therapy, measurable disease per RECISTv1.1, ECOG PS 0-1, and absence of autoimmune disease or chronic steroid use. The limited phase Ib portion evaluated 10 pts to determine the recommended phase 2 dose (RP2D) based on the probability of dose-limiting toxicity (DLT) rate <30% during days 1-29. Study treatment included 5FU 2400 mg/m2 over 46 hrs, LV 400 mg/m2, liposomal-irinotecan 70 mg/m2 at dose level 0 along with nivolumab 240 mg every 2 wks for up to 2 yrs in absence of disease progression or unacceptable toxicity. The primary endpoint was median progression-free survival (PFS) rate with an alternative and null hypothesis of 5.0 mo and 2.9 mo (two-sided alpha 0.05, power 80%), respectively. Secondary endpoints included best overall response rate (ORR) per immune related (ir)RECIST, median overall survival (OS), 75th percentile estimates of PFS and OS, and safety. Exploratory objectives include biomarker analysis using include targeted panel exome/transcriptome and immune cell subsets in tissue. Results: 30 eligible pts (60% men, 83% Caucasian) including 10 pts in phase Ib and 20 pts in phase II with a median age of 63.5 yrs (range 36-75) were enrolled across 4 US sites between June 2019 and July 2021. In phase Ib, one pt experienced DLT (grade 3 enterocolitis); RP2D was confirmed at dose level 0. All 30 pts were included in study reported outcomes with a median follow-up time of 10.7 mo. Median PFS was 4.2 mo (95% CI, 1.9-10.2) and failed to reject the null hypothesis. Median OS was 7.5 mo (95% CI, 5.8-21.4). The 75th percentile estimates for PFS and OS are 10.2 mo (95% CI, 5.4-NE) and 21.4 mo (95% CI, 7.8-21.4). ORR estimates and toxicity data are pending and will be presented at the meeting. Conclusions: The observed median PFS is insufficient to reject the null hypothesis. The 75th percentile estimates for PFS and OS are suggestive of prolonged benefit with chemoimmunotherapy in a small fraction of patients with BTC. Clinical trial information: NCT03785873.

Ramucirumab for patients with advanced hepatocellular carcinoma and elevated α-fetoprotein following a non-sorafenib based first-line therapy: Final results from an expansion cohort of REACH-2.

423 Background: Patients (pts) with advanced hepatocellular carcinoma (HCC) and elevated α-fetoprotein (AFP) have poor prognosis, and need effective, well-tolerated treatment options. Ramucirumab has been shown to improve survival and is currently approved as second-line therapy for pts with a baseline elevated AFP that have progressed on prior sorafenib. However, new options now exist in the front-line setting. This global open-label expansion cohort of REACH-2 (NCT02435433) was initiated to study ramucirumab in pts with advanced HCC and baseline AFP ≥400 ng/mL following a non-sorafenib based systemic therapy, representing one of the first sequencing studies in HCC. Methods: This single-arm study investigated ramucirumab in pts with advanced HCC (BCLC stage C or B disease), Child-Pugh A, ECOG PS 0/1, and baseline AFP ≥400 ng/mL who received 1-2 prior systemic regimens for advanced HCC, excluding prior sorafenib or chemotherapy. Enrolled pts received ramucirumab 8 mg/kg IV once every 14 days. The primary endpoint was safety. Secondary endpoints included overall survival (OS), progression-free survival (PFS) objective response rate (RECIST 1.1) and time to progression (TTP). Final analysis occurred after all enrolled pts completed ≥ 3 treatment cycles or discontinued treatment. Results: 47 pts were treated at 21 investigative sites in the USA (n = 12), Taiwan (n = 10), mainland China (n = 8), Hong Kong (n = 8), Germany (n = 8), and Switzerland (n = 1). At baseline, these pts with 2nd to 3rd+ line advanced HCC had ECOG PS 1 (51%), with vascular invasion or extrahepatic spread (85%), viral hepatitis B (55%), BCLC stage C disease (92%), and a median AFP of 3236 ng/mL (IQR: 1332, 18210). Prior systemic regimens included lenvatinib (n = 20), checkpoint inhibitor (CPI) monotherapy (n = 11), CPI + antiangiogenic (n = 15), and CPI + CPI (n = 4). Grade ≥ 3 treatment-emergent adverse events (AEs) were reported in 27 (57%) pts and were deemed to be treatment-related in 11 (23%) pts. Grade ≥ 3 AEs occurring in ≥ 5% pts were hypertension (n = 5; 11%), proteinuria (n = 3; 6%), hyponatremia (6%) and AST increased (6%). Two deaths occurred due to treatment-related AEs on therapy or within 30 days of treatment discontinuation (myocardial infarction and upper GI hemorrhage). Median OS was 8.7 months (95% CI 4.6-12.2), median PFS was 1.7 months (95% CI 1.5-4.1), and median TTP was 2.8 months (95% CI 1.5-4.2). The number of pts achieving an objective response was 5 (10.6%, 95% CI 1.8-19.5), with a median duration of response of 8.3 months (95% CI 2.4-NR). Conclusions: This expansion cohort of REACH-2 represents a non-sorafenib sequencing study in pts with advanced HCC. The safety/efficacy profile of ramucirumab following a non-sorafenib based systemic therapy was consistent with that observed in pts who received prior sorafenib in the Ph3 REACH-2 study. Clinical trial information: NCT02435433.

Safety and Efficacy of Daratumumab with Ixazomib and Dexamethasone in Patients with One Prior Lenalidomide-Based Regimen: Outcomes of the Phase 2 Daria Study

Safety and Efficacy of Daratumumab with Ixazomib and Dexamethasone in Patients with One Prior Lenalidomide-Based Regimen: Outcomes of the Phase 2 Daria Study

Natural history of patients (pts) with advanced cholangiocarcinoma (CCA) with FGFR2 gene fusion/rearrangement or wild-type (WT) FGFR2.

