Post-baseline Tumor Assessment Research Articles

Correlation of MYC gene signature variations with clinical response to fimepinostat in patients with aggressive B-cell lymphoma.

e15654 Background: Fimepinostat (F), a small molecule dual inhibitor of PI3K α, β, and δ isoforms and Class I and II histone deacetylases (HDACs), is currently under investigation for the treatment of aggressive hematological cancers. Preclinical studies demonstrated that F both decreases transcription of myc and MYC-targeted genes (via HDAC inhibition) and increases destruction of MYC protein (via PI3K inhibition). This study sought to identify differences in transcript-level signatures of gene networks in pre-treatment tumor samples associated with future clinical response to F. Methods: Among 105 patients (pts) with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) treated in phase 1/2 clinical trials of F (± rituximab), 33 pts had pre-treatment tumor biopsy samples available for molecular testing. All pts had measurable disease at baseline and had at least 1 post-baseline tumor assessment. To be included in the analysis set, pts must have been on study for ≥42 days. RNA libraries were created and sequenced on the Illumina HiSeq platform. Gene Set Enrichment Analysis (GSEA; Subramanian et al., 2005) was used to study changes in transcript expression patterns that correlate with responder (complete/partial response) or non-responder (progressive disease) pt populations. ~20,000 genes were rank-ordered by log2-fold change and tested against the MSigDB (Liberzon et al., 2011) collection of gene expression signatures. Results: > 1500 Gene Sets with False Discovery Rate (FDR) < = 0.05 and Normalized Enrichment Score (NES) > 1.3 for genes upregulated in the F-responder population were identified. These Gene Sets represent transcriptional activity associated with well characterized biological pathways or gene expression signatures determined empirically. The top 20 signatures by NES were associated with general transcription functions (E2F, RNA polymerase), chromosomal structure (meiotic recombination, telomere maintenance) and specifically, MYC transcription targets (NES: 2.7; FDR q-val: 0). Additional signatures consistent with PI3K (GSK3b) and HDAC activity in the responder population were also identified, as would be expected for a dual inhibitor of PI3Ks and HDACs. Conclusions: GSEA analysis of genes upregulated in the F-treated responder DLBCL pts are consistent with preclinical data showing that F functions to suppress MYC in tumor cells. F is currently undergoing active clinical study in combination with venetoclax for the treatment of R/R DLBCL or high grade B-cell lymphoma (HGBL): NCT01742988.

Phase II study of savolitinib in patients (pts) with pulmonary sarcomatoid carcinoma (PSC) and other types of non-small cell lung cancer (NSCLC) harboring MET exon 14 skipping mutations (METex14+).

9519 Background: There are unmet medical needs for pts with METex14+ NSCLC. PSC is a rare type of NSCLC with high incidence of MET exon 14 mutations and poor prognosis. Savolitinib (AZD6094, HMPL-504, volitinib) is a highly selective oral MET tyrosine kinase inhibitor, and its anti-tumor activity has been shown in combination with osimertinib in pts with EGFR-mutant, MET-amplified NSCLC (Yu H, et al. 2019 AACR, Abstract CT032). Methods: This was a multicenter, multi-cohort, single-arm phase II study (NCT02897479) to evaluate the efficacy, safety, and pharmacokinetics of savolitinib in pts with unresectable or metastatic METex14+ PSC and other NSCLC. MET mutation was tested or retrospectively confirmed by central laboratory. Savolitinib was taken orally, once daily (QD) (600mg for weight ≥50kg or 400mg weight < 50kg) until disease progression or intolerable toxicity. Tumor was evaluated every 6 weeks during the 1st year and every 12 weeks thereafter. The primary endpoint was independent review committee (IRC) assessed objective response rate (ORR) (RECIST version 1.1). Here we report the results of one cohort of prior MET-treatment naïve patients. Results: As of October 31, 2019, 593 pts were pre-screened/screened, 87 identified with METex14+ and 70 treated. Among treated pts, median age was 68.7 years (range 51.7-85.0), 58.6% pts were male, 92.9% stage IV, 60.0% previously treated, 57.1% with adenocarcinoma, 35.7% with PSC and the rest with other pathological types. Sixty-one pts were efficacy evaluable by IRC assessment (N = 61) (including pts who had at least one measurable lesion at baseline and had ≥1 scheduled post-baseline tumor assessment or evidence of any post-baseline radiological disease progression): ORR was 47.5% (95% CI: 34.6%, 60.7%), disease control rate 93.4% (95% CI: 84.1%, 98.2%) and median duration of response not reached yet. The median progression-free survival was 6.8 months (95% CI 4.2, 13.8) among all treated pts. Efficacy results were consistent with investigators’assessments. The most common (≥20%) treatment-related adverse events (TRAEs) were peripheral edema, nausea, increased AST/ALT, vomiting and hypoalbuminemia. The incidence of ≥ grade 3 TRAEs was 41.4%. TRAEs leading to treatment discontinuation occurred in 14.3% pts, among which liver injury and hypersensitivity were most common (each 2.9%). Conclusions: Savolitinib demonstrated promising anti-tumor activity and acceptable tolerability in METex14+ NSCLC pts. Clinical trial information: NCT02897479 .

Abstract P1-19-08: Neratinib + trastuzumab + fulvestrant for HER2-mutant, hormone receptor-positive, metastatic breast cancer: Updated results from the phase 2 SUMMIT ‘basket’ trial

