Discontinuation of anti-PD-1 mAb after complete response in advanced melanoma pts.

BackgroundThe indoleamine 2,3-dioxygenase (IDO) pathway is a key counter-regulatory mechanism that, in cancer, is exploited by tumors to evade antitumor immunity. Indoximod is a small-molecule IDO pathway inhibitor that reverses the immunosuppressive effects of low tryptophan (Trp) and high kynurenine (Kyn) that result from IDO activity. In this study, indoximod was used in combination with a checkpoint inhibitor (CPI) pembrolizumab for the treatment for advanced melanoma.MethodsPatients with advanced melanoma were enrolled in a single-arm phase II clinical trial evaluating the addition of indoximod to standard of care CPI approved for melanoma. Investigators administered their choice of CPI including pembrolizumab (P), nivolumab (N), or ipilimumab (I). Indoximod was administered continuously (1200 mg orally two times per day), with concurrent CPI dosed per US Food and Drug Administration (FDA)-approved label.ResultsBetween July 2014 and July 2017, 131 patients were enrolled. (P) was used more frequently (n=114, 87%) per investigator’s choice. The efficacy evaluable population consisted of 89 patients from the phase II cohort with non-ocular melanoma who received indoximod combined with (P).The objective response rate (ORR) for the evaluable population was 51% with confirmed complete response of 20% and disease control rate of 70%. Median progression-free survival was 12.4 months (95% CI 6.4 to 24.9). The ORR for Programmed Death-Ligand 1 (PD-L1)-positive patients was 70% compared with 46% for PD-L1-negative patients. The combination was well tolerated, and side effects were similar to what was expected from single agent (P).ConclusionIn this study, the combination of indoximod and (P) was well tolerated and showed antitumor efficacy that is worth further evaluation in selected patients with advanced melanoma.

Download Full-text

Retreatment with talimogene laherparepvec for advanced melanoma

Immunotherapy ◽

10.2217/imt-2020-0029 ◽

2020 ◽

Vol 12 (16) ◽

pp. 1167-1172

Author(s):

Janice Hu ◽

Sabran J Masoud ◽

Surya Ravichandran ◽

Georgia M Beasley ◽

Paul J Mosca

Keyword(s):

Adverse Event ◽

Disease Progression ◽

Initial Treatment ◽

Relevant Literature ◽

Complete Response ◽

Advanced Melanoma ◽

Severe Adverse Event ◽

Stage Iiib ◽

Talimogene Laherparepvec ◽

Mixed Response

Aim: Talimogene laherparepvec (T-VEC) is a genetically modified oncolytic herpesvirus approved for the treatment of unresectable, locoregionally advanced and recurrent melanoma. There is little relevant literature in the context of retreatment with T-VEC. Materials & methods: We reviewed four patients aged 71–87 years old with stage IIIB–IV melanoma at treatment who were rechallenged with T-VEC after experiencing recurrence of locoregional disease or prior treatment-limiting toxicity. Results: Cessation of initial treatment was due to one of the following reasons: severe adverse event (one case), mixed response (one case) or complete response (two cases). Three males and one female underwent T-VEC retreatment with a mean of 5.5 injection cycles. Three patients experienced a complete response to retreatment, while one experienced disease progression. Conclusion: Intralesional T-VEC may be effective and well-tolerated in patients who have completed prior T-VEC therapy.

Download Full-text

Clinical and Immune Responses in Advanced Melanoma Patients Immunized With an Anti-Idiotype Antibody Mimicking Disialoganglioside GD2

Journal of Clinical Oncology ◽

10.1200/jco.2000.18.2.376 ◽

2000 ◽

Vol 18 (2) ◽

pp. 376-376 ◽

Cited By ~ 92

Author(s):

Kenneth A. Foon ◽

Jose Lutzky ◽

Rathindra N. Baral ◽

John R. Yannelli ◽

Laura Hutchins ◽

...

Keyword(s):

