Articles

A grant from the Melanoma Research Foundation powers the initial stages of the project.

Mouse Model May Shed Light on APC mutations in brain metastases

Study shows nearly 50% reduction in benign lesions excised. 

Reflectance confocal microscopy slashes needless excisions

New synthetic small molecule aims to counter drug resistance in BRAF-mutated melanomas.

Novel Molecule Shows Preclinical Success in Treating Vemurafenib-Resistant Melanoma

Immunotherapy, intralesional treatments, multidisciplinary care teams define rapidly-evolving multimodal approach.

What’s Ahead for Melanoma Management

Data shows that the overall rate of melanoma diagnosis rose sixfold over the last 4 decades at a time when melanoma mortality stayed relatively stable.

Study Reports Melanoma Overdiagnosis in White Patients  

The FDA has approved the fixed-dose combination of relatlimab plus nivolumab for the treatment of adult and pediatric patients who are 12 years of age or older and who have unresectable or metastatic melanoma.

FDA Approves Relatlimab Plus Nivolumab for Unresectable or Metastatic Melanoma

A phase 1 study of davoceticept and pembrolizumab for advanced malignancies received a partial clinical hold from the FDA following a patient death.

FDA Places Partial Clinical Hold on Phase 1 Trial of Davoceticept Pembrolizumab in Advanced Malignancies

The addition of bempegaldesleukin to nivolumab did not significantly improve progression-free survival, objective response rate, or overall survival vs nivolumab alone in the frontline treatment of patients with unresectable or metastatic melanoma, missing the primary end points of the phase 3 PIVOT IO-001 trial.

Frontline Bempegaldesleukin Nivolumab Combo Misses Primary End Points in Unresectable or Metastatic Melanoma

Researchers at the University of California in San Diego have discovered extrafollicular skin cells that transform into antimicrobial fat cells and fight acne, according to a study published in Science Translational Medicine.

Newly Discovered Antimicrobial Fat Cells May Offer New Treatment Options for Acne

The FDA has accepted an investigational new drug application for the photoimmunotherapy treatment, RM-1995, for patients with advanced cutaneous squamous cell carcinoma or head and neck squamous cell carcinoma.


FDA Accepts IND for RM-1995 Photoimmunotherapy in Advanced Cutaneous or Head and Neck SCC

The European Medicines Agency has validated its marketing authorization application for the fixed-dose combination of relatlimab and nivolumab (Opdivo) in the frontline treatment of adult and pediatric patients with advanced melanoma.

The filing follows primary results from the 

(NCT03470922), which showed that the doublet resulted in a median progression-free survival (PFS) of 10.12 months (95% CI, 6.37-15.74) vs 4.63 months (95% CI, 3.38-5.62) with nivolumab monotherapy (hazard ratio [HR], 0.75; 95% CI, 0.62-0.92; 

 = .0055); this translated to a 5.49-month improvement.

Moreover, the PFS rate at 12 months in the investigative arm was 47.7% (95% CI, 41.8%-53.2%) vs 36.0% (95% CI, 30.5%-41.6%) in the control arm. Notably, the PFS benefit demonstrated with the fixed-dose regimen was observed regardless of prespecified subgroups and stratification factors.

“Melanoma can be a devastating disease and cases have been on the rise for years. The results from the RELATIVITY-047 trial demonstrate the potential that the relatlimab and nivolumab fixed-dose combination holds for people with advanced forms of this cancer,” Jonathan Cheng, senior vice president and head of oncology development at Bristol Myers Squibb, stated in a press release. “If approved, this treatment would become the first of its kind available to patients in the European Union. We look forward to working with the EMA as they evaluate this combination – which includes our third distinct check point inhibitor – and are proud of this first step toward making it available for patients with advanced melanoma.”

The global, double-blind, phase 2/3 RELATIVITY-047 trial enrolled 714 treatment-naïve patients with unresectable or metastatic melanoma who had an ECOG performance status of 0 or 1. Participants were randomized in a 1:1 fashion to intravenous (IV) relatlimab at 160 mg plus nivolumab at 480 mg every 4 weeks or IV nivolumab alone, given at 480 mg every 4 weeks.

