scholarly journals The Evolving Role of Immunotherapy in Stage III Non-Small Cell Lung Cancer

2021 ◽  
Vol 28 (6) ◽  
pp. 5408-5421
Author(s):  
Kirstin Perdrizet ◽  
Parneet K. Cheema
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Concurrent Chemotherapy ◽  
Small Cell ◽  
Stage Iii ◽  
Small Cell Lung ◽  
The Pacific ◽  
Stage Iii Nsclc

The management of Stage III non-small cell lung cancer (NSCLC) is complex and requires multidisciplinary input. Since the publication of the PACIFIC trial (consolidative durvalumab post concurrent chemotherapy and radiation in Stage III disease) which showed improved survival for patients in the immunotherapy arm, there has been much interest in the use of immunotherapy in the Stage III setting. In this review, we explore the biologic and clinical rationale for the use of immunotherapy in Stage III NSCLC, present previously published and upcoming data in the neoadjuvant, adjuvant, and concurrent realms of Stage III management, and discuss unanswered questions and challenges moving forward.

Doubling of median overall survival in a nationwide cohort of veterans with stage III non-small cell lung cancer in the durvalumab era.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 8546-8546
Author(s):  
Kamya Sankar ◽  
Alex K. Bryant ◽  
Michael Green ◽  
Nithya Ramnath
Keyword(s):  
Lung Cancer ◽  
Overall Survival ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Median Number ◽  
Small Cell ◽  
Stage Iii ◽  
Small Cell Lung ◽  
The Pacific ◽  
Stage Iii Nsclc

8546 Background: The standard of care for patients with unresectable stage III non-small cell lung cancer (NSCLC) is concurrent chemoradiotherapy followed by durvalumab maintenance based on outcomes from the PACIFIC trial. However, PACIFIC did not include Veterans, a unique population with significant co-morbidities; thus, the impact of durvalumab on survival of Veterans with stage III NSCLC is unknown. Methods: Using the U.S. Department of Veterans Affairs Corporate Data Warehouse, patients with stage III non-small cell lung cancer who received chemoradiotherapy and at least one dose of durvalumab were selected. Kaplan-Meier survival analysis and univariate Cox proportional hazards modeling were used to determine progression-free survival (PFS), overall survival (OS) and independent predictors of PFS and OS. PFS was manually extracted by review of serial surveillance scans. All statistical computations were performed using SAS 9.4 software. Results: 1106 Veterans met our inclusion criteria. The median age was 69. 95.1% (n = 1052) were male. The median Charlson Comorbidity Index was 1. 86.4% (n = 956) reported current or former tobacco use. 48.1% (n = 532) had adenocarcinoma histology, 48.4% (n = 535) squamous cell, 0.5% (n = 5) large cell, 0.3% (n = 3) neuroendocrine, and 0.1% (n = 1) sarcomatoid. 60% (n = 619) had AJCC 8th edition stage IIIA disease, 34.5% (n = 382) stage IIIB, and 3.3% (n = 36) stage IIIC. Median PFS was 19.9 months (95% CI: 16.9 – 23.6) and median OS was 34.9 months (95% CI: 29.7 – not reached). In univariate survival analyses, adenocarcinoma histology (HR 1.14, p = 0.03) predicted progression. Older age (HR 1.03, p < 0.0001) and stage IIIB/IIIC disease (HR 1.05, p = 0.008) predicted inferior OS. 18.4% (n = 204) of patients completed all planned cycles of adjuvant durvalumab. The median number of durvalumab infusions received was 6 (range: 1 – 38). Among evaluable patients, 175 (19.4%) discontinued durvalumab for progression, 211 (23.4%) discontinued for suspected immune-related toxicity and 17 (1.9%) died during treatment. Conclusions: While several factors have led to the improvement of OS in patients with stage III NSCLC over time, we report a doubling of median OS in Veterans with stage III NSCLC who received chemoradiotherapy plus durvalumab as compared to historical cohorts who received chemoradiotherapy alone (1). Veterans in our study received a lower median number of durvalumab infusions as compared to patients in the PACIFIC trial (6 vs. 14), and a significant proportion discontinued durvalumab due to suspected immune-mediated toxicity (23.4%). If further analyses confirm our findings, investigation of alternative dosing regimens and/or dosing intervals of durvalumab in order to balance safety and efficacy of durvalumab therapy in Veterans is warranted. (1) Santana-Davila R et al. J Clin Oncol. 2015 Feb 20;33(6):567-74.

