Prior Therapy For Metastatic Disease Research Articles

Pembrolizumab for advanced prostate adenocarcinoma: findings of the KEYNOTE-028 study

BackgroundPatients with castration-resistant prostate cancer derive only modest clinical benefit from available therapies. Blockade of the inhibitory programmed death 1 (PD-1) receptor by monoclonal antibodies has been effective in several malignancies. Results from the prostate adenocarcinoma cohort of the nonrandomized phase Ib KEYNOTE-028 trial of pembrolizumab in advanced solid tumors are presented. Materials and methodsKey eligibility criteria included advanced prostate adenocarcinoma, unsuccessful standard therapy, measurable disease per Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1), and PD-1 ligand (PD-L1) expression in ≥1% of tumor or stromal cells. Patients received pembrolizumab 10mg/kg every 2weeks until disease progression or intolerable toxicity for up to 24months. Primary end point was objective response rate (ORR) per RECIST v1.1 by investigator review. ResultsMedian patient age in this cohort (n=23) was 65years; 73.9% of patients received at least two prior therapies for metastatic disease. There were four confirmed partial responses, for an ORR of 17.4% [95% confidence interval (CI) 5.0%–38.8%]; 8 of 23 (34.8%) patients had stable disease. Median duration of response was 13.5months. Median progression-free survival (PFS) and overall survival (OS) were 3.5 and 7.9months, respectively; 6-month PFS and OS rates were 34.8% and 73.4%, respectively. One patient remained on treatment at data cutoff. After a median follow-up of 7.9months, 14 (60.9%) patients experienced treatment-related adverse events (TRAEs), most commonly nausea (n=3, 13.0%). Four (17.3%) experienced grade 3/4 TRAEs: grade 3 peripheral neuropathy, grade 3 asthenia, grade 3 fatigue, and grade 4 lipase increase. No pembrolizumab-related deaths or discontinuations occurred. ConclusionPembrolizumab resulted in durable objective response in a subset of patients with heavily pretreated, advanced PD-L1–positive prostate cancer, and its side effect profile was favorable. ClinicalTrials.gov IdentifierNCT02054806

Abstract P1-16-02: Phase II study of the feasibility and safety of radium-223 dichloride in combination with hormonal therapy and denosumab for the treatment of patients with hormone receptor-positive breast cancer with bone-dominant metastasis

Abstract Background Radium-223 dichloride (Ra-223) is a therapeutic alpha particle-emitting radiopharmaceutical compound which have antitumor effect targeted on bone metastases. Alpha particles induces double strand DNA breaks and localized cytotoxic effect to cancer cells with limiting harm on normal tissues. We are conducting a phase II clinical trial of combination of Ra-223, hormonal therapy, and denosumab treatment in patients with hormone receptor (HR)-positive bone-dominant metastatic breast cancer (NCT02366130). In this preliminary analysis of the study, we aimed to evaluate the feasibility and safety of this combination therapy. Methods This single-center phase II study seeks to determine the efficacy and safety of Ra-223 in combination with hormonal therapy and denosumab. Major eligibility criteria include HR-positive breast cancer with bone and/or marrow predominant metastases. Patients with two or more visceral metastases were not eligible. There was no limit in the number of prior hormonal therapies in the metastatic setting. Patients received Ra-223 injection (55 kBq/kg intravenously) on day 1 of the study and then every 4 weeks thereafter for 6 cycles. Patients were also administered a single hormonal agent (i.e., tamoxifen, aromatase inhibitor, or fulvestrant at standard doses) daily and denosumab (120 mg subcutaneously) every 4 weeks. For this analysis, adverse events (AEs) were summarized using descriptive statistics. Results A total of 25 patients were enrolled and 22 were evaluable between March 2015 and December 2016. Median age was 58.5 years (range 31-79), and 59% of patients were postmenopausal. ECOG performance status was 0 in 16 patients (73%), and 1 in six patients (27%). HER2/neu was positive in only one patient. Four patients (18%) were de novo metastasis, no patients had visceral metastasis, and multiple bone metastases in 20 patients (91%) vs. focal metastasis in 2 (9%). Median time from diagnosis of bone metastasis was 4.8 months (range 0.5-96.6). Prior therapy for metastatic disease consisted of hormonal therapy in 50% of the patients (eight patients with one line and three patients with two lines), chemotherapy (9%), palbociclib (14%), radiation to bone metastasis (50%), and bone-supportive therapy (27% with zoledronic acid, 27% with denosumab). The median number of cycles of Ra-223 administered was 6 (range 4-6). The median follow-up time was 4 months (range 2-8). There were no grade 3 or 4 AEs. Major non-hematological grade 1 and 2 AEs were bone pain (77%), fatigue (45%), nausea (36%), diarrhea (32%), AST/ALT elevation (23%), hot flashes (23%), and headache (18%). The most common hematological AEs were grade 1 or 2 neutropenia (23%), anemia (14%), and thrombocytopenia (18%). There was no treatment delay or discontinuation due to AEs. Conclusion Our results suggest that the addition of Ra-223 to hormonal therapy and denosumab is a feasible and safe combination therapy in patients with HR-positive breast cancer with bone-dominant metastasis. We continue to enroll patients in the phase II trial to evaluate the efficacy of the treatment. Citation Format: Tahara RK, Fujii T, Saigal B, Ibrahim NK, Damodaran S, Barcenas CH, Murray JL, Chasen BA, Shen Y, Liu DD, Hortobagyi GN, Tripathy D, Ueno NT. Phase II study of the feasibility and safety of radium-223 dichloride in combination with hormonal therapy and denosumab for the treatment of patients with hormone receptor-positive breast cancer with bone-dominant metastasis [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P1-16-02.

