J.V. van Thienen

Targeted treatment and immunotherapy in leptomeningeal metastases from melanoma

BACKGROUND Historically leptomeningeal metastases (LM) from melanoma have a poor prognosis, with a median survival of only 2 months despite treatment. Targeted therapy and immune checkpoint inhibitors are promising new treatment options in advanced melanoma. We sought to determine the impact of targeted therapy and immunotherapy on the outcome of melanoma patients with LM and to evaluate the influence of prognostic factors. PATIENTS AND METHODS We analyzed a series of 39 consecutive patients diagnosed with LM from melanoma between May 2010 and March 2015 treated at the Netherlands Cancer Institute. Thirty-four of these patients also had brain metastases (BM). Statistical analyses assessed the influence of clinical and biological characteristics on survival. RESULTS Median overall survival of the entire cohort was 6.9 weeks (95% confidence interval 0.9-12.8). Due to a poor performance status or rapidly progressive disease, 14 patients received no treatment. Median overall survival of untreated patients after the diagnosis of LM was 2.9 versus 16.9 weeks for treated patients (P < 0.001). The median survival of 21 patients treated with systemic targeted therapy and/or immunotherapy, with or without RT was 21.7 weeks (range 2-235 weeks). Five patients had LM without BM. Three of these patients died within 3 weeks before any treatment was given, whereas 2 patients are in ongoing remission for 26 weeks (following dabrafenib) and 235 weeks (following WBRT and ipilimumab). Elevated serum lactate dehydrogenase and S100B at diagnosis of LM were associated with shorter survival. CONCLUSION LM from melanoma still has an extremely poor prognosis. As observed in extracranial metastatic disease, new treatment modalities such as systemic targeted therapy and immune checkpoint inhibitors seem to increase overall survival in LM, and may result in long-term remission. These new treatment options should be considered in patients with LM.

Vemurafenib for BRAF V600 mutated advanced melanoma: Results of treatment beyond progression

BACKGROUND Selective BRAF inhibition (BRAFi) by vemurafenib or dabrafenib has become approved standard treatment in BRAF V600 mutated advanced stage melanoma. While the response rate is high, the response duration is limited with a progression-free survival (PFS) of 5-6months. Our observation of accelerated disease progression within some patients after stopping vemurafenib treatment has fostered the idea of treatment beyond progression (BRAFi TBP). METHOD In this retrospective study, we analysed 70 metastatic melanoma patients, treated at our institute, who experienced progression after prior objective response upon treatment with vemurafenib. Thirty-five patients that continued treatment beyond progression are compared with 35 patients who stopped BRAFi treatment at disease progression. RESULTS Median overall survival beyond documented progression was found to be 5.2months versus 1.4months (95% confidence interval (CI): 3.8-7.4 versus 0.6-3.4; Log-Rank p=0.002) in favour of BRAFi TBP. In the multivariate survival analysis, stopping treatment at disease progression was significantly associated with shorter survival (hazard ratio: 1.92; 95% CI: 1.04-3.55; p=0.04). CONCLUSION Our results suggest that continuing vemurafenib treatment beyond progression may be beneficial in advanced melanoma patients, who prior to progression responded to vemurafenib.

Immune checkpoint inhibition-related colitis: symptoms, endoscopic features, histology and response to management

