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The association between depth of response (DpR) and treatment outcomes has been documented across various types of cancer. Immune checkpoint inhibitor (ICI)-based treatment is globally used as first-line treatment for non-small cell lung cancer (NSCLC) with programmed death-ligand 1 (PD-L1) expression ≥ 50%. However, in this population, the significance of DpR is not elucidated. Patients with advanced NSCLC and PD-L1 expression ≥ 50% who received ICI-monotherapy or ICI plus chemotherapy were retrospectively enrolled into this study. Treatment responses were grouped into DpR 'quartiles' by percentage of maximal tumor reduction (Q1 = 1-25%, Q2 = 26-50%, Q3 = 51-75%, and Q4 = ≥ 76%), and no tumor reduction (NTR). The association between DpR and survival rates were determined using hazard ratios (HR) generated by the Cox proportional hazards model. The Kaplan-Meier method was used to determine survival outcomes. A total of 349 patients were included, of which 214 and 135 patients received pembrolizumab monotherapy and ICI plus chemotherapy, respectively, as first-line treatments. The majority of the patients were male. All DpR quartiles, especially Q4, showed an association with progression-free survival (PFS)/overall survival (OS). In the Q4 cohort, patients who received pembrolizumab had a longer PFS than those who received ICI plus chemotherapy. High DpR was associated with longer PFS and OS, with a more pronounced effect observed with pembrolizumab monotherapy than with ICI plus chemotherapy.
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One of the immune-related adverse events from immune checkpoint inhibitors (ICIs) is skin toxicity. Oral corticosteroids are the first-line treatment for severe cutaneous immune-related adverse events. However, corticosteroids may conflict with the efficacy of ICIs. A 55-year-old Japanese man with a history of psoriasis vulgaris was diagnosed with small-cell lung cancer (Stage â £A) and administered combined chemoimmunotherapy, including atezolizumab, which resulted in exacerbation of psoriasis. In response, he was treated with biological agents, such as anti-IL-23 and IL-17 antibodies, risankizumab, and secukinumab, respectively, and achieved long-term survival with continued treatment with atezolizumab. This case report suggests that biological agents might be the best course of treatment against autoimmune-related adverse events caused by ICI therapy.
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Introduction: Several studies explored the association between thyroid transcription factor-1 (TTF-1) and the therapeutic efficacy of immunotherapy. However, the effect of TTF-1 on the therapeutic efficacy of programmed death-1 (PD-1) inhibitor/chemoimmunotherapy in patients with non-squamous non-small cell lung cancer (non-Sq NSCLC) with a programmed death-ligand 1 (PD-L1) tumor proportion score of 50% or more who are highly susceptible to immunotherapy remains unresolved. Therefore, we evaluated whether TTF-1 has a clinical impact on this population. Methods: Patients with non-Sq NSCLC and high PD-L1 expression who received PD-1 inhibitor monotherapy or chemoimmunotherapy between May 2017 and December 2020 were retrospectively enrolled. Treatment efficacy was compared after adjusting for baseline differences using propensity score matching. Results: Among the 446 patients with NSCLC with high PD-L1 expression, 266 patients with non-Sq NSCLC were analyzed. No significant differences in therapeutic efficacy were observed between the TTF-1-positive and -negative groups in the overall and propensity score-matched populations. Of chemoimmunotherapy, pemetrexed containing regimen significantly prolonged progression-free survival compared to chemoimmunotherapy without pemetrexed, regardless of TTF-1 expression (TTF1 positive; HR: 0.46 (95% Confidence interval: 0.26-0.81), p<0.01, TTF-1 negative; HR: 0.29 (95% Confidence interval: 0.09-0.93), p=0.02). Discussion: TTF-1 expression did not affect the efficacy of PD-1 inhibitor monotherapy or chemoimmunotherapy in patients with non-Sq NSCLC with high PD-L1 expression. In this population, pemetrexed-containing chemoimmunotherapy demonstrated superior anti-tumor efficacy, irrespective of TTF-1 expression.
