Nicholas Iannotti

Relationship of Circulating Tumor Cells to Tumor Response, Progression-Free Survival, and Overall Survival in Patients With Metastatic Colorectal Cancer

PURPOSE As treatment options expand for metastatic colorectal cancer (mCRC), a blood marker with a prognostic and predictive role could guide treatment. We tested the hypothesis that circulating tumor cells (CTCs) could predict clinical outcome in patients with mCRC. PATIENTS AND METHODS In a prospective multicenter study, CTCs were enumerated in the peripheral blood of 430 patients with mCRC at baseline and after starting first-, second-, or third-line therapy. CTCs were measured using an immunomagnetic separation technique. RESULTS Patients were stratified into unfavorable and favorable prognostic groups based on CTC levels of three or more or less than three CTCs/7.5 mL, respectively. Patients with unfavorable compared with favorable baseline CTCs had shorter median progression-free survival (PFS; 4.5 v 7.9 months; P = .0002) and overall survival (OS; 9.4 v 18.5 months; P < .0001). Differences persisted at 1 to 2, 3 to 5, 6 to 12, and 13 to 20 weeks after therapy. Conversion of baseline unfavorable CTCs to favorable at 3 to 5 weeks was associated with significantly longer PFS and OS compared with patients with unfavorable CTCs at both time points (PFS, 6.2 v 1.6 months; P = .02; OS, 11.0 v 3.7 months; P = .0002). Among nonprogressing patients, favorable compared with unfavorable CTCs within 1 month of imaging was associated with longer survival (18.8 v 7.1 months; P < .0001). Baseline and follow-up CTC levels remained strong predictors of PFS and OS after adjustment for clinically significant factors. CONCLUSION The number of CTCs before and during treatment is an independent predictor of PFS and OS in patients with metastatic colorectal cancer. CTCs provide prognostic information in addition to that of imaging studies.

Cetuximab and First-Line Taxane/Carboplatin Chemotherapy in Advanced Non–Small-Cell Lung Cancer: Results of the Randomized Multicenter Phase III Trial BMS099

PURPOSE To evaluate the efficacy of cetuximab plus taxane/carboplatin (TC) as first-line treatment of advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS This multicenter, open-label, phase III study enrolled 676 chemotherapy-naïve patients with stage IIIB (pleural effusion) or IV NSCLC, without restrictions by histology or epidermal growth factor receptor expression. Patients were randomly assigned to cetuximab/TC or TC. TC consisted of paclitaxel (225 mg/m(2)) or docetaxel (75 mg/m(2)), at the investigators discretion, and carboplatin (area under the curve = 6) on day 1 every 3 weeks for < or = six cycles; cetuximab (400 mg/m(2) on day 1, 250 mg/m(2) weekly) was administered until progression or unacceptable toxicity. The primary end point was progression-free survival assessed by independent radiologic review committee (PFS-IRRC); overall response rate (ORR), overall survival (OS), quality of life (QoL), and safety were key secondary end points. PFS and ORR assessed by investigators were also evaluated. Results Median PFS-IRRC was 4.40 months with cetuximab/TC versus 4.24 months with TC (hazard ratio [HR] = 0.902; 95% CI, 0.761 to 1.069; P = .236). Median OS was 9.69 months with cetuximab/TC versus 8.38 months with TC (HR = 0.890; 95% CI, 0.754 to 1.051; P = .169). ORR-IRRC was 25.7% with cetuximab/TC versus 17.2% with TC (P = .007). The safety profile of this combination was manageable and consistent with its individual components. CONCLUSION The addition of cetuximab to TC did not significantly improve the primary end point, PFS-IRRC. There was significant improvement in ORR by IRRC. The difference in OS favored cetuximab but did not reach statistical significance.

Prognostic significance of circulating tumor cells in patients with metastatic colorectal cancer

