The value of innovation: association between improvements in survival of advanced and metastatic non-small cell lung cancer and targeted and immunotherapy

Abstract Background Significant improvements in mortality among patients with non-small cell lung cancer (NSCLC) in the USA over the past two decades have been reported based on Surveillance, Epidemiology, and End Results (SEER) data. The timing of these improvements led to suggestions that they result from the introduction of new treatments; however, few studies have directly investigated this. The aim of this study was to investigate the extent to which population level improvements in survival of advanced and/or metastatic NSCLC (admNSCLC) patients were associated with changes in treatment patterns. Methods We utilized a de-identified database to select three cohorts of patients with admNSCLC: (1) patients with non-oncogene (EGFR/ALK/ROS1/BRAF) positive tumors, (2) patients with ALK-positive (ALK+) tumors, and (3) patients with EGFR-positive (EGFR+) tumors. All patients were diagnosed with admNSCLC between 2012 and 2019. Multivariable Cox models adjusting for baseline characteristics and receipt of targeted and immunotherapy were utilized to explore the relationship between these variables and changes in the hazard of death by calendar year in each cohort. Results We included 28,154 admNSCLC patients with non-oncogene positive tumors, 598 with ALK+ tumors, and 2464 with EGFR+ tumors eligible for analysis. After adjustment for differences in baseline characteristics, the hazard of death in patients who had non-oncogene positive tumors diagnosed in 2015, 2016, 2017, 2018 ,and 2019 was observed to be 12%, 11%, 17%, 20%, and 21% lower respectively than that for those diagnosed in 2012. Upon additionally adjusting for receipt of first line or second line immunotherapy, the decrease in the hazard of death by calendar year was no longer observed, suggesting improvements in survival observed over time may be explained by the introduction of these treatments. Similarly, decreases in the hazard of death were only observed in patients with ALK+ tumors diagnosed between 2017 and 2019 relative to 2012 but were no longer observed following adjustment for the use of 1st and later generation ALK inhibitors. Among patients with EGFR+ tumors, the hazard of death did not improve significantly over time. Conclusion Our findings expand on the SEER data and provide additional evidence suggesting improvements in survival of patients with advanced and metastatic NSCLC over the past decade could be explained by the change in treatment patterns over this period.

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Treatment patterns and survival outcomes for patients with non-small cell lung cancer in the UK in the preimmunology era: a REAL-Oncology database analysis from the I-O Optimise initiative

BMJ Open ◽

10.1136/bmjopen-2020-046396 ◽

2021 ◽

Vol 11 (9) ◽

pp. e046396

Author(s):

Michael Snee ◽

Sue Cheeseman ◽

Matthew Thompson ◽

Majid Riaz ◽

Will Sopwith ◽

...

Keyword(s):

Lung Cancer ◽

Squamous Cell Carcinoma ◽

Small Cell Lung Cancer ◽

Initial Treatment ◽

Treatment Patterns ◽

Small Cell ◽

Stage I ◽

Small Cell Lung ◽

Stage Iiia ◽

Over Time

ObjectivesTo report characteristics, treatment and overall survival (OS) trends, by stage and pathology, of patients diagnosed with non-small cell lung cancer (NSCLC) at Leeds Teaching Hospital NHS Trust in 2007–2018.DesignRetrospective cohort study based on electronic medical records.SettingLarge NHS university hospital in Leeds.Participants3739 adult patients diagnosed with incident NSCLC from January 2007 to August 2017, followed up until March 2018.Main outcome measuresPatient characteristics at diagnosis, treatment patterns and OS.Results34.3% of patients with NSCLC were clinically diagnosed (without pathological confirmation). Among patients with known pathology, 45.2% had non-squamous cell carcinoma (NSQ) and 33.3% had squamous cell carcinoma (SQ). The proportion of patients diagnosed at stage I increased (16.4%–27.7% in 2010–2017); those diagnosed at stage IV decreased (57.0%–39.1%). Surgery was the most common initial treatment for patients with pathologically confirmed stage I NSCLC. Use of radiotherapy alone increased over time in patients with clinically diagnosed stage I NSCLC (39.1%–60.3%); chemoradiation increased in patients with stage IIIA NSQ (21.6%–33.3%) and SQ (24.2%–31.9%). Initial treatment with systemic anticancer therapy (SACT) increased in patients with stages IIIB–IV NSQ (49.0%–67.5%); the proportion of untreated patients decreased (30.6%–15.0%). Median OS improved for patients diagnosed with stage I NSQ and SQ and stage IIIA NSQ over time. Median OS for patients with stages IIIB–IV NSQ and SQ remained stable, <10% patients were alive 3 years after diagnosis. Median OS for clinically diagnosed stages IIIB–IV patients was 1.2 months in both periods.ConclusionsOS for stage I and IIIA patients improved over time, likely due to increased use of stereotactic ablative radiation, surgery (stage I) and chemoradiation (stage IIIA). Conversely, OS outcomes remained poor for stage IIIB–IV patients despite increasing use of SACT for NSQ. Many patients with advanced-stage disease remained untreated.