Phase II study of epacadostat with pembrolizumab in metastatic or unresectable gastroesophageal junction and gastric adenocarcinoma requiring paired biopsies.

TPS191 Background: Gastroesophageal junction (GEJ) and gastric adenocarcinomas constitute a major health problem worldwide. Gastric cancer is the fourth most prevalent malignancy and the second leading cause of cancer death worldwide. Furthermore, the incidence of adenocarcinoma of the esophagus, GEJ and gastric cardia has risen faster than any other malignancy in the last 25 years in the United States and other Western countries. Cytotoxic chemotherapy remains the standard treatment, with progression free survival (PFS) for advanced disease of 4 to 6 months and median overall survival (OS) of 7 to 10 months. Pembrolizumab, a PD-1 inhibitor, was recently approved for advanced gastric or gastroesophageal junction adenocarcinoma whose tumors express PD-1, on the basis of a response rate of 13% seen in KEYNOTE 059 (NCT02335411). Combination immunotherapies are hypothesized to build on this response. Methods: This is a single arm, phase II clinical trial of epacadostat, a novel inhibitor of the enzyme indoleamine 2,3 dioxygenase-1 (IDO-1), in combination with pembrolizumab, in metastatic or unresectable gastroesophageal junction or gastric adenocarcinoma. A 6-month PFS of 20% with single agent pembrolizumab is the basis for the null hypothesis. We will enroll 30 patients over 18 months and follow patients for at least 6 months. This design has 80% power to reject a 20% PFS rate, if the true PFS is 39%. Eligible patients must have: adenocarcinoma of the distal esophagus, gastroesophageal junction or stomach; progression on at least one line of prior therapy for metastatic disease, and for HER2+ disease should have received prior trastuzumab; ECOG performance status 0 or 1; willing to undergo two newly-obtained biopsies - before and on-treatment, provided the procedure is not deemed high-risk and is clinically feasible. Notably, PDL-1 expression is not required. The primary endpoint is 6-month PFS, with secondary endpoints of response rate (RR), OS, and the safety and tolerability of the combination. Furthermore, comprehensive immune profiling from patient blood and tumor tissue will be performed. The study opened to accrual in September 2017 (NCT03196232). Clinical trial information: NCT03196232.

Eribulin mesylate in advanced breast cancer: retrospective review of a single institution experience

Purpose: Eribulin is a non-taxane microtubule inhibitor, which can be used after anthracycline and taxane treatment in patients with metastatic breast cancer (MBC). The purpose of this study was to investigate the efficacy and safety of eribulin monotherapy in heavily pretreated MBC patients. Materials and methods: This was a single institution retrospective analysis of MBC patients treated with eribulin from August 2012 to May 2016. These patients had received at least 2 lines of prior therapy for metastatic disease. Patients received standard doses of eribulin and were monitored for responses. Results: Forty-four patients were included in this analysis who received at least one cycle of eribulin were identified. Median patient age was 58 years (range 43-76). All were pretreated with anthracyclines and taxanes and 72% with capecitabine. Brain metastases were present in 9 (20%) patients at the time of initial eribulin administration. Most patients were heavily pretreated with a median of 3 (range 2-7) previous chemotherapy lines prior to eribulin and had significant visceral involvement (median 3 organs). A median of 5 cycles of eribulin was delivered. There were no complete responses; partial responses were 20% (9/44) with a 54,5% of disease control rate (25/44), progressive disease was seen on eribulin in 44,5% (19/44) patients. The median progression-free survival was 4.5 months (95% CI 2.8- 6,2) and median overall survival was 12 months (95% CI 7.8-16.4). Only one patient experienced grade 3 neurotoxicity. Three patients (6,8%) stopped eribulin due to fatigue grade 3. No hypersensitivity reactions and no toxic deaths were observed. Conclusion: Eribulin monotherapy is an effective and safe regimen for MBC patients. In our experience, eribulin maintains its activity out of clinical trials, without unexpected toxicities.

Molecular profiling of advanced pancreatic cancer (PC) patients from a phase I/II study using circulating tumor DNA.

4124 Background: PC has a poor prognosis with a 5-year survival of 9%. Targeted therapies have yet to demonstrate improved outcomes in this disease. Circulating tumour DNA (ctDNA) may be used as a non-invasive method for the detection and quantification of genomic abnormalities. We performed a retrospective-prospective study to assess molecular alterations in the ctDNA of advanced PC patients. Methods: Plasma samples were banked from patients enrolled in the previously reported Phase Ib/II trial of gemcitabine with placebo or vismodegib (NCT01064622; Catenacci et al JCO 2015). Eligible patients had unresectable PC and no prior therapy for metastatic disease. Patient samples ( < 3ml) collected pre-treatment and at regular intervals and stored for ~6-8 years were analyzed using InVision (enhanced tagged-amplicon sequencing) for “hotspot” regions of 34 genes, including KRAS (exons 2 and 3), and select full gene coverage. Results: Of 113 patients enrolled in the trial, a cohort of 72 patients were included in this study. Baseline plasma ctDNA profiling detected any genomic event in 88% of patients (SNV/indels found at range of 0.07%-23% allele fraction (AF) with 20% detected at < 0.5% AF). Patients had between 1-5 mutations (median, 2): KRAS mutations were detected in 80% of patients tested, of which 86% had concurrent KRAS/TP53 mutation(s) and 16% with concurrent KRAS/TP53/CDK2NA. Of note, 2 cases presented with IDH1 point mutations (R132C, R132H). An ERBB2 amplification and a FGFR2 amplification were detected in 2 individuals. An update on the analyses will include serial ctDNA testing during treatment and correlation with outcomes. Conclusions: ctDNA analysis of this cohort of banked PC plasma samples described the landscape of genomic aberrations at baseline and over time, including rare but potentially important actionable events including ERBB2 and FGFR2 amplifications and IDH1 mutation. We demonstrate a sensitive method for re-analysing trial outcomes, despite limiting plasma volume and time lapse since samples were collected.

