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Purpose: In the phase III CheckMate 238 study, adjuvant nivolumab significantly improved recurrence-free survival (RFS) and distant metastasis-free survival versus ipilimumab in patients with resected stage IIIB–C or stage IV melanoma, with benefit sustained at 4 years. We report updated 5-year efficacy and biomarker findings. Patients and Methods: Patients with resected stage IIIB–C/IV melanoma were stratified by stage and baseline programmed death cell ligand 1 (PD-L1) expression and received nivolumab 3 mg/kg every 2 weeks or ipilimumab 10 mg/kg every 3 weeks for four doses and then every 12 weeks, both intravenously for 1 year until disease recurrence, unacceptable toxicity, or withdrawal of consent. The primary endpoint was RFS. Results: At a minimum follow-up of 62 months, RFS with nivolumab remained superior to ipilimumab (HR = 0.72; 95% confidence interval, 0.60–0.86; 5-year rates of 50% vs. 39%). Five-year distant metastasis-free survival (DMFS) rates were 58% with nivolumab versus 51% with ipilimumab. Five-year overall survival (OS) rates were 76% with nivolumab and 72% with ipilimumab (75% data maturity: 228 of 302 planned events). Higher levels of tumor mutational burden (TMB), tumor PD-L1, intratumoral CD8+ T cells and IFNγ-associated gene expression signature, and lower levels of peripheral serum C-reactive protein were associated with improved RFS and OS with both nivolumab and ipilimumab, albeit with limited clinically meaningful predictive value. Conclusions: Nivolumab is a proven adjuvant treatment for resected melanoma at high risk of recurrence, with sustained, long-term improvement in RFS and DMFS compared with ipilimumab and high OS rates. Identification of additional biomarkers is needed to better predict treatment outcome.

DATA SUPPLEMENT Adjuvant Nivolumab Versus Ipilimumab in Resected Stage III/IV Melanoma: 5-Year Efficacy and Biomarker Results From CheckMate 238

Purpose:In the phase III CheckMate 238 study, adjuvant nivolumab significantly improved recurrence-free survival (RFS) and distant metastasis-free survival versus ipilimumab in patients with resected stage IIIB–C or stage IV melanoma, with benefit sustained at 4 years. We report updated 5-year efficacy and biomarker findings.Patients and Methods:Patients with resected stage IIIB–C/IV melanoma were stratified by stage and baseline programmed death cell ligand 1 (PD-L1) expression and received nivolumab 3 mg/kg every 2 weeks or ipilimumab 10 mg/kg every 3 weeks for four doses and then every 12 weeks, both intravenously for 1 year until disease recurrence, unacceptable toxicity, or withdrawal of consent. The primary endpoint was RFS.Results:At a minimum follow-up of 62 months, RFS with nivolumab remained superior to ipilimumab (HR = 0.72; 95% confidence interval, 0.60–0.86; 5-year rates of 50% vs. 39%). Five-year distant metastasis-free survival (DMFS) rates were 58% with nivolumab versus 51% with ipilimumab. Five-year overall survival (OS) rates were 76% with nivolumab and 72% with ipilimumab (75% data maturity: 228 of 302 planned events). Higher levels of tumor mutational burden (TMB), tumor PD-L1, intratumoral CD8+ T cells and IFNγ-associated gene expression signature, and lower levels of peripheral serum C-reactive protein were associated with improved RFS and OS with both nivolumab and ipilimumab, albeit with limited clinically meaningful predictive value.Conclusions:Nivolumab is a proven adjuvant treatment for resected melanoma at high risk of recurrence, with sustained, long-term improvement in RFS and DMFS compared with ipilimumab and high OS rates. Identification of additional biomarkers is needed to better predict treatment outcome.

