Sequential or combined immune checkpoint inhibitors and targeted therapy: Navigating uncharted waters

2021 ◽  
Vol 79 ◽  
pp. 100820
Author(s):  
K. El Husseini ◽  
M. Wislez
Keyword(s):  
Targeted Therapy ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors

scholarly journals Salvage Ipilimumab and Nivolumab in Patients With Metastatic Renal Cell Carcinoma After Prior Immune Checkpoint Inhibitors

2020 ◽  
Vol 38 (27) ◽  
pp. 3088-3094 ◽  
Author(s):  
Anita Gul ◽  
Tyler F. Stewart ◽  
Charlene M. Mantia ◽  
Neil J. Shah ◽  
Emily Stern Gatof ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Targeted Therapy ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Response Rate ◽  
Checkpoint Inhibitors ◽  
Objective Response ◽  
Progression Free Survival ◽  
Free Survival ◽  
Metastatic Rcc

PURPOSE Immune checkpoint inhibitors (ICIs) are standard therapy in metastatic renal cell carcinoma (RCC). The safety and activity of the combination of ipilimumab and nivolumab in patients who have received prior ICI targeting the programmed death 1 (PD-1) pathway remains unknown. We evaluated ipilimumab and nivolumab in patients with metastatic RCC after prior treatment with anti–PD-1 pathway–targeted therapy. PATIENTS AND METHODS Patients with metastatic RCC who received prior anti–PD-1 pathway-targeted therapy and subsequently received ipilimumab and nivolumab were reviewed. Objective response rate and progression-free survival per investigator assessment were recorded. Toxicity of ipilimumab and nivolumab was also assessed. RESULTS Forty-five patients with metastatic RCC were included. All patients (100%) received prior ICIs targeting the PD-1 pathway. The median age was 62 years (range, 21-82 years). At a median follow-up of 12 months, the objective response rate to ipilimumab and nivolumab was 20%. The median progression-free survival while on ipilimumab and nivolumab was 4 months (range, 0.8-19 months). Immune-related adverse events (irAEs) of any grade with ipilimumab and nivolumab were recorded in 29 (64%) of the 45 patients; grade 3 irAEs were recorded in 6 (13%) of the 45 patients. CONCLUSION Ipilimumab and nivolumab demonstrated antitumor activity with acceptable toxicity in patients with metastatic RCC who had prior treatment with checkpoint inhibition.

The genomic landscape of metastatic clear cell renal cell carcinoma (ccRCC) after treatment with systemic therapy.

2019 ◽  
Vol 37 (7_suppl) ◽  
pp. 675-675
Author(s):  
Johannes Van Der Mijn ◽  
Kenneth Eng ◽  
Evan Fernandez ◽  
Clara Oromendia ◽  
Tuo Zhang ◽  
...  
Keyword(s):  
Targeted Therapy ◽  
Systemic Therapy ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Vegf Inhibitors ◽  
Cell Renal Cell Carcinoma ◽  
Primary Tumors ◽  
Anti Vegf ◽  
Genomic Landscape

675 Background: The most frequent genomic alterations in patients (pts) with ccRCC have been identified in primary tumors. Here we investigated the genomic landscape of ccRCC in a cohort enriched for metastatic tumors after treatment with systemic therapy. Methods: We prospectively enrolled pts with ccRCC in a clinical study in which Whole-Exome Sequencing (WES) of normal and tumor tissue was performed. Clinical features, treatment outcome and survival were evaluated. Results: Forty-five pts with ccRCC with a median age of 65 years (range 38–86) were enrolled. According to the Heng risk criteria, 15 pts (33.3%) were classified as favorable-risk 23 pts (51.1%) were intermediate-risk and 7 pts (15.6%) were poor-risk. Pts received a median number of 3 lines (range 0–9) of therapy including cytokines (n=7), anti-VEGF (n=36), mTOR inhibitors (n=10) and/or immune checkpoint inhibitors (n=23). The median progression free survival (PFS) after treatment was 3.5 months (0.7-13.1), 11.1 months (1.1–54.2), 2.7 months (0.7-36.2) and 4.9 months (1.4–29.2) after cytokines, VEGF-, mTOR- and immune checkpoint inhibitors, respectively. The median overall survival (OS) from start of treatment to last follow up was 2.2 years (range 0.2–14.9 years). A total of 68 samples were sequenced. These included 9 (12.5%) primary tumors, 38 (55.9%) collected after treatment with anti-VEGF, 16 (23.5%) after mTOR- and 8 (11.8%) after immune checkpoint inhibitor. VHL, KDM5C, SETD2 and PBRM1 were the most frequent somatic mutations detected in this cohort. In two cases with a short and long response to VEGF targeted therapy (PFS 2.8 versus 50.3 months) rapid autopsies were performed which allowed multiregional (n=7, n=4) sampling. The multiregional sequencing in the rapid autopsy case with a prolonged response to VEGF targeted therapy revealed recurrent KDM5C mutations. Conclusions: We present the genomic landscape of metastatic ccRCC after treatment with systemic therapy. We report an increased frequency of KDM5C mutations, previously described to be associated with a favorable response to VEGF-inhibitors.

