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Purpose: Consensus is lacking regarding the androgen receptor (AR) as a prognostic marker in breast cancer. The objectives of this study were to comprehensively review the literature on AR prognostication and determine optimal criteria for AR as an independent predictor of breast cancer survival.Experimental Design: AR positivity was assessed by immunostaining in two clinically validated primary breast cancer cohorts [training cohort, n = 219; validation cohort, n = 418; 77% and 79% estrogen receptor alpha (ERα) positive, respectively]. The optimal AR cut-point was determined by ROC analysis in the training cohort and applied to both cohorts.Results: AR was an independent prognostic marker of breast cancer outcome in 22 of 46 (48%) previous studies that performed multivariate analyses. Most studies used cut-points of 1% or 10% nuclear positivity. Herein, neither 1% nor 10% cut-points were robustly prognostic. ROC analysis revealed that a higher AR cut-point (78% positivity) provided optimal sensitivity and specificity to predict breast cancer survival in the training (HR, 0.41; P = 0.015) and validation (HR, 0.50; P = 0.014) cohorts. Tenfold cross-validation confirmed the robustness of this AR cut-point. Patients with ERα-positive tumors and AR positivity ≥78% had the best survival in both cohorts (P < 0.0001). Among the combined ERα-positive cases, those with comparable or higher levels of AR (AR:ERα-positivity ratio >0.87) had the best outcomes (P < 0.0001).Conclusions: This study defines an optimal AR cut-point to reliably predict breast cancer survival. Testing this cut-point in prospective cohorts is warranted for implementation of AR as a prognostic factor in the clinical management of breast cancer. Clin Cancer Res; 24(10); 2328–41. ©2018 AACR.

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Supplementary Methods

Supplementary Figures 1-3

Purpose:Combination therapy with reduced-dose programmed death 1 inhibitor plus standard-dose cytotoxic T-lymphocyte–associated antigen 4 inhibitor demonstrated efficacy, but substantial toxicity, in melanoma. We present long-term results of part 1B of KEYNOTE-029, which assessed safety and efficacy of standard-dose pembrolizumab plus reduced-dose ipilimumab in advanced melanoma.Patients and Methods:Part 1B was an expansion cohort of the open-label, phase Ib portion of KEYNOTE-029. Eligible patients had advanced melanoma and no previous immune checkpoint inhibitor therapy. Patients received pembrolizumab 2 mg/kg (amended to 200 mg) every 3 weeks plus ipilimumab 1 mg/kg every 3 weeks (four cycles), then pembrolizumab alone for up to 2 years. Primary end point was safety; secondary end points included objective response rate (ORR), progression-free survival (PFS), duration of response (DOR), and overall survival (OS).Results:A total of 153 patients received at least one dose of pembrolizumab plus ipilimumab. At a median follow-up of 36.8 months, 71.9% had received four doses of ipilimumab and 30.7% had completed 2 years of pembrolizumab; 26.1% completed both treatments. Treatment-related adverse events occurred in 96.1% (47.1% grade 3/4; no deaths), leading to discontinuation of one or both study drugs in 35.9%. ORR was 62.1% with 42 (27.5%) complete and 53 (34.6%) partial responses. Median DOR was not reached; 36-month ongoing response rate was 84.2%. Median PFS and OS were not reached; 36-month rates were 59.1% and 73.4%, respectively.Conclusions:Standard-dose pembrolizumab plus reduced-dose ipilimumab demonstrated robust antitumor activity, durable response, and favorable long-term survival with manageable toxicity.

Supplementary Methods, Tables 1-3, Figures 1-4 from Hedgehog Overexpression Is Associated with Stromal Interactions and Predicts for Poor Outcome in Breast Cancer

Fanconi anaemia due to biallelic loss of BRCA2 (Fanconi anaemia subtype D1) is traditionally diagnosed during childhood with cancer rates historically reported as 97% by 5.2 years. This report describes an adult woman with a history of primary ovarian failure, who was diagnosed with gastrointestinal adenocarcinoma and BRCA2-associated Fanconi anaemia at 23 years of age, only after she suffered severe chemotherapy toxicity. The diagnostic challenges include atypical presentation, initial false-negative chromosome fragility testing and variant classification. It highlights gastrointestinal adenocarcinoma as a consideration for adults with biallelic BRCA2 pathogenic variants with implications for surveillance. After over 4 years, the patient has no evidence of gastrointestinal cancer recurrence although the tumour was initially considered only borderline resectable. The use of platinum-based chemotherapy, to which heterozygous BRCA2 carriers are known to respond, may have had a beneficial anticancer effect, but caution is advised given its extreme immediate toxicity at standard dosing. Fanconi anaemia should be considered as a cause for women with primary ovarian failure of unknown cause and referral to cancer genetic services recommended when there is a family history of cancer in the hereditary breast/ovarian cancer spectrum.

PURPOSE: Fear of cancer recurrence (FCR) affects 50%-70% of cancer survivors. This multicenter, single-arm study sought to determine the participant-rated usefulness of an oncologist-delivered FCR intervention. METHODS: Women who completed treatment for early breast cancer (could be receiving endocrine therapy) with baseline FCR > 0 were invited to participate. FCR was measured using a validated 42-item FCR Inventory. The brief oncologist-delivered intervention entailed (1) FCR normalization; (2) provision of personalized prognostic information; (3) recurrence symptoms education, (4) advice on managing worry, and (5) referral to psycho-oncologist if FCR was high. FCR, depression, and anxiety were assessed preintervention (T0), at 1 week (T1), and 3 months (T2) postintervention. The primary outcome was participant-rated usefulness. Secondary outcomes included feasibility and efficacy. RESULTS: Five oncologists delivered the intervention to 61/255 women invited. Mean age was 58 ± 12 years. Mean time since breast cancer diagnosis was 2.5 ± 1.3 years. Forty-three women (71%) were on adjuvant endocrine therapy. Of 58 women who completed T1 assessment, 56 (97%) found the intervention to be useful. FCR severity decreased significantly at T1 (F = 18.5, effect size = 0.39, P < .0001) and T2 (F = 24, effect size = 0.68, P < .0001) compared with baseline. There were no changes in unmet need or depression or anxiety. Mean consultation length was 22 minutes (range, 7-47 minutes), and mean intervention length was 8 minutes (range, 2-20 minutes). The intervention was perceived as useful and feasible by oncologists. CONCLUSION: A brief oncologist-delivered intervention to address FCR is useful and feasible, and has preliminary efficacy in reducing FCR. Plans for a cluster randomized trial are underway.