4089 Background: CCA is a rare, heterogeneous malignancy with poor prognosis due to late onset of symptoms and relative resistance to available therapies. FGFR2 fusions are common, occurring in 10–16% of intrahepatic CCA (iCCA). There is increasing awareness of the importance of molecular profiling to inform treatment choices, although real-world data (RWD) are lacking on the natural history of pts with CCA and FGFR2 fusions/rearrangements receiving therapies for advanced disease. This retrospective, observational, natural history study used a nationwide (US-based) de-identified clinico-genomic database (CGDB) to compare overall survival (OS) in pts with advanced CCA and FGFR2 fusions/rearrangements vs. those with wild-type (WT) FGFR2. Methods: This study used the nationwide (US-based) de-identified Flatiron Health-Foundation Medicine CCA CGDB (FH-FMI-CGDB). The data originated from approximately 280 US cancer clinics (̃800 sites of care). Pts were ≥18y of age, had chart-confirmed advanced CCA, comprehensive genomic profiling, and ≥2 visits within the Flatiron Health network since Jan 1, 2011. Primary objective: evaluate OS in pts with FGFR2 fusions/rearrangements and WT FGFR2 from the index date (date of diagnosis of advanced CCA) to date of death from any cause. A key secondary objective was to evaluate the influence of FGFR status on OS after adjusting for potential prognostic variables. Risk-set adjustment was used to account for left truncation for all time-to-event analyses. Results: As of May 2020, 571 pts from the CCA FH-FMI-CGDB met the inclusion criteria; 75 pts with FGFR2 fusions/rearrangements (median age 63y; 64% female; 95% iCCA; 68% stage IV at initial diagnosis), and 496 pts FGFR2 WT (median age 65y; 48% female; 74% iCCA; 55% stage IV at initial diagnosis). Median OS was numerically higher, but not statistically different, for pts with FGFR2 fusions/rearrangements vs FGFR2 WT (12.1m [95% CI 8.5−17.1] vs 7.1m [95% CI 5.7−8.8]; log rank p = 0.184). Median OS was also numerically higher, but not statistically different, for FGFR2 fusions/rearrangements vs FGFR WT in the subset of 437 pts with iCCA (12.1m [95% CI 8.4−17.1] vs 7.8m [95% CI 6.1−10.0]; log rank p = 0.375). FGFR2 status was not a significant factor contributing to OS in univariate, bivariate, or multivariate models after adjusting for potential prognostic covariates. Conclusions: This analysis of RWD did not demonstrate a clear survival advantage for pts with FGFR2 fusions/rearrangements vs FGFR2 WT CCA receiving therapies for advanced disease, although a non-significant trend towards longer OS was observed in pts with FGFR2 fusions/rearrangements. FGFR2 status was not a significant predictor of OS after adjusting for potential prognostic covariates. An additional sub-analysis is ongoing to determine OS from time of initiation of second-line therapy in pts with FGFR2 fusions/rearrangements.

Lisocabtagene Maraleucel (liso-cel) for Treatment of Second-Line Transplant Noneligible (TNE) Relapsed/Refractory (R/R) Aggressive Non-Hodgkin Lymphoma (NHL): Initial Results from the PILOT Study

Lisocabtagene Maraleucel (liso-cel) for Treatment of Second-Line Transplant Noneligible (TNE) Relapsed/Refractory (R/R) Aggressive Non-Hodgkin Lymphoma (NHL): Initial Results from the PILOT Study

Pembrolizumab vs chemotherapy as 2L therapy for advanced esophageal cancer: Japanese Subgroup Analysis in KEYNOTE-181

Abstract Background Safe and effective treatment of advanced esophageal cancer is an area of unmet need. KEYNOTE-181 is a global, randomized, open-label, phase 3 study of pembrolizumab (PBR) vs chemotherapy (SoC) as second-line therapy for pts with advanced or metastatic esophageal cancer. Methods Eligible pts were aged ≥18 y, had confirmed, advanced adenocarcinoma (AC) or squamous cell carcinoma of the esophagus (ESCC), or HER2-negative Siewert type 1 AC of the gastroesophageal junction, documented progression on 1 prior-line therapy, measurable disease per RECIST v1.1, ECOG PS 0 or 1, and provision of a tumor sample for biomarker analysis. Pts were randomized 1:1 to PBR 200 mg Q3W for 2 years or investigator’s choice of paclitaxel 80-100 mg/m 2 on days 1, 8, and 15 of every 28-day cycle, docetaxel 75 mg/m 2 Q3W, or irinotecan 180 mg/m 2 Q2W. Stratification was by histology and geographic region. Primary endpoints were OS in the ITT, ESCC, and PD-L1 combined positive score (CPS) ≥10 populations. Secondary endpoints were PFS and ORR, by RECIST v1.1, and safety. Results Of the 152 Japanese pts enrolled, 133 (88%) were male, 94 (62%) had ECOG PS 0, 149 (98%) had ESCC, and 79 (52%) had PD-L1 CPS ≥10. Pts were randomized to PBR (77 pts) or SoC (75 pts), and median follow-up durations were 11.5 mo (range, 1.0-29.2) and 8.2 mo (range, 0.8-32.2), respectively. Median OS was improved with PBR vs SoC in pts with PD-L1 CPS ≥10 (12.5 vs 8.4 mo; HR 0.70; 95%CI 0.43-1.13; P = 0.0682), in pts with ESCC (11.9 vs 8.2 mo; HR 0.68; 95%CI 0.48-0.97; P = 0.0156) and in the ITT population (11.5 vs 8.2 mo; HR 0.68; 95%CI 0.48-0.96; P = 0.0147). These 3 primary OS data in Japanese were consistent to entire global populations, respectively. Fewer pts had any-grade (74% vs 96%) or grade 3-5 (17% vs 50%) drug-related AEs with PBR vs SoC. Conclusion PBR improved OS compared with SoC as second-line therapy for advanced esophageal cancer in Japanese patients, with a more favorable safety profile than SoC.

Exceptional responders to abexinostat (ABX) plus pazopanib (PAZ) in pretreated renal cell carcinoma (RCC) and other solid tumors: Long-term follow-up of a phase 1b study.

