BAMM (BRAF Autophagy and MEK Inhibition in Melanoma): A Phase I/II Trial of Dabrafenib, Trametinib, and Hydroxychloroquine in Advanced <i>BRAFV600</i>-mutant Melanoma

Mehnert, Janice M.; Mitchell, Tara C.; Huang, Alexander C.; Alemán, Tomás S.; Kim, Benjamin J.; Schuchter, Lynn M.; Linette, Gerald P.; Karakousis, Giorgos C.; Mitnick, Sheryl; Giles, Lydia; Carberry, Mary; Frey, Noelle V.; Kossenkov, Andrew V.; Groisberg, Roman; Hernandez‐Aya, Leonel F.; Ansstas, George; Silk, Ann W.; Chandra, Sunandana; Sosman, Jeffrey A.; Gimotty, Phyllis A.; Amaravadi, Ravi K.

doi:10.1158/1078-0432.ccr-21-3382

Cited by 36 publications

(28 citation statements)

References 35 publications

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“…Extensive studies demonstrate that autophagy is pivotal for cancer survival and progression ( 97 , 98 ). Present autophagy-related clinical trials are mainly aimed at the lysosome inhibitors chloroquine (CQ) and hydroxychloroquine (HCQ) ( 99 , 100 ). In initial clinical trials, patients who received a combinative treatment with either CQ or HCQ and radio- or chemotherapy could have a much better prognosis in various tumors, including advanced solid tumors and hematological malignancies ( 101 – 104 ).…”

Section: Discussionmentioning

confidence: 99%

Crosstalk between autophagy and immune cell infiltration in the tumor microenvironment

Yang

Zhang²,

Chen³

et al. 2023

Front. Med.

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Autophagy is a conserved process for self-degradation and provides cells with a rescue mechanism to respond to circumstances such as stress and starvation. The role of autophagy in cancer is extremely complex and often paradoxical. Most of the related published studies on tumors are always focused on cancer cells. However, present studies gradually noticed the significance of autophagy in the tumor microenvironment. These studies demonstrate that autophagy and immunity work synergistically to affect tumor progression, indicating that autophagy could become a potential target for cancer immunotherapy. Therefore, it is crucial to clarify the correlation between autophagy and various tumor-infiltrating immune cells in the tumor microenvironment. The context-dependent role of autophagy is critical in the design of therapeutic strategies for cancer.

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Section: Discussionmentioning

confidence: 99%

Crosstalk between autophagy and immune cell infiltration in the tumor microenvironment

Yang

Zhang²,

Chen³

et al. 2023

Front. Med.

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“…The LDH levels were considered as a surrogate of tumor burden and tissue destruction, as well as tumor metabolism [ 45 , 46 , 47 ]. The prognostic role of LDH is well-defined in melanoma patients treated with ICIs, and the LDH levels are being used as stratification criteria in melanoma clinical trials [ 31 , 48 , 49 , 50 ]. Similarly, a worse prognosis was observed in ICI-treated patients with other indications, such as NSCLC and RCC in the observational studies [ 31 , 51 , 52 , 53 , 54 ].…”

Section: Discussionmentioning

confidence: 99%

The Association between Early Changes in Neutrophil-Lymphocyte Ratio and Survival in Patients Treated with Immunotherapy

Güven

Şahin

Erul

et al. 2022

JCM

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Dynamic changes in the blood-based biomarkers could be used as a prognostic biomarker in patients treated with immune checkpoint inhibitors (ICIs), although the data are limited. We evaluated the association between the neutrophil–lymphocyte ratio (NLR) and early NLR changes with survival in ICI-treated patients. We retrospectively evaluated the data of 231 patients with advanced-stage cancer. We recorded baseline clinical characteristics, baseline NLR and fourth-week NLR changes, and survival data. A compound prognostic score, the NLR2-CEL score, was developed with the following parameters: baseline NLR (<5 vs. ≥5), ECOG status (0 vs. ≥1), Charlson Comorbidity Index (CCI, <9 vs. ≥9), and fourth-week NLR change (10% or over NLR increase). In the multivariable analyses, higher NLR (HR: 1.743, p = 0.002), 10% or over NLR increase in the fourth week of treatment (HR: 1.807, p = 0.001), higher ECOG performance score (HR: 1.552, p = 0.006), higher LDH levels (HR: 1.454, p = 0.017), and higher CCI (HR: 1.400, p = 0.041) were associated with decreased OS. Compared to patients with the lowest scores, patients in the highest score group had significantly lower OS (HR: 7.967, 95% CI: 3.531–17.979, p < 0.001) and PFS. The composite score had moderate success for survival prediction, with an AUC of 0.702 (95% CI: 0.626–0.779, p < 0.001). We observed significantly lower survival in patients with higher baseline NLR values and increased NLR values under treatment.

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“…-Randomized study has been launched. [79] AEs: adverse events, CQ: chloroquine, HCQ: hydroxychloroquine, MTD: maximum tolerated dose, OS: overall survival, PD; progressive disease, PG: nab-paclitaxel and gemcitabine, PR: partial response, SD: stable disease, QoL: quality of life.…”

Section: Resectable Pancreatic Adenocarcinomamentioning

confidence: 99%

A Critical Review of Chloroquine and Hydroxychloroquine as Potential Adjuvant Agents for Treating People with Cancer

Abdel-Aziz

Saadeldin

Salem

et al. 2022

Future Pharmacology

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Chloroquine (CQ) and hydroxychloroquine (HCQ) have been used to treat malaria and autoimmune diseases for more than 70 years; they also have immunomodulatory and anticancer effects, which are linked to autophagy and autophagy-independent mechanisms. Herein, we review the pharmacokinetics, preclinical studies and clinical trials investigating the use of CQ and HCQ as adjuvant agents in cancer therapy. We also discuss their safety profile, drug–drug and drug–disease interactions. Systematic studies are required to define the use of CQ/HCQ and/or their analogues in cancer treatment and to identify predictive biomarkers of responder subpopulations.

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BAMM (BRAF Autophagy and MEK Inhibition in Melanoma): A Phase I/II Trial of Dabrafenib, Trametinib, and Hydroxychloroquine in Advanced BRAFV600-mutant Melanoma

Abstract: Conflicts of interest:RKA is inventor of patents related to novel chloroquine derivatives for cancer that were licensed to Pinpoint Therapeutics. RA is Founder of Pinpoint Therapeutics. He is a consultant for Deciphera, Sprint Biosciences and Immunacell, Merck.Research.

Cited by 36 publications

References 35 publications

Crosstalk between autophagy and immune cell infiltration in the tumor microenvironment

Crosstalk between autophagy and immune cell infiltration in the tumor microenvironment

The Association between Early Changes in Neutrophil-Lymphocyte Ratio and Survival in Patients Treated with Immunotherapy

A Critical Review of Chloroquine and Hydroxychloroquine as Potential Adjuvant Agents for Treating People with Cancer

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