Introduction The coronavirus disease 2019 (COVID-19) pandemic has resulted in a widespread adoption of telehealth (phone and video consultations) in cancer care worldwide. The aim of this study was to determine patient satisfaction with telehealth consultations with their medical oncologist at a tertiary cancer centre in Sydney, Australia. Methods Patients who attended a routine telehealth appointment at the medical oncology outpatient clinic were recruited to complete a questionnaire containing 16 items, each on a 5-point Likert scale regarding satisfaction levels in various aspects of telehealth and their willingness to continue telehealth after the pandemic. Patients were also invited to provide suggestions for improvement. Results In total, 150 patients were invited to participate, and 103 valid questionnaires were returned. Median age was 63 years (range: 25–90), 49% of patients were male, 63% of patients had advanced cancer and 81% were on active treatment. In total, 95% of participants indicated that they were satisfied (score ≥4) with telehealth. 82% of participants preferred to continue telehealth consultations after the coronavirus disease 2019 pandemic, but ideally with a mix of telehealth and in-person consultations. Phone appointments (vs. video, p Discussion Patients were overwhelmingly satisfied with telehealth during the study period and were willing to continue telehealth for some appointments beyond the coronavirus disease 2019 pandemic. More research into the effectiveness, safety and implementation of telehealth to compliment traditional face-to-face services for patient-centred cancer care is required.

Aim: To explore the value of rate of cancer progression (ROP) prior to starting PD-1 inhibitors as a predictive and prognostic biomarker. Materials & methods: Retrospective data of patients with metastatic non-small-cell lung cancer treated with second-line PD-1 inhibitors were collected. Patients were divided into two groups: slow and rapid based on their ROP. Results: A total of 73 patients were eligible. Progression-free survival (PFS) was significantly shorter in rapid ROP, compared with slow (1.7 vs 4.8 months; HR: 2.42; 95% CI: 1.36–4.30; p = 0.008), as was the overall survival (OS; 5.6 vs 18.7 months; HR: 2.30; 95% CI: 1.13–4.69; p = 0.02). Overall response rate (40 vs 17%) was numerically higher in slow ROP than rapid (p = 0.19). PFS/OS did not correlate with the best response to their last chemotherapy or time to progression from previous line of therapy. Presence of a targetable mutation negatively correlated with PFS/OS. Conclusion: ROP prior to starting PD-1 inhibitors correlates with survival. PFS/OS were shorter in rapid ROP.

Modern breast cancer care is a complex multidisciplinary undertaking in which the integrated function of multiple constituent parts is critical, and where changes to one therapeutic component may profoundly influence the delivery and outcomes of another. Oncoplastic and reconstructive breast surgery has evolved in the era of longer survival rates for women with breast cancer and aims to enhance oncological and cosmetic outcomes. However, concurrently there has been an expansion in the indications for post-mastectomy radiation therapy (Abdulkarim et al., 2011; Early Breast Cancer Trialists' Collaborative Group (EBCTCG), 2014; Poortmans et al., 2015; Wang et al., 2011), the recognition of several biologically distinct breast cancer subtypes (Perou et al., 2000; Sørlie et al., 2001, 2003; Cheang et al., 2008, 2009; Sotiriou et al., 2003; Millar et al., 2011; Blows et al., 2010; Schnitt, 2010; Haque et al., 2012; Dai et al., 2015) and the development of recommendations for prophylactic surgery for high-risk women, including BRCA-mutation carriers (James et al., 2006; Domchek et al., 2010). Primary systemic therapy is increasingly utilised yet has varying efficacy depending on tumour biology (Cortazar et al., 2014). In this paper we review the evidence which informs the multidisciplinary team opinion in the era of oncoplastic and reconstructive breast surgery. We aim to describe an optimal multidisciplinary approach which balances competing risks of multimodal therapies to optimise oncological and cosmetic outcomes.

Background: The European Organisation for Research and Treatment of Cancer (EORTC) 1325/KEYNOTE-054 trial assessed pembrolizumab versus placebo in patients with resected high-risk stage III melanoma. At 15-month median follow-up, pembrolizumab improved recurrence-free survival (hazard ratio [HR] 0·57 [98·4% CI 0·43–0·74], p1 mm), IIIB, or IIIC (without in-transit metastasis), and with an Eastern Cooperative Oncology Group performance status of 0 or 1 were eligible. Patients were randomly assigned (1:1) via a central interactive voice response system to receive intravenous pembrolizumab 200 mg or placebo every 3 weeks for up to 18 doses or until disease recurrence or unacceptable toxicity. Randomisation was stratified according to disease stage and region, using a minimisation technique, and clinical investigators, patients, and those collecting or analysing the data were masked to treatment assignment. The two coprimary endpoints were recurrence-free survival in the intention-to-treat (ITT) population and in patients with PD-L1-positive tumours. The secondary endpoint reported here was distant metastasis-free survival in the ITT and PD-L1-positive populations. This study is registered with ClinicalTrials.gov, NCT02362594, and EudraCT, 2014-004944-37. Findings: Between Aug 26, 2015, and Nov 14, 2016, 1019 patients were assigned to receive either pembrolizumab (n=514) or placebo (n=505). At an overall median follow-up of 42·3 months (IQR 40·5–45·9), 3·5-year distant metastasis-free survival was higher in the pembrolizumab group than in the placebo group in the ITT population (65·3% [95% CI 60·9–69·5] in the pembrolizumab group vs 49·4% [44·8–53·8] in the placebo group; HR 0·60 [95% CI 0·49–0·73]; p

Purpose The information women receive about the type and timing of breast reconstruction (BR) from healthcare providers is crucial to help them make an informed decision, and this is particularly important in complex cases and/or high-risk cases. This study sought to provide qualitative insights into Australian women's BR decision-making experiences. Method Twenty-nine women who had received a mastectomy and made decisions about BR, including the type (expander, implant and/or autologous) and timing (immediate, delayed or immediate-delayed), participated in semi-structured telephone interviews. Interviews were analysed thematically using the Framework method. Results Seven themes were identified: 1) information provision and needs; 2) values and preferences; 3) pressure to decide; 4) feasibility (e.g. clinical and/or financial factors); 5) social influence and support; 6) multidisciplinary team and organisational structures; and 7) decision implementation and outcomes. Breast care nurse support, as well as collaboration and communication within multidisciplinary teams were perceived by women as facilitating the BR decision-making process. Conclusions The identified themes offer an in-depth explanation of how a sample of Australian women make BR decisions. The current findings highlight the often limited clinician-patient information-sharing and demonstrate the overarching influence of the multidisciplinary medical team and organisational structures on BR decision-making. Development of in-consult decision-aids and strategies to improve multidisciplinary care are discussed.