Molecular analysis of thymic epithelial tumors (TETs): A report by The Cancer Genome Atlas (TCGA) research network.

8520 Background: Thymoma (T) and thymic carcinoma (TC) are the most common malignancies of the anterior mediastinum. Additionally, thymoma has an unique association with autoimmune disorders, notably myasthenia gravis (MG). Histologic classification of TETs has been largely based on the gross description of the epithelial cell appearance and the relative abundance of associated lymphocytes. A comprehensive molecular analysis of TETs has not heretofore been conducted. Methods: The TCGA Research Network conducted multi-platform analyses of 117 TETs (T = 105; TC = 10 and micronodular T = 2), which included whole-exome, transcriptome, methylome and targeted proteome analysis. Patient characteristics: median age = 60 years (range 17-84); M:F (%) = 52:48; Masaoka Stage (I-36, IIA-39, IIB-19; III-15; IVA-1; IVB-5); mg was present in 32 patients. No patient had prior therapy for metastatic disease, but 14 had prior chemotherapy and 39 had prior radiation therapy in adjuvant setting. WHO histologic classification (blinded review) revealed A = 10; A/B = 48, B1 = 12, B2 = 25, B3 = 10, micronodular T = 2 and TC = 10. Results: T has one of the lowest mutational loads of any tumor in the TCGA. A unique transcription factor, GTF2I, was the most commonly observed mutation in WHO Types A and A/B. All GTF2I mutations were exclusively at the amino acid 424 locus. This is the only tumor with this specific mutation within the entire TCGA database. HRAS, NRAS and TP53 mutations were less commonly noted among all TETs. Four distinct molecular-driven subtypes of TETs were identified that strongly correlated with the current WHO histologic classification. Increased aneuploidy and overexpression of muscle auto-antigens were associated with mg phenotype. Conclusions: Based on molecular analysis, four clusters were identified that correlated strongly with the current WHO Histologic Classification. Also identified was a unique mutation in GTF2I, which was associated with WHO Type A and A/B thymoma. This international effort represents the largest and most comprehensive molecular analysis of TETs conducted to date is expected to have important clinical and translational implications for this rare disease.

SUNSHINE: Randomized double-blind phase II trial of vitamin D supplementation in patients with previously untreated metastatic colorectal cancer.

3506 Background: In prospective observational studies of mCRC patients, higher plasma levels of 25-hydroxyvitamin D have been associated with improved progression-free (PFS) and overall survival (OS), but the role of vitamin D supplementation in the treatment of mCRC is unknown. Methods: SUNSHINE was a multi-center double-blind phase II randomized controlled trial in previously untreated mCRC patients. Patients were eligible if they had histologically confirmed mCRC, no prior therapy for metastatic disease, ECOG PS 0-1, and were not taking vitamin D >2,000 IU/day x 1 year. All subjects received standard treatment with mFOLFOX6 + bevacizumab with 1:1 randomization to concurrent: HiVitD (vitamin D3 po 8,000 IU/d x 2 wks as loading dose followed by 4,000 IU/d) or LowVitD (standard vitamin D3 400 IU/d) until disease progression, intolerable toxicity, or withdrawal of consent. The primary endpoint was PFS, with the sample size designed to provide 80% power to detect a HR of 0.66 for PFS at a 1-sided alpha=0.2. Results: From April 2012 to November 2016, 139 patients were randomized. Median age was 54 yrs (range 24-82), 57% were male, 77% were white, and 7% had received prior adjuvant chemo. Baseline characteristics were balanced between arms except ECOG PS = 0 was 42% vs. 60% in HiVitD vs. LowVitD. Median follow-up was 16.1 mos (range 0-45.9) and median compliance with VitD capsules was 98%. Patients randomized to HiVitD experienced longer PFS than those receiving LowVitD (median PFS, 12.4 vs. 10.7 mos, respectively; log rank P=0.03). After multivariate adjustment for prognostic variables, HR was 0.66 (95% CI, 0.45-0.99, 2-sided P=0.04). Comparing HiVitD vs LowVitD, RR was 58% vs. 63% ( P=0.54) and disease control rate was 100% vs. 94% ( P=0.05). The most common grade 3-4 toxicities were as expected for FOLFOX-bevacizumab, and none were related to vitamin D. Currently, 14 patients are still actively receiving treatment, and OS data are not yet mature. Conclusion: SUNSHINE met its prespecified primary endpoint, with patients randomized to HiVitD experiencing longer PFS compared to those randomized to LowVitD. A larger confirmatory phase III randomized trial appears warranted. Clinical trial information: NCT01516216.

Pembrolizumab (pembro) plus low-dose ipilimumab (ipi) for patients (pts) with advanced renal cell carcinoma (RCC): Phase 1 KEYNOTE-029 study.