3022 Background: We previously reported the initial phase 1b study results of PAZ + ABX, a potent pan-HDAC inhibitor, demonstrating acceptable toxicity profile and encouraging anti-tumor activity (Aggarwal et al. JCO 2017). We report the long-term follow up of exceptional responders and additional correlative analyses associated with clinical outcomes. Methods: Key efficacy endpoints included objective response rate and duration of response. Peripheral blood histone acetylation, HDAC expression, and plasma VEGF levels were analyzed and associated with clinical outcomes. Results: 51 pts (RCC subset; N = 22) were enrolled between June 2012 and October 2015. 10 pts (20%) had experienced disease progression on prior PAZ; 59% had received any prior VEGF-targeting therapy. 9 evaluable pts (18%) (N = 6 RCC; 2 thyroid; 1 mesothelioma) achieved partial tumor response (PR), of which 6 had prior progression on VEGF-targeting therapy. 7/10 (70%) of pts with prior disease progression on PAZ monotherapy had reduction in tumor burden on study. The median duration of response was 9.1 months (range 1.2 to 70+), and clinical benefit rate (PR or stable disease > 6 months) was 33%. Five treatment-refractory pts achieved durable PRs lasting for > 2 years duration, and one previously PAZ-refractory patient with RCC remains on treatment with ongoing PR for > 6 years. Higher HDAC2 expression was associated with prolonged progression-free survival (median PFS 5.9 vs. 3.5 months, log-rank p = 0.02). Induction of histone acetylation on ABX lead-in treatment was associated with subsequent time to progression (p = 0.002). On-treatment plasma VEGF levels were inversely correlated with PBMC histone acetylation (p = 0.02). Conclusions: Markedly durable responses with PAZ + ABX are achievable, including in pts with PAZ- and VEGF-refractory RCC and other solid tumor malignancies. Host factors including HDAC expression and acetylation status may identify those most likely to benefit. A randomized phase 3 study is underway of PAZ + ABX as a first- or second-line therapy in pts with locally advanced or metastatic RCC (RENAVIV; NCT03592472). Clinical trial information: NCT01543763.

A multi-center phase Ib/II study of nal-irinotecan, 5-fluouracil and leucovorin in combination with nivolumab as second-line therapy for patients with advanced unresectable biliary tract cancer.

TPS4154 Background: Patients (pts) with advanced biliary tract cancers (BTC) have poor prognosis despite systemic chemotherapy, and treatment beyond first-line platinum doublet remains investigational. The immunomodulatory properties of conventional cytotoxic therapy, particularly in regard to the upregulation of PD-L1 expression rendering tumor cells more sensitive to T cell-mediated lysis and neoantigen production, rapid emergence of chemotherapy resistance, and known modest efficacy of single agent PD-1 antibody in BTC provide a rationale for combining chemotherapy and immunotherapy. This multi-center, phase Ib/II, single-arm study is designed to investigate the role of nal-irinotecan, 5-FU and leucovorin in combination with nivolumab as second-line therapy in pts with advanced BTC. Methods: Key eligibility criteria include histologically confirmed advanced, unresectable biliary carcinoma (intra- or extra-hepatic and gallbladder) with progression or intolerance of first-line systemic therapy (excluding irinotecan and PD-1/PD-L1 antibody), measurable disease per RECIST v1.1, ECOG PS 0-1, Child Pugh A or B7, and absence of autoimmune disease or chronic steroid use. Primary objective of the phase Ib portion is to determine the recommended phase 2 dose, and of the phase II portion is to evaluate the median progression-free survival. Secondary objectives include evaluation of objective response rate per immune related (ir)RECIST, median OS and safety in this patient population. Exploratory objectives include identification of biomarker predictors of response and mechanisms of resistance through serial biopsies and blood collection (pre, on and post therapy), including sequential whole exome/transcriptomic analysis and immune cell subset analysis (tissue and blood). Therapy includes nal-irinotecan 70 mg/m2, leucovorin 200 (dose level -1) or 400 mg/m2 (dose level 0), 5-fluouracil 2400 mg/m2 IV over 46 hours, and nivolumab 240 mg on day 1 every 2 weeks for 6 months. In the absence of disease progression, pts may continue therapy for up to 2 years. Accrual goal is 30 evaluable pts. Using a null hypothesis value of median PFS of 2.9 months, and an alternative hypothesis of 5.0 months, this ongoing study has > 80% power, with a two-sided alpha of 0.05 to identify treatment efficacy of study arm. Clinical trial information: NCT03785873.

NET-02: A multi-center, randomised, phase II trial of liposomal irinotecan (nal-IRI) and 5-fluorouracil (5-FU)/folinic acid or docetaxel as second-line therapy in patients (pts) with progressive poorly differentiated extra-pulmonary neuroendocrine carcinoma (PD-EP-NEC).

TPS4158 Background: The prognosis for pts with PD-EP-NEC is poor. First-line treatment for advanced disease is etoposide/platinum-based chemotherapy, analogous to that of high grade lung NEC, with no standard second-line treatment, and is an area of unmet need. Methods: This is a multi-centre, randomised, phase II trial of nal-IRI; 80mg/m2 intravenously (IV) over 90 mins, prior to 5-FU; 2400 mg/m2 infusion over 46 hrs and folinic acid, Q14 days, or docetaxel; 75mg/m2 IV over 60 mins, Q21 days, as second-line therapy in pts with progressive PD-EP-NEC (Ki-67 > 20%), with the overall aim of selecting a treatment for continuation to a phase III trial. The standard arm is that used in high-grade lung NEC, of which docetaxel is a second-line therapy option (NCCN guidelines) and combination regimens such as Irinotecan/5-FU are a second-line therapy option currently used without trial evidence for this subset of pts. Pts must have had prior treatment with first-line platinum-based chemotherapy, have documented disease progression and have an ECOG performance status of ≤2. This study plans to recruit 102 pts from 16 UK centres (over 37 mths). Primary endpoint is 6-mth progression-free survival (PFS) rate; trial is designed to have an 80% chance of demonstrating that the one-sided 95% confidence interval of the 6 mth PFS rate excludes 15%, if the true rate is at least 30%, where 30% is the required level of efficacy, and a rate of < 15% would give grounds for rejection. If both treatment arms exceed the required level of efficacy to warrant further evaluation in a phase III trial, treatment with the higher PFS rate at 6 mths will be selected. Secondary endpoints include overall survival, objective response rate, toxicity, quality of life, serum neuron-specific enolase. Exploratory endpoints include quantification of circulating tumour cells (CTCs), circulating tumour deoxyribonucleic acid (ctDNA) and molecular profiling of CTCs, ctDNA and tumour tissue, and generation of CTC-derived xenografts. This trial is open and has enrolled 6 pts at time of submission. Clinical trial information: 10996604.