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Treatment patterns in patients with metastatic non-small-cell lung cancer in the era of immunotherapy

Future Oncology ◽

10.2217/fon-2021-0230 ◽

2021 ◽

Author(s):

David Stenehjem ◽

Solomon Lubinga ◽

Keith A Betts ◽

Wenxi Tang ◽

Mads Jenkins ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Stage Iv ◽

Treatment Patterns ◽

Small Cell ◽

Small Cell Lung ◽

First Line ◽

Programmed Death ◽

Baseline Characteristics

Background: Chemotherapy (CT) alone was previously standard first-line (1L) therapy for metastatic non-small-cell lung cancer (NSCLC) but alternative treatments, including immunotherapy (I-O), are now available. Patients & methods: In this retrospective study, adults with stage IV NSCLC who initiated 1L treatment between 1 August 2018 and 31 December 2019 and had ≥2 visits were identified in the Flatiron database. Patients were followed up until 30 June 2020. Baseline characteristics and treatment patterns were described by treatment group: CT, I-O + CT, I-O monotherapy and other. Results: Approximately 20% of patients received 1L CT in the 2018–2019 timeframe studied; these patients tended to have squamous histology and low (≤49%) programmed death ligand-1 expression. Conclusion: A proportion of patients with metastatic NSCLC still receive 1L CT despite the availability and widespread use of I-O therapies.

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Corrigendum: Survival and treatment patterns in elderly patients with advanced non-small-cell lung cancer in Manitoba

Current Oncology ◽

10.3747//co.19.1012 ◽

2012 ◽

Vol 19 (1) ◽

Author(s):

Current Oncology

Keyword(s):

Lung Cancer ◽

Elderly Patients ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Treatment Patterns ◽

Small Cell ◽

Small Cell Lung

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Challenges and Novel Opportunities of Radiation Therapy for Brain Metastases in Non-Small Cell Lung Cancer

Cancers ◽

10.3390/cancers13092141 ◽

2021 ◽

Vol 13 (9) ◽

pp. 2141

Author(s):

Paola Anna Jablonska ◽

Joaquim Bosch-Barrera ◽

Diego Serrano ◽

Manuel Valiente ◽

Alfonso Calvo ◽

...

Keyword(s):

Lung Cancer ◽

Radiation Therapy ◽

Brain Metastases ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Small Cell ◽

Small Cell Lung ◽

The Past ◽

Systemic Treatments ◽

Systemic Therapies

Approximately 20% patients with non-small cell lung cancer (NSCLC) present with CNS spread at the time of diagnosis and 25–50% are found to have brain metastases (BMs) during the course of the disease. The improvement in the diagnostic tools and screening, as well as the use of new systemic therapies have contributed to a more precise diagnosis and prolonged survival of lung cancer patients with more time for BMs development. In the past, most of the systemic therapies failed intracranially because of the inability to effectively cross the blood brain barrier. Some of the new targeted therapies, especially the group of tyrosine kinase inhibitors (TKIs) have shown durable CNS response. However, the use of ionizing radiation remains vital in the management of metastatic brain disease. Although a decrease in CNS-related deaths has been achieved over the past decade, many challenges arise from the need of multiple and repeated brain radiation treatments, which carry along not insignificant risks and toxicity. The combination of stereotactic radiotherapy and systemic treatments in terms of effectiveness and adverse effects, such as radionecrosis, remains a subject of ongoing investigation. This review discusses the challenges of the use of radiation therapy in NSCLC BMs in view of different systemic treatments such as chemotherapy, TKIs and immunotherapy. It also outlines the future perspectives and strategies for personalized BMs management.

