Showing papers by "Christopher D. Lao published in 2020"
TL;DR: Nivolumab administered approximately 4 weeks before surgery in MCC was generally tolerable and induced pCRs and radiographic tumor regressions in approximately one half of treated patients, and early markers of response significantly predicted improved RFS.
Abstract: PURPOSEMerkel cell carcinoma (MCC) is a rare, aggressive skin cancer commonly driven by the Merkel cell polyomavirus (MCPyV). The programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) immunos...
128 citations
University of California, San Francisco1, Fred Hutchinson Cancer Research Center2, University of California, Los Angeles3, Rutgers University4, Kaiser Permanente5, University of Alabama at Birmingham6, Ohio State University7, University of Kansas Hospital8, Loyola University Chicago9, University of Michigan10, Missouri Baptist Medical Center11, University of Arkansas at Little Rock12, Medical College of Wisconsin13, Eisenhower Medical Center14, Huntsman Cancer Institute15
TL;DR: Continuous dosing did not improve progression-free survival in patients, contrary to the initial hypothesis, and there were no differences in the secondary outcomes, including overall survival and the overall incidence of treatment-associated toxicity, between the two groups.
Abstract: Preclinical modeling suggests that intermittent BRAF inhibitor therapy may delay acquired resistance when blocking oncogenic BRAFV600 in melanoma1,2. We conducted S1320, a randomized, open-label, phase 2 clinical trial (NCT02196181) evaluating whether intermittent dosing of the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib improves progression-free survival in patients with metastatic and unresectable BRAFV600 melanoma. Patients were enrolled at 68 academic and community sites nationally. All patients received continuous dabrafenib and trametinib during an 8-week lead-in period, after which patients with non-progressing tumors were randomized to either continuous or intermittent dosing of both drugs on a 3-week-off, 5-week-on schedule. The trial has completed accrual and 206 patients with similar baseline characteristics were randomized 1:1 to the two study arms (105 to continuous dosing, 101 to intermittent dosing). Continuous dosing yielded a statistically significant improvement in post-randomization progression-free survival compared with intermittent dosing (median 9.0 months versus 5.5 months, P = 0.064, pre-specified two-sided α = 0.2). Therefore, contrary to the initial hypothesis, intermittent dosing did not improve progression-free survival in patients. There were no differences in the secondary outcomes, including overall survival and the overall incidence of treatment-associated toxicity, between the two groups. The randomized phase 2 trial S1320 comparing different dosing schedules of BRAF/MEK inhibitor combination in BRAF-mutated advanced melanoma shows intermittent therapy does not result in superior progression-free survival in patients.
59 citations
Memorial Sloan Kettering Cancer Center1, Swansea University2, Princess Margaret Cancer Centre3, University of Michigan4, Hospital General Universitario Gregorio Marañón5, European Institute of Oncology6, University of Manchester7, Cross Cancer Institute8, Bristol-Myers Squibb9, Harvard University10, The Royal Marsden NHS Foundation Trust11
TL;DR: 5-y outcomes in a subgroup of patients with mucosal melanoma treated in CheckMate 067 with a positive prognosis for mucosal skin cancer are reported.
Abstract: 10019Background: Mucosal melanoma is a rare but aggressive malignancy with a poor prognosis. Here we report 5-y outcomes in a subgroup of patients with mucosal melanoma treated in CheckMate 067 wit...
47 citations
TL;DR: Long-term follow up indicates that SLNB showcases durable accuracy, safety, and prognostic importance for cutaneous HNCM, and immunosuppression was the only factor significantly associated with regional recurrence.
Abstract: ObjectiveTo evaluate the long-term outcomes of sentinel lymph node biopsy (SLNB) for head and neck cutaneous melanoma (HNCM).Study DesignRetrospective cohort study.SettingTertiary academic medical ...
9 citations
TL;DR: The addition of RRx-001 to WBRT is well-tolerated with favorable intracranial response rates and anti-angiogenic activity associated with longer-term tumor response, and the RP2D is 10 mg twice weekly.
