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BACKGROUND: The combination of monalizumab (anti-NKG2A/CD94) and durvalumab (anti-programmed death ligand-1) may promote antitumor immunity by targeting innate and adaptive immunity. This phase 1/2 study of monalizumab and durvalumab evaluated safety, antitumor activity, and pharmacodynamics in patients with advanced solid tumors. MAIN BODY: Immunotherapy-naïve patients aged ≥18 years with advanced disease, Eastern Cooperative Oncology Group performance status of 0-1, and 1-3 prior lines of systemic therapy in the recurrent/metastatic setting were enrolled. In part 1 (dose escalation), patients received durvalumab 1500 mg every 4 weeks (Q4W) with increasing doses of monalizumab Q2W/Q4W (n=15). Dose expansion in part 1 included patients with cervical cancer (n=15; durvalumab 1500 mg Q4W and monalizumab 750 mg Q2W) or metastatic microsatellite stable (MSS)-colorectal cancer (CRC) (n=15; durvalumab 1500 mg Q4W and monalizumab 750 mg Q4W). In part 2 (dose expansion), patients with MSS-CRC (n=40), non-small cell lung cancer (NSCLC; n=20), MSS-endometrial cancer (n=40), or ovarian cancer (n=40) received durvalumab 1500 mg Q4W and monalizumab 750 mg Q2W. The primary endpoint was safety. Secondary endpoints included antitumor activity per Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST v1.1). Exploratory analyses included assessment of T-cell and natural killer (NK) cell activation and proliferation in peripheral blood and the tumor microenvironment (TME). The study enrolled 185 patients (part 1, 45; part 2, 140). No dose-limiting toxicities were observed and the maximum tolerated dose was not reached. In part 2, the most common treatment-related adverse events were fatigue (12.1%), asthenia (9.3%), diarrhea (9.3%), pruritus (7.9%), and pyrexia (7.1%). In the expansion cohorts, response rates were 0% (cervical), 7.7% (MSS-CRC), 10% (NSCLC), 5.4% (ovarian), and 0% (MSS-endometrial). Sustained NK cell activation, CD8+ T-cell proliferation, increased serum levels of CXCL10 (C-X-C motif chemokine ligand 10) and CXCL11, and increased tumor infiltration of CD8+ and granzyme B+ cells were observed. CONCLUSIONS: Although efficacy was modest, monalizumab plus durvalumab was well tolerated and encouraging immune activation was observed in the peripheral blood and TME. TRIAL REGISTRATION NUMBER: NCT02671435.

BACKGROUND: POLARIS (phase 2 [ph2]; NCT03911869) evaluated encorafenib (BRAF inhibitor) in combination with binimetinib (MEK1/2 inhibitor) in BRAF/MEK inhibitor-naïve patients with BRAF V600-mutant melanoma with asymptomatic brain metastases. METHODS: The safety lead-in (SLI) assessed tolerability for high-dose encorafenib 300 mg twice daily (BID) plus binimetinib 45 mg BID. If the high dose was tolerable in ph2, patients would be randomized to receive high or standard dose (encorafenib 450 mg once daily [QD] plus binimetinib 45 mg BID). Otherwise, standard dose was evaluated as the recommended ph2 dose (RP2D). Patients who tolerated standard dosing during Cycle 1 could be dose escalated to encorafenib 600 mg QD plus binimetinib 45 mg BID in Cycle 2. Safety, efficacy, and pharmacokinetics were examined. RESULTS: RP2D was standard encorafenib dosing, as >33% of evaluable SLI patients (3/9) had dose-limiting toxicities. Overall, of 13 safety-evaluable patients (10 SLI, 3 ph2), 9 had prior immunotherapy. There were 9 treatment-related adverse events in the SLI and 3 in ph2. Of the SLI efficacy-evaluable patients (n = 10), 1 achieved complete response and 5 achieved partial responses (PR); the brain metastasis response rate (BMRR) was 60% (95% CI: 26.2, 87.8). In ph2, 2 of 3 patients achieved PR (BMRR, 67% [95% CI: 9.4, 99.2]). Repeated encorafenib 300 mg BID dosing did not increase steady-state exposure compared with historical 450 mg QD data. CONCLUSIONS: Despite small patient numbers due to early trial termination, BMRR appeared similar between the SLI and ph2, and the ph2 safety profile appeared consistent with previous reports of standard-dose encorafenib in combination with binimetinib.

