scholarly journals Case Report: Rechallenge With BRAF and MEK Inhibitors in Metastatic Melanoma: A Further Therapeutic Option in Salvage Setting?

2021 ◽  
Vol 11 ◽  
Author(s):  
Anna Stagno ◽  
Sabrina Vari ◽  
Alessio Annovazzi ◽  
Vincenzo Anelli ◽  
Michelangelo Russillo ◽  
...  
Keyword(s):  
Targeted Therapy ◽  
Clinical Benefit ◽  
Kinase Inhibitors ◽  
Checkpoint Inhibitors ◽  
Therapeutic Option ◽  
Local Treatment ◽  
Standard Of Care ◽  
Serum Levels ◽  
High Serum ◽  
Mek Inhibitors

BackgroundThe combination of BRAF and MEK inhibitors represents the standard of care treatment for patients with metastatic BRAF-mutated melanoma, notwithstanding the high frequency of emergent resistance. Moreover, therapeutic options outside clinical trials are scarce when patients have progressed after both targeted therapy and therapy with immune checkpoint inhibitors. In this article, we report our experience with targeted therapy rechallenging with BRAF and MEK inhibitors in patients with metastatic BRAF-mutated melanoma after progression with kinase inhibitors and immunotherapy.MethodsFour patients with metastatic BRAF-mutated melanoma were rechallenged with BRAF and MEK inhibitors after progression with targeted therapy and subsequent immunotherapy (checkpoint inhibitors).ResultsTwo patients (one of them was heavily pretreated) had partial response over 36 months (with local treatment on oligoprogression disease) and 10 months, respectively. A third patient with multisite visceral disease and high serum levels of lactate dehydrogenase had a short-lived clinical benefit rapidly followed by massive progression of disease (early progressor). The fourth patient, currently on treatment with BRAF/MEK inhibitors, is showing a clinical benefit and radiological stable disease over 3 months of therapy. Adverse events were manageable, similar to those reported during the first targeted therapy; the treatment was better tolerated at rechallenge compared with the first treatment by two out of four patients.

scholarly journals Gastrointestinal Metastases From Primary Renal Cell Cancer: A Single Center Review

2021 ◽  
Vol 11 ◽  
Author(s):  
Rony Maelle ◽  
Ratone Jean-Philippe ◽  
Walz Jochen ◽  
Pignot Geraldine ◽  
Caillol Fabrice ◽  
...  
Keyword(s):  
Retrospective Analysis ◽  
Median Time ◽  
Renal Cell Cancer ◽  
Renal Cell ◽  
Kinase Inhibitors ◽  
Checkpoint Inhibitors ◽  
Cell Cancer ◽  
Local Treatment ◽  
Standard Of Care ◽  
Success Rates

Introduction: Digestive metastases (DMs) from renal cell cancer (RCC) are rare. Over the past decade, the overall survival of metastatic RCC (mRCC) has been improved by tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors. The main objective of this study was to assess the incidence of metastases of the digestive tract in this new field of treatment. The secondary objectives were to evaluate the clinical characteristics, prognosis, treatments used for DMs, and median time between the diagnosis of RCC or mRCC and DMs.Materials and Methods: A retrospective analysis of data collected from all patients with mRCC between 2007 (the time of TKI was a standard of care) and 2019 was carried out at the Paoli-Calmettes Institute (Marseille, France). Computer research software using artificial intelligence (ConSoRe®) was used to identify patients and assess their characteristics.Results: Between January 2007 and December 2019, 11 out of 660 (1.6%) mRCC patients had metastases of the gastrointestinal tract. The median age was 62 years. Of the 11 patients, 81.8% experienced digestive bleeding or anemia. Only 2 patients were asymptomatic. The metastases were mainly duodenal (50%) and gastric (41.6%). The median time from cancer diagnosis and from metastatic disease to gastrointestinal metastasis was 4.3 years (3 months−19.2 years) and 2.25 years (0 days−10.2 years), respectively. Local treatment was performed in 38.5% of cases by endoscopy (60%), surgery (20%) and radiotherapy (40%) with success rates of 33, 100, and 50%, respectively. Etiological treatment was modified following the discovery of DM in 84.6% of the cases. The median survival was 1 year from the diagnosis of DM (13 days−9.4 years). Two patients were still alive 2.9 and 9.4 years after the diagnosis of DM.Conclusion: This is the largest monocentric retrospective analysis of DM in patients with RCC. It seems to be a rare and late event in the course of the disease. Local treatment combined with systemic treatment could improve survival. In the context of prolonged survival with the new based immunotherapy treatments in mRCC, we suggest that unexplained anemia or persistent digestive symptoms could be explored by endoscopy.

