Managing Resistance to Immune Checkpoint Inhibitors in Lung Cancer: Treatment and Novel Strategies

2022 ◽  
Author(s):  
Antonio Passaro ◽  
Julie Brahmer ◽  
Scott Antonia ◽  
Tony Mok ◽  
Solange Peters
Keyword(s):  
Lung Cancer ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Acquired Resistance ◽  
Resistance Mechanisms ◽  
Primary Resistance ◽  
Previous Response ◽  
Immune Resistance ◽  
Clinical Resistance

A proportion of patients with lung cancer experience long-term clinical benefit with immune checkpoint inhibitors (ICIs). However, most patients develop disease progression during treatment or after treatment discontinuation. Definitions of immune resistance are heterogeneous according to different clinical and biologic features. Primary resistance and acquired resistance, related to tumor-intrinsic and tumor-extrinsic mechanisms, are identified according to previous response patterns and timing of occurrence. The clinical resistance patterns determine differential clinical approaches. To date, several combination therapies are under development to delay or prevent the occurrence of resistance to ICIs, including the blockade of immune coinhibitory signals, the activation of those with costimulatory functions, the modulation of the tumor microenvironment, and the targeting T-cell priming. Tailoring the specific treatments with distinctive biologic resistance mechanisms would be ideal to improve the design and results of clinical trial. In this review, we reviewed the available evidence on immune resistance mechanisms, clinical definitions, and management of resistance to ICIs in lung cancer. We also reviewed data on novel strategies under investigation in this setting.

scholarly journals Ipilimumab and nivolumab/pembrolizumab in advanced hepatocellular carcinoma refractory to prior immune checkpoint inhibitors

2021 ◽  
Vol 9 (2) ◽  
pp. e001945 ◽  
Author(s):  
Jeffrey Sum Lung Wong ◽  
Gerry Gin Wai Kwok ◽  
Vikki Tang ◽  
Bryan Cho Wing Li ◽  
Roland Leung ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Objective Response ◽  
Acquired Resistance ◽  
Survival Rates ◽  
Advanced Hepatocellular Carcinoma ◽  
Primary Resistance ◽  
Advanced Hcc

BackgroundProgrammed cell death protein 1 (PD-1) pathway blockade with immune checkpoint inhibitors (ICIs) is a standard therapy in advanced hepatocellular carcinoma (HCC) nowadays. No strategies to overcome ICI resistance have been described. We aimed to evaluate the use of ipilimumab and anti-PD-1 ICIs (nivolumab or pembrolizumab) combinations in patients with advanced HCC with progression on prior ICIs.MethodsPatients with advanced HCC with documented tumor progression on prior ICIs and subsequently received ipilimumab with nivolumab/pembrolizumab were analyzed. Objective response rate (ORR), median duration of response (DOR), time-to-progression (TTP), overall survival (OS), and treatment-related adverse events (TRAEs) were assessed.ResultsTwenty-five patients were included. The median age was 62 (range: 51–83). About 68% were of Child-Pugh (CP) Grade A and 48% had primary resistance to prior ICI. At median follow-up of 37.7 months, the ORR was 16% with a median DOR of 11.5 months (range: 2.76–30.3). Three patients achieved complete response. The median TTP was 2.96 months (95% CI: 1.61 to 4.31). Median OS was 10.9 months (95% CI: 3.99 to 17.8) and the 1 year, 2 year and 3 year survival rates were 42.4%, 32.3% and 21.6%, respectively. The ORR was 16.7% in primary resistance group and 15.4% in acquired resistance group (p=1.00). All responders were of CP A and Albumin-Bilirubin (ALBI) Grade 1 or 2. CP and ALBI Grades were significantly associated with OS (p=0.006 and p<0.001, respectively). Overall, 52% of patients experienced TRAEs and 12% experienced Grade 3 or above TRAEs.ConclusionsIpilimumab and nivolumab/pembrolizumab can achieve durable antitumor activity and encouraging survival outcomes with acceptable toxicity in patients with advanced HCC who had prior treatment with ICIs.

A Career in Lung Cancer: Pushing Beyond Chemotherapy

2019 ◽  
pp. 583-589
Author(s):  
Pradnya Dinkar Patil ◽  
Frances Shepherd ◽  
David H. Johnson
Keyword(s):  
Lung Cancer ◽  
Targeted Therapies ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Acquired Resistance ◽  
Genetic Alterations ◽  
Disease Biology ◽  
Formidable Challenge ◽  
Treatment Paradigm

The landscape of treatments for non–small cell lung cancer (NSCLC) has evolved dramatically over the past 3 decades. A better understanding of the disease biology and identification of actionable genetic alterations heralded an era of targeted therapies that has led to unprecedented survival benefits in patients with oncogene-driven NSCLC. More recent breakthroughs in immunotherapy led to the development of immune checkpoint inhibitors that have changed the treatment paradigm for patients with advanced NSCLC because of their ability to produce durable responses, resulting in improved survival outcomes. Despite the unparalleled success of these agents, primary and acquired resistance to these therapies pose a formidable challenge. In this article, we provide an overview of the therapeutic advances in the treatment of NSCLC, mechanisms of resistance, and potential strategies to overcome resistance to targeted therapies and immune checkpoint inhibitors.

