Advances in Metastatic Non-small Cell Lung Cancer–Implications on Diagnosis and Treatment as We Head towards 2024

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Metastasis".

Deadline for manuscript submissions: closed (31 May 2024) | Viewed by 7810

Special Issue Editors


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Guest Editor
Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY 11549, USA
Interests: non-small cell lung cancer; predictive and prognostic biomarkers in lung cancers; immuno-oncology; precision medicine; health related quality of life; drug toxicity; patient-reported outcomes; health care disparities

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Guest Editor
Northwell Health Cancer Institute, Lenox Hill Hospital, New York, NY 10021, USA
Interests: lung cancer; brain metastases; leptomeningeal disease; translational research

Special Issue Information

Dear Colleagues,

Non-small-cell lung cancer (NSCLC) has the highest cancer-related mortality rate worldwide to this day. Oncogenes, tumor heterogeneity and variabilities in the tumor microenvironment may all contribute to cancer progression and metastases, with >50% being metastatic at diagnosis (mainly brain, bone, liver, and adrenal glands). 

In the past decade, advances in identifying driver mutations have completely changed the therapeutic landscape of this disease. Targeted therapies such as osimertinib and other small-molecule tyrosine kinase inhibitors, are now widely used in clinical practice. At the same time, new therapeutic targets are also emerging, greatly extending the life expectancy of patients who carry these alterations. Immunotherapy has also significantly improved the prognosis and survival of NSCLC patients, even for traditionally frail patients who are not candidates for chemotherapy. We are increasingly able to apply the concept of “precision oncology” in our clinics today and focus on delivering therapies to our patients that are individualized to their specific needs. 

This Special Issue aims to publish high-quality research and reviews on the pathogenesis and evolving treatment landscape (immunotherapy, targeted therapy, etc.) of metastatic NSCLC with a joint mission of combating this deadly cancer.

Dr. Nagashree Seetharamu
Dr. Morana Vojnic
Guest Editors

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Keywords

  • NSCLC
  • oncogene
  • metastases
  • targeted therapy
  • immunotherapy
  • pathogenesis

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Published Papers (4 papers)