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in the treatment of patients with brain metastases (BM) from renal cell cancer (RCC).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e15546-e15546
Author(s):  
David Naskhletashvili ◽  
Vera Gorbunova ◽  
Mark Bychkov ◽  
Ali Bekyashev ◽  
Vladislav Karahan ◽  
...  
Keyword(s):  
Overall Survival ◽  
Targeted Therapy ◽  
Stable Disease ◽  
Kinase Inhibitors ◽  
Cell Cancer ◽  
Objective Response ◽  
Local Treatment ◽  
Whole Brain Radiotherapy ◽  
Previous Treatment ◽  
The Brain

e15546 Background: About 2–11% of all patients (pts) with RCC develop BM, leading to a poor prognosis and a median survival of <6 months after whole brain radiotherapy. The role of targeted therapy in the management of BM is controversial. This study was designed to evaluate EGFR TKIs in RCC pts with BM. Methods: eligible pts had confirmed RCC and BM (≥1 lesion of ≥10mm diameter) aged >18 years with ECOG performanse status (PS) of 0–2. From June 2009 to January 2013, 11 pts with RCC and BM were enrolled in this study. 10 pts (91%) had extracranial metastases. 6 pts received sunitinib (50mg/day, 4 weeks, every cycle), 4 pts received sorafenib (800 mg/day) and 1 patient received pazopanib (800 mg/day) until radiologically-verified progressive disease. The primary endpoints were objective response rate (ORR) - complete and partial response in the brain and in the extracranial lesions, progressive-free survival (PFS) and overall survival. Demographics were: median age - 59 years (range 44–74 years); male/female - 10/1; PS 1/2 - 7/4; previously treated/untreated - 10/1; number of BM: ≤3/>3 - 6/5. Previous treatment: nephrectomy – 10 pts (91%), cytokines – 6 pts (54,5%), targeted therapy (before BM) – 4 pts (36,4%). Local control of BM: previous neurosurgery – 2 pts (18,2%), radiosurgery – 4 pts (36,4%), previous neurosurgery + radiosurgery – 2 pts (18,2%). Results: ORR in the brain was 27,3% (3 partial responses). All partial responses in the brain achieved in patients who received targeted therapy and radiosurgery. Stable disease in the brain was 54,5% (6 pts). 1 patient with stable in the brain received targeted therapy and radiosurgery, 5 pts received targeted therapy. ORR in the extracranial lesions was 20% (2 partial responses). Stable disease in the extracranial lesions was 50% (5 pts). The median of PFS was 6 months. The median of overall survival was 10 months. Conclusions: surgery and radiotherapy, including radiosurgery, must be considered as optimal local treatment for pts with RCC and BM. Targeted drugs have demonstrated their ability to achive a clinical and X-ray verified objective effect (as stabilization in most cases) in treating of pts with disseminated RCC and BM.

Analysis of real-world data (RWD) on treatment (tx) sequencing in patients with advanced non-small cell lung cancer (aNSCLC).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e20642-e20642
Author(s):  
Meng Ma ◽  
Xiang Zhou ◽  
Howard Goldsweig ◽  
Nicholas Hahner ◽  
Dianwei Han ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Targeted Therapy ◽  
Kinase Inhibitors ◽  
Checkpoint Inhibitors ◽  
Rank Test ◽  
Real World Data ◽  
Therapeutic Modalities ◽  
Platinum Based Chemotherapy ◽  
Line Of Therapy ◽  
Line Setting