Abstract: Purpose To determine the recommended phase 2 dose of RRx-001, a radiosensitizer with vascular normalizing properties, when used with whole-brain radiation therapy (WBRT) for brain metastases and to assess whether quantitative changes in perfusion magnetic resonance imaging (MRI) after RRx-001 correlate with response. Methods and Materials Five centers participated in this phase 1/2 trial of RRx-001 given once pre-WBRT and then twice weekly during WBRT. Four dose levels were planned (5 mg/m2, 8.4 mg/m2, 16.5 mg/m2, 27.5 mg/m2). Dose escalation was managed by the time-to-event continual reassessment method algorithm. Linear mixed models were used to correlate change in 24-hour T1, Ktrans (capillary permeability), and fractional plasma volume with change in tumor volume. Results Between 2015 and 2017, 31 patients were enrolled. Two patients dropped out before any therapy. Median age was 60 years (range, 30-76), and 12 were male. The most common tumor types were melanoma (59%) and non-small cell lung cancer (18%). No dose limiting toxicities were observed. The most common severe adverse event was grade 3 asthenia (6.9%, 2 of 29). The median intracranial response rate was 46% (95% confidence interval, 24-68) and median overall survival was 5.2 months (95% confidence interval, 4.5-9.4). No neurologic deaths occurred. Among 10 patients undergoing dynamic contrast-enhanced MRI, a reduction in Vp 24 hours after RRx-001 was associated with reduced tumor volume at 1 and 4 months (P ≤ .01). Conclusions The addition of RRx-001 to WBRT is well tolerated with favorable intracranial response rates. Because activity was observed across all dose levels, the recommended phase 2 dose is 10 mg twice weekly. A reduction in fractional plasma volume on dynamic contrast-enhanced MRI 24 hours after RRx-001 suggests antiangiogenic activity associated with longer-term tumor response.
6 citations
University of California, San Francisco1, Fred Hutchinson Cancer Research Center2, University of California, Los Angeles3, Rutgers University4, Kaiser Permanente5, University of Alabama at Birmingham6, Ohio State University7, University of Kansas Hospital8, Loyola University Chicago9, University of Michigan10, Missouri Baptist Medical Center11, University of Arkansas at Little Rock12, Medical College of Wisconsin13, Eisenhower Medical Center14, University of Utah15
TL;DR: Continuous dosing with the BRAF and MEK inhibitors dabrafenib and trametinib yields superior PFS compared with intermittent dosing, and there was no difference in overall survival between groups.
Abstract: Background: BRAF and MEK inhibitors yield objective responses in the majority of BRAFV600E/K mutant melanoma patients, but acquired resistance limits response durations. Preclinical data suggests that intermittent dosing of these agents may delay acquired resistance by deselecting tumor cells that grow optimally in the presence of these agents. S1320 is a randomized phase 2 clinical trial designed to determine whether intermittent versus continuous dosing of dabrafenib and trametinib improves progression-free survival (PFS) in patients with advanced BRAFV600E/K melanoma. Methods: All patients received continuous dabrafenib and trametinib for 8-weeks after which non-progressing patients were randomized to receive either continuous treatment or intermittent dosing of both drugs on a 3-week-off, 5-week-on schedule. Unscheduled treatment interruptions of both drugs for > 14 days were not permitted. Responses were assessed using RECIST v1.1 at 8-week intervals scheduled to coincide with on-treatment periods for patients on the intermittent dosing arm. Adverse events were assessed using CTCAE v4 monthly. The design assumed exponential PFS with a median of 9.4 months using continuous dosing, 206 eligible patients and 156 PFS events. It had 90% power with a two-sided α = 0.2 to detect a change to a median with an a priori hypothesis that intermittent dosing would improve the median PFS to 14.1 months using a Cox model stratified by the randomization stratification factors. Results: 242 patients were treated and 206 patients without disease progression after 8 weeks were randomized, 105 to continuous and 101 to intermittent treatment. 