Real-World Outcomes of Immunotherapy for Melanoma Brain Metastases in New Zealand.

PURPOSE: Melanoma brain metastases (BMs) are associated with poor survival. Combination immune checkpoint inhibitors (ICIs) with anti-PD1 and anti-CTLA-4 are the international standard-of-care treatment. Most landmark clinical trials excluded real-world patients with symptomatic disease, poor performance status (PS), and steroid use. Despite the high incidence of melanoma in New Zealand (NZ), the only publicly funded systemic treatment is anti-PD1 monotherapy. The real-world outcomes for BMs after ICIs in NZ are unknown. METHODOLOGY: Medical records of patients with melanoma BMs in seven cancer centers across NZ between September 1, 2016, and September 1, 2020, were evaluated. Clinicopathologic characteristics, treatment, intracranial (IC) tumor response rates, IC progression-free survival, and overall survival (OS) are reported. RESULTS: One hundred and forty-four patients received at least one dose of ICI. One hundred and thirty-three (93%) patients received anti-PD1 monotherapy. Almost a quarter of patients had poor baseline PS, 56% were symptomatic, and 33% had corticosteroids. Patients also received local therapies: 61 (42%) patients underwent surgery, 42 (29%) received whole brain radiation, and 47 (33%) received stereotactic radiation. The median OS was 15 months, and a third of patients were alive at 2 years. The toxicity of ICIs was at 28% and 15% for Common Terminology Criteria for Adverse Events grade 1-2 and 3-4 events, respectively. Of the patients who are still alive, 76% of patients remained symptomatic neurologically at last follow-up. CONCLUSION: Most patients in this NZ real-world study were symptomatic and received anti-PD1 monotherapy. Approximately one-third of treated patients are alive at 2 years, but most patients remained symptomatic. This highlights the need for more effective treatment and prospective management of their neurologic rehabilitation needs.

Dynamic ctDNA Mutational Complexity in Patients with Melanoma Receiving Immunotherapy.

BACKGROUND: Circulating tumour DNA (ctDNA) analysis promises to improve the clinical care of people with cancer, address health inequities and guide translational research. This observational cohort study used ctDNA to follow 29 patients with advanced-stage cutaneous melanoma through multiple cycles of immunotherapy. METHOD: A melanoma-specific ctDNA next-generation sequencing (NGS) panel, droplet digital polymerase chain reaction (ddPCR) and mass spectrometry analysis were used to identify ctDNA mutations in longitudinal blood plasma samples from Aotearoa New Zealand (NZ) patients receiving immunotherapy for melanoma. These technologies were used in conjunction to identify the breadth and complexity of tumour genomic information that ctDNA analysis can reliably report. RESULTS: During the course of immunotherapy treatment, a high level of dynamic mutational complexity was identified in blood plasma, including multiple BRAF mutations in the same patient, clinically relevant BRAF mutations emerging through therapy and co-occurring sub-clonal BRAF and NRAS mutations. The technical validity of this ctDNA analysis was supported by high sample analysis-reanalysis concordance, as well as concordance between different ctDNA measurement technologies. In addition, we observed > 90% concordance in the detection of ctDNA when using cell-stabilising collection tubes followed by 7-day delayed processing, compared with standard EDTA blood collection protocols with rapid processing. We also found that the undetectability of ctDNA at a proportion of treatment cycles was associated with durable clinical benefit (DCB). CONCLUSION: We found that multiple ctDNA processing and analysis methods consistently identified complex longitudinal patterns of clinically relevant mutations, adding support for expanded clinical trials of this technology in a variety of oncology settings.

KEYNOTE-022 part 3: a randomized, double-blind, phase 2 study of pembrolizumab, dabrafenib, and trametinib in BRAF-mutant melanoma.

BACKGROUND: In the KEYNOTE-022 study, pembrolizumab with dabrafenib and trametinib (triplet) improved progression-free survival (PFS) versus placebo with dabrafenib and trametinib (doublet) without reaching statistical significance. Mature results on PFS, duration of response (DOR), and overall survival (OS) are reported. METHODS: The double-blind, phase 2 part of KEYNOTE-022 enrolled patients with previously untreated BRAFV600E/K-mutated advanced melanoma from 22 sites in seven countries. Patients were randomly assigned 1:1 to intravenous pembrolizumab (200 mg every 3 weeks) or placebo plus dabrafenib (150 mg orally two times per day) and trametinib (2 mg orally one time a day). Primary endpoint was PFS. Secondary endpoints were objective response rate, DOR, and OS. Efficacy was assessed in the intention-to-treat population, and safety was assessed in all patients who received at least one dose of study drug. This analysis was not specified in the protocol. RESULTS: Between November 30, 2015 and April 24, 2017, 120 patients were randomly assigned to triplet (n=60) or doublet (n=60) therapy. With 36.6 months of follow-up, median PFS was 16.9 months (95% CI 11.3 to 27.9) with triplet and 10.7 months (95% CI 7.2 to 16.8) with doublet (HR 0.53; 95% CI 0.34 to 0.83). With triplet and doublet, respectively, PFS at 24 months was 41.0% (95% CI 27.4% to 54.2%) and 16.3% (95% CI 8.1% to 27.1%); median DOR was 25.1 months (95% CI 14.1 to not reached) and 12.1 months (95% CI 6.0 to 15.7), respectively. Median OS was not reached with triplet and was 26.3 months with doublet (HR 0.64; 95% CI 0.38 to 1.06). With triplet and doublet, respectively, OS at 24 months was 63.0% (95% CI 49.4% to 73.9%) and 51.7% (95% CI 38.4% to 63.4%). Grade 3-5 treatment-related adverse events (TRAEs) occurred in 35 patients (58%, including one death) receiving triplet and 15 patients (25%) receiving doublet. CONCLUSION: In BRAFV600E/K-mutant advanced melanoma, pembrolizumab plus dabrafenib and trametinib substantially improved PFS, DOR, and OS with a higher incidence of TRAEs. Interpretation of these results is limited by the post hoc nature of the analysis.

Patterns of referral and uptake of BReast CAncer (BRCA) gene testing of eligible women with ovarian cancer in New Zealand.

AIMS: To determine the proportion of eligible patients with high-grade serous carcinoma of the ovary, fallopian tube or peritoneum discussed at gynaecological oncology multidisciplinary meetings (MDMs) in New Zealand and subsequently referred for genetic counselling and BRCA pathogenic variant testing. METHODS: Eligible cases were identified from Auckland, Wellington, Christchurch and Dunedin gynaecologic oncology MDM databases between 1 January 2015 to 31 December 2016. Patients who met the eligibility criteria for genetics referral were identified, and cross-referenced against genetic services databases to ascertain the rates of referrals received, the numbers attending appointments, genetic testing offered and range of results. RESULTS: During the two-year period, 205 patients were eligible for referral. Of these, 143 (70%) patients were referred for genetic counselling with 128 (90%) of this group recommended for BRCA pathogenic variant testing. Of the 126 who undertook the test, results were available for 120 (95%). Nineteen patients (16%) tested positive for a germline BRCA pathogenic variant. CONCLUSIONS: The New Zealand rate of referral to genetic counselling for women with high-grade serous cancer, (HGSC), of the ovary, fallopian tube or peritoneum diagnosed between 2015-2016 is encouraging when compared with others internationally. The rate of BRCA positive pathogenic variants is comparable to international data.