PURPOSE The CheckMate 066 trial investigated nivolumab monotherapy as first-line treatment for patients with previously untreated BRAF wild-type advanced melanoma. Five-year results are presented herein. PATIENTS AND METHODS In this multicenter, double-blind, phase III study, 418 patients with previously untreated, unresectable, stage III/IV, wild-type BRAF melanoma were randomly assigned 1:1 to receive nivolumab 3 mg/kg every 2 weeks or dacarbazine 1,000 mg/m2 every 3 weeks. The primary end point was overall survival (OS), and secondary end points included progression-free survival (PFS), objective response rate (ORR), and safety. RESULTS Patients were followed for a minimum of 60 months from the last patient randomly assigned (median follow-up, 32.0 months for nivolumab and 10.9 months for dacarbazine). Five-year OS rates were 39% with nivolumab and 17% with dacarbazine; PFS rates were 28% and 3%, respectively. Five-year OS was 38% in patients randomly assigned to dacarbazine who had subsequent therapy, including nivolumab (n = 37). ORR was 42% with nivolumab and 14% with dacarbazine; among patients alive at 5 years, ORR was 81% and 39%, respectively. Of 42 patients treated with nivolumab who had a complete response (20%), 88% (37 of 42) were alive as of the 5-year analysis. Among 75 nivolumab-treated patients alive and evaluable at the 5-year analysis, 83% had not received subsequent therapy; 23% were still on study treatment, and 60% were treatment free. Safety analyses were similar to the 3-year report. CONCLUSION Results from this 5-year analysis confirm the significant benefit of nivolumab over dacarbazine for all end points and add to the growing body of evidence supporting long-term survival with nivolumab mono-therapy. Survival is strongly associated with achieving a durable response, which can be maintained after treatment discontinuation, even without subsequent systemic therapies.

10013 Background: 5-year follow-up of the phase 3 KEYNOTE-006 study (NCT01866319) showed pembro improved OS vs ipilimumab (ipi) in patients (pts) with advanced melanoma. 3-y OS rate from pembro completion for pts who completed 2 y of pembro was 93.8%. Results with 8 mo of additional follow-up are presented to inform clinical care. Methods: Eligible pts with ipi-naive advanced melanoma, ≤1 prior therapy for BRAF-mutant disease, and ECOG PS 0 or 1 were randomized to pembro 10 mg/kg Q2W or Q3W for ≤2 y or ipi 3 mg/kg Q3W for 4 doses. Pts discontinuing pembro with CR, PR, or SD after ≥94 weeks were considered pts with 2-y pembro. Pts who stopped pembro with SD, PR or CR could receive ≤12 mo of additional pembro (2nd course) upon disease progression if still eligible. ORR was assessed per immune-related response criteria by investigator review. OS was estimated using the Kaplan-Meier method. Pembro arm data were pooled. Post hoc ITT efficacy analyses are shown. Results: Median follow-up from randomization to data cutoff (Jul 31, 2019) was 66.7 mo in the pembro and 66.9 mo in the ipi arms. OS outcomes are shown in Table. For the 103 pts with 2-y pembro (30 CR, 63 PR, 10 SD), median follow-up from completion was 42.9 mo (95% CI, 39.9-46.3).Median DOR was not reached. 36-mo OS from pembro completion was 100% (95% CI, 100.0-100.0) for pts with CR, 94.8% (95% CI, 84.7-98.3) for pts with PR, and 66.7% (95% CI, 28.2-87.8) for pts with SD. 15 pts received 2nd-course pembro; BOR in 1st course was 6 CR, 6 PR, and 3 SD. Median time from end of 1st course to start of 2ndcourse was 24.5 mo (range, 4.9-41.4). Median follow-up in pts who received 2nd-course pembro was 25.3 mo (range, 3.5-39.4). Median duration of 2nd-course pembro was 8.3 mo (range, 1.4-12.6). BOR on 2ndcourse was 3 CR, 5 PR (ongoing responses, 7 pts), 3 SD (ongoing, 2 pts), and 2 PD (1 death); 2 pts pending. Conclusions: Pembro improves the long-term survival vs ipi in pts with advanced melanoma, with all pts who completed therapy in CR still alive at 5 years. Retreatment with pembro at progression in pts who stopped at SD or better can provide additional clinical benefit in a majority of pts. Clinical trial information: NCT01866319. [Table: see text]

Purpose: Combination therapy with reduced-dose programmed death 1 inhibitor plus standard-dose cytotoxic T-lymphocyte–associated antigen 4 inhibitor demonstrated efficacy, but substantial toxicity, in melanoma. We present long-term results of part 1B of KEYNOTE-029, which assessed safety and efficacy of standard-dose pembrolizumab plus reduced-dose ipilimumab in advanced melanoma. Patients and Methods: Part 1B was an expansion cohort of the open-label, phase Ib portion of KEYNOTE-029. Eligible patients had advanced melanoma and no previous immune checkpoint inhibitor therapy. Patients received pembrolizumab 2 mg/kg (amended to 200 mg) every 3 weeks plus ipilimumab 1 mg/kg every 3 weeks (four cycles), then pembrolizumab alone for up to 2 years. Primary end point was safety; secondary end points included objective response rate (ORR), progression-free survival (PFS), duration of response (DOR), and overall survival (OS). Results: A total of 153 patients received at least one dose of pembrolizumab plus ipilimumab. At a median follow-up of 36.8 months, 71.9% had received four doses of ipilimumab and 30.7% had completed 2 years of pembrolizumab; 26.1% completed both treatments. Treatment-related adverse events occurred in 96.1% (47.1% grade 3/4; no deaths), leading to discontinuation of one or both study drugs in 35.9%. ORR was 62.1% with 42 (27.5%) complete and 53 (34.6%) partial responses. Median DOR was not reached; 36-month ongoing response rate was 84.2%. Median PFS and OS were not reached; 36-month rates were 59.1% and 73.4%, respectively. Conclusions: Standard-dose pembrolizumab plus reduced-dose ipilimumab demonstrated robust antitumor activity, durable response, and favorable long-term survival with manageable toxicity.

