Adjuvant use of combination therapy with dabrafenib plus trametinib resulted in a significantly lower risk of recurrence in patients with stage III melanoma with BRAF V600E or V600K mutations than the adjuvant use of placebo and was not associated with new toxic effects. (Funded by GlaxoSmithKline and Novartis; COMBI-AD ClinicalTrials.gov, NCT01682083 ; EudraCT number, 2012-001266-15 .).

Summary Background Dabrafenib plus trametinib (D+T) improves outcomes in BRAF V600–mutant metastatic melanoma without brain metastases; however, activity of D+T has not been studied in active melanoma brain metastases (MBM). Here, we report results from the phase 2 trial COMBI-MB. Our aim was to build upon the current body of evidence of targeted therapy in melanoma brain metastases through an evaluation of D+T in patients with BRAF V600–mutant melanoma brain metastases. Methods This ongoing open-label, phase 2 study (NCT02039947) evaluated dabrafenib 150 mg twice daily plus trametinib 2 mg once daily in four melanoma patient cohorts: (A) BRAF V600E, asymptomatic MBM, no prior local brain therapy; (B) BRAF V600E, asymptomatic MBM, prior local brain therapy; (C) BRAF V600D/K/R, asymptomatic MBM, with or without prior local brain therapy; and (D) BRAF V600D/E/K/R, symptomatic MBM, with or without prior local brain therapy. The primary objective was to assess intracranial response rate (IRR) in cohort A in the all-treated-subjects population. Secondary endpoints included IRR in cohorts B–D; extracranial and overall response rates; disease control rates; duration of intracranial, extracranial, and overall response; progression-free survival; overall survival; and safety. Findings A total of 125 patients were enrolled (A: n=76; B: n=16; C: n=16; D: n=17). At the data cutoff (November 28, 2016; median follow-up 8·5 months) investigator-assessed IRR was 58% (n=44/76) in cohort A. Intracranial response by investigator assessment was also achieved in 9 (56%) of 16 patients in cohort B, 7 (44%) of 16 patients in cohort C, and 10 (59%) of 17 patients in cohort D. Safety results were consistent with prior D+T studies, with 60 (48%) of 125 patients across cohorts experiencing grade 3/4 adverse events. The most common serious adverse events across cohorts were pyrexia (n=9/125; 7%) and ejection fraction decreased (n=5/125; 4%). Interpretation D+T was active with a manageable safety profile in patients with BRAF V600–mutant MBMs, but the median duration of response was relatively short. These results provide evidence of clinical benefit with D+T and support the need for additional research to further improve outcomes in patients with MBMs. Funding Novartis.

GenoMEL, comprising major familial melanoma research groups from North America, Europe, Asia, and Australia has created the largest familial melanoma sample yet available to characterize mutations in the high-risk melanoma susceptibility genes CDKN2A/alternate reading frames (ARF), which encodes p16 and p14ARF, and CDK4 and to evaluate their relationship with pancreatic cancer (PC), neural system tumors (NST), and uveal melanoma (UM). This study included 466 families (2,137 patients) with at least three melanoma patients from 17 GenoMEL centers. Overall, 41% (n = 190) of families had mutations; most involved p16 (n = 178). Mutations in CDK4 (n = 5) and ARF (n = 7) occurred at similar frequencies (2-3%). There were striking differences in mutations across geographic locales. The proportion of families with the most frequent founder mutation(s) of each locale differed significantly across the seven regions (P = 0.0009). Single founder CDKN2A mutations were predominant in Sweden (p.R112_L113insR, 92% of family's mutations) and the Netherlands (c.225_243del19, 90% of family's mutations). France, Spain, and Italy had the same most frequent mutation (p.G101W). Similarly, Australia and United Kingdom had the same most common mutations (p.M53I, c.IVS2-105A>G, p.R24P, and p.L32P). As reported previously, there was a strong association between PC and CDKN2A mutations (P < 0.0001). This relationship differed by mutation. In contrast, there was little evidence for an association between CDKN2A mutations and NST (P = 0.52) or UM (P = 0.25). There was a marginally significant association between NST and ARF (P = 0.05). However, this particular evaluation had low power and requires confirmation. This GenoMEL study provides the most extensive characterization of mutations in high-risk melanoma susceptibility genes in families with three or more melanoma patients yet available. (Cancer Res 2006; 66(20): 9818-28)