Ruxolitinib for the Treatment of Inadequately Controlled Polycythemia Vera without Splenomegaly: 156-Week Follow-up from the Phase 3 Response-2 Study

BACKGROUNDRuxolitinib (RUX), a potent Janus kinase (JAK)1/JAK2 inhibitor, is approved for hydroxyurea (HU)-resistant/-intolerant patients (pts) with polycythemia vera (PV) based on findings from the RESPONSE study (NCT01243944). RUX proved superior to best available therapy (BAT) in maintaining hematocrit (Hct) control without phlebotomy eligibility, normalizing blood cell count, reducing spleen volume, and improving symptoms in pts with PV with splenomegaly who are resistant to or intolerant of HU. RESPONSE-2 (NCT02038036) is a global, multicenter, open-label, phase 3 trial comparing RUX with BAT in HU-resistant or -intolerant pts with PV without splenomegaly. In the primary analysis at wk 28, RUX proved superior to BAT in controlling Hct without phlebotomy eligibility, normalizing blood cell count, and improving symptoms. Responses were durable at 80 wk of follow-up. Here we evaluate the long-term safety and efficacy of RUX after a follow-up of 156 wk.METHODSPatients were randomized 1:1 to RUX 10 mg twice daily or BAT; BAT patients could cross over to RUX starting at wk 28. The primary endpoint was Hct control at wk 28 (absence of phlebotomy eligibility [Hct >45% and ≥3% higher than baseline, or >48%] from wk 8 to 28, with ≤1 phlebotomy eligibility up to wk 8). The key secondary endpoint was complete hematologic remission (CHR; Hct control, white blood cell count <10×109/L, platelet count ≤400×109/L) at wk 28. Other endpoints included changes in patient-reported outcomes and in JAK2 V617F allele burden over time. Durability of Hct control (ie, primary response), CHR, and safety were evaluated at wk 156.RESULTSAt data cutoff (April 6, 2018), 65/74 RUX pts were still on treatment. Primary reasons for discontinuation were adverse events (AEs; 5.4%), consent withdrawal (2.7%), death, disease progression, and physician decision (1.4% each). All 75 BAT pts had discontinued; 58 pts had crossed over to RUX; 46 were ongoing. Reasons for early discontinuation in crossover pts were AEs (13.8%), consent withdrawal (3.4%), death (1.7%), and disease progression (1.7%). Median exposure was 168.5 wk for RUX, 28.4 wk for BAT, and, in crossover pts, 137.0 wk for RUX.At wk 156, durable Hct control was achieved in 41.9% of RUX pts (31/74). The Kaplan-Meier estimated median duration of Hct control had not been reached (Figure A). Durable CHR was achieved in 24.3% of RUX pts (18/74; estimated median duration, 35.9 weeks; Figure B). RUX also led to durable improvements in PV-associated symptoms, with approximately half of RUX pts (48%) continuing to achieve a ≥50% reduction in MPN-SAF TSS at wk 156. Pts in the RUX arm also continued to experience improvements in all 5 dimensions of the EQ-5D-5L assessment. Pts who crossed over to RUX derived benefits from RUX therapy as well, achieving Hct control following crossover, with Hct decreasing over time. As seen in RUX pts, crossover pts experienced a reduction in JAK2 V617F allele burden over time from the time of crossover.The safety profile of RUX was consistent with previous reports. The most common AEs were anemia (exposure-adjusted rate per 100 pt-years, 10.7), increased weight (8.5), arthralgia (6.8), and hypertension (6.0) in the RUX arm and anemia (12.8), nasopharyngitis (7.1), and increased weight (6.4) in pts after crossover. Of interest, exposure-adjusted rates of herpes zoster were 3.8 with RUX and 5.0 in crossover pts. Overall, exposure-adjusted rates of AEs with RUX were lower than those reported at 80 wk of follow-up. The exposure-adjusted rate of thromboembolic events was higher in the BAT arm (3.7; RUX, 2.6). As expected given prior HU exposure, nonmelanoma skin cancer was the most common second malignancy in RUX-treated pts (randomized, 3.4; crossover, 2.8). No RUX-treated pts developed AML; 1 pt (RUX arm; 0.4) developed myelofibrosis. Three pts died on study: 1 in the RUX arm (metastatic melanoma), 1 in the BAT arm (septic shock), and 1 after crossover (general health deterioration).CONCLUSIONSIn this 156-wk follow-up, RUX provided durable Hct control and CHR in pts with PV without splenomegaly. RUX was well tolerated, with 88% of randomized pts and 79% of crossover pts still receiving RUX at the time of this analysis. AEs were consistent with previous reports, and no new safety signals were observed. Overall, findings are consistent with those from RESPONSE and support RUX as the standard of care for second-line therapy in pts with inadequately controlled PV. [Display omitted] DisclosuresPassamonti:Novartis: Consultancy, Honoraria, Speakers Bureau. Palandri:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Saydam:Gilead: Honoraria; Celgene: Honoraria; Novartis: Honoraria, Research Funding, Speakers Bureau; BMS: Honoraria. Devos:Novartis: Consultancy; Takeda: Consultancy; Celgene: Consultancy. Vannucchi:Celgene: Membership on an entity's Board of Directors or advisory committees; ITALFARMACO: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Bensasson:Novartis: Employment. Kandra:Novartis: Employment, Research Funding. Morando:Novartis: Employment, Equity Ownership. Griesshammer:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Prognostic factors for overall survival (OS) in metastatic melanoma (MM) patients (pts) treated with immune checkpoint inhibitors: A single institution study of 696 pts.