Patients were stratified based on LAG-3 and PD-L1 status, 

 mutational status, and American Joint Committee on Cancer (AJCC) version 8 metastatic stage.

The primary end point of the research was PFS per blinded independent central review (BICR). Secondary end points comprised overall survival (OS) and overall response rate (ORR) by BICR.

The median age of participants across the treatment arms was 63 years and 41.7% were female. Moreover, 66.9% of patients had an ECOG performance status of 0 and 36.1% had a serum lactate dehydrogenase level that was greater than the upper limit of normal; 38.9% of patients had a AJCC v.8 metastatic stage of M1C, and 2.4%had a stage of M1D.

Just over 8% of patients (8.4%) received prior neoadjuvant or adjuvant therapy. In the combination arm, the median tumor burden was 59.0 mm vs 54.5 mm in the monotherapy arm. Moreover, 75.2% of patients had a LAG-3 expression of 1% or higher, 59.0% had a PD-L1 expression that was less than 1%, 61.5% had 

wild-type disease, and 65.7% had a AJCC metastatic stage of M0/M1any(0).

 revealed that the HR for PFS in the subset of patients with cutaneous acral melanoma was 0.84 (95% CI, 0.50-1.39); in those with cutaneous non-acral disease, mucosal disease, and other subtypes, the HRs for PFS were 0.73 (95% CI, 0.57-0.93), 0.72 (95% CI, 0.36-1.45), and 0.77 (95% CI, 0.44-1.36), respectively.

The PFS benefit was found to favor the fixed-dose doublet over the monotherapy, irrespective of LAG-3 expression status. Among those with a LAG-3 expression of 1% or higher who were randomized to the investigative (n = 268) or control (n = 269) arms, the median PFS was 12.58 months (95% CI, 6.67-23.10) and 4.76 months (95% CI, 4.47-8.61), respectively (HR, 0.75; 95% CI, 0.59-0.95). In those with an expression of less than 1%, the median PFS with the doublet (n = 87) was 4.83 months (95% CI, 2.86-10.05) vs 2.79 months (95% CI, 2.79-4.63) with the monotherapy (n = 90; HR, 0.78; 95% CI, 0.54-1.15).

 demonstrated that those who received the fixed-dose combination and who discontinued treatment (n = 167) experienced a longer treatment-free interval (TFI) vs those who were given single-agent nivolumab (n = 151).

 The median TFI in the investigative and control arms was 3.32 months (range, 0.1-30.4) and 1.41 months (range, 0.1-25.6), respectively.

Relatlimab/nivolumab also resulted in reduced risk of progression after the next line of systemic therapy (PFS2), according to investigator assessment, or death vs single-agent nivolumab. The median PFS2 had not yet been reached (95% CI, 21.75–not reached) with the doublet vs 20.04 months (95% CI, 15.44-25.13) with the monotherapy (HR, 0.77; 95% CI, 0.61-0.97).

The median duration of treatment in the investigative and control arms was 5.6 months and 4.9 months, respectively, and 66.8% and 64.9% of patients, respectively, discontinued treatment. The most common reasons for therapy discontinuation included disease progression (36.3% vs 46.0%, respectively), treatment-related adverse effects (AEs; 17.7% vs 8.9%), patient request (5.4% vs 3.3%), and a toxicity that was not associated with the treatment (3.4% vs 3.9%).

Moreover, 37.3% of patients who received nivolumab only received subsequent therapy compared with 35.5% of those who were given the doublet; 29.8% and 27.9% of patients, respectively, received systemic therapy.

In the investigative and control arms, subsequent treatments included PD-1 and/or CTLA-4 inhibitors (9.0% vs 12.8%, respectively), BRAF and/or MEK inhibitors (11.5% vs 13.9%), or other systemic options (10.7% vs 12.3%). Additionally, 11.5% of those on relatlimab/nivolumab vs 10.0% of those on nivolumab monotherapy went on to receive radiotherapy; 5.1% vs 2.7%, respectively, went on to undergo surgery.