Checkpoint inhibitors represent an effective treatment approach for a variety of cancers through their inhibition of immune regulatory pathways within the tumor microenvironment (TME). Unfortunately only a minority of patients with cancer achieve clinical benefit from immunotherapy, with the TME emerging as an important predictor of outcomes and sensitivity to therapy. The extent and pattern of T-cell infiltration can vary prominently within/across tumors and represents a biological continuum. Three immune profiles have been identified along this continuum: 'immune-desert' or 'T-cell cold' phenotype, 'immune-active', 'inflamed', or 'T-cell hot' phenotype, and 'immune excluded' phenotype. Of the three profiles, immune excluded remains the most ill-defined with no clear, universally accepted definition even though it is commonly associated with lack of response to immune checkpoint inhibitors and poor clinical outcomes. To address this, 16 multidisciplinary cancer experts from around the world were invited to participate in a symposium using a three-round modified Delphi approach. The first round was an open-ended questionnaire distributed via email and the second was an in-person discussion of the first round results that allowed for statements to be revised as necessary to achieve a maximum consensus (75% agreement) among the rating committee (RC). The final round questionnaire was distributed to the RC via email and had a 100% completion rate. The Delphi process resulted in moving us closer to a consensus definition for immune exclusion that is practical, clinically pertinent, and applicable across a wide range of cancer histologies. A general consensus of the role of immune exclusion in resistance to checkpoint therapy and five research priorities emerged from this process. Together, these tools could help efforts designed to address the underlying mechanisms of immune exclusion that span cancer types and, ultimately, aid in the development of treatments to target these mechanisms to improve patient outcomes.

PurposeNo approved targeted therapy for the treatment of patients with neuroblastoma RAS viral (v-ras) oncogene homolog (NRAS)-mutant melanoma is currently available.Patients and methodsIn this phase Ib escalation/expansion study (ClinicalTrials.gov identifier: NCT02974725), the safety, tolerability, and preliminary antitumor activity of naporafenib (LXH254), a BRAF/CRAF protein kinases inhibitor, were explored in combination with trametinib in patients with advanced/metastatic KRAS- or BRAF-mutant non-small-cell lung cancer (escalation arm) or NRAS-mutant melanoma (escalation and expansion arms).ResultsThirty-six and 30 patients were enrolled in escalation and expansion, respectively. During escalation, six patients reported grade ≥3 dose-limiting toxicities, including dermatitis acneiform (n = 2), maculopapular rash (n = 2), increased lipase (n = 1), and Stevens-Johnson syndrome (n = 1). The recommended doses for expansion were naporafenib 200 mg twice a day plus trametinib 1 mg once daily and naporafenib 400 mg twice a day plus trametinib 0.5 mg once daily. During expansion, all 30 patients experienced a treatment-related adverse event, the most common being rash (80%, n = 24), blood creatine phosphokinase increased, diarrhea, and nausea (30%, n = 9 each). In expansion, the objective response rate, median duration of response, and median progression-free survival were 46.7% (95% CI, 21.3 to 73.4; 7 of 15 patients), 3.75 (95% CI, 1.97 to not estimable [NE]) months, and 5.52 months, respectively, in patients treated with naporafenib 200 mg twice a day plus trametinib 1 mg once daily, and 13.3% (95% CI, 1.7 to 40.5; 2 of 15 patients), 3.75 (95% CI, 2.04 to NE) months, and 4.21 months, respectively, in patients treated with naporafenib 400 mg twice a day plus trametinib 0.5 mg once daily.ConclusionNaporafenib plus trametinib showed promising preliminary antitumor activity in patients with NRAS-mutant melanoma. Prophylactic strategies aimed to lower the incidence of skin-related events are under investigation.