Supplementary Figure 1 Growth kinetics for all 786-0 xenografts included in the analysis from Figure 1; Supplementary Figure 2 Details of the in vitro angiogenesis assay; Supplementary Figure 3 Isolation of a sunitinib-refractory sub-line (786-0-R) from the parental 786-0 cell line; Supplementary Figure 4 Anti-angiogenic activity of sunitinib combined with trametinib within an in vitro tubule formation assay; Supplementary Figure 5 Quantification of tumor vessel density in treated tumors; Supplementary Table 1 Genotyping of the original patient sample and each generation of the PDX by STR typing

Sunitinib and pazopanib are antiangiogenic tyrosine kinase inhibitors (TKI) used to treat metastatic renal cell carcinoma (RCC). However, the ability of these drugs to extend progression-free and overall survival in this patient population is limited by drug resistance. It is possible that treatment outcomes in RCC patients could be improved by rationally combining TKIs with other agents. Here, we address whether inhibition of the Ras-Raf-MEK-ERK1/2 pathway is a rational means to improve the response to TKIs in RCC. Using a xenograft model of RCC, we found that tumors that are resistant to sunitinib have a significantly increased angiogenic response compared with tumors that are sensitive to sunitinib in vivo. We also observed significantly increased levels of phosphorylated ERK1/2 in the vasculature of resistant tumors, when compared with sensitive tumors. These data suggested that the Ras-Raf-MEK-ERK1/2 pathway, an important driver of angiogenesis in endothelial cells, remains active in the vasculature of TKI-resistant tumors. Using an in vitro angiogenesis assay, we identified that the MEK inhibitor (MEKI) trametinib has potent antiangiogenic activity. We then show that, when trametinib is combined with a TKI in vivo, more effective suppression of tumor growth and tumor angiogenesis is achieved than when either drug is utilized alone. In conclusion, we provide preclinical evidence that combining a TKI, such as sunitinib or pazopanib, with a MEKI, such as trametinib, is a rational and efficacious treatment regimen for RCC. Mol Cancer Ther; 15(1); 172–83. ©2015 AACR.

Supplementary Figures from Role of Tumor-Infiltrating B Cells in Clinical Outcome of Patients with Melanoma Treated With Dabrafenib Plus Trametinib

Purpose:Although patients with unresectable or metastatic melanoma can experience long-term survival with BRAF- and MEK-targeted agents or immune checkpoint inhibitors over 5 years, resistance develops in most patients. There is a distinct lack of pretherapeutic biomarkers to identify which patients are likely to benefit from each therapy type. Most research has focused on the predictive role of T cells in antitumor responses as opposed to B cells.Patients and Methods:We conducted prespecified exploratory biomarker analysis using gene expression profiling and digital pathology in 146 patients with previously untreated BRAF V600–mutant metastatic melanoma from the randomized, phase III COMBI-v trial and treated with dabrafenib plus trametinib who had available tumor specimens from screening.Results:Baseline cell-cycle gene expression signature was associated with progression-free survival (P = 0.007). Patients with high T-cell/low B-cell gene signatures had improved median overall survival (not reached [95% confidence interval (CI), 33.8 months–not reached]) compared with patients with high T-cell/high B-cell signatures (19.1 months; 95% CI, 13.4–38.6 months). Patients with high B-cell signatures had high B-cell infiltration into the tumor compartment, corresponding with decreased MAPK activity and increased expression of immunosuppressive markers.Conclusions:B cells may serve as a potential biomarker to predict clinical outcome in patients with advanced melanoma treated with dabrafenib plus trametinib. As separate studies have shown an opposite effect for B-cell levels and response to immunotherapy, B cells may serve as a potential biomarker to facilitate treatment selection. Further validation in a larger patient cohort is needed.

Supplementary Data from Role of Tumor-Infiltrating B Cells in Clinical Outcome of Patients with Melanoma Treated With Dabrafenib Plus Trametinib

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.