Background In the previously reported primary analysis of this phase 3 trial, 12 months of adjuvant dabrafenib plus trametinib resulted in significantly longer relapse-free survival than placebo in patients with resected stage III melanoma with BRAF V600E or V600K mutations. To confirm the stability of the relapse-free survival benefit, longer-term data were needed. Methods We randomly assigned 870 patients who had resected stage III melanoma with BRAF V600E or V600K mutations to receive 12 months of oral dabrafenib (at a dose of 150 mg twice daily) plus trametinib (2 mg once daily) or two matched placebos. The primary end point was relapse-free survival. Here, we report 5-year results for relapse-free survival and survival without distant metastasis as the site of the first relapse. Overall survival was not analyzed, since the required number of events to trigger the final overall survival analysis had not been reached. Results The minimum duration of follow-up was 59 months (median patient followup, 60 months for dabrafenib plus trametinib and 58 months for placebo). At 5 years, the percentage of patients who were alive without relapse was 52% (95% confidence interval [CI], 48 to 58) with dabrafenib plus trametinib and 36% (95% CI, 32 to 41) with placebo (hazard ratio for relapse or death, 0.51; 95% CI, 0.42 to 0.61). The percentage of patients who were alive without distant metastasis was 65% (95% CI, 61 to 71) with dabrafenib plus trametinib and 54% (95% CI, 49 to 60) with placebo (hazard ratio for distant metastasis or death, 0.55; 95% CI, 0.44 to 0.70). No clinically meaningful between-group difference in the incidence or severity of serious adverse events was reported during the follow-up period. Conclusions In the 5-year follow-up of a phase 3 trial involving patients who had resected stage III melanoma with BRAF V600E or V600K mutations, 12 months of adjuvant therapy with dabrafenib plus trametinib resulted in a longer duration of survival without relapse or distant metastasis than placebo with no apparent longterm toxic effects. (Funded by GlaxoSmithKline and Novartis; COMBI-AD ClinicalTrials.gov number, NCT01682083. opens in new tab; EudraCT number, 2012-001266-15. opens in new tab.

Objective Immune checkpoint inhibitors (ICIs) for cancer therapy frequently induce immune‐related adverse effects (IRAEs). Therefore, most patients with preexisting autoimmune diseases have been excluded from clinical trials of ICIs. This study was undertaken to evaluate the safety and efficacy of ICIs in patients with preexisting autoimmune disease and cancer. Methods A retrospective cohort study was conducted from January 2017 to January 2018 via 3 French national networks of experts in oncology and autoimmunity. Adults with preexisting autoimmune disease who were receiving ICIs were assessed for the occurrence of flare of preexisting autoimmune disease, other IRAEs, and cancer response. Results The study included 112 patients who were followed up for a median of 8 months. The most frequent preexisting autoimmune diseases were psoriasis (n = 31), rheumatoid arthritis (n = 20), and inflammatory bowel disease (n = 14). Twenty‐four patients (22%) were receiving immunosuppressive therapy at ICI initiation. Autoimmune disease flare and/or other IRAE(s) occurred in 79 patients (71%), including flare of preexisting autoimmune disease in 53 patients (47%) and/or other IRAE(s) in 47 patients (42%), with a need for immunosuppressive therapy in 48 patients (43%) and permanent discontinuation of ICI in 24 patients (21%). The median progression‐free survival was shorter in patients receiving immunosuppressive therapy at ICI initiation (3.8 months versus 12 months; P = 0.006), confirmed by multivariable analysis. The median progression‐free survival was shorter in patients who experienced a flare of preexisting autoimmune disease or other IRAE, with a trend toward better survival in the subgroup without immunosuppressant use or ICI discontinuation. Conclusion Our findings indicate that flares or IRAEs occur frequently but are mostly manageable without ICI discontinuation in patients with a preexisting autoimmune disease. Immunosuppressive therapy at baseline is associated with poorer outcomes.