9574 Background: Limited OS data, including prognostic and predictive factors of response, is available in mm pts treated with immune checkpoint inhibitors. Methods: A single-institution retrospective review was conducted on 696 mm pts treated with single-agent anti CTLA-4 or anti PD-1 on and off clinical trial between 2011-2015. Median OS was calculated from mm diagnosis. Results:Median age at mm diagnosis was 60 years old (range 15-86) and 65.2% were male. Subtypes were 63.2% non-acral cutaneous, 17.2% unknown primary, 7.8% mucosal, 6.5% acral, and 5.3% uveal. AJCC v7 staging at diagnosis was 7.9% M1a, 16.5% M1b, 33.0% M1c, and 42.5% not staged due to unknown LDH. LDH was elevated in 18.0% (400 pts). Mutation rates were 30.0% BRAF V600E/K (636 pts tested) and 24.5% NRAS (429 pts tested). First-line therapy for BRAF V600E/K mm pts included anti CTLA-4 (24.1%), BRAF/MEK targeted therapy (21.5%) and anti PD-1 (8.9%). First-line therapy for BRAF WT mm pts included anti CTLA-4 (28.1%) and anti PD-1 (12.8%). Median OS from mm for the cohort was 36.5 months (95% CI 33.3-44.9). Elevated LDH and staging correlated with OS (p &lt; 0.001, p &lt; 0.001, respectively) on univariate analysis. Age, gender, subtype and mutation status were not significantly associated with OS. Compared to BRAF WT, pts with BRAF V600E/K mutation were younger (median = 53 vs 62 yrs, p &lt; 0.001), more likely to have non-acral cutaneous mm (83.2% vs 58.0%, p &lt; 0.001) and have a diagnosis of brain metastasis during the disease course (57.0% vs 28.8%, p &lt; 0.001). While adjusting for stage, there was no significant difference in OS based on first or second line therapy in pts with BRAF V600E/K mm or first line therapy in BRAF WT MM; however, BRAF WT pts treated second line with anti-PD1 were observed to have improved OS compared with pts receiving anti-CTLA 4 (HR 0.43 95% CI:0.23-0.84 p = 0.012). Conclusions: This study demonstrates that LDH and stage are prognostic of OS in all mm pts treated with single agent immune therapy. Second line therapy in BRAF WT pts treated with single agent immune therapy is also prognostic of OS thus prompting further investigation to determine advantageous therapy sequencing in MM.

Final phase Ib data for the oral c-Met inhibitor tepotinib in patients with previously treated advanced hepatocellular carcinoma.

e15676 Background: The prognosis for patients (pts) with advanced hepatocellular carcinoma (HCC) after failure of sorafenib is poor, with few systemic therapy options. c-Met is a receptor tyrosine kinase implicated in the progression of HCC. Tepotinib, a highly selective c-Met inhibitor, has shown activity first-line in patients with c-Met+ HCC. We report final results of a phase Ib study of tepotinib in pts with advanced HCC after failure of first-line sorafenib. Methods: Eligible pts were ≥18 years with advanced HCC, Child-Pugh Class A, ECOG PS 0-1, and progression after ≥4 weeks of sorafenib. Tepotinib doses of 300 and 500 mg/day on a 21-day cycle were explored to establish the recommended phase II dose (RP2D) of tepotinib. Secondary objectives included antitumor activity by RECIST v1.1, biochemical response, and safety. Results: Seventeen pts were enrolled: 4 pts received tepotinib 300 mg/day and 13 pts 500 mg/day, confirmed as the RP2D. Fourteen pts experienced treatment-related adverse events (TRAEs), the most frequent being peripheral edema (n = 5, 2 grade 3), lipase increase (2, 1 grade 3), acute kidney injury (2, 1 grade 3), renal impairment (2, 1 grade 3), fatigue (2), nausea (2), asthenia (2). One pt with peripheral edema permanently discontinued treatment. No grade ≥4 TRAEs and no dose-limiting toxicities (DLTs) were reported. The best overall response was partial response (PR) in 2 pts and stable disease (SD) in 4 pts. The duration of the PRs was 57 and 91 weeks. In the first of these pts, tumor size decreased by 55% and serum alfa-fetoprotein (AFP) levels had decreased from 15,923 μg/L at baseline to &lt; 3,000 μg/L by day 15 of cycle 2 and remained at this level until progression. In the second pt, tumor size decreased by &gt; 60% from baseline. No consistent change in AFP was seen in pts with SD. Median overall survival was 7.2 months (range 0.7–22.9 months). Conclusions: The RP2D of tepotinib as second-line therapy for pts with advanced HCC who progress after sorafenib treatment is 500 mg/day. Tepotinib was well tolerated at this dose and showed signs of activity. The ongoing phase II part of this trial is investigating the efficacy and safety of tepotinib 500 mg/day in pts with c-Met+ HCC. Clinical trial information: NCT02115373.

Seven-Year (yr) Follow-up of Patients (pts) with Imatinib-Resistant or -Intolerant Chronic-Phase Chronic Myeloid Leukemia (CML-CP) Receiving Dasatinib in Study CA180-034, Final Study Results