scholarly journals Patterns of treatment and BRAF testing with immune checkpoint inhibitors and targeted therapy in patients with metastatic melanoma presumed to be BRAF positive

2019 ◽  
Vol 29 (3) ◽  
pp. 301-310 ◽  
Author(s):  
Sameer Ghate ◽  
Raluca Ionescu-Ittu ◽  
Rebecca Burne ◽  
Briana Ndife ◽  
François Laliberté ◽  
...  
Keyword(s):  
Targeted Therapy ◽  
Metastatic Melanoma ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors

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.

Targeted therapies and checkpoint inhibitors in sarcoma

QJM ◽  
2021 ◽  
Author(s):  
M Vasella ◽  
E Gousopoulos ◽  
M Guidi ◽  
G Storti ◽  
S Y Song ◽  
...  
Keyword(s):  
Targeted Therapy ◽  
Solid Tumors ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Treatment Options ◽  
Treatment Strategies ◽  
Suppressor Gene ◽  
Treatment Practice ◽  
Therapeutic Concepts

Abstract Sarcomas are defined as a group of mesenchymal malignancies with over 100 heterogeneous subtypes. As a rare and difficult to diagnose entity, micrometastasis is already present at the time of diagnosis in many cases. Current treatment practice of sarcomas consists mainly of surgery, (neo)adjuvant chemo- and/or radiotherapy. Although the past decade has shown that particular genetic abnormalities can promote the development of sarcomas, such as translocations, gain-of-function mutations, amplifications or tumor suppressor gene losses, these insights have not led to established alternative treatment strategies so far. Novel therapeutic concepts with immunotherapy at its forefront have experienced some remarkable success in different solid tumors while their impact in sarcoma remains limited. In this review, the most common immunotherapy strategies in sarcomas, such as immune checkpoint inhibitors, targeted therapy and cytokine therapy are concisely discussed. The programmed cell death (PD)-1/PD-1L axis and apoptosis-inducing cytokines, such as TNF-related apoptosis-inducing ligand (TRAIL), have not yielded the same success like in other solid tumors. However, in certain sarcoma subtypes, e.g. liposarcoma or undifferentiated pleomorphic sarcoma, encouraging results in some cases when employing immune checkpoint inhibitors in combination with other treatment options were found. Moreover, newer strategies such as the targeted therapy against the ancient cytokine macrophage migration inhibitory factor (MIF) may represent an interesting approach worth investigation in the future.

Impact of the azoximer bromide concomitant therapy on patient outcomes in patients with melanoma.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e21574-e21574
Author(s):  
Natalya Shendaleva ◽  
Aleksei Viktorovich Novik ◽  
Anton Zozulya ◽  
Tatyana Leonidovna Nekhaeva ◽  
Anna Semenova ◽  
...  
Keyword(s):  
Targeted Therapy ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Single Agent ◽  
Treatment Modalities ◽  
Current Therapy ◽  
Metastatic Setting ◽  
Male Sex ◽  
The Impact