BACKGROUND: There is a strong need to determine the best technique for O 6 -methylguanine-DNA-methyltranferase (MGMT) analysis, because MGMT status is currently used in clinical trials and occasionally in routine clinical practice for glioblastoma patients. METHODS:The authors compared analytical performances and predictive values of 5 techniques in a series of 100 glioblastoma patients who received standard of care treatment (Stupp protocol). RESULTS: MGMT promoter was considered methylated in 33%, 33%, 42%, and 60% of patients by methylation-sensitive high-resolution melting, MethyLight, pyrosequencing (with an optimal risk cutoff at 8% for the average percentage of the 5 CpGs tested), and methylation-specific polymerase chain reaction (MS-PCR), respectively. Fifty-nine percent of the samples had <23% (the optimal risk cutoff) of MGMT-positive tumor cells. The best predictive values for overall survival (OS), after adjustment for age and performance status, were obtained by pyrosequencing (hazard ratio [HR], 0.32; P < .0001), MS-PCR (HR, 0.37; P < .0001), and immunohistochemistry (HR, 0.43; P ¼ .0005) as compared with methylation-sensitive high-resolution melting (HR, 0.52 P ¼ .02) and MethyLight (HR, 0.6; P ¼ .05). For progression-free survival (PFS), the best predictive values were obtained with pyrosequencing (HR, 0.35; P < .0001), methylation-sensitive high-resolution melting (HR, 0.46; P ¼ .002), and MS-PCR (HR, 0.49; P ¼ .002). Combining pyrosequencing and immunohistochemistry slightly improved predictive power for OS, but not for PFS. Poor reproducibility and interobserver variability were, however, observed for immunohistochemistry. CONCLUSIONS: Good prediction of survival in addition to high reproducibility and sensitivity made pyrosequencing the best among the 5 techniques tested in this study. Cancer 2012;118:4201-11.

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Summary Background The role of temozolomide chemotherapy in newly diagnosed 1p/19q non-co-deleted anaplastic gliomas, which are associated with lower sensitivity to chemotherapy and worse prognosis than 1p/19q co-deleted tumours, is unclear. We assessed the use of radiotherapy with concurrent and adjuvant temozolomide in adults with non-co-deleted anaplastic gliomas. Methods This was a phase 3, randomised, open-label study with a 2 × 2 factorial design. Eligible patients were aged 18 years or older and had newly diagnosed non-co-deleted anaplastic glioma with WHO performance status scores of 0–2. The randomisation schedule was generated with the electronic EORTC web-based ORTA system. Patients were assigned in equal numbers (1:1:1:1), using the minimisation technique, to receive radiotherapy (59·4 Gy in 33 fractions of 1·8 Gy) alone or with adjuvant temozolomide (12 4-week cycles of 150–200 mg/m2 temozolomide given on days 1–5); or to receive radiotherapy with concurrent temozolomide 75 mg/m2 per day, with or without adjuvant temozolomide. The primary endpoint was overall survival adjusted for performance status score, age, 1p loss of heterozygosity, presence of oligodendroglial elements, and MGMT promoter methylation status, analysed by intention to treat. We did a planned interim analysis after 219 (41%) deaths had occurred to test the null hypothesis of no efficacy (threshold for rejection p<0·0084). This trial is registered with ClinicalTrials.gov, number NCT00626990. Findings At the time of the interim analysis, 745 (99%) of the planned 748 patients had been enrolled. The hazard ratio for overall survival with use of adjuvant temozolomide was 0·65 (99·145% CI 0·45–0·93). Overall survival at 5 years was 55·9% (95% CI 47·2–63·8) with and 44·1% (36·3–51·6) without adjuvant temozolomide. Grade 3–4 adverse events were seen in 8–12% of 549 patients assigned temozolomide, and were mainly haematological and reversible. Interpretation Adjuvant temozolomide chemotherapy was associated with a significant survival benefit in patients with newly diagnosed non-co-deleted anaplastic glioma. Further analysis of the role of concurrent temozolomide treatment and molecular factors is needed. Funding Schering Plough and MSD.