Showing papers by "Jean-Jacques Grob published in 2018"

Adjuvant Pembrolizumab versus Placebo in Resected Stage III Melanoma

Abstract: Background The programmed death 1 (PD-1) inhibitor pembrolizumab has been found to prolong progression-free and overall survival among patients with advanced melanoma. We conducted a phase 3 double-blind trial to evaluate pembrolizumab as adjuvant therapy in patients with resected, high-risk stage III melanoma. Methods Patients with completely resected stage III melanoma were randomly assigned (with stratification according to cancer stage and geographic region) to receive 200 mg of pembrolizumab (514 patients) or placebo (505 patients) intravenously every 3 weeks for a total of 18 doses (approximately 1 year) or until disease recurrence or unacceptable toxic effects occurred. Recurrence-free survival in the overall intention-to-treat population and in the subgroup of patients with cancer that was positive for the PD-1 ligand (PD-L1) were the primary end points. Safety was also evaluated. Results At a median follow-up of 15 months, pembrolizumab was associated with significantly longer recurrence...

Nivolumab plus ipilimumab or nivolumab alone versus ipilimumab alone in advanced melanoma (CheckMate 067): 4-year outcomes of a multicentre, randomised, phase 3 trial.

Abstract: Summary Background Previously reported results from the phase 3 CheckMate 067 trial showed a significant improvement in objective responses, progression-free survival, and overall survival with nivolumab plus ipilimumab or nivolumab alone compared with ipilimumab alone in patients with advanced melanoma. The aim of this report is to provide 4-year updated efficacy and safety data from this study. Methods In this phase 3 trial, eligible patients were aged 18 years or older with previously untreated, unresectable, stage III or stage IV melanoma, known BRAFV600 mutation status, and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were randomly assigned 1:1:1 to receive intravenous nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks for four doses, followed by nivolumab 3 mg/kg every 2 weeks, or nivolumab 3 mg/kg every 2 weeks plus placebo, or ipilimumab 3 mg/kg every 3 weeks for four doses plus placebo. Randomisation was done via an interactive voice response system with a permuted block schedule (block size of six) and stratification by PD-L1 status, BRAF mutation status, and metastasis stage. The patients, investigators, study site staff, and study funder were masked to the study drug administered. The co-primary endpoints were progression-free survival and overall survival. Efficacy analyses were done on the intention-to-treat population, whereas safety was assessed in all patients who received at least one dose of study drug. The results presented in this report reflect the 4-year update of the ongoing study with a database lock date of May 10, 2018. This study is registered with ClinicalTrials.gov, number NCT01844505. Findings Between July 3, 2013, and March 31, 2014, 945 patients were enrolled and randomly assigned to nivolumab plus ipilimumab (n=314), nivolumab (n=316), or ipilimumab (n=315). Median follow-up was 46·9 months (IQR 10·9–51·8) in the nivolumab plus ipilimumab group, 36·0 months (10·5–51·4) in the nivolumab group, and 18·6 months (7·6–49·5) in the ipilimumab group. At a minimum follow-up of 48 months from the date that the final patient was enrolled and randomised, median overall survival was not reached (95% CI 38·2–not reached) in the nivolumab plus ipilimumab group, 36·9 months (28·3–not reached) in the nivolumab group, and 19·9 months (16·9–24·6) in the ipilimumab group. The hazard ratio for death for the combination versus ipilimumab was 0·54 (95% CI 0·44–0·67; p Interpretation The results of this analysis at 4 years of follow-up show that a durable, sustained survival benefit can be achieved with first-line nivolumab plus ipilimumab or nivolumab alone in patients with advanced melanoma. Funding Bristol-Myers Squibb.

Association of body-mass index and outcomes in patients with metastatic melanoma treated with targeted therapy, immunotherapy, or chemotherapy: a retrospective, multicohort analysis