BackgroundWe have previously reported significantly longer overall survival (OS) with ipilimumab 10 mg/kg versus ipilimumab 3 mg/kg in patients with advanced melanoma, with higher incidences of adverse events (AEs) at 10 mg/kg. This follow-up analysis reports a 5-year update of OS and safety.MethodsThis randomized, multicenter, double-blind, phase III trial included patients with untreated or previously treated unresectable stage III or IV melanoma. Patients were randomly assigned (1:1) to ipilimumab 10 mg/kg or 3 mg/kg every 3 weeks for 4 doses. The primary end point was OS.ResultsAt a minimum follow-up of 61 months, median OS was 15.7 months (95% CI 11.6 to 17.8) at 10 mg/kg and 11.5 months (95% CI 9.9 to 13.3) at 3 mg/kg (HR 0.84, 95% CI 0.71 to 0.99; p=0.04). In a subgroup analysis, median OS of patients with asymptomatic brain metastasis was 7.0 months (95% CI 4.0 to 12.8) in the 10 mg/kg group and 5.7 months (95% CI 4.2 to 7.0) in the 3 mg/kg group. In patients with wild-type or mutantBRAFtumors, median OS was 13.8 months (95% CI 10.2 to 17.0) and 33.2 months (95% CI 19.4 to 45.2) in the 10 mg/kg group, and 11.2 months (95% CI 9.2 to 13.8) and 19.7 months (95% CI 11.6 to 25.3) in the 3 mg/kg group, respectively. The incidence of grade 3/4 treatment-related AEs was 36% in the 10 mg/kg group vs 20% in the 3 mg/kg group, and deaths due to treatment-related AEs occurred in four (1%) and two patients (1%), respectively.ConclusionsThis 61-month follow-up of a phase III trial showed sustained long-term survival in patients with advanced melanoma who started metastatic treatment with ipilimumab monotherapy, and confirmed the significant benefit for those who received ipilimumab 10 mg/kg vs 3 mg/kg. These results suggest the emergence of a plateau in the OS curve, consistent with previous ipilimumab studies.Trial registration numberNCT01515189.

Increasing numbers of metastatic melanoma (MM) patients are receiving immunotherapy treatment, including pembrolizumab, and the impact on their well-being is underexplored. To assess the feasibility of a multimodal supportive care program to MM patients being treated with pembrolizumab. This pre-post-test feasibility cohort study recruited MM participants treated with pembrolizumab: (i) supportive care intervention with usual care and (ii) usual care. The intervention comprised comprehensive medical assessment by supportive care physician (SCP), exercise physiologist (EP), and dietitian then a tailored supportive care program. Programs included exercise, dietary advice, non-invasive complementary therapies, and psychology consultation. Outcome measures included adherence, patient-reported symptoms, anxiety and depression, and toxicity. Descriptive data are reported. We recruited 28 participants: 13 intervention and 15 control; three did not complete the study. Most were male, with median age 66 (range 42–85) years. All intervention participants completed baseline assessments with SCP, EP, and dietitian. Two missed follow-up with EP or dietitian. Symptoms most troubling at baseline were as follows: fatigue (n = 6), sleep (n = 6), general aches and pains (n = 5), and memory (n = 4). All intervention participants were prescribed 16 exercise sessions; 8 (50%) completed all; overall exercise adherence was 85%. Integrative therapies were accessed by 85% (11) participants. Immunotherapy-related adverse event rates were low and SCP consultation identified symptoms not captured by CTCAE 4.0. A holistic supportive care intervention tailored to individual needs is feasible. The symptom burden in MM patients was low. Further investigation of the intervention is warranted, focused on populations with higher symptom burden to improve outcomes.

In HIV-infected individuals on antiretroviral therapy (ART), latent HIV is enriched in CD4 T cells expressing immune checkpoint molecules, in particular programmed cell death-1 (PD-1). We therefore assessed the effect of blocking PD-1 on latency, both in vitro and in vivo.HIV latency was established in vitro following coculture of resting CD4+ T cells with myeloid dendritic cells. Expression of PD-1 was quantified by flow cytometry, and latency assessed in sorted PD-1high and PD-1low/-nonproliferating CD4+ memory T cells. The role of PD-1 in the establishment of latency was determined by adding anti-PD-1 (pembrolizumab) to cocultures before and after infection. In addition, a single infusion of anti-PD-1 (nivolumab) was administered to an HIV-infected individual on ART with metastatic melanoma, and cell-associated HIV DNA and RNA, and plasma HIV RNA were quantified.HIV latency was significantly enriched in PD-1high compared with PD-1low/- nonproliferating, CD4 memory T cells. Sorting for an additional immune checkpoint molecule, T-cell immunoglobulin domain and mucin domain-3, in combination with PD-1, further enriched for latency. Blocking PD-1 prior to HIV infection, in vitro, resulted in a modest but significant decrease in latently infected cells in all donors (n = 6). The administration of anti-PD-1 to an HIV-infected individual on ART resulted in a significant increase in cell-associated HIV RNA in CD4 T cells, without significant changes in HIV DNA or plasma HIV RNA, consistent with reversal of HIV latency.PD-1 contributes to the establishment and maintenance of HIV latency and should be explored as a target, in combination with other immune checkpoint molecules, to reverse latency.

We report a case of isolated immune-related pancreatic exocrine insufficiency in a patient treated with pembrolizumab for metastatic melanoma. This patient presented with explosive diarrhea and was treated with high dose corticosteroids for possible immune-related colitis. However, biopsies from colon and duodenum did not show any histological evidence of colitis/enteritis. Serum amylase and lipase were not elevated. There was no evidence of pancreatitis or pancreatic metastases on imaging. Significantly lower fecal elastase test on two occasions confirmed the diagnosis of pancreatic exocrine insufficiency. He was treated with pancreatic enzyme supplementation with complete resolution of diarrhea. This case reinforces the importance of awareness and anticipation of unusual immune-related adverse events related to checkpoint inhibitors.

BACKGROUND: A phase 2 trial suggested increased overall survival and increased incidence of treatment-related grade 3-4 adverse events with ipilimumab 10 mg/kg compared with ipilimumab 3 mg/kg in patients with advanced melanoma. We report a phase 3 trial comparing the benefit-risk profile of ipilimumab 10 mg/kg versus 3 mg/kg.METHODS: This randomised, double-blind, multicentre, phase 3 trial was done in 87 centres in 21 countries worldwide. Patients with untreated or previously treated unresectable stage III or IV melanoma, without previous treatment with BRAF inhibitors or immune checkpoint inhibitors, were randomly assigned (1:1) with an interactive voice response system by the permuted block method using block size 4 to ipilimumab 10 mg/kg or 3 mg/kg, administered by intravenous infusion for 90 min every 3 weeks for four doses. Patients were stratified by metastasis stage, previous treatment for metastatic melanoma, and Eastern Cooperative Oncology Group performance status. The patients, investigators, and site staff were masked to treatment assignment. The primary endpoint was overall survival in the intention-to-treat population and safety was assessed in all patients who received at least one dose of study treatment. This study is completed and was registered with ClinicalTrials.gov, number NCT01515189.FINDINGS: Between Feb 29, and July 9, 2012, 727 patients were enrolled and randomly assigned to ipilimumab 10 mg/kg (365 patients; 364 treated) or ipilimumab 3 mg/kg (362 patients; all treated). Median follow-up was 14·5 months (IQR 4·6-42·3) for the ipilimumab 10 mg/kg group and 11·2 months (4·9-29·4) for the ipilimumab 3 mg/kg group. Median overall survival was 15·7 months (95% CI 11·6-17·8) for ipilimumab 10 mg/kg compared with 11·5 months (9·9-13·3) for ipilimumab 3 mg/kg (hazard ratio 0·84, 95% CI 0·70-0·99; p=0·04). The most common grade 3-4 treatment-related adverse events were diarrhoea (37 [10%] of 364 patients in the 10 mg/kg group vs 21 [6%] of 362 patients in the 3 mg/kg group), colitis (19 [5%] vs nine [2%]), increased alanine aminotransferase (12 [3%] vs two [1%]), and hypophysitis (ten [3%] vs seven [2%]). Treatment-related serious adverse events were reported in 133 (37%) patients in the 10 mg/kg group and 66 (18%) patients in the 3 mg/kg group; four (1%) versus two (INTERPRETATION: In patients with advanced melanoma, ipilimumab 10 mg/kg resulted in significantly longer overall survival than did ipilimumab 3 mg/kg, but with increased treatment-related adverse events. Although the treatment landscape for advanced melanoma has changed since this study was initiated, the clinical use of ipilimumab in refractory patients with unmet medical needs could warrant further assessment.FUNDING: Bristol-Myers Squibb.

