Localized therapy using anti-PD-L1 anchored and NIR-responsive hollow gold nanoshell (HGNS) loaded with doxorubicin (DOX) for the treatment of locally advanced melanoma

e21512 Background: Anti-PD-1 therapy has improved the outcome of advanced melanoma patients with a 5-year survival rate of about 40-45%. However, biomarkers predictive of response to immune checkpoint blockade therapy are lacking. There is limited data on the utility of host germline human leucocyte antigen (HLA) genotype as a predictor of response to anti-PD-1 therapy in advanced melanoma. Here, we investigate the prognostic value of HLA in predicting survival outcomes of patients with unresectable locally advanced, metastatic melanoma on anti-PD-1 therapy. Methods: Blood was collected from 113 metastatic melanoma patients who were treated with anti-PD-1 therapy at two major oncology centres in Western Australia. High quality DNA was extracted from white blood cells and subsequently HLA-I and HLA-II typed using clinically validated assay. Univariate analyses were conducted using Cox regression model correlating homozygosity at HLA-I and HLA-II loci with overall survival (OS). HLA-A and HLA-B were classified into 12 supertypes and correlated with OS. Multivariate analyses were performed while controlling for age, gender, prior therapy, BRAF mutation status, ECOG performance status and presence of liver and brain metastases. Results: Homozygosity at HLA-I or HLA-II loci was not associated with OS. However, the absence of HLA-B62 supertype was associated with a trend towards improved OS (HR: 0.53 [95% CI:0.25-1.10]; P = 0.09) as reported previously. Notably, the absence of HLA-B27 supertype was associated with improved OS which was statistically significant (HR: 0.45 [95% CI:0.24-0.85]; P = 0.01). In multivariate analyses, the prognostic value of HLA-B27 supertype (HR: 0.38 [95% CI:0.19-0.76]; P = 0.006) was maintained, whereas the prognostic value of HLA-B62 supertype significantly improved (HR: 0.42 [95% CI:0.19-0.94]; P = 0.03). Conclusions: Our results suggest a limited role of HLA homozygosity in predicting survival of melanoma patients treated with anti-PD-1 therapy. However, we identified that the absence of HLA-B62 and HLA-B27 supertype is associated with improved survival benefit. Therefore, HLA-B27 and HLA-B62 supertype may be used as adjunct biomarkers of response to anti-PD-1 therapy in patients with melanoma in addition to PD-L1 status, pending validation in prospective randomised clinical trials.

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Locally advanced melanoma

Cancer ◽

10.1002/(sici)1097-0142(20000101)88:1<88::aid-cncr13>3.0.co;2-k ◽

2000 ◽

Vol 88 (1) ◽

pp. 88-94 ◽

Cited By ~ 86

Author(s):

Graham Stevens ◽

John F. Thompson ◽

Ian Firth ◽

Christopher J. O'Brien ◽

William H. McCarthy ◽

...

Keyword(s):

Locally Advanced ◽

Advanced Melanoma

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A randomized phase II study of vemurafenib plus cobimetinib continuous versus intermittent in previously untreated BRAF V600-mutation positive patients with unresectable locally advanced or metastatic melanoma.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.tps9599 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. TPS9599-TPS9599 ◽

Cited By ~ 1

Author(s):

Jose A. Lopez-Martin ◽

Alfonso Berrocal ◽

María González-Cao

Keyword(s):

Metastatic Melanoma ◽

Phase Ii ◽

Phase Ii Study ◽

Mapk Pathway ◽

Locally Advanced ◽

Advanced Melanoma ◽

Drug Resistant ◽

Randomized Phase Ii ◽

Melanoma Patients ◽

Resistant Cells

TPS9599 Background: Previous clinical trials have shown that vemurafenib significantly increases PFS and OS in untreated BRAFV600 mutant advanced melanoma patients. Nevertheless, disease progression occurs after a median of 6-7 months since start of vemurafenib. Several mechanisms of acquired resistance to vemurafenib result in reactivation of MAPK pathway. Upfront addition of a MEK inhibitor (MEKi) to vemurafenib delays secondary resistance to BRAFi. The combination of cobimetinib, a MEKi, plus vemurafenib as a continuous administration was approved by FDA in 2,015 in untreated metastatic BRAFV600 advanced melanoma patients based on an increase in PFS and OS achieved in a phase III trial (coBRIM trial). Preclinical models have shown that continuous vemurafenib dosing promotes the clonal expansion of drug-resistant cells, and intermittent dosing could serve to eliminate the fitness advantage of the resistant cells and delay the onset of drug-resistant disease (Das Thakur, Nature 2013). These observations and some clinical case reports support upfront evaluation of alternative dosing regimens of MAPK pathway inhibition. Methods: This is a randomized phase II study to explore the efficacy and safety of two schedules of administration of vemurafenib in combination with cobimetinib (continuous – 28-day cycles with vemurafenib 960 mg PO BID, Days 1-28, and cobimetinib 60 mg PO QD, Days 1-21 – and intermittent – same dose/schedule during first 12 weeks, and then, same doses with the following schedule: vemurafenib 4 weeks on /2 weeks off, and cobimetinib 3 weeks on/ 3 weeks off), in patients with untreated, BRAFV600 mutated, unresectable, measurable (RECIST 1.1), locally advanced or metastatic melanoma. Prior adjuvant immunotherapy is allowed. Primary endpoint is PFS. Secondary endpoints include: OS, ORR, pharmacokinetic and pharmacodynamic profiles and safety. Additional translational research to analyze predictive factors and mechanism of resistance will be explored. The trial is in progress; 56 of up to 116 planned pts have been recruited at the end of December 2016 (enrollment started in June 2015). Clinical trial information: NCT02583516.