Additionally, 40.7% of the off-treatment patients included in the TFI analysis who were given the doublet did not go on to receive subsequent systemic therapy compared with 29.1% of those who had been given single-agent nivolumab. In the doublet and monotherapy arms, 31.1% and 37.7% of patients, respectively, went on to receive subsequent treatment.

Regarding safety, the doublet was found to be tolerable and did not showcase any new signals.

Follow-up of the secondary end points of OS and ORR is ongoing.

FDA granted priority review to a biologics license application for relatlimab plus nivolumab

for use in adult and pediatric patients aged 12 years and older who weigh at least 40 kg and who have unresectable or metastatic melanoma. The application is based on data from RELATIVITY-047.

This article was initially published by our sister publication

European Medicines Agency validates Bristol Myers Squibb’s application for LAG-3-blocking antibody relatlimab and nivolumab fixed-dose combination as first-line treatment for patients with unresectable or metastatic melanoma. News release. Bristol Myers Squibb. October 1, 2021. Accessed October 1, 2021. 

Lipson EJ, Tawbi HA, Schadendorf D, et al. Relatlimab (RELA) plus nivolumab (NIVO) versus NIVO in first-line advanced melanoma: primary phase III results from RELATIVITY-046 (CA224-047). 

. 2021;39(suppl 15):9503. doi:10.1200/JCO.2021.39.15_suppl.9503

Hodi FS, Tawbi HA, Lipson EJ, et al. Relatlimab (RELA) + nivolumab (NIVO) versus NIVO in previously untreated metastatic or unresectable melanoma: additional efficacy in RELATIVITY-047. Presented at: 2021 ESMO Congress; September 16-21, 2021; Virtual. Abstract 1036O.

US Food and Drug Administration accepts for priority review Bristol Myers Squibb’s application for LAG-3-blocking antibody relatlimab and nivolumab fixed-dose combination as treatment for patients with unresectable or metastatic melanoma. News release. Bristol Myers Squibb. September 20, 2021. Accessed October 1, 2021. 

The European Medicines Agency has validated its marketing authorization application for the fixed-dose combination of relatlimab and nivolumab in the frontline treatment of adult and pediatric patients with advanced melanoma.

Relatlimab/Nivolumab Application for Frontline Advanced Melanoma Validated by EMA

From orphan drug designations to biologics license applications, dermatologists have a lot to pay attention to in the melanoma treatment pipeline over the coming months.

Merck & Co, Inc, announced its phase 3 KEYNOTE-716 (NCT03553836) trial investigating pembrolizumab (Keytruda) has met its primary end point of recurrence-free survival (RFS) for the treatment of patients with surgically removed stage II melanomas.

Based on that data, the FDA has accepted a new supplemental biologics license application (sBLA) for pembrolizumab to treat patients 12 aged years or older with stage IIB or IIC melanoma following removal and has set a Prescription Drug User Fee Act (PDUFA) date for December 4, 2021.

Pembrolizumab is a humanized monoclonal antibody that blocks the interaction between an anti-programmed death receptor (PD)-1 and its ligands, PD-L1 and PD-L2, thus activating T-lymphocytes, which may affect both tumor and healthy cells. 

An analysis of the current data showed that treatment with pembrolizumab as a single agent demonstrated statistically significant improvement in RFS compared with placebo as adjuvant therapy for patients. No new safety signals were observed.

KEYNOTE-716 is a randomized, 2-part, phase 3 trial evaluating the adjuvant treatment of patients with completely resected high-risk stage II melanoma. There were 954 patients aged 12 years and older enrolled in the study and the primary end point was RFS. The secondary end points were distant metastasis-free survival, overall survival, safety, and quality of life.

Part 1 of the study was double blind and the adult patients were randomized to be treated either with pembrolizumab 200 mg intravenously (IV) or placebo by IV every 3 weeks for up to 17 cycles (1 year). The pediatric patients were randomized to be treated with pembrolizumab 2 mg/kg with a maximum dose of 200 mg or placebo every 3 weeks for up to 17 cycles (1 year).