70% of patients had not previously received immune checkpoint inhibitors. There were no significant differences between groups in terms of baseline patient characteristics. The median PFS was statistically significantly longer, 9.0 months from randomization, with continuous dosing vs. 5.5 months from randomization with intermittent dosing (p = 0.064). There was no difference in overall survival between groups (median OS = 29.2 months in both arms p = 0.93) at a median follow up of 2 years. 77% of patient treated continuously discontinued treatment due to disease progression vs. 84% treated intermittently (p = 0.34). Conclusions: Continuous dosing with the BRAF and MEK inhibitors dabrafenib and trametinib yields superior PFS compared with intermittent dosing. Support: NIH/NCI grants CA180888, CA180819, CA180820 Citation Format: Alain Algazi, Megan Othus, Adil Daud, Roger Lo, Janice Mehnert, Thach-Giao Truong, Robert Conry, Kari Kendra, Gary Doolittle, Joseph I. Clark, Michael Messino, Dennis F. Moore, Christopher Lao, Bryan A. Faller, Rangaswamy Govindarajan, Amy Harker-Murray, Luke Dreisbach, James Moon, Kenneth Grossman, Antoni Ribas. SWOG S1320: Improved progression-free survival with continuous compared to intermittent dosing with dabrafenib and trametinib in patients with BRAF mutated melanoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT013.
4 citations
TL;DR: The study suggests the poor prognosis associated with LM can be substantially mitigated by treatment with combination I/N over anti-PD-1 monotherapy and combination ipilimumab/nivolumab (I/N).
Abstract: Background Recent studies report of liver metastases (LM) as a poor prognostic factor in patients treated with immune checkpoint inhibitors (ICIs),1 but clinical outcomes associated with different ICI regimens remains uncertain. In this study, we investigate melanoma patients with and without LM and assess differential treatment outcomes associated with anti-PD-1 monotherapy and combination ipilimumab/nivolumab (I/N). Methods We conducted a single-center, retrospective review of advanced stage melanoma patients with and without LM treated with anti-PD-1 monotherapy (nivolumab or pembrolizumab) or I/N between 2012 and 2018. Overall survival (OS) and progression free survival (PFS) were measured from the first dose of treatment to date of death and clinical or radiographic progression, respectively. Univariate and multivariate analysis were performed using Cox proportional hazard (CPH) models and logistic regression models. Inverse probability of treatment weighting using propensity scores in CPH models was used to account for the following baseline covariates: age, ECOG performance status, BRAF status, pre-treatment LDH level, prior therapy status, and number and sites of metastases. Results 327 patients were identified, 87 with LM and 240 without LM. Patients with LM was associated with worse PFS [HR: 2.1, 95% CI, 1.5 – 3.1] (figure 1) and OS [HR: 3.4, 95% CI, 2.2 – 5.2] (figure 2). Respective 3-year PFS and OS estimates associated with anti-PD-1 monotherapy were 21.8% and 28.7% in patients with LM (figure 3, figure 4); and 36.5% and 57.6% without LM (figure 5, figure 6). Respective 3-year PFS and OS estimates associated with I/N were 46.7% and 56.7% in patients with LM; and 58.0% and 74.4% without LM. Conclusions In melanoma patients treated with PD-1 inhibitor-based regimens, the presence of LM leads to poorer survival outcomes. Our study suggests the poor prognosis associated with LM can be substantially mitigated by treatment with combination I/N over anti-PD-1 monotherapy. Further studies are warranted to investigate the anti-immunotherapy effect associated with LM. Ethics Approval The study was approved by the University of Michigan institutional ethical guidelines and patients‘ consents were waived following Institutional Review Board protocol review (HUM00156014). Reference Bilen MA, Shabto JM, Martini DJ, et al. Sites of metastasis and association with clinical outcome in advanced stage cancer patients treated with immunotherapy. BMC Cancer 2019; 19(1):857.
2 citations