Background Immune checkpoint inhibitors are successfully introduced as anticancer treatment. However, they may induce severe immune-related adverse events (irAEs). One of the most frequent irAEs is diarrhoea. The main objective of this study was to analyse symptoms (ie, grade of diarrhoea), endoscopic and histological features and response to management in immune checkpoint inhibition-related colitis (IRC). Patients and methods We retrospectively analysed patients who developed diarrhoea on checkpoint inhibition and therefore underwent an endoscopy and/or were treated with corticosteroids. Patients were treated between August 2010 and March 2016 for metastatic melanoma or non-small cell lung cancer. Severity of IRC was scored using the endoscopic Mayo score and the van der Heide score. Results Out of a cohort of 781 patients, 92 patients were identified who developed diarrhoea and therefore underwent an endoscopy and/or were treated with corticosteroids. Patients were treated with monotherapy anticytotoxic T-lymphocyte antigen-4, antiprogrammed death receptor-1 or a combination of both. All patients had symptoms of diarrhoea (grade 1: 16%; grade 2: 39% and grade 3: 44%). A complete colonoscopy was performed in 62 (67%) patients, of whom 42 (68%) had a pancolitis (≥3 affected segments). Ulcers were seen in 32% of endoscopies. There was no significant correlation between the grade of diarrhoea at presentation and endoscopic severity scores, the presence of ulcers or histological features. In 54 episodes of diarrhoea (56%), patients received one or more cycles infliximab for steroid-refractory colitis. Patients with higher endoscopic severity scores, ulcers and/or a pancolitis needed infliximab more often. Conclusions The correlation between grade of diarrhoea and endoscopic or histological features for severity of colitis is poor. Patients with higher endoscopic severity scores, ulcers or a pancolitis needed the addition of infliximab more often. Therefore, endoscopy may have value in the evaluation of the severity of IRC and may help in decision making for optimal management.

Clinical Pharmacokinetics of Vemurafenib in BRAF‐Mutated Melanoma Patients

Vemurafenib is an oral tyrosine kinase inhibitor that inhibits mutated serine/threonine protein kinase B-Raf (BRAF) and is approved as monotherapy or in combination with the MEK inhibitor cobimetinib for the treatment of adult patients with BRAFV600mutationpositive unresectable or metastatic melanoma.1–3 Currently, vemurafenib is given in a fixed dose regimen of 960 mg twice daily (BID). The pharmacokinetics of vemurafenib was previously investigated in a phase 1 trial, and a mean steady-state plasma concentration of 40 ± 20 μg/mL was found.4 Concomitant intake of food (high-fat meal) increased the Cmax (2.5 times) and the vemurafenib plasma AUC0(4.7 times).5 In addition a dose-exposure relationship has been established for vemurafenib at steady state from 240 mg BID to 960 mg BID.6 Recent studies have shown that low vemurafenib plasma concentrations are associated with tumor progression. Funck-Brentano et al found in a study in 21 patients that the mean steady state (>14 days of treatment) plasma concentration was lower at the time of first progression (38.8 ± 19.7 μg/mL) than when the tumor was stable or in partial or complete response (56.4 ± 21.0 μg/mL).7 In another study Kramkimel et al found that vemurafenib plasma concentrations below 40.4 μg/mL at day 15 were associated with a shorter progression-free survival (PFS).8 The relationship between tumor progression and exposure was further established by Goldwirt et al, who found that the plasma concentrations in patients who were progressing were lower (51 ± 22 μg/mL) than those in complete or partial responders or patients with stable disease (67 ± 24 μg/mL), although this was not significant.9 They also showed that patients with a plasma concentration >42 μg/mL had a lower risk for progressive disease than patients with a median plasma concentration below 42 μg/mL during the first year of vemurafenib treatment (P= .005). These results combined suggested a steady-state pharmacokinetic target of >42 μg/mL for vemurafenib.10 Given the strong evidence for an exposure-response relationship, therapeutic drug monitoring (TDM) might be beneficial for patients who are treated with vemurafenib. Because most data on exposure-response relationships have been obtained in clinical trials, the first step to study the potential of TDM in regular care is to evaluate the vemurafenib plasma concentrations in a cohort of patients treated with vemurafenib.

Short-term CTLA-4 blockade directly followed by PD-1 blockade in advanced melanoma patients: a single-center experience