510 Background: The CTLA-4 antibody ipi and the PD-1 antibody pembro have demonstrated efficacy in pts with advanced malignancies. While these immune checkpoint inhibitors have shown robust activity as monotherapy, combination therapy may further improve outcomes. KEYNOTE-029 (NCT02089685) is a phase 1/2 study designed to assess the safety and efficacy of pembro + ipi or pegylated interferon alfa-2b (IFN-α) in pts with advanced melanoma or RCC. Here we report data from the phase 1 portion of the study in pts with RCC treated with pembro + ipi. Methods: Pts ≥18 years with advanced/unresectable or metastatic clear cell RCC who received ≥1 prior therapy for metastatic disease, had ≥1 measurable lesion per RECIST v1.1, and ECOG PS 0-1 were enrolled. Pts received pembro 2 mg/kg Q3W + low-dose ipi (1 mg/kg Q3W for 4 doses) until disease progression, unacceptable toxicity, investigator/patient decision, or 2 years of pembro treatment. AEs were monitored throughout treatment and for 30 days thereafter and graded per NCI CTCAE v4.0. Primary end point was safety; primary efficacy end point was ORR assessed per RECIST v1.1 by independent central imaging vendor review. Results: As of the March 17, 2016, data cutoff, 10 pts with RCC received pembro + low-dose ipi. 60% were male, 70% were white, median age was 61 years (range, 48-70 years), 40% received 2 prior lines of therapy, and 40% received prior immunotherapy. With a median follow-up of 17.4 months (0.9-23.5 months), 70% of pts experienced treatment-related AEs (TRAEs) of any grade, most commonly fatigue (30%); and 50% experienced grade 3/4 TRAEs, most commonly increased lipase (20%). 50% of pts discontinued pembro because of TRAEs, most commonly increased lipase (40%). There were no treatment-related deaths. ORR was 20% (2 partial responses); median duration of response was not reached (14.1+-17.1 months+). An additional 3 pts had stable disease; disease control rate was 50%. Conclusions: The combination of pembro + low-dose ipi for 4 doses, followed by pembro monotherapy, demonstrates a manageable toxicity profile and preliminary antitumor activity in pts with advanced RCC. Clinical trial information: NCT02089685.

KEYNOTE-177: Randomized phase III study of pembrolizumab versus investigator-choice chemotherapy for mismatch repair-deficient or microsatellite instability-high metastatic colorectal carcinoma.

TPS815 Background: A subset of colorectal carcinomas (CRCs) are characterized by mismatch repair (MMR) deficiency resulting in microsatellite instability (MSI). MSI-high tumors contain high levels of lymphocyte infiltrates and express the PD-1 immune checkpoint receptor and its ligand, PD-L1. In the phase 2 KEYNOTE-016 study, the anti–PD-1 antibody pembrolizumab demonstrated antitumor activity against MMR-deficient tumors in patients with treatment-refractory metastatic CRC. KEYNOTE-177 (ClinicalTrials.gov, NCT02563002) is an international, randomized, open-label, phase 3 study of pembrolizumab versus standard-of-care (SOC) chemotherapy in first-line MMR-deficient or MSI-high metastatic CRC. Methods: Key eligibility criteria include age ≥18 years, confirmed MSI-high or MMR-deficient metastatic CRC, ECOG PS 0-1, no active autoimmune disease or brain metastases, and no prior therapy for metastatic disease. ~270 patients will be randomly assigned 1:1 to receive either pembrolizumab 200 mg every 3 weeks or investigator's choice of SOC chemotherapy (mFOLFOX6 or FOLFIRI alone or in combination with bevacizumab or cetuximab, chosen before randomization). Treatment is to continue until progressive disease (PD), unacceptable toxicity, patient/investigator decision, or completion of 35 cycles (pembrolizumab only). Response is to be assessed every 9 weeks per RECIST v1.1 by central imaging vendor review and per RECIST adapted for immunotherapy response patterns. Eligible patients may continue pembrolizumab beyond initial RECIST-defined progression. Patients in the SOC arm who have PD and meet crossover criteria may be eligible to receive pembrolizumab for up to 17 treatment cycles. AEs are to be assessed throughout treatment and for 30 days thereafter (90 days for serious AEs) and graded per NCI CTCAE v4.0. Patients are to be followed up for survival every 9 weeks. The primary end point is PFS per RECIST v1.1; key secondary end points include OS and ORR. Enrollment in KEYNOTE-177 is ongoing. Clinical trial information: NCT02563002.

Updated results for the advanced esophageal carcinoma cohort of the phase Ib KEYNOTE-028 study of pembrolizumab (MK-3475).