The second part of the study was an open label trial for adult and pediatric patients who were treated with up to 35 cycles, up to 2 years, of pembrolizumab. To be eligible for part 2, patients had to have recurred after receiving placebo or completed 17 cycles of pembrolizumab and patients on pembrolizumab must not have experienced disease recurrence within 6 months of completing treatment. 

“KEYNOTE-716 is the first phase 3 study to evaluate adjuvant therapy solely for stage IIB and IIC melanoma—an area with high unmet need,” said Jason Luke, MD, director, Cancer Immunotherapeutics Center at University of Pittsburgh Medical Center Hillman Cancer Center in Pennsylvania. “By moving immunotherapy with Keytruda to earlier stages of melanoma, we have the opportunity to reduce the risk of recurrence for high-risk stage II patients compared to observation alone following complete resection.”

Pembrolizumab has been established as an important treatment option for the adjuvant treatment of patients with resected stage III melanoma since 2019 and is approved in more than 90 countries based on results from the EORTC 1325/KEYNOTE-054 (NCT02362594). Also, it is approved for treatment of patients with unresectable or metastatic cancer worldwide. KEYNOTE-716 contributes to data seen in earlier stages of disease in 4 tumor types (melanoma, renal cell carcinoma, triple-negative breast cancer, and non-muscle invasive bladder cancer).

“The phase 3 KEYNOTE-716 clinical trial results by Merck are very encouraging for patients with stage IIB or IIC melanoma,” said Christopher Bunick, a physician-scientist practicing general medical and surgical dermatology at Yale University in New Haven, Connecticut, and a 

 board member. “It means that dermatologists and stage II melanoma patients will have a new option for therapy after surgical resection to lengthen recurrence-free survival. Cancer patients want a long, high-quality life, and pembrolizumab offers improvements in this regard for stage IIB or IIC melanoma patients.

The FDA has given fast track designation for nemvaleukin alfa (ALKS 4230; Alkermes plc), an investigational engineered interleukin (IL)-2 variant immunotherapy, for the treatment of mucosal melanoma.

 This comes after the FDA granted orphan drug designation to nemvaleukin alfa for the treatment of mucosal melanoma.

the start of its investigational phase 2 trial, ARTISTRY-6 (NCT04830124), a global study evaluating the anti-tumor activity, safety, and tolerability of nemvaleukin alfa monotherapy, intravenously (IV) administered in patients who have mucosal melanoma and subcutaneously in patients with advanced cutaneous melanoma, who have previously treated with an anti-programmed death-ligand (PD-L)1 therapy.

“Nemvaleukin alfa is a very exciting therapy because it is molecularly unique. It is a fusion protein comprised of modified IL-2 and the high-affinity IL-2 alpha receptor chain, and its mission is to enhance the body’s immune cells to target and destroy tumors,” said Bunick. “The FDA fast track designation is particularly promising for patients with mucosal melanoma, as more types of effective melanoma therapies are needed to improve patient survival.”

The FDA has granted an orphan drug designation (ODD) to alrizomadlin (APG-115; Ascentage Pharma), a mouse double minute 2 homolog (MDM2)-p53 inhibitor, for the treatment of IIB-IV melanoma.

This is the fifth ODD granted to alrizomadlin, the others being for the treatment of gastric cancer, acute myeloid leukemia, soft tissue sarcoma, and retinoblastoma. The FDA granting the ODD to alrizomadlin qualifies it for tax credit on expenditures incurred in clinical studies, a waiver of the new drug application (NDA) fee, a possible research grant awarded by the FDA, and 7 years of US market exclusivity upon approval.

At the virtual 2021 American Society of Clinical Oncology (ASCO) Annual Meeting held June 4-8, 2021, Ascentage Pharma reported results from a phase 1/2 trial (NCT03611868) in which alrizomadlin was examined in combination with pembrolizumab in patients who received a diagnosis of metastatic melanoma or advanced solid tumors.