Subject(s)
B7-H1 Antigen , Carcinoma, Non-Small-Cell Lung , Immune Checkpoint Inhibitors , Immunotherapy , Lung Neoplasms , Humans , Carcinoma, Non-Small-Cell Lung/immunology , Carcinoma, Non-Small-Cell Lung/therapy , Carcinoma, Non-Small-Cell Lung/mortality , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/metabolism , Female , Male , Lung Neoplasms/immunology , Lung Neoplasms/therapy , Lung Neoplasms/mortality , Lung Neoplasms/drug therapy , Lung Neoplasms/metabolism , Retrospective Studies , Aged , B7-H1 Antigen/metabolism , Middle Aged , Immunotherapy/methods , Immune Checkpoint Inhibitors/therapeutic use , Treatment Outcome , Thyroid Nuclear Factor 1/metabolism , Biomarkers, Tumor , Aged, 80 and overABSTRACT
PURPOSE: This study aimed to examine the prognostic impact of concomitant pH-regulating drug use in patients with epidermal growth factor receptor (EGFR)-mutation-positive non-small-cell lung cancer (NSCLC) receiving EGFR-tyrosine kinase inhibitors (TKIs). METHODS: We conducted a nationwide retrospective cohort study and reviewed clinical data of consecutive patients with NSCLC treated with the first-line EGFR-TKIs in 46 hospitals between April 2010 and March 2020. Cox regression analyses were conducted to examine the differences in overall survival (OS) between patients treated with and without concomitant pH-regulating drugs, including potassium-competitive acid blockers (P-CABs), proton pump inhibitors (PPIs), and H2-receptor antagonists (H2RAs). RESULTS: A total of 758 patients were included in the final dataset, of which 307 (40%) were administered concomitant pH-regulating drugs while receiving frontline EGFR-TKIs. After adjusting for basic patient characteristics, patients administered gefitinib, erlotinib, afatinib, and osimertinib with concomitant pH-regulating drugs had lower OS than those without concomitant pH-regulating drugs, with hazard ratios of 1.74 (with a 95% confidence interval of 1.34-2.27), 1.33 (0.80-2.22), 1.73 (0.89-3.36), and 5.04 (1.38-18.44), respectively. The 2-year OS rates of patients receiving gefitinib with or without concomitant pH-regulating drugs were 65.4 and 77.5%, those for erlotinib were 55.8 and 66.6%, and those for afatinib were 63.2 and 76.9%, respectively. The 1-year OS rates of patients receiving osimertinib with or without concomitant pH-regulating drugs were 88.1% and 96.9%, respectively. CONCLUSION: In addition to the first-generation EGFR-TKIs, the second- and third-generation EGFR-TKIs also resulted in OS deterioration in patients with EGFR mutation-positive NSCLC when used concurrently with pH-regulating drugs.
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BACKGROUND: Although osimertinib is a promising therapeutic agent for advanced epidermal growth factor receptor (EGFR) mutation-positive lung cancer, the incidence of pneumonitis is particularly high among Japanese patients receiving the drug. Furthermore, the safety and efficacy of subsequent anticancer treatments, including EGFR-tyrosine kinase inhibitor (TKI) rechallenge, which are to be administered after pneumonitis recovery, remain unclear. OBJECTIVE: This study investigated the safety of EGFR-TKI rechallenge in patients who experienced first-line osimertinib-induced pneumonitis, with a primary focus on recurrent pneumonitis. PATIENTS AND METHODS: We retrospectively reviewed the data of patients with EGFR mutation-positive lung cancer who developed initial pneumonitis following first-line osimertinib treatment across 34 institutions in Japan between August 2018 and September 2020. RESULTS: Among the 124 patients included, 68 (54.8%) patients underwent EGFR-TKI rechallenge. The recurrence rate of pneumonitis following EGFR-TKI rechallenge was 27% (95% confidence interval [CI] 17-39) at 12 months. The cumulative incidence of recurrent pneumonitis was significantly higher in the osimertinib group than in the first- and second-generation EGFR-TKI (conventional EGFR-TKI) groups (hazard ratio [HR] 3.1; 95% CI 1.3-7.5; p = 0.013). Multivariate analysis revealed a significant association between EGFR-TKI type (osimertinib or conventional EGFR-TKI) and pneumonitis recurrence, regardless of severity or status of initial pneumonitis (HR 3.29; 95% CI 1.12-9.68; p = 0.03). CONCLUSIONS: Osimertinib rechallenge after initial pneumonitis was associated with significantly higher recurrence rates than conventional EGFR-TKI rechallenge.
