Trends in the epidemiology of small-cell lung cancer:a Dutch nationwide population-based study over 1989–2020

Introduction: This study describes the evolving characteristics of patients with small-cell lung cancer (SCLC) from 1989 to 2020 in the Netherlands to analyse how the population of patients with SCLC has changed in the last decades, hypothesising that this might explain the little progress made in SCLC. Methods: Patients with SCLC diagnosed from 1989 to 2020 were selected from the Dutch cancer registry. Incidence, patient and disease characteristics, treatments, and overall survival (OS) were analysed. Joinpoint analyses were used to test annual percentage changes for statistical significance. Results: A total of 52,527 patients were diagnosed with SCLC. The absolute numbers of patients with SCLC remained equal over the years; however, the incidence rates decreased from 15.01 to 8.93 per 100,000 person-years. The proportion of women increased from 22% to 50%, and those aged ≥75 years increased from 20% to 25%. The latter coincided with a higher proportion receiving only the best supportive care (BSC) over the years (18–24%). The use of surgery in stage I increased from 2% to 37%. The proportion of patients diagnosed with stage IV increased from 46% to 70% due to better staging. The OS improved for all stages, with a 2-year OS rate for stage IV doubling from 3% to 6%.Conclusion: The incidence of SCLC has significantly decreased over the last 30 years, with an increasing proportion of elderly and women. The male–female ratio became similar, and the OS improved. As a consequence of more elderly and probably more vulnerable patients, more patients received only the BSC.</p

Immunotherapy in small cell lung cancer:One step at a time: A narrative review

Chemotherapy with or without radiotherapy has been the standard of care for many years for patients with small cell lung cancer (SCLC). Despite exceptionally high responses (up to 80%) with chemotherapy, the majority of patients relapse rapidly within weeks to months after treatment completion. Therefore, new and better treatment options are necessary. Recently, synergistic activity has been reported for the addition of immune checkpoint inhibitors (ICI) to standard platinum-based chemotherapy in the therapeutic strategy of advanced SCLC. For the first time after several decades, a significant survival improvement was achieved for this population. However, the overwhelming majority of patients do not respond to ICI, or relapse rapidly. There is need for better knowledge about the biology, histopathologic features, and molecular pathways of SCLC. This can probably help to identify the optimal predictive biomarkers, which are warranted to develop an individual therapeutic strategy including the rational use of a combination of immunotherapeutic agents. Here, we provide an overview of the rationale for and clinical results of the completed and ongoing trials using different strategies of immunotherapy in SCLC. In addition, opportunities for further improvement of therapies will be discussed, including the addition of radiotherapy, co-stimulatory antibodies, and other immune modifying agents.</p

Combining Genomic Biomarkers to Guide Immunotherapy in Non-Small Cell Lung Cancer

PURPOSE:The clinical value of STK11, KEAP1, and EGFR alterations for guiding immune checkpoint blockade (ICB) therapy in non-small cell lung cancer (NSCLC) remains controversial, as some patients with these proposed resistance biomarkers show durable ICB responses. More specific combinatorial biomarker approaches are urgently needed for this disease. EXPERIMENTAL DESIGN: To develop a combinatorial biomarker strategy with increased specificity for ICB unresponsiveness in NSCLC, we performed a comprehensive analysis of 254 patients with NSCLC treated with ligand programmed death-ligand 1 (PD-L1) blockade monotherapy, including a discovery cohort of 75 patients subjected to whole-genome sequencing (WGS), and an independent validation cohort of 169 patients subjected to tumor-normal large panel sequencing. The specificity of STK11/KEAP1/EGFR alterations for ICB unresponsiveness was assessed in the contexts of a low (&lt;10 muts/Mb) or high (≥10 muts/Mb) tumor mutational burden (TMB).RESULTS:In low TMB cases, STK11/KEAP1/EGFR alterations were highly specific biomarkers for ICB resistance, with 0/15 (0.0%) and 1/34 (2.9%) biomarker-positive patients showing treatment benefit in the discovery and validation cohorts, respectively. This contrasted with high TMB cases, where 11/13 (85%) and 15/34 (44%) patients with at least one STK11/KEAP1/EGFR alteration showed durable treatment benefit in the discovery and validation cohorts, respectively. These findings were supported by analyses of progression-free survival and overall survival. CONCLUSIONS: The unexpected ICB responses in patients carrying resistance biomarkers in STK11, KEAP1, and EGFR were almost exclusively observed in patients with a high TMB. Considering these alterations in context, the TMB offered a highly specific combinatorial biomarker strategy for limiting overtreatment in NSCLC.</p

Combining Genomic Biomarkers to Guide Immunotherapy in Non-Small Cell Lung Cancer

