Search

Supplemental Digital Content is available in the text., Patients with advanced melanoma treated with immune checkpoint inhibitors can experience ongoing disease control after treatment discontinuation without subsequent systemic anticancer therapy. We previously defined a novel outcome, treatment-free survival (TFS), as the time between protocol therapy cessation and subsequent therapy initiation/death. We assessed the effect of established prognostic variables [lactate dehydrogenase (LDH), programmed death ligand 1 status, BRAF mutation status, performance status, and sex] on TFS in different treatment scenarios: treatment until toxicity/progression with frequent early cessation (nivolumab plus ipilimumab), treatment until toxicity/progression with a well-tolerated regimen (nivolumab), and treatment for a short fixed duration (ipilimumab). Data were pooled from 1077 patients with advanced melanoma treated in the CheckMate 069 and 067 trials. TFS was defined as the area between the Kaplan–Meier curves for time to therapy cessation and time to subsequent therapy initiation/death. TFS was estimated by restricted mean (r-mean) survival time at 36 months since randomization. Clinically meaningful TFS (r-mean TFS 3.7–12.7 months) was observed across all patient subgroups. TFS was longest in patients treated with nivolumab plus ipilimumab. The largest differences in r-mean TFS were observed with LDH in the nivolumab plus ipilimumab and ipilimumab treatment groups (TFS difference 4.7 and 4.9 months, respectively). In the nivolumab group, there was little difference in TFS across subgroups (r-mean TFS 3.7–5.5 months). TFS was sensitive to prognostic subgroup differences; however, duration of treatment affected the sensitivity of TFS. These results provide further support for TFS as a clinical outcome measure.

Background In patients with melanoma and asymptomatic brain metastases (MBM), nivolumab plus ipilimumab provided an intracranial response rate of 55%. Here, we present the first report for patients who were symptomatic and/or required corticosteroids and updated data for asymptomatic patients. Methods Patients with measurable MBM, 0.5-3.0 cm, were enrolled into Cohort A (asymptomatic) or Cohort B (stable neurologic symptoms and/or receiving corticosteroids). Nivolumab, 1 mg/kg, and ipilimumab, 3 mg/kg, were given intravenously every 3 weeks ×4, followed by nivolumab, 3 mg/kg, every 2 weeks until progression, unacceptable toxicity, or 24 months. The primary endpoint was intracranial clinical benefit rate (CBR; complete response [CR], partial response [PR], or stable disease ≥6 months). Results Symptomatic patients (N = 18) received a median of one nivolumab and ipilimumab combination dose and had an intracranial CBR of 22.2%. Two of 12 patients on corticosteroids had CR; 2 responded among the 6 not on corticosteroids. Median intracranial progression-free survival (PFS) and overall survival (OS) were 1.2 and 8.7 months, respectively. In contrast, with 20.6 months of follow-up, we confirmed an intracranial CBR of 58.4% in asymptomatic patients (N = 101); median duration of response, PFS, and OS were not reached. No new safety signals were observed. Conclusions Nivolumab plus ipilimumab provides durable clinical benefit for asymptomatic patients with MBM and should be considered for first-line therapy. This regimen has limited activity in MBM patients with neurologic symptoms and/or requiring corticosteroids, supporting the need for alternative approaches and methods to reduce the dependency on corticosteroids. Clinical trial registration. ClinicalTrials.gov, NCT02320058.

Purpose:Neoadjuvant immunotherapy may improve the clinical outcome of regionally advanced operable melanoma and allows for rapid clinical and pathologic assessment of response. We examined neoadjuvant pembrolizumab and high-dose IFNα-2b (HDI) therapy in patients with resectable advanced melanoma.Patients and Methods:Patients with resectable stage III/IV melanoma were treated with concurrent pembrolizumab 200 mg i.v. every 3 weeks and HDI 20 MU/m2/day i.v., 5 days per week for 4 weeks, then 10 MU/m2/day subcutaneously 3 days per week for 2 weeks. Definitive surgery followed, as did adjuvant combination immunotherapy, completing a year of treatment. Primary endpoint was safety of the combination. Secondary endpoints included overall response rate (ORR), pathologic complete response (pCR), recurrence-free survival (RFS), and overall survival (OS). Blood samples for correlative studies were collected throughout. Tumor tissue was assessed by IHC and flow cytometry at baseline and at surgery.Results:A total of 31 patients were enrolled, and 30 were evaluable. At data cutoff (October 2, 2019), median follow-up for OS was 37.87 months (range, 33.2–43.47). Median OS and RFS were not reached. Radiographic ORR was 73.3% [95% confidence interval (CI): 55.5–85.8], with a 43% (95% CI: 27.3–60.1) pCR rate. None of the patients with a pCR have had a recurrence. HDI and pembrolizumab were discontinued in 73% and 43% of patients, respectively. Correlative analyses suggested that intratumoral PD-1/PD-L1 interaction and HLA-DR expression are associated with pCR (P = 0.002 and P = 0.008, respectively).Conclusions:Neoadjuvant concurrent HDI and pembrolizumab demonstrated promising clinical activity despite high rates of treatment discontinuation. pCR is a prognostic indicator.See related commentary by Menzies et al., p. 4133

The association among pathological response, recurrence-free survival (RFS) and overall survival (OS) with neoadjuvant therapy in melanoma remains unclear. In this study, we pooled data from six clinical trials of anti-PD-1-based immunotherapy or BRAF/MEK targeted therapy. In total, 192 patients were included; 141 received immunotherapy (104, combination of ipilimumab and nivolumab; 37, anti-PD-1 monotherapy), and 51 received targeted therapy. A pathological complete response (pCR) occurred in 40% of patients: 47% with targeted therapy and 33% with immunotherapy (43% combination and 20% monotherapy). pCR correlated with improved RFS (pCR 2-year 89% versus no pCR 50%, P

We conducted a randomized phase III trial to evaluate whether adjuvant pembrolizumab for one year (647 patients) improved recurrence-free survival (RFS) or overall survival (OS) in comparison with high-dose IFNα-2b for one year or ipilimumab for up to three years (654 patients), the approved standard-of-care adjuvant immunotherapies at the time of enrollment for patients with high-risk resected melanoma. At a median follow-up of 47.5 months, pembrolizumab was associated with significantly longer RFS than prior standard-of-care adjuvant immunotherapies [HR, 0.77; 99.62% confidence interval (CI), 0.59–0.99; P = 0.002]. There was no statistically significant association with OS among all patients (HR, 0.82; 96.3% CI, 0.61–1.09; P = 0.15). Proportions of treatment-related adverse events of grades 3 to 5 were 19.5% with pembrolizumab, 71.2% with IFNα-2b, and 49.2% with ipilimumab. Therefore, adjuvant pembrolizumab significantly improved RFS but not OS compared with the prior standard-of-care immunotherapies for patients with high-risk resected melanoma. Significance: Adjuvant PD-1 blockade therapy decreases the rates of recurrence, but not survival, in patients with surgically resectable melanoma, substituting the prior standard-of-care immunotherapies for this cancer. See related commentary by Smithy and Shoushtari, p. 599. This article is highlighted in the In This Issue feature, p. 587

Over 90 000 people are expected to be diagnosed with melanoma in the United States this year. The development of brain metastases is particularly difficult to manage. Over the past few years, melanoma patients with multiple unresectable brain metastases for which stereotactic surgery might also not be a viable option have fortunately experienced a dramatic expansion in available management options given improvements made to targeted agents, immunotherapy, and radiotherapy. Whole-brain radiation therapy (WBRT) is a long-standing radiation technique that has become increasingly sophisticated. In this review, we summarize retrospective and prospective studies on individual advances in targeted agents, immunotherapy, and WBRT, highlighting important variables such as overall survival, intracranial progression-free survival, control and response rates, and toxicities. We also discuss the recent integration of these therapies into a multimodality approach, which has shown promise in the clinical setting although toxicities have not been insignificant. Finally, we describe ongoing prospective trials relevant to melanoma with brain metastases, and we conclude with our own thoughts on the optimal approach for these patients.

PURPOSE Phase III adjuvant trials have reported significant benefits in both relapse-free survival (RFS) and overall survival (OS) for high-dose interferon alfa (HDI) and ipilimumab at 10 mg/kg (ipi10). E1609 evaluated the safety and efficacy of ipilimumab at 3 mg/kg (ipi3) and ipi10 versus HDI. PATIENTS AND METHODS E1609 was a phase III trial in patients with resected cutaneous melanoma (American Joint Committee on Cancer 7th edition stage IIIB, IIIC, M1a, or M1b). It had 2 coprimary end points: OS and RFS. A 2-step hierarchic approach first evaluated ipi3 versus HDI followed by ipi10 versus HDI. RESULTS Between May 2011 and August 2014, 1,670 adult patients were centrally randomly assigned (1:1:1) to ipi3 (n = 523), HDI (n = 636), or ipi10 (n = 511). Treatment-related adverse events grade ≥ 3 occurred in 37% of patients receiving ipi3, 79% receiving HDI, and 58% receiving ipi10, with adverse events leading to treatment discontinuation in 35%, 20%, and 54%, respectively. Comparison of ipi3 versus HDI used an intent-to-treat analysis of concurrently randomly assigned patient cases (n = 1,051) and showed significant OS difference in favor of ipi3 (hazard ratio [HR], 0.78; 95.6% repeated CI, 0.61 to 0.99; P = .044; RFS: HR, 0.85; 99.4% CI, 0.66 to 1.09; P = .065). In the second step, for ipi10 versus HDI (n = 989), trends in favor of ipi10 did not achieve statistical significance. Salvage patterns after melanoma relapse showed significantly higher rates of ipilimumab and ipilimumab/anti–programmed death 1 use in the HDI arm versus ipi3 and ipi10 ( P ≤ .001). CONCLUSION Adjuvant therapy with ipi3 benefits survival versus HDI; for the first time to our knowledge in melanoma adjuvant therapy, E1609 has demonstrated a significant improvement in OS against an active control regimen. The currently approved adjuvant ipilimumab dose (ipi10) was more toxic and not superior in efficacy to HDI.

