BRAF V600 Mutation-positive Metastatic Melanoma Research Articles

1335P - Efficacy and safety of dabrafenib and trametinib in patients with metastatic BRAFV600 mutation-positive melanoma in the real-world setting: Interim results of the non-interventional COMBI-r study

1335P - Efficacy and safety of dabrafenib and trametinib in patients with metastatic BRAFV600 mutation-positive melanoma in the real-world setting: Interim results of the non-interventional COMBI-r study

Effect of concomitant dosing with acid-reducing agents and vemurafenib dose on survival in patients with BRAFV600 mutation–positive metastatic melanoma treated with vemurafenib ± cobimetinib

BackgroundWe conducted a retrospective analysis to evaluate the impact of concomitant acid-reducing agents (ARAs) and vemurafenib dose on the efficacy of vemurafenib in patients with BRAFV600 mutation–positive unresectable or metastatic melanoma treated with vemurafenib or cobimetinib plus vemurafenib. MethodsData were pooled for patients treated with vemurafenib or cobimetinib plus vemurafenib in the BRIM-2, BRIM-3, BRIM-7, and coBRIM studies. The primary end-points were progression-free survival and overall survival across patient subgroups defined by vemurafenib dose (full vs reduced) and concomitant ARA use (yes vs no). Objective response rate (ORR) was also analysed. Steady-state vemurafenib concentrations were evaluated according to vemurafenib dosing and concomitant ARA use across treatment cohorts in a subset of patients from BRIM-7 and coBRIM with available concentration data. ResultsEfficacy analyses included 920 patients: 641 in the vemurafenib cohort and 279 in the cobimetinib plus vemurafenib cohort. Overall, no significant differences in survival outcomes were observed across subgroups according to vemurafenib dose and ARA use, with or without adjustment for known prognostic covariates, in both treatment cohorts. ORR was also similar across subgroups in both treatment cohorts. Steady-state vemurafenib concentrations were analysed in 389 patients (193 in the vemurafenib cohort and 196 in the cobimetinib plus vemurafenib cohort) and were generally similar across vemurafenib dose subgroups, regardless of ARA use in both treatment cohorts. ConclusionsResults of this retrospective pooled analysis suggest that ARAs can be used concomitantly with vemurafenib, alone or in combination with cobimetinib, without compromising the efficacy of vemurafenib.

A multi-center phase II study of high dose interleukin-2 sequenced with vemurafenib in patients with BRAF-V600 mutation positive metastatic melanoma

BackgroundPreclinical studies suggest that BRAF inhibitors enhance anti-tumor immunity and antigen presentation. Combination BRAF inhibition with immunotherapy is an appealing therapeutic approach. We sequenced vemurafenib with HD IL-2 in patients with BRAF-mutated metastatic melanoma to improve long term outcomes.MethodsEligible patients were HD IL-2 eligible with metastatic BRAF V600 mutated melanoma. Cohort 1 was treatment naïve and received vemurafenib 960 mg BID for 6 weeks before HD IL-2. Cohort 2 received vemurafenib for 7–18 weeks before enrollment. Both cohorts received HD IL-2 at 600,000 IU/kg every 8 h days 1–5 and days 15–19. The primary objective was to assess complete responses (CR) at 10 weeks ±3 (assessment 1) and 26 weeks ±3 (assessment 2) from the start of HD IL-2.ResultsFifty-three patients were enrolled, (cohort 1, n = 38; cohort 2, n = 15). Of these, 39 underwent assessment 1 and 15 assessment 2. The CR rate at assessment 1 was 10% (95% CI 3–24) for both cohorts combined, and 27% (95% CI 8–55) at assessment 2. Three-year survival was 30 and 27% for cohort 1 and cohort 2, respectively. No unexpected toxicities occurred. A shift in the melanoma treatment landscape during this trial adversely affected accrual, leading to early trial closure.ConclusionsVemurafenib in sequence with HD IL-2 did not change the known toxicity profile for either agent. Lower than expected response rates to vemurafenib were observed. Overall response rates and durability of responses appear similar to that observed with HD IL-2 alone.Trial registrationNCTN, NCT01683188. Registered 11 September 2012, http://www.clinicaltrials.gov/NCT01683188

Vemurafenib in patients with BRAFV600 mutation-positive metastatic melanoma: final overall survival results of the randomized BRIM-3 study.