Soft Tissue ◽

Immune Responses ◽

Disease Progression ◽

San Francisco ◽

Median Survival ◽

Complete Response ◽

Advanced Melanoma ◽

Visceral Metastasis ◽

Prior Therapy ◽

Kaplan Meier

PURPOSE: To determine immune responses and toxicity to the anti-idiotype vaccine, as well as clinical responses and survival, we initiated a clinical trial for patients with advanced melanoma treated with an anti-idiotype antibody (TriGem) that mimics the disialoganglioside GD2. PATIENTS AND METHODS: Forty-seven patients with advanced melanoma received either 1-, 2-, 4-, or 8-mg doses of TriGem (Titan Pharmaceuticals Inc, South San Francisco, CA) mixed with QS-21 adjuvant (Aquila Biopharmaceuticals, Inc, Worcester, MA) 100 μg subcutaneously weekly for 4 weeks and then monthly until disease progression. Median age was 57 years, there were 32 men and 15 women, 43% of patients had undergone prior therapy for metastatic disease, 55% had disease confined to soft tissue, and 45% had visceral metastasis. RESULTS: Hyperimmune sera from 40 of 47 patients showed an anti–anti-idiotype (Ab3) response. Patient Ab3 was truly Ab1′ because it specifically bound purified disialoganglioside GD2. The isotypic specificity of the Ab3 antibody consisted of predominantly immunoglobulin (Ig)G, and all IgG subclasses were represented. One patient had a complete response that persisted at 24 months, and 12 patients were stable from 14+ to 37+ months (median, 18+ months). Disease progression occurred in 32 patients on study from 1 to 17 months (median, 5.5 months), and 21 have died at 1 to 16 months (median, 6 months). The Kaplan-Meier–derived overall median survival has not been reached. Median survival has not been reached for the 26 patients with soft tissue disease only and was 13 months for 21 patients with visceral metastasis. Toxicity consisted of local reaction at the site of injection and mild fever and chills. CONCLUSION: TriGem has minimal toxicity and generates robust and specific IgG immune responses against GD2. Objective responses were minimal, but there may be a favorable impact on disease progression and survival that will require prospective randomized trials.

Download Full-text

High-dose interleukin-2 (HD IL-2) in the treatment of advanced melanoma: The University of Pittsburgh experience.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.9075 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. 9075-9075

Author(s):

Diwakar Davar ◽

Melissa Saul ◽

Ahmad A. Tarhini ◽

An Tran ◽

Kerry Trent ◽

...

Keyword(s):

Proportional Hazards ◽

Interleukin 2 ◽

Complete Response ◽

Median Number ◽

Cox Proportional Hazards ◽

Advanced Melanoma ◽

High Dose ◽

Severe Toxicity ◽

University Of Pittsburgh ◽

Radiological Data

9075 Background: IL-2 is a T-cell growth factor tested in a variety of regimens for advanced melanoma (MEL) and renal cell carcinoma (RCC). High-dose IL-2 (600,000-720,000 IU/kg administered intravenously every 8 hours for up to 14 consecutive doses) was approved by FDA for advanced MEL and RCC in 1998 based upon the durability of responses observed. Early studies of HD IL-2 reported overall (OR) and complete response (CR) rates of 16% and 8% respectively. Severe toxicity limited use to specialized centers with standardized protocols, either intensive care (ICU) or oncology specialty settings. The U Pittsburgh has treated 1022 patients with IL-2 at any dosage and we here present outcomes of 550 MEL pts treated with HD IL-2 in an oncology specialty non-ICU setting. Methods: Clinical and radiological data were collected on all pts treated with IL-2 using the UPCI Cancer Registry and Medical Archival System (MARS). Pharmacy records were reviewed for dosing details. The influence of baseline characteristics on treatment outcomes was assessed using Cox proportional hazards analysis. Results: A total of 848 pts received HD IL-2, of which 298 pts had RCC while 550 had MEL. Detailed pharmacy dosing records were reviewed from 176 pts treated over the past 12 years (2000-2012) who received a total of 3738 cycles. Of 165 pts evaluable for response, OR was documented in 24 pts (14.8%) and CR in 5 pts (3.0%). Median overall survival (OS) was 10.0 mos for all patients and 21.5 mos for responders (CR+PR). Median number of doses per cycle was 7. Toxicity was consistent with prior reports. HD IL-2 required ICU transfers in 5% and 1 death was attributed to HD IL-2. Pts with higher baseline lactate dehydrogenase (LDH) had poorer OS (p < 0.05). Conclusions: In this large and uniformly treated series of recent patients treated with IL-2 OR/CR rates with HD IL-2 are 14.8% and 3.0% respectively. Higher LDH is associated with poorer outcome. Biomarkers of response are currently being evaluated in banked clinical specimens collected from patients under the SPORE in Skin Cancer (P50 CA121973).

Download Full-text

Outcomes of advanced melanoma patients who discontinued pembrolizumab (pembro) after complete response (CR) in the French early access program (EAP)

Annals of Oncology ◽

10.1093/annonc/mdz255.033 ◽

2019 ◽

Vol 30 ◽

pp. v549

Author(s):

P. Saiag ◽

L. Mortier ◽

C. Dutriaux ◽

L. Benmahammed ◽

O. Morsli ◽

...