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Differential influence of antibiotic therapy and other medications on oncological outcomes of patients with non-small cell lung cancer treated with first-line pembrolizumab versus cytotoxic chemotherapy

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2021-002421 ◽

2021 ◽

Vol 9 (4) ◽

pp. e002421

Author(s):

Alessio Cortellini ◽

Massimo Di Maio ◽

Olga Nigro ◽

Alessandro Leonetti ◽

Diego L Cortinovis ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Objective Response ◽

Multivariable Analysis ◽

Small Cell ◽

Small Cell Lung ◽

First Line ◽

Metastatic Nsclc ◽

The Impact

BackgroundSome concomitant medications including antibiotics (ATB) have been reproducibly associated with worse survival following immune checkpoint inhibitors (ICIs) in unselected patients with non-small cell lung cancer (NSCLC) (according to programmed death-ligand 1 (PD-L1) expression and treatment line). Whether such relationship is causative or associative is matter of debate.MethodsWe present the outcomes analysis according to concomitant baseline medications (prior to ICI initiation) with putative immune-modulatory effects in a large cohort of patients with metastatic NSCLC with a PD-L1 expression ≥50%, receiving first-line pembrolizumab monotherapy. We also evaluated a control cohort of patients with metastatic NSCLC treated with first-line chemotherapy. The interaction between key medications and therapeutic modality (pembrolizumab vs chemotherapy) was validated in pooled multivariable analyses.Results950 and 595 patients were included in the pembrolizumab and chemotherapy cohorts, respectively. Corticosteroid and proton pump inhibitor (PPI) therapy but not ATB therapy was associated with poorer performance status at baseline in both the cohorts. No association with clinical outcomes was found according to baseline statin, aspirin, β-blocker and metformin within the pembrolizumab cohort. On the multivariable analysis, ATB emerged as a strong predictor of worse overall survival (OS) (HR=1.42 (95% CI 1.13 to 1.79); p=0.0024), and progression free survival (PFS) (HR=1.29 (95% CI 1.04 to 1.59); p=0.0192) in the pembrolizumab but not in the chemotherapy cohort. Corticosteroids were associated with shorter PFS (HR=1.69 (95% CI 1.42 to 2.03); p<0.0001), and OS (HR=1.93 (95% CI 1.59 to 2.35); p<0.0001) following pembrolizumab, and shorter PFS (HR=1.30 (95% CI 1.08 to 1.56), p=0.0046) and OS (HR=1.58 (95% CI 1.29 to 1.94), p<0.0001), following chemotherapy. PPIs were associated with worse OS (HR=1.49 (95% CI 1.26 to 1.77); p<0.0001) with pembrolizumab and shorter OS (HR=1.12 (95% CI 1.02 to 1.24), p=0.0139), with chemotherapy. At the pooled analysis, there was a statistically significant interaction with treatment (pembrolizumab vs chemotherapy) for corticosteroids (p=0.0020) and PPIs (p=0.0460) with respect to OS, for corticosteroids (p<0.0001), ATB (p=0.0290), and PPIs (p=0.0487) with respect to PFS, and only corticosteroids (p=0.0033) with respect to objective response rate.ConclusionIn this study, we validate the significant negative impact of ATB on pembrolizumab monotherapy but not chemotherapy outcomes in NSCLC, producing further evidence about their underlying immune-modulatory effect. Even though the magnitude of the impact of corticosteroids and PPIs is significantly different across the cohorts, their effects might be driven by adverse disease features.