Abstract: Summary Background Obesity has been linked to increased mortality in several cancer types; however, the relation between obesity and survival outcomes in metastatic melanoma is unknown The aim of this study was to examine the association between body-mass index (BMI) and progression-free survival or overall survival in patients with metastatic melanoma who received targeted therapy, immunotherapy, or chemotherapy Methods This retrospective study analysed independent cohorts of patients with metastatic melanoma assigned to treatment with targeted therapy, immunotherapy, or chemotherapy in randomised clinical trials and one retrospective study of patients treated with immunotherapy Patients were classified according to BMI, following the WHO definitions, as underweight, normal, overweight, or obese Patients without BMI and underweight patients were excluded The primary outcomes were the associations between BMI and progression-free survival or overall survival, stratified by treatment type and sex We did multivariable analyses in the independent cohorts, and combined adjusted hazard ratios in a mixed-effects meta-analysis to provide a precise estimate of the association between BMI and survival outcomes; heterogeneity was assessed with meta-regression analyses Analyses were done on the predefined intention-to-treat population in the randomised controlled trials and on all patients included in the retrospective study Findings The six cohorts consisted of a total of 2046 patients with metastatic melanoma treated with targeted therapy, immunotherapy, or chemotherapy between Aug 8, 2006, and Jan 15, 2016 1918 patients were included in the analysis Two cohorts containing patients from randomised controlled trials treated with targeted therapy (dabrafenib plus trametinib [n=599] and vemurafenib plus cobimetinib [n=240]), two cohorts containing patients treated with immunotherapy (one randomised controlled trial of ipilimumab plus dacarbazine [n=207] and a retrospective cohort treated with pembrolizumab, nivolumab, or atezolizumab [n=331]), and two cohorts containing patients treated with chemotherapy (two randomised controlled trials of dacarbazine [n=320 and n=221]) were classified according to BMI as normal (694 [36%] patients), overweight (711 [37%]), or obese (513 [27%]) In the pooled analysis, obesity, compared with normal BMI, was associated with improved survival in patients with metastatic melanoma (average adjusted hazard ratio [HR] 0·77 [95% CI 0·66–0·90] for progression-free survival and 0·74 [0·58–0·95] for overall survival) The survival benefit associated with obesity was restricted to patients treated with targeted therapy (HR 0·72 [0·57–0·91] for progression-free survival and 0·60 [0·45–0·79] for overall survival) and immunotherapy (HR 0·75 [0·56–1·00] and 0·64 [0·47–0·86]) No associations were observed with chemotherapy (HR 0·87 [0·65–1·17, p interaction =0·61] for progression-free survival and 1·03 [0·80–1·34, p interaction =0·01] for overall survival) The association of BMI with overall survival for patients treated with targeted and immune therapies differed by sex, with inverse associations in men (HR 0·53 [0·40–0·70]), but no associations observed in women (HR 0·85 [0·61–1·18, p interaction =0·03]) Interpretation Our results suggest that in patients with metastatic melanoma, obesity is associated with improved progression-free survival and overall survival compared with those outcomes in patients with normal BMI, and that this association is mainly seen in male patients treated with targeted or immune therapy These results have implications for the design of future clinical trials for patients with metastatic melanoma and the magnitude of the benefit found supports further investigation of the underlying mechanism of these associations Funding ASCO/CCF Young Investigator Award, ASCO/CCF Career Development Award, MD Anderson Cancer Center (MDACC) Melanoma Moonshot Program, MDACC Melanoma SPORE, and the Dr Miriam and Sheldon G Adelson Medical Research Foundation

Efficacy and Safety of First-line Avelumab Treatment in Patients With Stage IV Metastatic Merkel Cell Carcinoma: A Preplanned Interim Analysis of a Clinical Trial