Keyword(s):

Complete Response ◽

Advanced Melanoma ◽

Early Access ◽

Melanoma Patients ◽

Access Program

Download Full-text

Retrospective study comparing survival when ipilimimab used with and without radiotherapy in patients with advanced melanoma.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.7_suppl.83 ◽

2017 ◽

Vol 35 (7_suppl) ◽

pp. 83-83

Author(s):

Dominique Siobhan Parslow ◽

Toby Laurence James Talbot

Keyword(s):

Median Survival ◽

Braf Mutation ◽

Complete Response ◽

Advanced Melanoma ◽

Prognostic Indicators ◽

Wild Type ◽

Survival Difference ◽

Significant Survival ◽

Impact On Survival ◽

Autoimmune Phenomena

83 Background: Ipilimumab, a monoclonal antibody targeting CTLA-4, has increased median survival in patients with advanced melanoma from 6.4 to 10 months, with 20% of patients showing a sustained response. Preclinical and clinical studies have shown possible synergistic and abscopal effects between ipilimumab and radiotherapy. The aim of this study was to compare survival curves of patients who have received ipilimumab with and without radiotherapy, and also look at other potential prognostic indicators for patients with advanced melanoma. Methods: Data was collected retrospectively from patients with advanced melanoma treated with ipilimumab at Royal Cornwall Hospital (RCH), United Kingdom. The data collection proforma included: demographic details, BRAF status, treatments prior to and since ipilimumab, whether and when radiotherapy given, response, autoimmune phenomena documented, overall survival, and survival time since ipilimumab. Results: 43 patients (20 men and 23 women) have received ipilimumab for metastatic melanoma at RCH between 2011 and 2015. Age range 27-88 years, with a median age of 60 years. 13 were BRAF mutated, 28 were BRAF wild-type and 2 were unknown. 33% of patients who received ipilimumab had some response to it, with 21% achieving a complete response. 25% of patient who displayed autoimmune phenomena clinically responded to ipilimumab; only 15% of those who did not display autoimmune phenomena clinically responded. 20 patients received radiotherapy and 23 did not; there was no significant survival difference related to radiotherapy usage. Patients with the BRAF mutation had a shorter median survival than those who were BRAF wild-type. Conclusions: Although this study was retrospective and not randomised, it appears to show an increased likelihood of a response to ipilimumab in patients who also had autoimmune side effects from treatment. Patients with a BRAF mutation had a shorter median survival than those who were BRAF wild type. The addition of radiotherapy to ipilimumab did not appear to impact on survival or response, although, as the patients were not randomised as to whether they received radiotherapy it is difficult to draw firm conclusions from this.

Download Full-text

A phase I study of neoadjuvant combination immunotherapy in locally/regionally advanced melanoma.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.9586 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. 9586-9586 ◽

Cited By ~ 2

Author(s):

Yana Najjar ◽

Dustin McCurry ◽

Huang Lin ◽

Yan Lin ◽

Diwakar Davar ◽

...

Keyword(s):

Immune Cell ◽

Pathologic Complete Response ◽

Complete Response ◽

Advanced Melanoma ◽

Post Treatment ◽

Interferon Α ◽

Clinical Activity ◽

High Dose ◽

Standard Regimen ◽

Definitive Surgery

9586 Background: A trial of neoadjuvant pembrolizumab (P) in combination with high dose interferon-α (HDI) in high-risk patients (pts) with locoregionally advanced melanoma (mel) has completed enrollment. Methods: Primary endpoint: safety of combination P-HDI. Pts were treated with P x 2 doses followed by definitive surgery, then x1 year. HDI was given concurrently, and both agents were per standard regimen. Tumor and blood samples were obtained at baseline and at surgery (wk 6-8), blood at 6 wks, 3,6,12 months (mos). Results: 30 pts were treated (22 male, 8 female, age 26-83). 16 had cutaneous primary, 3 mucosal, 11 unknown. At enrollment, 16 had recurrent disease, 6 received prior adjuvant therapy with ipilimumab (4) or HDI (2). 16 had AJCC 7 stage IIIB, 9 IIIC, 5 IV. 332 P cycles have been delivered (median 13), 496 doses of HDI induction (median 17), 1329 doses of HDI maintenance (median 44). HDI was dose reduced in 20 pts, discontinued in 27, P discontinued in 8. Radiologic preoperative RR was 77% (95% CI, 59-88) (6 CR, 17 PR). 20% (6) had SD and 1 had PD. All pts underwent definitive surgery. The pathologic complete response (pCR) of 26 pts was 32% (95% CI, 18-51). 6 pts recurred and 3 died. No pt with pCR has recurred. Median f/u time is 17.4 mos, median PFS/OS not reached. Most common grade (Gr) 3 toxicities: hypophosphatemia (10; 33%), fatigue (10; 33%), ↑CPK (6; 20%), ↑lipase (4; 13%). 3 Gr 4 events (↑CPK, hyperglycemia, lymphocyte count decreased). 1 suspected grade 5 event occurred 6 months after completion of therapy. PD-L1 expression at baseline did not correlate with clinical outcomes. In 8 pts with pre and post treatment tumor samples, IHC expression of PD-1, PD-L1, CD11b, CD8, Foxp3 and CD25 increased post-treatment (p < 0.05). Conclusions: Neoadjuvant P-HDI has promising clinical activity, although treatment is limited by HDI toxicity. Treatment increases the immune cell infiltrate, and outcomes do not correlate with baseline expression of PD-L1. Longer follow up and further mechanistic studies are underway. Clinical trial information: NCT02339324.