Uptake and disparities of neoadjuvant therapy for stage III non-small cell lung cancer.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 6571-6571
Author(s):  
Daniel Jacob Becker ◽  
Benjamin Philip Levy ◽  
Michael L. Grossbard
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Neoadjuvant Therapy ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
Stage Iii ◽  
Small Cell Lung ◽  
Stage Iii Nsclc ◽  
The Relationship

6571 Background: The optimal use and sequence of radiation therapy (RT), chemotherapy, and surgery for patients with stage III non-small cell lung cancer (NSCLC) is unknown. We conducted a cross-sectional study using the Surveillance Epidemiology and End Results (SEER) population-based cancer registry to examine the relationship between year of diagnosis and receipt of neoadjuvant RT for patients with stage III NSCLC diagnosed in the United States from 2000 to 2008, with additional focus on the role of race and treatment location. Methods: Thirteen SEER registries were used for data analysis. Patients diagnosed with stage III NSCLC treated with both surgery and RT between the years 2000 and 2008 were included. We used multiple logistic regression to describe the relationship between type of therapy for lung cancer and year of diagnosis. Covariates identified for analysis included age, grade, sex, race, ethnicity, and SEER registry. Results: The total sample size was 393,711 of which 5,949 patients met our inclusion criteria. The cohort had a mean age of 64, was predominantly white (85.8%) and had predominantly high grade tumors (50.9%). Use of neoadjuvant RT for stage III NSCLC was lowest in 2000 and higher in every year from 2002 to 2008 (OR 1.325 in 2002, p= 0.035; 1.921 in 2007, p<0.0001). Substantial heterogeneity among registries existed, with more neoadjuvant RT use in Seattle and San Francisco-Oakland (OR 1.83, 1.698 p<0.0001 and 0.0002 respectively) and less use in Metropolitan Detroit, New Jersey and Louisiana (OR 0.754, 0.570, 0.493, p=0.25, <0.0001, and <0.0001 respectively). Black race was significantly associated with lack of neoadjuvant therapy without controlling for registry, but the association weakened after controlling for registry (OR 0.81, p=0.072). Conclusions: The use of neoadjuvant RT for stage III NSCLC substantially increased from 2000 to 2008. Location of treatment was strongly associated with receipt of neoadjuvant therapy and outweighed the association of race and therapy. The effort to equitably distribute care should focus additional study on the important role of regional and local medical culture in determination of medical care.

scholarly journals 244 Genomic determinants of response to chemoradiation and durvalumab consolidation for stage III non-small cell lung cancer

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A263-A263
Author(s):  
Matthew Guo ◽  
Joseph Murray ◽  
Paola Ghanem ◽  
Khinh Ranh Voong ◽  
Russell Hales ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Overall Survival ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Molecular Profiling ◽  
Small Cell ◽  
Stage Iii ◽  
Small Cell Lung ◽  
Definitive Chemoradiation ◽  
Stage Iii Nsclc