PURPOSE:The clinical value of STK11, KEAP1, and EGFR alterations for guiding immune checkpoint blockade (ICB) therapy in non-small cell lung cancer (NSCLC) remains controversial, as some patients with these proposed resistance biomarkers show durable ICB responses. More specific combinatorial biomarker approaches are urgently needed for this disease. EXPERIMENTAL DESIGN: To develop a combinatorial biomarker strategy with increased specificity for ICB unresponsiveness in NSCLC, we performed a comprehensive analysis of 254 patients with NSCLC treated with ligand programmed death-ligand 1 (PD-L1) blockade monotherapy, including a discovery cohort of 75 patients subjected to whole-genome sequencing (WGS), and an independent validation cohort of 169 patients subjected to tumor-normal large panel sequencing. The specificity of STK11/KEAP1/EGFR alterations for ICB unresponsiveness was assessed in the contexts of a low (&lt;10 muts/Mb) or high (≥10 muts/Mb) tumor mutational burden (TMB).RESULTS:In low TMB cases, STK11/KEAP1/EGFR alterations were highly specific biomarkers for ICB resistance, with 0/15 (0.0%) and 1/34 (2.9%) biomarker-positive patients showing treatment benefit in the discovery and validation cohorts, respectively. This contrasted with high TMB cases, where 11/13 (85%) and 15/34 (44%) patients with at least one STK11/KEAP1/EGFR alteration showed durable treatment benefit in the discovery and validation cohorts, respectively. These findings were supported by analyses of progression-free survival and overall survival. CONCLUSIONS: The unexpected ICB responses in patients carrying resistance biomarkers in STK11, KEAP1, and EGFR were almost exclusively observed in patients with a high TMB. Considering these alterations in context, the TMB offered a highly specific combinatorial biomarker strategy for limiting overtreatment in NSCLC.</p

Exploring the Cost Effectiveness of a Whole-Genome Sequencing-Based Biomarker for Treatment Selection in Patients with Advanced Lung Cancer Ineligible for Targeted Therapy

Objective: We aimed to perform an early cost-effectiveness analysis of using a whole-genome sequencing-based tumor mutation burden (WGS-TMB), instead of programmed death-ligand 1 (PD-L1), for immunotherapy treatment selection in patients with non-squamous advanced/metastatic non-small cell lung cancer ineligible for targeted therapy, from a Dutch healthcare perspective. Methods: A decision-model simulating individual patients with metastatic non-small cell lung cancer was used to evaluate diagnostic strategies to select first-line immunotherapy only or the immunotherapy plus chemotherapy combination. Treatment was selected using PD-L1 [A, current practice], WGS-TMB [B], and both PD-L1 and WGS-TMB [C]. Strategies D, E, and F take into account a patient’s disease burden, in addition to PD-L1, WGS-TMB, and both PD-L1 and WGS-TMB, respectively. Disease burden was defined as a fast-growing tumor, a high number of metastases, and/or weight loss. A threshold of 10 mutations per mega-base was used to classify patients into TMB-high and TMB-low groups. Outcomes were discounted quality-adjusted life-years (QALYs) and healthcare costs measured from the start of first-line treatment to death. Healthcare costs includes drug acquisition, follow-up costs, and molecular diagnostic tests (i.e., standard diagnostic techniques and/or WGS for strategies involving TMB). Results were reported using the net monetary benefit at a willingness-to-pay threshold of €80,000/QALY. Additional scenario and threshold analyses were performed. Results: Strategy B had the lowest QALYs (1.84) and lowest healthcare costs (€120,800). The highest QALYs and healthcare costs were 2.00 and €140,400 in strategy F. In the base-case analysis, strategy A was cost effective with the highest net monetary benefit (€27,300), followed by strategy B (€26,700). Strategy B was cost effective when the cost of WGS testing was decreased by at least 24% or when immunotherapy results in an additional 0.5 year of life gained or more for TMB high compared with TMB low. Strategies C and F, which combined TMB and PD-L1 had the highest net monetary benefit (≥ €76,900) when the cost of WGS testing, immunotherapy, and chemotherapy acquisition were simultaneously reduced by at least 47%, 39%, and 43%, respectively. Furthermore, strategy C resulted in the highest net monetary benefit (≥ €39,900) in a scenario where patients with both PD-L1 low and TMB low were treated with chemotherapy instead of immunotherapy plus chemotherapy. Conclusions: The use of WGS-TMB is not cost effective compared to PD-L1 for immunotherapy treatment selection in non-squamous metastatic non-small cell lung cancer in the Netherlands. WGS-TMB could become cost effective provided there is a reduction in the cost of WGS testing or there is an increase in the predictive value of WGS-TMB for immunotherapy effectiveness. Alternatively, a combination strategy of PD-L1 testing with WGS-TMB would be cost effective if used to support the choice to withhold immunotherapy in patients with a low expected benefit of immunotherapy.</p

Exploring the Cost Effectiveness of a Whole-Genome Sequencing-Based Biomarker for Treatment Selection in Patients with Advanced Lung Cancer Ineligible for Targeted Therapy