BACKGROUND We demonstrated that circulating tumor cell (CTC) number at baseline and follow-up is an independent prognostic factor in metastatic colorectal cancer (mCRC). This analysis was undertaken to explore whether patient and treatment characteristics impact the prognostic value of CTCs. PATIENTS AND METHODS CTCs were enumerated with immunomagnetic separation from the blood of 430 patients with mCRC at baseline and on therapy. Patients were stratified into unfavorable and favorable prognostic groups based on CTC levels of > or = 3 or <3 CTCs/7.5 ml, respectively. Subgroups were analyzed by line of treatment, liver involvement, receipt of oxaliplatin, irinotecan, or bevacizumab, age, and Eastern Cooperative Oncology Group performance status (ECOG PS). RESULTS Seventy-one percent of deaths have occurred. Median follow-up for living patients is 25.8 months. For all patients, progression-free survival (PFS) and overall survival (OS) for unfavorable compared with favorable baseline CTCs is shorter (4.4 versus 7.8 m, P = 0.004 for PFS; 9.4 versus 20.6 m, P < 0.0001 for OS). In all patient subgroups, unfavorable baseline CTC was associated with inferior OS (P < 0.001). In patients receiving first- or second-line therapy (P = 0.003), irinotecan (P = 0.0001), having liver involvement (P = 0.002), >/=65 years (P = 0.0007), and ECOG PS of zero (P = 0.04), unfavorable baseline CTC was associated with inferior PFS. CONCLUSION Baseline CTC count is an important prognostic factor within specific subgroups defined by treatment or patient characteristics.

Skin Toxicity Evaluation Protocol With Panitumumab (STEPP), a Phase II, Open-Label, Randomized Trial Evaluating the Impact of a Pre-Emptive Skin Treatment Regimen on Skin Toxicities and Quality of Life in Patients With Metastatic Colorectal Cancer

PURPOSE Panitumumab, a fully human monoclonal antibody targeting the epidermal growth factor receptor (EGFR), is approved in the United States and Europe for the treatment of refractory metastatic colorectal cancer (mCRC). Skin toxicities are the most common adverse events with EGFR inhibitors. This is the first study designed to examine differences between pre-emptive and reactive skin treatment for specific skin toxicities in patients with mCRC for any EGFR inhibitor. PATIENTS AND METHODS Patients receiving panitumumab-containing therapy were randomly assigned 1:1 to pre-emptive or reactive treatment (after skin toxicity developed). Pre-emptive treatment included use of skin moisturizers, sunscreen, topical steroid, and doxycycline. The primary end point of the study was the incidence of protocol-specified >or= grade 2 skin toxicities during the 6-week skin treatment period. Quality of life (QOL) was assessed with the Dermatology Life Quality Index (DLQI). RESULTS Of 95 enrolled patients, 48 received pre-emptive treatment, and 47 received reactive treatment. The incidence of protocol-specified >or= grade 2 skin toxicities during the 6-week skin treatment period was 29% and 62% for the pre-emptive and reactive groups, respectively. Mean DLQI score change from baseline to week 3 was 1.3 points and 4.2 points in the pre-emptive and reactive groups, respectively. CONCLUSION The pre-emptive skin treatment regimen was well tolerated. The incidence of specific >or= grade 2 skin toxicities during the 6-week skin treatment period was reduced by more than 50% in the pre-emptive group compared with the reactive group. Patients in the pre-emptive group reported less QOL impairment than patients in the reactive group.

Relationship among circulating tumor cells, CEA and overall survival in patients with metastatic colorectal cancer

BACKGROUND We previously reported results of a prospective trial evaluating the significance of circulating tumor cells (CTCs) in patients with metastatic colorectal cancer (mCRC). This secondary analysis assessed the relationship of the CTC number with carcinoembryonic antigen (CEA) and overall survival. PATIENTS AND METHODS Patients with mCRC had CTCs measured at baseline and specific time points after the initiation of new therapy. Patients with a baseline CEA value ≥10 ng/ml and CEA measurements within ±30 days of the CTC collection were included. RESULTS We included 217 patients with mCRC who had a CEA value of ≥10 ng/ml. Increased baseline CEA was associated with shorter survival (15.8 versus 20.7 months, P = 0.012). Among all patients with a baseline CEA value of ≥25 ng/ml, patients with low baseline CTCs (<3, n = 99) had longer survival than those with high CTCs (≥3, n = 58; 20.8 versus 11.7 months, P = 0.001). CTCs added prognostic information at the 3-5- and 6-12-week time points regardless of CEA. In a multivariate analysis, CTCs at baseline but not CEA independently predicted survival and both CTCs and CEA independently predicted survival at 6-12 weeks. CONCLUSIONS This study demonstrates that both CEA and CTCs contribute prognostic information for patients with mCRC.BACKGROUND We previously reported results of a prospective trial evaluating the significance of circulating tumor cells (CTCs) in patients with metastatic colorectal cancer (mCRC). This secondary analysis assessed the relationship of the CTC number with carcinoembryonic antigen (CEA) and overall survival. PATIENTS AND METHODS Patients with mCRC had CTCs measured at baseline and specific time points after the initiation of new therapy. Patients with a baseline CEA value ≥ 10 ng/ml and CEA measurements within ± 30 days of the CTC collection were included. RESULTS We included 217 patients with mCRC who had a CEA value of ≥ 10 ng/ml. Increased baseline CEA was associated with shorter survival (15.8 versus 20.7 months, P = 0.012). Among all patients with a baseline CEA value of ≥ 25 ng/ml, patients with low baseline CTCs (<3, n = 99) had longer survival than those with high CTCs (≥ 3, n = 58; 20.8 versus 11.7 months, P = 0.001). CTCs added prognostic information at the 3-5- and 6-12-week time points regardless of CEA. In a multivariate analysis, CTCs at baseline but not CEA independently predicted survival and both CTCs and CEA independently predicted survival at 6-12 weeks. CONCLUSIONS This study demonstrates that both CEA and CTCs contribute prognostic information for patients with mCRC.