BackgroundThe BRIM-3 trial showed improved progression-free survival (PFS) and overall survival (OS) for vemurafenib compared with dacarbazine in treatment-naive patients with BRAFV600 mutation–positive metastatic melanoma. We present final OS data from BRIM-3.Patients and methodsPatients were randomly assigned in a 1 : 1 ratio to receive vemurafenib (960 mg twice daily) or dacarbazine (1000 mg/m2 every 3 weeks). OS and PFS were co-primary end points. OS was assessed in the intention-to-treat population, with and without censoring of data for dacarbazine patients who crossed over to vemurafenib.ResultsBetween 4 January 2010 and 16 December 2010, a total of 675 patients were randomized to vemurafenib (n = 337) or dacarbazine (n = 338, of whom 84 crossed over to vemurafenib). At the time of database lock (14 August 2015), median OS, censored at crossover, was significantly longer for vemurafenib than for dacarbazine {13.6 months [95% confidence interval (CI) 12.0–15.4] versus 9.7 months [95% CI 7.9–12.8; hazard ratio (HR) 0.81 [95% CI 0.67–0.98]; P = 0.03}, as was median OS without censoring at crossover [13.6 months (95% CI 12.0–15.4) versus 10.3 months (95% CI 9.1–12.8); HR 0.81 (95% CI 0.68–0.96); P = 0.01]. Kaplan–Meier estimates of OS rates for vemurafenib versus dacarbazine were 56% versus 46%, 30% versus 24%, 21% versus 19% and 17% versus 16% at 1, 2, 3 and 4 years, respectively. Overall, 173 of the 338 patients (51%) in the dacarbazine arm and 175 of the 337 (52%) of those in the vemurafenib arm received subsequent anticancer therapies, most commonly ipilimumab. Safety data were consistent with the primary analysis.ConclusionsVemurafenib continues to be associated with improved median OS in the BRIM-3 trial after extended follow-up. OS curves converged after ≈3 years, likely as a result of crossover from dacarbazine to vemurafenib and receipt of subsequent anticancer therapies.ClinicalTrials.govNCT01006980.

Open-label, multicentre safety study of vemurafenib in 3219 patients with BRAFV600 mutation-positive metastatic melanoma: 2-year follow-up data and long-term responders' analysis

BackgroundThe orally available BRAF kinase inhibitor vemurafenib is an effective and tolerable treatment option for patients with metastatic melanoma harbouring BRAFV600 mutations. We assessed the safety of vemurafenib in a large population of patients with few alternative treatment options; we report updated 2-year safety. MethodsThis was an open-label, multicentre study of vemurafenib (960 mg bid) in patients with previously treated or untreated BRAF mutation-positive metastatic melanoma (cobas® 4800 BRAF V600 Mutation Test). The primary end-point was safety; efficacy end-points were secondary. An exploratory analysis was performed to assess safety outcomes in patients with long duration of response (DOR) (≥12 or ≥24 months). ResultsAfter a median follow-up of 32.2 months (95% CI, 31.1–33.2 months), 3079/3219 patients (96%) had discontinued treatment. Adverse events (AEs) were largely consistent with previous reports; the most common all-grade treatment-related AEs were arthralgia (37%), alopecia (25%) and hyperkeratosis (23%); the most common grade 3/4 treatment-related AEs were squamous cell carcinoma of the skin (8%) and keratoacanthoma (8%). In the exploratory analysis, patients with DOR ≥12 months (n = 287) or ≥24 months (n = 133) were more likely to experience grade 3/4 AEs than the overall population. No new specific safety signals were observed with longer vemurafenib exposure. ConclusionsAfter 2 years' follow-up, safety was maintained in this large group of patients with BRAFV600 mutation-positive metastatic melanoma who are more representative of routine clinical practice than typical clinical trial populations. These data suggest that long-term vemurafenib treatment is effective and tolerable without the development of new safety signals.

346PD Evaluation of safety, tolerability, pharmacokinetics (PK) and efficacy of dabrafenib and trametinib combination (Dab + Tra) therapy in Japanese patients (pts) with BRAF V600 mutation-positive advanced cutaneous melanoma: a phase (Ph) I/II study