Abstract Background: HER2 mutations define a subset of metastatic breast cancers (MBCs) with a unique mechanism of oncogenic addiction to HER2 signaling. Neratinib, an irreversible pan-HER tyrosine kinase inhibitor, has been shown to have encouraging clinical activity when combined with fulvestrant in HER2-mutant, hormone receptor-positive (HR+) MBC [Smyth et al. SABCS 2018]. Genomic analyses suggest that acquired resistance to neratinib may occur by the acquisition of additional HER2 alterations, which may amplify HER2 pathway signaling [Won et al. AACR 2019]. We therefore explored whether dual HER2-targeted therapy may improve clinical benefit in this setting. Here we describe initial results from a cohort of patients with HER2-mutant, HR+ MBC treated with neratinib + trastuzumab + fulvestrant (N+T+F) from the phase 2 SUMMIT ‘basket’ trial (NCT01953926). Methods: Patients with HR+ MBC and known oncogenic driver HER2 mutations identified by genomic sequencing were eligible to receive combination treatment with oral neratinib 240 mg daily, intravenous trastuzumab 8 mg/kg initially followed by 6 mg/kg every 3 weeks, and intramuscular fulvestrant 500 mg on days 1 and 15 of month 1, then on day 1 every 4 weeks (N+T+F). Loperamide prophylaxis was mandatory during cycle 1. There was no restriction on the number of prior lines of systemic treatment for MBC. Efficacy endpoints included: confirmed objective response rate and clinical benefit rate - all defined according to RECIST v1.1 - as well as duration of response and progression-free survival. Genomic profiling from fresh/archival tumor tissues and/or plasma cfDNA was performed retrospectively by next-generation sequencing (MSK-IMPACT). Results: As of 01-May-2019, 19 patients were enrolled into the N+T+F cohort and received study treatment (safety population). 20 HER2 mutations were identified in the 19 patients: 14 kinase domain missense mutations, 3 extracellular domain missense mutations, and 3 exon-20 insertion mutations. Median number of prior systemic regimens for metastatic disease was 4 (range 0-10) and histologies were evenly split between lobular and ductal carcinomas. While the majority of patients remain on study treatment (n=15), only 13 of the 19 enrolled patients are efficacy evaluable at this time (having had ≥1 post-baseline tumor assessment). Clinical activity is summarized in the Table. Diarrhea was the most commonly reported adverse event (84.2% any grade) with 5 patients reporting Grade 3 diarrhea (there were no Grade 4 diarrhea events). Three patients (15.8%) reduced neratinib dose due to diarrhea but no patient discontinued treatment due to diarrhea. Conclusions: The combination of N+T+F resulted in an encouraging response rate and was a well-tolerated regimen in predominantly heavily pretreated HER2-mutant HR+ breast cancers. Based on a pre-planned interim analysis, the cohort has been expanded to enroll a total of 50 patients. Updated efficacy and safety data will be presented. Neratinib + trastuzumab + fulvestrant(n=13)Confirmed objective response rate, % (95% CI)39 (13.9-68.4)Complete response0Partial response5 (39)Duration of responses range, months4.2*-10.4*Median progression-free survivala,b, months (95% CI)NA (1.9-NA)*Response ongoing; aKaplan-Meier analysis; bincludes all patients enrolled (n=19); NA, not applicable. Citation Format: Hans Wildiers, Valentina Boni, Cristina Saura, Mafalda Oliveira, Komal Jhaveri, Helen Won, François-Clément Bidard, Adam M Brufsky, Mark E Burkard, Andrés Cervantes, Carlos Fernández-Martos, Barbara Haley, Sherene Loi, Iben Spanggaard, Stefano Panni, Janice Lu, Melanie E Dujka, Feng Xu, Sonia Macia, Lisa D Eli, Alshad S Lalani, Sarina Piha-Paul, Funda Meric-Bernstam, David B Solit, David M Hyman. Neratinib + trastuzumab + fulvestrant for HER2-mutant, hormone receptor-positive, metastatic breast cancer: Updated results from the phase 2 SUMMIT ‘basket’ trial [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-19-08.

Response Rate Following Albumin-Bound Paclitaxel Plus Gemcitabine Plus Cisplatin Treatment Among Patients With Advanced Pancreatic Cancer

Genomes of metastatic pancreatic cancers frequently contain intrachromosomal aberrations, indicating a DNA repair deficiency associated with sensitivity to DNA damaging agents, such as platinum. To determine response rate following treatment with nab-paclitaxel plus gemcitabine plus platinum-based cisplatin for patients with metastatic pancreatic ductal adenocarcinoma (PDA). This was a single-arm, open-label, phase 1b/2 clinical trial of nab-paclitaxel plus gemcitabine plus cisplatin treatment in which 25 patients with previously untreated metastatic PDA were enrolled. The trial was conducted from December 2013 to July 2016 at 3 US sites, with the last patient receiving study treatment at the end of October 2016, and the study closing January 2018. Patients were treated with nab-paclitaxel plus gemcitabine plus various doses of cisplatin, 25 mg/m2, 37.5 mg/m2, and 50 mg/m2, on days 1 and 8 of a 21-day cycle. Primary end point was complete response rate as assessed by Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST), and levels of carbohydrate antigen 19-9 (or in nonexpressers, carbohydrate antigen 125 or carcinoembryonic antigen). Efficacy analysis included evaluable patients (those who received at least 1 dose of study treatment and had at least 1 postbaseline tumor assessment). Of 25 patients enrolled in the study, the median (range) age was 65.0 (47.0-79.0) years, 14 (56%) were men, and most (24) were white (96%). The maximum tolerable dose of cisplatin was 25 mg/m2. The most common treatment-related adverse events grade 3 or higher were thrombocytopenia (17 patients [68%]), anemia (8 patients [32%]), and neutropenia (6 patients [24%]). Fatal events occurred for 3 patients (12%); 2 were related to study participation. A median (range) of 8 (1-15) cycles was completed. The RECIST responses in 24 evaluable patients included 2 complete responses (8%), which was below the primary end point of 25%, 15 partial responses (62%), 4 stable disease (17%), and 3 progressive disease (12%), with median overall survival of 16.4 (95% CI, 10.2-25.3) months; 16 patients (64%) were alive at 1 year, 10 (40%) at 2 years, 4 (16%) at 3 years, and 1 (4%) at 4 plus years. Overall survival ranged from 36 to 59 months. Median progression-free survival was 10.1 (95% CI, 6.0-12.5) months. Thus, the overall response rate was 71%, and the disease control rate was 88%. This triple drug regimen showed substantial clinical activity in this small study. Although the primary end point was not reached, the high overall response rate, disease control rate, and median survival time among patients with advanced PDA treated with this combination are encouraging. The regimen is being studied in patients with PDA in the neoadjuvant setting and in patients with advanced biliary cancers. ClinicalTrials.gov identifier: NCT01893801.

452PD - Safety, antitumor activity, and pharmacokinetics (PK) of pamiparib (BGB-290), a PARP1/2 inhibitor, in patients (pts) with advanced solid tumours: Updated phase I dose-escalation/expansion results