The trial has 2 phases: the dose-escalation phase and the dose-expansion phase. In the first phase, alrizomadlin was given in once-daily doses for 2 weeks consecutively that ranged from 50 mg, 100 mg, 150 mg, to 200 mg. After the 2 weeks, there was 1 week off in a 21-day treatment cycle. This part was to help determine a phase 2 dose.

The dose for the second phase was 150 mg once every other day for 2 consecutive weeks with 1 week off and combined with pembrolizumab at 200 mg dose via IV infusion for 30 minutes on day 1 of a 21-day cycle, according to the research article.6 This phase will feature 6 cohorts: melanoma (n = 26), non–small cell lung cancer (NSCLC) (n = 23), ataxia telangiectasia mutated (ATM) mutation (n = 9), liposarcoma (n = 14), urothelial (n = 9), and malignant peripheral nerve sheath tumor (MPNST) (n = 3).

To be included in the trial, patients had to be aged 18 years or older, have histologically confirmed unresectable or metastatic solid tumors, be resistant to standard of care (SOC) approaches, have an Eastern Cooperative Oncology Group performance status of 0 to 2, and have a measurable disease per RECIST v1.1 criteria. If patients received a diagnosis of melanoma, NSCLC, or urothelial carcinoma, the cancer would need to have relapsed or be resistant following PD-1 or PD-L1 inhibitor treatment.

The results found that in the PD-1/PD-L1 inhibitor-failed melanoma cohort, there was 1 confirmed partial response (PR) out of 5 patients with uveal melanoma, 2 PR (1 confirmed and 1 unconfirmed) of 5 patients with mucosal melanoma, and 1 confirmed PR of 11 patients with cutaneous melanoma, according to the research. The tumor objective response rate (ORR) in the melanoma cohort was 17.4%, and the disease control rate was 60.9%. In the MPNST cohort, 1 of 3 patients had an unconfirmed ongoing PR. In the NSCLC and urothelial cohorts, each reported 1 confirmed PR.

The common treatment related adverse events (TRAEs) were nausea (63.1%), thrombocytopenia (36.9%), vomiting (33.3%), fatigue (31.0%), decreased appetite (27.4%), diarrhea (21.4%), neutropenia (15.4%), and anemia (11.9%). Grade greater than or equal to 3 TRAEs (greater than or equal to 5%) included thrombocytopenia (20.2%), neutropenia (14.2%), and anemia (8.3%). The 3 treatment-related serious adverse events (SAEs) were posterior reversible encephalopathy syndrome (PRES), pyrexia, and asthenia.

There were 11 patients who discontinued treatment because of adverse effects, of which 5 were treatment related (2 of grade 4 thrombocytopenia, 1 of grade 2 vomiting, 1 of grade 2 fatigue, and 1 of grade 2 PRES).

“It is hard to predict what single agent, if any, will be completely effective against melanoma,” Bunick explained. “The next year or so is likely to see results from trials of combinations of these newer anti-melanoma medicines with immune checkpoint inhibitors or other anti-cancer drugs. It will be interesting to see if a more powerful anti-melanoma combination or ‘melanoma cocktail’ will emerge from those studies.”

1. Merck’s Keytruda (pembrolizumab) significantly prolonged recurrence-free survival (RFS) compared to placebo as adjuvant therapy for patients with stage II resected high-risk melanoma in phase 3 keynote-716 trial. News release. Merck. August 5, 2021. Accessed August 10, 2021. 

https://www.merck.com/news/mercks-keytruda-pembrolizumab-significantly-prolonged-recurrence-free-survival-rfs-compared-to-placebo-as-adjuvant-therapy-for-patients-with-stage-ii-resected-high-risk-melanoma-in/

2. Alkermes receives FDA fast track designation for nemvaleukin alfa for the treatment of mucosal melanoma. News release. Alkermes plc. August 2, 2021. Accessed September 2, 2021. 

https://investor.alkermes.com/news-releases/news-release-details/alkermes-receives-fda-fast-track-designation-nemvaleukin-alfa/

3. Alkermes announces FDA orphan drug designation for nemvaleukin alfa for treatment of mucosal melanoma. News release. Alkermes plc. March 11, 2021. Accessed September 2, 2021. 