Aim/Background: Combination of dabrafenib (Dab, 150 mg twice daily [BID]), a BRAF inhibitor, and trametinib (Tra, 2 mg once daily [QD]), a MEK inhibitor, is clinically active in BRAF V600 mutation-positive metastatic melanoma, and approved in the US and elsewhere. The tolerability, safety, PK and efficacy of the combination in Asians have not been evaluated. We investigated this combination in Japanese pts. Methods: In Ph I, pts with BRAF V600E/K mutation-positive advanced solid tumors, refractory to standard therapies, received Dab 150 mg BID + Tra 2 mg QD; dose-limiting toxicity, safety and PK were assessed. In Ph II, pts with BRAF V600E/K mutation-positive unresectable (stage IIIC) or metastatic (stage IV) cutaneous melanoma were enrolled and the confirmed overall response rate (ORR) was evaluated (NCT01928940). Results: Japanese pts with BRAF V600E mutation-positive advanced cutaneous melanoma (n = 12) received Dab + Tra (6 in Ph I and 6 in Ph II), and comprised 7 men and 5 women. Mean age was 55.6 years (range 21–77). No DLT was seen in Ph I. AEs (≥ 50%) reported in Ph I were pyrexia, nasopharyngitis, rash maculo-papular, erythema, aspartate aminotransferase (AST) increased, decreased appetite, headache, alopecia, dermatitis acneiform, and blood alkaline phosphatase increased. AEs (≥ 50%) reported in Ph II were pyrexia, oedema peripheral, AST increased, and stomatitis. No squamous cell carcinoma was seen. PK results in repeat dosing in Ph I showed absorption of both drugs was rapid with a median plasma Tmax of ≈2 h for Dab and 1 h for Tra. Steady-state was achieved within ≈21 days after the first dose of Tra. Best confirmed responses per investigator in Ph II (n = 6) were 2 (33%) complete responses (CR), 3 (50%) partial responses (PR) and 1 (17%) stable disease. The confirmed ORR (CR + PR) was 83% (95% CI 35.9–99.6). Conclusions: Dab + Tra was well tolerated with a manageable safety profile in Japanese pts, and clinically meaningful antitumor activity was seen. Japanese clinical and PK outcomes were comparable to those of Caucasian pts. Dab + Tra should be further investigated in Japanese pts. Clinical trial identification: NCT01928940 Disclosure: Y. Fujiwara: research funding: AstraZeneca, Chugai, Eisai, Eli Lilly, GlaxoSmithKline. A. Suzuki: other substantive relationships: GlaxoSmithKline; employee until 30 April 2015; currently a Novartis Pharma employee as of 1 May 2015. A. Mukaiyama: stock ownership: GlaxoSmithKline. Y. Kiyohara: research funding: Ono Pharmaceutical, Chugai Pharmaceutical Co, BMS, MSD, Merck Serono, GSK; other substantive relationships: Ono Pharamceutical, received payment in role of safety review; Chugai Pharmaceutical Co, received renumeration as a speaker. All other authors have declared no conflicts of interest.

Vemurafenib-associated neutrophilic panniculitis in a patient with metastatic amelanotic melanoma presenting as cancer of unknown primary origin

Abstract The treatment of metastatic melanoma is challenging. BRAF gene mutation is found in 40–60% of melanoma cases, the most common being the V600E mutation. Vemurafenib was approved by the Food and Drug Administration in 2011 as target therapy for the treatment with BRAF V600 mutation-positive metastatic melanoma. We report a case of metastatic amelanotic melanoma with unknown primary cancer as the initial presentation. The patient presented with neutrophilic septal panniculitis 1 week after vemurafenib treatment, which is a rare cutaneous toxicity of BRAF inhibitor. We also review the current literature on management of BRAF inhibitor-related adverse skin effects.

BRAFV600E mutation positive metastatic melanoma in a young woman treated with anti-BRAF/anti MEK combination: a case report

Compassionate Use program. Just after one month of treatment she reported clinical benefit in terms of deambulation improvement and pain relief. During the second month of therapy the treatment with Dabrafenib was withdrawn for some days, due to two episodes of hyperpyrexia up to 39°C, treated with Paracetamol. Progressively the antiBRAF drug was reintroduced with no further interruption. The CT/PET performed after three and six month of treatment showed a good response to the therapy with a dimensional decrease and SUV reduction of more than 50% in all target lesions. Currently the patient is continuing the treatment; her ECOG PS is 0. She does not require any antalgic drugs. Our aim is obtain the maximum reduction to allow a surgical approach.