Abstract: Importance Merkel cell carcinoma (MCC) is an aggressive skin cancer that is associated with poor survival outcomes in patients with distant metastatic disease. Results of part A of the JAVELIN Merkel 200 trial (avelumab in patients with Merkel cell carcinoma) showed that avelumab, an anti–programmed cell death ligand 1 (PD-L1) antibody, demonstrated efficacy in second-line or later treatment of patients with metastatic MCC (mMCC). Objective To evaluate the efficacy and safety of avelumab as first-line treatment for patients with distant mMCC. Design, Setting, and Participants JAVELIN Merkel 200 part B is an international, multicenter, single-arm, open-label clinical trial of first-line avelumab monotherapy. Eligible patients were adults with mMCC who had not received prior systemic treatment for metastatic disease. Patients were not selected for PD-L1 expression or Merkel cell polyomavirus status. Data were collected from April 15, 2016, to March 24, 2017, and enrollment is ongoing. Interventions Patients received avelumab, 10 mg/kg, by 1-hour intravenous infusion every 2 weeks until confirmed disease progression, unacceptable toxic effects, or withdrawal occurred. Main Outcomes and Measures Tumor status was assessed every 6 weeks and evaluated by independent review committee per Response Evaluation Criteria in Solid Tumors version 1.1. The primary end point was durable response, defined as an objective response with a duration of at least 6 months. Secondary end points include best overall response, duration of response, progression-free survival, safety, and tolerability. Results As of March 24, 2017, 39 patients were enrolled (30 men and 9 women; median age, 75 years [range, 47-88 years]), with a median follow-up of 5.1 months (range, 0.3-11.3 months). In a preplanned analysis, efficacy was assessed in 29 patients with at least 3 months of follow-up; the confirmed objective response rate was 62.1% (95% CI, 42.3%-79.3%), with 14 of 18 responses (77.8%) ongoing at the time of analysis. In responding patients, the estimated proportion with duration of response of at least 3 months was 93% (95% CI, 61%-99%); duration of response of at least 6 months, 83% (95% CI, 46%-96%). First-line avelumab treatment was generally well tolerated, and no treatment-related deaths or grade 4 adverse events occurred. Conclusions and Relevance High rates of response to first-line avelumab therapy in patients with distant mMCC build on previously reported antitumor activity after second-line or later treatment, and maturing progression-free survival data suggest that responses are durable. These data further support avelumab’s approval in the United States and European Union and use as a standard-of-care treatment for mMCC. Trial Registration clinicaltrials.gov Identifier:NCT02155647

Adjuvant vemurafenib in resected, BRAFV600 mutation-positive melanoma (BRIM8): a randomised, double-blind, placebo-controlled, multicentre, phase 3 trial

Abstract: Summary Background Systemic adjuvant treatment might mitigate the high risk of disease recurrence in patients with resected stage IIC–III melanoma. The BRIM8 study evaluated adjuvant vemurafenib monotherapy in patients with resected, BRAF V600 mutation-positive melanoma. Methods BRIM8 was a phase 3, international, double-blind, randomised, placebo-controlled study that enrolled 498 adults (aged ≥18 years) with histologically confirmed stage IIC–IIIA–IIIB (cohort 1) or stage IIIC (cohort 2) BRAF V600 mutation-positive melanoma that was fully resected. Patients were randomly assigned (1:1) by an interactive voice or web response system to receive twice-daily adjuvant oral vemurafenib 960 mg tablets or matching placebo for 52 weeks (13 × 28-day cycles). Randomisation was done by permuted blocks (block size 6) and was stratified by pathological stage and region in cohort 1 and by region in cohort 2. The investigators, patients, and sponsor were masked to treatment assignment. The primary endpoint was disease-free survival in the intention-to-treat population, evaluated separately in each cohort. Hierarchical analysis of cohort 2 before cohort 1 was prespecified. This trial is registered with ClinicalTrials.gov, number NCT01667419. Findings The study enrolled 184 patients in cohort 2 (93 were assigned to vemurafenib and 91 to placebo) and 314 patients in cohort 1 (157 were assigned to vemurafenib and 157 to placebo). At the time of data cutoff (April 17, 2017), median study follow-up was 33·5 months (IQR 25·9–41·6) in cohort 2 and 30·8 months (25·5–40·7) in cohort 1. In cohort 2 (patients with stage IIIC disease), median disease-free survival was 23·1 months (95% CI 18·6–26·5) in the vemurafenib group versus 15·4 months (11·1–35·9) in the placebo group (hazard ratio [HR] 0·80, 95% CI 0·54–1·18; log-rank p=0·026). In cohort 1 (patients with stage IIC–IIIA–IIIB disease) median disease-free survival was not reached (95% CI not estimable) in the vemurafenib group versus 36·9 months (21·4–not estimable) in the placebo group (HR 0·54 [95% CI 0·37–0·78]; log-rank p=0·0010); however, the result was not significant because of the prespecified hierarchical prerequisite for the primary disease-free survival analysis of cohort 2 to show a significant disease-free survival benefit. Grade 3–4 adverse events occurred in 141 (57%) of 247 patients in the vemurafenib group and 37 (15%) of 247 patients in the placebo group. The most common grade 3–4 adverse events in the vemurafenib group were keratoacanthoma (24 [10%] of 247 patients), arthralgia (17 [7%]), squamous cell carcinoma (17 [7%]), rash (14 [6%]), and elevated alanine aminotransferase (14 [6%]), although all keratoacanthoma events and most squamous cell carcinoma events were by default graded as grade 3. In the placebo group, grade 3–4 adverse events did not exceed 2% for any of the reported terms. Serious adverse events were reported in 40 (16%) of 247 patients in the vemurafenib group and 25 (10%) of 247 patients in the placebo group. The most common serious adverse event was basal cell carcinoma, which was reported in eight (3%) patients in each group. One patient in the vemurafenib group of cohort 2 died 2 months after admission to hospital for grade 3 hypertension; however, this death was not considered to be related to the study drug. Interpretation The primary endpoint of disease-free survival was not met in cohort 2, and therefore the analysis of cohort 1 showing a numerical benefit in disease-free survival with vemurafenib versus placebo in patients with resected stage IIC–IIIA–IIIB BRAF V600 mutation-positive melanoma must be considered exploratory only. 1 year of adjuvant vemurafenib was well tolerated, but might not be an optimal treatment regimen in this patient population. Funding F Hoffman–La Roche Ltd.