When a patient receiving anti-cancer treatment presents acutely unwell, an understanding of associated side effects of their therapy is critical. This review will discuss the approach to patients receiving anti-cancer treatment with immunotherapy presenting with autoimmune toxicities in the emergency setting. These toxicities are commonly referred to as immune-related adverse events (irAE). IrAE might consist of, but are not limited to, dermatologic, gastrointestinal (diarrhoea, colitis), hepatic, endocrine (thyroid dysfunction, hypophysitis, adrenal crisis), renal, ocular and pulmonary toxicity. General principles of managing these irAE in the acute setting will be outlined. Steroid therapy is a critical component of the treatment algorithm, being administered at high doses and for prolonged periods to switch off immune over-activation. Prompt intervention might prevent multi-organ failure and fatality, and allow patients to remain on effective anti-cancer therapy.

Background Immunotherapy agents show anti-cancer activity in several solid cancers. Efficacy in non-melanoma solid tumours for non-approved indications is unknown. Aim To evaluate patient and disease characteristics, rate and duration of response, and toxicity of self-funded pembrolizumab in patients with non-melanoma solid cancers. Method Retrospective review describing outcomes and toxicity of self-funded pembrolizumab in patients with non-melanoma solid cancers treated at Chris O'Brien Lifehouse. Results From April 2015 to December 2015, 21 patients received or were planned to receive self-funded pembrolizumab. The median age was 50 years (16–76), 28 and 10% had an Eastern Cooperative Oncology Group performance status of 2, and 3–4 respectively. Sixty-two percent received at least two to four lines of prior drug treatment. Median follow-up was 3.0 months (range, 0.4–9.6). Fourteen (67%) patients requested pembrolizumab. Pembrolizumab was clinician offered for 7 (33%) patients. Patients who requested pembrolizumab had worse outcomes. Three patients died before receiving pembrolizumab. Of the 18 patients that received at least one dose, a partial response was observed in 3 (17%). Progressive disease occurred in 83%. Four patients received only one cycle of pembrolizumab and died after a median of 27 days (range 13–43). Immune-related adverse events of any grade occurred in 33%. No grade 3–4 events were observed. Conclusion Pembrolizumab was well tolerated. Meaningful responses were observed in 17% of treated patients. Response continues after 5–6.5 months follow-up in 11% and >8 months of follow-up for the other responding patient. Financial impact to the patient can be substantial. Outcomes for 33% were poor with three patients dying prior to receiving therapy and four dying within weeks of receiving one dose. This highlights issues regarding the careful selection of patients, futility of anti-cancer therapy at the end-of-life and patients' perceived benefit of receiving this therapy.

AIMS Apolipoprotein D (ApoD) is a protein that is regulated by androgen and oestrogen, and is a major constituent of breast cysts. Although ApoD has been reported to be a marker of breast cancer, its prognostic importance in invasive breast cancer is unclear. The aim of this study was to investigate the relationship between ApoD protein expression, oestrogen receptor-α (ERα) expression and androgen receptor (AR) expression in predicting breast cancer outcome. METHODS AND RESULTS ApoD levels were measured by the use of immunohistochemistry and video image analysis on tissue sections from a breast cancer cohort (n = 214). We assessed the associations of ApoD expression with disease-free survival (DFS), metastasis-free survival (MFS), and overall survival (OS). We also assessed the relationship between ApoD expression, AR expression and ERα expression in predicting OS. ApoD expression (>1% ApoD positivity) was found in 72% (154/214) of tissues. High ApoD positivity (≥20.7%, fourth quartile) was an independent predictor of MFS and OS, and conferred a 2.2-fold increased risk of developing metastatic disease and a 2.1-fold increased risk of breast cancer-related death. ApoD positivity was not associated with AR or ERα nuclear positivity. However, patients with (≥1%) ERα-positive cancers with low (

BACKGROUND: Pembrolizumab improved progression-free survival and overall survival versus ipilimumab in patients with advanced melanoma and is now a standard of care in the first-line setting. However, the optimal duration of anti-PD-1 administration is unknown. We present results from 5 years of follow-up of patients in KEYNOTE-006. METHODS: KEYNOTE-006 was an open-label, multicentre, randomised, controlled, phase 3 study done at 87 academic institutions, hospitals, and cancer centres in 16 countries. Patients aged at least 18 years with Eastern Cooperative Oncology Group performance status of 0 or 1, ipilimumab-naive histologically confirmed advanced melanoma with known BRAFV600 status and up to one previous systemic therapy were randomly assigned (1:1:1) to intravenous pembrolizumab 10 mg/kg every 2 weeks or every 3 weeks or four doses of intravenous ipilimumab 3 mg/kg every 3 weeks. Treatments were assigned using a centralised, computer-generated allocation schedule with blocked randomisation within strata. Exploratory combination of data from the two pembrolizumab dosing regimen groups was not protocol-specified. Pembrolizumab treatment continued for up to 24 months. Eligible patients who discontinued pembrolizumab with stable disease or better after receiving at least 24 months of pembrolizumab or discontinued with complete response after at least 6 months of pembrolizumab and then progressed could receive an additional 17 cycles of pembrolizumab. Co-primary endpoints were overall survival and progression-free survival. Efficacy was analysed in all randomly assigned patients, and safety was analysed in all randomly assigned patients who received at least one dose of study treatment. Exploratory assessment of efficacy and safety at 5 years' follow-up was not specified in the protocol. Data cutoff for this analysis was Dec 3, 2018. Recruitment is closed; the study is ongoing. This study is registered with ClinicalTrials.gov, number NCT01866319. FINDINGS: Between Sept 18, 2013, and March 3, 2014, 834 patientswere enrolled and randomly assigned to receive pembrolizumab (every 2 weeks, n=279; every 3 weeks, n=277), or ipilimumab (n=278). After a median follow-up of 57·7 months (IQR 56·7-59·2) in surviving patients, median overall survival was 32·7 months (95% CI 24·5-41·6) in the combined pembrolizumab groups and 15·9 months (13·3-22·0) in the ipilimumab group (hazard ratio [HR] 0·73, 95% CI 0·61-0·88, p=0·00049). Median progression-free survival was 8·4 months (95% CI 6·6-11·3) in the combined pembrolizumab groups versus 3·4 months (2·9-4·2) in the ipilimumab group (HR 0·57, 95% CI 0·48-0·67, p