e20642 Background: While optimal sequencing of systemic therapy in aNSCLC is critical to achieve maximal clinical benefit, it is practically challenging to study tx sequencing through clinical trials. RWD allow retrospective, observational studies to examine tx patterns and associated clinical outcomes. Methods: 1,609 aNSCLC patients who received systemic therapies at Mount Sinai hospitals were analyzed for the number of line of therapy (LOT), therapeutic modalities (chemotherapy, targeted therapy and immunotherapy), and the sequence in which treatments were given when LOT > 1. Time to tx discontinuation (TTD) was used as a surrogate clinical endpoint for outcomes. Results: 578 of the 1,609 (36%) patients received more than one LOT. 356 (22%) received tyrosine kinase inhibitors (TKIs), and 297 (16%) received immune checkpoint inhibitors (CPIs). Kaplan-Meier analysis revealed that among 297 patients who received CPIs, median TTD was longer in the 1st line setting (295 days, 95% CI 169 to 523; n=132) than when LOT > 1 (169 days, 95% CI 113 to 269; n=165), although the difference was not statistically significant (P=0.092, log-rank test). No difference of TTD on TKIs was observed between LOT = 1 and LOT > 1 (P=0.51). With respect to tx sequencing, when patients (n=94) received TKIs as the 1st LOT, 60%, 35%, and 5% of them received another TKI, chemotherapy, or a CPI-containing regimen, respectively, as the 2nd LOT. Among patients (n=370) who progressed on 1st line platinum-based chemotherapy, 52%, 32%, and 16% received another chemo regimen, a CPI-containing regimen, or a targeted therapy, respectively, as the 2nd LOT; these percentages shifted significantly toward more CPIs (24%, 66%, 10% for chemo, CPI, targeted, respectively) when only 2016-2018 data were examined. In the 2nd line setting after platinum therapy, TTD was significantly longer in the CPI group (332 days, 95% CI 169-484) compared to the chemo group (88 days, 95% CI 65-100; P<0.0001), consistent with results from pivotal clinical trials. Conclusions: As the tx algorithm of aNSCLC has been evolving rapidly, we observed diverse tx patterns in RWD. Various tx sequences may impact patient outcomes, and therefore warrant further investigation.

scholarly journals A novel mouse model for checkpoint inhibitor-induced adverse events

PLoS ONE ◽  
2021 ◽  
Vol 16 (2) ◽  
pp. e0246168
Author(s):  
Kieran Adam ◽  
Alina Iuga ◽  
Anna S. Tocheva ◽  
Adam Mor
Keyword(s):  
Adverse Events ◽  
Mouse Model ◽  
Therapeutic Potential ◽  
Checkpoint Inhibitor ◽  
Checkpoint Inhibitors ◽  
Serum Levels ◽  
High Serum ◽  
Treatment Modalities ◽  
Susceptibility Factors ◽  
Significant Efficacy

Immune checkpoint inhibitors have demonstrated significant efficacy in the treatment of a variety of cancers, however their therapeutic potential is limited by abstruse immune related adverse events. Currently, no robust animal model exists of checkpoint inhibitor-induced adverse events. Establishing such a model will improve our mechanistic understanding of this process, which in turn will inform design of improved therapies. We developed a mouse model to determine inflammatory toxicities in response to dual checkpoint blockade in the presence of syngeneic tumors. Mice from susceptible genetic backgrounds received intraperitoneal injections of anti-mouse PD-1 and CTLA-4 antibodies. The mice were monitored for weight loss and histologic evidence of inflammation. Blood was collected for basic metabolic panels and titers of anti-nuclear antibodies. In parallel, mice were also treated with prednisolone, which is commonly used to treat immune related adverse events among cancer patients. Among all the genetic backgrounds, B6/lpr mice treated with anti-CTLA-4 and anti-PD-1 antibodies developed more substantial hepatitis, pancreatitis, colitis, and pneumonitis characterized by organ infiltration of immune cells. Mice that developed tissue infiltration demonstrated high serum levels of glucose and high titers of anti-nuclear antibodies. Finally, while administration of prednisolone prevented the development of the inflammatory adverse events, it also abrogated the protective anti-tumor effect of the checkout inhibitors. Genetic background and treatment modalities jointly modified the inflammatory adverse events in tumor bearing mice, suggesting a complex mechanism for checkpoint inhibitor-related inflammation. Future studies will assess additional genetic susceptibility factors and will examine possible contributions from the administration of other anti-inflammatory drugs.