Epacadostat (E) plus pembrolizumab (P) versus pembrolizumab alone in patients (pts) with unresectable or metastatic melanoma: Results of the phase 3 ECHO-301/KEYNOTE-252 study.

Abstract: 108Background: In a phase 1/2 study, the combination of E, a selective oral inhibitor of the IDO1 enzyme, plus P, a PD-1 inhibitor, suggested promising antitumor activity with minimal additive toxicity. ECHO-301/KEYNOTE-252 (NCT02752074) is a phase 3, randomized, double-blind study evaluating the efficacy and safety of E + P vs placebo + P in pts with untreated unresectable or metastatic melanoma. Methods: Pts had histologically confirmed unresectable stage III or IV melanoma and were treatment naive for advanced or metastatic disease, except for pts with the BRAF V600 mutation who could have received prior BRAF/MEK therapy. Pts were stratified by PD-L1 expression and BRAF mutation status (BRAF mutant with prior BRAF-directed therapy, BRAF mutant without prior BRAF-directed therapy, and BRAF wild type) and randomized 1:1 to E 100 mg BID + P 200 mg Q3W or matched E placebo + P 200 mg Q3W. Response was assessed per RECIST v1.1 and irRECIST (both by central review). The primary endpoints were PFS per RECIST ...

MAGE-A3 immunotherapeutic as adjuvant therapy for patients with resected, MAGE-A3-positive, stage III melanoma (DERMA): a double-blind, randomised, placebo-controlled, phase 3 trial.

Abstract: Summary Background Despite newly approved treatments, metastatic melanoma remains a life-threatening condition. We aimed to evaluate the efficacy of the MAGE-A3 immunotherapeutic in patients with stage IIIB or IIIC melanoma in the adjuvant setting. Methods DERMA was a phase 3, double-blind, randomised, placebo-controlled trial done in 31 countries and 263 centres. Eligible patients were 18 years or older and had histologically proven, completely resected, stage IIIB or IIIC, MAGE-A3-positive cutaneous melanoma with macroscopic lymph node involvement and an Eastern Cooperative Oncology Group performance score of 0 or 1. Randomisation and treatment allocation at the investigator sites were done centrally via the internet. We randomly assigned patients (2:1) to receive up to 13 intramuscular injections of recombinant MAGE-A3 with AS15 immunostimulant (MAGE-A3 immunotherapeutic; 300 μg MAGE-A3 antigen plus 420 μg CpG 7909 reconstituted in AS01B to a total volume of 0·5 mL), or placebo, over a 27-month period: five doses at 3-weekly intervals, followed by eight doses at 12-weekly intervals. The co-primary outcomes were disease-free survival in the overall population and in patients with a potentially predictive gene signature (GS-positive) identified previously and validated here via an adaptive signature design. The final analyses included all patients who had received at least one dose of study treatment; analyses for efficacy were in the as-randomised population and for safety were in the as-treated population. This trial is registered with ClinicalTrials.gov, number NCT00796445. Findings Between Dec 1, 2008, and Sept 19, 2011, 3914 patients were screened, 1391 randomly assigned, and 1345 started treatment (n=895 for MAGE-A3 and n=450 for placebo). At final analysis (data cutoff May 23, 2013), median follow-up was 28·0 months [IQR 23·3–35·5] in the MAGE-A3 group and 28·1 months [23·7–36·9] in the placebo group. Median disease-free survival was 11·0 months (95% CI 10·0–11·9) in the MAGE-A3 group and 11·2 months (8·6–14·1) in the placebo group (hazard ratio [HR] 1·01, 0·88–1·17, p=0·86). In the GS-positive population, median disease-free survival was 9·9 months (95% CI 5·7–17·6) in the MAGE-A3 group and 11·6 months (5·6–22·3) in the placebo group (HR 1·11, 0·83–1·49, p=0·48). Within the first 31 days of treatment, adverse events of grade 3 or worse were reported by 126 (14%) of 894 patients in the MAGE-A3 group and 56 (12%) of 450 patients in the placebo group, treatment-related adverse events of grade 3 or worse by 36 (4%) patients given MAGE-A3 vs six (1%) patients given placebo, and at least one serious adverse event by 14% of patients in both groups (129 patients given MAGE-A3 and 64 patients given placebo). The most common adverse events of grade 3 or worse were neoplasms (33 [4%] patients in the MAGE-A3 group vs 17 [4%] patients in the placebo group), general disorders and administration site conditions (25 [3%] for MAGE-A3 vs four [ vs seven [2%] for placebo). No deaths were related to treatment. Interpretation An antigen-specific immunotherapeutic alone was not efficacious in this clinical setting. Based on these findings, development of the MAGE-A3 immunotherapeutic for use in melanoma has been stopped. Funding GlaxoSmithKline Biologicals SA.

