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Relevant Articles About Melanoma Research and Clinical Trials

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OncWeekly Featured Trials

MelanomaABP 206NivolumabActiveArgentinaBosnia and HerzegovinaCanadaChileCroatiaCzech RepublicEstoniaFranceGeorgiaGermanyItalyLithuaniaMalaysiaMexicoMoldova, Republic ofPhilippinesPortugalRomaniaSerbiaSouth AfricaSpainTaiwanThailandTurkeyUnited States 9NCT06054555Phase 3
A Study to Evaluate ABP 206 Compared With OPDIVO® (Nivolumab) in Subjects With Unresectable or Metastatic Melanoma

A Study to Evaluate ABP 206 Compared With OPDIVO® (Nivolumab) in Subjects With Unresectable or Metastatic Melanoma

MelanomaNSCLC (Non-Small Cell Lung Cancer)Other CancersSCC (Squamous Cell Carcinoma)Biological: T3011Combination Product: T3011 + pembrolizumabRecruitingAustraliaUnited States 0NCT04370587Phase 1Phase 2
A Clinical Study of Intratumoral MVR-T3011 (T3011) Given as a Single Agent and in Combination With Intravenous Pembrolizumab in Participants With Advanced or Metastatic Solid Tumors

A Clinical Study of Intratumoral MVR-T3011 (T3011) Given as a Single Agent and in Combination With Intravenous Pembrolizumab in Participants With Advanced or Metastatic Solid Tumors

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Role of AXL in SCC Development Among Patients With CLL

KEY TAKEAWAYS

  • The study aimed to investigate the role of AXL activation in the progression of SCC in early-stage, untreated patients with CLL.
  • Researchers found that AXL drives SCC in CLL, suggesting AXL inhibition as a potential therapy.

Occurrence of squamous cell carcinoma (SCC), even in patients with early-stage, untreated chronic lymphocytic leukemia (CLL), presents a significant morbidity risk, with instances of transformation into metastatic skin lesions.

Sutapa Sinha and the team aimed to investigate the underlying mechanisms contributing to SCC development in patients with CLL, focusing on the potential role of AXL signaling in driving cancer progression.

They performed an inclusive analysis involving the purification of CLL cells and extracellular vesicles (EVs) from the blood/plasma of patients with CLL. The expression and activation of AXL were assessed, focusing on its functions in normal keratinocytes (HEKa) using an in vitro co-culture system. Additionally, AXL activity was evaluated in SCC tissues to understand its role in the progression of squamous cell carcinoma in patients with CLL.

About the results, researchers detected aberrant activation of AXL, AKT, and ERK-1/2 in SCC cell lines compared to HEKa. They also observed increased expression of AXL in primary SCC tissues obtained from patients with CLL. Increased activation of AXL, AKT, ERK-1/2, and Src was discernible in HEKa upon co-culturing with CLL cells.

Further analysis suggests that Gas6, a ligand of AXL, regulates AXL activation in co-cultured HEKa. Interestingly, exposure of HEKa cells to CLL plasma-derived EVs induced the expression of AXL, P-AKT, and EMT-associated markers, leading to cell migration. Finally, pharmacologic inhibition of AXL-induced cell death in SCC lines in a dose-dependent manner.

The study concluded that CLL cells are likely involved in driving SCC progression, at least in part, via activation of the AXL signaling axis. This indicates that AXL inhibition may be beneficial for CLL patients with SCC.

This study was funded by Mayo Internal Funding.

Source: https://pubmed.ncbi.nlm.nih.gov/38886556/

Sinha S, Guo R, Del Busso MD, et al. (2024). “Aberrant activation of AXL may drive progression of squamous cell carcinoma in CLL patients: a mechanistic study with clinical implications.” Br J Cancer. 2024 Aug;131(3):589-600. doi: 10.1038/s41416-024-02752-1. Epub 2024 Jun 17. PMID: 38886556; PMCID: PMC11300914.

Impact of Cemiplimab on QoL in Patients With mBCC

KEY TAKEAWAYS

  • The phase 2 trial aimed to assess the impact of cemiplimab on QoL in patients with mBCC unsuitable for HHI.
  • Researchers noticed that cemiplimab treatment in patients with mBCC led to improved or maintained GHS.

A phase 2 cemiplimab study (NCT03132636) demonstrated a 24.1% objective response rate (ORR) in patients diagnosed with metastatic basal cell carcinoma (mBCC) who were not candidates for continued hedgehog inhibitor (HHI) therapy due to intolerance to previous HHI therapy, disease progression while receiving HHI therapy, or having not better than stable disease on HHI therapy after 9 months. This abstract reports on the health-related quality of life (QoL) for this patient population.