scholarly journals Immunotherapy Strategies for Gastrointestinal Stromal Tumor

Cancers ◽  
2021 ◽  
Vol 13 (14) ◽  
pp. 3525
Author(s):  
Junaid Arshad ◽  
Philippos A. Costa ◽  
Priscila Barreto-Coelho ◽  
Brianna Nicole Valdes ◽  
Jonathan C. Trent
Keyword(s):  
Monoclonal Antibodies ◽  
Soft Tissue ◽  
Kinase Inhibitors ◽  
Checkpoint Inhibitors ◽  
Locally Advanced ◽  
Soft Tissue Sarcomas ◽  
Standard Of Care ◽  
Current Standard ◽  
Molecular Alterations

Gastrointestinal stromal tumors (GIST) are the most common mesenchymal soft tissue sarcoma of the gastrointestinal tract. The management of locally advanced or metastatic unresectable GIST involves detecting KIT, PDGFR, or other molecular alterations targeted by imatinib and other tyrosine kinase inhibitors. The role of immunotherapy in soft tissue sarcomas is growing fast due to multiple clinical and pre-clinical studies with no current standard of care. The potential therapies include cytokine-based therapy, immune checkpoint inhibitors, anti-KIT monoclonal antibodies, bi-specific monoclonal antibodies, and cell-based therapies. Here we provide a comprehensive review of the immunotherapeutic strategies for GIST.

Use of single-arm trials to support malignant hematology and oncology drug and biologic approvals: A 20-year FDA experience.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e13572-e13572
Author(s):  
Sundeep Agrawal ◽  
Shaily Arora ◽  
Jonathon Joseph Vallejo ◽  
Thomas Gwise ◽  
Meredith Kathleen Chuk ◽  
...  
Keyword(s):  
Drug Development ◽  
Clinical Benefit ◽  
Randomized Clinical Trials ◽  
Kinase Inhibitors ◽  
Response Rate ◽  
Checkpoint Inhibitors ◽  
Unmet Need ◽  
Cancer Drug ◽  
Cancer Therapies ◽  
Oncology Drug

e13572 Background: Improved understanding of the underlying biology of cancer has led to a paradigm shift in cancer drug development and has paved the way for many products to receive accelerated or regular approval based on non-randomized/single arm trials (SATs). Given the high unmet medical need of cancer patients, challenges with lengthy and confounded survival endpoints, and difficulty enrolling rare biomarker-defined subsets of disease, SATs have been used to evaluate a variety of cancer therapies. Unlike time to event endpoints, the objective and clinically relevant endpoint of response rate (RR) and duration of response is interpretable in SATs, as spontaneous tumor shrinkage is not expected. Methods: A search of FDA databases identified all drugs and biologics approved for malignant hematology and oncology indications from January 1, 2001, to December 31, 2020 based on SATs. Data sources included approval letters, U.S. prescribing information, and clinical review documents. The definition of response varied by setting and time period (e.g. RECIST, WHO, IWG, etc.). Results: Between January 1, 2001 and December 31, 2020, FDA granted 153 new indications based on SATs, including 102 accelerated approvals (AAs) and 51 regular approvals (RAs). Overall, 69 approvals (45%) were for new molecular entities and 84 (55%) were expanded indications. Response rate was the most common endpoint used in the trial providing substantial evidence of efficacy to support approval [120/153, (78%)]. The durability of response was also considered to support evidence of clinical benefit. Of the 102 AAs, 38 (37%) have fulfilled their post-marketing requirement (PMR) to verify clinical benefit, 59 (58%) are pending verification of benefit, and 5 (5%) have been withdrawn from the market. Of note, 88% (52/59) of AAs pending verification of benefit occurred in the last 5 years alone (22 AAs in 2020, 8 in 2019, 8 in 2018, 12 in 2017, and 2 in 2016). Between 2001-2020, 58 (38%) new indications were granted for kinase inhibitors, 34 (22%) for immune checkpoint inhibitors (CPIs), and 61 (40%) for drugs with other mechanisms of action including but not limited to antibody-drug conjugates, cytotoxic drugs, and non-CPI monoclonal antibodies. Conclusions: In the last two decades, SATs have been effectively used to study anti-cancer therapies in well-defined patient populations using durable RR as an objective and interpretable clinical endpoint. Although randomized clinical trials remain the gold standard in clinical research, SATs have allowed for rapid advancements in oncology drug development and will continue to serve an important role in bringing new therapies to patients with unmet need.