The combination of immune checkpoint inhibitors and chemotherapy in advanced non-small-cell lung cancer: the rational choice

Immunotherapy ◽  
2021 ◽  
Author(s):  
Joseph Zouein ◽  
Fady G Haddad ◽  
Roland Eid ◽  
Hampig R Kourie
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Acquired Resistance ◽  
Small Cell ◽  
Cancer Prognosis ◽  
Small Cell Lung

Lung cancer is the second most common cancer worldwide and the leading cause of death among cancers. The progressive approvals of immunotherapy as first-line treatment options have helped improve cancer prognosis. However, longer follow-up has confirmed the possibility of acquired resistance to immune checkpoint inhibitors (ICIs) which can lead to late relapses. Chemotherapy can act as a priming therapy to increase a tumor’s response to immunotherapy. We aim through this review to explain the mechanism behind ICI resistance and the value of chemotherapy in escaping this resistance. Finally, all US FDA approvals regarding the management of metastatic non-small-cell lung cancer using a combination of ICIs and chemotherapy are summarized.

Cabozantinib in advanced HCC patients previously treated with immune checkpoint inhibitors: A territory-wide cohort study.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e16179-e16179
Author(s):  
Jeffrey Sum Lung Wong ◽  
Yawen Dong ◽  
Vikki Tang ◽  
Thomas Wai-Tong Leung ◽  
Cynthia SY Yeung ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Single Agent ◽  
Acquired Resistance ◽  
Previous Treatment ◽  
Phase Iii ◽  
Advanced Hepatocellular Carcinoma ◽  
Primary Resistance ◽  
Grade 3

e16179 Background: Cabozantinib is licensed for use as second- or third-line treatment for sorafenib-exposed advanced hepatocellular carcinoma (aHCC) based on the phase III CELESTIAL trial. However, its use in the post-immune checkpoint inhibitors (ICI) setting has yet to be described. We evaluated the pattern of use, efficacy, survival and tolerability of cabozantinib in aHCC patients with previous treatment by ICIs. Methods: We did a multi-centre, territory-wide study analysing aHCC patients who received cabozantinib after prior ICIs. Objective response rate (ORR), disease control rate (DCR), time-to-progression (TTP), overall survival (OS) and treatment related adverse events (TRAEs) were assessed. Results: Thirty-one patients were included. The median age was 58.0 (range 41-85) and 77.4% had Child-Pugh A cirrhosis. 51.6% of patients received single agent cabozantinib and 48.4% received cabozantinib in combination with ICIs. ≥80% of patients received cabozantinib beyond the second-line and 93.5% of patients had prior TKIs. All patients received prior anti-PD-1 and 61.3% had prior anti-CTLA-4. The median follow-up was 15.2 months. For single agent cabozantinib patients, the ORR was 6.3%, DCR was 31.3% and median TTP was 3.5 months (95% C.I. 1.2-5.8). For cabozantinib-ICI combination patients, the ORR was 6.7%, DCR was 26.7% and median TTP was 2.3 months (95% C.I. 1.4-3.1). The overall median OS was 8.9 months (95% C.I. 5.7-11.9). Single agent cabozantinib patients had a significantly shorter OS compared to cabozantinib-ICI combination patients (8.3 months (95% C.I. 1.3-15.2) vs. 15.1 months (95% C.I. 11.1-19.2), p = 0.047). There was no significant difference in OS among patients with primary resistance to prior ICI regimes compared to those with acquired resistance (primary resistance 8.28 months (95% C.I. 5.04-11.5) vs. acquired resistance 8.90 months (95% C.I. 3.49-14.3), p = 0.472). Overall, 67.7% and 6.5% of patients experienced TRAEs of all grade and grade ≥3 respectively. The most common TRAE was hand-foot syndrome. 62.5% of single agent cabozantinib patients had any grade TRAE and no such patients had grade ≥3 TRAE. Conclusions: Cabozantinib had good anti-tumour activity and survival outcomes with acceptable toxicity in aHCC patients with previous treatment by ICIs.

scholarly journals Molecular Mechanisms of Resistance to Immune Checkpoint Inhibitors in Melanoma Treatment: An Update

Biomedicines ◽  
2021 ◽  
Vol 9 (7) ◽  
pp. 835
Author(s):  
Sonja Vukadin ◽  
Farah Khaznadar ◽  
Tomislav Kizivat ◽  
Aleksandar Vcev ◽  
Martina Smolic
Keyword(s):  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Molecular Mechanisms ◽  
Checkpoint Inhibitors ◽  
Acquired Resistance ◽  
Significant Proportion ◽  
Resistance Mechanisms ◽  
Advanced Melanoma ◽  
Mutational Status ◽  
Primary Drug Resistance

Over the past decade, immune checkpoint inhibitors (ICI) have revolutionized the treatment of advanced melanoma and ensured significant improvement in overall survival versus chemotherapy. ICI or targeted therapy are now the first line treatment in advanced melanoma, depending on the tumor v-raf murine sarcoma viral oncogene homolog B1 (BRAF) mutational status. While these new approaches have changed the outcomes for many patients, a significant proportion of them still experience lack of response, known as primary resistance. Mechanisms of primary drug resistance are not fully elucidated. However, many alterations have been found in ICI-resistant melanomas and possibly contribute to that outcome. Furthermore, some tumors which initially responded to ICI treatment ultimately developed mechanisms of acquired resistance and subsequent tumor progression. In this review, we give an overview of tumor primary and acquired resistance mechanisms to ICI and discuss future perspectives with regards to new molecular targets and combinatorial therapies.

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