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CA: a Cancer Journal For Clinicians 2023Small cell lung cancer (SCLC) is characterized by rapid growth and high metastatic capacity. It has strong epidemiologic and biologic links to tobacco carcinogens.... (Review)
Review
Small cell lung cancer (SCLC) is characterized by rapid growth and high metastatic capacity. It has strong epidemiologic and biologic links to tobacco carcinogens. Although the majority of SCLCs exhibit neuroendocrine features, an important subset of tumors lacks these properties. Genomic profiling of SCLC reveals genetic instability, almost universal inactivation of the tumor suppressor genes TP53 and RB1, and a high mutation burden. Because of early metastasis, only a small fraction of patients are amenable to curative-intent lung resection, and these individuals require adjuvant platinum-etoposide chemotherapy. Therefore, the vast majority of patients are currently being treated with chemoradiation with or without immunotherapy. In patients with disease confined to the chest, standard therapy includes thoracic radiotherapy and concurrent platinum-etoposide chemotherapy. Patients with metastatic (extensive-stage) disease are treated with a combination of platinum-etoposide chemotherapy plus immunotherapy with an anti-programmed death-ligand 1 monoclonal antibody. Although SCLC is initially very responsive to platinum-based chemotherapy, these responses are transient because of the development of drug resistance. In recent years, the authors have witnessed an accelerating pace of biologic insights into the disease, leading to the redefinition of the SCLC classification scheme. This emerging knowledge of SCLC molecular subtypes has the potential to define unique therapeutic vulnerabilities. Synthesizing these new discoveries with the current knowledge of SCLC biology and clinical management may lead to unprecedented advances in SCLC patient care. Here, the authors present an overview of multimodal clinical approaches in SCLC, with a special focus on illuminating how recent advancements in SCLC research could accelerate clinical development.
Topics: Humans; Small Cell Lung Carcinoma; Lung Neoplasms; Etoposide; Combined Modality Therapy; Antineoplastic Combined Chemotherapy Protocols; Biological Products
PubMed: 37329269
DOI: 10.3322/caac.21785 -
Journal of Hematology & Oncology Jun 2023Small cell lung cancer (SCLC) is an aggressive neuroendocrine carcinoma with a poor prognosis. Initial responses to standard-of-care chemo-immunotherapy are,... (Review)
Review
Small cell lung cancer (SCLC) is an aggressive neuroendocrine carcinoma with a poor prognosis. Initial responses to standard-of-care chemo-immunotherapy are, unfortunately, followed by rapid disease recurrence in most patients. Current treatment options are limited, with no therapies specifically approved as third-line or beyond. Delta-like ligand 3 (DLL3), a Notch inhibitory ligand, is an attractive therapeutic target because it is overexpressed on the surface of SCLC cells with minimal to no expression on normal cells. Several DLL3-targeted therapies are being developed for the treatment of SCLC and other neuroendocrine carcinomas, including antibody-drug conjugates (ADCs), T-cell engager (TCE) molecules, and chimeric antigen receptor (CAR) therapies. First, we discuss the clinical experience with rovalpituzumab tesirine (Rova-T), a DLL3-targeting ADC, the development of which was halted due to a lack of efficacy in phase 3 studies, with a view to understanding the lessons that can be garnered for the rapidly evolving therapeutic landscape in SCLC. We then review preclinical and clinical data for several DLL3-targeting agents that are currently in development, including the TCE molecules-tarlatamab (formerly known as AMG 757), BI 764532, and HPN328-and the CAR T-cell therapy AMG 119. We conclude with a discussion of the future challenges and opportunities for DLL3-targeting therapies, including the utility of DLL3 as a biomarker for patient selection and disease progression, and the potential of rational combinatorial approaches that can enhance efficacy.