Melanoma brain metastases (MBM) are clinically challenging to treat and exhibit variable responses to immune checkpoint therapies. Prior research suggests that MBM exhibit poor tumor immune responses and are enriched in oxidative phosphorylation. Here, we report results from a multi-omic analysis of a large, real-world melanoma cohort. MBM exhibited lower interferon-gamma (IFNγ) scores and T cell-inflamed scores compared to primary cutaneous melanoma (PCM) or extracranial metastases (ECM), which was independent of tumor mutational burden. Among MBM, there were fewer computationally inferred immune cell infiltrates, which correlated with lower TNF and IL12B mRNA levels. Ingenuity pathway analysis (IPA) revealed suppression of inflammatory responses and dendritic cell maturation pathways. MBM also demonstrated a higher frequency of pathogenic PTEN mutations and angiogenic signaling. Oxidative phosphorylation (OXPHOS) was enriched in MBM and negatively correlated with NK cell and B cell-associated transcriptomic signatures. Modulating metabolic or angiogenic pathways in MBM may improve responses to immunotherapy in this difficult-to-treat patient subset.

As part of the 2021 Immunotherapy Bridge virtual congress (December 1-2, Naples, Italy), the Great Debate sessions featured experts who were assigned counter opposing views on four important questions in immunotherapy today. The first topic was whether oncolytic viruses or other specific immunomodulators were the more promising approach for intralesional therapy. The second was whether early surrogate endpoints, such as response rate or progression-free survival, correlate with long-term overall survival was considered. Thirdly, whether vaccines can transform cold into hot tumors was discussed and, finally, broad versus deep analytic profiling approaches to gain insights into immune-oncology development were compared. As with previous Bridge congresses, presenters were invited by the meeting Chairs and positions taken during the debates may not have reflected their respective personal view. In addition, the views summarised in this article are based on available evidence but may reflect personal interpretation of these data, clinical experience and subjective opinion of the speaker.

BackgroundThe randomized phase 3 COMBI-i trial did not meet its primary endpoint of improved progression-free survival (PFS) with spartalizumab plus dabrafenib and trametinib (sparta-DabTram) vs placebo plus dabrafenib and trametinib (placebo-DabTram) in the overall population of patients with unresectable/metastatic BRAF V600-mutant melanoma. This prespecified exploratory biomarker analysis was performed to identify subgroups that may derive greater treatment benefit from sparta-DabTram.MethodsIn COMBI-i (ClinicalTrials.gov, NCT02967692), 532 patients received spartalizumab 400 mg intravenously every 4 weeks plus dabrafenib 150 mg orally two times daily and trametinib 2 mg orally one time daily or placebo-DabTram. Baseline/on-treatment pharmacodynamic markers were assessed via flow cytometry-based immunophenotyping and plasma cytokine profiling. Baseline programmed death ligand 1 (PD-L1) status and T-cell phenotype were assessed via immunohistochemistry; BRAF V600 mutation type, tumor mutational burden (TMB), and circulating tumor DNA (ctDNA) via DNA sequencing; gene expression signatures via RNA sequencing; and CD4+/CD8+ T-cell ratio via immunophenotyping.ResultsExtensive biomarker analyses were possible in approximately 64% to 90% of the intention-to-treat population, depending on sample availability and assay. Subgroups based on PD-L1 status/TMB or T-cell inflammation did not show significant differences in PFS benefit with sparta-DabTram vs placebo-DabTram, although T-cell inflammation was prognostic across treatment arms. Subgroups defined by BRAF V600K mutation (HR 0.45 (95% CI 0.21 to 0.99)), detectable ctDNA shedding (HR 0.75 (95% CI 0.58 to 0.96)), or CD4+/CD8+ ratio above median (HR 0.58 (95% CI 0.40 to 0.84)) derived greater PFS benefit with sparta-DabTram vs placebo-DabTram. In a multivariate analysis, ctDNA emerged as strongly prognostic (p=0.007), while its predictive trend did not reach significance; in contrast, CD4+/CD8+ ratio was strongly predictive (interaction p=0.0131).ConclusionsThese results support the feasibility of large-scale comprehensive biomarker analyses in the context of a global phase 3 study. T-cell inflammation was prognostic but not predictive of sparta-DabTram benefit, as patients with high T-cell inflammation already benefit from targeted therapy alone. Baseline ctDNA shedding also emerged as a strong independent prognostic variable, with predictive trends consistent with established measures of disease burden such as lactate dehydrogenase levels. CD4+/CD8+ T-cell ratio was significantly predictive of PFS benefit with sparta-DabTram but requires further validation as a biomarker in melanoma. Taken together with previous observations, further study of checkpoint inhibitor plus targeted therapy combination in patients with higher disease burden may be warranted.Trial registration numberNCT02967692.