BackgroundPamiparib is an investigational PARP1/2 inhibitor that has demonstrated brain penetration and PARP–DNA complex trapping in preclinical studies. In the phase 1 dose-escalation/expansion study of pts with advanced solid tumors, pamiparib was generally well tolerated and showed preliminary antitumor activity. Here we report updated antitumor activity focused on the ovarian cancer cohort and safety data. MethodsThis is a two-stage dose-escalation/expansion study (NCT02361723). The dose-escalation study component established the pamiparib PK profile, and the recommended phase 2 dose (RP2D) of pamiparib administered orally 60mg BID in pts with solid tumors. The dose-expansion component was conducted in pts with ovarian, breast, prostate, gastric, and small cell lung cancer. ResultsAs of 1 January 2019, 97 pts (median age, 60 years; Eastern Cooperative Oncology Group performance status of 0, 1, or 2 [37%, 62%, and 1%, respectively]) were enrolled in the dose-escalation (n=60) and dose-expansion (n=37) components. Among the 97 enrolled pts, 48 pts (n=30, ovarian pts) received 60mg BID, the RP2D. Of 57 ovarian pts in the efficacy evaluable population (≥1 postbaseline tumor assessment), 22 (39%) achieved a confirmed objective response (complete response, n=4; partial response, n=18) per RECIST v1.1 criteria. Median duration of response was 12.3 months (range, 1.3–40.8). Biomarker data will be included in future analyses. In the safety population (n=97), drug-related adverse events (AEs) in≥10% of pts were nausea, fatigue, anemia, diarrhea, vomiting, and decreased appetite. The most common drug-related G3 (no G4 or G5) AEs were anemia (18.6%) and neutropenia (6.2%). AEs led to treatment discontinuation in 6.2% of pts. Four pts died due to disease progression with non-drug–related AEs. Pamiparib plasma exposure generally increased with increased dose, with a median t1/2 of ∼13hours. ConclusionsPamiparib continues to be generally well tolerated and demonstrates antitumor activity in this update of an ongoing, phase 1 dose-escalation/expansion study in pts with advanced solid tumors. Clinical trial identificationNCT02361723. Editorial acknowledgementEditorial/writing support was provided by Ira Mills, PhD, and Shannon Davis at Ashfield Healthcare Communications, Middletown, CT. Legal entity responsible for the studyBeiGene. FundingBeiGene. DisclosureM. Voskoboynik: Honoraria (self): AstraZeneca; Honoraria (self): MSD Oncology; Travel / Accommodation / Expenses: Bristol-Myers Squibb. L. Mileshkin: Travel / Accommodation / Expenses, Beigene paid for flights and accommodation for me to attend and present at the ASCO STIC meeting Jan 2018: Beigene. M. Millward: Research grant / Funding (self), Per patient payments for clinical trials: Beigene; Advisory / Consultancy, Advisory Board for Immuno-Oncology: Bristol-Myers Squibb; Advisory / Consultancy, Advisory Board for Immuno-Oncology: Merck Sharp & Dohme; Advisory / Consultancy, Advisory Board for Immuno-Oncology: Roche; Advisory / Consultancy, Advisory Board for Immuno-Oncology: AstraZeneca. K. Zhang: Full / Part-time employment: Beigene. M. Zhang: Full / Part-time employment: Beigene. S. Mu: Full / Part-time employment: Beigene. All other authors have declared no conflicts of interest.

1670O - ADP-A2M4 (MAGE-A4) in patients with synovial sarcoma

1670O - ADP-A2M4 (MAGE-A4) in patients with synovial sarcoma

Abstract CT004: A Phase Ib study of CD40 agonistic monoclonal antibody APX005M together with gemcitabine (Gem) and nab-paclitaxel (NP) with or without nivolumab (Nivo) in untreated metastatic ductal pancreatic adenocarcinoma (PDAC) patients

Abstract Background: Checkpoint inhibitors such as anti-PD-1 are ineffective as single agents for patients (pts) with PDAC. Preclinical data suggest that chemotherapy with agonistic CD40 antibodies can be combined with anti-PD-1 to trigger effective T cell immunity. We conducted a multi-center, open label clinical trial to evaluate the combination of APX005M with nivo and standard chemotherapy (gem and NP). Herein, we report safety and efficacy from the ongoing study. Methods: Pts with previously untreated PDAC were enrolled in 4 cohorts: Gem/NP/APX005M 0.1 mg/kg (B1), Gem/NP/APX005M 0.3 mg/kg (B2), Gem/NP/Nivo/APX005M 0.1 mg/kg (C1) and Gem/NP/Nivo/APX005M 0.3 mg/kg (C2). Primary objectives were to evaluate safety and determine the recommended Phase II dose (RP2D) of APX005M. Secondary objectives included tumor response and immune pharmacodynamics. Analyses were performed on dose-limiting toxicity (DLT)-evaluable subjects, defined as receiving 1 dose of APX005M and ≥ 2 doses of gem/NP during Cycle 1 and remaining on study through Cycle 2 Day 1. Results: N=30 pts dosed; 24 DLT-evaluable (6 per cohort). Median follow up is 32.2 weeks. N=13 (54%) pts experienced an AE leading to discontinuation, and 10 (42%) pts experienced a treatment-related serious AE. Two DLTs were observed, 1 each in cohorts B2 and C1 (grade 3 and 4 febrile neutropenia, respectively). AE rates were similar across cohorts. Four (17%) subjects died (2 each in Cohorts B1 and C1) due to disease progression (n=2) and AE (n=2, sepsis and septic shock in the setting of neutropenia). Within the DLT-evaluable population, best overall responses included 14 (58%) PR (11 confirmed, 3 unconfirmed), 8 (33%) SD, 1 (4%) PD and 1 (4%) NE. Post-baseline tumor assessments were available for 2 of the 6 DLT-inevaluable pts (best overall responses of SD and confirmed PR). Multiplexed IHC analysis of baseline tumors revealed a low CD8 T cell and high macrophage infiltrate. Analysis of circulating mutant KRAS DNA showed marked and rapid decrease with therapy in some pts. Immune profiling of PBMCs at baseline and on-treatment by CyTOF revealed remodeling of the myeloid compartment in response to treatment, with rapid activation of dendritic cells in most pts. Conclusions: Gem/NP/APX005M ± nivo demonstrated manageable safety profiles and promising antitumor activity in untreated metastatic PDAC pts. APX005M 0.3 mg/kg was selected as the dose for a randomized Phase II study in which the primary endpoint is 1-year overall survival. Clinical trial information: NCT02482168. Citation Format: Mark H. O'Hara, Eileen M. O'Reilly, Mick Rosemarie, Gauri Varadhachary, Zev A. Wainberg, Andrew Ko, George A. Fisher, Osama Rahma, Jaclyn P. Lyman, Christopher R. Cabanski, Erica L. Carpenter, Travis Hollmann, Pier Federico Gherardini, Lacey Kitch, Cheryl Selinsky, Theresa LaVallee, Ovid C. Trifan, Ute Dugan, Vanessa M. Hubbard-Lucey, Robert H. Vonderheide. A Phase Ib study of CD40 agonistic monoclonal antibody APX005M together with gemcitabine (Gem) and nab-paclitaxel (NP) with or without nivolumab (Nivo) in untreated metastatic ductal pancreatic adenocarcinoma (PDAC) patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT004.