e15125 Background: APL-501 is a humanized monoclonal antibody targeting programmed cell death-1 (PD-1). APL-501 is being evaluated in patients (pts) with advanced recurrent and relapsed solid tumors who had not been previously treated with an immune checkpoint inhibitor in an ongoing 3-part Phase 1 trial (NCT03053466). Herein, we present the emerging pharmacokinetic (PK) and receptor occupancy (RO), safety and preliminary efficacy. Methods: Weight-based dose escalation (1, 3, and 10 mg/kg, Part 1) and Extension (Part 2) has been completed and the study is currently enrolling specific tumor types (MSI-H/dMMR and Carcinoma of Unknown Primary [CUP]) into the Expansion Cohorts (Part 3). Relapsed/refractory solid tumor pts were enrolled in Part 1 and Part 2. Key exclusion criteria included prior therapy targeting PD-1/PD-L1 and uncontrolled CNS metastases. APL-501 was administered IV over 1 hour every 14 days. Serum and PBMCs were collected for PK and RO analysis, respectively. RO was assessed using different T-cell markers measured by flow cytometry of PBMC. Anti-tumor activity was assessed by investigators using RECIST and irRECIST. Safety was assessed using CTCAE, v4.03. Results: As of 31 Dec 2019, 22 pts were enrolled with a mean age of 62.1 (SD: 12.2) years. ECOG PS 0/1 reported at 10/12 pts, respectively. Pts had a median number of 3 prior lines of therapy (range, 1 – 9) and median time to treatment from initial diagnosis was 30.1 months (range, 6.7 – 184.8). Across doses evaluated, APL-501 demonstrated dose proportional PK. One hundred percent (100%) RO was observed across all doses evaluated. No dose limiting toxicities were reported. Fifteen pts (68.2%) had related AEs; two pts (9.1%) had Grade ≥ 3 related AEs to APL-501. Eight pts had stable disease and two pts had partial response by RECIST (esophageal adenocarcinoma and CUP). Seven pts remained on therapy for ≥ 24 weeks. The recommended phase 2 dose (RP2D) has been determined to be 400 mg IV every 14 days (non-weight-based) based on safety and PK modeling. Conclusions: Preliminary results indicate clinical activity of APL-501 in relapsed/refractory malignant disease with a generally tolerable safety profile. The PK and RO profile, across all doses evaluated, appears comparable to marketed PD-1 inhibitors. Continued exploration of APL-501 with the RP2D in CUP and MSI-H/dMMR tumors is being planned. Clinical trial information: NCT03053466 .

12115 Background: FCR affects 50-70% of cancer survivors. There are no validated oncologist-delivered FCR interventions. This multicentre, single-arm study sought to determine the helpfulness, feasibility and efficacy of an oncologist-delivered FCR intervention. Methods: Women were invited to participate if they had completed local treatment, chemotherapy and/or HER2 targeted therapy for early stage breast cancer and had a FCR score >0 on the 42-item FCR Inventory. The brief intervention, delivered by their medical oncologist at routine follow-up, entailed 1) FCR normalisation; 2) provision of personalised prognostic information; 3) take-home education sheet on recurrence symptoms; and 4) advice on managing worry. Consultations were audio-recorded. FCR, need for help, depression and anxiety were assessed before the intervention (T0), and at one week (T1) and three months (T2) after the intervention. Satisfaction with the intervention was assessed at T1. The primary outcome was participant-rated helpfulness. Secondary outcomes included feasibility (response rate, time taken for intervention) and efficacy. Results: Five oncologists delivered the intervention to 61 women (255 women invited; response rate 24%). The mean age was 57 ± 13 years. The mean time since breast cancer diagnosis was 2.5 ± 1.3 years. Forty-three (72%) were on adjuvant hormonal therapy. Overall, 58 women (95%) found the intervention helpful and 59 (98%) would recommend it to others. FCR severity, and the proportion of women with clinically significant FCR decreased significantly over time. There were no significant changes in unmet need, depression, or anxiety. Forty (66%) of consultations were recorded. Mean consultation length was 22 minutes (range 12-37 minutes) and mean intervention length was 9 minutes (3-20 minutes). The intervention was perceived as useful and feasible by oncologists, all of whom have used components of the intervention to help manage FCR in other breast cancer patients. Conclusions: A brief oncologist-delivered intervention to address FCR is helpful and feasible, and has shown preliminary efficacy in reducing FCR. Plans for an implementation study amongst oncologists in Australia are underway. Clinical trial information: ACTRN12618001615279 . [Table: see text]

A Cup of Coffee The secretary looks upset as she types a letter about a patient. “I just wish I could just write a different ending to her story,” she explains. We recognize the psychological impac...

Little is known about the lived experiences of patients with metastatic melanoma undergoing checkpoint inhibitor treatment. We conducted a feasibility study of a supportive care intervention for melanoma patients being treated with pembrolizumab. Here, we report a secondary objective of the study, which was to explore the lived experience of being on pembrolizumab treatment for advanced melanoma. Twenty-eight participants with metastatic melanoma were recruited across two cohorts, all receiving 3-weekly immunotherapy treatment. Semi-structured interviews were conducted with 26 participants once at 9 weeks. Thematic analysis using interpretative phenomenological analysis (IPA) was performed with multiple iterations of data review to achieve consensus. Three overarching themes were identified; here, we report the first and most dominant theme: how metastatic melanoma patients live within uncertain spaces. Although immunotherapy increases overall survival, metastatic melanoma patients live within an uncertain spectrum. They confront uncertainty related to immunotherapy treatment, their disease trajectory, family relationships, and decision-making. Melanoma patients attempt to normalize their lives, engaging in their usual activities. Uncertainty increases prior to active treatment and intensifies during investigation phases. Despite progress in melanoma patient treatment and outcomes, these patients face sustained uncertainty about their disease trajectory.