Subject(s)
Acrylamides , Aniline Compounds , ErbB Receptors , Lung Neoplasms , Pneumonia , Protein Kinase Inhibitors , Humans , Acrylamides/therapeutic use , Acrylamides/pharmacology , Male , Female , Aniline Compounds/therapeutic use , Aniline Compounds/pharmacology , Aniline Compounds/adverse effects , Aged , Pneumonia/chemically induced , Retrospective Studies , Lung Neoplasms/drug therapy , Protein Kinase Inhibitors/adverse effects , Protein Kinase Inhibitors/therapeutic use , Protein Kinase Inhibitors/pharmacology , Middle Aged , Aged, 80 and over , Japan , Indoles , PyrimidinesABSTRACT
Introduction: Multiple programmed death-ligand 1 (PD-L1) immunohistochemistry assays performed using different antibodies including DAKO 22C3, DAKO 28-8, and Ventana SP142 PD-L1-predictive markers for response to various immune checkpoint inhibitors in NSCLC-have been approved in several countries. The differences in multiple PD-L1 immunohistochemistry assay results in predicting the therapeutic response to combined chemoimmunotherapy in patients with NSCLC remain unclear. Methods: In this multicenter prospective observational study, we monitored 70 patients with advanced NSCLC treated with combined chemoimmunotherapy at 10 institutions in Japan. The expression of PD-L1 in pretreatment tumors was evaluated using the 22C3, 28-8, and SP142 assays in all patients. Results: The PD-L1 level in tumor cells determined using the 22C3 assay was the highest among the three assays performed with different antibodies. According to the 22C3 assay results, the PD-L1 tumor proportion score greater than or equal to 50% group had a significantly longer progression-free survival period than the PD-L1 tumor proportion score less than 50% group. Nevertheless, the other assays did not reveal remarkable differences in the objective response rate or progression-free survival. Conclusions: In our study, PD-L1 expression determined using the 22C3 assay was more correlated with the therapeutic response of patients with NSCLC treated with combined chemoimmunotherapy than that determined using the 28-8 and SP142 assays. Therefore, the 22C3 assay may be useful for clinical decision-making for patients with NSCLC treated with combined chemoimmunotherapy. Trial registration number: UMIN 000043958.
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Introduction: The proportion of older patients diagnosed with advanced-stage non-small cell lung cancer (NSCLC) has been increasing. Immune checkpoint inhibitor (ICI) monotherapy (MONO) and combination therapy of ICI and chemotherapy (COMBO) are standard treatments for patients with NSCLC and programmed cell death ligand-1 (PD-L1) tumor proportion scores (TPS) ≥ 50%. However, evidence from the clinical trials specifically for older patients is limited. Thus, it is unclear which older patients benefit more from COMBO than MONO. Methods: We retrospectively analyzed 199 older NSCLC patients of Eastern Cooperative Oncology Group performance status (ECOG PS) 0-1 and PD-L1 TPS ≥ 50% who were treated with MONO or COMBO. We analyzed the association between treatment outcomes and baseline patient characteristics in each group, using propensity score matching. Results: Of the 199 patients, 131 received MONO, and 68 received COMBO. The median overall survival (OS; MONO: 25.2 vs. COMBO: 42.2 months, P = 0.116) and median progression-free survival (PFS; 10.9 vs. 11.8 months, P = 0.231) did not significantly differ between MONO and COMBO group. In the MONO group, OS was significantly shorter in patients without smoking history compared to those with smoking history [HR for smoking history against non-smoking history: 0.36 (95% CI: 0.16-0.78), P = 0.010]. In the COMBO group, OS was significantly shorter in patients with PS 1 than those with PS 0 [HR for PS 0 against PS 1: 3.84 (95% CI: 1.44-10.20), P = 0.007] and for patients with squamous cell carcinoma (SQ) compared to non-squamous cell carcinoma (non-SQ) [HR for SQ against non-SQ: 0.17 (95% CI: 0.06-0.44), P < 0.001]. For patients with ECOG PS 0 (OS: 26.1 months vs. not reached, P = 0.0031, PFS: 6.5 vs. 21.7 months, P = 0.0436) or non-SQ (OS: 23.8 months vs. not reached, P = 0.0038, PFS: 10.9 vs. 17.3 months, P = 0.0383), PFS and OS were significantly longer in the COMBO group. Conclusions: ECOG PS and histological type should be considered when choosing MONO or COMBO treatment in older patients with NSCLC and PD-L1 TPS ≥ 50%.
Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Humans , Aged , Carcinoma, Non-Small-Cell Lung/pathology , Immune Checkpoint Inhibitors/therapeutic use , Lung Neoplasms/pathology , B7-H1 Antigen , Prognosis , Retrospective Studies , Antibodies, Monoclonal, Humanized/therapeutic useABSTRACT
BACKGROUND: Combination therapy with docetaxel (DTX) and ramucirumab (RAM) has been used as a second-line treatment for advanced or recurrent lung cancer. However, there is insufficient evidence regarding the safety of angiogenesis inhibitors in older patients. OBJECTIVE: This multicenter retrospective study aimed to investigate the efficacy and safety of second-line treatment regimens in older patients with advanced or recurrent non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: We retrospectively analyzed 145 patients aged ≥ 70 years with advanced or recurrent NSCLC treated with second-line chemotherapy after platinum-based therapy between April 1, 2016, and March 31, 2021. Patients were subdivided into the DTX + RAM (n = 38) and single-agent (n = 107) groups. RESULTS: The median time to treatment failure was 6.3 months (95% confidence interval [CI] 3.6-9.6) in the DTX + RAM group and 2.3 months (95% CI 1.7-3.0) in the single-agent group (p < 0.01). The median overall survival was 15.9 months (95% CI 12.3-Not Achieved) in the DTX + RAM group and 9.4 months (95% CI 6.9-15.1) in the single-agent group (p = 0.01). Grade ≥ 3 adverse events frequency was not significantly different between the two groups, except for edema. Patients in the DTX + RAM group who did not discontinue treatment owing to adverse events exhibited the most favorable prognosis. CONCLUSIONS: These findings suggest that the DTX + RAM combination is an effective second-line therapy for older patients with advanced or recurrent NSCLC, offering favorable efficacy without treatment discontinuation owing to adverse events.
Subject(s)
Antibodies, Monoclonal, Humanized , Antineoplastic Combined Chemotherapy Protocols , Carcinoma, Non-Small-Cell Lung , Docetaxel , Lung Neoplasms , Ramucirumab , Humans , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/pathology , Docetaxel/therapeutic use , Docetaxel/pharmacology , Antibodies, Monoclonal, Humanized/therapeutic use , Antibodies, Monoclonal, Humanized/pharmacology , Male , Aged , Female , Lung Neoplasms/drug therapy , Lung Neoplasms/pathology , Retrospective Studies , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Aged, 80 and over , Neoplasm Recurrence, Local/drug therapyABSTRACT
Introduction: The efficacy of second-line immune checkpoint inhibitor (ICI) therapy is limited in non-small cell lung cancer (NSCLC) patients with ≤ 49% PD-L1 expression. Although chemoimmunotherapy is a promising strategy, platinum-based chemotherapy followed by ICI monotherapy is often used to avoid synergistic adverse events. However, predictors of the efficacy of ICI monotherapy after platinum-based chemotherapy in NSCLC with ≤ 49% PD-L1 expression remain scarce. Methods: This multicenter retrospective study evaluated 54 advanced or recurrent NSCLC patients with ≤ 49% PD-L1 expression who were treated with second-line ICI monotherapy following disease progression on first-line platinum-based chemotherapy at nine hospitals in Japan. The impact of response to platinum-based chemotherapy on the efficacy of subsequent ICI monotherapy was investigated. Results: The response to first-line platinum-based chemotherapy was divided into two groups: the non-progressive disease (PD) group, which included patients who did not experience disease progression after four cycles of chemotherapy, and the PD group, which included patients who showed initial PD or could not maintain disease control during the four cycles of chemotherapy and switched to second-line ICI monotherapy. Among the 54 patients, 32 and 22 were classified into the non-PD and PD groups, respectively. The non-PD group showed better response rates (p = 0.038) and longer overall survival (OS) with ICI monotherapy (p = 0.023) than the PD group. Multivariate analysis identified that maintaining a non-PD status after four cycles of chemotherapy was an independent prognostic factor for ICI monotherapy (p = 0.046). Moreover, patients with a modified Glasgow Prognostic Score (mGPS) of 0 showed a tendency for longer OS with ICI monotherapy (p = 0.079), and there was a significant correlation between maintaining non-PD after four cycles of chemotherapy and an mGPS of 0 (p = 0.045). Conclusion: Maintaining a non-PD status after four cycles of platinum-based chemotherapy was a predictor of OS after second-line ICI monotherapy. These findings will help physicians select the most suitable treatment option for NSCLC patients who were treated with platinum-based chemotherapy and switched to second-line treatment. Those who experienced early PD during platinum-based chemotherapy should not be treated with ICI monotherapy in the second-line setting.