4-year survival and outcomes after cessation of pembrolizumab (pembro) after 2-years in patients (pts) with ipilimumab (ipi)-naive advanced melanoma in KEYNOTE-006.

Abstract: 9503Background: KEYNOTE-006 (NCT01866319) established superiority of pembro over ipi in advanced melanoma We provide 4-y outcomes, long-term data for pts who completed 2 y pembro, and data for sec

Adjuvant therapy with nivolumab (NIVO) versus ipilimumab (IPI) after complete resection of stage III/IV melanoma: Updated results from a phase III trial (CheckMate 238).

Abstract: 9502Background: In the initial report of data from CheckMate 238, at a minimum follow-up of 18 mo, NIVO demonstrated significantly longer recurrence-free survival (RFS) vs IPI in patients (pts) with resected stage III or IV melanoma. Here, we report updated efficacy results from this phase III study with an additional 6 mo of follow-up. Methods: Eligible pts included those ≥15 yrs of age who underwent complete resection of stage IIIB/C or IV melanoma. 906 pts were randomized 1:1 (stratified by disease stage and PD-L1 status at a 5% cutoff) to receive NIVO 3 mg/kg Q2W (N=453) or IPI 10 mg/kg Q3W for 4 doses, then Q12W (from week 24) (N=453) for up to 1 yr, or until disease recurrence or unacceptable toxicity. The primary endpoint was RFS; distant metastasis-free survival (DMFS) in pts with stage III disease was an exploratory endpoint. Results: At a minimum follow-up of 24 mo, RFS continued to be significantly longer for NIVO vs IPI (hazard ratio 0.66, P<0.0001), with 171/453 and 221/453 events, respective...

Metastatic Melanoma: Recent Therapeutic Progress and Future Perspectives.

Abstract: The prognosis of patients with metastatic melanoma has dramatically improved in recent years with the introduction of two new therapeutic strategies. BRAF and MEK inhibitors are small molecules that are able to block the mitogen-activated protein kinase (MAPK) pathway, which is constitutively activated by recurrent BRAF V600 mutations in 45% of melanoma patients. These agents were shown to provide a rapid and strong response but are often limited by a high rate of secondary resistance. Monoclonal antibodies against the immune checkpoints cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and programmed death 1 (PD-1) can restore an efficient and durable anti-tumor immunity, even following treatment discontinuation. Anti-PD-1 antibodies were shown to prolong survival of metastatic melanoma patients and a real cure seems to be obtainable in some patients. Many more therapies are currently under investigation, given that 50% of patients still do not have long-term benefits from approved treatments. The main goal is to avoid or circumvent primary or secondary immune resistance to anti-PD-1 therapy not only by targeting other players in the tumor microenvironment but also by optimizing treatment sequencing and combining anti-PD-1 with other treatments, especially with BRAF and MEK inhibitors. The unexpected major successes of immunotherapies in melanoma have opened the way for the development of these treatments in other cancers. In this review, we describe the different available treatments, their toxicities, and the key components of our decisional algorithms, and give an overview of what we expect to be the near future of melanoma treatment.