Avelumab for patients with previously treated metastatic or recurrent non-small-cell lung cancer (JAVELIN Solid Tumor): dose-expansion cohort of a multicentre, open-label, phase 1b trial

BACKGROUND Avelumab, a human Ig-G1 monoclonal antibody targeting PD-L1 and approved in the USA for the treatment of metastatic Merkel cell carcinoma, has shown antitumour activity and an acceptable safety profile in patients with advanced solid tumours in a dose-escalation phase 1a trial. In this dose-expansion cohort of that trial, we assess avelumab treatment in a cohort of patients with advanced, platinum-treated non-small-cell lung cancer (NSCLC). METHODS In this dose-expansion cohort of a multicentre, open-label, phase 1 study, patients with progressive or platinum-resistant metastatic or recurrent NSCLC were enrolled at 58 cancer treatment centres and academic hospitals in the USA. Eligible patients had confirmed stage IIIB or IV NSCLC with squamous or non-squamous histology, measurable disease by Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST v1.1), tumour biopsy or archival sample for biomarker assessment, and Eastern Cooperative Oncology Group performance status 0 or 1, among other criteria. Patient selection was not based on PD-L1 expression or expression of other biomarkers, including EGFR or KRAS mutation or ALK translocation status. Patients received infusional avelumab monotherapy 10 mg/kg every 2 weeks until disease progression or toxicity. The primary objective was to assess safety and tolerability. This trial is registered with ClinicalTrials.gov, number NCT01772004; enrolment in this cohort is closed and the trial is ongoing. FINDINGS Between Sept 10, 2013, and June 24, 2014, 184 patients were enrolled and initiated treatment with avelumab. Median follow-up duration was 8·8 months (IQR 7·2-11·9). The most common treatment-related adverse events of any grade were fatigue (46 [25%] of 184 patients), infusion-related reaction (38 [21%]), and nausea (23 [13%]). Grade 3 or worse treatment-related adverse events occurred in 23 (13%) of 184 patients; the most common (occurring in more than two patients) were infusion-related reaction (four [2%] patients) and increased lipase level (three [2%]). 16 (9%) of 184 patients had a serious adverse event related to treatment with avelumab, with infusion-related reaction (in four [2%] patients) and dyspnoea (in two [1%]) occurring in more than one patient. Serious adverse events irrespective of cause occurred in 80 (44%) of 184 patients. Those occurring in more than five patients (≥3%) were dyspnoea (ten patients [5%]), pneumonia (nine [5%]), and chronic obstructive pulmonary disease (six [3%]). Immune-related treatment-related events occurred in 22 patients (12%). Of 184 patients, 22 (12% [95% CI 8-18]) achieved a confirmed objective response, including one complete response and 21 partial responses. 70 (38%) had stable disease. Overall, 92 (50%) of 184 patients achieved disease control (they had a confirmed response or stable disease as their best overall response). One patient was initially thought to have died from grade 5 radiation pneumonitis during the study; however, this adverse event was subsequently regraded to grade 3 and the death was attributed to disease progression. INTERPRETATION Avelumab showed an acceptable safety profile and antitumour activity in patients with progressive or treatment-resistant NSCLC, providing a rationale for further studies of avelumab in this disease setting. FUNDING Merck KGaA and Pfizer.