9503Background: KEYNOTE-006 (NCT01866319) established superiority of pembro over ipi in advanced melanoma. We provide 4-y outcomes, long-term data for pts who completed 2 y pembro, and data for sec...

Aims Accurate assessment of anaplastic lymphoma kinase (ALK) gene rearrangement in non-small-cell lung cancers (NSCLCs) is critical to identify patients who are likely to respond to crizotinib. The aim of this study was to evaluate the ALK/EML4 TriCheck FISH probe in a series of NSCLCs enriched for tumours with equivocal ALK status. Methods and results ALK FISH was prospectively performed on 45 NSCLCs with the ALK/EML4 TriCheck probe (ZytoVision) and the Vysis ALK break-apart probe (Abbott Molecular). ALK immunohistochemistry was performed with 5A4 and D5F3 antibodies. Fourteen cases had equivocal ALK status, based on borderline or focal FISH positivity, an atypical FISH pattern, or discrepancy between ALK FISH and immunohistochemistry. Four of the 14 equivocal cases showed discordance between the two FISH probes. All other cases were concordant. The TriCheck probe showed that, of 31 unequivocal cases, 15 were ALK-rearranged, and 60% of these had EML4 as the translocation partner. Within the group of 14 equivocal cases, 12 showed rearrangement with the Tricheck probe; only one of these showed EML4 rearrangement. Of the six equivocal cases that received crizotinib, four showed clinical benefit. Conclusions The ALK/EML4 TriCheck FISH probe may be useful for the detection of ALK rearrangements, especially in borderline or atypical cases, where an additional unique ALK FISH probe may provide further confirmation of rearrangement.

Ipilimumab has been shown to improve overall survival in patients with advanced melanoma. Ipilimumab acts through immune-modulation, and is recognized to cause potentially severe immune-related adverse events (irAEs) including dermatitis, colitis, thyroiditis, hypophysitis, and hepatitis. The acceptance of ipilimumab as a treatment for metastatic melanoma means patients will continue to be treated with this agent and gastroenterologists will be increasingly called upon to assist in managing severe autoimmune-related hepatitis and colitis. To date, the recommendations for managing irAEs secondary to ipilimumab have been steroids at a moderate dose of prednisolone (1 mg/kg) as well as immunosuppressive agents such as mycophenolate mofetil (MMF) for steroid-refractory hepatitis and infliximab in the management of corticosteroid-refractory colitis. However, the dosing and the duration of immunosuppressive therapy have not been systematically studied in the setting of treating ipilimumab-induced irAEs. Therefore, additional immune-modifying agents and/or a change in dosing may be required to manage severe irAEs unresponsive to existing treatment recommendations. We describe a treatment paradigm illustrated by a series of five patients who experienced irAEs. In three cases of metastatic melanoma, ipilimumab-induced hepatitis was successfully treated with high-dose parenteral pulsed methylprednisolone. In two other melanoma patients with ipilimumab-induced colitis, one patient had satisfactory resolution of his colitis with high-dose corticosteroid therapy alone and the other patient required infliximab infusion. We have reviewed the current literature and management algorithms for ipilimumab-induced irAEs. Treatment options and the rationale for their use are discussed, including the use of pulsed high-dose steroids, MMF, azathioprine and calcineurin inhibitors.

Toxicities of systemic cancer therapies are often less frequently observed in clinical trials than in clinical practice, due to the careful selection of patients with fewer comorbidities. Although guidelines exist for the estimation of chemotherapy dose, clinical factors like age, comorbid illness and extremes of body habitus are not considered in the method of dose calculation, which can result in significant toxicity. We reviewed the referenced clinical trials from which the evidence-based curative-intent cancer treatment protocols were developed for EVIQ, which is an Australian government, online resource. This review shows that a significant proportion of patients in curative-intent clinical trials experience toxicities that result in dose modifications-dose reduction, dose delays or missed doses-despite strict selection criteria and intense monitoring. Thus, even in ideal, clinical-trial settings chemotherapy dose calculation remains imprecise and subject to adjustment as clinically appropriate. In real-world clinical practice, dose alterations or modifications in response to toxicities need to be thoroughly discussed and implemented with clear understanding of the patient with appropriate documentation. This review may be used as a reference in these situations to elaborate the extent of toxicities seen in clinical trials with optimal settings.

Background Targeted therapy and immunotherapy agents for advanced melanoma are associated with novel toxicities. Melanoma clinical nurse consultants (CNCs) provide multifaceted clinical care. . Objectives The objective was to evaluate the type of support, excluding clinic and inpatient care, provided by CNCs for patients not enrolled in a clinical trial. . Methods A prospective review of CNC support provided during a 12-week period was conducted. . Findings From May to August 2015, 105 patients attended clinic, and 72 received CNC support. Initial patient encounters with CNCs were documented (n = 150), as well as additional interactions (n = 291). The most common problem identified per initial encounter was symptom/drug toxicity. The most common therapy-related concern was related to anti-programmed cell death protein 1 immunotherapy and BRAF plus MEK inhibition. CNC interventions commonly involved clinical advice and counseling and care coordination.

Aim Sarcoidosis is a multisystem granulomatous disease. This condition has a documented association with the diagnosis of melanoma and can be induced in melanoma patients receiving anti-neoplastic therapy. We evaluated a case series of melanoma patients who developed immunotherapy-induced sarcoidosis. Methods Three patients with melanoma (n = 1 resected Stage III, n = 2 metastatic) treated with anti-programmed cell death (PD)-1 antibody therapy at two institutions developed biopsy-proven sarcoidosis. We used mass cytometry to determine expression of the relevant chemokine receptors (CR) by peripheral blood mononuclear cells for two of the three patients who developed sarcoidosis and 13 melanoma patients who did not. Blood samples were collected before receiving PD-1 checkpoint inhibitor therapy. Results Immunophenotypic analysis demonstrated abnormally high numbers of circulating Th17.1 (CCR6+CCR4−CXCR3+CCR10−) cells prior to commencing PD-1 checkpoint inhibitor therapy in five of 15 melanoma patients, including both the patients who developed sarcoidosis during the course of therapy. Conclusion Our findings support prior literature implicating Th17.1 cells in the pathogenesis of sarcoidosis. However, we demonstrate these findings in patients with melanoma prior to administration of checkpoint therapy and before the onset of clinically symptomatic sarcoidosis. The identification of elevated Th17.1 cells in melanoma patients who have not developed sarcoidosis may reflect the established association between melanoma and sarcoidosis. With some patients receiving these agents over a prolonged period, the clinical course of immunotherapy-induced sarcoidosis is uncertain.