Background: Dasatinib is a potent BCR-ABL tyrosine kinase inhibitor (TKI) currently approved at 100 mg once daily (QD) as a first-line therapy in CML-CP pts and a second-line therapy in pts with CML resistant/intolerant to prior therapy. CA180-034 (NCT00123474), a prospective, randomized phase 3 study, was designed to compare the dose and schedule of dasatinib therapy for the optimal benefit/risk ratio among pts with imatinib-resistant or -intolerant CML-CP. Results from this study have previously demonstrated significant efficacy of dasatinib in this pt population. Here, we report the final 7-yr analysis of efficacy and safety outcomes of CA180-034, which represents the longest follow-up of any second-generation BCR-ABL TKI to date. Methods: The CA180-034 2 X 2 factorial study design has previously been described (Shah 2010, J Clin Oncol). Pts (n=670) were randomized to dasatinib: 100 mg QD (n=167), 50 mg twice daily (BID; n=168), 140 mg QD (n=167), or 70 mg BID (n=168). To manage inadequate response or adverse events (AEs), dose escalation (up to a total daily dose [TDD] of 180 mg) and dose interruption or reduction (down to a TDD of 20 mg) were allowed. After 2 yrs, the protocol was amended to allow switching to a QD regimen with the same TDD after at least one dose reduction for recurrent anemia, thrombocytopenia, neutropenia, pleural effusion, or any other fluid retention during study progress or at the investigator’s discretion (Shah 2014, Blood). Results: Approximately 55% (50 mg BID) and 51% (70 mg BID) of pts treated after the protocol amendment switched to QD dosing by the last recorded dose. The overall median duration of therapy was longer for the 100 mg QD group (37.4 months [mos]) compared with the 50 mg BID, 140 mg QD, and 70 mg BID groups (28.1 mos, 26.6 mos, and 28.9 mos, respectively).At 7 yrs of follow-up, progression-free survival (PFS) andoverall survival (OS) rates were similar for all doses, as were the proportions of pts with a best on-study molecular response of MMR (Table 1). In an exploratory landmark analysis, pts in the 100 mg QD arm with BCR-ABL ≤10% (on the International Scale) at 3 mos had improved PFS and OS rates at 7 yrs relative to pts with BCR-ABL>10% (Table 2). BCR-ABL mutations were assessed in pts prior to the start of dasatinib (baseline), at the time of disease progression, or at end of treatment. Three mutations persisted or developed in pts who discontinued dasatinib due to loss of response on 100 mg QD: V299L (n=3), T315I (n=6), and F317L (n=7). For 100 mg QD, most nonhematologic and hematologic AEs (all grades) typically first occurred within the first 24 mos of treatment. Rates of nonhematologic AEs (all grades) over 7 yrs for 100 mg QD compared with other treatment arms included fluid retention (51% vs 54%), diarrhea (42% vs 47%), nausea/vomiting (27% vs 43%), myalgias/arthralgias (38% vs 33%), fatigue (37% vs 34%), and rash (33% vs 36%). Within yr 7 of the study, new cases of pleural effusion occurred in 5% (2/42) of pts at risk treated with dasatinib 100 mg QD compared with 8% (7/88) in other treatment arms. Severe (grade 3–4) AEs (any relationship) occurred less frequently in the 100 mg QD group (98/165, 59%) relative to other treatment arms (341/497, 69%). Three pts died due to study drug toxicity (1 due to sepsis; 1 due to pulmonary edema, congestive heart failure, neck pain, and pleural effusion; 1 due to necrosis of the colon). Conclusions: Long-term follow-up of dasatinib continues to demonstrate durable efficacy and benefit for pts with CML-CP following imatinib therapy, particularly if achieving BCR-ABL ≤10% at 3 mos. Dasatinib is well-tolerated amongst pts, with most AEs occurring early on during the course of treatment; however, pleural effusion did occur through 7 yrs of treatment. No new safety signals were detected. Disclosures Shah:ARIAD: Research Funding; Bristol-Myers Squibb: Research Funding. Rousselot:Bristol-Myers Squibb: Consultancy, Research Funding. Schiffer:Bristol-Myers Squibb: Research Funding; Novartis: Research Funding; Ariad: Research Funding; Teva: Membership on an entity9s Board of Directors or advisory committees; Pfizer: DSMB Other. Rea:Bristol-Myers Squibb: Honoraria; Pfizer: Honoraria; Novartis: Honoraria; Ariad: Honoraria. Cortes:Ariad: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Consultancy, Research Funding. Milone:Roche: Membership on an entity9s Board of Directors or advisory committees, Speakers Bureau; Bristol-Myers Squibb: Membership on an entity9s Board of Directors or advisory committees, Speakers Bureau. Mohamed:BMS: Employment. Healey:Bristol-Myers Squibb: Employment. Kantarjian:ARIAD: Research Funding; Pfizer: Research Funding; Amgen: Research Funding. Hochhaus:Bristol-Myers Squibb: Research Funding; Novartis: Research Funding; Pfizer: Research Funding; Ariad: Research Funding; MSD: Research Funding. Saglio:BMS: Consultancy, Fees for occasional speeches Other; Novartis: Consultancy, Fees for occasional speeches, Fees for occasional speeches Other; Pfizer: Consultancy, Fees for occasional speeches, Fees for occasional speeches Other; ARIAD: Consultancy, Fees for occasional speeches, Fees for occasional speeches Other.

720P - Second Line Therapy with Sunitinib As Single Agent in Patients with Advanced Intrahepatic Cholangiocarcinoma (Update on Sun-Ck Phase Ii Trial)