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Research

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11 pages, 1254 KiB  
Article
HLA-A01 and HLA-B27 Supertypes, but Not HLA Homozygocity, Correlate with Clinical Outcome among Patients with Non-Small Cell Lung Cancer Treated with Pembrolizumab in Combination with Chemotherapy
by Afaf Abed, Anna Reid, Ngie Law, Michael Millward and Elin S. Gray
Cancers 2024, 16(17), 3102; https://doi.org/10.3390/cancers16173102 - 7 Sep 2024
Viewed by 759
Abstract
Introduction: Maximal heterozygosity on the human leukocyte antigen (HLA) loci has been found to be associated with improved survival and development of immune-related adverse events (irAEs) among NSCLC patients treated with immunotherapy. Here, we investigated the effect of germline HLA-I/-II on clinical outcomes [...] Read more.
Introduction: Maximal heterozygosity on the human leukocyte antigen (HLA) loci has been found to be associated with improved survival and development of immune-related adverse events (irAEs) among NSCLC patients treated with immunotherapy. Here, we investigated the effect of germline HLA-I/-II on clinical outcomes among NSCLC patients treated with first-line pembrolizumab in combination with chemotherapy. Method: We prospectively recruited patients with NSCLC who were commencing first-line pembrolizumab in combination with chemotherapy. DNA from white blood cells was used for high-resolution HLA-I/II typing. Results: Of the 65 patients recruited, 53 complied with the inclusion criteria. We did not find an association between HLA-I/-II homozygosity and clinical outcome among the studied population. However, the presence of HLA-A01 was associated with unfavourable PFS (HR = 2.32, 95%CI 1.13–4.77, p = 0.022) and worsening OS (HR = 2.86, 95%CI 1.06–7.70, p = 0.038). The presence of HLA-B27 was associated with improved PFS (HR = 0.35, 95%CI 0.18–0.71, p = 0.004) and trends toward improving OS. None of the HLA-I supertypes were associated with the development or worsening of irAEs. Conclusions: The absence of association between genomic HLA-I/-II homozygosity and clinical outcome among patients with advanced NSCLC treated with pembrolizumab in combination with chemotherapy might reflect a diminished role for HLA molecules among patients with low or no PD-L1. HLA-A01 and HLA-B27 might have a role in predicting clinical outcomes among this cohort of patients. Further studies are needed to explore biomarkers for this group of patients. Full article
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18 pages, 3572 KiB  
Article
Association of Clostridium butyricum Therapy Using the Live Bacterial Product CBM588 with the Survival of Patients with Lung Cancer Receiving Chemoimmunotherapy Combinations
by Yusuke Tomita, Shinya Sakata, Kosuke Imamura, Shinji Iyama, Takayuki Jodai, Koichi Saruwatari, Shohei Hamada, Kimitaka Akaike, Moriyasu Anai, Kazuaki Fukusima, Akira Takaki, Hirotake Tsukamoto, Yoshihiko Goto, Chihiro Motozono, Kenji Sugata, Yorifumi Satou, Takamasa Ueno, Tokunori Ikeda and Takuro Sakagami
Cancers 2024, 16(1), 47; https://doi.org/10.3390/cancers16010047 - 21 Dec 2023
Cited by 3 | Viewed by 2756
Abstract
The gut microbiota has emerged as a key regulator of immune checkpoint inhibitor (ICI) efficacy. Therapeutic approaches aimed at manipulating the microbiota through targeted reconstitution to enhance cancer treatment outcomes have garnered considerable attention. A single live microbial biotherapeutic bacterium, Clostridium butyricum MIYAIRI [...] Read more.
The gut microbiota has emerged as a key regulator of immune checkpoint inhibitor (ICI) efficacy. Therapeutic approaches aimed at manipulating the microbiota through targeted reconstitution to enhance cancer treatment outcomes have garnered considerable attention. A single live microbial biotherapeutic bacterium, Clostridium butyricum MIYAIRI 588 strain (CBM588), has been shown to enhance the effects of ICI monotherapy in patients with advanced lung cancer. However, whether CBM588 affects the outcomes of chemoimmunotherapy combinations in lung cancer remains unknown. We hypothesized that CBM588 augments the effect of chemoimmunotherapy combinations and restores diminished effectiveness in patients with non-small cell lung cancer (NSCLC) receiving dysbiosis-inducing drugs. To validate this hypothesis, we retrospectively analyzed 106 patients with stage IV or recurrent metastatic NSCLC consecutively treated with chemoimmunotherapy combinations. A survival analysis was performed employing univariate and multivariate Cox proportional hazard models with inverse probability of treatment weighting (IPTW) using propensity scores. Forty-five percent of patients received Clostridium butyricum therapy. CBM588 significantly extended overall survival in patients with NSCLC receiving chemoimmunotherapy. The favorable impact of CBM588 on the efficacy of chemoimmunotherapy combinations varied based on tumor-programmed cell death ligand 1 (PD-L1) expression. The survival benefit of CBM588 in the PD-L1 <1% cohort was higher than that in the PD-L1 1–49% and PD-L1 ≥ 50% cohorts. Furthermore, CBM588 was associated with improved overall survival in patients receiving proton pump inhibitors and/or antibiotics. CBM588-induced manipulation of the commensal microbiota holds the potential to enhance the efficacy of chemoimmunotherapy combinations, warranting further exploration of the synergy between CBM588 and immunotherapy. Full article
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14 pages, 482 KiB  
Article
Epidermal Growth Factor Receptor T790M Mutation Testing in Non-Small Cell Lung Cancer: An International Collaborative Study to Assess Molecular EGFR T790M Testing in Liquid Biopsy
by Martin Filipits, Verena Kainz, Viktor Sebek, Herwig Zach and on behalf of the Liquid Biopsy Collaborative Study Group
Cancers 2023, 15(13), 3528; https://doi.org/10.3390/cancers15133528 - 7 Jul 2023
Cited by 3 | Viewed by 1738
Abstract
Background: The detection of the EGFR T790M (T790M) mutation in non-small cell lung cancer (NSCLC) patients who progressed under treatment with first- or second-generation EGFR-tyrosine kinase inhibitors (TKIs) is important to offer a subsequent therapy with a third-generation EGFR-TKI. Liquid biopsy is a [...] Read more.
Background: The detection of the EGFR T790M (T790M) mutation in non-small cell lung cancer (NSCLC) patients who progressed under treatment with first- or second-generation EGFR-tyrosine kinase inhibitors (TKIs) is important to offer a subsequent therapy with a third-generation EGFR-TKI. Liquid biopsy is a powerful tool to determine the T790M mutation status. Several liquid biopsy platforms with varying degrees of accuracy are available to test for T790M mutations, and sensitivities may differ among these methods. Methods: As no standard exists for the testing of T790M mutation in liquid biopsy, we performed a collaborative study to describe and compare the sensitivity of different in-house liquid biopsy platforms for the detection of the T790M mutation, EGFR exon 19 deletion (del19) and EGFR L858R mutation (L858R) across multiple participating laboratories in seven Central and Eastern European countries. Results: Of the 25 invited laboratories across Central and Eastern Europe, 21 centers participated and received 10 plasma samples spiked with cell-line DNA containing the T790M, del19, or L858R mutation in different concentrations. In-house PCR-based and NGS-based methods were used accordingly, and results were reported as in routine clinical practice. Two laboratories, which used the AmoyDx® EGFR 29 Mutations Detection Kit (AmoyDx) with Cobas® cfDNA Sample Preparation Kit and QX200 Droplet Digital PCR (ddPCR) with the QIAamp Circulating Nucleic Acid Kit identified all ten samples correctly. Cobas® EGFR Mutation Test v2 (Cobas), the NGS methods, and the IdyllaTM detection method used in this study performed within the known sensitivity range of each detection method. Conclusions: If a negative result was obtained from methods with lower sensitivity (e.g., Cobas), repeated liquid biopsy testing and/or tissue biopsy analysis should be performed whenever possible, to identify T790M-positive patients to allow them to receive the optimal second-line treatment with a third-generation EGFR TKI. Full article
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Review