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Real World Analysis of Small Cell Lung Cancer Patients: Prognostic Factors and Treatment Outcomes

Current Oncology ◽

10.3390/curroncol28010036 ◽

2021 ◽

Vol 28 (1) ◽

pp. 317-331

Author(s):

Sarah Sharman Moser ◽

Jair Bar ◽

Inna Kan ◽

Keren Ofek ◽

Raanan Cohen ◽

...

Keyword(s):

Lung Cancer ◽

Prognostic Factors ◽

Small Cell Lung Cancer ◽

Real World ◽

Treatment Patterns ◽

Small Cell ◽

Multivariable Model ◽

Small Cell Lung ◽

Limited Stage ◽

Extensive Stage

In this observational study, we assessed treatment patterns and prognostic factors in patients with small cell lung cancer (SCLC) in a large state-mandated healthcare organization in Israel. Methods: All incident cases with histologically confirmed SCLC who initiated systemic anti-cancer treatment between 2011 and 2017 were identified. Treatment patterns and overall survival (OS) were evaluated for each line of therapy. Results: A total of 235 patients were identified (61% male, median age 64 years, 95% ever smokers, 64% had extensive stage). The first-line treatment was platinum–etoposide regimen for 98.7% of the cohort. The second and third-line regimen were given to 43% and 12% of patients, respectively. Mean OS for extensive and limited stage patients was 9.1 and 23.5 months respectively. In a multivariable model, increased risk for mortality was observed among patients with an ECOG performance status (PS) of 2 compared to a PS of 0–1 for the extensive stage patients (Hazard ratio (HR) = 1.63, 95% confidence ratios (CI): 1.00–2.65); and for males compared to females for the limited stage patients (HR = 2.17; 95% CI: 1.12–4.20). Regarding all 2nd line patients in a multivariable model incorporating relevant confounding factors, demonstrated a significantly better outcome with platinum–based regimens compared to topotecan. Median survival after initiation of 2nd line in platinum-sensitive patients was longer (p = 0.056) for those re-challenged with platinum–based regimen (n = 7): 6.8mo (6.1-not reported (NR)), compared with those switched to a different treatment (n = 27): 4.5 mo (2.6–6.6) for extensive stage patients, and a non-significant difference was also observed for limited stage patients. Conclusion: To our knowledge, this is one of the largest real-world studies of SCLC patients. OS for SCLC patients was similar to that reported in clinical trials. PS for extensive stage patients and sex for limited stage patients were significant correlates of prognosis. Re-challenge of the platinum–based doublet was associated with longer OS compared to switching treatment in extensive stage patients.

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Diagnoses And Treatment Patterns For Non-Small Cell Lung Cancer (Nsclc) Within The Private Health System In Brazil

Value in Health ◽

10.1016/j.jval.2015.09.283 ◽

2015 ◽

Vol 18 (7) ◽

pp. A825

Author(s):

G Lopes ◽

A Piedade ◽

L Goes ◽

M Alves ◽

S Balu

Keyword(s):

Lung Cancer ◽

Health System ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Treatment Patterns ◽

Small Cell ◽

Small Cell Lung

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Improving time to molecular testing results in patients with newly diagnosed, metastatic non-small cell lung cancer (NSCLC).

Journal of Clinical Oncology ◽

10.1200/jco.2020.39.28_suppl.244 ◽

2021 ◽

Vol 39 (28_suppl) ◽

pp. 244-244

Author(s):