ABSTRACT Aim: Beyond platinum-based first line chemotherapy for advanced cholangiocarcinoma (CK), second line 5FU-based treatments yield median progression-free survival (PFS) of Methods: This multicenter phase 2 study enrolled pts with locally advanced intrahepatic CK failing prior first-line platinum-based chemotherapy, ECOG PS 0-1, and adequate liver function with bilirubin 6.3 months (primary objective) other endpoints being PFS, response (RECIST 1.1 & Choi criteria), safety, pharmacokinetics (PK), and pharmacodynamic (PD) biomarkers (VEGFA, VEGFC, sKIT, HGF, SDF1, and osteopontin). Results: Among 51 pts yet enrolled in this ongoing trial, 34 are currently evaluable for safety and efficacy. Median age was 62 years (range 36–80), 19 females/15 males were included, and ECOG PS was 0/1 in 23/11 pts. With a median follow-up of 15.4 months and a median duration of treatment of 3.8 months, the median OS was 9.6 months [95%CI: 5.8-13.1], exceeding the primary objective. Five pts (15%) had partial responses and 24 stable diseases (71%) by RECIST (disease control rate 85%) with 10 pts having disease control > 6 months (range 6-14 months). Among 12 evaluable patients for Choi criteria, 11 (92%) had objective responses. Median PFS was 5.2 months. Frequently reported adverse events were grade (Gr) 1-2 asthenia (80% of pts), mucositis (80%), diarrhea (60%), and hand-foot syndrome (43%). Gr 3/4 asymptomatic hematological toxicity occurred in 24% of patients (neutropenia 8 pts, thrombocytopenia 7 pt), Gr 3 hypertension was observed in 7 pts, and Gr 3 asthenia in 4 pts. PK & PD data will be updated at the meeting. Conclusions: Sunitinib (continuous daily dose of 37.5 mg) is well tolerated and shows promising activity with 9.6 months OS in second line therapy in pts with intrahepatic advanced CK. Disclosure: J. Seitz: Honoraria Support from: Merck Serono, Novartis, Amgen, Sanofi-Aventis, Pfizer, Amgen SAS, Bayer-Schering-Pharma, Lilly; L. Fartoux: Honoraria Support from: Bayer and Bristol Myer Squibb; D. Malka: Grant Support from: Amgen, Roche, Merck Serono, Sanofi-Aventis Honoraria Support from: Merck Serono, Ipsen, Celgene, Novartis, Amgen, Roche, Sanofi-Aventis, Imclone, Teva, Keocyt, Boehringer-Ingelheim; M. Bouattour: Honoraria Support from: Bayer; E. Raymond: Honoraria Support from: Bayer, Pfizer, Novartis; S. Faivre: Honoraria Support from: Bayer, Pfizer, Novartis; All other authors have declared no conflicts of interest.

Olaparib plus paclitaxel in patients with recurrent or metastatic gastric cancer: A randomized, double-blind phase II study.

4013 Background: Our multicenter study compared the efficacy of the oral PARP inhibitor olaparib plus paclitaxel (O/P) vs paclitaxel alone (P) as second-line therapy in pts with recurrent/metastatic gastric cancer (GC) (NCT01063517). As initial preclinical data suggested that responsiveness of GC cell lines to olaparib was associated with low ATM protein levels, our study was enriched for pts with low ATM tumors (ATM–) by IHC (50% randomized vs 14% screening prevalence). Methods: Eligible pts were randomized 1:1 (stratified by ATM status) to receiveolaparib 100 mg bid (tablet form) plus paclitaxel (80 mg/m2 iv on days 1, 8, 15 per 28-day cycle) or placebo plus paclitaxel until progression or investigator decision. After combination therapy, pts could take olaparib 200 mg bid monotherapy or placebo until progression. Co-primary endpoints: progression-free survival (PFS; RECIST v1.1) in all pts and ATM– pts. Secondary endpoints: overall survival (OS), objective response rate (ORR), safety. Results: 123/124 randomized pts were treated (O/P=61; P=62). Baseline characteristics were generally well balanced. Use of post-progression therapy was similar in both arms (O/P=48.4%; P=43.5%) as was median paclitaxel duration (O/P=17 wks; P=16 wks); 18 pts received monotherapy (O/P=11; P=7). More pts in the O/P than P arm had delays (79 vs 63%) and reductions (41 vs 27%) in paclitaxel dosing. The most common grade ≥3 AEs in the O/P and P arms were neutropenia (56 vs 39%) and anemia (11 vs 11%). Conclusions: Olaparib plus paclitaxel was well tolerated and led to a statistically significant improvement in OS, but not PFS, vs paclitaxel alone in both all pts and ATM– pts, with a larger benefit in ATM– pts. Clinical trial information: NCT01063517. [Table: see text]

P-0143 The Role of Chemotherapy in Advanced Biliary Tract Cancers: Clinical Experience from a Specialist UK Cancer Centre

ABSTRACT Introduction Since 2010, treatment of advanced biliary tract cancers (ABTC) has evolved with the results of the ABC-02 trial, which demonstrated that first-line chemotherapy with gemcitabine plus cisplatin (GEM-CIS) improves survival without the addition of substantial toxicity. There is no standard second line therapy for patients (pts) with progressive disease. We evaluated the outcome and toxicity of GEM-CIS as first line and FOLFOX-6 as second line therapy in pts with ABTC. Methods We retrospectively reviewed 36 pts with ABTC treated at Guy's Hospital, between May 2008 and February 2012. Of these, 32 pts received as first line GEM (1000 mgr/m2)- CIS (25 mgr/m2), each administered on days 1 and 8, every 3 weeks, for 8 cycles or until progression or unacceptable toxicities. Among the 14 pts who progressed and were eligible for second line therapy. 11 pts were treated with FOLFOX-6 (oxaliplatin 85 mgr/m2 and folinic acid 400 mgr/m2 on day 1, followed by a 5-FU bolus 400 mgr/m2 and 46-h infusion 2400 mgr/m2) every 2 weeks, for 12 cycles or until progression or unacceptable toxicities. The primary endpoint was median overall survival (mOS), and secondary endpoints were median progression free-survival (mPFS), tumour control rate (TCR)- [complete response (CR) plus partial response (PR) plus stable disease (SD)]- and toxicity. Results Pts had a median age of 65 years (range 35-79); 58% pts were women. Primary tumour sites of the 36 pts were extrahepatic (7), intrahepatic (14), gallbladder (11) and unknown (4). 23/36 pts immunophenotyped, with biliary type adenocarcinoma observed in 19, and intestinal type in 4 pts. The median number cycles of GEM-CIS administered was 4 (1-8). The mOS was 16.3 months (95%, CI 9.62-23.04), and the mPFS was 9.1 months (95%, CI 6.24-11.95). The TCR was 70%, including 13 patients with PR and 8 patients with SD. Neutropenia grade 3 and 4 was recorded in 26.7% of pts. When they relapsed, 11 pts were eligible to receive FOLFOX-6, 4 women and 7 men. A median number of 6 cycles (2-11) were administered. The mOS was 6.7 months (95%, CI 4.45-8.94), and the mPFS was 3.6 months (95%, CI 1.50-5.69). TCR observed was 45.5% (95%, CI 16.8-76.6). Among the 5 pts who responded, 2 pts achieved PR, one who had previously achieved PR and another who had progressed with GEM-CIS, and 3 patients achieved SD, who had previously achieved PR (1) and SD (2) with the first line. 4 pts who had progressed with GEM-CIS, did not respond with FOLFOX-6, and 2 pts who had achieved PR with GEM-CIS, progressed with FOLFOX-6. Neutropenia grade 3 and 4 was recorded just in 1 patient and grade 2 neurotoxicity was reported in 3 pts. Neither GEM-CIS nor FOLFOX-6 caused any treatment-related death. Conclusion We confirm that GEM-CIS is an effective and well-tolerated first line regimen for treatment of ABTC. FOLFOX-6 should be considered as a potential second-line therapy for pts who progress after GEM-CIS, and clinical trials to evaluate this further are warranted.