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BACKGROUND: A history of pre-administration of immune checkpoint inhibitors has been reported to be associated with good outcomes of ramucirumab (RAM) plus docetaxel (DOC) combination therapy for advanced non-small-cell lung cancer (NSCLC). However, existing knowledge on the clinical significance of RAM and DOC following combined chemoimmunotherapy is limited. Therefore, we evaluated the efficacy and safety of RAM plus DOC therapy after combined chemoimmunotherapy and attempted to identify the predictors of its outcomes. PATIENTS AND METHODS: This multicenter, prospective study investigated the efficacy and safety of RAM plus DOC after combined chemoimmunotherapy. The primary endpoint was progression-free survival (PFS). Secondary endpoints were the objective response rate (ORR), disease control rate (DCR), overall survival (OS), and incidence of adverse events. An exploratory analysis measured serum cytokine levels at the start of treatment. RESULTS: Overall, 44 patients were enrolled from 10 Japanese institutions between April 2020 and June 2022. The median PFS and OS were 6.3 and 22.6 months, respectively. Furthermore, the ORR and DCR were 36.4% and 72.7%, respectively. The high vascular endothelial growth factor D (VEGF-D) group had a significantly shorter PFS and OS. A combination of high VEGF-A and low VEGF-D levels was associated with a longer PFS. CONCLUSION: Our results showed that RAM plus DOC after combined chemoimmunotherapy might be an effective and relatively feasible second-line treatment for patients with advanced NSCLC in a real-world setting.
Subject(s)
Antibodies, Monoclonal, Humanized , Antineoplastic Combined Chemotherapy Protocols , Carcinoma, Non-Small-Cell Lung , Docetaxel , Lung Neoplasms , Ramucirumab , Humans , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/pathology , Docetaxel/administration & dosage , Docetaxel/therapeutic use , Male , Lung Neoplasms/drug therapy , Lung Neoplasms/pathology , Lung Neoplasms/mortality , Female , Prospective Studies , Aged , Antibodies, Monoclonal, Humanized/therapeutic use , Antibodies, Monoclonal, Humanized/administration & dosage , Middle Aged , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Aged, 80 and over , Immunotherapy/methods , AdultABSTRACT
OBJECTIVE: The introduction of new-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) has afforded promising overall survival outcomes in clinical trials for non-small-cell lung cancer. We aim to investigate the current adoption rate of these agents and the real-world impact on overall survival among institutions. METHODS: In a nationwide retrospective cohort study of 46 Tokushukai Medical Group hospitals in Japan, we analyzed clinical data of consecutive patients with non-small-cell lung cancer receiving EGFR-TKIs between April 2010 and March 2020. Univariate and multivariate Cox regression analyses examined the associations between overall survival and patient/tumor-related factors and first-line EGFR-TKIs. RESULTS: A total of 758 patients (58.5% females; median age, 73 years) were included. Of 40 patients diagnosed in 2010, 72.5% received gefitinib, whereas 81.3% of 107 patients diagnosed in 2019 received osimertinib as the first-line EGFR-TKI. With a median follow-up of 15.8 months, the median overall survival was 28.4 months (95% confidence interval, 15.3-31.0). In a multivariate Cox regression analysis, age, body mass index, disease status, EGFR mutational status and first-line epidermal growth factor receptor tyrosine kinase inhibitor were identified as significant prognostic factors after adjusting for background factors including study period, hospital volume and hospital type. The estimated 2-year overall survival rates for gefitinib, erlotinib, afatinib and osimertinib were 70.1% (95% confidence interval 59.7-82.4), 67.8% (95% confidence interval 55.3-83.2), 75.5% (95% confidence interval 64.7-88.0) and 90.8% (95% confidence interval 84.8-97.3), respectively. The median time to treatment failure of gefitinib, erlotinib, afatinib and osimertinib were 12.8, 8.8, 12.0 and 16.9 months or more, respectively. CONCLUSIONS: Our real-world data revealed that the swift and widespread utilization of newer-generation EGFR-TKIs in patients with EGFR mutation-positive non-small-cell lung cancer, and that these newer-generation EGFR-TKIs can prolong overall survival regardless of hospital volume or type. Therefore, osimertinib could be a reasonable first choice treatment for these patients across various clinical practice settings.
Subject(s)
Acrylamides , Aniline Compounds , Carcinoma, Non-Small-Cell Lung , Indoles , Lung Neoplasms , Pyrimidines , Female , Humans , Aged , Male , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , Gefitinib/therapeutic use , Erlotinib Hydrochloride/therapeutic use , Afatinib/therapeutic use , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Retrospective Studies , Protein Kinase Inhibitors/therapeutic use , ErbB Receptors/genetics , ErbB Receptors/therapeutic use , MutationABSTRACT
With the increased use of granulocyte colony-stimulating factor (G-CSF) preparations, there is concern about the increase in G-CSF-associated large-vessel vasculitis; however, there have been no previous reports of vasculitis caused by multiple types of G-CSF preparations. We experienced a case of drug-induced large-vessel vasculitis caused by two different G-CSF products, which was difficult to diagnose. When treating patients with a history of large-vessel vasculitis caused by pegfilgrastim, we need to pay attention to its recurrence when using other G-CSF preparations.