Ketty Peris and the team aimed to assess the impact of cemiplimab treatment on health-related QoL in these patients.

They performed an inclusive analysis of adult patients with mBCC treated with intravenous cemiplimab at a dose of 350 mg every 3 weeks for 5 treatment cycles of 9 weeks each, followed by 4 treatment cycles of 12 weeks each.

Patients completed the European Organisation for Research and Treatment of Cancer Quality of Life-Core 30 (QLQ-C30) and Skindex-16 questionnaires at baseline and on Day 1 of each cycle. Across Cycles 2 to 9, the overall change from baseline was analyzed using a mixed model with repeated measures. Responder analyses determined clinically meaningful improvement or deterioration (changes ≥10 points) or maintenance across all scales.

About patients reported low symptom burden and moderate-to-high functioning at baseline. Maintenance for QLQ-C30 global health status (GHS)/QoL and across all functioning and symptom scales was indicated by overall mean changes from baseline.

Clinically meaningful improvement or maintenance was reported at Cycle 2 for GHS/QoL (77%), functioning scales (77% to 86%), and symptom scales (70% to 93%), with similar proportions of improvement or maintenance at Cycles 6 and 9, excluding fatigue.

On the Skindex-16, clinically meaningful improvement or maintenance was reported across the emotional, symptom, and functional subscales, in 76%-88% of patients at Cycle 2, which were generally maintained at Cycles 6 and 9. Overall mean changes from baseline showed maintenance across these subscales.

The study concluded that the majority of patients treated with cemiplimab reported improvement or maintenance in GHS/QoL and functioning while maintaining a low symptom burden.

Funding support was provided by Regeneron Pharmaceuticals, Inc., and Sanofi.

Source: https://pubmed.ncbi.nlm.nih.gov/39031963/

Clinical Trial: https://clinicaltrials.gov/study/NCT03132636

Peris K, Inocencio TJ, Stratigos AJ, et al. (2024). “Health-related quality of life in patients with metastatic basal cell carcinoma treated with cemiplimab: Analysis of a phase 2 trial.” Cancer Med. 2024 Jul;13(14):e7360. doi: 10.1002/cam4.7360. PMID: 39031963; PMCID: PMC11259569.

END and Occult Metastasis in cT2N0 Maxillary Sinus Cancer

KEY TAKEAWAYS

  • The study aimed to assess the impact of END on the prognosis and explore subgroup-specific biomarkers for pts with cT2N0 MS-SCC.
  • The key outcomes of the study were to evaluate the effect of END on DSS and OS.
  • Researchers validated that END did not confer significant survival benefits in cT2N0 MS-SCC.

Maxillary sinus squamous cell carcinoma (MS-SCC) is a rare malignancy, yet it constitutes the predominant cancer type affecting the nasal cavity and paranasal sinus. Due to its typically asymptomatic early stages, over 80% of newly diagnosed MS-SCC cases present at an advanced T3/4 stage. Standard curative treatment involves surgical intervention alongside radiotherapy, often complemented by chemotherapy.

Jingjing Wang and the team aimed to evaluate the effect of elective neck dissection (END) on the prognosis of patients (pts) diagnosed with cT2N0 MS-SCC and identify predictive factors associated with the occurrence of occult metastasis in this specific patient group.

Researchers conducted a retrospective analysis using SEER database data, focusing on pts diagnosed with cT2N0 MS-SCC. Those pts were divided into 2 groups: those who underwent END and those who did not.

They utilized data from the SEER database to investigate the impact of END on disease-specific survival (DSS) and overall survival (OS) in pts with cT2N0 MS-SCC.

About 180 pts meeting inclusion criteria were analyzed after exclusion based on specific parameters. The study employed propensity score matching to compare outcomes between pts who underwent END and those who did not. Statistical analyses included univariate and multivariable models, presenting HR with 95% confidence intervals (CI). Ethical approval and patient consent were waived due to the study’s use of publicly accessible data from the SEER database.

The study assessed the impact of END on DSS and OS using propensity score matching. Multivariate logistic regression analysis was employed to identify predictors of occult metastasis. In total, the study included 180 pts, with 40 cases undergoing END.

Results indicated that following propensity score matching, there were no significant differences in DSS OS rates between pts who underwent END and those who did not. Occult metastasis was observed in 9 pts, corresponding to a rate of 22.5%.