PurposePreclinical data suggest the combination of an anti-programmed death receptor 1 antibody plus dabrafenib and trametinib to have superior antitumor activity compared with dabrafenib plus trametinib alone. These observations are supported by translational evidence suggesting that immune checkpoint inhibitors plus targeted therapy may improve treatment outcomes in patients with BRAF V600-mutant metastatic melanoma. COMBI-i is a phase III trial evaluating spartalizumab, an anti-programmed death receptor 1 antibody, in combination with dabrafenib and trametinib (sparta-DabTram), versus placebo plus dabrafenib and trametinib (placebo-DabTram) in patients with BRAF V600-mutant unresectable or metastatic melanoma.MethodsPatients received spartalizumab 400 mg intravenously every 4 weeks plus dabrafenib 150 mg orally twice daily and trametinib 2 mg orally once daily or placebo-DabTram. Participants were age ≥ 18 years with unresectable or metastatic BRAF V600-mutant melanoma. The primary end point was investigator-assessed progression-free survival. Overall survival was a key secondary end point (ClinicalTrials.gov identifier: NCT02967692).ResultsAt data cutoff (July 1, 2020), the median progression-free survival was 16.2 months (95% CI, 12.7 to 23.9 months) in the sparta-DabTram arm versus 12.0 months (95% CI, 10.2 to 15.4 months) in the placebo-DabTram arm (hazard ratio, 0.82 [95% CI, 0.66 to 1.03]; P = .042 [one-sided; nonsignificant]). The objective response rates were 69% (183 of 267 patients) versus 64% (170 of 265 patients), respectively. Grade ≥ 3 treatment-related adverse events occurred in 55% (146 of 267) of patients in the sparta-DabTram arm and 33% (88 of 264) in the placebo-DabTram arm.ConclusionThe study did not meet its primary end point; broad first-line use of sparta-DabTram is not supported by these results. Further biomarker-driven investigation may identify patient subpopulations who could benefit from checkpoint inhibitor plus targeted therapy combinations.

As part of the 2020 Immunotherapy Bridge virtual congress (December 2nd-3rd, Italy), the Great Debate session featured counterpoint views from leading experts on three clinical questions in immunotherapy today. The first of these was whether antitumoral vaccination is still a treatment option. The second topic debated whether anti-programmed death (PD)-1/PD-ligand (L)1 blockade should be the backbone for immunotherapy combination. Finally, the use of innovative study designs and surrogate endpoints was considered from both an academic and industry perspective. For each topic, two experts presented the argument and counter-argument in support of two different points of view. As with previous Bridge congresses, the debates were assigned by meeting Chairs and positions taken by experts during the debates may not have necessarily reflected their respective personal view. The views summarised in this article are based on available evidence but may reflect personal interpretation of these data, clinical experience and subjective opinion of the speaker.