631 Background: Combination therapy with A + Ax in patients with previously untreated aRCC has shown superior progression-free survival (PFS) and objective response rate (ORR) vs sunitinib across all International Metastatic RCC Database Consortium (IMDC) risk groups. This study reports 24-month real-world outcomes in patients with aRCC receiving A + Ax in the UK. Methods: Patients were recruited from 9 UK sites. Inclusion criteria were diagnosis of aRCC, initiation of A + Ax on or after August 1, 2019, via the Early Access to Medicines Scheme, and age ≥18 years. The primary endpoints were overall survival (OS), PFS, ORR, and best response at 24 months post-A + Ax initiation. Data were analyzed descriptively. Total recruitment was 130 patients. Follow-up will continue until July 2023. Results: This analysis includes 78 patients with a minimum follow-up of 24 months. Median age at baseline was 66.6 years (range, 39.8-84.1 years); 76% (n=59) of patients were male, 63% (n=49) were White, 5% (n=4) were Asian/Asian British, and ethnicity was not recorded in 32% (n=25); 91% (n=71) had an Eastern Cooperative Oncology Group score of 0 or 1. IMDC risk status was favorable in 42% (n=33) of patients, intermediate in 41% (n=32), and poor in 17% (n=13). Median time between aRCC diagnosis and A + Ax initiation was 2.5 months (range, 0.03-90.4 months; n=77). Clear cell histology was the most prevalent (81% [n=63]); 68% (n=53) of patients had undergone nephrectomy, and 74% (n=58) had 1 or 2 metastatic sites at the index date. The OS rate at 24 months was 60% (95% CI, 49.4%-71.1%). The OS rates by IMDC risk status were: favorable, 76% (95% CI, 61.1%-90.4%); intermediate, 63% (95% CI, 45.7%-79.3%); and poor, 15% (95% CI, 0%-35.0%). The PFS rate at 24 months was 31% (95% CI, 20.5%-41.0%); median PFS was 9.1 months (95% CI, 7.9-13.4 months). ORR (n=76) at 24 months was 59% (95% CI, 48.2%-70.3%), with 4% (n=3) achieving complete response (CR) and 55% (n=42) partial response (PR). Best responses observed within 24 months were CR in 4% (n=3), PR in 54% (n=42), stable disease in 29% (n=23), and progressive disease in 10% (n=8) (2 not recorded). Median duration of response was 11.9 months (range, 0.4-23.7 months). Median time to discontinuation (TTD) of either A or Ax was 5.5 months (range, 0.5-20.5 months; n=50). Median TTD of A + Ax combined was 5.6 months (range, 0.8-20.5 months; n=43). Of 78 patients, 62 experienced an adverse event (AE) due to A + Ax treatment, 8 of whom had 14 serious AEs in total. The most common AEs were diarrhea (n=31), fatigue (n=22), and rash or oral mucositis (n=18 each); 3 patients discontinued Ax due to AEs including diarrhea (n=2), abnormal hepatic function (n=1), and abdominal pain (n=1). Conclusions: This UK-based real-world study of A + Ax treatment reports 24-month clinical outcomes in patients with aRCC. OS, PFS, ORR, and best response were in line with findings from prior clinical trials, with no new emerging AEs.