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BACKGROUND: The long overall survival (OS) observed among patients with non-small cell lung cancer (NSCLC) with high programmed death-ligand 1 (PD-L1) expression in chemoimmunotherapy (CIT) groups in previous phase III trials suggests the limited efficacy of CIT among the subgroup with ≤49% PD-L1 expression on tumor cells. Hence, sequential treatment with first-line platinum-based chemotherapy followed by second-line immune checkpoint inhibitor treatment (SEQ) is an option. This study examined whether first-line CIT would provide better outcomes than SEQ in patients with advanced NSCLC with ≤49% PD-L1 expression. METHODS: This retrospective study evaluated patients with untreated NSCLC who received first-line CIT or SEQ at nine hospitals in Japan. OS, progression-free survival (PFS), PFS-2 (the time from first-line treatment to progression to second-line treatment or death), and other related outcomes were evaluated between the CIT and SEQ groups. RESULTS: Among the 305 enrolled patients, 234 eligible patients were analyzed: 165 in the CIT group and 69 in the SEQ group. The COX proportional hazards model suggested a significant interaction between PD-L1 expression and OS (p = 0.006). OS in the CIT group was significantly longer than that in the SEQ group in the 1-49% PD-L1 expression subgroup but not in the <1% PD-L1 expression subgroup. Among the subgroup with 1-49% PD-L1 expression, the CIT group exhibited longer median PFS than the SEQ group (CIT: 9.3 months (95% CI: 6.7-14.8) vs. SEQ:5.5 months (95% CI: 4.5-6.1); p < 0.001), while the median PFS in the CIT group was not statistically longer than the median PFS-2 in the SEQ group (p = 0.586). There was no significant difference between the median PFS in the CIT and SEQ groups among the <1% PD-L1 expression subgroup (p = 0.883); the median PFS-2 in the SEQ group was significantly longer than the median PFS in the CIT group (10.5 months (95% CI: 5.9-15.3) vs. 6.4 months (95% CI: 4.9-7.5); p = 0.024). CONCLUSIONS: CIT is recommended for patients with NSCLC with 1-49% PD-L1 expression because it significantly improved OS and PFS compared to SEQ. CIT had limited benefits in patients with <1% PD-L1 expression, and the median PFS-2 in the SEQ group was significantly longer than the median PFS in the CIT group. These findings will help physicians select the most suitable treatment option for patients with NSCLC, considering PD-L1 expressions.
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BACKGROUND: Immune checkpoint inhibitor (ICI) monotherapy and ICI plus chemotherapy are approved first-line treatments for patients with non-small cell lung cancer (NSCLC) expressing high levels of programmed cell death-ligand 1 (PD-L1). However, appropriate treatment for patients showing high PD-L1 expression and poor performance status (PS) is not well defined. OBJECTIVE: The aim of this study was to identify a treatment option that is better for these patients in a real-world setting. PATIENTS AND METHODS: A total of 425 patients with NSCLC and high PD-L1 expression were included retrospectively. All patients received either pembrolizumab monotherapy or ICI plus chemotherapy as the first-line treatment. Patients were subdivided into good (PS score 0 or 1; n = 354) and poor PS groups (PS score 2 or 3; n = 71). Early progressive disease (PD) was defined as PD within 3 months of ICI-based therapy initiation. RESULTS: The good PS group had significantly longer progression-free survival (PFS) and overall survival (OS) than the poor PS group upon ICI-based therapy administration. In the poor PS group, no significant difference was observed in PFS and OS between pembrolizumab monotherapy and ICI plus chemotherapy. In the good PS group, pembrolizumab monotherapy, PD-L1 50-89%, and liver metastasis were associated with early PD, as determined using multivariate logistic regression analyses. However, in the poor PS group, the multivariate logistic regression analyses did not show an association between pembrolizumab monotherapy and early PD. CONCLUSIONS: In patients with NSCLC exhibiting poor PS and high PD-L1 expression, ICI plus chemotherapy did not confer PFS or OS benefit compared with pembrolizumab monotherapy.