PurposeThe randomized phase III coBRIM study (NCT01689519) demonstrated improved progression-free survival (PFS) and overall survival (OS) with addition of cobimetinib to vemurafenib compared with vemurafenib in patients with previously untreated BRAFV600 mutation-positive advanced melanoma. We report long-term follow-up of coBRIM, with at least 5 years since the last patient was randomized.Patients and methodsEligible patients were randomized 1:1 to receive either oral cobimetinib (60 mg once daily on days 1-21 in each 28-day cycle) or placebo in combination with oral vemurafenib (960 mg twice daily).Results495 patients were randomized to cobimetinib plus vemurafenib (n = 247) or placebo plus vemurafenib (n = 248). Median follow-up was 21.2 months for cobimetinib plus vemurafenib and 16.6 months for placebo plus vemurafenib. Median OS was 22.5 months (95% CI, 20.3-28.8) with cobimetinib plus vemurafenib and 17.4 months (95% CI, 15.0-19.8) with placebo plus vemurafenib; 5-year OS rates were 31% and 26%, respectively. Median PFS was 12.6 months (95% CI, 9.5-14.8) with cobimetinib plus vemurafenib and 7.2 months (95% CI, 5.6-7.5) with placebo plus vemurafenib; 5-year PFS rates were 14% and 10%, respectively. OS and PFS were longest in patients with normal baseline lactate dehydrogenase levels and low tumor burden, and in those achieving complete response. The safety profile remained consistent with previously published reports.ConclusionsExtended follow-up of coBRIM confirms the long-term clinical benefit and safety profile of cobimetinib plus vemurafenib compared with vemurafenib monotherapy in patients with BRAFV600 mutation-positive advanced melanoma.

Tumor immunology has changed the landscape of cancer treatment. Yet, not all patients benefit as cancer immune responsiveness (CIR) remains a limitation in a considerable proportion of cases. The multifactorial determinants of CIR include the genetic makeup of the patient, the genomic instability central to cancer development, the evolutionary emergence of cancer phenotypes under the influence of immune editing, and external modifiers such as demographics, environment, treatment potency, co-morbidities and cancer-independent alterations including immune homeostasis and polymorphisms in the major and minor histocompatibility molecules, cytokines, and chemokines. Based on the premise that cancer is fundamentally a disorder of the genes arising within a cell biologic process, whose deviations from normality determine the rules of engagement with the host's response, the Society for Immunotherapy of Cancer (SITC) convened a task force of experts from various disciplines including, immunology, oncology, biophysics, structural biology, molecular and cellular biology, genetics, and bioinformatics to address the complexity of CIR from a holistic view. The task force was launched by a workshop held in San Francisco on May 14-15, 2018 aimed at two preeminent goals: 1) to identify the fundamental questions related to CIR and 2) to create an interactive community of experts that could guide scientific and research priorities by forming a logical progression supported by multiple perspectives to uncover mechanisms of CIR. This workshop was a first step toward a second meeting where the focus would be to address the actionability of some of the questions identified by working groups. In this event, five working groups aimed at defining a path to test hypotheses according to their relevance to human cancer and identifying experimental models closest to human biology, which include: 1) Germline-Genetic, 2) Somatic-Genetic and 3) Genomic-Transcriptional contributions to CIR, 4) Determinant(s) of Immunogenic Cell Death that modulate CIR, and 5) Experimental Models that best represent CIR and its conversion to an immune responsive state. This manuscript summarizes the contributions from each group and should be considered as a first milestone in the path toward a more contemporary understanding of CIR. We appreciate that this effort is far from comprehensive and that other relevant aspects related to CIR such as the microbiome, the individual's recombined T cell and B cell receptors, and the metabolic status of cancer and immune cells were not fully included. These and other important factors will be included in future activities of the taskforce. The taskforce will focus on prioritization and specific actionable approach to answer the identified questions and implementing the collaborations in the follow-up workshop, which will be held in Houston on September 4-5, 2019.

Following publication of the original article [1], the author reported that an author name, Roberta Zappasodi, was missed in the authorship list.

Over the last few years, numerous clinical trials and real-world experience have provided a large amount of evidence demonstrating the potential for long-term survival with immunotherapy agents across various malignancies, beginning with melanoma and extending to other tumours. The clinical success of immune checkpoint blockade has encouraged increasing development of other immunotherapies. It has been estimated that there are over 3000 immuno-oncology trials ongoing, targeting hundreds of disease and immune pathways. Evolving topics on cancer immunotherapy, including the state of the art of immunotherapy across various malignancies, were the focus of discussions at the Immunotherapy Bridge meeting (4-5 December, 2019, Naples, Italy), and are summarised in this report.