7 Background: PD-L1 and PD-L2 expression have been associated with poor prognosis in esophageal cancer. Pembrolizumab (pembro) is a humanized monoclonal antibody against PD-1 that blocks interaction with PD-L1 and PD-L2. The multicohort, phase Ib KEYNOTE-028 (NCT02054806) trial was designed to evaluate the safety and efficacy of pembro in patients (pts) with PD-L1+advanced solid tumors. We report updated results from the esophageal carcinoma cohort of this study. Methods: Key eligibility criteria included advanced squamous cell carcinoma or adenocarcinoma of the esophagus or gastroesophageal junction, PD-L1 expression in tumor or stroma determined centrally by IHC, failure of standard therapy, and ECOG PS 0-1. Pts received pembro 10 mg/kg every 2 wk for up to 2 y or until confirmed progression, intolerable toxicity, or investigator decision. Response was assessed every 8 wk for the first 6 mo and every 12 wk thereafter. Primary end point was ORR per RECIST v1.1 by investigator review. Results: Of the 23 pts enrolled, median age was 65 y, 82.6% were men, 73.9% had squamous histology, and 87.0% received ≥ 2 prior therapies for metastatic disease. As of the Aug 4, 2015 data cutoff date, median follow-up duration was 31 wk (range 5.7-71). Nine pts (39.1%) had drug-related adverse events (DRAEs), most commonly decreased appetite (n = 3, 13.0%). Four pts (17.4%) had grade 3 DRAEs, with only decreased lymphocytes reported in > 1 pt (n = 2, 8.7%). No pts died or discontinued pembro due to a DRAE. Immune-mediated AEs, regardless of attribution by investigator, were grade 2 hypothyroidism (n = 2, 8.7%) and adrenal insufficiency (n = 1, 4.3%). ORR was 30.4% (95% CI 13.2-52.9), and the stable disease rate was 13.0% (n = 3, 95% CI 2.8-33.6); 6-mo and 12-mo PFS rates were 30.4% and 21.7%. Five of 7 responses were ongoing at data cutoff, with a median duration of response of 40.0 wk (range 24.1+ to 46.1+). Analysis of the relationship between PD-L1 expression level and antitumor activity is ongoing. Conclusions: Pembro continued to show manageable toxicity and durable antitumor activity in pts with heavily pretreated, PD-L1+ advanced esophageal carcinoma. Phase II and III trials of pembro in pts with esophageal carcinoma are ongoing. Clinical trial information: NCT02054806.

KEYNOTE-177: First-line, open-label, randomized, phase III study of pembrolizumab (MK-3475) versus investigator-choice chemotherapy for mismatch repair deficient or microsatellite instability-high metastatic colorectal carcinoma.

TPS789 Background: Mismatch repair deficient (dMMR) tumors are characterized by high mutational load and lymphocyte infiltration and may be good candidates for immune checkpoint blockade. Pembrolizumab is a monoclonal antibody against PD-1 that is designed to block its interaction with PD-L1 and PD-L2 and thus allow an antitumor immune response. In the KEYNOTE-016 proof-of-concept study, pembrolizumab showed promising antitumor activity against dMMR tumors in patients (pts) with treatment-refractory metastatic colorectal carcinoma (mCRC). KEYNOTE-177 is an international, randomized trial designed to evaluate the efficacy and safety of pembrolizumab compared with standard-of-care (SOC) chemotherapy in the first-line setting for dMMR or microsatellite instability-high (MSI-H) mCRC. Methods: Key eligibility criteria include age ≥ 18 y, confirmed MSI-H or dMMR mCRC, ECOG PS 0-1, no active autoimmune disease or brain metastases, and no prior therapy for metastatic disease. Pts will be randomized 1:1 to receive either pembrolizumab 200 mg Q3W or investigator’s choice of SOC chemotherapy. Chemotherapy must be chosen prior to randomization; options include mFOLFOX6 or FOLFIRI alone or in combination with bevacizumab or cetuximab. Treatment will continue until PD, unacceptable toxicity, pt/investigator decision, or completion of 35 cycles (pembrolizumab only). Response will be evaluated every 9 wk per RECIST v1.1 by central review and per RECIST adapted for immunotherapy response patterns. Eligible pts may continue pembrolizumab beyond initial RECIST-defined progression. Pts in the SOC arm who have PD and meet crossover criteria may be eligible to receive pembrolizumab for up to 17 treatment cycles. AEs will be assessed throughout treatment and for 30 d thereafter (up to 90 d for serious AEs) and graded per NCI CTCAE v4.0. Pts will be followed for survival every 9 wk. PFS per RECIST v1.1 is the primary end point; OS and ORR are key secondary end points. Other end points include duration of response and health-related quality of life. Planned enrollment in KEYNOTE-177 is 270 pts.

Pembrolizumab (MK-3475) plus 5-fluorouracil (5-FU) and cisplatin for first-line treatment of advanced gastric cancer: Preliminary safety data from KEYNOTE-059.

161 Background: Standard first-line treatment for advanced gastric cancer includes combination chemotherapy with a platinum agent and a fluoropyrimidine. The anti–PD-1 humanized monoclonal antibody pembrolizumab (pembro) has shown promising antitumor activity as monotherapy in patients (pts) with advanced gastric cancer. We report preliminary safety data for pts with advanced gastric cancer treated with pembro + cisplatin and 5-FU in the multicohort, phase 2 KEYNOTE-059 study (NCT02335411). Methods: Eligible pts were aged ≥ 18 y and had HER2– relapsed or metastatic gastric or gastroesophageal junction adenocarcinoma, ECOG PS 0-1, and no prior therapy for metastatic disease. Pts received pembro 200 mg + 5-FU 800 mg/m2 (or capecitabine 1000 mg/m2 in Japan) + cisplatin 80 mg/m2 Q3W for 6 cycles followed by pembro + 5-FU for up to 2 y or until confirmed progression, intolerable toxicity, or investigator decision. Primary end point was safety and tolerability of the combination. Results: Of the 17 pts enrolled (10 from Asia, 7 from outside Asia), 70.6% were men, and median age was 58.0 y. Three pts (17.6%) had a prior gastrectomy—2 total, 1 partial. As of the Aug 12, 2015, data cutoff date, median follow-up duration was 3.6 mo (range 2.6-5.4), and pts received a median of 5 treatment cycles (range 3-7). Only 1 pt (5.9%) discontinued treatment (due to progressive disease). There were no treatment-related deaths or discontinuations. Twelve pts (70.6%) experienced treatment-related adverse events (AEs) of any grade, most commonly neutropenia/decreased neutrophils (n = 7, 41.2%), stomatitis (n = 6, 35.3%), and decreased appetite (n = 5, 29.4%). Eight pts (47.1%) experienced ≥ 1 grade 3-4 treatment-related AE; only neutropenia/decreased neutrophils (n = 4 [23.5%] grade 3, n = 3 [17.6%] grade 4) occurred in > 1 pt. AEs of interest based on immune etiology, regardless of attribution by investigator, were grade 2 infusion-related reaction and grade 2 pruritus (n = 1 [5.9%] each). Conclusions: Preliminary data from KEYNOTE-059 suggest the combination of pembro, cisplatin, and 5-FU has a manageable safety profile as first-line therapy in pts with advanced gastric cancer. Clinical trial information: NCT02335411.