Topics: Humans; Small Cell Lung Carcinoma; Lung Neoplasms; Ligands; Neoplasm Recurrence, Local; Membrane Proteins; Intracellular Signaling Peptides and Proteins
PubMed: 37355629
DOI: 10.1186/s13045-023-01464-y -
Journal of Clinical Oncology : Official... Sep 2023Adagrasib, a KRAS inhibitor, has demonstrated clinical activity in patients with -mutated non-small-cell lung cancer (NSCLC) and colorectal cancer (CRC). mutations...
PURPOSE
Adagrasib, a KRAS inhibitor, has demonstrated clinical activity in patients with -mutated non-small-cell lung cancer (NSCLC) and colorectal cancer (CRC). mutations occur rarely in other solid tumor types. We report evaluation of the clinical activity and safety of adagrasib in patients with other solid tumors harboring a mutation.
METHODS
In this phase II cohort of the KRYSTAL-1 study (ClinicalTrials.gov identifier: NCT03785249; phase Ib cohort), we evaluated adagrasib (600 mg orally twice daily) in patients with -mutated advanced solid tumors (excluding NSCLC and CRC). The primary end point was objective response rate. Secondary end points included duration of response, progression-free survival (PFS), overall survival, and safety.
RESULTS
As of October 1, 2022, 64 patients with -mutated solid tumors were enrolled and 63 patients treated (median follow-up, 16.8 months). The median number of prior lines of systemic therapy was 2. Among 57 patients with measurable disease at baseline, objective responses were observed in 20 (35.1%) patients (all partial responses), including 7/21 (33.3%) responses in pancreatic and 5/12 (41.7%) in biliary tract cancers. The median duration of response was 5.3 months (95% CI, 2.8 to 7.3) and median PFS was 7.4 months (95% CI, 5.3 to 8.6). Treatment-related adverse events (TRAEs) of any grade were observed in 96.8% of patients and grade 3-4 in 27.0%; there were no grade 5 TRAEs. TRAEs did not lead to treatment discontinuation in any patients.
CONCLUSION
Adagrasib demonstrates encouraging clinical activity and is well tolerated in this rare cohort of pretreated patients with -mutated solid tumors.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Proto-Oncogene Proteins p21(ras); Lung Neoplasms; Mutation
PubMed: 37099736
DOI: 10.1200/JCO.23.00434 -
Clinical Cancer Research : An Official... Jun 2023Patients with small-cell lung cancer (SCLC) have an exceptionally poor prognosis, calling for improved real-time noninvasive biomarkers of therapeutic response.
PURPOSE
Patients with small-cell lung cancer (SCLC) have an exceptionally poor prognosis, calling for improved real-time noninvasive biomarkers of therapeutic response.
EXPERIMENTAL DESIGN
We performed targeted error-correction sequencing on 171 serial plasmas and matched white blood cell (WBC) DNA from 33 patients with metastatic SCLC who received treatment with chemotherapy (n = 16) or immunotherapy-containing (n = 17) regimens. Tumor-derived sequence alterations and plasma aneuploidy were evaluated serially and combined to assess changes in total cell-free tumor load (cfTL). Longitudinal dynamic changes in cfTL were monitored to determine circulating cell-free tumor DNA (ctDNA) molecular response during therapy.
RESULTS
Combined tiered analyses of tumor-derived sequence alterations and plasma aneuploidy allowed for the assessment of ctDNA molecular response in all patients. Patients classified as molecular responders (n = 9) displayed sustained elimination of cfTL to undetectable levels. For 14 patients, we observed initial molecular responses, followed by ctDNA recrudescence. A subset of patients (n = 10) displayed a clear pattern of molecular progression, with persistence of cfTL across all time points. Molecular responses captured the therapeutic effect and long-term clinical outcomes in a more accurate and rapid manner compared with radiographic imaging. Patients with sustained molecular responses had longer overall (log-rank P = 0.0006) and progression-free (log-rank P < 0.0001) survival, with molecular responses detected on average 4 weeks earlier than imaging.