Combining targeted and immunotherapy: BRAF inhibitor dabrafenib (D) ± the MEK inhibitor trametinib (T) in combination with ipilimumab (Ipi) for V600E/K mutation-positive unresectable or metastatic melanoma (MM)

Dabrafenib, trametinib, and Ipilimumab are each indicated for treatment of patients (pts) with metastatic melanoma (Dabrafenib+trametinib in BRAF V600 mutation–positive metastatic melanoma). Dabrafenib and trametinib can be safely combined and prolong progression-free survival compared with monotherapy. Combining Dabrafenib+trametinib with the CTLA-4 antibody Ipi has the potential to improve treatment outcomes, but the safety profile is unknown. A recent report suggested caution in combining the BRAF inhibitor vemurafenib (V) with Ipilimumab; V+Ipilimumab resulted in G3 elevations of ALT in 6/10 pts leading to study discontinuation (NEJM2013 368; 14). The present study was designed to characterize the safety of Dabrafenib±trametinib+Ipilimumab, select recommended phase 2 doses (RP2Ds), and report efficacy.

Evaluation of Safety, Tolerability, Pharmacokinetics and Efficacy of Dabrafenib, a Braf Inhibitor, in Japanese Patients with Braf V600 Mutation-Positive Advanced Solid Tumors: a Phase I Study

ABSTRACT Aim: Dabrafenib, a potent and selective BRAF inhibitor, has demonstrated clinical significance for BRAF V600 mutation-positive metastatic melanoma and has been approved in the US and EU. However, there is less clinical experience of treatment with dabrafenib in the Japanese population. Therefore, this study has been designed and conducted to evaluate safety, tolerability, pharmacokinetics (PK) and efficacy of dabrafenib in Japanese patients with BRAF V600 mutation-positive advanced solid tumors as the first clinical trial. Methods: Patients with BRAF V600 mutation-positive advanced solid tumors refractory to standard therapies were enrolled. Dose escalation was performed according to a standard 3 + 3 design. Dabrafenib was given twice a day (BID), which started 7 days after a single dose administration for a single-dose PK analysis. Antitumor activity was evaluated based on RECIST version 1.1. This study was registered at www.clinicaltrials.gov as NCT01582997. Results: Twelve patients (11 melanoma and 1 papillary thyroid cancer) with BRAF V600E mutation received dabrafenib at doses of 75 mg (n = 3), 100 mg (n = 3), or 150 mg (n = 6). The median duration of treatment was approximately 39 weeks. No dose-limiting toxicities were observed in these three dose cohorts. The most common adverse events (AEs) included alopecia, leucopenia, pyrexia and arthralgia. Most AEs were reported as grade 1 or 2. Squamous-cell carcinoma or keratoacanthoma, which is a well-documented BRAF inhibitor class toxicity, was not observed in this study. Preliminary PK results showed no obvious ethnic difference. Partial responses were confirmed in 7 patients (58.3%), 6 melanoma patients and 1 papillary thyroid cancer patient. The data also suggested dabrafenib had an antitumor activity in Japanese patients with BRAF V600 mutation-positive melanoma as well as papillary thyroid cancer. Conclusions: Compared with the data published for the caucasian population, dabrafenib exhibited comparable tolerability, safety and PK profiles in Japanese patients at the dose of 150 mg BID. This dose also gave a suggestive outcome for the potential efficacy to the Japanese population. Disclosure: A. Suzuki: A. Suzuki is an employee of GlaxoSmithKline K.K; A. Mukaiyama: A. Mukaiyama is an employee of GlaxoSmithKline K.K. All other authors have declared no conflicts of interest.

Phase 1 study of the BRAF inhibitor dabrafenib (D) with or without the MEK inhibitor trametinib (T) in combination with ipilimumab (Ipi) for V600E/K mutation–positive unresectable or metastatic melanoma (MM).

2511 Background: D, T, and Ipi are each indicated for treatment of patients (pts) with MM (D+T in BRAF V600 mutation–positive MM). D and T can be safely combined and prolong progression-free surviv...

A multi-center study of high dose Aldesleukin (Proleukin® (HD IL-2) + Vemurafenib Zelboraf® ) therapy in patients with BRAFV600 mutation positive metastatic melanoma (proclivity 01)

Meeting abstracts To investigate whether the Vemurafenib-induced increased tumor antigen expression, T lymphocyte infiltration and tumor debulking improve the complete response rate induced by HD IL-2 in metastatic melanoma and if there is synergistic toxicity using the drugs in close approximation

Vemurafenib in patients with BRAFV600 mutation-positive melanoma with symptomatic brain metastases: Final results of an open-label pilot study