Eribulin in heavily pretreated metastatic breast cancer: A tertiary care center experience from India

Heavily pretreated metastatic breast cancer (MBC) remains a major therapeutic challenge with limited treatment options this. Eribulin, an anti-microtubule agent, has been recently approved for this indication. There are sparse data from the Asian region for eribulin and merits exploration. This was a single institution retrospective analysis of MBC patients treated with eribulin from 2013 to 2014. These patients had received at least 2 lines of prior therapy for metastatic disease. Patients received standard doses of eribulin and were monitored for toxicity and responses. Eighteen patients were included in this analysis. They had received a median of 6 lines of therapy previously (including adjuvant treatment) and had significant visceral involvement (median 3 organs). A median of 4 cycles of eribulin was delivered. There were no complete responses; partial responses were seen in 33% (6/18), stable disease status in 28% (5/18) patients, and progressive disease on eribulin in 39% (7/18) patients. The median progression-free survival was 15 weeks (3.5 months), and median overall survival was 27 weeks (6.2 months). Significant Grade 3/4 toxicities seen included peripheral neuropathy in 28% (5/18) and neutropenia in 28% (5/18) of patients while dose reductions were required in 22% (4/18) of patients. Eribulin offers a viable, well-tolerated regimen that provides meaningful clinical benefit in Indian patients with MBC.

Abiraterone acetate, exemestane or the combination in postmenopausal patients with estrogen receptor-positive metastatic breast cancer

Androgen receptor (AR) signaling and incomplete inhibition of estrogen signaling may contribute to metastatic breast cancer (MBC) resistance to a nonsteroidal aromatase inhibitor (NSAI; letrozole or anastrozole). We assessed whether combined inhibition of androgen biosynthesis with abiraterone acetate plus prednisone and estradiol synthesis with exemestane (E) may be of clinical benefit to postmenopausal patients with NSAI-pretreated estrogen receptor-positive (ER+) MBC. Patients (N = 297) were stratified by the number of prior therapies for metastatic disease (0-1 versus 2) and by prior NSAI use (adjuvant versus metastatic), and randomized (1 : 1 : 1) to receive oral once daily 1000 mg abiraterone acetate plus 5 mg prednisone (AA) versus AA with 25 mg E (AAE) versus 25 mg E alone (E). Each treatment arm was well balanced with regard to the proportion of patients with AR-positive breast cancer. The primary end point was progression-free survival (PFS). Secondary end points included overall survival, clinical benefit rate, duration of response, and overall response rate. There was no significant difference in PFS with AA versus E (3.7 versus 3.7 months; hazard ratio [HR] = 1.1; 95% confidence interval [CI] 0.82-1.60; P = 0.437) or AAE versus E (4.5 versus 3.7 months; HR = 0.96; 95% CI 0.70-1.32; P = 0.794). Increased serum progesterone concentrations were observed in both arms receiving AA, but not with E. Grade 3 or 4 treatment-emergent adverse events associated with AA, including hypokalemia and hypertension, were less common in patients in the E (2.0% and 2.9%, respectively) and AA arms (3.4% and 1.1%, respectively) than in the AAE arm (5.8% for both). Adding AA to E in NSAI-pretreated ER+ MBC patients did not improve PFS compared with treatment with E. An AA-induced progesterone increase may have contributed to this lack of clinical activity. NCT01381874.

398P - Lapatinib and Capecitabine in the Treatment of Her2-Positive Breast Cancer with Brain Metastases

ABSTRACT Aim: Brain metastases (BM) are a common clinical problem in patients with HER2-positive metastatic breast cancer. The retrospective study was designed to evaluate the efficacy of lapatinib and capecitabine in this group of advanced breast cancer patients. Methods: Group of 83 patients with HER-2 positive metastatic breast cancer receiving lapatinib and capecitabine between July 2007 and May 2013 was retrospectivelly evaluated. Patients received lapatinib 1250 mg once daily and capecitabine 2000 mg/m(2) daily in two doses, days 1-14, every 21 days. All patients were treated with trastuzumab either in adjuvant or metastatic setting and most of the patients (90%) received prior therapy for metastatic disease. Patients were assessed for median time to progression (mTTP) and toxicity of treatment. Results: Among 83 patients 19 (23%) had brain metastases. Median time to progression was 35 weeks in patients with BM and 28 weeks in patients without BM (P = 0.028). Among adverse events the most common were hand-foot syndrome (59% of patients) and diarrhoea (42%). All toxicities were well manageable. Conclusions: Lapatinib plus capecitabine is effective and well tolerated treatment in breast cancer patients with brain metastases. Disclosure: All authors have declared no conflicts of interest.