Summary Background Interim analyses of the phase 3 KEYNOTE-006 study showed superior overall and progression-free survival of pembrolizumab versus ipilimumab in patients with advanced melanoma. We present the final protocol-specified survival analysis. Methods In this multicentre, open-label, randomised, phase 3 trial, we recruited patients from 87 academic institutions, hospitals, and cancer centres in 16 countries (Australia, Austria, Belgium, Canada, Chile, Colombia, France, Germany, Israel, Netherlands, New Zealand, Norway, Spain, Sweden, UK, and USA). We randomly assigned participants (1:1:1) to one of two dose regimens of pembrolizumab, or one regimen of ipilimumab, using a centralised, computer-generated allocation schedule. Treatment assignments used blocked randomisation within strata. Eligible patients were at least 18 years old, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, at least one measurable lesion per Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST v1.1), unresectable stage III or IV melanoma (excluding ocular melanoma), and up to one previous systemic therapy (excluding anti-CTLA-4, PD-1, or PD-L1 agents). Secondary eligibility criteria are described later. Patients were excluded if they had active brain metastases or active autoimmune disease requiring systemic steroids. The primary outcome was overall survival (defined as the time from randomisation to death from any cause). Response was assessed per RECIST v1.1 by independent central review at week 12, then every 6 weeks up to week 48, and then every 12 weeks thereafter. Survival was assessed every 12 weeks, and final analysis occurred after all patients were followed up for at least 21 months. Primary analysis was done on the intention-to-treat population (all randomly assigned patients) and safety analyses were done in the treated population (all randomly assigned patients who received at least one dose of study treatment). Data cutoff date for this analysis was Dec 3, 2015. This study was registered with ClinicalTrials.gov, number NCT01866319. Findings Between Sept 18, 2013, and March 3, 2014, 834 patients with advanced melanoma were enrolled and randomly assigned to receive intravenous pembrolizumab every 2 weeks (n=279), intravenous pembrolizumab every 3 weeks (n=277), or intravenous ipilimumab every 3 weeks (ipilimumab for four doses; n=278). One patient in the pembrolizumab 2 week group and 22 patients in the ipilimumab group withdrew consent and did not receive treatment. A total of 811 patients received at least one dose of study treatment. Median follow-up was 22·9 months; 383 patients died. Median overall survival was not reached in either pembrolizumab group and was 16·0 months with ipilimumab (hazard ratio [HR] 0·68, 95% CI 0·53–0·87 for pembrolizumab every 2 weeks vs ipilimumab; p=0·0009 and 0·68, 0·53–0·86 for pembrolizumab every 3 weeks vs ipilimumab; p=0·0008). 24-month overall survival rate was 55% in the 2-week group, 55% in the 3-week group, and 43% in the ipilimumab group. Interpretation Substantiating the results of the interim analyses of KEYNOTE-006, pembrolizumab continued to provide superior overall survival versus ipilimumab, with no difference between pembrolizumab dosing schedules. These conclusions further support the use of pembrolizumab as a standard of care for advanced melanoma. Funding Merck & Co.

Introduction: Pembro significantly improved OS vs ipi in advanced melanoma in the KEYNOTE-006 study (NCT01866319). We present outcomes from the 5-year follow-up of this study−the longest to date in a randomized phase 3 trial of pembro in advanced cancer. Long-term follow-up for pts completing 2 years of pembro and data for pts treated with a second course (2nd course) of pembro are also reported. Methods: Eligible pts (N=834) were randomly assigned (1:1:1) to pembro 10 mg/kg Q2W or Q3W for up to 2 years or ipi 3 mg/kg Q3W for 4 doses. Eligible pts who completed pembro or stopped for CR and then progressed could receive an additional 12 mo of pembro if they met inclusion criteria. End points included OS and ORR per irRC by investigator review. Pembro completion was defined as discontinuation with CR, PR, or SD after ≥94 weeks of pembro. Results were pooled from the 2 pembro arms. Results: At data cutoff (Dec 3, 2018), median follow-up of surviving pts was 57.7 mo (range, 0.03-62.1). Median OS (95% CI) was 32.7 mo (24.5-41.6) in the combined pembro arms (n=556) and 15.9 mo (13.3-22.0) in the ipi arm (n=278) (HR, 0.73). Five-year OS rates (95% CI) were estimated to be 38.7% (34.2-43.1) and 31.0% (25.3-36.9), respectively. For pts receiving first-line pembro, median OS (95% CI) was 38.7 mo (27.3-50.7) in the combined pembro arms (n=368) and 17.1 mo (13.8-26.2) in the ipi arm (n=181) (HR, 0.73); 5-year OS rates (95% CI) were estimated to be 43.2% (38.0-48.3) and 33.0% (25.8-40.3), respectively. A total of 103 (18.5%) pts completed 2 years of pembro; median survival follow-up from pembro completion was 34.5 mo; OS rate at 36 mo was 93.8%. Of the 103 pts, 76 were progression-free and 27 had PD. Median time from pembro end to progression was 16.8 mo (range, 0.99-33.9). Thirteen pts received 2nd course pembro; best overall response (BOR) in 1st course was 6 CR, 6 PR, and 1 SD. Median duration of 2nd-course pembro was 9.7 mo; BOR on 2nd course was 3 CR, 4 PR, 3 SD, and 1 PD (response assessment was pending for 2 pts). All 3 pts with 2nd-course CR and 2 of 4 with PR had ongoing response; the remaining 2 pts who had 2nd-course PR subsequently progressed. Four pts discontinued 2nd-course treatment before 12 mo (2 due to PD, 1 due to G2 interstitial pneumonia, and 1 due to physician decision). Six pts had grade1/2 TRAEs during 2nd-course pembro; there were no grade 3/4 TRAEs or deaths. Conclusions: Pembro continued to show improved OS vs ipi in 5-year follow-up of pts with advanced melanoma with 43.2% estimated to be alive at 5 years versus 33.0% with ipi. Almost one-fifth of pts completed 2 years of pembro, and 93.8% are estimated to be alive 3 years after pembro completion. Second-course pembro treatment was generally well tolerated and provided additional antitumor activity. These results confirm that 2-year pembro is an effective treatment for pts with advanced melanoma. Citation Format: Caroline Robert, Jacob Schachter, Georgina V. Long, Ana Arance, Jean-Jacques Grob, Laurent Mortier, Adil Daud, Matteo S. Carlino, Catriona McNeil, Michal Lotem, James Larkin, Paul Lorigan, Bart Neyns, Christian U. Blank, Omid Hamid, Teresa M. Petrella, James Anderson, Clemens Krepler, Scott J. Diede, Antoni Ribas. 5-year survival and other long-term outcomes from KEYNOTE-006 study of pembrolizumab (pembro) for ipilimumab (ipi)-naive advanced melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT188.