BackgroundA first-in-human, randomized pilot phase II clinical trial combining vaccines targeting overexpressed, non-mutated tumor blood vessel antigens (TBVA) and tyrosine kinase inhibitor dasatinib was conducted in human leukocyte antigen (HLA)-A2+ patients with advanced melanoma.MethodsPatient monocyte-derived type-1-polarized dendritic cells were loaded with HLA-A2-presented peptides derived from TBVA (DLK1, EphA2, HBB, NRP1, RGS5, TEM1) and injected intradermally as a vaccine into the upper extremities every other week. Patients were randomized into one of two treatment arms receiving oral dasatinib (70 mg two times per day) beginning in week 5 (Arm A) or in week 1 (Arm B). Trial endpoints included T cell response to vaccine peptides (interferon-γ enzyme-linked immunosorbent spot), objective clinical response (Response Evaluation Criteria in Solid Tumors V.1.1) and exploratory tumor, blood and serum profiling of immune-associated genes/proteins.ResultsSixteen patients with advanced-stage cutaneous (n=10), mucosal (n=1) or uveal (n=5) melanoma were accrued, 15 of whom had previously progressed on programmed cell death protein 1 (PD-1) blockade. Of 13 evaluable patients, 6 patients developed specific peripheral blood T cell responses against ≥3 vaccine-associated peptides, with further evidence of epitope spreading. All six patients with specific CD8+ T cell response to vaccine-targeted antigens exhibited evidence of T cell receptor (TCR) convergence in association with preferred clinical outcomes (four partial response and two stabilization of disease (SD)). Seven patients failed to respond to vaccination (one SD and six progressive disease). Patients in Arm B (immediate dasatinib) outperformed those in Arm A (delayed dasatinib) for immune response rate (IRR; 66.7% vs 28.6%), objective response rate (ORR) (66.7% vs 0%), overall survival (median 15.45 vs 3.47 months; p=0.0086) and progression-free survival (median 7.87 vs 1.97 months; p=0.063). IRR (80% vs 25%) and ORR (60% vs 12.5%) was greater for females versus male patients. Tumors in patients exhibiting response to treatment displayed (1) evidence of innate and adaptive immune-mediated inflammation and TCR convergence at baseline, (2) on-treatment transcriptional changes associated with reduced hypoxia/acidosis/glycolysis, and (3) increased inflammatory immune cell infiltration and tertiary lymphoid structure neogenesis.ConclusionsCombined vaccination against TBVA plus dasatinib was safe and resulted in coordinating immunologic and/or objective clinical responses in 6/13 (46%) evaluable patients with melanoma, particularly those initiating treatment with both agents.Trial registration numberNCT01876212.

Summary Background Combination nivolumab plus ipilimumab was efficacious in patients with asymptomatic melanoma brain metastases (MBM) in CheckMate 204, but showed low efficacy in patients with symptomatic MBM. Here, we provide final 3-year follow-up data from the trial. Methods This open-label, multicentre, phase 2 study (CheckMate 204) included adults (aged ≥18 years) with measurable MBM (0·5–3·0 cm in diameter). Asymptomatic patients (cohort A) had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 and no neurological symptoms or baseline corticosteroid use; symptomatic patients (cohort B) had an ECOG performance status of 0–2 with stable neurological symptoms and could be receiving low-dose dexamethasone. Nivolumab 1 mg/kg plus ipilimumab 3 mg/kg was given intravenously every 3 weeks for four doses, followed by nivolumab 3 mg/kg every 2 weeks for up to 2 years, until disease progression or unacceptable toxicity. The primary endpoint was intracranial clinical benefit rate (complete responses, partial responses, or stable disease lasting ≥6 months) assessed in all treated patients. Intracranial progression-free survival and overall survival were key secondary endpoints. This study is registered with ClinicalTrials.gov , NCT02320058 . Findings Between Feb 19, 2015, and Nov 1, 2017, 119 (72%) of 165 screened patients were enrolled and treated: 101 patients were asymptomatic (cohort A; median follow-up 34·3 months [IQR 14·7–36·4]) and 18 were symptomatic (cohort B; median follow-up 7·5 months [1·2–35·2]). Investigator-assessed intracranial clinical benefit was observed in 58 (57·4% [95% CI 47·2–67·2]) of 101 patients in cohort A and three (16·7% [3·6–41·4]) of 18 patients in cohort B; investigator-assessed objective response was observed in 54 (53·5% [43·3–63·5]) patients in cohort A and three (16·7% [3·6–41·4]) patients in cohort B. 33 (33%) patients in cohort A and three (17%) patients in cohort B had an investigator-assessed intracranial complete response. For patients in cohort A, 36-month intracranial progression-free survival was 54·1% (95% CI 42·7–64·1) and overall survival was 71·9% (61·8–79·8). For patients in cohort B, 36-month intracranial progression-free survival was 18·9% (95% CI 4·6–40·5) and overall survival was 36·6% (14·0–59·8). The most common grade 3–4 treatment-related adverse events (TRAEs) were increased alanine aminotransferase and aspartate aminotransferase (15 [15%] of 101 patients each) in cohort A; no grade 3 TRAEs occurred in more than one patient each in cohort B, and no grade 4 events occurred. The most common serious TRAEs were colitis, diarrhoea, hypophysitis, and increased alanine aminotransferase (five [5%] of each among the 101 patients in cohort A); no serious TRAE occurred in more than one patient each in cohort B. There was one treatment-related death (myocarditis in cohort A). Interpretation The durable 3-year response, overall survival, and progression-free survival rates for asymptomatic patients support first-line use of nivolumab plus ipilimumab. Symptomatic disease in patients with MBM remains difficult to treat, but some patients achieve a long-term response with the combination. Funding Bristol Myers Squibb.

BackgroundThe impact of immune-related adverse events (irAEs) occurring from adjuvant use of immunotherapy and of their management on relapse-free survival (RFS) and overall survival (OS) outcomes is currently not well understood.Patients and methodsE1609 enrolled 1673 patients with resected high-risk melanoma and evaluated adjuvant ipilimumab 3 mg/kg (ipi3) and 10 mg/kg (ipi10) versus interferon-α. We investigated the association of irAEs and of use of immunosuppressants with RFS and OS for patients treated with ipilimumab (n=1034).ResultsOccurrence of grades 1–2 irAEs was associated with RFS (5 years: 52% (95% CI 47% to 56%) vs 41% (95% CI 31% to 50%) with no AE; p=0.006) and a trend toward improved OS (5 years: 75% (95% CI 71% to 79%) compared with 67% (95% CI 56% to 75%) with no AE; p=0.064). Among specific irAEs, grades 1–2 rash was most significantly associated with RFS (p=0.002) and OS (p=0.003). In multivariate models adjusting for prognostic factors, the most significant associations were seen for grades 1–2 rash with RFS (pConclusionsRash and endocrine irAEs were independent prognostic factors of RFS and OS in patients treated with adjuvant ipilimumab. Patients experiencing lower grade irAEs derived the most benefit, but we found no significant evidence supporting a negative impact of high dose corticosteroids and immunosuppressants more commonly used to manage grades 3–4 irAEs.

Aim: To describe treatment patterns and outcomes of patients with unresectable stage III and metastatic/stage IV melanoma. Materials & methods: An observational retrospective chart review of patients diagnosed with advanced melanoma before 1 November 2015 who initiated a new line of therapy (LOT) from 1 January 2015 to 31 May 2016. Results: Among 487 patients, ipilimumab monotherapy (27.5%) was the most common first line of therapy (1LOT) in 2015, surpassed by nivolumab monotherapy (21.5%) in 2016. 12-month survival was ≥80.1%; proportions were highest forpatients treated with nivolumab + ipilimumab (86.6%). All treatments relatively well tolerated in real-world setting and adverse events were consistent with the previously reported safety profiles. Conclusion: This study provides important insights into real-world advanced melanoma treatment patterns and demonstrates encouraging treatment safety and patient survival data.