626 Background: First-line (1L) checkpoint inhibitor (CPI)-based combinations have become standard of care for patients with advanced renal cell carcinoma (aRCC). Data are required to inform optimal sequencing of aRCC therapies. CARINA is a non-interventional study of treatment sequencing and outcomes in patients with aRCC initiated on 1L CPI-based combination therapy. We report the results of a pre-planned interim analysis. Methods: We reviewed electronic prescribing records from participating UK specialist centers to identify patients (aged ≥ 18 years) with aRCC who received 2L therapy after 1L CPI-based combination therapy. The primary objective was to determine the treatment pathway for patients with aRCC who initiated treatment with a CPI-based combination and received subsequent therapy. Secondary objectives included treatment duration and objective response rate (ORR). Outcomes were evaluated for all patients (enrolled population [EP]) and for the patient subgroup who received 2L cabozantinib. Results: In total, 129 patients were eligible for inclusion in this interim analysis of the EP (mean [SD] age at diagnosis, 60.0 [9.9] years; 75.2% male; 77.3% clear-cell aRCC). Of these patients, 82.9% received 1L ipilimumab + nivolumab (Ipi + Nivo, n = 107) and 17.1% received axitinib + avelumab (Axi + Ave, n = 22); median (95% CI) duration of 1L treatment was 10.2 (9.1–17.1) weeks, ORR was 18.4%. The most commonly prescribed 2L therapies after Ipi + Nivo were cabozantinib (74.8%) and sunitinib (13.1%); the most commonly prescribed 2L therapies after Axi + Ave were lenvatinib + everolimus (45.5%) and cabozantinib (31.8%). Median (95% CI) duration of all 2L therapies was 23.6 (14.0–28.3) weeks, and median duration of 2L cabozantinib was 28.1 (20.1–37.1) weeks. ORR to 2L therapy was 30.4% for the EP, and 38.8% for the subgroup of patients who received 2L cabozantinib. Conclusions: In this interim analysis, the most commonly prescribed 2L therapies were cabozantinib and sunitinib after Ipi + Nivo, and lenvatinib + everolimus and cabozantinib after Axi + Ave. Antitumor response with 2L cabozantinib was observed after prior CPI-based therapy. Clinical trial information: NCT04957160 .

9527 Background: Combination of immune checkpoint inhibitors and targeted therapy may produce durable and deep response in a higher proportion of pts with BRAF V600–mutant unresectable or metastatic melanoma. A recent report from the randomized, double-blind, placebo (PBO)-controlled Part 3 of the Phase 3 COMBI-i trial (NCT02967692) failed to show a statistically significant progression-free survival (PFS) benefit (hazard ratio (HR) of 0.82 (95% CI, 0.66‒1.03, p=.042)). Here, we report 3-year OS data from COMBI-i part 3. Methods: Eligible pts were randomized 1:1 to receive either S+D+T (n = 267; S 400 mg IV Q4W + D 150 mg orally BID + T 2 mg orally QD) or PBO+D+T (n = 265), until progression or unacceptable toxicity. Although the primary endpoint of PFS was not met, exploratory OS and safety analyses were performed. OS was summarized descriptively using Kaplan–Meier methods and HR was estimated using a stratified cox regression model. Results: As of October 19, 2021 (median follow-up, 42.8 months), the median OS was not reached in S+D+T arm and was 40.4 months with PBO+D+T (HR 0.796; 95% CI, 0.615‒1.029). There were 113 (42.3%) deaths in the S+D+T and 126 (47.5%) in the PBO+D+T. Estimated 2-year and 3-year OS rates were 67.7% (95% CI 61.6‒73.1) and 60.1% (95% CI 53.8‒65.8) with S+D+T vs 61.9% (95% CI 55.6‒67.5) and 52.9% (95% CI 46.6‒58.9) with PBO+D+T, respectively. An OS benefit was observed with S+D+T in these prespecified subgroups – Eastern Cooperative Oncology Group Performance Status (ECOG PS) 1 (HR 0.50; 95% CI, 0.32‒0.8), age ≥65 years (HR 0.58; 95% CI, 0.36‒0.94), PD-L1 negative ( < 1%) (HR 0.62; 95% CI, 0.42‒0.91), sum of lesion diameters ≥ 66 mm at baseline (HR 0.63; 95% CI, 0.43‒0.91) and metastatic sites ≥ 3 (HR 0.66; 95% CI, 0.47‒0.94). Adverse events (AEs) irrespective of study treatment relationship were observed in 99.3% of pts in S+D+T vs 97.3% in PBO+D+T. The most common AEs (in > 30%; all grades) were pyrexia, diarrhea, and nausea. Grade ≥3 treatment-related AEs (TRAEs) occurred in 56.9% vs 35.2% of pts treated with S+D+T vs PBO+D+T, respectively. Dose reductions of D and T due to AEs were more frequent in the S+D+T arm than PBO+D+T arm (47.2% vs 25.4% and 45.7% vs 25.4%, respectively), contributing to a lower relative dose intensity; the TRAEs leading to discontinuation of all 3 study drugs occurred in 13.5% vs 8% of pts, respectively. Conclusions: Results from this landmark 3-year OS analysis from COMBI-i- part 3 was consistent with the primary analysis, while the PBO+D+T showed a higher OS rate than previously observed for D+T alone in COMBI D/V studies, with a longer median follow-up. Subgroup analyses showed that ECOG PS 1, age ≥65 years, negative PD-L1 status and high tumor burden were associated with better OS in S+D+T in terms of HR. Clinical trial information: NCT02967692.