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Postoperative radiation therapy in locally-advanced melanoma

Melanoma Research ◽

10.1097/00008390-199706001-00060 ◽

1997 ◽

Vol 7 (Supplement 1) ◽

pp. S18

Author(s):

G Stevens ◽

I Firth

Keyword(s):

Radiation Therapy ◽

Locally Advanced ◽

Advanced Melanoma ◽

Postoperative Radiation ◽

Postoperative Radiation Therapy

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P24 Electrochemotherapy: a technique for multiple approaches in the treatment of locally advanced melanoma

Melanoma Research ◽

10.1097/01.cmr.0000382856.60253.ac ◽

2010 ◽

Vol 20 ◽

pp. e53-e54

Author(s):

V. Farricha ◽

H. Vasques ◽

S. Carvalhal ◽

J.C. Mendes de Almeida

Keyword(s):

Locally Advanced ◽

Advanced Melanoma

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ASO Author Reflection: Isolated Limb Infusion for Locally Advanced Melanoma in the Extremely Old Patient is Safe and Effective

Annals of Surgical Oncology ◽

10.1245/s10434-020-08314-y ◽

2020 ◽

Vol 27 (5) ◽

pp. 1430-1431

Author(s):

Jüri Teras ◽

Hidde M. Kroon ◽

Jonathan S. Zager

Keyword(s):

Locally Advanced ◽

Advanced Melanoma

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Neoadjuvant cytoreductive treatment with BRAF/MEK inhibition of prior unresectable regionally advanced melanoma to allow complete surgical resection: REDUCTOR trial.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.9587 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. 9587-9587 ◽

Cited By ~ 1

Author(s):

Stephanie A. Blankenstein ◽

Maartje W. Rohaan ◽

W. Martin. C. Klop ◽

Bernies Van Der Hiel ◽

Bart A. Van De Wiel ◽

...

Keyword(s):

Surgical Resection ◽

Metabolic Response ◽

Locally Advanced ◽

Neoadjuvant Treatment ◽

Stage Iv ◽

Advanced Melanoma ◽

Stage Iii ◽

Advanced Stage ◽

Pet Ct ◽

Cytoreductive Treatment

9587 Background: The aim of this study is to evaluate the potency of short-term neoadjuvant cytoreductive therapy with dabrafenib and trametinib (BRAF and MEK inhibitor respectively) to allow radical surgical resection in patients with unresectable BRAF-mutated, locally advanced stage III or oligometastatic stage IV melanoma. Methods: A total of 25 patients with BRAF-mutated, unresectable locally advanced stage III or oligometastatic stage IV (≤3 metastases) melanoma will be treated with dabrafenib and trametinib for 8 weeks. Response evaluation by positron emission tomography/computed tomography (PET/CT) will occur at 2 and 8 weeks. If sufficient downsizing occurs, surgical resection will be performed. Biopsies for translational research will be taken at baseline and 2 weeks. The dissection specimen will be stored at 8 weeks. Results: Currently 20 patients have been included. Of these, 2 patients showed PD upon treatment and did not proceed to surgery. In 17/18 (94%) patients resection was possible after neoadjuvant treatment, of which 16 (94%) were R0 resections. Median follow-up time is 28 months with a median recurrence free survival of 9 months in patients undergoing surgery. The 1-year overall survival (OS) was 94% and 2-year OS 82%. Median OS was not reached. Metabolic response rates (RR) on PET/CT at 8 weeks were: 4 (20%) CR, 14 (70%) PR, 0 (0%) SD, 2 (10%) PD. Pathologic RR differed: 7 (35%) CR, 7 (35%) PR, 3 (15%) SD, 0 (0%) PD and in 3 patients (15%) no pathologic response was measured, since no resection was performed. Most patients (85%) experienced any toxicity, of which 50% was grade 1, 20% grade 2 and 3 patients (15%) experienced grade 3 toxicity. The most common reported toxicity was fever. Conclusions: Neoadjuvant dabrafenib and trametinib shows to be a potent cytoreductive treatment, allowing radical resection of metastases in 16/20 (80%) patients with prior unresectable locally advanced melanoma. Patients with no recurrence remained disease-free for a prolonged period of time. If there was recurrent disease, this usually occurred within months after surgery and this may present an opportunity for further tailored adjuvant therapy. Clinical trial information: NTR4654.