The Efficacy and Safety of Panitumumab Administered Concomitantly With FOLFIRI or Irinotecan in Second-Line Therapy for Metastatic Colorectal Cancer: The Secondary Analysis From STEPP (Skin Toxicity Evaluation Protocol With Panitumumab) by KRAS Status

BACKGROUND Panitumumab, a fully human monoclonal antibody targeting the epidermal growth factor receptor (EGFR), is used as monotherapy for chemorefractory metastatic colorectal cancer (mCRC) in patients with wild-type (WT) KRAS tumors. Although skin toxicities are the most common adverse events associated with EGFR inhibitors, the differences in efficacy and safety between pre-emptive and reactive skin treatment according to KRAS tumor status has not been reported. PATIENTS AND METHODS Eligible patients had mCRC with disease progression or unacceptable toxicity with first-line treatment containing fluoropyrimidine and oxaliplatin-based chemotherapy ± bevacizumab. Patients were randomized 1:1 to pre-emptive or reactive skin treatment (after skin toxicity developed). Patients received either panitumumab 6 mg/kg + FOLFIRI every 2 weeks or panitumumab 9 mg/kg + irinotecan every 3 weeks. Key study endpoints included overall response rate (ORR), overall survival, progression-free survival (PFS), and safety according to KRAS tumor status. RESULTS Eighty-seven (92%) of 95 enrolled patients had evaluable KRAS tumor status: 49 (56%) patients with WT and 38 (44%) patients with mutant (MT) KRAS tumors, respectively. The ORR was 16% and 8% for patients with WT and MT KRAS tumors, respectively. Median PFS was 5.5 and 3.3 months for patients with WT and MT KRAS tumors, respectively. The most commonly observed adverse events by KRAS tumor status included dermatitis acneiform and pruritus. CONCLUSION Panitumumab in combination with irinotecan-based chemotherapy has an acceptable toxicity profile in second-line therapy for mCRC. Numerical differences trending in favor of the patients with WT KRAS tumors were observed for most efficacy endpoints.

A Phase II Study of Eribulin Mesylate (E7389) in Patients With Advanced, Previously Treated Non–Small-Cell Lung Cancer

BACKGROUND The efficacy of third-line and further-line chemotherapy for advanced non-small-cell lung cancer (NSCLC) remains unknown. PATIENTS AND METHODS We evaluated the clinical outcome of third- and fourth-line chemotherapy for the treatment of advanced NSCLC in consecutive patients who received first-line chemotherapy at our institute between July 2002 and June 2006. From a hospital-based registry, the following data were extracted: (a) patient characteristics, (b) type of chemotherapeutic agents, and (c) objective response and survival data. RESULTS A total of 599 patients were included in this analysis. Overall, 69.3%, 38.4%, 17.7%, and 6.0% of the patients received second-, third-, fourth-, and fifth-line chemotherapy, respectively. Significant differences in age (P < .0001), performance status at the start of first-line chemotherapy (P < .0001), and histology (P = .0175) were observed between patients who received third-line chemotherapy and those who did not. Docetaxel, gefitinib, and S-1 were the most frequently used regimens for third- or fourth-line chemotherapy. Five percent of the patients had participated in phase I trials of investigational new drugs. The objective response rates and disease control rates of third- and fourth-line chemotherapy were 17.0% and 34.4% and 11.3% and 24.5%, respectively. The median survival times (95% confidence interval [CI]) from the start of first-, second-, third-, and fourth-line chemotherapy until death were 15.3 months (95% CI, 13.8-16.5 months), 12.8 months (95% CI, 10.7-14.5 months), 12.0 months (95% CI, 9.3-14.2 months), and 9.9 months (95% CI, 8.6-12.0 months), respectively. CONCLUSION As many as 38% of patients with advanced NSCLC who received first-line chemotherapy could receive third-line chemotherapy. This result emphasizes the need for randomized controlled trials of third-line treatment in patients with advanced NSCLC.INTRODUCTION This open-label phase II study assessed the efficacy and tolerability of eribulin, a non-taxane microtubule dynamics inhibitor with novel mechanism of action, as monotherapy in patients who have advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS Enrolled patients had progressed during or after platinum-based doublet chemotherapy. Initially, two patient cohorts (taxane-pre-treated and taxane-naïve) received eribulin mesylate (1.4 mg/m(2)) as a 2- to 5-minute intravenous infusion on days 1, 8, and 15 of a 28-day cycle. To assess tolerability of a second dosing schedule, a cohort of taxane-pre-treated patients received eribulin on days 1 and 8 of a 21-day cycle. The primary endpoint was objective response rate (ORR) evaluated using Response Evaluation Criteria in Solid Tumors (RECIST) by independent radiographic review. RESULTS One hundred three patients received eribulin. The ORR was 9.7% (all partial responses [PR]). Overall disease control rate (PR + stable disease) was 55.3%. Median duration of response, progression-free survival, and overall survival were 5.8, 3.4, and 9.4 months, respectively. The most common drug-related adverse events were neutropenia (54%; 49% grade 3/4); fatigue (49%; 11% grade 3, no grade 4); nausea (38%; 1% grade 3, no grade 4); alopecia (32%); anemia (29%, 4% grade 3/4) and neuropathy (23%; 2% grade 3, no grade 4). The 28-day schedule was associated with many dose delays, interruptions, or omissions due to neutropenia (day 15). The 21-day cycle was well-tolerated. CONCLUSIONS Eribulin monotherapy administered on days 1 and 8 of a 21-day cycle is active and tolerated as second- or later-line chemotherapy for NSCLC.