9584 Background: All immune therapies that rapidly activate T cells, including T cell engagers, can induce cytokine release syndrome (CRS). Tebentafusp (tebe), a T cell receptor bispecific (gp100 x CD3) can also induce skin adverse events (AEs), due to gp100+ cutaneous melanocytes. CRS and skin AEs may require management with short term corticosteroids, which may also be used as premedication for subsequent tebe doses. Here we report the first analysis of systemic corticosteroid use and correlation with efficacy from a Phase (Ph) 3 trial for any T cell engager. Methods: Post hoc analyses were performed on the tebe arm of the Ph3 [NCT03070392] study in previously untreated HLA-A*02:01+ metastatic uveal melanoma (mUM) (N = 245). Due to the low rate of severe AEs in Ph1 trials, prophylactic corticosteroids were not mandated. The association between overall survival (OS) and corticosteroid use (new start within 30 days of first tebe dose) was investigated using landmark analyses in the safety population. Multivariate analyses were adjusted for key patient characteristics and AEs of special interest: CRS, rash, and liver function test (LFT) elevation. Steroid type (hydrocortisone vs. others) and treatment duration (1 vs. > 1 day) were also investigated. Results: In the Ph3 trial, 64/245 (26%) patients received new systemic corticosteroid within 30 days after the first dose of tebe, mostly for treatment of AEs (56/64, 88%) or pre-medication due to previous AE (14/64, 22%). 25 of the 64 patients received corticosteroids only for a single day. The most frequent AEs (≥15%) were rash (18/64, 28%), CRS (15/64, 23%), and hypotension (12/64, 19%). In a logistic regression model, elevated baseline LDH, the dominant prognostic marker, was most strongly associated with use of corticosteroids (p = 0.01). In the multivariate analysis, corticosteroids were not associated with any significant OS difference (HR 1.41, 95% CI 0.83-2.4, p = 0.2) and this effect did not differ in patients with or without CRS, rash or LFT elevation (all interaction tests p > 0.2). There was no difference in OS according to corticosteroid type or whether administered for 1 vs > 1 day. Conclusions: This is the first analysis from a phase 3 trial of the impact of systemic corticosteroids on survival for a T cell engaging cancer therapy. The vast majority of tebe-treated patients (84%) either did not require corticosteroids (74%) or only received them on a single day (10%). The most frequent reason for corticosteroid use was an emergent AE, including CRS and rash. Corticosteroid use following the pre-specified AE guidelines was not associated with any significant impact on OS. Clinical trial information: NCT03070392.