Combining PD-L1 blockade with inhibition of oncogenic mitogen-activated protein kinase (MAPK) signaling may result in long-lasting responses in patients with advanced melanoma. This phase 1, open-label, dose-escalation and -expansion study (NCT02027961) investigated safety, tolerability and preliminary efficacy of durvalumab (anti-PD-L1) combined with dabrafenib (BRAF inhibitor) and trametinib (MEK inhibitor) for patients with BRAF-mutated melanoma (cohort A, n = 26), or durvalumab and trametinib given concomitantly (cohort B, n = 20) or sequentially (cohort C, n = 22) for patients with BRAF-wild type melanoma. Adverse events and treatment discontinuation rates were more common than previously reported for these agents given as monotherapy. Objective responses were observed in 69.2% (cohort A), 20.0% (cohort B) and 31.8% (cohort C) of patients, with evidence of improved tumor immune infiltration and durable responses in a subset of patients with available biopsy samples. In conclusion, combined MAPK inhibition and anti-PD-L1 therapy may provide treatment options for patients with advanced melanoma.

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. 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. 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. 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.

BackgroundWe sought to identify patient subgroups with distinct postprogression overall survival (ppOS) outcomes and investigate the impact of original treatment assignment and initial postprogression treatment (ppRx) on ppOS.MethodsRecursive partitioning analysis (RPA) was performed to model relationships between prespecified covariates and ppOS in patients with BRAFV600-mutated metastatic melanoma who had experienced progressive disease (PD) following treatment with cobimetinib plus vemurafenib, vemurafenib monotherapy, or dacarbazine in the BRIM-2, BRIM-3, BRIM-7, and coBRIM studies. Prognostic subgroups identified by RPA were then applied to pooled treatment cohorts. The primary endpoint was ppOS, defined as time from first PD to death from any cause.ResultsRPA identified baseline lactate dehydrogenase (LDH), baseline disease stage, Eastern Cooperative Oncology Group performance status at PD, and ppRx as significant prognostic factors for ppOS. Median ppOS was longest in patients with normal baseline LDH, stage M1c disease at baseline, and ppRx with immunotherapy or targeted therapy (12.2 months; 95% CI 10.3-16.1) and shortest in those with elevated baseline LDH > 2 × upper limit of normal (2.3 months; 95% CI 1.8-2.7). Original treatment assignment did not impact ppOS. Across treatment cohorts, patients treated with immunotherapy or targeted therapy after PD had better ppOS than those given other treatments.ConclusionA combination of factors at baseline (LDH, disease stage) and PD (performance status, ppRx) impact ppOS outcomes. ppRx with immunotherapy or targeted therapy is an independent prognostic factor for improved overall survival following progression regardless of original treatment. Trial registration The trials included in this analysis are registered with ClinicalTrials.gov: NCT00949702 (BRIM-2), NCT01006980 (BRIM-3), NCT01271803 (BRIM-7), and NCT01689519 (coBRIM).

As part of the 2019 Immunotherapy Bridge congress (December 4-5, Naples, Italy), the Great Debate session featured counterpoint views from leading experts on six topical issues in immunotherapy today. These were the use of chimeric antigen receptor T cell therapy in solid tumors, whether the Immunoscore should be more widely used in clinical practice, whether antibody-dependent cellular cytotoxicity is important in the mode of action of anticytotoxic T-lymphocyte-associated protein 4 antibodies, whether the brain is immunologically unique or just another organ, the role of microbiome versus nutrition in affecting responses to immunotherapy, and whether chemotherapy is immunostimulatory or immunosuppressive. Discussion of these important topics are summarized in this report.