Aim: The cost–effectiveness of treatment sequences in BRAF-mutant advanced melanoma. Materials & methods: A discrete event simulation model was developed to estimate total costs and health outcomes over a patient's lifetime (30 years). Efficacy was based on the CheckMate 067/069 trials and a matching-adjusted-indirect comparison between immuno-oncology and targeted therapies. Safety, cost (in US dollars; US third-party payer perspective) and health-related quality-of-life inputs were based on published literature. Results: Estimated survival gain was higher for sequences initiating with anti-PD-1 + anti-CTLA-4 than for anti-PD-1 monotherapy or BRAF+MEK inhibitors. The incremental cost–effectiveness ratio per QALY gained for first-line anti-PD-1 + anti-CTLA-4 was US$54,273 versus first-line anti-PD-1 and $79,124 versus first-line BRAF+MEK inhibitors. Conclusion: Initiating treatment with anti-PD-1 + anti-CTLA-4 was more cost–effective than initiation with anti-PD-1 monotherapy or BRAF+MEK inhibitors.

Aim: To estimate incidence of stage III melanoma using the American Joint Committee on Cancer (AJCC) staging, 7th and 8th edition. Patients & methods: The SEER US cancer registry was analyzed (2010–2014). AJCC7 stages were recorded in the data; AJCC8 stages were inferred. Results: Of 106,195 melanoma patients, 7669 and 7342 had stage III melanoma by AJCC7 and AJCC8, respectively (95% overlap). Nearly 30% of patients with AJCC7 stage III melanoma were reclassified in a higher stage III group by AJCC8 versus 7% in lower stage group. Regardless of the AJCC edition, incidence of stage III melanoma has increased from 2010 to 2014 both overall and within each stage III group. Conclusion: Providing appropriate management to this growing population of high-risk patients is a priority.

Purpose: Interferon-α favors a Th1 shift in immunity, and combining with ipilimumab (ipi) at 3 or 10 mg/kg may downregulate CTLA4-mediated suppressive effects, leading to more durable antitumor immune responses. A study of tremelimumab and high-dose interferon-α (HDI) showed promising efficacy, supporting this hypothesis. Patients and Methods: E3611 followed a 2-by-2 factorial design (A: ipi10+HDI; B: ipi10; C: ipi3+HDI; D: ipi3) to evaluate (i) no HDI versus HDI (across ipilimumab doses) and (ii) ipi3 versus ipi10 (across HDI status). We hypothesized that median progression-free survival (PFS) would improve from 3 to 6 months with HDI versus no HDI and with ipi10 versus ipi3. Results: For eligible and treated patients (N = 81) at a median follow-up time of 29.8 months, median PFS was 4.4 months [95% confidence interval (CI), 2.7–8.2] when ipilimumab was used alone and 7.5 months (95% CI, 5.1–11.0) when HDI was added. Median PFS was 3.8 months (95% CI, 2.6–7.5) with 3 mg/kg ipilimumab and 6.5 months (95% CI, 5.1–13.5) with 10 mg/kg. By study arm, median PFS was 8.0 months (95% CI, 2.8–20.2) in arm A, 6.2 months (95% CI, 2.7–25.7) in B, 5.7 months (95% CI, 1.5–11.1) in C, and 2.8 months (95% CI, 2.6–5.7) in D. The differences in PFS and overall survival (OS) did not reach statistical significance. Adverse events were consistent with the known profiles of ipilimumab and HDI and significantly higher with HDI and ipi10. Conclusions: Although PFS was increased, the differences resulting from adding interferon-α or a higher dose of ipilimumab did not reach statistical significance and do not outweigh the added toxicity risks.

Objective: To describe treatment trends and outcomes of liver metastasis from uveal melanoma. Methods: Retrospective case series of 73 patients with uveal melanoma liver metastasis. Patients were treated first-line with systemic therapy (not including checkpoint inhibitors), checkpoint inhibitors, local therapy or no treatment. Time to metastasis, detection method, and survival data were collected. Time periods were divided between 2004–2011 and 2012–2016. Cox proportional hazards models were used to compare progression-free survival (PFS) and overall survival (OS). Results: Median PFS and OS for the entire cohort was 4 months (95% CI 3–5) and 15 months (95% CI 11–18), respectively. There was no statistically significant difference in PFS and OS across the two time periods. Patients who received no treatment had the shortest OS (median 4.9 months), whereas those treated with local therapy had the longest PFS (median 4.6 months) and OS (median 18.7 months). Having liver metastasis diagnosed by symptoms was associated with a greater risk of mortality (p < 0.001). Conclusion: Patients who received first-line local treatment had the longest PFS and OS, while patients who received no treatment had the shortest OS. Survival outcomes did not improve for patients including those receiving check point inhibitors.

Supplemental Digital Content is available in the text., Surgery is the mainstay treatment for operable nonmetastatic melanoma, but recurrences are common and limit patients’ survival. This study aimed to describe real-world patterns of treatment and recurrence in patients with melanoma and to quantify healthcare resource utilization (HRU) and costs associated with episodes of locoregional/distant recurrences. Adults with nonmetastatic melanoma who underwent melanoma lymph node surgery were identified from the Truven Health MarketScan database (1 January 2008 to 31 July 2017). Locoregional and distant recurrence(s) were identified on the basis of postsurgery recurrence indicators (i.e. initiation of new melanoma pharmacotherapy, new radiotherapy, or new surgery; secondary malignancy diagnoses). Of 6400 eligible patients, 219 (3.4%) initiated adjuvant therapy within 3 months of surgery, mostly with interferon α-2b (n=206/219, 94.1%). A total of 1191/6400 (18.6%) patients developed recurrence(s) over a median follow-up of 23.1 months (102/6400, 1.6% distant recurrences). Among the 219 patients initiated on adjuvant therapy, 73 (33.3%) experienced recurrences (distant recurrences: 13/219, 5.9%). The mean total all-cause healthcare cost was $2645 per patient per month (PPPM) during locoregional recurrence episodes and $12 940 PPPM during distant recurrence episodes. In the year after recurrence, HRU was particularly higher in patients with distant recurrence versus recurrence-free matched controls: by 9.2 inpatient admissions, 54.4 inpatient days, 8.8 emergency department admissions, and 185.9 outpatient visits (per 100 person-months), whereas all-cause healthcare costs were higher by $14 953 PPPM. It remains to be determined whether the new generation of adjuvant therapies, such as immune checkpoint inhibitors and targeted agents, will increase the use of adjuvant therapies, and reduce the risk of recurrences and associated HRU/cost.

BACKGROUND Interleukin 2 (IL-2) is a growth factor for T and natural killer cells, promotes proinflammatory cytokines, and can lead to durable responses in patients with melanoma. Vascular endothelial growth factor (VEGF) promotes angiogenesis and modulates host innate and adaptive immunity. High VEGF levels were found to be associated with nonresponse to IL-2. Ziv-aflibercept may deplete VEGF and thereby enhance antitumor T-cell responses, thus supporting a combination immunotherapeutic strategy with IL-2. METHODS NCI 8628 was a phase 2 trial of ziv-aflibercept and IL-2 (arm A) versus IL-2 alone (arm B) randomized at 2:1, respectively. Eligible patients had inoperable American Joint Committee on Cancer stage III or stage IV melanoma. The primary endpoint was progression-free survival (PFS). RESULTS A total of 89 patients were enrolled and 84 patients were treated. The median follow-up was 41.4 months. Among treated patients (55 patients in arm A and 29 patients in arm B), PFS was significantly improved in favor of arm A, with a median of 6.9 months (95% confidence interval [95% CI], 4.1-8.7 months) versus 2.3 months (95% CI, 1.6-3.5 months) (P

Background Neoadjuvant immunotherapy utilizing novel combinations has the potential to transform the standard of care for locally/regionally advanced melanoma. We hypothesized that neoadjuvant ipilimumab in combination with high dose IFNα2b (HDI) is safe and associated with durable pathologic complete responses (pCR). Methods Patients with locally/regionally advanced melanoma were randomized to ipilimumab 3 or 10 mg/kg × 4 doses bracketing definitive surgery, then every 12 weeks × 4. HDI was given concurrently. We evaluated the safety and efficacy of the combination with ipilimumab 3 or 10 mg/kg. The impact on T-cell fraction and clonality were investigated in tumor and blood. Results Thirty patients (age 37–76), 15 each at 3 and 10 mg/kg, 18 male and 12 female were treated. Considering immune related adverse events (irAEs) of interest, more grade 3/4 irAEs were seen with ipilimumab 10 mg/kg versus 3 mg/kg (p = 0.042). Among 28 evaluable patients, 11 relapsed, of whom 5 died. Median follow-up for 17 patients who have not relapsed was 32 months. The radiologic preoperative response rate was 36% (95% CI, 21–54); 4 patients at ipilimumab 3 mg/kg and 6 at 10 mg/kg and 2 (at 10 mg/kg) later relapsed. The pCR was 32% (95% CI, 18–51); 5 patients at ipilimumab 3 mg/kg and 4 at 10 mg/kg and one (at 3 mg/kg) had a late relapse. In patients with pCR, T-cell fraction was significantly higher when measured in primary melanoma tumors (p = 0.033). Higher tumor T-cell clonality in primary tumor and more so following neoadjuvant therapy was significantly associated with improved relapse free survival. Conclusions Neoadjuvant ipilimumab-HDI was relatively safe and exhibited promising tumor response rates with an associated measurable impact on T-cell fraction and clonality. Most pCRs were durable supporting the value of pCR as a primary endpoint in neoadjuvant immunotherapy trials. Trial registration ClinicalTrials.gov, NCT01608594. Registered 31 May 2012. Electronic supplementary material The online version of this article (10.1186/s40425-018-0428-5) contains supplementary material, which is available to authorized users.