9563 Background: DMFS is an important endpoint for patients with stage III cutaneous melanoma, as delaying or preventing systemic disease is associated with improved clinical and patient-reported outcomes. Prior results from the phase 3 COMBI-AD trial (NCT01682083) showed 5-year DMFS rates of 65% with adjuvant D + T vs 54% with placebo (PBO; hazard ratio [HR] = 0.55; 95% CI: 0.44-0.70). An analysis of DMFS by AJCC-7 stages IIIA-C suggested a similar benefit of D + T vs PBO regardless of stage (Dummer R et al. N Engl J Med. 2020). Here, we report 5-year DMFS rates by AJCC-8 stages IIIA-D, other prognostic subgroups, and results of a regression tree analysis with DMFS. Methods: Patients with resected AJCC-7 stage III BRAFV600E/K-mutant melanoma were randomized to either D (150 mg twice daily) + T (2 mg once daily) or 2 matched PBOs for 12 months. Primary endpoint was relapse-free survival (RFS); DMFS was a secondary endpoint. Kaplan-Meier survival analyses were performed to assess the long-term benefits for DMFS rates with D + T vs PBO. The regression tree analysis (data cutoff: 5 years) for all patients (N = 870) evaluated potential prognostic/predictive factors of long-term DMFS including baseline age, sex, region, BRAF mutation type, body mass index, lactate dehydrogenase levels, ECOG, T and N categories, histology, primary tumor ulceration, treatment type, number of lymph nodes with metastases, tumor mutational burden, and interferon-gamma gene expression signature (IFN-γ GES). Results: At 5 years, DMFS rates were higher for patients with AJCC-8 stages IIIB-D disease receiving adjuvant D + T vs PBO (table). Five-year DMFS rates also favored D + T vs PBO in subgroups of patients with microscopic or macroscopic lymph node involvement (table) and those with or without primary tumor ulceration and/or in-transit metastases. A regression tree revealed T and N stage, treatment type, and IFN-γ GES as important variables defining 5-year DMFS subgroups. Conclusions: In this retrospective analysis, adjuvant D + T provided long-term DMFS benefit vs PBO in stage IIIB-D patients with resected BRAFV600E/K-mutant melanoma. Key clinical and patient factors impacting DMFS were similar to prior RFS findings (ESMO 2021; Robert C et al. Ann Oncol. 2021) and included T and N stage, treatment type, and IFN-γ GES. These results further validate the robust long-term clinical benefit of adjuvant D + T for patients with melanoma. Clinical trial information: NCT01682083. [Table: see text]

301 Background: The combination therapy avelumab + axitinib (A + Ax) has demonstrated superior progression-free survival (PFS) and objective response rate (ORR) benefit across all International Metastatic RCC Database Consortium (IMDC) risk groups (favourable, intermediate, and poor) vs sunitinib in patients with previously untreated aRCC. A + Ax is now approved and funded in the UK; on 29 October 2019, the European Commission approved A + Ax for first-line treatment of adult patients with aRCC, and it has been funded by the Cancer Drugs Fund since 30 July 2020. Here we report 12-month real-world outcomes of A + Ax in patients with aRCC in the UK. Methods: Patients ≥18 years with diagnosed aRCC who initiated A + Ax treatment outside of a clinical trial on or after 1 August 2019 via an early access to medicines scheme were recruited at 4 UK sites. Patient informed consent was obtained. Primary endpoints of interest include overall survival (OS), best response, PFS and ORR at 12 months. Descriptive statistics are provided. Recruitment is ongoing until Jan 2022 and follow-up until July 2023. Results: This analysis includes 36 patients with a minimum 12 month follow up. Median age at baseline was 66.2 (range, 39.8-84.1) years. 78% were male, 69% were White, and 6% were Asian/Asian British; ethnicities of 25% of patients were not recorded. Patient IMDC risk statuses were: 39% favourable, 42% intermediate, 17% poor, and 3% unknown; 89% had an ECOG PS of 0 or 1. Median time between aRCC diagnosis and A + Ax initiation was 1.8 months. Most patients had clear cell (72%) or other (25%) histology, had undergone nephrectomy (61%), and had 1 or 2 sites of metastatic disease (69%). The most common metastatic sites were lung (50%), bone (36%), and lymph node (25%). The 12 month OS rate was 86% (95% CI 74.8-97.4), and ORR was 53% (95% CI 36.5-69.1) with 6% achieving a complete response and 47% achieving partial response. Median duration of follow up and PFS was 12 months. Best responses within 12 months of observation were: complete response = 2 (6%), partial response = 17 (47%), stable disease = 14 (39%), and progressive disease = 3 (8%). At the time of the first and second infusions, 39% of patients received Ax at the starting dose of 5 mg twice daily, 47% had a dose escalation, and 14% had a dose reduction. Infusion-related reactions (IRRs) were recorded in 9 patients (25%) in the first 12 months, with 10 events total. All 10 IRRs required the use of high-dose corticosteroids. Median time from A + Ax initiation to IRR was 1.3 months. A + Ax was discontinued in 1 patient (3%) due to toxicity and 4 patients (11%) due to disease progression. Conclusions: In this real-world study of A + Ax treatment in the UK, A + Ax displayed comparable clinical responses to previously published data. OS, ORR, and best response figures were in line with published randomised controlled trials, which is encouraging in a nontrial population.