Safety profile of avelumab in patients with advanced solid tumors: A pooled analysis of data from the phase 1 JAVELIN solid tumor and phase 2 JAVELIN Merkel 200 clinical trials

Antibodies targeting the programmed death‐ligand 1 (PD‐L1)/programmed cell death protein 1 (PD‐1) checkpoint may cause adverse events (AEs) that are linked to the mechanism of action of this therapeutic class and unique from those observed with conventional chemotherapy.

Abstract P2-11-03: Incidence and severity of diarrhea with neratinib + intensive loperamide prophylaxis in patients (pts) with HER2+ early-stage breast cancer (EBC): Interim analysis from the multicenter, open-label, phase II control trial

Background: Neratinib (Puma Biotechnology Inc) is an irreversible pan-HER inhibitor in late-phase development for the treatment of early-stage and metastatic HER2+ BC. Diarrhea, the main toxicity of neratinib, requires active management with loperamide prophylaxis given early in the course of treatment. CONTROL (PUMA-NER-6201) is an international, open-label, phase II study investigating the efficacy of loperamide prophylaxis in the prevention of neratinib-associated diarrhea. CONTROL has recently been expanded to include prophylaxis with loperamide + budesonide, which targets inflammation identified in a preclinical model of neratinib induced diarrhea. Methods: Pts with HER2+ early-stage BC who had completed trastuzumab-based adjuvant therapy were eligible. All pts were to receive oral neratinib 240 mg/day for 1 year + structured loperamide prophylaxis on d1–56 (2 cycles). Adverse events were graded according to NCI-CTCAE, v4.0. Primary endpoint: incidence of grade ≥3 diarrhea. A protocol defined interim analysis (data cut-off July 2016) was performed when ∼120 pts had completed ≥2 cycles of neratinib + loperamide prophylaxis. A preliminary analysis of the loperamide + budesonide cohort was also performed at this time. Clinicaltrials.gov: NCT02400476. Results: For the interim analysis, 133 pts received neratinib + loperamide prophylaxis. A further 16 (of 40 planned) pts received neratinib + loperamide prophylaxis (2 cycles) + budesonide (1 cycle). Key results are shown in the table. Incidence of grade ≥3 diarrhea was 27.1% with loperamide prophylaxis and 12.5% with loperamide + budesonide prophylaxis vs 39.9% without protocol-mandated loperamide prophylaxis (ExteNET). Grade 2 diarrhea also decreased (20.3%, 18.8% vs 32.5%, respectively). Grade 3 diarrhea events were uncommon after cycle 1 in all CONTROL cohorts. Conclusions: A structured loperamide prophylactic regimen for 2 cycles is associated with a lower incidence and severity of neratinib associated diarrhea, with notably less grade 2/3 diarrhea compared to ExteNET events. There appears to be some adaptation to the effects of neratinib, as higher-grade diarrhea occurs early and does not typically recur. Preliminary data suggest that adding budesonide may further improve outcomes; enrollment into the budesonide cohort continues. Citation Format: Barcenas C, Olek E, Hunt D, Tripathy D, Ibrahim E, Wilkinson M, Hurvitz S, Iannotti N, Kellum A, Manalo Y, Wong S, Hansen V, Alvarez R, Chan A, Gore I, Kendall D, Wade J, Ruiz R, Fang P, Bryce R, Moran S. Incidence and severity of diarrhea with neratinib + intensive loperamide prophylaxis in patients (pts) with HER2+ early-stage breast cancer (EBC): Interim analysis from the multicenter, open-label, phase II control trial [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 P2-11-03.