Abstract P2-16-01: A randomized, phase II, multicenter, double-blind, placebo-controlled trial evaluating onartuzumab with or without bevacizumab in combination with weekly paclitaxel in locally recurrent or metastatic triple-negative breast cancer (TNBC)

Abstract Background: Dysregulation of the hepatocyte growth factor (HGF)/MET pathway has been observed in many malignancies. In patients with TNBC, overexpression of MET has been shown to be associated with poor prognosis. Onartuzumab (MetMAb) is a recombinant, humanized, monovalent, monoclonal antibody directed against MET, which selectively blocks ligand binding and subsequent HGF activation. A recent phase 2 trial demonstrated improved progression-free survival (PFS) and overall survival (OS) when onartuzumab was added to erlotinib for patients with MET 2+/3+ non-small-cell lung cancer (NSCLC). Methods: Patients with locally recurrent or metastatic TNBC who had received 0 or 1 prior therapies for metastatic disease were enrolled, provided tumor sample, and randomized (1:1:1) to receive paclitaxel (P) + bevacizumab (B) + onartuzumab (O); P+O; or P+B. Dosing regimens were given IV q4w: P 90 mg/m2 d1, 8 & 15; B 10 mg/kg d1 & 15; O 10 mg/kg d1 & 15. Treatment continued until disease progression or unacceptable toxicity or death; crossover was not permitted. Stratification was by number of metastatic sites (<3, ≥3), number of prior MBC regimens (1 vs 2), and disease-free interval for first-line patients (≤6 months, >6 months). The primary endpoint was PFS; secondary endpoints included OS, objective response rate (ORR), and safety. MET immunohistochemistry (IHC) was performed centrally for exploratory analyses. Results: 185 patients were enrolled from 30 US and 37 EU sites: median age was 53 years (range 30-79); 77% and 23% were treated in the first- and second-line settings, respectively. Baseline characteristics were balanced. Efficacy data for the ITT population are shown in Table 1. The distribution of MET expression using the NSCLC diagnostic algorithm is shown in Table 2. The MET 2+/3+ group was too small for efficacy analyses. Frequently observed AEs (all grades) included peripheral edema (58% vs 59% vs 18%), fatigue (47% vs 41% vs 48%) and diarrhea (53% vs 22% vs 50%), in the P+B+O vs P+O vs P+B arms, respectively. No new safety signals were observed. Table 1Table 1ITT populationP+B+O n = 63P+O n = 60P+B (control) n = 62Median PFS, months7.35.47.2HR vs control (95% CI)1.08 (0.69 - 1.70)1.74 (1.13 - 2.78)-Median OS, months14.713.417.4HR vs control (95% CI)1.35 (0.74 - 2.44)1.88 (1.00 - 3.54)-ORR,% (95% CI)42 (29 - 57)28 (16 - 41)55 (41 - 68) Conclusions: In the ITT population, the addition of O to either P+B or to P alone did not improve PFS and other clinical outcomes compared with P+B alone. Further exploratory subgroup analyses are ongoing. Table 2Table 2MET IHC score01+2+3+Not availablen (%)81 (44)75 (41)21 (11)1 (0.5)7 (4) Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-16-01.

Impact of Response to Prior Chemotherapy in Patients With Advanced Urothelial Carcinoma Receiving Second-Line Therapy: Implications for Trial Design

BackgroundThe prognostic impact of response to prior chemotherapy independent of performance status (PS), hemoglobin (Hb), liver metastasis (LM), and time from prior chemotherapy (TFPC) in the context of second-line therapy for advanced urothelial carcinoma (UC) is unknown. MethodsSix phase II trials evaluating second-line therapy (n = 504) were pooled. Patients who received prior therapy for metastatic disease were eligible for analysis if Hb, LM, PS, and TFPC were available. Response by Response Evaluation Criteria in Solid Tumors 1.0 to first-line therapy was recorded. Progression-free survival (PFS) and overall survival (OS) were calculated from the date of registration using the Kaplan–Meier method. ResultsA total of 275 patients were evaluable for analysis. Patients received gemcitabine-paclitaxel, cyclophosphamide-paclitaxel, pazopanib, docetaxel plus vandetanib/placebo, or vinflunine (2 trials). Those with prior response (n = 111) had a median OS of 8.0 months (95% confidence interval [CI], 6.8-9.4), compared with 5.9 months (95% CI, 5.0-6.6) for those without prior response (n = 164). Those with prior response had a median PFS of 3.0 months (95% CI, 2.6-4.0) compared with 2.6 months (95% CI, 2.0-2.8) in patients without response. Multivariable analysis did not reveal a significant independent impact of prior response on PFS and OS. ConclusionsBest prior response in patients receiving prior chemotherapy for metastatic disease did not confer an independent prognostic impact with second-line therapy for advanced UC. Given that the setting of prior chemotherapy (metastatic or perioperative) has not appeared significant in a prior study, patients who received prior chemotherapy in perioperative or metastatic settings may be enrolled in the same second-line trial stratified for PS, Hb, LM, and TFPC.

An exploratory study of the biologic effects of nivolumab (Anti-PD-1; BMS-936558; ONO-4538) treatment in patients (pts) with advanced (unresectable or metastatic) melanoma (MEL).