Sunitinib and pazopanib are antiangiogenic tyrosine kinase inhibitors (TKI) used to treat metastatic renal cell carcinoma (RCC). However, the ability of these drugs to extend progression-free and overall survival in this patient population is limited by drug resistance. It is possible that treatment outcomes in RCC patients could be improved by rationally combining TKIs with other agents. Here, we address whether inhibition of the Ras-Raf-MEK-ERK1/2 pathway is a rational means to improve the response to TKIs in RCC. Using a xenograft model of RCC, we found that tumors that are resistant to sunitinib have a significantly increased angiogenic response compared with tumors that are sensitive to sunitinib in vivo. We also observed significantly increased levels of phosphorylated ERK1/2 in the vasculature of resistant tumors, when compared with sensitive tumors. These data suggested that the Ras-Raf-MEK-ERK1/2 pathway, an important driver of angiogenesis in endothelial cells, remains active in the vasculature of TKI-resistant tumors. Using an in vitro angiogenesis assay, we identified that the MEK inhibitor (MEKI) trametinib has potent antiangiogenic activity. We then show that, when trametinib is combined with a TKI in vivo, more effective suppression of tumor growth and tumor angiogenesis is achieved than when either drug is utilized alone. In conclusion, we provide preclinical evidence that combining a TKI, such as sunitinib or pazopanib, with a MEKI, such as trametinib, is a rational and efficacious treatment regimen for RCC.

Biological therapies are claiming a place in the routine management of some solid tumours. In this review we focus on the biological treatment of melanoma and renal-cell carcinoma, identifying the background to current practice and areas of promise that may be in routine clinical use in the near future. Melanomas and renal-cell carcinomas are particularly resistant to chemotherapy and radiotherapy and are characterised by the host immune response to the tumours. For this reason there has been particular interest in the biological therapy of these diseases. Biological therapies differ from chemotherapeutic approaches in their mechanism of action, time to response, and side-effect profiles. Although biological treatment has a long history, it is only with recent advances in immunology and molecular biology that progress has been made. In the next few years investigators expect to build on their research experience with biotherapeutic agents to provide tangible benefits for patients.

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; pV600E/K mutant MM.

Six monoclonal antibodies (McAbs) were identified as plasma cell-reactive when screened on sections of human tonsil. They were all produced following immunisation of mice with cells of a human plasmacytoid line. Three of the antibodies also stained the cytoplasm (but not the surface) of blood B cells and were unreactive with other leucocytes; one McAb showed broad lymphocyte reactivity and two were completely unreactive with blood leucocytes; on testing with a panel of cell lines specificity for the plasmacy-toid line was demonstrated by three of the McAbs. In spite of the marked restriction shown by the reactivity of these antibodies in tests on cells of haemopoietic origin, tests on other human tissues — including thyroid and pancreas — showed that a related antigen was present in the cytoplasm of secretory epithelial cells. The overall patterns of reactivity of the individual McAbs on various tissues and blood lymphocytes were different. Comparisons were made with the established McAb OKT10, which binds to plasma cells, early stem cells and activated lymphocytes; its binding to plasma cells was confirmed and it was shown that it did not stain secretory epithelia. The potent reactions obtained with the new McAbs suggest that antibodies to antigens associated with epithelial cell secretory apparatus provide potentially useful reagents for studying plasma cells.