scholarly journals Recent advances in molecular targeted therapy for unresectable and metastatic BRAF-mutated melanoma

2020 ◽  
Author(s):  
Yukiko Kiniwa ◽  
Ryuhei Okuyama
Keyword(s):  
Targeted Therapy ◽  
Lactate Dehydrogenase ◽  
Targeted Therapies ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Molecular Targeted Therapy ◽  
Checkpoint Inhibitors ◽  
The United States ◽  
Braf Inhibitors ◽  
Mek Inhibitors

Abstract The clinical outcome of BRAF-mutated advanced melanoma has been improved by both molecular targeted therapies and immune checkpoint inhibitors. Long-term follow-up data reveal durable clinical responses in patients receiving first-line combinations of BRAF inhibitors plus MEK inhibitors, particularly those showing a complete response. Clinical outcomes are also associated with the lactate dehydrogenase levels and the number of metastatic organs. Although brain metastasis is frequently difficult to control, systemic therapy is preferred in cases with small and asymptomatic brain metastases associated with progressive extra-cranial disease. Control of intra-cranial disease with BRAF inhibitors plus MEK inhibitors is comparable with that of immune checkpoint inhibitors, although immune checkpoint inhibitors are superior to targeted therapies with respect to survival. The BRAF inhibitors plus MEK inhibitors regimen is well-tolerated, and toxicities are usually manageable and reversible, but differ according to the specific regimen used. Guidelines in the United States, Europe, and Japan recommend targeted therapy for patients who need early tumor responses. A meta-analysis of retrospective data shows that the baseline lactate dehydrogenase level is significantly higher in patients treated with BRAF inhibitors plus MEK inhibitors than in those treated with immune checkpoint inhibitors, suggesting that clinicians tend to use BRAF inhibitors plus MEK inhibitors for more advanced disease. Since there is insufficient efficacy and safety data on the use of targeted therapies for acral and mucosal melanoma, a retrospective analysis may be useful. The combination of molecular targeted therapy plus immune checkpoint inhibitors is expected to elicit further improvement. The results of several trials using combination or sequential therapies will be available in the next few years.

scholarly journals Immunotherapy and Metastatic Renal Cell Carcinoma: A Review of New Treatment Approaches

Life ◽  
2021 ◽  
Vol 12 (1) ◽  
pp. 24
Author(s):  
Nikhita Kathuria-Prakash ◽  
Claire Drolen ◽  
Christopher A. Hannigan ◽  
Alexandra Drakaki
Keyword(s):  
Immune Checkpoint ◽  
Renal Cell ◽  
Immune Checkpoint Inhibitors ◽  
Kinase Inhibitors ◽  
Checkpoint Inhibitors ◽  
Progression Free Survival ◽  
Standard Of Care ◽  
New Combination ◽  
Combination Therapies ◽  
New Treatment