Aim: To evaluate the cost–effectiveness of treatment sequences with checkpoint inhibitors in patients with BRAF wild-type melanoma. Materials & methods: Using a discrete event simulation model, cost and health outcomes were estimated. Pooled data from CheckMate 067/069 trials were used to calculate survival outcomes including treatment-free interval extrapolated over a patient's lifetime. Costs accounted for treatment, administration, toxicity, and disease management. Results: First-line anti-PD-1 + anti-CTLA-4 initiating sequences had the highest estimated mean survival gain (7.6–7.7 years), driven by a longer estimated mean treatment-free interval (5.3 years). Incremental costs per incremental quality-adjusted life year gained for anti-PD-1 + anti-CTLA-4 followed by chemotherapy were US$30,955 versus anti-PD-1 initiating sequences, within the willingness-to-pay threshold. Conclusion: Anti-PD-1 + anti-CTLA-4 initiating sequences for BRAF wild-type melanoma are cost-effective versus anti-PD-1.

as adjuvant therapy for high-risk melanoma was extensively studied in regimens that varied by dosage, route of administration, formulation, and therapy duration. The high-dose regimen (HDI) showed significant improvements in relapse-free survival (RFS) in 3 trials and overall survival (OS) in 2. Ipilimumab at 3 mg/kg demonstrated significant OS benefits compared with HDI and less toxicity compared with ipilimumab at 10 mg/kg. More recently, the standard of care has changed in favor of nivolumab and pembrolizumab and BRAF-MEK inhibitors dabrafenib plus trametinib (for BRAF mutated melanoma), based on significant RFS benefits and more favorable toxicity profiles.

Background Patients with BRAF mutant advanced melanoma can be treated sequentially with immunotherapies (IO) and BRAF+MEK inhibitors. We evaluated the clinical outcomes associated with various treatment sequences for BRAF mutant advanced melanoma based on the 5-year follow-up data from clinical trials. Methods In the absence of head-to-head trial data, a matching-adjusted indirect comparison (MAIC) was conducted for IO vs. BRAF+MEK inhibitors, using the longest follow-up available in the published literature. Multivariate risk equations were developed to predict time-to-event outcomes based on patient-level data from pooled CheckMate-067 &-069 trials. Risk equations were inserted into a discrete event simulation to estimate the average life-years (LYs) and quality-adjusted life-years (QALYs) that can be gained with various treatment sequences over a lifetime horizon. Treatment sequences and corresponding efficacy data sources are presented below (table 1). Utility weights for quality-adjustment of LYs were obtained from published literature. Results Treatment sequences starting with IO followed by BRAF+MEK were associated with 2.9–4.3 years of additional survival and 2.2–3.3 years of quality-adjusted survival versus sequences starting with BRAF+MEK followed by anti-PD-1. After 1L IO, the time spent in the treatment-free interval (TFI) is 3.3–5.0 years. LYs, QALYs, and time spent in TFI were higher with sequences starting with anti-PD-1+anti-CTLA-4 vs. anti-PD-1 alone. Conclusions In this sequencing model with 5-year data from randomized clinical trials, initiating 1L treatment with IO provided prolonged survival compared to initiating 1L treatment with BRAF+MEK. Time spent in TFI represents a significant proportion of survival time for patients on IO initiating sequences. Limitations of the study are the reliance on published information for BRAF+MEK, which could lead to biases due to unmeasured differences in the patient populations or trial conduct and the absence of data on 2L combination IO. Anti-PD-1+anti-CTLA-4 as second line option has not been included because of a lack of clinical evidence. Findings from this analysis will require validation in ongoing prospective randomized clinical trials.

Background Sex differences in tumor immunity and response to immunotherapy were shown in murine models and descriptive analyses from recent clinical trials. Female sex hormones have been implicated in melanoma development and response to systemic therapy. We hypothesized a gender difference in response to adjuvant immunotherapy with ipilimumab (3 or 10 mg/kg; ipi3 or ipi10) versus high dose IFNα (HDI) as tested in the E1609 trial. Methods E1609 demonstrated significant overall survival (OS) benefit with ipi3 versus HDI.1 We investigated treatment efficacy between ipi and HDI in the subgroups by sex (female, male), age ( Results The subgroups of female, stage IIIC, PS=1, ulcerated, in-transit without lymph node involvement demonstrated significant improvement in overall survival (OS) and/or relapse free survival (RFS) with ipi3 versus HDI as summarized in table 1. Female sex was significant for both OS and RFS and was further explored. In investigating RFS with ipi3 versus HDI, a multivariate Cox regression model including sex, treatment and interaction term of sex*treatment, indicated a significant interaction between sex and treatment (P = 0.026). Including sex, PS (0 vs. 1), age ( Conclusions Female sex was independently associated with RFS adjuvant immunotherapeutic benefit from ipi3, supporting a potentially important role for female related factors in the immune response against melanoma, and these warrant further investigation. Trial Registration NCT01274338 Ethics Approval The study protocol was approved by the institutional review board (IRB) of each participating institution and conducted in accordance with Good Clinical Practice guidelines as defined by the International Conference on Harmonisation. This study was monitored by the ECOG-ACRIN DataSafety Monitoring Committee and the NCI. Consent All patients provided IRB-approved written informed consent. Reference Tarhini AA, Lee SJ, Hodi FS, Rao UNM, Cohen GI, Hamid O, Hutchins LF, Sosman JA, Kluger HM, Eroglu Z, Koon HB, Lawrence DP, Kendra KL, Minor DR, Lee CB, Albertini MR, Flaherty LE, Petrella TM, Streicher H, Sondak VK, Kirkwood JM. Phase III Study of Adjuvant Ipilimumab (3 or 10 mg/kg) Versus High-Dose Interferon Alfa-2b for Resected High-Risk Melanoma: North American Intergroup E1609. J Clin Oncol. 2020 Feb 20;38(6):567–575. PMID: 31880964.

IMPORTANCE: The optimal sequencing of immune checkpoint inhibitors and targeted therapy for BRAF V600E/K-mutant melanoma is not well established. OBJECTIVE: To assess the association of BRAF wild-type (WT) or BRAF V600E/K-mutant status and BRAF inhibitor (BRAFi) with or without MEK inhibitor (MEKi) therapy with response to pembrolizumab. DESIGN, SETTING, AND PARTICIPANTS: This study is a post hoc subgroup analysis of pooled data from 3 multinational, multisite studies: KEYNOTE-001 (data cutoff September 1, 2017), KEYNOTE-002 (data cutoff May 30, 2018), and KEYNOTE-006 (data cutoff December 4, 2017). Patients included in this analysis were adults with advanced melanoma and known BRAF V600E/K tumor status who had received pembrolizumab. INTERVENTIONS: Patients received pembrolizumab in dosages of 2 mg/kg every 3 weeks, 10 mg/kg every 2 weeks, or 10 mg/kg every 3 weeks. MAIN OUTCOMES AND MEASURES: End points were objective response rate (ORR) and progression-free survival (PFS) assessed by Response Evaluation Criteria in Solid Tumors, version 1.1, and overall survival (OS). Objective response rates, 4-year PFS, and OS rates were compared in the following patient subgroups: BRAF WT vs BRAF V600E/K-mutant melanoma and BRAF V600E/K-mutant melanoma with vs without previous treatment with BRAFi with or without MEKi therapy. RESULTS: The overall study population (N = 1558) included 944 men (60.6%) and 614 women (39.4%). The mean (SD) age was 60.0 years (14.0). The ORR was 38.3% (596/1558), 4-year PFS rate was 22.0%, and 4-year OS rate was 36.9%. For patients with BRAF WT (n = 1124) and BRAF V600E/K-mutant melanoma (n = 434), ORR was 39.8% (n = 447) and 34.3% (n = 149), 4-year PFS rate was 22.9% and 19.8%, and 4-year OS rate was 37.5% and 35.1%, respectively. Patients with BRAF V600E/K-mutant melanoma who had (n = 271) vs had not (n = 163) previously received BRAFi with or without MEKi therapy had baseline characteristics with worse prognosis; ORR was 28.4% (n = 77) and 44.2% (n = 72), 4-year PFS rate was 15.2% and 27.8%, and 4-year OS rate was 26.9% and 49.3%, respectively. CONCLUSIONS AND RELEVANCE: Results of this subgroup analysis support the use of pembrolizumab for treatment of advanced melanoma regardless of BRAF V600E/K mutation status or receipt of prior BRAFi with or without MEKi therapy.

Background: Leptomeningeal disease (LMD) from melanoma is rapidly fatal with median overall survival between 6.9 weeks and 3.5 months. It is not known whether immune checkpoint inhibitors have a role in treating LMD. Case presentation: We report a 33-year-old male patient who developed LMD from a BRAF V600E-mutated melanoma brain metastasis, despite prior treatment with surgical resection, radiotherapy and dabrafenib/trametinib. He underwent whole brain radiotherapy with stereotactic radiotherapy to the lumbosacral spine, and was started on nivolumab, which led to prolonged remission lasting 2 years and 3 months, before disease progression and death. Conclusion: This is the first case report to highlight a potential long-term efficacy of radiotherapy and anti-PD-1 immunotherapy, in treating LMD from metastatic melanoma that is resistant to targeted therapy.