The autocrine growth profile of human B lymphocytes transformed with Epstein-Barr virus (EBV) was found to comprise three distinct components: a B-cell growth factor (BCGF); an interleukin-1 (IL-1)-like activity; an activity requiring cell-to-cell contact for its action. Observations on the inhibition of the EBV-carrying Daudi lymphoma line by alpha-interferon indicated that loss of response to these autostimulatory factors was underlying growth cessation. Furthermore, a putative receptor for BCGF was found to be down-regulated on B cells stimulated with non-transforming mitogens but constitutively expressed following EBV-transformation. Taken together with recent evidence that normal B cells produce autostimulatory factors, these findings suggest that the special feature of autocrine growth by EBV-immortalized cells is a maintenance of what should normally be a transient phenotype, possibly through deregulation of receptor expression. This hypothesis is discussed.

The B cell and leukemia Workshop antibodies were tested on tissue sections by immunofluorescence and immunoenzyme staining. This identified 16 which showed unequivocal reactivity with follicular dendritic cells (FDC) in germinal centers (GC). It was observed that patterns of FDC staining obtained with different antibodies were not identical—some gave extensive staining of the GC and others a restricted pattern involving fewer FDC or possibly a smaller part of each FDC. The antibodies were therefore compared by double immunofluorescence (using conjugates specific for mouse immunoglobulin isotypes) with two established anti-FDC monoclonal antibodies (mAbs), and a third anti-FDC antibody produced in this Department, all of which give completely coincident staining of FDC when paired with each other.

Treatment of Daudi B-lymphoblastoid cells with low concentrations of either natural or recombinant human alpha-interferons inhibits cell proliferation and modulates the expression of a number of cell-surface antigens. Using a panel of monoclonal antibodies (MAbs) identifying determinants expressed at the surface of normal plasma cells, and polyclonal antibodies against surface and cytoplasmic immunoglobulin, we have found that growth inhibition is accompanied by plasmacytoid differentiation. Assays of growth stimulation of heterologous cells indicate that the culture medium from interferon-treated Daudi cells contains substantially more B-cell growth factor activity than that from control cells. However, the interferon-treated cells exhibit an impaired ability to respond to both these autocrine factors and exogenous factors produced by another Burkitt lymphoma line. These findings show that, in the case of Daudi cells, growth inhibition by interferons is closely associated with both terminal differentiation and a refractoriness to growth factors. In this system IFN-alpha may therefore be considered to be a B-cell differentiation factor, suggesting a possible basis for the anti-proliferative effects observed with certain human B-cell malignancies.

B lymphocyte subgroups can be identified by phenotypic analysis of isolated lymphocyte preparations; further information about changes in these cells on activation can be gained by culture with antigen or polyclonal B cell mitogens. Most of the markers applied to isolated cells can also be used in tissue sections. Immunohistology allows several different cell types to be screened at the same time. Sections also enable functional subsets of cells to be identified by their location in the tissues. In addition to general T and B cell areas a number of different B cell compartments can be identified. These include: 1. The small lymphocyte mantle of follicles which contain recirculating B cells (Figs. 21.1 and 21.2) (1); 2. Germinal centers with mixtures of centroblasts, centrocytes, follicular dendritic cells, and tingible body macrophages [Figs. 21.1(A) and 21.2(A)] (2); 3. The marginal zone B cells of the spleen which do not recirculate and which, unlike recirculating follicular B cells, do not express surface IgD (Fig. 2.2) (3).