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Background: Talimogene laherparepvec (T-VEC), an oncolytic virus, was designed to selectively replicate in and lyse tumor cells, releasing tumor-derived antigen to stimulate a tumor-specific immune response., Methods: In this phase II study in patients with unresectable stage IIIB-IV melanoma, we evaluated non-injected lesions to establish whether baseline or change in intratumoral CD8 + T-cell density (determined using immunohistochemistry) correlated with T-VEC clinical response., Results: Of 112 enrolled patients, 111 received ≥1 dose of T-VEC. After a median follow-up of 108.0 weeks, objective/complete response rates were 28%/14% in the overall population and 32%/18% in patients with stage IIIB-IVM1a disease. No unexpected toxicity occurred. Baseline and week 6 change from baseline CD8 + T-cell density results were available for 91 and 65 patients, respectively. Neither baseline nor change in CD8 + T-cell density correlated with objective response rate, changes in tumor burden, duration of response or durable response rate. However, a 2.4-fold median increase in CD8 + T-cell density in non-injected lesions from baseline to week 6 was observed. In exploratory analyses, multiparameter immunofluorescence showed that after treatment there was an increase in the proportion of infiltrating CD8 + T-cells expressing granzyme B and checkpoint markers (programmed death-1, programmed death-ligand 1 (PD-L1) and cytotoxic T-lymphocyte antigen-4) in non-injected lesions, together with an increase in helper T-cells. Consistent with T-cell infiltrate, we observed an increase in the adaptive resistance marker PD-L1 in non-injected lesions., Conclusions: This study indicates that T-VEC induces systemic immune activity and alters the tumor microenvironment in a way that will likely enhance the effects of other immunotherapy agents in combination therapy., Trial Registration Number: NCT02366195., Competing Interests: Competing interests: JM has acted as a consultant/advisor for and has received honoraria from Almirall, Amgen, Bristol-Myers Squibb, GlaxoSmithKline, Merck Sharp & Dohme, Leo Pharma, Novartis, Pierre Fabre and Roche. IS has acted as a consultant and served on a speaker’s bureau for Biocad, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis and Roche. DS has received research support from Bristol-Myers Squibb and Novartis; has acted as a consultant for and received royalties from Amgen, Array, AstraZeneca, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, and Roche; and has acted as a consultant for Immunocore, Incyte, LeoPharma, Merck Serono, Pfizer, Philogen, and Regeneron. RG has received research support from Johnson & Johnson, Novartis, Merck Serono, Amgen and Pfizer; has received honoraria for advice and/or lectures from Almirall Hermal, Amgen, Bayer, Bristol-Myers Squibb, Merck Serono, Merck Sharp & Dohme, Novartis, Pierre Fabre, Roche, Sanofi/Regeneron, SUN Pharma and 4SC. J-JG has acted as a consultant/in an advisory role for and has received honoraria from Bristol-Myers Squibb, GlaxoSmithKline, Merck Sharp & Dohme, Merck-Pfizer, Pierre Fabre, and Roche. JJS has received research support from AstraZeneca, Bristol-Myers Squibb and Immunocore; has acted as a consultant/in an advisory role for Immunocore, Delcath, Merck Sharp & Dohme, Amgen and Pierre Fabre; and served on a speaker’s bureau for Bristol-Myers Squibb. KSG and AA are employees and stock holders of Amgen. KL is an employee of Amgen. CAP was previously an employee of Amgen. HG has acted as a consultant/in an advisory role for Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Amgen, Roche and Pierre Fabre., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Talimogene laherparepvec, a herpes simplex virus type 1-based intralesional oncolytic immunotherapy, is approved in Europe for the treatment of adults with unresectable stage IIIB-IVM1a melanoma, with no bone, brain, lung or other visceral disease. It has direct oncolytic effects in injected lesions, leading to the release of tumour-derived antigens and systemic immune effects mediated by the induction of anti-tumour immunity, which is enhanced by the production of granulocyte macrophage colony-stimulating factor. Responses (which occur in >40% of stage IIIB-IVM1a patients) are often durable (>50% last ≥6 months) and occur in injected and uninjected lesions (in stage IIIB-IVM1c patients, 64%/34% of evaluable injected/uninjected non-visceral lesions, respectively, decreased in size by ≥50%). As with other immunotherapies, responses may be delayed or can arise after pseudoprogression. The pattern of treatment-emergent adverse events is distinct, being mostly grade 1/2, easy to manage, and rarely leading to treatment discontinuation. Systemic therapy represents the backbone of care for many metastatic melanoma patients. Nonetheless, the potential for durable locoregional control with a locally injected agent may make talimogene laherparepvec suitable for selected patients with stage IIIB/C disease, for whom surgery is not possible (e.g. with in-transit metastases, multiple melanoma lesions at different body sites, or those relapsing rapidly after repeated rounds of surgery) and slowly progressing disease. Here, we discuss which patients could be suitable for talimogene laherparepvec monotherapy based on the European indication, review the patterns/timing of response, and discuss the incidence/management of adverse events. Its potential use combined with immune checkpoint inhibitors is also discussed.