High-grade tumors were independently associated with a higher risk of occult metastasis compared to low-grade tumors (HR 1.52, 95% CI 1.17-2.00). Overall, cT2N0 MS-SCC exhibited an occult metastasis rate of 22.5%, with histologic grade identified as the primary determinant of occult metastasis.

These findings concluded that END did not provide a significant survival benefit in cT2N0 MS-SCC.

The study was funded by the Henan provincial Medical Science and Technology Research Project (No.LHGJ20220196) and Project of Science and Technology in Science and Technology Department of Henan Province (No. 232102310285).

Source: https://pubmed.ncbi.nlm.nih.gov/39004629/

Wang J, Fang Q, Zhang X, et al. (2024). “Role of elective neck dissection in cT2N0 maxillary sinus squamous cell carcinoma.” Sci Rep. 2024 Jul 14;14(1):16230. doi: 10.1038/s41598-024-66179-7. PMID: 39004629; PMCID: PMC11247074.

Jet-Injected ALA PDT: Effective for Nodular BCC

Jet-Injected ALA PDT: Effective for Nodular BCC

KEY TAKEAWAYS

  • The phase II pilot study aimed to assess the safety and efficacy of JI-PDT in treating pts with BCC.
  • The results revealed that the Jet-injected ALA-PDT shows promise as a viable treatment option.

Photodynamic therapy (PDT) using δ-Aminolevulinic acid (ALA) topically demonstrated effectiveness in basal cell carcinoma (BCC) treatment but faced challenges due to inadequate penetration of ALA into deeper skin layers.

In this pilot trial, Leore Lavin and the team aimed to assess the safety and efficacy of photosensitizer jet injection (JI-PDT) for treating BCC. This open-label prospective study enrolled 15 patients (pts) with histologically confirmed, untreated, low-risk nodular BCCs.

Researchers noted that the intervention, JI-PDT pts (n = 11) received 2 sessions of jet-injected ALA with PDT separated by four to 6 weeks. Another group of pts (n = 4) underwent jet-injected ALA followed by tumor excision and fluorescence microscopy (JI-E). Treatment tolerability was assessed by local skin responses (LSR) score at 5 distinct time intervals.

Fluorescence microscopy evaluated protoporphyrin IX penetration depth and biodistribution within the tumor. At the primary endpoint, tumor clearance was evaluated via visual inspection, dermoscopy, and reflectance confocal microscopy. Postinjection and postillumination pain levels, and pts satisfaction, were scored on a 0-10 scale.

Results revealed that 15 participants, with a mean age of 58.3 years and all non-Hispanic White, enrolled in the study. The median composite LSR score immediately after JI-PDT was 5 (IQR = 3), decreasing significantly to 0.5 (IQR = 1) at the primary endpoint (P < 0.01). Immunofluorescence analysis of excised BCC tumors treated with jet-injected ALA revealed effective photosensitizer penetration into both papillary and reticular dermis.

Among the 13 tumors treated with JI-PDT, 11 achieved confirmed tumor clearance, while 1 recurred and 1 was lost to follow-up. 1 patient experienced a serious adverse event of cellulitis. At 3 months, 70% of pts exhibited local scarring. Pts reported an average pain level of 5.6 (SD = 2.3) during jet injection and 3.7 (SD = 1.8) during light illumination.

In conclusion, the JI of ALA for PDT in nodular low-risk BCC is viable and tolerable, which can prospectively offer a promising treatment approach.

The trial was sponsored by Memorial Sloan Kettering Cancer Center and the study was financially supported by LEO Pharma and P30 CA008748/NH/NIH HHS/United States.

Source: https://pubmed.ncbi.nlm.nih.gov/38804170/

Clinical Trial: https://www.clinicaltrials.gov/study/NCT04552990

Lavin L., Erlendsson A.M., Aleissa S., et al. (2024). “Jet-injection assisted photodynamic therapy for superficial and nodular basal cell carcinoma: A pilot study.” Lasers Surg Med. 2024 Jul;56(5):446-453. doi: 10.1002/lsm.23793. Epub 2024 May 28. PMID: 38804170.

Enhancing EC Management With cfDNA/ctDNA Monitoring

KEY TAKEAWAYS

  • The study aimed to investigate the role of cfDNA and ctDNA monitoring in anticipating disease relapse in patients with EC.
  • Researchers noticed that cfDNA and ctDNA monitoring improve risk stratification and relapse prediction in EC.