Adjuvant melanoma therapy with new drugs: should physicians continue to focus on metastatic disease or use it earlier in primary melanoma?

Abstract: It is important to differentiate between two concepts of adjuvant therapy in melanoma-what we have come to call late adjuvant and early adjuvant therapy. Early adjuvant therapy is defined as a medical intervention that is done after resection of a primary melanoma to eradicate possible undetectable minimal residual disease, whereas late adjuvant therapy is done when an overt metastatic disease (nodal or visceral) has been completely resected, to control disease better than if the same treatment were given at a later time, in the presence of multiple metastases. Early adjuvant therapy is thus a preventive treatment strategy, whereas late adjuvant therapy aims at anticipating treatment of metastatic disease. For patients with melanoma, 1-year treatment with targeted therapies and immunotherapy have only been assessed in late adjuvant settings, the outcomes of which more or less reproduce the same dramatic effect as they have in metastatic disease. However, early adjuvant therapy could provide greater benefits in terms of public health, since thin melanomas without nodal metastases are so common that they account for most deaths by melanoma. In the early adjuvant setting, a treatment course of less than 1 year might be sufficient to control the disease, with less toxicity and at reduced costs. In this Personal View, we discuss the potential benefit of short-term early adjuvant treatment in patients with stage II melanoma, with the hope that sentinel-node biopsy and the American Joint Committee on Cancer staging will soon be replaced by more relevant biomarkers to identify the most suitable candidates for early adjuvant therapy for this disease.

Diabetes and Blood Glucose Disorders Under Anti-PD1.

Abstract: Acute type 1 diabetes (AD1) is a rare but definitive immune-related adverse event associated with anti-PD1. Most of the reported cases are close to what has been described as "fulminant type 1 diabetes." We sought to determine whether anti-PD1 could impair glycoregulation and whether occurrence of AD1 could be anticipated by prior glycemic changes. Fasting glycemia collected before, under, and after treatment in melanoma patients treated with anti-PD1 over a period of 36 months were retrospectively analyzed. Glycemic trend analyses were performed using linear regression analysis. In total, 1470 glucose values were monitored in 163 patients treated for a mean duration of 5.96 months. Three patients developed an AD1 (1, 84%). Two other cases were observed in the same period in a still-blinded trial of anti-PD1 versus ipilimumab. All cases of AD1 occurred in patients with a normal pretreatment glycemia, and there was no detectable drift of glycemia before ketoacidosis onset. In 4 of 5 cases of AD1, the HLA subgroups were DRB01* 03 or 04, known to increase type 1 diabetes risk in the general population. In the 28 patients with preexisting type 2 diabetes, there was a slight trend for glycemia increase with anti-PD1 infusions (0.05 mmol/L/infusion P=0.004). In the 132 patients with normal pretreatment glycemia, there was a slight trend for a decrease of glycemia with anti-PD1 infusions (-0.012/mmol/L/infusion P=0.026). These data suggest that the monitoring of glycemia under anti-PD1 cannot help to anticipate AD1, and there is no general tendency to glycemic disorder. HLA genotyping before treatment may help to focus surveillance in patients with the HLA DRB1*03/04 group.

Pembrolizumab as first line therapy in patients with unresectable squamous cell carcinoma of the skin: Interim results of the phase 2 CARSKIN trial.

Abstract: 9534Background: Patients (pts) with advanced squamous cell carcinoma of the skin (SCCS) have a poor prognosis. Response rate (RR) of 46% with an anti PD-1 (REGN2810) was recently shown in 25 pre-tr...

Assessment of quality of life using Skindex-16 in patients with advanced basal cell carcinoma treated with vismodegib in the STEVIE study

Abstract: Health-related quality of life (HRQoL) data are limited in patients with advanced basal cell carcinoma. To report HRQoL outcomes based on STEVIE (NCT01367665), a phase 2 study of vismodegib safety in patients with metastatic BCC or locally advanced BCC that is unsuitable for surgery or radiotherapy. Skindex-16 and MD Anderson Symptom Inventory (MDASI) questionnaires were completed at baseline and at three subsequent visits. Clinically meaningful improvement was defined as a ≥10-point decrease from baseline (Skindex-16) or improvement of at least 3 points from baseline (MDASI). HRQoL-evaluable patients with locally advanced BCC (n = 730) had ≥10-point improvements in Skindex-16 emotion domain scores at all time points. Changes in symptom and function scores in these patients or in any domain scores at any time point in patients with metastatic BCC (n = 10) were not clinically meaningful. Of 10 patients with symptomatic metastatic BCC at baseline, six had ≥3-point improvements in MDASI symptom severity. Skindex-16 and MDASI showed improvement in HRQoL in vismodegib-treated patients with locally advanced or metastatic BCC or BCC.