TPS3114 Background: Programmed death-1 (PD-1) is an immune checkpoint receptor expressed by T cells that negatively regulates T-cell activity and may promote tumor immune evasion by binding to its ligands (PD-L1/L2) on tumor cells and/or antigen-presenting cells. Nivolumab is a fully human IgG4 PD-1 receptor blocking monoclonal antibody that has shown antitumor activity in phase I trials in pts with solid tumors, including advanced MEL. Objective responses were observed in pts whose diseases were refractory to multiple prior therapies. We describe an ongoing exploratory, open-label, multicenter translational study designed to further investigate the immunoregulatory activity and mechanisms of action of nivolumab in advanced MEL, including ipilimumab (anti-CTLA-4) naïve and refractory pts. Methods: This study is enrolling advanced MEL pts who are either ipilimumab naive (n=40) or refractory (n=40). Eligible pts must not have received >3 prior therapies for metastatic disease and must consent to pre-and on-treatment biopsy (after 2 doses of nivolumab [Day 28]) of an accessible tumor. Nivolumab will be administered IV every 2 weeks (wks) at a dose of 3mg/kg and may continue for up to 13 cycles (104 wks) until clinically significant progression or treatment discontinuation criteria are met. Tumor responses will be assessed every 8 wks using RECIST 1.1 criteria. The primary objective is to investigate the pharmacodynamic (immunoregulatory) activity of nivolumab in the peripheral blood (PB), tumor, and tumor microenvironment. Secondary objectives include evaluation of safety and tolerability, preliminary antitumor activity, and immunogenicity of nivolumab, as well as the association between tumor PD-L1 expression and clinical efficacy. Exploratory objectives include characterization of pharmacokinetics (PK) and evaluation of the potential association between selected PB and/or tumor biomarkers and PK, clinical safety, and efficacy (eg, progression-free and overall survival). Clinical trial information: NCT01621490.

A phase II study of cabazitaxel in patients with previously treated metastatic gastroesophageal adenocarcinoma.

e15095 Background: Cabazitaxel is a semi-synthetic novel taxane with activity in docetaxel refractory prostate cancer. We sought to determine the response rate of cabazitaxel in patients with advanced gastroesophageal adenocarcinoma that had progressed after at least 1 prior therapy for metastatic disease. Methods: This open label single arm phase II study followed a Simon two-stage design. The study was designed to differentiate between a 10% level of activity and a 30% level of activity and was to be terminated if the response rate was unlikely to be > 10%. Eligibility criteria included patients with gastroesophageal cancer with measurable disease after at least 1 prior regimen for metastatic disease. ECOG PS 0-2; ANC > 1,500/µL, AST/ALT ≤ 3x ULN, total bili ≤ ULN. Pts initially received cabazitaxel 25 mg/m2 IV every 21 days but after 9 patients were entered, the dose was reduced to 20 mg/m2due to toxicity. Results: The data safety monitoring board (DSMB) reviewed data after 13 pts were entered. Pt characteristics included 11 men, 2 women; median age, 70 yrs [range, 55-80]. Nine pts had ≥ 2 prior regimens. Ten pts had previous treatment with a taxane. Of 13 pts, no objective antitumor responses were observed and all 13 developed evidence of disease progression. A median of 2 cycles were given, up to a maximum of 6 cycles in 2 pts. The PFS rate at 3 months was 15%. The DSMB considered cabazitaxel ineffective and terminated the study. The probability of erroneously concluding the treatment was active (p ≥ 0.3) was < 0.0419. Grade 3 or 4 adverse events occurred in 6 pts (46.1%), in which neutropenia (n=4) and pneumonia (n=1) were grade 4. Grade 3 toxicities included ANC (n=1), anemia (n=2), nausea (n=2), weakness (n=2), diarrhea (n=1), pleural effusion (n=1), typhilitis (n=1), vomiting (n=1). Conclusions: Cabazitaxel monotherapy demonstrated no antitumor efficacy in previously treated gastroesophageal cancer. Clinical trial information: NCT01365130.

Impact of response to prior chemotherapy (RTPC) on outcomes in second-line therapy for advanced urothelial carcinoma (UC): Implications for trial design.

4539 Background: Performance status (PS), hemoglobin (Hb), liver metastasis (LM), and time from prior chemotherapy (TFPC) are significant prognostic factors in second-line therapy for advanced UC. Setting of prior chemotherapy, i.e., metastatic or perioperative, has not appeared significant. However, the impact of prior chemosensitivity is unclear, which may confound trial interpretation. Hence, we examined the prognostic impact of RTPC, when prior therapy was given for metastatic disease. Methods: Six phase II trials evaluating second-line chemotherapy and/or biologics (n=504) were pooled. Patients who received prior therapy for metastatic disease were eligible for analysis if data regarding Hb, LM, PS, and TFPC were available. Response by RECIST to first-line therapy was recorded. Progression-Free Survival (PFS) and overall survival (OS) were calculated from the date of registration using the Kaplan-Meier method. Results: 275 pts were evaluable for analysis. Patients received gemcitabine-paclitaxel, cyclophosphamide-paclitaxel, pazopanib, docetaxel plus vandetanib/placebo or vinflunine (2 trials). Those with prior response (n=111) had a median (95% CI) OS of 8.0 (6.8-9.4) months (mo) and PFS of 3.0 (2.6-4.0), compared with OS and PFS of 5.9 (5.0-6.6) mo and 2.6 (2.0-2.8) for those without prior response (n=164). Multivariable analysis did not reveal an independent impact of RTPC on PFS or OS (Table). Conclusions: RTPC in patients receiving prior chemotherapy for metastatic disease did not confer an independent prognostic impact with second-line therapy for advanced UC. Patients who received prior chemotherapy in peri-operative or metastatic settings may be enrolled in the same second-line trial stratified for PS, anemia, LM and TFPC. [Table: see text]