Background & AimBrain metastases are frequent in patients with metastatic melanoma, indicating poor prognosis. We investigated the BRAF kinase inhibitor vemurafenib in patients with advanced melanoma with symptomatic brain metastases. MethodsThis open-label trial assessed vemurafenib (960mg twice a day) in patients with BRAFV600 mutation-positive metastatic melanoma with non-resectable, previously treated brain metastases. The primary end-point was safety. Secondary end-points included best overall response rate, and progression-free and overall survival. ResultsTwenty-four patients received vemurafenib for a median treatment duration of 3.8 (0.1–11.3) months. The majority of discontinuations were due to disease progression (n=22). Twenty-three of 24 patients reported at least one adverse event (AE). Grade 3 AEs were reported in four (17%; 95% confidence interval [CI], 4.7–37.4%) patients and included cutaneous squamous cell carcinoma in four patients. Median progression-free survival was 3.9 (95% CI, 3.0–5.5) months, and median survival was 5.3 (95% CI, 3.9–6.6) months. An overall partial response (PR) at both intracranial and extracranial sites was achieved in 10 of 24 (42%; 95% CI, 22.1–63.4) evaluable patients, with stable disease in nine (38%; 95% CI, 18.8–59.4) patients. Of 19 patients with measurable intracranial disease, seven (37%) achieved >30% intracranial tumour regression, and three (16%; 95% CI, 3.4–39.6%) achieved a confirmed PR. Other signs of improvement included reduced need for corticosteroids and enhanced performance status. ConclusionsVemurafenib can be safely used in patients with advanced symptomatic melanoma that has metastasised to the brain and can result in meaningful tumour regression.

Predictive Value For Disease Progression Of Thrombin Generation and D-Dimer Levels In Melanoma Patients Receiving BRAF Inhibitor Therapy

Introduction Abnormalities of markers of blood clotting activation characterize the development of most cancers, including malignant melanoma, which still remains a largely incurable disease. Recently, the advent of therapy targeting the oncogene BRAF V600E mutation, expressed by about 50% of melanoma patients, has opened new perspectives for this disease outcome, with response rates in metastatic melanoma of >50%. In this study we wanted to evaluate the impact of a direct inhibitor of BRAF V600E, i.e. Vemurafenib, on the hemostatic profile of patients with melanoma, and analyze the relation of hemostatic parameters to the disease outcome. Methods Twenty BRAF V600E mutation-positive metastatic melanoma patients (10M/10F, age: 23-74 years) receiving Vemurafenib (960 mg twice daily) were enrolled at our Oncology Division upon informed consent. Blood was collected before (T0), and after one (T1) and four weeks (T2) of therapy. Thrombin generation (TG) was assessed by the calibrated automated thrombogram assay (CAT, Stago) in plasma samples, both in the absence and the presence of exogenous tissue factor (TF, 1 and 5 pM). TG curves were described in terms of lag-time, endogenous thrombin potential (ETP), peak height and time to peak (ttpeak). Plasma D-Dimer levels were measured by a turbidimetric immunoassay by D-Dimer-HS (Instrumentation Laboratory) and results expressed in ng/ml. Thirty-four healthy subjects acted as a control group. Results Before therapy, TG performed in the absence of exogenous TF was significantly (p<0.01) increased in plasma from melanoma patients compared to controls, as determined by a higher thrombin peak (135±110 vs 51±35 nM), and ETP (1,474±984 vs 699±510 nM*min) and a shorter lag-time (15.8±4.2 vs 23.2±6.2 min) and ttpeak (20.2±4.6 vs 28.2±6.3 min). Significantly (p<0.05) higher thrombin peaks were also found in TG induced by 1 (304±122 nM) and 5 pM TF (329±72 nM) versus controls (1 pM TF: 232±96 nM; 5 pM TF: 284±78 nM). During BRAF V600E inhibitor therapy, TG in the absence of TF remained statistically unchanged. Differently, TG induced by 1pM TF increased in terms of ETP and thrombin peak, reaching the statistical significance at T2 (T0 vs T2: ETP: 1,587±475 vs 1,780±522 nM*min, p<0.01; thrombin peak: 304±122 vs 336±132 nM, p<0.05), simultaneously to a significant (p<0.01) prolongation of the lag-time (5.2±1 vs 6.3±1.1 min) and ttpeak (8.5±1.2 vs 9.5±1.4 min). Similar results were observed with 5 pM TF. D-dimer levels, significantly (p<0.01) elevated at T0 in patients (325±296 ng/ml) compared to controls (83±50 ng/ml), further increased at T1 (431±240 ng/ml, p=n.s.), and returned to pre-treatment values at T2 (286±221 ng/ml). The tumor response to therapy was evaluated by computed tomography after 2 months treatment. Five patients achieved >85% disease remission, 5 patients had between 85 and 25% remission, and 10 were non-responders. In patients with >85% remission response compared to the other patients, TG in the absence of TF showed a significant increase from T0 to T2 in the lag-time (17% vs 8%), and ttpeak (18% vs 6%) together with a decrease in ETP (14% vs 2%) and thrombin peak (-44% vs 7%). Accordingly, the same patients showed at T0 and T2 lower levels of D-dimer values compared to the other patients (T0: 152±101 vs 383±393 ng/ml; T2: 224±168 vs 307±296). Conclusions Before therapy the study group of melanoma patients presented with a hypercoagulable state as determined by high levels of TG and D-dimer. In patients who responded >85% to BRAF V600E inhibitor therapy a down-regulation of these markers was observed as compared to patients who responded <85% or did not respond. The data suggest a possible association between hypercoagulation, BRAF V600E mutation, and response to therapy. Therefore, further research is worth in this field to establish whether thrombotic markers, namely TG and D-dimer, may be a useful tool to select patients who may benefit from BRAF V600E inhibitor therapy. Disclosures: No relevant conflicts of interest to declare.