Ipilimumab combined with stereotactic radiosurgery in melanoma patients with brain metastases: A multicenter, open label, phase 2 trial.

Abstract: 9520Background: Brain metastasis commonly occur in patients with metastatic melanoma (MM) and are managed with surgery or stereotactic radiosurgery (SRS) and/or systemic treatment based on BRAF sta

Abstract CT087: Early tumor immune microenvironment (TME) modulation by the BRAF inhibitor (BRAFi) dabrafenib (D) and/or the MEK inhibitor (MEKi) trametinib (T) in patients (pts) with BRAF V600E/K-mutant melanoma in the COMBAT trial

Abstract: Several trials are evaluating combinations of BRAFi/MEKi and immunotherapy (IO) treatment (Tx) in melanoma. This descriptive biomarker study explored tumor cell and TME modification during BRAFi, MEKi or combination Tx in pts with BRAF V600E/K–mutant unresectable or metastatic melanoma and their potential impact on biomarkers implicated in response to IO. 48 pts enrolled and were randomized 1:1:1 to receive D+T, D, or T (n = 16 each). In the D and T arms, pts received D+T after 8 wk of D or T alone. Tumor biopsies were collected at baseline (BL), wk 2, 8, and 10, and at disease progression. Phosphorylated ERK (pERK), PD-L1, CD8, and CD68 protein expression was analyzed by IHC. RNA expression was assessed by NanoString immune profiling of 770 genes covering adaptive, innate, and humoral immune responses. The primary objectives were to evaluate pERK reduction from BL and characterize safety and efficacy in each Tx arm with changes in pERK H-score. At the final data cutoff, 21 pts (44%) completed the study, including 3 deaths and disease progression. Across Tx arms serious adverse events were reported in 19 pts (40%); no new safety signals were observed. In the biomarker population (pts with BL and ≥ 1 on-Tx biopsy; n = 42), the number of evaluable samples decreased with time due to insufficient tumor material (often due to good tumor response). Due to this limitation, the correlation between biomarker changes and clinical response could not be analyzed, but early biomarker changes are reported. pERK H-score, a MAPK pathway activity marker, decreased from BL to wk 2 in 13 of 17 pts (D, 4/5 pts; T, 6/7 pts; D+T, 3/5 pts) and from BL to wk 8 in 5 of 8 pts (D, 2/3 pts; T, 2/3 pts; D+T, 1/2 pts). IHC showed an early increase in CD8+ and CD68+ cells in the center of tumors compared with the periphery in all 3 arms. Innate immune response, chemotaxis, MHC class II antigen presentation, and complement pathway genes were upregulated. RNA expression of PD-L1, IFNγ pathway genes, and immunosuppressive cytokines IL-6 and CCL2 were slightly increased. Intriguingly, both M1 (IRF5) and M2 (CD163) macrophage genes were upregulated, with an increase of protumoral cytokines (eg, VEGF, TNF) and the MDSC-related cytokine CSF-1. These results indicate that D and T, alone or combined, induced early modification of the melanoma TME, with a tendency to recruit cytotoxic CD8+ cells and increase antigen presentation, which may, however, be offset by induction of immunosuppressive events. Early induction of complement pathways is a novel finding that needs further investigation as it can be both cytotoxic and cytoprotective for tumor cells. These findings provide additional rationale for evaluation of IO and/or agents targeting MDSC following or combined with BRAFi/MEKi in BRAF-mutant melanoma. Additional efficacy and safety analyses will be presented. Citation Format: Caroline Robert, Shensi Shen, Delphine Allard, Ana Arance Fernandez, Caroline Dutriaux, Egbert de Jong, Matthew Squires, Jean-Jacques Grob. Early tumor immune microenvironment (TME) modulation by the BRAF inhibitor (BRAFi) dabrafenib (D) and/or the MEK inhibitor (MEKi) trametinib (T) in patients (pts) with BRAF V600E/K-mutant melanoma in the COMBAT trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT087.