Results of a Phase II Placebo-controlled Randomized Discontinuation Trial of Cabozantinib in Patients with Non–small-cell Lung Carcinoma

IntroductionCabozantinib, an orally bioavailable tyrosine kinase inhibitor with activity against MET, vascular endothelial growth factor receptor 2, AXL, ROS1, and RET was assessed in patients with non–small-cell lung carcinoma (NSCLC) as part of a phase II randomized discontinuation trial with cohorts from 9 tumor types. Patients and MethodsPatients received cabozantinib 100 mg/day during a 12-week open-label lead-in stage. Those with stable disease per Response Evaluation Criteria in Solid Tumors version 1.0 at week 12 were randomized to cabozantinib or placebo. Primary endpoints were objective response rate (ORR) at week 12 and progression-free survival (PFS) after randomization. ResultsSixty patients with NSCLC who had received a median of 2 prior lines of therapy were enrolled. ORR at week 12 was 10%; 6 patients had a confirmed partial response, and no patients had a complete response. Overall disease-control rate (ORR + stable disease) at week 12 was 38%. Tumor regression was observed in 30 (64%) of 47 patients with post-baseline radiographic tumor assessments, including 3 or 4 patients with KRAS or epidermal growth factor receptor mutations, respectively. Median PFS after randomization was 2.4 months for both the cabozantinib and placebo arms. Median PFS from first dose for the entire cohort was 4.2 months. The most common grade 3/4 adverse events were fatigue (13%), palmar-plantar erythrodysesthesia (10%), diarrhea (7%), hypertension (7%), and asthenia (5%); 1 treatment-related grade 5 adverse event (hemorrhage) was reported during the lead-in stage. ConclusionCabozantinib exhibited clinical activity based on ORR and regression of tumor lesions in pretreated patients with NSCLC, including in patients with KRAS mutations.

Detection of EGFR mutations in plasma circulating tumour DNA as a selection criterion for first-line gefitinib treatment in patients with advanced lung adenocarcinoma (BENEFIT): a phase 2, single-arm, multicentre clinical trial

Detection of EGFR mutations in tumour tissue is the gold-standard approach to ascertain if a patient will benefit from treatment with an EGFR tyrosine kinase inhibitor. However, if tissue is scant, another strategy is to use circulating tumour DNA (ctDNA), but this method needs validation in clinical trials. We did a prospective clinical trial to assess ctDNA-based EGFR mutation detection as a selection criterion for patients with lung adenocarcinoma receiving gefitinib as first-line treatment. BENEFIT is a multicentre, single-arm, phase 2 clinical trial at 15 centres in China. Patients aged 18-75 years with stage IV metastatic lung adenocarcinoma and EGFR mutations detected in ctDNA were given oral gefitinib 250 mg once daily as first-line treatment. The primary endpoint was the proportion achieving an objective response. Secondary endpoints included median progression-free survival and safety. Next-generation sequencing (NGS) of a 168-gene panel was used for genetic analysis of baseline blood samples. The primary efficacy analysis was done by intention to treat in patients who had at least one post-baseline tumour assessment. The safety analysis was done in all patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, number NCT02282267. Between Dec 25, 2014, and Jan 16, 2016, 426 patients were screened for the trial, of whom 188 with EGFR mutations in ctDNA were enrolled and received gefitinib. 183 patients had one or more post-baseline tumour assessment and were included in the primary efficacy analysis. Median follow-up was 14·5 months (IQR 12·2-16·5). At the time of data cutoff (Jan 31, 2017), 152 patients had progressive disease or had died. The proportion achieving an objective response was 72·1% (95% CI 65·0-78·5). Median progression-free survival was 9·5 months (95% CI 9·07-11·04). Of 167 patients with available blood samples, 147 (88%) showed clearance of EGFR mutations in ctDNA at week 8, and median progression-free survival was longer for these patients than for the 20 patients whose EGFR mutations persisted at week 8 (11·0 months [95% CI 9·43-12·85] vs 2·1 months [1·81-3·65]; hazard ratio [HR] 0·14, 95% CI 0·08-0·23; p<0·0001). From baseline NGS data in 179 patients, we identified three subgroups of patients: those with EGFR mutations only (n=58), those with mutations in EGFR and tumour-suppressor genes (n=97), and those with mutations in EGFR and oncogenes (n=24). Corresponding median progression-free survival in these subgroups was 13·2 months (95% CI 11·5-15·0), 9·3 months (7·6-11·0), and 4·7 months (1·9-9·3), respectively (EGFR mutations only vs mutations in EGFR and tumour-suppressor genes, HR 1·78, 95% CI 1·23-2·58; p=0·002; EGFR mutations only vs mutations in EGFR and oncogenes, 2·66, 1·58-4·49; p=0·0003). The most common grade 3 or 4 adverse events were hepatic function abnormalities (n=24). Serious adverse events were reported in 17 (9%) patients. No unexpected safety events for gefitinib were recorded. Detection of EGFR mutations in ctDNA is an effective method to identify patients who might benefit from first-line gefitinib treatment. Further analyses of dynamic alterations of EGFR mutations and accompanying gene aberrances could predict resistance to gefitinib. Guangdong Association of Clinical Trials, AstraZeneca, National Natural Sciences Foundation Key Programme, and National Key Research and Development Programme of China.

Voxtalisib (XL765) in patients with relapsed or refractory non-Hodgkin lymphoma or chronic lymphocytic leukaemia: an open-label, phase 2 trial

Patients with relapsed or refractory lymphoma or chronic lymphocytic leukaemia have a poor prognosis. Therapies targeting more than one isoform of PI3K, as well as mTOR, might increase antitumour activity. We aimed to investigate the efficacy and safety of voxtalisib (also known as XL765 or SAR245409), a pan-PI3K/mTOR inhibitor, in patients with relapsed or refractory lymphoma, or chronic lymphocytic leukaemia/small lymphocytic lymphoma. We did a non-randomised, open-label, phase 2 trial at 30 oncology clinics in the USA, Belgium, Germany, France, the Netherlands, and Australia. Patients aged 18 years or older with Eastern Cooperative Oncology Group (EGOG) performance status score of 2 or lower and relapsed or refractory mantle cell lymphoma, follicular lymphoma, diffuse large B-cell lymphoma, or chronic lymphocytic leukaemia/small lymphocytic lymphoma were enrolled and treated with voxtalisib 50 mg orally twice daily in 28-day continuous dosing cycles until progression or unacceptable toxicity. The primary endpoint was the proportion of patients in each disease-specific cohort who achieved an overall response, defined as a complete response or partial response. All patients who received more than 4 weeks of treatment and who completed a baseline and at least one post-baseline tumour assessment were analysed for efficacy and all patients were analysed for safety. This study is registered with ClinicalTrials.gov, number NCT01403636, and has been completed. Between Oct 19, 2011, and July 24, 2013, 167 patients were enrolled (42 with mantle cell lymphoma, 47 with follicular lymphoma, 42 with diffuse large B-cell lymphoma, and 36 with chronic lymphocytic leukaemia/small lymphocytic lymphoma. The median number of previous anticancer regimens was three (IQR 2-4) for patients with lymphoma and four (2-5) for patients with chronic lymphocytic leukaemia/small lymphocytic lymphoma. Of 164 patients evaluable for efficacy, 30 (18·3%) achieved an overall response (partial, n=22; complete, n=8); 19 (41·3%) of 46 with follicular lymphoma, five (11·9%) of 42 with mantle cell lymphoma, two (4·9%) of 41 with diffuse large B-cell lymphoma, and four (11·4%) of 35 with chronic lymphocytic leukaemia/small lymphocytic lymphoma. The safety profile was consistent with that of previous studies of voxtalisib. The most frequently reported adverse events were diarrhoea (in 59 [35%] of 167 patients), fatigue (in 53 [32%]), nausea (in 45 [27%]), pyrexia (in 44 [26%,]), cough (in 40 [24%]), and decreased appetite (in 35 [21%]). The most frequently reported grade 3 or worse adverse events were anaemia (in 20 [12%] of 167 patients), pneumonia (in 14 [8%]), and thrombocytopenia (in 13 [8%]). Serious adverse events occurred in 97 (58·1%) of 167 patients. Voxtalisib 50 mg given orally twice daily had an acceptable safety profile, with promising efficacy in patients with follicular lymphoma but limited efficacy in patients with mantle cell lymphoma, diffuse large B-cell lymphoma, or chronic lymphocytic leukaemia/small lymphocytic lymphoma. Sanofi.