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16 pages, 9633 KiB  
Review
Targeted Therapies for Kirsten Rat Sarcoma (KRAS) G12C Mutant Metastatic Non-Small-Cell Lung Cancers
by Cian O’Leary, Grace Murphy, Yong Yeung, Ming Tang, Vikram Jain and Connor G O’Leary
Cancers 2023, 15(23), 5582; https://doi.org/10.3390/cancers15235582 - 25 Nov 2023
Cited by 2 | Viewed by 1761
Abstract
Non-small-cell lung cancer (NSCLC) is a prevalent and often fatal malignancy. Advancements in targeted therapies have improved outcomes for NSCLC patients in the last decade. Kirsten rat sarcoma virus (KRAS) is a commonly mutated oncogene in NSCLC, contributing to tumorigenesis and proliferation. Though [...] Read more.
Non-small-cell lung cancer (NSCLC) is a prevalent and often fatal malignancy. Advancements in targeted therapies have improved outcomes for NSCLC patients in the last decade. Kirsten rat sarcoma virus (KRAS) is a commonly mutated oncogene in NSCLC, contributing to tumorigenesis and proliferation. Though classically difficult to target, recently developed KRAS G12C inhibitors (sotorasib and adagrasib) have now overcome this therapeutic hurdle. We discuss the evidence for these medications, their pitfalls and adverse effects, as well as future directions in this space. Though these medications demonstrate substantial response rates in a heavily pre-treated advanced NSCLC cohort, as phase-3 evidence does not yet demonstrate an overall survival benefit versus standard-of-care chemotherapy, docetaxel. Additionally, these medications appear to have a negative interaction in combination with immunotherapies, with substantially greater hepatotoxicity rates observed. Despite this, it is undeniable that these medications represent an important advancement in targeted and personalised oncological treatment. Current and future trials assessing these medications in combination and through sequencing strategies will likely yield further clinically meaningful outcomes to guide treatment in this patient cohort. Full article
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