Carlos Casas-Arozamena and the team aimed to evaluate the effectiveness of cfDNA and ctDNA monitoring in enhancing the clinical management of patients with localized and recurrent endometrial cancer (EC).

Given the increasing incidence and mortality rates associated with EC, it is crucial to refine post-surgery recurrence risk stratification and predict disease relapse and treatment resistance. Liquid biopsy analyses present a promising solution to these clinical challenges, yet the optimal application strategies for these tools in EC remain to be established.

They performed an inclusive analysis of plasma samples and uterine aspirates (UA) from 198 patients with EC collected at surgery and during follow-up. The genetic landscape of the UA was characterized using targeted sequencing, and total cfDNA was analyzed for the presence of ctDNA based on the mutational profile identified in the UA.

About high cfDNA levels and detectable ctDNA at baseline correlated with poor prognosis for disease-free survival (DFS) (P-value < 0.0001; HR = 9.25) and disease-specific survival (DSS) (P-value < 0.0001; HR = 11.20).

This correlation remained clinically significant when stratifying tumors by histopathological risk factors. Notably, cfDNA/ctDNA analyses distinguished patients with early post-surgery relapse, and ctDNA kinetics identified patients experiencing relapse before any clinical evidence became apparent.

The study concluded that this is the most comprehensive analysis of cfDNA/ctDNA characterization in EC, highlighting its effectiveness in enhancing risk stratification and predicting disease relapse in patients with localized disease.

The assessment of ctDNA kinetics complements existing strategies for monitoring disease progression and treatment response. Consequently, the implementation of cfDNA/ctDNA monitoring in clinical practice presents a unique opportunity to advance the management of EC.

The study was funded by the Instituto de Salud Carlos III (ISCIII) (PI20/00969, PI21/00990 and PI20/01566)/Co-fund by the European Union for A.G-M, M.A and L.M-R; the Ministerio de Ciencia, Innovación y Universidades, Agencia Estatal de Investigación (PID2022-136854OB-I00) for G.M-B, the CIBERONC CB16/12/00328 for L.M-R, EC, A.G-M and MA) and CB16/12/00295 for G.M-B) and the Fundación científica AECC, Proyectos de Excelencia (IN607D2021/05) for L.M-R and ERA PerMed ERA-NET cofunded by the European Union, NextGeneration-EU through ISCIII and FCAECC (AC21_2/00020) for G.M-B and L.M-R. L.M-R and EC are supported by a contract “Miguel Servet” from ISCIII (CP20/00119, CP22/00147, respectively). SO is funded by an FCAECC-postdoctoral grant (PI21/00990). C.C-A is funded by an IDIS-predoctoral grant (2020). J.R-B is supported by a Juan Rodés contract (JR21/00019) from ISCIII.

Source: https://pubmed.ncbi.nlm.nih.gov/39304963/

Casas-Arozamena C, Vilar A, Cueva J, et al. (2024). “Role of cfDNA and ctDNA to improve the risk stratification and the disease follow-up in patients with endometrial cancer: towards the clinical application.” J Exp Clin Cancer Res. 2024;43(1):264. Published 2024 Sep 20. doi:10.1186/s13046-024-03158-w

SIRT1-FOXO3 Axis Enhances Mitophagy & Hormone Resistance in EC

KEY TAKEAWAYS

  • The study aimed to investigate the role of SIRT1-mediated deacetylation of FOXO3 in regulating mitophagy and hormone resistance in endometrial cancer.
  • Researchers found that SIRT1-mediated FOXO3 deacetylation is key to mitophagy and hormone resistance in EC.

Endometrial cancer (EC) is a common gynecological malignancy, particularly prevalent in developed countries, with its incidence rising due to lifestyle changes and an aging population. Treatment for EC varies and includes surgery, radiation therapy, chemotherapy, and hormone therapy. Despite its significance, the complex relationship between Sirtuin 1 (SIRT1) and FOXO3 in EC remains poorly understood.

Xuehua Wei and the team sought to evaluate how SIRT1-mediated deacetylation of FOXO3 influences these factors, uncovering its essential role in regulating both mitophagy and hormone resistance.

They performed an inclusive analysis using high-throughput sequencing, cell experiments, and bioinformatics tools to explore the roles and interactions of SIRT1 and FOXO3 in EC. Co-immunoprecipitation (Co-IP) assays were conducted to evaluate the interaction between SIRT1 and FOXO3 in RL95-2 cells.