Introduction: Renal cell carcinomas (RCC) have been treated with immunotherapy for decades; the use of immune checkpoint inhibitors represents the most recent advance. In this review, we compare these new RCC immunotherapies, with a focus on achieving durable complete responses (CR). Review: Sorafenib and sunitinib were the first Food and Drug Administration (FDA)-approved targeted agents for RCC, with sunitinib eventually becoming the standard-of-care agent against which novel therapies are compared. In the last five years, many combination therapies based on the use of immune checkpoint inhibitors (ICIs) and receptor tyrosine kinase inhibitors (TKIs), including ipilimumab/nivolumab, nivolumab/cabozantinib, avelumab/axitinib, pembrolizumab/axitinib, and pembrolizumab/lenvatinib, have demonstrated superior overall survival (OS) and progression-free survival (PFS) compared to sunitinib. Ongoing clinical trials of hypoxia-induced factor-2 alpha (HIF-2a) inhibitors, chimeric antigen receptor T cell (CAR-T) therapy targeting CD70, and other new combination therapies have also shown promise and are currently under investigation. Conclusions: Many new combination therapies are approved for RCC treatment, and CR rates suggest that, in the era of immunotherapy, it may be possible to achieve durable responses and survival benefit in patients with metastatic RCC.

scholarly journals Targeted Therapy in Management of Advanced Follicular Thyroid Carcinoma

2020 ◽  
pp. 1-3
Author(s):  
Leong Tung Ong ◽  
Keyword(s):  
Targeted Therapy ◽  
Thyroid Carcinoma ◽  
Radioactive Iodine ◽  
Kinase Inhibitors ◽  
Follicular Thyroid Carcinoma ◽  
Therapeutic Option ◽  
External Beam Radiation ◽  
Beam Radiation ◽  
Thyroid Glands ◽  
Common Malignancy

Follicular thyroid carcinoma (FTC) is the second most common malignancy involving the thyroid glands. Early stages of FTC are managed with total thyroidectomy followed by 131I ablation and external beam radiation therapy. Targeted therapy with tyrosine kinase inhibitors (TKIs) is an essential therapeutic option for the management of advanced cases of radioactive iodine refractory. This review will investigate the clinical data for the therapeutic use of targeted therapy in advanced FTC and compare the efficacy of different targeted therapy used in managing the patients

scholarly journals The Landscape of Novel Therapeutics and Challenges in Glioblastoma Multiforme: Contemporary State and Future Directions

2020 ◽  
Vol 13 (11) ◽  
pp. 389 ◽  
Author(s):  
Karam Khaddour ◽  
Tanner Johanns ◽  
George Ansstas
Keyword(s):  
Clinical Trials ◽  
Targeted Therapy ◽  
Glioblastoma Multiforme ◽  
Kinase Inhibitors ◽  
Checkpoint Inhibitors ◽  
Tumor Biology ◽  
Adoptive Cell Transfer ◽  
High Morbidity ◽  
Future Directions ◽  
Treatment Approaches

Background: Glioblastoma multiforme is a malignant intracranial neoplasm that constitutes a therapeutic challenge because of the associated high morbidity and mortality given the lack of effective approved medication and aggressive nature of the tumor. However, there has been extensive research recently to address the reasons implicated in the resistant nature of the tumor to pharmaceutical compounds, which have resulted in several clinical trials investigating promising treatment approaches. Methods: We reviewed literature published since 2010 from PUBMED and several annual meeting abstracts through 15 September 2020. Selected articles included those relevant to topics of glioblastoma tumor biology, original basic research, clinical trials, seminal reviews, and meta-analyses. We provide a discussion based on the collected evidence regarding the challenging factors encountered during treatment, and we highlighted the relevant trials of novel therapies including immunotherapy and targeted medication. Results: Selected literature revealed four main factors implicated in the low efficacy encountered with investigational treatments which included: (1) blood-brain barrier; (2) immunosuppressive microenvironment; (3) genetic heterogeneity; (4) external factors related to previous systemic treatment that can modulate tumor microenvironment. Investigational therapies discussed in this review were classified as immunotherapy and targeted therapy. Immunotherapy included: (1) immune checkpoint inhibitors; (2) adoptive cell transfer therapy; (3) therapeutic vaccines; (4) oncolytic virus therapy. Targeted therapy included tyrosine kinase inhibitors and other receptor inhibitors. Finally, we provide our perspective on future directions in treatment of glioblastoma. Conclusion: Despite the limited success in development of effective therapeutics in glioblastoma, many treatment approaches hold potential promise including immunotherapy and novel combinational drugs. Addressing the molecular landscape and resistant immunosuppressive nature of glioblastoma are imperative in further development of effective treatments.

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