CONCLUSIONS
ctDNA analyses provide a precise approach for the assessment of early on-therapy molecular responses and have important implications for the management of patients with SCLC, including the development of improved strategies for real-time tumor burden monitoring. See related commentary by Pellini and Chaudhuri, p. 2176.
Topics: Humans; Circulating Tumor DNA; Small Cell Lung Carcinoma; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Cell-Free Nucleic Acids; Prognosis; Neoplasm Recurrence, Local; Mutation
PubMed: 37071497
DOI: 10.1158/1078-0432.CCR-22-2242 -
Signal Transduction and Targeted Therapy Aug 2023Immune-checkpoint inhibitors (ICBs), in addition to targeting CTLA-4, PD-1, and PD-L1, novel targeting LAG-3 drugs have also been approved in clinical application. With... (Review)
Review
Immune-checkpoint inhibitors (ICBs), in addition to targeting CTLA-4, PD-1, and PD-L1, novel targeting LAG-3 drugs have also been approved in clinical application. With the widespread use of the drug, we must deeply analyze the dilemma of the agents and seek a breakthrough in the treatment prospect. Over the past decades, these agents have demonstrated dramatic efficacy, especially in patients with melanoma and non-small cell lung cancer (NSCLC). Nonetheless, in the field of a broad concept of solid tumours, non-specific indications, inseparable immune response and side effects, unconfirmed progressive disease, and complex regulatory networks of immune resistance are four barriers that limit its widespread application. Fortunately, the successful clinical trials of novel ICB agents and combination therapies, the advent of the era of oncolytic virus gene editing, and the breakthrough of the technical barriers of mRNA vaccines and nano-delivery systems have made remarkable breakthroughs currently. In this review, we enumerate the mechanisms of each immune checkpoint targets, associations between ICB with tumour mutation burden, key immune regulatory or resistance signalling pathways, the specific clinical evidence of the efficacy of classical targets and new targets among different tumour types and put forward dialectical thoughts on drug safety. Finally, we discuss the importance of accurate triage of ICB based on recent advances in predictive biomarkers and diagnostic testing techniques.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; Melanoma; Combined Modality Therapy; Drug Delivery Systems
PubMed: 37635168
DOI: 10.1038/s41392-023-01522-4 -
Critical Reviews in Oncology/hematology Oct 2023Non-small cell lung cancer (NSCLC) stages I-III were previously predominantly treated with surgery and chemotherapy. With the advent of Checkmate-816, neoadjuvant... (Review)
Review
Non-small cell lung cancer (NSCLC) stages I-III were previously predominantly treated with surgery and chemotherapy. With the advent of Checkmate-816, neoadjuvant nivolumab and chemotherapy was FDA approved for the treatment of resectable NSCLC. There are several ongoing trials evaluating other neoadjuvant combinations of chemotherapy and immunotherapy as well as targeted therapies towards driver mutations. Here, we review previous clinical trials and discuss current ongoing trials' potential benefits and challenges.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; Neoadjuvant Therapy; Nivolumab; Immunotherapy
PubMed: 37532102
DOI: 10.1016/j.critrevonc.2023.104080 -
JAMA Oncology Sep 2023MET inhibitors have recently demonstrated clinical activity in patients with MET exon 14 (METex14)-skipping non-small cell lung cancer (NSCLC); however, data with longer...
IMPORTANCE
MET inhibitors have recently demonstrated clinical activity in patients with MET exon 14 (METex14)-skipping non-small cell lung cancer (NSCLC); however, data with longer follow-up and in larger populations are needed to further optimize therapeutic approaches.
OBJECTIVE
To assess the long-term efficacy and safety of tepotinib, a potent and highly selective MET inhibitor, in patients with METex14-skipping NSCLC in the VISION study.