Functional assays assessed cell viability, proliferation, migration, invasion, apoptosis, and related gene and protein expression. A mouse model of EC was established to investigate tumor growth and hormone resistance under various interventions. Additionally, immunohistochemistry and TUNEL assays were employed to examine protein expression and apoptosis in tumor tissues. Patients with EC were included in the study to further validate the findings.

About high-throughput transcriptome sequencing, a close association was revealed between SIRT1, FOXO3, and EC development. Co-immunoprecipitation (Co-IP) demonstrated a protein-protein interaction between SIRT1 and FOXO3. Overexpression of SIRT1 enhanced FOXO3 deacetylation and activity, leading to increased BNIP3 transcription and PINK1/Parkin-mediated mitophagy.

This promotion of mitophagy resulted in enhanced cell proliferation, migration, and invasion, and inhibited apoptosis in vitro. Additionally, it contributed to increased tumor growth and hormone resistance in vivo. These results underscore SIRT1 as a key upstream regulator and a potential therapeutic target in EC.

The study concluded that SIRT1 regulates mitophagy and hormone resistance in EC through the deacetylation of FOXO3. This novel molecular mechanism highlights SIRT1 critical role and suggests potential new therapeutic strategies for targeting EC.

The study received no funds.

Source: https://pubmed.ncbi.nlm.nih.gov/39266959/

Wei X, Xiong X, Wang P, et al. (2024). “SIRT1-mediated deacetylation of FOXO3 enhances mitophagy and drives hormone resistance in endometrial cancer.” Mol Med. 2024;30(1):147. Published 2024 Sep 12. doi:10.1186/s10020-024-00915-7

Efficacy of Avutometinib and Defactinib in High-Grade EAC

KEY TAKEAWAYS

  • The study aimed to investigate the efficacy of avutometinib with FAK inhibitors in high-grade EAC.
  • Researchers observed that avutometinib and defactinib show promise for high-grade EAC, warranting clinical trials.

High-grade endometrial cancers (EAC) are aggressive tumors associated with a high risk of progression following treatment. Given that EAC often contains mutations in the RAS/MAPK pathways, this study assessed the preclinical efficacy of avutometinib, a RAF/MEK clamp, in combination with the focal adhesion kinase (FAK) inhibitors defactinib or VS-4718.

Tobias Max Philipp Hartwich and the team aimed to assess the potential of these drug combinations for treating high-grade EAC.

They performed an inclusive analysis using whole-exome sequencing (WES) to map the genetic landscape of 5 primary EAC cell lines. The in vitro efficacy of avutometinib and defactinib, both individually and in combination, was assessed through cell viability, cell cycle, and cytotoxicity assays. Mechanistic insights were obtained via Western blot assays. Additionally, in vivo, experiments were conducted using UTE10 engrafted mice, which were treated with vehicle, avutometinib, VS-4718, or their combination through oral gavage.

About the results, WES revealed that multiple EAC cell lines harbored genetic derangements in the RAS/MAPK pathway, including KRAS, PTEN, PIK3CA, BRAF, and ARID1A, which may sensitize these cells to FAK and RAF/MEK inhibition. All 5 EAC cell lines exhibited in vitro sensitivity to either FAK and/or RAF/MEK inhibition.

The western blot assays showed that exposure to defactinib, avutometinib, and their combination resulted in decreased phosphorylated FAK (p-FAK), as well as reduced p-MEK and p-ERK levels. In vivo, the combination of avutometinib and VS-4718 demonstrated superior tumor growth inhibition compared to single-agent treatments and controls, with significant differences observed starting at Day 9 (P < 0.02 and P < 0.04) in UTE10 xenografts.

The study concluded that avutometinib, defactinib, and, to a larger extent, their combinations exhibited promising in vitro and in vivo activity against EAC cell lines and xenografts. These preclinical findings support the potential for clinical evaluation of this combination in patients with high-grade EAC.

This study was funded by the NIH U01 CA176067-01A1, the Deborah Bunn Alley Foundation, the Domenic Cicchetti Foundation, the Discovery to Cure Foundation, and the Guido Berlucchi Foundation to A.D.S.

Source: https://pubmed.ncbi.nlm.nih.gov/39240189/

Hartwich TMP, Mansolf M, Demirkiran C, et al. (2024). “Preclinical evaluation of avutometinib and defactinib in high-grade endometrioid endometrial cancer.” Cancer Med. 2024;13(17):e70210. doi:10.1002/cam4.70210

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