Background: Acquired resistance to BRAF inhibitors (BRAFi) is a near-universal phenomenon caused by numerous genetic and non-genetic alterations. In this study, we evaluated the spectrum, onset, pattern of progression, and subsequent clinical outcomes associated with specific mechanisms of resistance., Methods: We compiled clinical and genetic data from 100 patients with 132 tissue samples obtained at progression on BRAFi therapy from 3 large, previously published studies of BRAFi resistance. These samples were subjected to whole-exome sequencing and/or polymerase chain reaction-based genetic testing., Results: Among 132 samples, putative resistance mechanisms were identified in 58%, including NRAS or KRAS mutations (20%), BRAF splice variants (16%), BRAF(V600E/K) amplifications (13%), MEK1/2 mutations (7%), and non-mitogen-activated protein kinase pathway alterations (11%). Marked heterogeneity was observed within tumors and patients; 18 of 19 patients (95%) with more than one progression biopsy had distinct/unknown drivers of resistance between samples. NRAS mutations were associated with vemurafenib use (p = 0.045) and intracranial metastases (p = 0.036), and MEK1/2 mutations correlated with hepatic progression (p = 0.011). Progression-free survival and overall survival were similar across resistance mechanisms. The median survival after disease progression was 6.9 months, and responses to subsequent BRAF and MEK inhibition were uncommon (2 of 15; 13%). Post-progression outcomes did not correlate with specific acquired BRAFi-resistance mechanisms., Conclusions: This is the first study to systematically characterise the clinical implications of particular acquired BRAFi-resistance mechanisms in patients with BRAF-mutant melanoma largest study to compile the landscape of resistance. Despite marked heterogeneity of resistance mechanisms within patients, NRAS mutations correlated with vemurafenib use and intracranial disease involvement., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: Patients with metastatic melanoma, 50% of whose tumours harbour a BRAF mutation, have a poor prognosis. Selumetinib, a MEK1/2 inhibitor, has shown antitumour activity in patients with BRAF-mutant melanoma and in preclinical models when combined with chemotherapy. This study was designed to look for a signal of improved efficacy by comparing the combination of selumetinib and dacarbazine with dacarbazine alone., Methods: This double-blind, randomised, placebo-controlled phase 2 study investigated selumetinib plus dacarbazine versus placebo plus dacarbazine as first-line treatment in patients older than 18 years with histologically or cytologically confirmed advanced BRAF-mutant cutaneous or unknown primary melanoma. Patients were randomly assigned by central interactive voice response system (1:1 ratio, block size four) to take either oral selumetinib (75 mg twice daily in a 21-day cycle) or placebo; all patients received intravenous dacarbazine (1000 mg/m(2) on day 1 of a 21-day cycle). Patients, investigators, and the study team were masked to the treatment assigned. The primary endpoint was overall survival analysed by intention to treat. This study is registered at ClinicalTrials.gov, NCT00936221., Findings: Between July 20, 2009, and April 8, 2010, 91 patients were randomly assigned to receive dacarbazine in combination with selumetinib (n=45) or placebo (n=46). Overall survival did not differ significantly between groups (median 13·9 months, 80% CI 10·2-15·6, in the selumetinib plus dacarbazine group and 10·5 months, 9·6-14·7, in the placebo plus dacarbazine group; hazard ratio [HR] 0·93, 80% CI 0·67-1·28, one-sided p=0·39). However, progression-free survival was significantly improved in the selumetinib plus dacarbazine group versus the placebo plus dacarbazine group (HR 0·63, 80% CI 0·47-0·84, one-sided p=0·021), with a median of 5·6 months (80% CI 4·9-5·9) versus 3·0 months (2·8-4·6), respectively. The most frequent adverse events included nausea (28 [64%] of 44 patients on selumetinib vs 25 [56%] of 45 on placebo), acneiform dermatitis (23 [52%] vs one [2%]), diarrhoea (21 [48%] vs 13 [29%]), vomiting (21 [48%] vs 15 [33%]), and peripheral oedema (19 [43%] vs three [7%]). The most common grade 3-4 adverse event was neutropenia (six [14%] patients in the selumetinib plus dacarbazine group vs four [9%] in the placebo plus dacarbazine group)., Interpretation: Selumetinib plus dacarbazine showed clinical activity in patients with BRAF-mutant cutaneous or unknown primary melanoma, reflected by a significant benefit in progression-free survival compared with placebo plus dacarbazine group, although no significant change in overall survival was noted. The tolerability of this combination was generally consistent with monotherapy safety profiles., Funding: AstraZeneca., (Copyright © 2013 Elsevier Ltd. All rights reserved.)