e21574 Background: Immunomodulators are used in the treatment of patients with melanoma. However, their role as anticancer therapeutic agents requires further investigation. Azoximer bromide (AB) is a well-tolerated immunomodulator that has been used in cases of melanoma. We investigated the impact of AB when used concomitantly with other melanoma treatment modalities on the overall survival (OS) and time to progression (TTP). Methods: We reviewed per protocol, a single-center real practice database that included 1,391 patients. Forty-two patients had received AB as a concomitant therapeutic agent. Concomitant medications included immune checkpoint inhibitors, cytokines, vaccines, targeted therapy and surgery alone in the adjuvant or metastatic setting. We built Cox proportional-hazards models for OS and TTP stratified by stage in SPSS v19. All known prognostic factors (LDH, TNM stage and sub-stage, mutations, sex, age, therapy by type, and by immunologic action) were included in the model along with AB therapy. Known factors were separated from unknown (AB therapy) by different variable blocks. A step forward method was used for model construction. Results: Significant (p < 0.05) factors to emerge in the OS model were LDH (Hazards ration [HR]: 1.458 for high LDH), sub-stage (HR: 1.718 for M1b-d sub-stage), BRAF mutation (HR: 0.698 if present), current therapy type (HR: 0.501 for immune checkpoint inhibitors (ICI), HR: 0.656 for targeted therapy (TT), HR: 1.275 for systemic immunotherapy, HR: 0.825 per added method for complex treatment, HR: 0.605 for surgery), previous treatment (HR: 0.778 for ICI, HR: 1.207 for single-agent chemotherapy, HR 1.176 for targeted or local treatment, HR: 1.315 for combination chemotherapy, HR: 2.039 for immunosuppressive factors reduction methods), male sex (HR: 1.204) and AB therapy (HR: 0.475). Significant factors in the TTP model were LDH (HR: 1.348 for high LDH), sub-stage (HR: 1.434 for B-D sub-stage), current therapy type (HR: 0.432 for (ICI), HR: 0.541 for TT, HR: 0.692 per added method for complex therapy HR: 0.705 for surgery), previous therapy (HR: 0.789 for ICI), male sex (HR: 1.167) and AB therapy (HR: 0.478). Conclusions: The addition of AB to standard therapy in melanoma appears to be an independent favorable prognostic factor. Prospective, randomized, clinical trials are needed to investigate these findings further.

scholarly journals Switching to Immune Checkpoint Inhibitors upon Response to Targeted Therapy; The Road to Long-Term Survival in Advanced Melanoma Patients with Highly Elevated Serum LDH?

Cancers ◽  
2019 ◽  
Vol 11 (12) ◽  
pp. 1940 ◽  
Author(s):  
Maartje G. Schouwenburg ◽  
Karijn P.M. Suijkerbuijk ◽  
Rutger H.T. Koornstra ◽  
Anouk Jochems ◽  
Michiel C.T. van Zeijl ◽  
...  
Keyword(s):  
Targeted Therapy ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Elevated Serum ◽  
Subsequent Treatment ◽  
Advanced Melanoma ◽  
Term Survival ◽  
Melanoma Patients

The prognosis of patients with advanced melanoma has improved dramatically. However, the clinical outcomes of patients with highly elevated serum lactate dehydrogenase (LDH) remain very poor. The aim of this study was to explore whether patients with normalized LDH after targeted therapy could benefit from subsequent treatment with immune checkpoint inhibitors (ICI). Data from all patients with BRAF-mutant metastatic melanoma with a highly elevated serum LDH at baseline (≥2× upper limit of normal) receiving first-line targeted therapy between 2012 and 2019 in the Netherlands were collected. Patients were stratified according to response status to targeted therapy and change in LDH at start of subsequent treatment with ICI. Differences in overall survival (OS) between the subgroups were compared using log-rank tests. After a median follow-up of 35.1 months, median OS of the total study population (n = 360) was 4.9 months (95% CI 4.4–5.4). Of all patients receiving subsequent treatment with ICI (n = 113), survival from start of subsequent treatment was significantly longer in patients who had normalized LDH and were still responding to targeted therapy compared to those with LDH that remained elevated (median OS 24.7 vs. 1.1 months). Our study suggests that introducing ICI upon response to targeted therapy with normalization of LDH could be an effective strategy in obtaining long-term survival in advanced melanoma patients with initial highly elevated serum LDH.

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