DESIGN, SETTING, AND PARTICIPANTS
The VISION phase 2 nonrandomized clinical trial was a multicohort, open-label, multicenter study that enrolled patients with METex14-skipping advanced/metastatic NSCLC (cohorts A and C) from September 2016 to May 2021. Cohort C (>18 months' follow-up) was an independent cohort, designed to confirm findings from cohort A (>35 months' follow-up). Data cutoff was November 20, 2022.
INTERVENTION
Patients received tepotinib, 500 mg (450 mg active moiety), once daily.
MAIN OUTCOMES AND MEASURES
The primary end point was objective response by independent review committee (RECIST v1.1). Secondary end points included duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety.
RESULTS
Cohorts A and C included 313 patients (50.8% female, 33.9% Asian; median [range] age, 72 [41-94] years). The objective response rate (ORR) was 51.4% (95% CI, 45.8%-57.1%) with a median (m)DOR of 18.0 (95% CI, 12.4-46.4) months. In cohort C (n = 161), an ORR of 55.9% (95% CI, 47.9%-63.7%) with an mDOR of 20.8 (95% CI, 12.6-not estimable [NE]) months was reported across treatment lines, comparable to cohort A (n = 152). In treatment-naive patients (cohorts A and C; n = 164), ORR was 57.3% (95% CI, 49.4%-65.0%) and mDOR was 46.4 (95% CI, 13.8-NE) months. In previously treated patients (n = 149), ORR was 45.0% (95% CI, 36.8%-53.3%) and mDOR was 12.6 (95% CI, 9.5-18.5) months. Peripheral edema, the most common treatment-related adverse event, occurred in 210 patients (67.1%) (35 [11.2%] experienced grade ≥3 events).
CONCLUSIONS AND RELEVANCE
The findings from cohort C in this nonrandomized clinical trial supported the results from original cohort A. Overall, the long-term outcomes of VISION demonstrated robust and durable clinical activity following treatment with tepotinib, particularly in the treatment-naive setting, in the largest known clinical trial of patients with METex14-skipping NSCLC, supporting the global approvals of tepotinib and enabling clinicians to implement this therapeutic approach for such patients.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT02864992.
Topics: Aged; Female; Humans; Male; Carcinoma, Non-Small-Cell Lung; Exons; Follow-Up Studies; Lung Neoplasms
PubMed: 37270698
DOI: 10.1001/jamaoncol.2023.1962 -
The Oncologist Sep 2023Non-small cell lung cancer (NSCLC) remains a major cause of morbidity and mortality worldwide. One-third of NSCLC patients present with surgically resectable,... (Review)
Review
Non-small cell lung cancer (NSCLC) remains a major cause of morbidity and mortality worldwide. One-third of NSCLC patients present with surgically resectable, non-metastatic disease; however, many of these patients will recur despite curative surgery and adjuvant therapy. The recent publication of randomized trials incorporating immune check-point inhibitors (ICI) to the standard neo-adjuvant and adjuvant treatment regimens has reported improved survival with manageable toxicity profiles. The IMpower 010 studied the use of adjuvant atezolizumab after standard surgery and adjuvant chemotherapy. They demonstrated an improvement in 3-year disease-free survival (DFS) prompting a change in treatment guidelines. The Checkmate 816 and NADIM II studies evaluated the addition of pembrolizumab and nivolumab, respectively, to standard neo-adjuvant chemotherapy. The results from both trials showed an improvement in 2-year event-free survival (EFS) and 2-year PFS (PFS), respectively. In this review, we summarize the prior data regarding adjuvant and neo-adjuvant chemotherapy in NSCLC and elaborate on results from the newer trials incorporating ICIs. We briefly discuss the pros and cons of each treatment approach along with areas that need further clarity to inform clinical practice and future directions for research in this disease.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Neoadjuvant Therapy; Lung Neoplasms; Antineoplastic Combined Chemotherapy Protocols; Neoplasm Recurrence, Local; Small Cell Lung Carcinoma; Immunotherapy
PubMed: 37338126
DOI: 10.1093/oncolo/oyad125