Targeted therapy for advanced salivary cancer with HER2 or hedgehog alterations: Interim data from MyPathway.

6086 Background: Salivary gland cancers comprise &lt;1% of cancers. Advanced cases have a 40% 5-year survival rate. Due to their rarity, no standard treatment guidelines exist. However, salivary duct carcinomas have morphological and gene expression profiles similar to breast cancers, and 20–40% of this subset have HER2 alterations. MyPathway (NCT02091141) is an ongoing, phase 2, multi-basket study evaluating the efficacy of targeted treatments in nonindicated tumor types with alterations in the HER2, BRAF, Hedgehog (Hh), or EGFR pathways. We present interim data for patients with salivary cancer. Methods: Patients had advanced salivary cancer with HER2 (amplification, overexpression, and/or mutation) or Hh (SMO or PTCH-1) alterations, locally assessed by gene sequencing, FISH, or IHC, as applicable. Patients received standard doses of pertuzumab + trastuzumab or vismodegib, respectively, until disease progression or unacceptable toxicity. The primary endpoint is investigator-assessed objective response rate (ORR) by RECIST v1.1. Results: As of Nov 30, 2016, 8 patients had been treated for salivary cancer, all carcinomas (7 had HER2 alterations; 1 had an Hh alteration). One HER2 patient without a post-baseline tumor assessment by data cut-off was not evaluable for efficacy. Characteristics and outcomes are shown (Table). Of 6 patients with a complete response (CR) or partial response (PR), 5 patients were still receiving study treatment by the data cut-off, with a median time on treatment of 4.6 months (range 1.4–12.5). There were no new safety signals. Conclusions: Six of 7 patients (86%) with advanced salivary carcinoma achieved CR or PR by targeting HER2 (n=5) or Hh (n=1) alterations. These promising results merit study of these treatments in additional patients. Accrual to MyPathway is ongoing. Clinical trial information: NCT02091141. [Table: see text]

Abstract P4-22-22: Cobimetinib (C) combined with paclitaxel (P) as a first-line treatment in patients (pts) with advanced triple-negative breast cancer (COLET study): Updated clinical and biomarker results

Abstract Resistance to standard taxane-based chemotherapy is common in triple-negative breast cancer (TNBC). Mutations and gene amplifications in the MAPK pathway that upregulate MAPK signaling are present in many TNBC tumors. Upregulation of the MAPK signaling pathway can result in degradation of the pro-apoptotic protein BIM and upregulation of anti-apoptotic proteins, including BCL-2, BCL-XL, and MCL-1, thus promoting cell survival and desensitizing tumor cells to the pro-apoptotic effects of taxane chemotherapy. Updated data on clinical safety and efficacy are presented along with biomarker data evaluating the effects of treatment on induction of apoptosis.The COLET study (ClinicalTrials.gov ID, NCT02322814; EudraCT number, 2014-002230-32) consisted of a safety run-in (n∼12) followed by a blinded 1:1 randomized expansion stage (n∼90) to C + P or placebo (PBO) + P. The safety stage is complete and the randomized stage is enrolling pts. Two additional cohorts investigating the effect of adding atezolizumab will be recruiting and are out of scope of this submission. Pts in cohort I were treated with P 80 mg/m2 on days 1, 8, and 15 and C/PBO 60 mg/day on days 3–23 of each 28-day cycle until disease progression or unacceptable toxicity. Gene expression and apoptotic index were measured by RNA-Seq and TUNEL staining, respectively, to assess the biologic activity of C + P.Sixteen women (median age, 55.5 years) were enrolled in the safety run-in stage. At data snapshot (April 22, 2016), all 16 pts had received ≥1 dose of study treatment. Median time on treatment was 116 days (range, 7-336) for C and 84 days (range, 0-351) for P. Fifteen (94%) pts had ≥1 adverse event (AE); 5 (31%) pts had grade 1/2 AEs and 10 (63%) pts had grade 3 AEs (Table). No pts experienced grade 4–5 AEs. Among the 16 safety run-in patients, responses to date include partial response (PR; n = 8 [50.0%]), stable disease (SD, n = 4 [25.0%]), and progressive disease (n = 2 [12.5%]), as well as 2 pts with no post-baseline tumor assessment. Six pts maintained a PR at ∼20 weeks and three maintained a PR at ≥40 weeks. To date, matched pre- and on-treatment biopsies were evaluable for 2 pts, 1 with a PR and 1 with SD. In the patient who attained a PR, increased expression of pro-apoptosis genes, including BIM, was observed; but this was not seen in the patient experiencing SD. The PR patient also had an increase in apoptotic index. Updated biomarker data will be reported.This is the first study to evaluate C + P in TNBC. The safety profile of C + P is consistent with that of known safety profiles. Efficacy and safety will be further evaluated in the ongoing randomized stage. Most common (any grade ≥20%) AEsTreatment-emergent AEs, n (%)C + P (safety run-in stage), N = 16 All gradesGrade 3Diarrhea10 (63)1 (6)Rash8 (50)0Nausea7 (44)0Alopecia5 (31)0Blood CPK level increase5 (31)1 (6)Stomatitis4 (25)2 (13)Asthenia4 (25)1 (6)Constipation4 (25)0Dyspnea4 (25)0Edema peripheral4 (25)0Pyrexia4 (25)0Vomiting4 (25)0AEs, adverse events; C, cobimetinib; CPK, creatinine phosphokinase; P, paclitaxel. Citation Format: Brufsky A, Kim S-B, Velu T, García-Saenz JA, Tan-Chiu E, Sohn JH, Dirix L, Borms MV, Liu M-C, Moezi MM, Kozloff MF, Sparano JA, Xu N, Wongchenko M, Simmons B, McNally V, Miles D. Cobimetinib (C) combined with paclitaxel (P) as a first-line treatment in patients (pts) with advanced triple-negative breast cancer (COLET study): Updated clinical and biomarker results [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-22-22.