Stephanie Ossowski ◽

Elad Neeman ◽

Charles Borden ◽

Amy Ying Ju Lin ◽

Raymond Liu

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Turnaround Time ◽

Small Cell ◽

Pathological Diagnosis ◽

Genomic Testing ◽

Newly Diagnosed ◽

Small Cell Lung ◽

First Line ◽

Metastatic Nsclc

244 Background: Next generation sequencing (NGS) is a crucial component of evaluation of newly diagnosed patients with metastatic non-small cell lung cancer (NSCLC) to determine appropriate first line treatment. Delays in NGS can lead to psychologic distress for patients and can affect choices in first line therapy, especially for patients with underlying targetable mutations. While more data is needed to benchmark turnaround time for NGS results, guidelines and expert consensus suggest time from diagnosis to treatment should be 15 days and turnaround time for genomic testing 10-14 days. This study was aimed at reducing time to NGS results in a large integrated health care system. Methods: Through the ASCO Quality Training Program, we reviewed electronic medical records of 25 patients with newly diagnosed, untreated metastatic NSCLC from 12/2018 to 9/2020 and determined number of days from pathological diagnosis to NGS results. We reviewed process maps for oncology, pathology, the internal data management division, and a genomic testing company to determine factors leading to significant preventable delays. Since 11/2020, we created an automated weekly report using CoPath to identify new pathological diagnoses of potential metastatic NSCLC. The oncology department reviewed these cases weekly and NGS orders were placed for patients with metastatic NSCLC. Eleven additional patients with newly diagnosed metastatic NSCLC were included in the prospective cohort. Results: Demographic characteristics are noted in Table. Our intervention reduced median time from pathological diagnosis to NGS results from 24 to 19 days. Median time from biopsy results to NGS order was reduced from 7 to 1 day. Time from specimen being sent from pathology to NGS vendor was a median of 6 days in both cohorts. Total time from pathological diagnosis to appropriate treatment was reduced from a median of 33 to 25 days. Conclusions: Delays in time to NGS results can be reduced by improved communication between departments and simple, automated interventions to ensure results are efficiently released to an oncologist. Additional Plan-Do-Study-Act cycles are currently being developed to further reduce time from biopsy results to NGS results. [Table: see text]

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Augmenting Real-World Data Through Modeling Key Clinical Trial Eligibility Criteria: An Example of Patients With Non–small-Cell Lung Cancer Treated With Pembrolizumab

JCO Clinical Cancer Informatics ◽

10.1200/cci.21.00042 ◽

2021 ◽

pp. 849-858

Author(s):

Thomas Jemielita ◽

Xiaoyun (Nicole) Li ◽

Thomas Burke ◽

Kai-Li Liaw ◽

Wei Zhou ◽

...

Keyword(s):

Lung Cancer ◽

Cell Death ◽

Programmed Cell Death ◽

Small Cell Lung Cancer ◽

Real World ◽

Small Cell ◽

Small Cell Lung ◽

Real World Data ◽

Eligibility Criteria ◽

Baseline Characteristics

PURPOSE To compare and characterize baseline characteristics and overall survival (OS) differences by key oncology eligibility criteria for real-world patients from the Flatiron Health database with advanced non–small-cell lung cancer (NSCLC) who received pembrolizumab monotherapy. METHODS Real world data (RWD) were from the Flatiron Health advanced NSCLC database and include patients who initiated pembrolizumab monotherapy (first, second, or third line of therapy) by November 30, 2019. At the data cutoff (May 31, 2020), the median survival follow-up time was 8.4 months. Eligible patients satisfy the criteria of Eastern Cooperative Oncology Group performance status of 0/1 and laboratory values indicative of adequate organ function. RWD were analyzed for all patients and patients with a programmed cell death ligand-1 tumor proportion score ≥ 1%. Patients were divided into three categories: ineligible, eligible, and unknown (who satisfy all observed criteria, with at least one missing). An augmented population was also formed, which combines the latter two groups through a propensity-based adjustment. RESULTS At the data cutoff, N = 3,877 patients with NSCLC received pembrolizumab monotherapy (1L = 2,682, 2L = 946, and 3L = 249). OS was consistently lower for the ineligible with similar survival for the eligible and augmented. Among all patients, the median OS in months (95% CI) was 8.2 (7.5 to 9.6), 16.3 (14.5 to 18.4), 16.4 (15.1 to 19.3), and 16.8 (15.6 to 18.5) for the ineligible (47%, n = 1,827), unknown (27%, n = 1,045), eligible (26%, n = 1,005), and augmented, respectively. The results were similar for patients with a programmed cell death ligand-1 tumor proportion score ≥ 1%. CONCLUSION Real-world patients who received pembrolizumab monotherapy and meet key clinical eligibility criteria exhibited similar baseline characteristics and OS profiles as the unknown and augmented patient groups. Population augmentation is a feasible approach for improving the power of RWD analysis.

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