Aim To conduct a systematic literature review of high-risk resectable cutaneous melanoma adjuvant therapeutics and compare safety and efficacy. Methods: The systematic literature review included randomized controlled trials investigating: dabrafenib plus trametinib (DAB + TRAM), nivolumab, pembrolizumab, ipilimumab, vemurafenib, chemotherapy and interferons. Outcomes included overall survival (OS), relapse-free survival, distant metastasis-free survival and safety. All outcomes were synthesized using Bayesian network meta-analysis. Results: Across relapse-free survival, distant metastasis-free survival and OS, DAB + TRAM had the lowest estimated hazards of respective events relative to all other treatments (exception relative to nivolumab in OS). Differences were significant relative to placebo, chemotherapy, interferons and ipilimumab. Conclusion: DAB + TRAM has improved efficacy over historical treatment options (ipilimumab, interferons and chemotherapy) and comparable efficacy with other targeted and immune checkpoint inhibitors.

BackgroundSex differences in tumor immunity and response to immunotherapy were shown in murine models and descriptive analyses from recent clinical trials. We recently reported that female gender is a favorable prognostic marker for survival benefit following ipilimumab and high dose interferon-alfa (HDI) adjuvant therapy of high-risk melanoma in the ECOG-ACRIN E1609 trial (N=1670). Therefore, we investigated differences in candidate immune biomarkers in the circulation and tumor microenvironment (TME) of female and male patients.MethodsGene expression profiling (GEP) was performed on the tumor biopsies of 718 (454 male, 264 female) patients. The primary endpoint was mRNA expression profiling using U133A 2.0 Affymetrix gene chips. Raw microarray data sets were normalized by using the Robust Multi-array Average (RMA) method using Affymetrix Power Tools (APT) as previously published. Multiple probe sets representing the same genes were collapsed by using the probe with maximum gene expression. Gene set enrichment analysis (GSEA) was performed by comparing the female and male tumor samples, and gene sets with FDR q-value ResultsAmong the subset of patients tested for circulating biomarkers, females were significantly younger than males (P=0.03). Testing PBMCs, the percentages of CD3+ T cells (P=0.04) and CD3+CD4+ helper T cells (P=0.0005) were significantly higher in female patients compared to males. Also, there were trends toward higher levels of proinflammatory cytokines IL1beta (P=0.07) and IL6 (P=0.06) in females. On the other hand, males had significantly higher percentages of monocytes (P=0.03). Further, there were trends toward higher percentages of CD3+/CD4+/CD25hi+/Foxp3+ (P=0.1) and CD3+/CD4+/CD25+/CD127low+ (P=0.1) T-reg in male patients compared to females. Among the cohort of patients (N=718) with tumor GEP data, females were significantly younger than males (P=0.0009). GEP identified pathways and genes related to immune cell infiltration and activation that were significantly enriched in the tumors of females compared to males (table 1).Abstract 88 Table 1Immune pathways significantly enriched in tumors of femalesConclusionsFemale gender was associated with adjuvant immunotherapeutic benefits and female patients were more likely to have evidence of immune activation within the TME and the circulation, supporting a potentially important role for female related factors in the immune response against melanoma, and these require further investigation.AcknowledgementsWe are grateful to the patients and family members who participated in the E1609 trial and the E1609 trial investigators. This study was conducted by the ECOG-ACRIN Cancer Research Group (Peter J. O’Dwyer, MD and Mitchell D. Schnall, MD, PhD, Group Co-Chairs) and supported by the National Cancer Institute of the National Institutes of Health under the following award numbers: U10CA180794, U10CA180820, U10CA180888, UG1CA233180, UG1CA233184. Biomarkers studies were supported under the following award number: P50CA12197310 (Tarhini and Kirkwood). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.Trial RegistrationNCT01274338Ethics ApprovalThe E1609 study protocol was approved by the institutional review board of each participating institution and conducted in accordance with Good Clinical Practice guidelines as defined by the International Conference on Harmonization. All patients provided an IRB-approved written informed consent.ConsentNot applicable.

BackgroundTreatment-free survival (TFS) characterizes disease control after discontinuation of immune checkpoint inhibitors (ICIs) until subsequent therapy or death. We previously evaluated TFS in a pooled analysis of the CheckMate 067 and CheckMate 069 trials of the ICIs nivolumab and ipilimumab, alone or in combination, in patients with advanced melanoma after minimum follow-up of 36 months. This analysis investigated TFS differences between treatments in CheckMate 067 after a minimum follow-up of 60 months, and their relation to overall survival (OS) differences.MethodsData were from 937 patients who initiated treatment (nivolumab plus ipilimumab, nivolumab, or ipilimumab) in CheckMate 067 (NCT01844505). TFS was defined as the area between the Kaplan-Meier curves for time to protocol therapy cessation and time to subsequent systemic therapy initiation or death, each measured from randomization. TFS was partitioned as time with and without toxicity. Toxicity included persistent and late-onset grade ≥2 select treatment-related adverse events (ie, those of potential immunologic etiology). The area between Kaplan-Meier curves was estimated by the difference in 60-month restricted-mean times of the endpoints. Between-group differences were estimated with bootstrapped 95% CIs.ResultsAt 60 months from randomization, 39%, 24%, and 11% of patients assigned to treatment with nivolumab plus ipilimumab, nivolumab, and ipilimumab, respectively, had survived and were treatment-free. The 60-month mean TFS was approximately twice as long with the combination (19.7 months) than with nivolumab (9.9 months; absolute difference, 9.8 (95% CI 6.7 to 12.8)) or ipilimumab (11.9 months; absolute difference, 7.8 (95% CI 4.6 to 11.0)). In the respective groups, mean TFS represented 33% (8% with and 25% without toxicity), 17% (2% and 14%), and 20% (3% and 17%) of the 60-month period. Compared with 36-month estimates, mean TFS over the 60-month period represented slightly greater percentages of time in the nivolumab-containing regimen groups and a lesser percentage in the ipilimumab group. TFS differences between the combination and either monotherapy increased with longer follow-up.ConclusionsAlong with improved long-term OS with the nivolumab-containing regimens versus ipilimumab, TFS without toxicity was sustained with nivolumab plus ipilimumab versus either monotherapy, demonstrating larger between-group differences with extended follow-up.

BackgroundWe recently reported data supporting the unknown primary status as a potentially distinct prognostic group among high-risk melanoma patients treated with ipilimumab and high dose interferon-alfa (HDI) in the ECOG-ACRIN E1609 trial (N=1670) with improved RFS and OS outcomes compared to known primary. Therefore, we investigated differences in candidate immune biomarkers in the circulation and tumor microenvironment (TME) of patients with unknown compared to those with known primary melanoma enrolled in this trial that tested adjuvant ipilimumab at 3 and 10 mg/kg versus HDI.MethodsGene expression profiling (GEP) was performed on the tumor biopsies of 718 (102 unknown, 616 known primary) melanoma patients. The primary endpoint was mRNA expression profiling using U133A 2.0 Affymetrix gene chips. Raw microarray data sets were normalized by using the Robust Multi-array Average (RMA) method using Affymetrix Power Tools (APT) as previously published. Multiple probe sets representing the same genes were collapsed by using the probe with maximum gene expression. Gene set enrichment analysis (GSEA) was performed by comparing the unknown and known primary tumor samples, and gene sets with FDR q-value ResultsUnknown primary melanoma cases represented 12.8% of the total E1609 study population (N=1670) including 11.7% on the ipilimumab arms and 14.7% on the HDI arm. Stratifying by stage, relapse free survival (RFS) (P=0.001) and overall survival (OS) (P=0.009) were significantly better for patients with unknown primary tumor compared to known primary. Including only ipilimumab-treated patients, RFS (P=0.005) and OS (P=0.023) were significantly better in favor of the unknown primary status. Among the cohort of patients with tumor GEP data (N=718), GEP identified pathways and genes related to autoimmunity, inflammation, immune cell infiltration and immune activation that were significantly enriched in the unknown primary tumors compared to known primaries (table 1). Among the subset of patients tested for circulating biomarkers, patients with unknown primary melanoma had significantly higher circulating levels of IL-2R than those with known primary (P=0.04).Abstract 87 Table 1Immune pathways enriched in unknown primary melanomaConclusionsUnknown primary high-risk melanoma patients had significantly better prognosis and evidence of significantly enhanced immune activation within the TME and the circulation, supporting the designation of unknown primary melanoma as a distinct prognostic marker in patients with high-risk melanoma.AcknowledgementsWe are grateful to the patients and family members who participated in the E1609 trial and the E1609 trial investigators. This study was conducted by the ECOG-ACRIN Cancer Research Group (Peter J. O’Dwyer, MD and Mitchell D. Schnall, MD, PhD, Group Co-Chairs) and supported by the National Cancer Institute of the National Institutes of Health under the following award numbers: U10CA180794, U10CA180820, U10CA180888, UG1CA233180, UG1CA233184. Biomarkers studies were supported under the following award number: P50CA12197310 (Tarhini and Kirkwood). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.Trial RegistrationNCT01274338Ethics ApprovalThe E1609 study protocol was approved by the institutional review board of each participating institution and conducted in accordance with Good Clinical Practice guidelines as defined by the International Conference on Harmonization. All patients provided an IRB-approved written informed consent.ConsentNot applicable.