A Phase 1b, Multi-Center, Open-Label Study of Novel Combinations of CC-122, CC-223, CC-292, and Rituximab in Diffuse Large B-Cell Lymphoma: CC-122-DLBCL-001

A Phase 1b, Multi-Center, Open-Label Study of Novel Combinations of CC-122, CC-223, CC-292, and Rituximab in Diffuse Large B-Cell Lymphoma: CC-122-DLBCL-001

Abstract IA20: Phase II study to evaluate the clinical efficacy and safety of MEDI4736 (durvalumab) in patients with glioblastoma (GBM): Results for cohort B (durvalumab monotherapy), bevacizumab-naïve patients with recurrent GBM

Abstract Background: Outcome for patients with glioblastoma (GBM), the most common primary malignancy of the central nervous system, remains poor. Inhibition of PD-1 signaling has been shown to improve survival in an orthotopic, syngeneic murine GBM model. PD-L1 is expressed by GBM tumors, and its level of expression has been shown to correlate with patient outcome. Durvalumab (DUR) is a human IgG1 monoclonal antibody against PD-L1. Blockade of PD-1/PD-L1 has shown benefit among solid tumors; data implicate PD-1/PD-L1 signaling as a significant contributor to immunosuppression in glioblastoma (GBM). Bevacizumab (BEV) is an approved angiogenesis inhibitor for recurrent GBM; angiogenesis inhibition may promote antitumor benefit of immunotherapies. Methods: This ongoing phase II open-label study (NCT02336165) evaluates the safety and efficacy of DUR (10 mg/kg every 2 weeks) in 5 GBM cohorts with and without BEV. This report presents the safety and efficacy for Cohort B (BEV-naïve recurrent GBM; DUR monotherapy). The primary efficacy endpoint for Cohort B is progression-free survival at 6 months (PFS-6), based on modified RANO criteria by investigator assessment; secondary endpoints include safety/tolerability. A PFS-6 of 10% is the comparative historical benchmark (pre-BEV), based on published meta-analyses. The null hypothesis (PFS-6 ≤ 10%) was tested in the Intent-to-Treat (ITT) population against the alternative hypothesis (PFS-6 &amp;gt; 10%) at α = 0.05, using 90% confidence interval (CI). The null hypothesis was rejected if the lower bound of the CI was &amp;gt; 10%. ITT includes patients receiving any dose of DUR and having at least baseline and 1 post-baseline tumor assessment. Results: The first patient was dosed on 05Mar2015, and the data cutoff was 05Feb2016. Cohort B completed enrollment of 31 patients (male: 83.9%; mean age: 54.0 [24-77] years; baseline ECOG Performance Status (PS) 0: 51.6%, PS 1: 48.4%; baseline measurable lesions: 77.4%). Incidences of treatment-related adverse events (TRAEs) by maximum CTCAE grade (Gr) were Gr1: 35.5%; Gr2: 41.9%; Gr3: 9.7%; and Gr4/5: 0%. Most common TRAEs (≥3 (9.7%) patients) were fatigue, headache, hemiparesis, increased AST, and decreased platelets, WBCs and lymphocytes. Thirty patients were evaluable for efficacy (PFS), and 6 were progression free at 6 months. Kaplan-Meier estimate for PFS-6 was 20%. Conclusions: DUR appears to be well tolerated and shows activity in BEV-naïve recurrent GBM, although the primary PFS-6 endpoint was not met. Further studies are warranted. Citation Format: David A. Reardon, Thomas Kaley, Jorg Dietrich, Michael Lim, Gavin P. Dunn, Hui K. Gan, Timothy Cloughesy, Jennifer L. Clarke, Andrew Park, Mary Macri, Aileen Ryan, Toni Ricciardi, Vijay Reddy, Ralph Venhaus. Phase II study to evaluate the clinical efficacy and safety of MEDI4736 (durvalumab) in patients with glioblastoma (GBM): Results for cohort B (durvalumab monotherapy), bevacizumab-naïve patients with recurrent GBM [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr IA20.

Abstract OT1-03-19: Design of a phase 1b/2 study to evaluate the efficacy and safety of eribulin mesylate in combination with pembrolizumab in patients with metastatic triple-negative breast cancer

Abstract Eribulin mesylate, a microtubule inhibitor, is indicated for treatment of patients (pts) with metastatic breast cancer (MBC) with ≥2 prior chemotherapies for metastatic disease, including an anthracycline or taxane. Pembrolizumab is a human programmed death receptor-1 (PD-1)-blocking antibody indicated for treatment of pts with unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAFV600-mutation positive, a BRAF inhibitor. Pembrolizumab is also being evaluated for treatment of metastatic triple-negative breast cancer (mTNBC) and multiple tumor types. We report the design of an open-label, single-arm, multicenter, phase 1b/2 study to evaluate safety and efficacy of the eribulin and pembrolizumab combination in pts with mTNBC previously treated with 0 to 2 lines of therapy in the metastatic setting. From August 2015 to February 2017, approximately 95 pts (aged ≥18 yrs) will be enrolled (n=12 phase 1b; n=83 phase 2) to reach 80 evaluable pts. Accrual has not yet commenced. Pts with measurable disease of ≥1 lesion &amp;gt;10 mm in long-axis diameter (nonlymph nodes) or &amp;gt;15 mm in short-axis diameter (lymph nodes) and an ECOG status of 0 or 1 will be included. Exclusion criteria include pts who received adjuvant chemotherapy within the past 6 months, chemotherapy/biological therapy within the past 3 wks, or radiation or small molecule targeted therapy within the past 2 wks. Pts will also be excluded if they have an autoimmune disease requiring immunosuppression or were previously treated with eribulin or any anti-PD-1, PD-ligand (L) 1, or PD-L2 agent. Phase 1b includes a safety run-in cohort in which ≥6 pts will receive intravenous (IV) eribulin 1.4 mg/m2 (equivalent to 1.23 mg/m2 eribulin [expressed as free base]) on day (d) 1 and d8 and IV pembrolizumab 200 mg on d1 of a 21d cycle. Dose-limiting toxicity (DLT) will be assessed in the first cycle. This dose will be selected as the recommended phase 2 dose (RP2D) if ≤1 pt has a DLT or, if necessary, alternative doses may be explored. Pts will be stratified by prior chemotherapy for MBC (0, ∼70%; 1–2, ∼30%) and will receive RP2D combination treatment. Pts can remain on 1 or both study drugs with clinical benefit until intercurrent illness, unacceptable toxicity, or disease progression. Bayesian predictive probability of response rate, based on the goal of claiming combination superiority at study end, will be used to monitor response rate after postbaseline tumor assessments for ≥38 pts. The study can be stopped early for efficacy or futility. Primary objectives include determination of safety and tolerability (phase 1b) and evaluation of objective response rate of the drug combination; secondary endpoints include evaluation of progression-free survival (PFS), overall survival (OS), and duration of response (DOR). PFS, OS, and DOR will be analyzed using Kaplan–Meier product-limit estimates. Median PFS, OS, and cumulative probability of PFS, OS, and DOR at 6 and 12 months will be presented with 2-sided 95% confidence intervals. Relationship between PD-L1 tumor status and efficacy endpoints will also be evaluated. For further information please contact Erhan Berrak (erhan_berrak@eisai.com). Citation Format: Berrak E, Atkan G, Song J, Almonte A, Karantza V, Yuan R. Design of a phase 1b/2 study to evaluate the efficacy and safety of eribulin mesylate in combination with pembrolizumab in patients with metastatic triple-negative breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr OT1-03-19.