Background Combination of T cell checkpoint blockade by CTLA-4- and PD-1-blockade is one of the most promising therapies in patients with advanced melanoma. It induces superior response rates when compared with single-agent therapy, but at the cost of a high percentage of grade 3 and 4 adverse events (AEs). This combination therapy was until July 2016 not available in the Netherlands, which prompted several physicians to treat patients with less than standard numbers of courses of ipilimumab followed directly by nivolumab or pembrolizumab. Patients and methods In this retrospective analysis, patients were included who were treated with two courses (day 0 and 21) anti-CTLA-4 (ipilimumab 3 mg/kg q3wk), directly followed by anti-PD-1 (starting at day 22 with nivolumab 3mg/kg q2wk or pembrolizumab 2 mg/kg q3wk). Data on treatment-related AEs were collected from electronic patient records and scored according to CTCAE 4.03 criteria. Overall response was evaluated using RECIST 1.1 for CT-scans and EORTC criteria for PET-scans. Results Forty advanced melanoma patients could be included (29/40 pembrolizumab, 11/40 nivolumab). Median follow-up (FU) was 51 weeks (range: 4–63 weeks) with a minimum FU of 26 weeks. Treatment-related AEs of grade 3 and 4 occurred in 38% of the patients. The best overall response rate (BORR) was 55% (95% CI 39–70) and disease control rate was 75% (95% CI 59–87). Ongoing responses were observed in 82% of responding patients. Conclusion Treatment with short-term CTLA-4 blockade directly followed by PD-1 blockade may have similar efficacy but potentially lower toxicity when compared with concurrent therapy with anti-CTLA-4 and anti-PD-1. These results warrant further investigation in a prospective randomized controlled clinical trial.

Abstract OT1-1-01: Optimizing neoadjuvant systemic treatment in HER2 positive breast cancer - The TRAIN-2 study

Background Anthracycline-based regimens are still commonly used in HER2 positive (HER2+) breast cancer (BC), despite added toxicity compared to non-anthracycline containing regimens. The benefit of antracyclines in the era of trastuzumab containing regimens is controversial. Moreover, the value of anthracyclines in combination with dual-HER2 blockade is uncertain. We recently showed high pathologic complete response (pCR) rates with a weekly neoadjuvant paclitaxel-trastuzumab-carboplatin (PTC) regimen. We now aim to evaluate the effect of replacing 3 PTC cycles in this regimen with 3 FE90C-trastuzumab cycles, while adding pertuzumab to all cycles in both arms. Secondly, combined blockade of the estrogen-receptor (ER) pathway and the HER2-pathway in the presence of chemotherapy has not previously been investigated in HER2+/ER+ tumors. Trial design This is a randomized comparative trial evaluating pCR rate (ypT0/is ypN0) at surgery as primary endpoint after neoadjuvant systemic therapy with 9 cycles PTC plus pertuzumab q3w (paclitaxel 80mg/m2 day 1, 8 – trastuzumab 6mg/kg (loading dose 8mg/kg) day 1 – carboplatin AUC = 6 day 1 – pertuzumab 420mg (loading dose 840mg) day 1) versus 3 cycles FE90C-T plus pertuzumab q3w followed by 6 cycles PTC plus pertuzumab q3w. An optional second randomization (2×2 factorial design) will compare concurrent endocrine treatment with an aromatase inhibitor (and ovarian function suppression in premenopausal women and men) during neoadjuvant chemotherapy in combination with dual HER2-blockade, in patients with HER2+/ER+ tumors. Eligibility criteria Patients aged ≥18 year with histologically confirmed invasive HER2+ BC, stage II or III. Eligible patients have a performance status of 0 to 1 and adequate cardiac and organ function. Specific aims The primary objective is to compare the efficacy of 6 cycles neoadjuvant PTC plus pertuzumab preceded by either 3 cycles FE90C-T plus pertuzumab or 3 cycles PTC plus pertuzumab in stage II and III HER2+ BC. Secondary objectives are to describe the efficacy of combined HER2 and ER pathway blockade in HER2+/ER+ BC, to describe the safety of the various regimens and to identify prognostic and predictive biomarkers for pCR. Statistical methods The sample size of the study will be based on the primary objective. To detect an increase in pCR rate from 44% in the PTC arm to 58% in the FE90C-T arm at the 5% (2-sided) level of significance with an 80% power 437 patients need to be randomized (assuming ∼10% of patients will be not evaluable). Target accrual Recruitment will start in the summer of 2013 across ∼30 sites in the Netherlands. Unrestricted research support and pertuzumab are kindly provided by Roche Netherlands. The trial is sponsored by the Dutch Breast Cancer Trialists’ Group (BOOG). Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT1-1-01.