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Second-line (2L) pembrolizumab (pembro) in Chinese patients (pts) with advanced melanoma: Three-year follow up (FU) of the phase 1 KEYNOTE-151 study.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e21511 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e21511-e21511

Author(s):

Jun Guo ◽

Xiaoshi Zhang ◽

Yongqian Shu ◽

Hongming Pan ◽

Di Wu ◽

...

Keyword(s):

Antitumor Activity ◽

Disease Progression ◽

Phase 1 ◽

Locally Advanced ◽

Response Duration ◽

Complete Response ◽

Advanced Melanoma ◽

Chinese Patients ◽

Recist 1.1 ◽

Grade 3

e21511 Background: Pembro as 2L therapy was well tolerated and had clinically meaningful antitumor activity in Chinese pts with advanced melanoma at first analysis of the phase 1b KEYNOTE-151 study. At median FU of 7.9 mo, ORR was 16.7% (1 complete response [CR]; 16 partial response [PR]), DCR was 38.2%, median DOR was 8.4 mo, median PFS was 2.8 mo, and median OS was 12.1 mo. Any grade and grade 3/4 treatment-related adverse events (TRAEs) occurred in 84.5% and 8.7% of pts, respectively. However, long-term efficacy and safety of 2L pembro in Chinese pts with advanced melanoma are unknown. Results from 3 y of FU are presented. Methods: Eligible pts were ≥18 y, of Chinese descent, had histologically confirmed locally advanced or metastatic melanoma, and had disease progression on or after first line therapy. Pts received pembro 2 mg/kg IV Q3W for ≤35 cycles. Eligible pts who discontinued pembro with stable disease or better could receive ≤17 additional cycles of pembro (second course) upon disease progression. Primary endpoints were safety and ORR per RECIST 1.1 by blinded independent central review (BICR). Secondary endpoints included DOR and PFS per RECIST 1.1 by BICR; ORR, DOR, and PFS per irRECIST by BICR; and OS. ORR was based on the exact binomial method; DOR, PFS, and OS analyses used the Kaplan-Meier method. The full analysis set (FAS) comprised all allocated pts who received ≥1 pembro dose and had baseline data for relevant analyses. Results: Of 103 enrolled pts, 43% were male, 51% had PD-L1 positive tumors, and 80% had BRAF wild-type tumors; median age was 52 y (range, 22-77). The FAS had 102 pts. Median time from first dose to database cutoff was 44.6 mo (IQR, 39.1-46.2). At database cutoff (July 13, 2020), 14 pts (13.5%) had completed treatment, 89 pts (86.4%) had discontinued. Any grade TRAEs occurred in 88 pts (85.4%); most commonly hypothyroidism (n = 27; 26.2%), increased ALT (n = 24; 23.3%), and hypertriglyceridemia (n = 23; 22.3%), all grade 1/2. Grade 3-5 TRAEs occurred in 13 pts (12.6%). Immune-mediated AEs and infusion reactions occurred in 35 pts (34.0%); most commonly grade 1/2 hypothyroidism (n = 27; 26.2%). 3 pts discontinued pembro because of a TRAE; none died because of a TRAE. ORR per RECIST 1.1 was 17.6% (95% CI 10.8-26.4; 1 CR/17 PR); DCR was 38.2% (95% CI 28.8-48.4). Median DOR per RECIST 1.1 was 13.8 mo (range, 2.7-37.4+); 1 pt had response duration ≥36 mo. Median PFS per RECIST 1.1 was 2.8 mo (95% CI 2.7-3.5); 36-mo PFS rate was 5.0%. ORR, DOR, and PFS were similar per RECIST 1.1 and irRECIST. Median OS was 13.2 mo (95% CI 10.4-16.5); 36-mo OS rate, 22.3%.1 pt completed the first and second courses of pembro and had investigator-confirmed CR. Conclusions: 2L pembro was well tolerated and continued to provide durable responses and clinically meaningful antitumor activity in Chinese pts with advanced melanoma. These results further support use of 2L pembro in Chinese pts with advanced melanoma. Clinical trial information: NCT02821000.

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