Abstract OT3-1-06: A phase 2 single-arm study to evaluate the clinical activity, safety and tolerability of enzalutamide (ENZA) with trastuzumab in patients with advanced human growth factor receptor 2 (HER2)-positive breast cancer

Abstract Background Androgen receptor (AR) expression is observed in ∼60% of patients (pts) with HER2+ breast cancer1. In vitro, ENZA inhibits proliferation of AR+/HER2+ cell lines and enhances the activity of trastuzumab. ENZA also inhibits proliferation of trastuzumab resistant HER2 positive cells2. Methods Any amount of AR expression (local or central) is allowed, submission of tissue is mandatory. Patients must have measurable disease per RECIST 1.1, and have received 1 to 4 prior lines of anti-HER2 therapy in the advanced / metastatic setting. Brain imaging is required to exclude patients with CNS metastases. Pts with a seizure history are excluded. Women with metastatic or locally advanced HER2+, AR+, and ER-/PgR- breast cancer will receive daily ENZA (160 mg) continuously and trastuzumab (6 mg/kg) administered every 21 days, until disease progression (NCT02091960). The primary endpoint (EP) is clinical benefit rate (CBR) where benefit is defined as complete or partial response (CR or PR) or stable disease (SD) ≥24 weeks according to RECIST 1.1 criteria. Additional EPs include safety and tolerability, and the relationship between AR expression and ENZA activity. If the CBR is ≥3 in 21 evaluable pts, the sample size will increase to 66 pts. The primary EP will be analyzed in pts with centrally confirmed AR expression (≥10% nuclear staining by IHC), who have received at least one dose of ENZA, and have ≥1 post-baseline tumor assessment. The null hypothesis (H0), that the true CBR is 10%, will be tested against a 1-sided alternative. This Simon’s two-stage design yields 90% power when the true response rate is 25% with a 1-sided type 1 error rate of 5%. Enrollment is expected to continue through 2016.

Abstract P5-19-09: Preliminary results from a phase 2 single-arm study of enzalutamide, an androgen receptor (AR) inhibitor, in advanced AR+ triple-negative breast cancer (TNBC)

Abstract Background AR expression has been observed in 10-30% of patients with TNBC. AR+ TNBC cell lines demonstrated enhanced growth in response to androgen stimulation that is inhibited by enzalutamide (ENZA), a potent oral inhibitor of AR signaling. AR+ TNBC may represent a subtype driven by AR signaling that may respond to ENZA. Methods MDV3100-11 is an open-label, Simon 2-stage study designed to evaluate single agent ENZA (160 mg PO daily) in women with advanced AR+ TNBC (NCT01889238). Patients must have measurable or bone-only non-measurable disease. Baseline CNS imaging is required to exclude patients with CNS metastases. Patients with a seizure history are excluded. "AR+" for eligibility is defined as any nuclear AR expression by immunohistochemistry (IHC); TNBC is defined as estrogen receptor and progesterone receptor &amp;lt;1% by IHC and human epidermal growth factor receptor 2 IHC 0 or 1+ or non-amplified for IHC 2+. The primary endpoint is clinical benefit rate (CBR), defined as complete or partial response (CR or PR) or stable disease ≥16 weeks as assessed by the Investigator according to RECIST 1.1 based on the evaluable patient population. Additional endpoints include CBR at 24 weeks, response rates, safety, and tolerability. An evaluable patient is defined as having ≥10% AR staining and a postbaseline tumor assessment for response by RECIST 1.1. The study enrolls a total of 62 evaluable patients if the primary endpoint is achieved by ≥3 patients among the first 26 evaluable patients in Stage 1. Results Preliminary results are available for a subset of the first 26 evaluable patients enrolled; 14 patients have discontinued study due to progressive disease at week 16 or earlier. Eight patients have achieved the primary endpoint; 4 additional active patients have not had their week 16 assessment but achieved stable disease or better at 8 weeks. The current CBR rate is therefore 31%, and could go as high as 46% if all 4 additional patients show at least stable disease or better at their week 16 assessment. Of the 8, 2 discontinued (1 each at weeks 21 and 37), 2 had objective responses (1 PR and 1 CR), and 6 have been on study for ≥24 weeks without disease progression. The toxicity profile of ENZA is so far consistent with other hormone therapies. Full safety and efficacy data on the first 26 evaluable patients enrolled in Stage 1 will be available for inclusion at the time of the late breaking abstract. Conclusion Currently, there is no targeted therapy approved for patients with TNBC. Cytotoxics remain the standard of care in this setting. Preliminary activity and tolerability observed with ENZA are encouraging and raise the possibility that some patients with TNBC may benefit from targeted inhibition of AR signaling, thereby avoiding or delaying cytotoxic regimens. Placeholder abstract: This is a placeholder abstract; we are expecting results from the first subset of 26 evaluable patients to be ready by September 2014. Citation Format: Tiffany A Traina, Joyce O'Shaughnessy, Rita Nanda, Lee Schwartzberg, Vandana Abramson, Javier Cortes, Amy Peterson, Iulia Cristina Tudor, Martha Blaney, Joyce L Steinberg, Catherine Kelly, Maureen Trudeau, Ahmad Awada, Eric Winer, Clifford Hudis, Peter Schmid, Denise A Yardley. Preliminary results from a phase 2 single-arm study of enzalutamide, an androgen receptor (AR) inhibitor, in advanced AR+ triple-negative breast cancer (TNBC) [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-19-09.