https://investor.alkermes.com/news-releases/news-release-details/alkermes-announces-fda-orphan-drug-designation-nemvaleukin-alfa/

4. Alkermes initiates ARTISTRY-6 trial of nemvaleukin alfa monotherapy in patients with melanoma. News release. Alkermes plc. April 27, 2021. Accessed September 2, 2021. 

https://investor.alkermes.com/news-releases/news-release-details/alkermes-initiates-artistry-6-trial-nemvaleukin-alfa-monotherapy/

5. Ascentage Pharma’s mdm2-p53 inhibitor apg-115 (Alrizomadlin) granted an orphan drug designation by the FDA for the treatment of stage IIB-IV melanoma, marking the twelfth obtained by the company. News release. Ascentage Pharma. July 21, 2021. Accessed September 2, 2021. https://www.ascentagepharma.com/press-releases/ascentage-pharmas-mdm2-p53-inhibitor-apg-115-alrizomadlin-granted-an-orphan-drug-designation-by-the-fda-for-the-treatment-of-stage-iib-iv-melanoma-marking-the-twelfth-obtained-by-the-compa/ 

6. Tolcher AW, Reeves JA, McKean M, et al. Preliminary results of a phase II study of alrizomadlin (APG-115), a novel, small molecule MDM2 inhibitor, in combination with pembrolizumab in patients (pts) with unresectable or metastatic melanoma or advanced solid tumors that have failed immuno-oncologic (I-O) drugs. J Clin Oncol. 2021;39(suppl 15):2506. doi:10.1200/JCO.2021.39.15_suppl.2506

7. FDA grants orphan drug designation to alrizomadlin for stage IIB-IV melanoma. OncLive®. July 21, 2021. Accessed September 2, 2021. https://www.onclive.com/view/fda-grants-orphan-drug-designation-to-alrizomadlin-for-stage-iib-iv-melanoma

Possible melanoma treatments have had multiple newsworthy events since July 2021.  

Pipeline Updates in Melanoma

Bristol Myers Squibb has announced today that the FDA accepted the priority review for the Biologics License Application (BLA) for the fixed combination dose of relatlimab (Bristal Myers Squibb) and nivolumab (Bristol Myers Squibb)—lymphocyte-activation gene (LAG)-3 blockers—administered as a single infusion, for the treatment of patients 12 years or older and weighting at least 40kg diagnosed with unresectable or metastatic melanoma. The Prescription Drug User Fee Act (PDUFA) date is set for March 19, 2022.

“Although we’ve seen significant advances in the treatment of melanoma since the introduction of immune checkpoint inhibitors, there continue to be patients who could benefit from a novel dual immunotherapy approach,” said Jonathan Cheng, senior vice president and head of oncology development, Bristol Myers Squibb, Princeton, New Jersey.

The BLA was supported by the efficacy and safety data results of the Phase 2/3 RELATIVITY-047 (NCT03470922) trial, which has demonstrated a statically significant and clinically meaningful progression-free survival benefit of a combination therapy over standard of care anti-PD-1 monotherapy in metastatic melanoma, according to the press release. Reportedly, relatlimab is the first LAG-3-blocking antibody to demonstrate a clinical benefit for patients with Phase 3 data.

The primary results from the trial were presented at the American Society of Clinical Oncology (ASCO) annual meeting in June of 2021. The fixed-dose combination of relatlimab and nivolumab is not approved for use and is still an investigational therapy. 

Chang said, “Based on the results of the RELATIVITY-047 trial, we believe that the relatlimab and nivolumab fixed-dose combination has the potential to improve outcomes for patients with metastatic or unresectable melanoma. We look forward to potentially introducing the first LAG-3-blocking antibody, and Bristol Myers Squibb’s third distinct checkpoint inhibitor, to help patients in need.”