9562 Background: Anti-PD1 (aPD1) monotherapy with cemiplimab-rwlc or pembrolizumab is now considered standard of care for first-line management of advanced CSCC not amenable to surgery or curative radiotherapy. Previously chemotherapy or anti-EGFR agents were commonly used for these patients albeit with modest efficacy and limited duration of response. In prospective evaluation, the overall response rate (ORR) to cetuximab was 28% with disease control rate (DCR) of 69% at 6 weeks. The efficacy of second-line treatment following primary or acquired resistance to aPD1 therapy is not known. We investigated the activity of cetuximab in patients who progressed on previous IO therapy. Methods: We performed a single institution retrospective review from 9/28/18 (US approval date of cemiplimab-rwlc for CSCC) through 11/30/20 of patients with locally advanced or metastatic CSCC who received cetuximab after prior IO therapy. We identified patients who received cetuximab either immediately following IO therapy (cohort A) or as a subsequent line not immediately following IO therapy (cohort B). Primary endpoint was ORR with secondary endpoints of DCR, survival and toxicity. Median follow-up and survival times were calculated using the Kaplan-Meier method. Results: Thirteen patients, median age 72 years (62-82), all Caucasian, and 11 males (85%) were included in this study. Eleven pts received cetuximab immediately post-IO progression; two had additional intervening therapy post-IO before receiving cetuximab. Three patients received concurrent radiotherapy (palliative or definitive) with cetuximab. The ORR to cetuximab was 54% (7/13) including 1 complete and 6 partial responses. The cumulative 6-month DCR was 77%. All responses were observed in cohort A; both patients in cohort B had progressive disease as best response. Six of 7 initial responses are ongoing, including 3 in whom cetuximab was discontinued. At a median follow-up of 9.1 months, the median PFS has not been reached for the entire cohort. There were no unanticipated toxicities to cetuximab with rash (77%) and hypomagnesemia (54%) being the most common adverse events. Conclusions: In advanced CSCC, cetuximab used immediately after progression on aPD1 therapy yields notably higher and durable overall response than previously reported in the pre-IO therapy era. If validated in a larger dataset, this should be the preferred therapy for second-line treatment in advanced CSCC. Further exploration into the mechanism of this high efficacy of anti-EGFR therapy post aPD1 therapy is warranted.

9582 Background: Granulomatous and sarcoid-like lesions (GSL) affecting the skin, lungs, thoracic lymph nodes, eyes and other organs following treatment with immune checkpoint inhibitors (ICIs) have been described in sporadic reports in the literature but the true incidence is unknown. Methods: We sought to estimate the incidence of GSL in the context of prospectively conducted ECOG-ACRIN E1609 phase III adjuvant trial in high-risk resected melanoma (N=1670 patients) testing ipilimumab 3 mg/kg (ipi3) and 10 mg/kg (ipi10) versus high-dose interferon-α (HDI). Descriptive statistics were used to calculate the incidence. Results: Among 1670 total patients treated with ICIs or with HDI in E1609, 1034 were treated with ipilimumab and 636 with HDI. Six GSL cases were reported among 1670 total patients treated with ipilimumab or with HDI as summarized in the table along with the corresponding CTCAE grades. More cases were observed with ipi10, followed by ipi3 and HDI, respectively. Organs involved included skin and subcutaneous tissue (granuloma annulare, granulomatous dermatitis), eye (ocular sarcoidosis), lymph nodes (noncaseating granulomatous lymphadenitis), lung and mediastinal lymph nodes (sarcoidosis, granulomatous inflammation). Conclusions: The incidence of granulomatous and sarcoid-like lesions (GSL) with adjuvant ipilimumab therapy in high-risk melanoma is rare. Reported cases ranged in grade from 1-3 and appeared manageable. Since most cases are asymptomatic, it is possible that GSLs are under-recognized and therefore, under-reported. A larger analysis including patients treated with anti-PD1 antibodies is currently underway. Clinical trial information: NCT01274338. [Table: see text]

9501 Background: We assessed whether or not adjuvant pembrolizumab given over 1 year would improve OS and RFS in comparison to high dose ipilimumab (ipi10) or HDI - the two FDA-approved adjuvant treatments for high risk resected melanoma at the time of study design. Methods: Patients age 18 or greater with resected stages IIIA(N2), B, C and IV were eligible. Patients with CNS metastasis were excluded. At entry, patients must have had complete staging and adequate surgery to render them free of melanoma including completion lymph node dissection for those with sentinel node positive disease. Prior therapy with PD-1 blockade, ipilimumab or interferon was not allowed. Two treatment arms were assigned based on stratification by stage, PD-L1 status (positive vs. negative vs. unknown), and intended control arm (HDI vs. Ipi10). Patients enrolled between 10/2015 and 8/2017 were randomized 1:1 to either the control arm [(1) interferon alfa-2b 20 MU/m2 IV days 1-5, weeks 1-4, followed by 10 MU/m2/d SC days 1, 3, and 5, weeks 5-52 (n=190), or (2) ipilimumab 10 mg/kg IV q3w for 4 doses, then q12w for up to 3 years (n=465)], or the experimental arm [pembrolizumab 200 mg IV q3w for 52 weeks (n=648)]. The study had three primary comparisons: 1) RFS among all patients, 2) OS among all patients, 3) OS among patients with PD-L1+ baseline biopsies. Results: 1,426 patients were screened and 1,345 patients were randomized with 11%, 49%, 34%, and 6% AJCC7 stage IIIA(N2), IIIB, IIIC and IV, respectively. This final analysis was performed per-protocol 3.5 years from the date the last patient was randomized, with 512 RFS and 199 OS events. The pembrolizumab group had a statistically significant improvement in RFS compared to the control group (pooled HDI and ipi10) with HR 0.740 (99.618% CI, 0.571 to 0.958). There was no statistically signifcant improvement in OS in the 1,303 eligible randomized overall patient population with HR 0.837 (96.3% CI, 0.622 to 1.297), or among the 1,070 (82%) patients with PD-L1 positive baseline biopsies with HR 0.883 (97.8% CI, 0.604 to 1.291). Gr 3/4/5 event rates were as follows: HDI 69/9/0%, ipi10 43/5/0.5% and pembrolizumab 17/2/0.3%. Conclusions: Pembrolizumab improves RFS but not OS compared to HDI or ipi10 in the adjuvant treatment of patients with high-risk resected melanoma. Pembrolizumab is a better tolerated adjuvant treatment regimen than HDI or Ipi10. Support: NIH/NCI NCTN grants CA180888, CA180819, CA180820, CA180863; and in part by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Editorial Acknowledgement: With special thanks to Elad Sharon, MD, MPH, and Larissa Korde, MD, MPH. National Cancer Institute, Investigational Drug Branch, for their contributions to this trial, as well as Nageatte Ibrahim, MD, and Sama Ahsan, MD Merck. Clinical trial information: NCT02506153.

Background Approved first-line treatments for patients with BRAF V600–mutant advanced melanoma include nivolumab (a programmed cell death protein 1 inhibitor) plus ipilimumab (a cytotoxic T lymphocyte antigen-4 inhibitor; NIVO+IPI) and the BRAF/MEK inhibitors dabrafenib plus trametinib (DAB+TRAM), encorafenib plus binimetinib (ENCO+BINI), and vemurafenib plus cobimetinib (VEM+COBI). Results from prospective randomized clinical trials (RCTs) comparing these treatments have not yet been reported. This analysis evaluated the relative efficacy and safety of NIVO+IPI versus DAB+TRAM, ENCO+BINI, and VEM+COBI in patients with BRAF-mutant advanced melanoma using a matching-adjusted indirect comparison (MAIC). Patients and methods A systematic literature review identified RCTs for DAB+TRAM, ENCO+BINI, and VEM+COBI in patients with BRAF-mutant advanced melanoma. Individual patient-level data for NIVO+IPI were derived from the phase III CheckMate 067 trial (BRAF-mutant cohort) and restricted to match the inclusion/exclusion criteria of the comparator trials. Treatment effects for overall survival (OS) and progression-free survival (PFS) were estimated using Cox proportional hazards and time-varying hazard ratio (HR) models. Safety outcomes (grade 3 or 4 treatment-related adverse events) with NIVO+IPI and the comparators were compared. Results In the Cox proportional hazards analysis, NIVO+IPI showed improved OS compared with DAB+TRAM (HR = 0.53; 95% confidence interval [CI], 0.39-0.73), ENCO+BINI (HR = 0.60; CI, 0.42-0.85), and VEM+COBI (HR = 0.50; CI, 0.36-0.70) for the overall study period. In the time-varying analysis, NIVO+IPI was associated with significant improvements in OS and PFS compared with the BRAF/MEK inhibitors 12 months after treatment initiation. There were no significant differences between NIVO+IPI and BRAF/MEK inhibitor treatment from 0 to 12 months. Safety outcomes favored DAB+TRAM over NIVO+IPI, whereas NIVO+IPI was comparable to VEM+COBI. Conclusion Results of this MAIC demonstrated durable OS and PFS benefits for patients with BRAF-mutant advanced melanoma treated with NIVO+IPI compared with BRAF/MEK inhibitors, with the greatest benefits noted after 12 months., Highlights • First-line treatments for BRAF V600-mutant melanoma include NIVO+IPI and BRAF/MEK inhibitors. • Results from prospective RCTs comparing NIVO+IPI and BRAF/MEK inhibitors have not yet been reported. • This MAIC evaluated NIVO+IPI versus BRAF/MEK inhibitors for BRAF-mutant advanced melanoma. • OS and PFS benefits were noted with NIVO+IPI versus BRAF/MEK inhibitors beginning at 12 months. • These findings may provide information relevant to the selection of treatments for BRAF-mutant advanced melanoma.