Download Full-text

Effects of baseline lactate dehydrogenase (LDH), interferon gamma (IFN-g) expression, and tumor mutational burden (TMB) on treatment response to first-line atezolizumab (A) + vemurafenib (V) and cobimetinib (C) in BRAFV600 mutation–positive advanced melanoma.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.9523 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 9523-9523

Author(s):

Caroline Robert ◽

Karl D. Lewis ◽

Paolo Antonio Ascierto ◽

Rodrigo Ramella Munhoz ◽

Gabriella Liszkay ◽

...

Keyword(s):

Group Performance ◽

Performance Status ◽

Recursive Partitioning ◽

Objective Response ◽

Eastern Cooperative Oncology Group ◽

Complete Response ◽

Advanced Melanoma ◽

First Line ◽

L1 Data ◽

Metastatic Sites

9523 Background: The phase 3 IMspire150 study showed that first-line A+V+C improved investigator-assessed PFS vs placebo (P)+V+C in BRAFV600E/K mutation–positive advanced melanoma (hazard ratio 0.78; P=.0249). Prior biomarker analyses showed that IFN-g or TMB > 10 mut/Mb were associated with greater PFS benefits with A+V+C (Lewis et al. J ImmunoTher Cancer 2020;8:A188-A189). We further evaluated the association of these biomarkers with outcomes. Methods: Exploratory recursive partitioning analysis (RPA) was used to model associations between PFS and age ( < 65 vs ≥65 y), Eastern Cooperative Oncology Group performance status (0 vs 1), liver metastases (yes vs no), metastatic sites (≤3 vs > 3), sum of longest tumor diameters ( < 44 mm vs ≥44 mm), baseline LDH (normal [n] vs elevated [e]), TMB ( < 10 vs ≥10 mut/Mb), PD-L1 (negative vs positive), and IFN-g (high [h; > Quartile 3; Q3] vs intermediate [ > Q1 and ≤Q3] vs low [≤Q1]). Time-to-event analyses were summarized using Kaplan-Meier estimates. Results: The RPA analysis included 208/256 (81.3%) patients (pts) from the A+V+C arm of IMspire150 for whom LDH, TMB, IFN-g, and PD-L1 data were available. RPA showed that LDH was associated with PFS. In pts treated with A+V+C and n-LDH, h-IFN-g signature was associated with longer PFS and higher rates of objective response (OR) and complete response (CR) vs low/intermediate (l/i) IFN-g (2-y PFS: 59% vs 38%; ORR: 77% vs 69%; CR: 38% vs 15%, respectively); TMB ≥10 mut/Mb was associated with more favorable outcomes in pts with e-LDH (Table). In contrast, neither IFN-g nor TMB discriminated PFS outcomes in n-LDH or e-LDH pt subgroups receiving P+V+C. Pts with e-LDH and TMB < 10 mut/Mb had poor PFS outcomes, with 2-y PFS rates of 9% and 3% and lower rates of OR (51% and 62%) and CR (5% and 9%) in the A+V+C and P+V+C arms, respectively. Similar trends were observed for duration of response (DOR), and for the subset of pts with BRAFV600E mutation–positive melanoma. A+V+C improved PFS vs P+V+C across all subgroups with the exception of e-LDH and TMB < 10. Conclusions: IFN-g and TMB discriminated PFS benefit in pts receiving A+V+C but not for those receiving P+V+C. Durable responses were observed for pts treated with A+V+C in the n-LDH + h-IFNg subgroups.[Table: see text]

Download Full-text

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.

Download Full-text