1. U. S. Food and drug administration accepts for priority review Bristol Myers Squibb’s application for lag-3-blocking antibody relatlimab and nivolumab fixed-dose combination as treatment for patients with unresectable or metastatic melanoma. Accessed September 21, 2021. 

https://news.bms.com/news/details/2021/U.S.-Food-and-Drug-Administration-Accepts-for-Priority-Review-Bristol-Myers-Squibbs-Application-for-LAG-3-Blocking-Antibody-Relatlimab-and-Nivolumab-Fixed-Dose-Combination-as-Treatment-for-Patients-with-Unresectable-or-Metastatic-Melanoma/default.aspx

Bristol Myers Squibb has announced that the FDA has accepted the Biologics License Application (BLA) for relatlimab and nivolumab, a fixed-dose combination treatment for unresectable or metastatic melanoma.  

FDA Accepts Priority Review for Melanoma Treatment

The FDA has granted priority review to a supplemental biologics license application (sBLA) for pembrolizumab for the use as an adjuvant treatment in adult and pediatric patients with stage IIB or IIC melanoma following complete resection.

The application is supported by data from the phase 3 KEYNOTE-716 trial (NCT03553836), which demonstrated that adjuvant pembrolizumab monotherapy resulted in a statistically significant and clinically meaningful improvement in recurrence-free survival (RFS) vs placebo in this patient population, meeting the primary end point of the trial. Moreover, no new safety signals were reported with the agent.

Data from KEYNOTE-716 will be shared at an upcoming medical conference, according to Merck.

Under the Prescription Drug User Fee Act, the regulatory agency is anticipated to reach a decision on the sBLA for the immunotherapy by December 4, 2021.

“KEYNOTE-716 is the first phase 3 study to evaluate adjuvant therapy solely for stage IIIB and IIC melanoma – an area with high unmet need,” Jason Luke, MD, director of the Cancer Immunotherapeutics Center at the UPMC Hillman Cancer Center, stated in a press release. “By moving immunotherapy with [pembrolizumab] to earlier stages of melanoma, we have the opportunity to reduce the risk of recurrence for [patients with] high-risk stage II [disease] compared with observation alone following complete resection.”

In the 2-part phase 3 trial, investigators set out to evaluate pembrolizumab as an adjuvant treatment in patients with completely resected, high-risk, stage II melanoma. To be eligible for enrollment, patients could not have received prior treatment for their disease beyond resection, at least 12 weeks needed to have passed between resection and trial randomization, and they could not have evidence of metastatic disease on imaging.

Moreover, patients had to have an ECOG performance status of 0 or 1 and have acceptably recovered from toxicity and/or complications from surgery before the start of the study. Patients could not have a known additional malignancy that was progressing or required active antineoplastic therapy, nor could they have a diagnosis of immunodeficiency or have received prior PD-1/L1 or CTLA-4 agents.

In the first part of the study, which was double blind, adult participants were randomized to receive either intravenous pembrolizumab at a dose of 200 mg or placebo every 3 weeks for up to 17 cycles, which translated to approximately 1 year. Pediatric patients were randomized to receive pembrolizumab at a dose of 2 mg/kg, with a maximum of 200 mg, or placebo for the same duration.

In part 2, which was open label, adult and pediatric patients who were determined to be eligible for inclusion were given up to 35 additional cycles of treatment with pembrolizumab; this translated to approximately 2 years. If patients recurred after receiving placebo or they completed 17 cycles of pembrolizumab, they were eligible to participate in the second portion of the research. If patients who received pembrolizumab experienced disease recurrence within 6 months of treatment completion, they were excluded.

The primary end point of the trial was RFS, and key secondary end points included distant metastasis-free survival, overall survival, safety, and quality of life.

“At Merck we are innovating to fight cancer earlier, and our data continue to build in this important area of research,” Roy Baynes, senior vice president and head of global clinical development, as well as chief medical officer at Merck Research Laboratories, stated in the press release. “Many patients with stage II melanoma have a high risk of their cancer returning after surgery. This is an important milestone for patients, and we look forward to sharing these results with the medical community as soon as possible. We thank the patients and investigators for their participation in this study.”