A phase I, randomized, open-label study of the multiple-dose pharmacokinetics of vemurafenib in patients with BRAF V600E mutation-positive metastatic melanoma

This study characterized the multiple-dose pharmacokinetics of vemurafenib 240-960 mg twice daily (bid) in BRAF(V600E) mutation-positive metastatic melanoma patients, using the commercial formulation (240-mg microprecipitated bulk powder film-coated tablets). Melanoma patients (N = 52) were randomly allocated to four vemurafenib dose cohorts (240, 480, 720, or 960 mg bid for 14 days). After the day 15 morning dose, doses were interrupted until day 22, at which point patients were restarted on vemurafenib. Serial pharmacokinetic samples were collected after the morning dose on days 1, 9, and 15; trough pharmacokinetic samples were collected on day 2. Vemurafenib concentration increased with multiple doses to steady state at day 15; C(max), AUC(0-8h), and AUC(0-168h) increased between 3.3- and 3.8-fold across the fourfold dose range tested. Statistical analysis indicated dose proportionality across the dose range of 240-960 mg bid. Day 15 mean accumulation ratios (ratio of AUC(0-8h) on day 15/AUC(0-8h) on day 1) ranged from ~19 to 25 across cohorts. At steady state, the peak-to-trough ratio for vemurafenib exhibited a relatively flat concentration-time profile throughout the bid dosing interval. During dose interruption (days 15-22), mean vemurafenib trough concentrations decreased to minimal levels; vemurafenib exhibited a mean terminal phase half-life of 31.5-38.4 h. Vemurafenib plasma concentration accumulates with multiple bid doses of 240 mg. Vemurafenib exposure (AUC and C(max)) is dose proportional over the 240- to 960-mg bid dose range and exhibits constant drug levels over the bid dosing interval.

Open-label, multicenter safety study of vemurafenib in patients with BRAFV600 mutation–positive metastatic melanoma.

9046 Background: Vemurafenib (VEM), a BRAF kinase inhibitor, has demonstrated high response rates and improved progression-free and overall survival in pts with BRAFV600mutation–positive metastatic melanoma (mM). We present interim results from predefined subgroups from a large multicenter, open-label safety study of VEM in pts with mM (NCT01307397). Methods: Pts with BRAFV600mutation–positive histologically confirmed mM received VEM (960 mg BID) as first-line therapy or subsequent to previous therapies. Assessments for safety and efficacy were made every 28 days. Results: As of Feb 29, 2012, 2,265 pts have received VEM. Pts had a median age of 54.0 (13-95) yrs and median time since diagnosis of mM of 6.2 (0-351.9) mos. 59% had received prior systemic therapy. Median time of exposure to VEM as of the cut-off date was 3 (0.03-11.24) mos for the overall population and majority of subgroups, and approximately 2.5 mos for pts with ECOG ≥2 and age ≥75 yrs. 1537 (68%) pts were still receiving VEM at the cut-off date. 728 (32%) pts discontinued, most frequently because of PD (538/728 pts; 74%). Adverse events (AEs) were reported for 87% of all patients, with arthralgia (32%) and rash (26%) the most frequent. The incidences of AEs in the subgroups are summarized (Table). Although efficacy analyses are limited by the short duration of follow-up, six-month OS rate was 76% (95% CI 72-79%) and median PFS was 4.1 mos (95% CI 3.9-4.5 mos). Postbaseline tumor assessments were available for 63% and 30% of pts at wk 8 and 16, respectively. At wk 8 CR: 2%, PR: 57%, SD: 30%, PD: 6%. At wk 16 CR: 3%, PR: 46%, SD: 31%, PD: 15%. Conclusions: Although the overall safety profile of VEM in this study was consistent with previous clinical data, interim analyses of subgroups suggest that very elderly pts may be at higher risk of G3 AEs. Clinical trial information: NCT01307397. [Table: see text]