Objective: We aimed to perform an early cost-effectiveness analysis of using a whole-genome sequencing-based tumor mutation burden (WGS-TMB), instead of programmed death-ligand 1 (PD-L1), for immunotherapy treatment selection in patients with non-squamous advanced/metastatic non-small cell lung cancer ineligible for targeted therapy, from a Dutch healthcare perspective. Methods: A decision-model simulating individual patients with metastatic non-small cell lung cancer was used to evaluate diagnostic strategies to select first-line immunotherapy only or the immunotherapy plus chemotherapy combination. Treatment was selected using PD-L1 [A, current practice], WGS-TMB [B], and both PD-L1 and WGS-TMB [C]. Strategies D, E, and F take into account a patient’s disease burden, in addition to PD-L1, WGS-TMB, and both PD-L1 and WGS-TMB, respectively. Disease burden was defined as a fast-growing tumor, a high number of metastases, and/or weight loss. A threshold of 10 mutations per mega-base was used to classify patients into TMB-high and TMB-low groups. Outcomes were discounted quality-adjusted life-years (QALYs) and healthcare costs measured from the start of first-line treatment to death. Healthcare costs includes drug acquisition, follow-up costs, and molecular diagnostic tests (i.e., standard diagnostic techniques and/or WGS for strategies involving TMB). Results were reported using the net monetary benefit at a willingness-to-pay threshold of €80,000/QALY. Additional scenario and threshold analyses were performed. Results: Strategy B had the lowest QALYs (1.84) and lowest healthcare costs (€120,800). The highest QALYs and healthcare costs were 2.00 and €140,400 in strategy F. In the base-case analysis, strategy A was cost effective with the highest net monetary benefit (€27,300), followed by strategy B (€26,700). Strategy B was cost effective when the cost of WGS testing was decreased by at least 24% or when immunotherapy results in an additional 0.5 year of life gained or more for TMB high compared with TMB low. Strategies C and F, which combined TMB and PD-L1 had the highest net monetary benefit (≥ €76,900) when the cost of WGS testing, immunotherapy, and chemotherapy acquisition were simultaneously reduced by at least 47%, 39%, and 43%, respectively. Furthermore, strategy C resulted in the highest net monetary benefit (≥ €39,900) in a scenario where patients with both PD-L1 low and TMB low were treated with chemotherapy instead of immunotherapy plus chemotherapy. Conclusions: The use of WGS-TMB is not cost effective compared to PD-L1 for immunotherapy treatment selection in non-squamous metastatic non-small cell lung cancer in the Netherlands. WGS-TMB could become cost effective provided there is a reduction in the cost of WGS testing or there is an increase in the predictive value of WGS-TMB for immunotherapy effectiveness. Alternatively, a combination strategy of PD-L1 testing with WGS-TMB would be cost effective if used to support the choice to withhold immunotherapy in patients with a low expected benefit of immunotherapy.</p

Ki67 (MIB-1) as a Prognostic Marker for Clinical Decision Making Before Extended Pleurectomy Decortication in Malignant Pleural Mesothelioma

INTRODUCTION: The role of surgery for early stage malignant pleural mesothelioma (MPM) remains controversial. Current expert opinion is only to treat patients surgically as part of multimodality therapy. It is still challenging to identify patients who will not benefit from surgery. We specifically evaluated tumor-related parameters in combination with clinical parameters to identify prognostic markers for survival. METHODS: Clinical data of 27 consecutive patients with MPM treated with extended pleurectomy and decortication within a multimodality approach were collected and analyzed. Several tumor (immuno-)histopathologic characteristics were determined on resected tumor material, among which MTAP and Ki67 (MIB-1). Univariable and multivariable analyses served to correlate clinical and tumor-related parameters to overall survival (OS) and progression-free survival (PFS). RESULTS: The median PFS (mPFS) was 15.3, and the median OS (mOS) was 26.5 months. Patients with a Ki67 score greater than 10% had a significantly shorter PFS (mPFS = 8.81 versus 25.35 mo, p = 0.001) and OS (mOS 19.7 versus 44.5 mo, p = 0.002) than those with a Ki67 score less than or equal to 10. Receiver operating characteristic curve analysis for Ki67 revealed an area under the curve of 0.756 with a sensitivity of 90% and specificity of 71% for a cutoff of 10% for Ki67. Patients with loss of MTAP had a significantly shorter mPFS (9 versus 21.1 mo, p = 0.014) and mOS (19.7 versus 42.6 mo, p = 0.047) than those without MTAP loss. CONCLUSIONS: In our study, Ki67 was prognostic for OS and PFS in patients with MPM treated with extended pleurectomy/decortication in a multimodality approach. Determination of Ki67 before surgery combined with specific clinical parameters could assist in clinical decision making by identifying patients, with high Ki67, who are unlikely to benefit from surgery