BackgroundDurvalumab consolidation after chemoradiation for unresectable stage III non-small cell lung cancer (NSCLC) improves overall survival. However, up to 25% of patients progress within 18 months following durvalumab consolidation. Little is known regarding the genomic determinants of response to therapy.1 2MethodsWe retrospectively reviewed medical records of 76 patients with stage III NSCLC who received definitive chemoradiation and durvalumab consolidation between 2015–2020 at a large tertiary academic center. Tumor characteristics, molecular profiling, and clinical outcomes including response, progression-free survival (PFS), and overall survival (OS) were documented in an IRB-approved database. Outcomes were assessed by molecular alterations identified from diagnostic biopsy samples using Kaplan-Meier analysis.ResultsOf 76 patients with stage III NSCLC treated with definitive chemoradiation and durvalumab consolidation, 74 were evaluable for PFS and OS. Median age at diagnosis was 66.5 years and 43% were women (n=32). Histology included adenocarcinoma (55%, n=41) and squamous cell carcinoma (32%, n=24). Median follow-up time was 23.0 months from start of durvalumab. The cohort’s median PFS was 15.9 months with 36 patients having documented radiographic progression. Overall survival for the cohort was 32.0 months with 28 deaths. Molecular profiling was performed at time of diagnosis in 35 patients (47%), of which 30 had adenocarcinoma histology. 18 patients had KRAS mutations including KRAS p.G12C (n=8), which were mutually exclusive with 8 patients who had other clinically targetable alterations (EGFR mutations n=1, ALK fusion n=1, RET fusion n=1, MET exon 14 skipping mutation n=1, or ERBB2 mutation n=4). Three patients had non-targetable mutations (BRAF non-p.V600E, STK11, KEAP1) and the remaining six patients lacked an identifiable alteration. There was no significant difference in PFS (p=0.92 by log-rank) or OS (p=0.36 by log-rank) between patients with KRAS mutations, other targetable alterations, non-targetable mutations, or those without molecular profiling. Within patients with KRAS mutations, there was no significant difference in PFS (p=0.33 by log-rank) or OS (p=0.69 by log-rank) when comparing KRAS p.G12C to non-p.G12C mutations.ConclusionsOur study of real-world cohort of patients with stage III NSCLC examined genomic determinants of response to treatment with definitive chemoradiation and durvalumab. Results from this retrospective study suggest that patients with KRAS-mutated tumors derive similar benefit from therapy than patients with other targetable, non-targetable or no identifiable genomic alterations. Future directions for this cohort include analysis of post-progression therapy, subgroup analysis comparing genomic alterations to patterns of progression, and examination of molecular signatures of patients with progression.ReferencesAntonia SJ, Villegas A, Daniel D, et al. Durvalumab after chemoradiotherapy in stage III non–small-cell lung cancer. N Engl J Med 2017;377(20):1919–1929. doi:10.1056/NEJMoa1709937Faivre-Finn C, Vicente D, Kurata T, et al. Four-year survival with durvalumab after chemoradiotherapy in stage III NSCLC—an update from the PACIFIC trial. Journal of Thoracic Oncology 2021;16(5):860–867. doi:10.1016/j.jtho.2020.12.015Ethics ApprovalThis retrospective chart review study has obtained ethics approval from the Institutional Review Board at the Johns Hopkins School of Medicine (number: IRB00232313).

scholarly journals Efficacy and cost of high-frequency IGRT in elderly stage III non-small-cell lung cancer patients

PLoS ONE ◽  
2021 ◽  
Vol 16 (5) ◽  
pp. e0252053
Author(s):  
Samuel P. Heilbroner ◽  
Eric P. Xanthopoulos ◽  
Donna Buono ◽  
Daniel Carrier ◽  
Ben Y. Durkee ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
High Frequency ◽  
Small Cell ◽  
Stage Iii ◽  
Small Cell Lung ◽  
Free Survival ◽  
Stage Iii Nsclc ◽  
The Impact

Background High-frequency image-guided radiotherapy (hfIGRT) is ubiquitous but its benefits are unproven. We examined the cost effectiveness of hfIGRT in stage III non-small-cell lung cancer (NSCLC). Methods We selected stage III NSCLC patients ≥66 years old who received definitive radiation therapy from the Surveillance, Epidemiology, and End-Results-Medicare database. Patients were stratified by use of hfIGRT using Medicare claims. Predictors for hfIGRT were calculated using a logistic model. The impact of hfIGRT on lung toxicity free survival (LTFS), esophageal toxicity free survival (ETFS), cancer-specific survival (CSS), overall survival (OS), and cost of treatment was calculated using Cox regressions, propensity score matching, and bootstrap methods. Results Of the 4,430 patients in our cohort, 963 (22%) received hfIGRT and 3,468 (78%) did not. By 2011, 49% of patients were receiving hfIGRT. Predictors of hfIGRT use included treatment with intensity-modulated radiotherapy (IMRT) (OR = 7.5, p < 0.01), recent diagnosis (OR = 51 in 2011 versus 2006, p < 0.01), and residence in regions where the Medicare intermediary allowed IMRT (OR = 1.50, p < 0.01). hfIGRT had no impact on LTFS (HR 0.97; 95% CI 0.86–1.09), ETFS (HR 1.05; 95% CI 0.93–1.18), CSS (HR 0.94; 95% CI 0.84–1.04), or OS (HR 0.95; 95% CI 0.87–1.04). Mean radiotherapy and total medical costs six months after diagnosis were $17,330 versus $15,024 (p < 0.01) and $71,569 versus $69,693 (p = 0.49), respectively. Conclusion hfIGRT did not affect clinical outcomes in elderly patients with stage III NSCLC but did increase radiation cost. hfIGRT deserves further scrutiny through a randomized controlled trial.