Improved Progression-Free Survival (PFS) of Alemtuzumab (Campath®, MabCampath®) Plus Fludarabine (Fludara®) Versus Fludarabine Alone as Second-Line Treatment of Patients with B-Cell Chronic Lymphocytic Leukemia: Preliminary Results From a Phase III Randomized Trial.

Improved Progression-Free Survival (PFS) of Alemtuzumab (Campath®, MabCampath®) Plus Fludarabine (Fludara®) Versus Fludarabine Alone as Second-Line Treatment of Patients with B-Cell Chronic Lymphocytic Leukemia: Preliminary Results From a Phase III Randomized Trial.

Second-line chemotherapy with FOLFIRI in patients with metastatic gastric cancer (MGC) not previously treated with fluoropyrimidines

4549 Background: No established second-line chemotherapy exists for patients (pts) with MGC failing to respond or progressing after first-line chemotherapy. This study was designed to determine the efficacy and safety of FOLFIRI combination used as second-line therapy in pts with MGC not previously treated with regimens containing fluoropyrimidines. Methods: Pts with measurable distant metastases, previously treated with a combination of epirubicin, docetaxel and cisplatin or oxaliplatin as first-line therapy, received irinotecan 180 mg/mq (150 mg/mq in pts &gt;70 ys old) as a 1-h infusion day 1; leucovorin 100 mg/mq/day followed by bolus fluorouracil (FU) 400 mg/mq and a 22-h infusion of FU 600 mg/mq day 1–2, every 2 weeks for a maximum of 12 cycles or until disease progression, unacceptable toxicity or patients refusal. Endpoints were response rate (RR), time to progression (TTP), overall survival (OS) and safety. Results: 38 pts were enrolled: M/F 23/15; median age 66 ys (34–75); median ECOG PS 1 (0–2); number of metastatic sites 1/2/≥3: 9/18/11 pts, respectively. A total of 223 cycles was performed (median 6, range 2–12). One CR and 8 PR were observed for an overall RR of 24% (95% CI, 11–39 %). Disease remained stable in 11 pts. Median TTP was 4.0 months (95% CI, 2.9–5.1) and median OS was 6.2 months (95% CI, 4.7–7.7). Grade 3/4 neutropenia, thrombocytopenia and anemia occurred in 29%, 3% and 8% of pts, respectively. Febrile neutropenia was seen in 2 pts (5%). Other grade 3 toxicities included diarrhea in 5 pts (13%), mucositis in 2 pts (5%) and vomiting in 2 pts (5%). There were no treatment related deaths. Conclusions: FOLFIRI is an active and well tolerated second-line regimen for MGC pts not previously treated with fluoropyrimidines. No significant financial relationships to disclose.

Phase I/II study of MKC-1 and pemetrexed (PEM) as second-line therapy in patients (pts) with advanced non-small cell lung cancer (NSCLC)

e19005 Background: MKC-1 is a novel oral cell cycle inhibitor with preclinical activity against NSCLC cell lines including multi-drug resistant lines, and single agent activity in NSCLC pts. Binding targets of MKC-1 include microtubules, members of the importin-β family and AKT-mTOR. This phase 1/2 study evaluated MKC-1 in combination with PEM as second-line therapy in pts with advanced NSCLC. Methods: Eligible pts had NSCLC previously treated with one regimen for metastatic disease or disease progression within one year following adjuvant and neoadjuvant therapy. Phase 1 dose escalation used 3+3 design. Phase 2 pts were treated with MKC-1 at 75 mg/m2 given p.o. BID for 14 days along with PEM at 500 mg/m2 given i.v. on day 1 of each 21 day cycle. Following 4 cycles of combined treatment, single agent MKC-1 was continued as maintenance therapy. An interim analysis after 17 pts in phase 2 would allow accrual to continue provided one response was confirmed. Results: 27 pts were enrolled (8 in phase 1 and 19 in phase 2). Median age/PS for phase 2 is 64/1 and 89% had adenocarcinoma. Total # of treatment cycles to date for phase 2 pts is 95, with a median of 4 cycles. Of the 19 phase 2 pts, 18 were evaluable for tumor response. The best response was confirmed PR, noted in 3 pts. 5 additional pts (4 confirmed) had minor responses (&gt;10% but &lt;30% shrinkage). One additional pt continues on study with stable disease for &gt;18 months. In phase 2 (n=19), all grade toxicities were anorexia (59%), fatigue (63%), nausea (58%), and dyspnea (48%). Grade 3/4 toxicities included fatigue (26%); neutropenia (22%); dyspnea, anorexia, AST and ALT elevation (11% each); nausea and constipation (5% each). 7 pts had at least one dose reduction of both PEM and MKC-1 and 3 additional pts had only MKC-1 reduced. Median PFS was 86 days with two pts continuing on study (treated for 530+ days and 140+ days, respectively). Conclusions: The phase 2 dose of MKC-1 (75 mg/m2 BID) and PEM (500 mg/m2) has been defined. The combination is well tolerated with 17% of patients achieving a confirmed PR thus far. A decision to proceed with additional accrual in this single arm study versus initiating a randomized phase 2 study of this combination is pending. [Table: see text]