BackgroundPrevious analyses of BREAK-2 and BREAK-3 showed that durable outcomes lasting ≥3 years are achievable with dabrafenib in some patients with BRAF V600-mutant metastatic melanoma (MM); however, additional follow-up is needed to fully characterise the long-term impact of dabrafenib in these patients.MethodsBREAK-2 was a single-arm phase 2 study evaluating dabrafenib in treatment-naive or previously treated BRAF V600E/K-mutant MM. BREAK-3, a randomised (3:1) phase 3 study, assessed dabrafenib versus dacarbazine in previously untreated unresectable or metastatic BRAF V600E-mutant melanoma. Five-year analyses were performed.ResultsAll BREAK-2 patients (N = 92 [V600E, n = 76; V600K, n = 16]) discontinued treatment by the data cutoff. Median follow-up was 13.0 months. In BRAF V600E patients, 5-year progression-free survival (PFS) and overall survival (OS) were 11% and 20%, respectively. Subsequent immunotherapy was received by 22% of patients. In BREAK-3, median follow-up was 17.0 and 12.0 months in the dabrafenib (n = 187) and dacarbazine (n = 63) arms, respectively. Thirty-seven patients (59%) receiving dacarbazine crossed over to dabrafenib following disease progression as per protocol. Five-year PFS was 12% in the dabrafenib arm; all dacarbazine-arm patients progressed or were censored by 5 years. Dabrafenib improved PFS versus dacarbazine, regardless of baseline lactate dehydrogenase levels. Five-year OS rates were 24% and 22% in the dabrafenib and dacarbazine arms, respectively. Subsequent therapy in each arm included anti-CTLA-4 (dabrafenib [24%] and dacarbazine [24%]) and/or anti-PD-1 (8% and 2%) treatment. No new safety signals were observed.Conclusions and relevanceThese data, representing extended follow-up for dabrafenib monotherapy, demonstrate that durable benefit lasting ≥5 years is achievable in a subset of patients.Trial registrationClinicalTrials.gov (BREAK-2, NCT01153763; BREAK-3, NCT01227889).

As part of the 2018 Immunotherapy Bridge congress (November 28-29, Naples, Italy), the Great Debate session featured counterpoint views from leading experts on four topical clinical issues in immunotherapy today. These were: the relative importance of adaptive versus innate immunity in the anti-cancer immune response; the merits of combination versus sequential immunotherapy regimens in the treatment of cancer; the advantages and disadvantages of murine models of cancer versus humans in order to evaluate immunotherapy; and whether or not mechanisms of resistance to immunotherapy differ between different cancers. Discussion of these important topics are summarised in this report.

Immunotherapy is now widely established as a potent and effective treatment option across several types of cancer. However, there is increasing recognition that not all patients respond to immunotherapy, focusing attention on the immune contexture of the tumor microenvironment (TME), drivers of the immune response and mechanisms of tumor resistance to immunity. The development of novel immunotherapeutics and their use in combination with checkpoint inhibitors and other standard of care and novel treatment modalities is an area of particular attention across several tumor types, including melanoma, lung, ovarian, breast, pancreatic, renal, head and neck, brain and non-melanoma skin cancers. The 4th Immunotherapy Bridge meeting (28-29 November, 2018, Naples, Italy) focused on a wide range of evolving topics and trends in the field of cancer immunotherapy and key presentations from this meeting are summarised in this report.

BackgroundThis pooled analysis investigated the prognostic value of depth of response in two cohorts of patients with BRAFV600-mutated metastatic melanoma treated with vemurafenib or cobimetinib plus vemurafenib.MethodsThe data were pooled from BRIM-2, BRIM-3, BRIM-7 and coBRIM. Association of depth of response with survival was estimated by Cox proportional hazards regression, adjusted for clinically relevant covariates. Depth of response was analysed in previously identified prognostic subgroups based on disease characteristics and gene signatures.ResultsGreater tumour reduction and longer time to maximal response were significantly associated with longer progression-free survival (PFS) and overall survival (OS) when evaluated as continuous variables. Patients with the deepest responses had long-lasting survival outcomes (median PFS: 14 months; OS: 32 months with vemurafenib; not estimable with cobimetinib plus vemurafenib). Cobimetinib plus vemurafenib improved depth of response versus vemurafenib monotherapy regardless of other prognostic factors, including gene signatures.ConclusionsGreater depth of response was associated with improved survival, supporting its utility as a measure of treatment efficacy in melanoma and further evaluation of its incorporation into existing prognostic models. Cobimetinib plus vemurafenib improved outcomes across quartiles of response regardless of prognostic factors or gene signatures and provided durable survival benefits in patients with deep responses.