scholarly journals Identification of Potential Prognostic and Predictive Immunological Biomarkers in Patients with Stage I and Stage III Non-Small Cell Lung Cancer (NSCLC): A Prospective Exploratory Study

Cancers ◽  
2021 ◽  
Vol 13 (24) ◽  
pp. 6259
Author(s):  
Rianne D. W. Vaes ◽  
Kobe Reynders ◽  
Jenny Sprooten ◽  
Kathleen T. Nevola ◽  
Kasper M. A. Rouschop ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Exploratory Study ◽  
Predictive Biomarkers ◽  
Small Cell ◽  
Stage I ◽  
Stage Iii ◽  
Small Cell Lung ◽  
Stage Iii Nsclc

Radiotherapy (RT) and chemotherapy can induce immune responses, but not much is known regarding treatment-induced immune changes in patients. This exploratory study aimed to identify potential prognostic and predictive immune-related proteins associated with progression-free survival (PFS) in patients with non-small cell lung cancer (NSCLC). In this prospective study, patients with stage I NSCLC treated with stereotactic body radiation therapy (n = 26) and patients with stage III NSCLC treated with concurrent chemoradiotherapy (n = 18) were included. Blood samples were collected before (v1), during (v2), and after RT (v3). In patients with stage I NSCLC, CD244 (HR: 10.2, 95% CI: 1.8–57.4) was identified as a negative prognostic biomarker. In patients with stage III NSCLC, CR2 and IFNGR2 were identified as positive prognostic biomarkers (CR2, HR: 0.00, 95% CI: 0.00–0.12; IFNGR2, HR: 0.04, 95% CI: 0.00–0.46). In addition, analysis of the treatment-induced changes of circulating protein levels over time (Δv2/v3−v1) also identified CXCL10 and IL-10 as negative predictive biomarkers (CXCL10, HR: 3.86, 95% CI: 1.0–14.7; IL-10, HR: 16.92 (2.74–104.36)), although serum-induced interferon (IFN) response was a positive prognostic. In conclusion, we identified several circulating immunogenic proteins that are correlated with PFS in patients with stage I and stage III NSCLC before and during treatment.

scholarly journals Role of Surgical Intervention in Unresectable Non-Small Cell Lung Cancer

2020 ◽  
Vol 9 (12) ◽  
pp. 3881
Author(s):  
Shigeki Suzuki ◽  
Taichiro Goto
Keyword(s):  
Lung Cancer ◽  
Surgical Treatment ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Surgical Intervention ◽  
Salvage Surgery ◽  
Small Cell ◽  
Stage Iii ◽  
Small Cell Lung

With the development of systemic treatments with high response rates, including tyrosine kinase inhibitors and immune checkpoint inhibitors, some patients with unresectable lung cancer now have a chance to undergo radical resection after primary treatment. Although there is no general consensus regarding the definition of “unresectable” in lung cancer, the term “resectable” refers to technically resectable and indicates that resection can provide a favorable prognosis to some extent. Unresectable lung cancer is typically represented by stage III and IV disease. Stage III lung cancer is a heterogeneous disease, and in some patients with technically resectable non-small cell lung cancer (NSCLC), multimodality treatments, including induction chemoradiotherapy followed by surgery, are the treatments of choice. The representative surgical intervention for unresectable stage III/IV NSCLC is salvage surgery, which refers to surgical treatment for local residual/recurrent lesions after definitive non-surgical treatment. Surgical intervention is also used for an oligometastatic stage IV NSCLC. In this review, we highlight the role of surgical intervention in patients with unresectable NSCLC, for whom an initial complete resection is technically difficult. We further describe the history of and new findings on salvage surgery for unresectable NSCLC and surgery for oligometastatic NSCLC.

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