BACKGROUND Activation of the mesenchymal-epidermal transition factor (MET) tyrosine kinase and its ligand, hepatocyte growth factor (HGF), is implicated in resistance to epidermal growth factor receptor (EGFR) inhibitors. In this phase 1/2 trial, rilotumumab (an anti-HGF antibody) combined with erlotinib was evaluated in patients with metastatic, previously treated non–small cell lung cancer. METHODS In phase 1, a dose de-escalation design was adopted with rilotumumab starting at 15 mg/kg intravenously every 3 weeks and oral erlotinib 150 mg daily. In phase 2, the disease control rate (DCR) (according to Response Evaluation Criteria in Solid Tumors) of the combination was evaluated using a Simon 2-stage design. The biomarkers examined included 10 plasma-circulating molecules associated with the EGFR and MET pathways. RESULTS Without indications for de-escalation, the recommended phase 2 dose was dose level 0. Overall, 45 response-evaluable patients were enrolled (13 with squamous carcinoma, 32 with adenocarcinoma; 2 had confirmed EGFR mutations, 33 had confirmed wild-type [WT] EGFR, and 7 had KRAS mutations). The DCR for all patients was 60% (90% confidence interval [CI], 47.1%-71.3%). Median progression-free survival was 2.6 months (90% CI, 1.4-2.7 months), and median overall survival was 6.6 months (90% CI, 5.6-8.9 months). Among patients with WT EGFR, the DCR was 60.6% (90% CI, 46.3%-73.3%), median progression-free survival was 2.6 months (90% CI, 1.4-2.7 months), and median overall survival was 7.0 months (90% CI, 5.6-13.4 months). Elevated baseline levels of neuregulin 1 were associated with longer progression-free survival (hazard ratio, 0.41; 95% CI, 0.19-0.87), whereas elevated amphiregulin levels were associated with more rapid progression (hazard ratio, 2.14; 95% CI, 1.48-3.08). CONCLUSIONS Combined rilotumumab and erlotinib had an acceptable safety profile, and the DCR met the prespecified criteria for success. In the EGFR WT group, the DCR exceeded published reports for erlotinib alone. High circulating levels of neuregulin 1 may indicate sensitivity to this combination. Cancer 2017;123:2936–44. © 2017 American Cancer Society.

BACKGROUND KIT-directed tyrosine kinase inhibitors such as imatinib have demonstrated benefits in KIT-mutant (KIT+) mucosal, acral, vulvovaginal, and chronically sun-damaged (CSD) melanoma. Dasatinib has superior preclinical activity in comparison with other tyrosine kinase inhibitors against cells with the most common KIT mutation, exon 11L576P. The ECOG-ACRIN E2607 trial assessed dasatinib in patients with these melanoma subtypes. METHODS Patients received 70 mg of oral dasatinib twice daily. The primary objective for this 2-stage phase 2 trial was response rate. Stage I was open to KIT+ and wild-type KIT (KIT–) mucosal, acral, and CSD melanoma (n = 57). Stage II accrued only KIT+ tumors (n = 30). To enrich the trial for KIT+ tumors, vulvovaginal melanoma was added, and CSD melanoma was removed from eligibility. Secondary objectives included progression-free survival (PFS), overall survival (OS), and safety. RESULTS From May 2009 to December 2010, the first stage enrolled 57 patients. Among the evaluable patients, 3 of 51 (5.9%) achieved a partial response: all were KIT–. Stage II closed early because of slow accrual (November 2011 to December 2015). In stage II, 4 of 22 evaluable patients (18.2%) had a partial response; the median duration was 4.2 months. The median PFS was 2.1 months (n = 73; 95% confidence interval [CI], 1.5-2.9 months). The median OS was 7.5 months (95% CI, 6.0-11.9 months). In exploratory analyses, no differences were seen in PFS or OS with the KIT status or subtype. Dasatinib was discontinued because of adverse events in 9 of 75 patients (12%). CONCLUSIONS The dasatinib response rate among KIT+ melanoma patients was low. In view of its clinical activity, it is recommended that imatinib remain the KIT tyrosine kinase inhibitor of choice for unresectable KIT+ melanoma. Cancer 2017;123:2688-97. © 2017 American Cancer Society.

Purpose To test the efficacy of 4 weeks of intravenous (IV) induction with high-dose interferon (IFN) as part of the Eastern Cooperative Oncology Group regimen compared with observation (OBS) in patients with surgically resected intermediate-risk melanoma. Patients and Methods In this intergroup international trial, eligible patients had surgically resected cutaneous melanoma in the following categories: (1) T2bN0, (2) T3a-bN0, (3) T4a-bN0, and (4) T1-4N1a-2a (microscopic). Patients were randomly assigned to receive IFN α-2b at 20 MU/m2/d IV for 5 days (Monday to Friday) every week for 4 weeks (IFN) or OBS. Stratification factors were pathologic lymph node status, lymph node staging procedure, Breslow depth, ulceration of the primary lesion, and disease stage. The primary end point was relapse-free survival. Secondary end points included overall survival, toxicity, and quality of life. Results A total of 1,150 patients were randomly assigned. At a median follow-up of 7 years, the 5-year relapse-free survival rate was 0.70 (95% CI, 0.66 to 0.74) for OBS and 0.70, (95% CI, 0.66 to 0.74) for IFN ( P = .964). The 5-year overall survival rate was 0.83 (95% CI, 0.79 to 0.86) for OBS and 0.83 (95% CI, 0.80 to 0.86) for IFN ( P = .558). Treatment-related grade 3 and higher toxicity was 4.6% versus 57.9% for OBS and IFN, respectively ( P < .001). Quality of life was worse for the treated group. Conclusion Four weeks of IV induction as part of the Eastern Cooperative Oncology Group high-dose IFN regimen is not better than OBS alone for patients with intermediate-risk melanoma as defined in this trial.

PURPOSE Outcome measures that comprehensively capture attributes of immuno-oncology agents, including prolonged treatment-free time and persistent treatment-related adverse events (TRAEs), are needed to complement conventional survival end points. METHODS We pooled data from the CheckMate 067 and 069 clinical trials of nivolumab and ipilimumab, as monotherapies or in combination, for patients with advanced melanoma. Treatment-free survival (TFS) was defined as the area between Kaplan-Meier curves for two conventional time-to-event end points, each defined from random assignment: time to immune checkpoint inhibitor (ICI) protocol therapy cessation and time to subsequent systemic therapy initiation or death. TFS was partitioned as time with and without toxicity by a third end point, time to cessation of both ICI therapy and toxicity. Toxicity included persistent and late-onset grade 3 or higher TRAEs. The area under each Kaplan-Meier curve was estimated by the 36-month restricted mean time. RESULTS At 36 months, many of the 1,077 patients who initiated ICI therapy were surviving free of subsequent therapy initiation (47% nivolumab plus ipilimumab, 37% nivolumab, 15% ipilimumab). The restricted mean TFS was longer for nivolumab plus ipilimumab (11.1 months) compared with nivolumab (4.6 months; difference, 6.5 months; 95% CI, 5.0 to 8.0 months) or ipilimumab (8.7 months; difference, 2.4 months; 95% CI, 0.8 to 4.1 months); restricted mean TFS represented 31% (3% with and 28% without toxicity), 13% (1% and 11%), and 24% (less than 1% and 23%) of the 36-month period, respectively, in the three treatment groups. TFS without toxicity was longer for nivolumab plus ipilimumab than nivolumab (difference, 6.0 months) or ipilimumab (difference, 1.7 months). CONCLUSION The analysis of TFS between ICI cessation and subsequent therapy initiation revealed longer TFS without toxicity for patients with advanced melanoma who received nivolumab plus ipilimumab compared with nivolumab or ipilimumab. Regardless of treatment, a small proportion of the TFS involved grade 3 or higher TRAEs.