Safety and activity of alisertib, an investigational aurora kinase A inhibitor, in patients with breast cancer, small-cell lung cancer, non-small-cell lung cancer, head and neck squamous-cell carcinoma, and gastro-oesophageal adenocarcinoma: a five-arm phase 2 study

Alisertib is an investigational, oral, selective inhibitor of aurora kinase A. We aimed to investigate the safety and activity of single-agent alisertib in patients with predefined types of advanced solid tumours. We did a multicentre phase 1/2 study at 40 centres in four countries (Czech Republic, France, Poland, and the USA). Here, we report results from phase 2; enrolment for the study began on Feb 16, 2010, and ended on May 3, 2013. Adult patients were eligible for the study if they had either breast cancer, small-cell lung cancer, non-small-cell lung cancer, head and neck squamous-cell carcinoma, or gastro-oesophageal adenocarcinoma that had relapsed or was refractory to chemotherapy. Patients had to have undergone two or fewer previous cytotoxic regimens (four or fewer for breast cancer patients), not including adjuvant or neoadjuvant treatments. Enrolment followed a two-stage design: to proceed to the second stage, two or more objective responses were needed in the first 20 response-assessable patients in each of the five tumour cohorts. Alisertib was administered orally in 21-day cycles at the recommended phase 2 dose of 50 mg twice daily for 7 days followed by a break of 14 days. The protocol-specified primary endpoint was the proportion of patients with an objective response, assessed by Response Evaluation Criteria In Solid Tumors version 1.1 in the response-assessable population (ie, patients with measurable disease who received at least one dose of alisertib and had undergone at least one post-baseline tumour assessment). This completed trial is registered with ClinicalTrials.gov, NCT01045421. By May 31, 2013, 249 patients had been treated, 53 with breast cancer, 60 with small-cell lung cancer, 26 with non-small-cell lung cancer, 55 with head and neck squamous-cell carcinoma, and 55 with gastro-oesophageal adenocarcinoma. Among response-assessable patients, an objective response was noted in nine (18%, 95% CI 9-32) of 49 women with breast cancer, ten (21%, 10-35) of 48 participants with small-cell lung cancer, one (4%, 0-22) of 23 patients with non-small-cell lung cancer, four (9%, 2-21) of 45 people with head and neck squamous-cell carcinoma, and four (9%, 2-20) of 47 individuals with gastro-oesophageal adenocarcinoma; all were partial responses. Adverse events were similar across tumour types. The most frequent drug-related grade 3-4 adverse events included neutropenia (n=107 [43%]), leukopenia (53 [21%]), and anaemia (26 [10%]). Serious drug-related adverse events were reported in 108 (43%) patients. These data support further clinical assessment of alisertib in patients with solid tumours, particularly those with breast cancer and small-cell lung cancer. Millennium Pharmaceuticals, Inc, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited.

Safety and activity of lenalidomide and rituximab in untreated indolent lymphoma: an open-label, phase 2 trial

Standard treatments for indolent non-Hodgkin lymphomas are often toxic, and most patients ultimately relapse. Lenalidomide, an immunomodulatory agent, is effective as monotherapy for relapsed indolent non-Hodgkin lymphoma. We assessed the efficacy and safety of lenalidomide plus rituximab in patients with untreated, advanced stage indolent non-Hodgkin lymphoma. In this phase 2 trial, undertaken at one instution, patients with follicular lymphoma and marginal zone lymphoma were given lenalidomide, orally, at 20 mg/day on days 1-21 of each 28-day cycle. For patients with small lymphocytic lymphoma, dosing began at 10 mg/day to avoid tumour flare, with an escalation of 5 mg/month to 20 mg/day. Rituximab was given at 375 mg/m(2) as an intravenous infusion on day 1 of each cycle. Patients responding after six cycles could continue therapy for up to 12 cycles. The primary endpoint was overall response, defined as the proportion of patients who achieved a partial or complete response; patients were assessed for response if they had any post-baseline tumour assessment. This trial is registered with ClinicalTrials.gov, number NCT00695786. 110 patients with follicular lymphoma (n=50), marginal zone lymphoma (n=30), and small lymphocytic lymphoma (n=30) were enrolled from June 30, 2008, until Aug 12, 2011. 93 of 103 evaluable patients had an overall response (90%, 95% CI 83-95). Complete responses occurred in 65 (63%, 95% CI 53-72) and partial responses in 28 patients (27%, 19-37). Of 46 evaluable patients with follicular lymphoma, 40 (87%) patients had a complete response and five (11%) had a partial response. Of 27 evaluable patients with marginal zone lymphoma, 18 (67%) had a complete response and six (22%) had a partial response. Of 30 evaluable patients with small lymphocytic lymphoma, seven (23%) had a complete response and 17 (57%) had a partial response. The most common grade 3 or 4 adverse events were neutropenia (38 [35%] of 110 patients), muscle pain (ten [9%]), rash (eight [7%]), cough, dyspnoea, or other pulmonary symptoms (five [5%]), fatigue (five [5%]), thrombosis (five [5%]), and thrombocytopenia (four [4%]). Lenalidomide plus rituximab is well tolerated and highly active as initial treatment for indolent non-Hodgkin lymphoma. An international phase 3 study (NCT01476787) to compare this regimen with chemotherapy in patients with untreated follicular lymphoma is in progress. Celgene Corporation and Richard Spencer Lewis Memorial Foundation and Cancer Center Support Grant.

Optimum duration of neoadjuvant letrozole to permit breast conserving surgery

The aim of this multicenter, prospective, longitudinal phase IV study was to establish the optimal duration of neoadjuvant letrozole that would allow breast conservation surgery (BCS) in patients with early breast cancer who were initially unsuitable. Primary, invasive, estrogen-receptor- and/or progesterone-receptor-positive breast cancer patients, with large tumors (≥T2 i.e., >20 mm) not initially suitable for BCS, received 2.5 mg letrozole p.o. daily. Patients continued treatment until they became eligible for BCS, progressed, failed to meet criteria for BCS and withdrew for scheduled mastectomy, withdrew for other reasons, or completed 12 months of letrozole treatment without a BCS decision being made. A total of 146 patients were enrolled; seven patients who did not have a valid postbaseline tumor assessment were excluded from the final efficacy analysis. At study closure, 69 % of patients (96 of 139) were eligible for BCS. The median time to achieve a tumor response sufficient to allow BCS with neoadjuvant letrozole was 7.5 months (95 % CI 6.3-8.5 months). Letrozole was well tolerated, and most adverse events were mild-to-moderate (grade 1-2). The results from this trial suggest that extended letrozole therapy in the neoadjuvant setting (7.5 months), as opposed to conventional treatment of 4 months, is optimal to achieve maximum reduction in tumor volume sufficient for BCS.