METRIC phase III study: Efficacy of trametinib (T), a potent and selective MEK inhibitor (MEKi), in progression-free survival (PFS) and overall survival (OS), compared with chemotherapy (C) in patients (pts) with BRAFV600E/K mutant advanced or metastatic melanoma (MM).

LBA8509 Background: Dacarbazine (D) and paclitaxel (P) have been used to treat MM pts with limited effect. The MM treatment landscape has recently changed with the approval of vemurafenib and ipilimumab in 2011, but secondary malignancies or other toxicities are of concerns. T is a reversible, highly selective allosteric inhibitor of MEK1/2 activation and kinase activity. In a PhII trial (NCT01037127), pts with BRAFV600E mutation MM had median PFS of 5.3 mos. This PhIII trial (NCT01245062) was conducted in pts with BRAFV600E/K mutant advanced or MM. Methods: Pts were randomized 2:1 to T (2mg QD) or C (D or P). Pts were stratified by baseline LDH level and prior C; pts in the C arm were allowed to crossover to receive T after confirmation of PD. Primary endpoint was PFS in pts with BRAFV600E mutation-positive MM and no prior brain mets; secondary endpoints were OS, ORR and safety in primary and ITT. PFS and OS were compared using a stratified log-rank test. The study was designed with ≥99% power and one-sided α = 0.025 to detect 57% reduction in the risk of PD or death in pts treated with T vs C. Results: Between Dec 2010 and Jul 2011, 322 pts were randomized to T (n=214) or C (n=108); 273 pts were BRAFV600E mutation-positive with no prior brain mets. HR for primary population for PFS by investigator was 0.44 (95% CI 0.31–0.64; p<0.0001) in favor of T with a median PFS of 4.8 mo vs 1.4 mo with C. PFS benefit in favor of T was observed in ITT; this was confirmed by an independent review. The confirmed ORR was 24% with T and 7% with C. HR for interim OS was 0.53 (95% CI 0.30–0.94; p=0.0181), in favor of T in primary population. OS benefit was consistent in ITT pop despite 51 pts crossover from C to T. The most frequent AEs with T were skin rash, diarrhea, edema, hypertension, fatigue. Known MEKi class effects were observed, e.g. chorioretinopathy (<1%) and decreased ejection fraction (7%). Grade 3 AEs in T arm were hypertenstion (12%) and rash (7%). Conclusions: T is the first in class MEKi associated with a significant improvement of PFS and OS compared to C in pts with BRAFV600E/K mutant MM.

CA184-161: A phase I/II trial of vemurafenib and ipilimumab in patients with BRAF V600 mutation-positive metastatic melanoma.

TPS8603 Background: Ipilimumab (ipi) is a fully human monoclonal antibody that blocks cytotoxic T-lymphocyte antigen-4 (CTLA-4) to augment antitumor immune responses. Ipi significantly improved overall survival (OS) in two separate phase III trials of metastatic melanoma (MM): (1) at 3 mg/kg as monotherapy in previously treated patients and (2) at 10 mg/kg combined with dacarbazine in previously untreated patients. The most common drug-related adverse events with ipi were immune-related, and were generally reversible using treatment guidelines. Vemurafenib (vem) is a potent inhibitor of BRAF V600E-mutated kinase, which occurs in ~50% of MM. In clinical studies, vem produced objective response rates of ~50% with a significant improvement in the rate of OS in patients with previously untreated BRAF V600-positive MM. The purpose of this phase I/II study is to determine the safety and feasibility of ipi plus vem in patients with BRAF V600-positive MM, and to evaluate the efficacy of the combination in comparison to historical results observed with each agent alone. Methods: In phase I, an escalating dose design is used to assess safety/tolerability and to determine the maximum tolerated dose (MTD) of each agent. Vem will initially be given alone for 28 days at 960 mg p.o. BID, followed by vem in combination with ipi i.v. at 3 mg/kg [induction (q3w x 4) and maintenance (q12w)]. The next cohort will receive vem at 960 mg plus ipi increased to a dose of 10 mg/kg. Phase I will enroll an estimated 20 patients who have not previously received a CTLA-4 antagonist or BRAF inhibitor. If new or heightened frequency or severity of toxicities is not observed, a phase II single-arm extension at the MTD of each agent will be conducted in patients with previously untreated MM. The primary objectives of phase II (estimated enrollment of 30 patients) are to obtain preliminary evidence of efficacy (OS, 1- and 2-year survival rates) and to evaluate safety of the combination. Major inclusion criteria are ≥ 18 years of age, BRAF V600-positive MM, measurable tumor, no active brain metastasis, and an ECOG PS of 0-1. The first patient was enrolled in November 2011 and enrollment is ongoing (ClinicalTrials.gov identifier: NCT01400451).