Locally/regionally advanced melanoma confers a major challenge in terms of surgical and medical management. Surgical treatment carries the risks of surgical morbidities and potential complications that could be lasting. In addition, these patients continue to have a high risk of relapse and death despite the use of standard adjuvant therapy. Neoadjuvant therapy has the potential to significantly improve the clinical outcome of these patients, particularly in this era of newer and effective targeted and immunotherapeutic agents. Previous neoadjuvant studies tested chemotherapy with temozolomide where the clinical activity was limited. Biochemotherapy (BCT) was tested in two studies in the neoadjuvant setting and showed high tumor response rates; however, BCT was ultimately abandoned following its failure to demonstrate survival benefits in randomized trials of metastatic disease. Success of immunotherapy and targeted therapy in prolonging the lives of patients with metastatic melanoma generated considerable interest to investigate these novel strategies in the adjuvant and neoadjuvant settings. A number of neoadjuvant targeted and immunotherapy studies have been completed in melanoma to date and have yielded promising clinical activity. Given these encouraging results, a number of studies with other molecularly targeted and immunotherapeutic agents and their combinations are ongoing in the neoadjuvant setting; long-term outcome data are eagerly awaited. Such studies also provide access to biospecimens before and during therapy, allowing for the conduct of biomarker and mechanistic studies that may have a significant impact in guiding adjuvant therapy choices and drug development.

Aim: Comparison of clinical outcomes of nivolumab + ipilimumab versus BRAF + MEK inhibitors (dabrafenib + trametinib or vemurafenib + cobimetinib) in BRAF-mutant advanced melanoma. Methods: Matching-adjusted indirect comparisons were conducted between nivolumab + ipilimumab (CheckMate 067/069 studies) and BRAF + MEK inhibitors (COMBI-d, COMBI-v and coBRIM studies). Overall survival (OS), progression-free survival and objective response rates were assessed. Results: After adjusting, nivolumab + ipilimumab showed improved OS versus dabrafenib + trametinib (hazard ratio [HR] = 0.64; 95% CI: 0.46–0.89) or vemurafenib + cobimetinib (HR = 0.56; 95% CI: 0.36–0.89); OS outcomes were similar at 1 year, with benefits emerging after 12 months; progression-free survival and objective response rates were similar. Grade 3/4 adverse events occurred in 54.1% with nivolumab + ipilimumab, 31.6% with dabrafenib + trametinib and 59.5% with vemurafenib + cobimetinib. Conclusion: Nivolumab + ipilimumab had significantly improved clinical outcomes versus BRAF + MEK inhibitors, with benefits increasing after longer follow-up. Ongoing randomized trials directly comparing these treatments are necessary to prospectively validate these findings.

International audience; BACKGROUND: Despite the completion of numerous phase II studies, a standard of care treatment has yet to be defined for metastatic uveal melanoma (mUM). To determine benchmarks of progression free survival (PFS) and overall survival (OS), we carried out a meta-analysis using individual patient level trial data.METHODS: Individual patient variables and survival outcomes were requested from 29 trials published from 2000 to 2016. Univariable and multivariable analysis were carried out for prognostic factors. The variability between trial arms and between therapeutic agents on PFS and OS was investigated.RESULTS: OS data were available for 912 patients. The median PFS was 3.3 months (95% CI 2.9-3.6) and 6-month PFS rate was 27% (95% CI 24-30). Univariable analysis showed male sex, elevated (i.e. > versus ≤ upper limit of normal) lactate dehydrogenase (LDH), elevated alkaline phosphatase (ALP) and diameter of the largest liver metastasis (≥3 cm versus

Although there are effective treatments for primary uveal melanoma, the prognosis for metastatic disease is poor. There is no curative therapy for metastatic uveal melanoma, but options include local interventions such as surgical resection, chemoembolization, radioembolization, radiofrequency ablation, or systemic therapy including chemotherapy, targeted therapy, and immunotherapy.

Purpose Objective responses are reported in 34% to 37% of patients with programmed death-1 (PD-1)–naïve advanced melanoma treated with PD-1 inhibitors. Pre-existing CD8+ T-cell infiltrate and interferon (IFN) gene signature correlate with response to PD-1 blockade. Here, we report a phase Ib/II study of pembrolizumab/pegylated (PEG)-IFN combination in PD-1–naïve advanced melanoma. Patients and Methods PEG-IFN (1, 2, and 3 μg/kg per week) was dose escalated using a modified toxicity probability interval design in three cohorts of four patients each, whereas pembrolizumab was dosed at 2 mg/kg every 3 weeks in the phase Ib portion. Thirty-one patients were enrolled in the phase II portion. Primary objectives were safety and incidence of dose-limiting toxicities. Secondary objectives included objective response rate, progression-free survival (PFS), and overall survival. Results Forty-three patients with stage IV melanoma were enrolled in the phase Ib and II portions of the study and included in the analysis. At the data cutoff date (December 31, 2017), median follow-up duration was 25 months (range, 1 to 38 months). All 43 patients experienced at least one adverse event; grade 3/4 treatment-related adverse events occurred in 21 of 43 patients (48.8%). Objective responses were seen at all three dose levels among 43 evaluable patients. The objective response rate was 60.5%, with 46.5% of patients exhibiting ongoing response. Median PFS was 11.0 months in all patients and unreached in responders, whereas median overall survival remained unreached in all patients. The 2-year PFS rate was 46%. Conclusion Pembrolizumab/PEG-IFN demonstrated an acceptable toxicity profile with promising evidence of clinical efficacy in PD-1–naïve metastatic melanoma. These results support the rationale to further investigate this pembrolizumab/PEG-IFN combination in this disease.

BRAF kinase gene V600 point mutations drive approximately 40% to 50% of all melanomas, and BRAF inhibitors (BRAFi) have been found to significantly improve survival outcomes. Although radiation therapy (RT) provides effective symptom palliation, there is a lack of toxicity and efficacy data when RT is combined with BRAFi, including vemurafenib and dabrafenib. This literature review provides a detailed analysis of potential increased dermatologic, pulmonary, neurologic, hepatic, esophageal, and bowel toxicity from the combination of BRAFi and RT for melanoma patients described in 27 publications. Despite 7 publications noting potential intracranial neurotoxicity, the rates of radionecrosis and hemorrhage from whole brain RT (WBRT), stereotactic radiosurgery (SRS), or both do not appear increased with concurrent or sequential administration of BRAFis. Almost all grade 3 dermatitis reactions occurred when RT and BRAFi were administered concurrently. Painful, disfiguring nondermatitis cutaneous reactions have been described from concurrent or sequential RT and BRAFi administration, which improved with topical steroids and time. Visceral toxicity has been reported with RT and BRAFi, with deaths possibly related to bowel perforation and liver hemorrhage. Increased severity of radiation pneumonitis with BRAFi is rare, but more concerning was a potentially related fatal pulmonary hemorrhage. Conversely, encouraging reports have described patients with leptomeningeal spread and unresectable lymphadenopathy rendered disease free from combined RT and BRAFi. Based on our review, the authors recommend holding BRAFi and/or MEK inhibitors ≥3 days before and after fractionated RT and ≥1 day before and after SRS. No fatal reactions have been described with a dose4 Gy per fraction, and time off systemic treatment should be minimized. Future prospective data will serve to refine these recommendations.

Purpose We conducted a double-blind, placebo-controlled trial to evaluate the effect of granulocyte-macrophage colony-stimulating factor (GM-CSF) and peptide vaccination (PV) on relapse-free survival (RFS) and overall survival (OS) in patients with resected high-risk melanoma. Patients and Methods Patients with completely resected stage IV or high-risk stage III melanoma were grouped by human leukocyte antigen (HLA) -A2 status. HLA-A2–positive patients were randomly assigned to receive GM-CSF, PV, both, or placebo; HLA-A2–negative patients, GM-CSF or placebo. Treatment lasted for 1 year or until recurrence. Efficacy analyses were conducted in the intent-to-treat population. Results A total of 815 patients were enrolled. There were no significant improvements in OS (stratified log-rank P = .528; hazard ratio, 0.94; 95% repeated CI, 0.77 to 1.15) or RFS (P = .131; hazard ratio, 0.88; 95% CI, 0.74 to 1.04) in the patients assigned to GM-CSF (n = 408) versus those assigned to placebo (n = 407). The median OS times with GM-CSF versus placebo treatments were 69.6 months (95% CI, 53.4 to 83.5 months) versus 59.3 months (95% CI, 44.4 to 77.3 months); the 5-year OS probability rates were 52.3% (95% CI, 47.3% to 57.1%) versus 49.4% (95% CI, 44.3% to 54.3%), respectively. The median RFS times with GM-CSF versus placebo were 11.4 months (95% CI, 9.4 to 14.8 months) versus 8.8 months (95% CI, 7.5 to 11.2 months); the 5-year RFS probability rates were 31.2% (95% CI, 26.7% to 35.9%) versus 27.0% (95% CI, 22.7% to 31.5%), respectively. Exploratory analyses showed a trend toward improved OS in GM-CSF–treated patients with resected visceral metastases. When survival in HLA-A2–positive patients who received PV versus placebo was compared, RFS and OS were not significantly different. Treatment-related grade 3 or greater adverse events were similar between GM-CSF and placebo groups. Conclusion Neither adjuvant GM-CSF nor PV significantly improved RFS or OS in patients with high-risk resected melanoma. Exploratory analyses suggest that GM-CSF may be beneficial in patients with resected visceral metastases; this observation requires prospective validation.