This article was originally published by our sister publication 

Merck’s KEYTRUDA (pembrolizumab) significantly prolonged recurrence-free survival (RFS) compared to placebo as adjuvant therapy for patients with stage II resected high-risk melanoma in phase 3 KEYNOTE-716 trial. News release. Merck. August 5, 2021. Accessed August 5, 2021. 

Safety and efficacy of pembrolizumab compared to placebo in resected high-risk stage II melanoma (MK-3475-716/KEYNOTE-716). ClinicalTrials.gov. Updated November 12, 2020. Accessed August 5, 2021. 

https://www.clinicaltrials.gov/ct2/show/NCT03553836

The FDA has granted priority review to a supplemental biologics license application for pembrolizumab for the use as an adjuvant treatment in adult and pediatric patients with stage IIB or IIC melanoma following complete resection.

FDA Grants Priority Review to Adjuvant Pembrolizumab for Stage II High-Risk Melanoma

Nemvaleukin alfa (Nemvaleukin) has been granted fast-track designation by the FDA for the treatment of patients with mucosal melanoma who have received prior treatment with an anti–PD-L1 therapy, according to a press release from Alkermes.

Nemvaleukin is an engineered interleukin-2 (IL-2) variant immunotherapy that was previously granted for orphan drug designation for mucosal melanoma.

Additionally, enrollment has begun for the global phase 2 ARTISTRY-6 (NCT04830124) trial, which will investigate the anti-tumor activity, safety, and tolerability of nemvaleukin alfa in patients with mucosal melanoma that have previously undergone treatment with anti-PD-L1 therapy.

"Receiving Fast Track designation from the FDA for nemvaleukin for the treatment of mucosal melanoma is an important milestone for the nemvaleukin development program and underscores nemvaleukin’s potential clinical utility to address an unmet medical need in this difficult-to-treat tumor type," Craig Hopkinson, MD, chief medical officer and executive vice president of research and development at Alkermes, said in a press release.

Investigators plan to enroll approximately 110 patients on ARTISTRY-6 trial , which is still currently recruiting. In this a non-randomized parallel assessment, patients with cutaneous melanoma with be treated with nemvaleukin subcutaneously every 7 days, and patients with mucosal melanoma with be treated with nemvaleukin intravenously for 30 minutes for 5 consecutive days.

The primary outcomes of this study are overall response rate assessed from 2 years after the first dose. Secondary end points are duration of response, progression-free survival, and disease control rate.

"We are committed to advancing this important research in mucosal melanoma, a rare and aggressive form of melanoma for which there are very limited treatment options, particularly for those patients previously treated with checkpoint inhibitors,” Hopkinson said.

A number of ARTISTRY trials are evaluating nemvaleukin both as a single agent and combination regimen across a number of tumor types. For example, investigators are currently using intravenous and subcutaneous doses of nemvaleukin in combination with anti–PD-1 therapy pembrolizumab (Keytruda) for patients with solid tumors.

1. Alkermes receives FDA fast track designation for nemvaleukin alfa for the treat of mucosal melanoma. News Release. Alkermes. August 2, 2021. Accessed August 2, 2021. 

2. Alkermes announces FDA orphan drug designation for nemvaleukin alfa for treatment of mucosal melanoma. News Release. Alkermes. March 11, 2021. Accessed August 2, 2021. 

Immunotherapy agent nemvaleukin alfa was granted an FDA fast track designation for the treatment of patient’s mucosal melanoma for previously undergone treatment with an anti-PD-L1 therapy.

FDA Grants Fast Track Designation to Nemvaleukin Alfa for Mucosal Melanoma

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Delve into the headline-making research, clinical trials, and FDA pipeline reports that are adding life-saving options for medical professionals caring for patients with melanoma.

Access the latest facts, figures, guidelines, survey data, and educational initiatives to keep the practice team ahead of the curve and get patients—and the community—more engaged.

Learn how the leaders in dermatology and related specialties are using new science, technology, genetics, and novel medications to improve outcomes across the staging spectrum.

Get a glimpse of the factors on the horizon that could become gamechangers—from the ripple effects of climate change and pollution to the needs of skin of color patients and costs of care.