Industry Update: the Latest Developments in Therapeutic Delivery

The present Industry Update covers the period 16 May to 15 June 2011, with information sourced from company press releases, media newswires, regulatory agencies and relevant patent offices. This period was dominated to a significant extent by events taking place at the 47th Annual Meeting of the American Society of Clinical Oncology held on 3–7 June in Chicago (IL, USA) where results from some of the larger studies were published concomitantly in The New England Journal of Medicine. Notable amongst these were the positive results of the Roche Phase III BRIM3 study on vemurafenib subjects with BRAF V600 mutation-positive metastatic melanoma. The announcement that Roche and Bristol-Myers Squibb have entered into an agreement to evaluate Yervoy™, currently the only CTLA-4 inhibitor approved for metastatic melanoma, in combination with vemurafenib is further good news. In terms of journal publications, an exceptional study led by researchers at The University of Texas MD Anderson Cancer Center (TX, USA) was published in the Journal of Clinical Oncology, in which a lymphoma vaccine, uniquely tailored for each patient, was shown to extend disease-free survival by 14 months, with signs of an even better response for patients with a specific biological marker.

Molecular testing for BRAF V600 mutations in the BRIM-2 trial of the BRAF inhibitor vemurafenib in metastatic melanoma.

10523 Background: The BRAF inhibitor vemurafenib (V) has shown dramatic activity in early clinical trials in patients with BRAFV600 mutation-positive melanoma. Preclinical and Phase 1 clinical data show the drug has minimal activity in tumors lacking BRAF mutations, creating a need for an accurate diagnostic test to identify appropriate patients for therapy. Methods: To assess eligibility for BRIM-2, a Phase 2 trial of V in patients with BRAFV600 mutation-positive metastatic melanoma, tumor samples were screened with an investigational PCR assay (cobas 4800 BRAF V600 Mutation Test) designed to detect the canonical V600E (1799T>A) mutation. 328 samples were tested of which 327 samples gave valid results. BRAF mutations were detected in 184 (56.3 %); 132 patients with BRAF-mutation positive melanoma were enrolled into the trial based on clinical eligibility criteria. Sanger sequencing was performed retrospectively on DNA samples from all enrolled patients. Results: Fifteen samples (11.4%) gave invalid Sanger results. Sanger detected a V600E mutation in 97 samples (73.5%), V600K mutation in 9 samples (6.8%) and a wild-type (WT) result in 11 cases (8.3%). Samples were also subjected to “deep” sequencing with a quantitative picotiter plate pyrosequencing method (454 GS-Titanium) to resolve differences between PCR and Sanger results. Using 454 sequencing of samples with invalid Sanger results revealed a V600E mutation in 14 cases and a V600K mutation in 1 case. Of 11 samples with a WT Sanger result, 454 sequencing detected a V600E mutation in all cases, with a median percentage of mutant alleles of 8%; ten of the 11 samples had a percentage < 25%. The presence of a V600K mutation was confirmed by 454 sequencing in all 9 samples identified as having V600K mutations by Sanger. Conclusions: 1) the investigational PCR test had a low failure rate; 2) the PCR test was more sensitive in the detection of V600E mutations than Sanger sequencing, which may miss mutations in cases with low % mutant alleles; 3) the PCR test detects V600K mutations, and 4) in all 132 cases, a codon 600 mutation was confirmed by Sanger and/or 454 sequencing. Robust, rapid and accurate molecular testing was achieved in this multi-center clinical trial.