Subject(s)
Antineoplastic Agents, Immunological , Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Humans , Antineoplastic Agents, Immunological/therapeutic use , B7-H1 Antigen/metabolism , Carcinoma, Non-Small-Cell Lung/pathology , Lung Neoplasms/pathology , Retrospective StudiesABSTRACT
BACKGROUND: Durvalumab consolidation after chemoradiotherapy (CRT) is a standard treatment for locally advanced non-small cell lung cancer (NSCLC). However, studies on immunological and nutritional markers to predict progression-free survival (PFS) and overall survival (OS) are inadequate. Systemic inflammation causes cancer cachexia and negatively affects immunotherapy efficacy, which also reflects survival outcomes. PATIENTS AND METHODS: We retrospectively investigated 126 patients from seven institutes in Japan. RESULTS: The modified Glasgow Prognostic Score (mGPS) values, before and after CRT, were the essential predictors among the evaluated indices. A systemic inflammation-based prognostic risk classification was created by combining mGPS values before CRT, and C-reactive protein (CRP) levels after CRT, to distinguish tumor-derived inflammation from CRT-induced inflammation. Patients were classified into high-risk (n = 31) and low-risk (n = 95) groups, and the high-risk group had a significantly shorter median PFS of 7.2 months and an OS of 19.6 months compared with the low-risk group. The hazard ratios for PFS and OS were 2.47 (95% confidence interval [CI]: 1.46-4.19, p < 0.001) and 3.62 (95% CI: 1.79-7.33, p < 0.001), respectively. This association was also observed in the subgroup with programmed cell death ligand 1 expression of ≥50%, but not in the <50% subgroup. Furthermore, durvalumab discontinuation was observed more frequently in the high-risk group than in the low-risk group. CONCLUSION: Combining pre-CRT mGPS values with post-CRT CRP levels in patients with locally advanced NSCLC helps to predict the PFS and OS of durvalumab consolidation after CRT.
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BACKGROUND: Osimertinib monotherapy is a common treatment for epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC); however, standard treatment strategies for acquired resistance to this drug have not been established. In addition, the clinical significance of first-generation (1G) or second-generation (2G) EGFR-tyrosine kinase inhibitors (TKI) in patients with EGFR-mutant NSCLC and osimertinib resistance has not yet been fully evaluated. OBJECTIVE: We aimed to conduct a prospective multicenter observational study to evaluate the efficacy and safety of 1G and 2G EGFR-TKIs after the development of osimertinib resistance. METHODS: Patients with EGFR-mutant NSCLC who received 1G or 2G EGFR-TKIs after developing resistance to osimertinib monotherapy were prospectively assessed at eight institutions in Japan. The primary endpoint was progression-free survival (PFS). RESULTS: A total of 29 patients with advanced or recurrent EGFR-mutant NSCLC were analyzed. The objective response and disease control rates were 6.9% (2/29) and 58.6% (17/29), respectively. The median PFS was 1.9 months [95% confidence interval (CI): 1.3-5.3]. There was no significant difference in PFS between the 1G and 2G EGFR-TKI groups (3.7 versus 1.5 months, log-rank test p = 0.20). However, patients with normal cytokeratin 19 fragment (CYFRA 21-1) and pro-gastrin-releasing peptide (ProGRP) levels experienced longer PFS than those with elevated CYFRA 21-1 and/or ProGRP (5.5 versus 1.3 months, log-rank test p < 0.001). CONCLUSION: Administration of 1G or 2G EGFR-TKIs after the development of osimertinib resistance has limited efficacy in patients with EGFR-mutant NSCLC. Moreover, normal CYFRA 21-1 and ProGRP levels could be promising indicators for 1G and 2G EGFR-TKI administration after osimertinib resistance development. TRIAL REGISTRATION NUMBER: UMIN000044049.
Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Humans , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , Prospective Studies , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Mutation , Neoplasm Recurrence, Local/drug therapy , Aniline Compounds/pharmacology , Aniline Compounds/therapeutic use , Treatment Outcome , ErbB ReceptorsABSTRACT
Importance: Immune checkpoint inhibitor (ICI) monotherapy with pembrolizumab and ICI plus chemotherapy have been approved as first-line treatments for non-small cell lung cancer (NSCLC) for patients with a programmed cell death ligand-1 (PD-L1) tumor proportion score (TPS) of 50% or more, but the choice between these 2 therapeutic options is unclear. Objective: To clarify the association of a history of concurrent medication use with treatment outcomes for ICIs with or without chemotherapy in patients with NSCLC with a high PD-L1 TPS and to determine whether these clinical histories are biomarkers for appropriate treatment selection. Design, Setting, and Participants: This retrospective, multicenter cohort study at 13 hospitals in Japan included patients with advanced NSCLC with a PD-L1 TPS of 50% or more who had received pembrolizumab ICI monotherapy or ICI plus chemotherapy as the initial treatment between March 2017 and December 2020. The median (IQR) follow-up duration was 18.5 (9.2-31.2) months. Data were analyzed from April 2022 through May 2023. Exposure: ICI monotherapy with pembrolizumab or ICI plus chemotherapy as first-line treatment. Main Outcomes and Measures: The primary analysis was the association of treatment outcomes with baseline patient characteristics, including concomitant drug history, after propensity score matching. Cox proportional hazard models were used to determine the associations of patient characteristics with survival outcomes. Logistic regression analysis was used to determine the association of concomitant medication history with treatment outcomes and other patient characteristics. Results: A total of 425 patients with NSCLC were enrolled in the study including 271 patients (median [range] age, 72 [43-90] years; 215 [79%] men) who were treated with pembrolizumab monotherapy as the first-line treatment and 154 patients (median [range] age, 69 [36-86] years; 121 [79%] men) who were treated with ICI plus chemotherapy as the first-line treatment. In multivariable analysis, a history of proton pump inhibitor (PPI) use was independently associated with shorter progression-free survival (PFS) in the pembrolizumab monotherapy group (hazard ratio [HR], 1.38; 95% CI, 1.00-1.91; P = .048), but not in the ICI plus chemotherapy group. In patients with a PPI history, both the median (IQR) PFS (19.3 [9.0 to not reached] months vs 5.7 [2.4 to 15.2] months; HR, 0.38; 95% CI, 0.20-0.72; P = .002) and the median (IQR) overall survival (not reached [9.0 months to not reached) vs 18.4 [10.5 to 50.0] months; HR, 0.43; 95% CI, 0.20-0.92; P = .03) were significantly longer in the ICI plus chemotherapy group than in the pembrolizumab monotherapy group. In patients without a history of PPI use, both the median (IQR) PFS (18.8 months [6.6 months to not reached] vs 10.6 months [2.7 months to not reached]; HR, 0.81; 95% CI, 0.56-1.17; P = .26) and the median (IQR) overall survival (not reached [12.6 months to not reached] vs 29.9 [13.3 to 54.3] months, HR, 0.75; 95% CI, 0.48-1.18; P = .21) did not differ between groups. Conclusions and Relevance: This cohort study found that a history of PPI use could be an important clinical factor in treatment decision-making for patients with NSCLC with a PD-L1 TPS of 50% or more.
Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Aged , Female , Humans , Male , B7-H1 Antigen , Carcinoma, Non-Small-Cell Lung/drug therapy , Cohort Studies , Immune Checkpoint Inhibitors/therapeutic use , Lung Neoplasms/drug therapy , Proton Pump Inhibitors , Retrospective Studies , Adult , Middle Aged , Aged, 80 and overABSTRACT
BACKGROUND: Programmed death-ligand 1 (PD-L1) inhibitor plus platinum-etoposide chemotherapy is used as a first-line treatment for extensive-stage small cell lung cancer (ES-SCLC), regardless of age. OBJECTIVE: We examined the role of the Geriatric 8 (G8) screening tool for evaluating treatment outcomes in patients with ES-SCLC treated with PD-L1 inhibitor plus platinum-etoposide chemotherapy as first-line therapy. PATIENTS AND METHODS: Between September 2019 and October 2021, we prospectively evaluated patients with ES-SCLC treated with immunochemotherapy at ten institutions in Japan. The G8 score was assessed before treatment initiation. RESULTS: We evaluated 44 patients with ES-SCLC. Patients with G8 score > 11 had longer overall survival (OS) than those with G8 score ≤ 11 (not reached versus 8.3 months; log-rank test, p = 0.005). In univariate and multivariate analyses, G8 score > 11 [hazard ratio (HR) 0.34; 95% confidence interval (CI) 0.15-0.75; p = 0.008 and HR 0.34; 95% CI 0.14-0.82; p = 0.02, respectively) and performance status (PS) of 2 (HR 5.42; 95% CI 2.08-14.2; p < 0.001 and HR 6.94; 95% CI 2.25-21.4; p < 0.001, respectively) were independent prognostic factors for OS. Among patients with good PS (0 or 1), the OS in patients with G8 score > 11 was significantly longer than that in patients with G8 score ≤ 11 (not reached versus 12.3 months; log-rank test, p = 0.02). CONCLUSIONS: G8 score evaluation before treatment initiation was useful as a prognostic factor for ES-SCLC patients who received PD-L1 inhibitors and platinum-etoposide chemotherapy, even with good PS.
Subject(s)
Lung Neoplasms , Small Cell Lung Carcinoma , Humans , Aged , Small Cell Lung Carcinoma/drug therapy , Etoposide/adverse effects , Immune Checkpoint Inhibitors/therapeutic use , B7-H1 Antigen , Lung Neoplasms/drug therapy , Prognosis , Platinum/therapeutic use , Early Detection of Cancer , Antineoplastic Combined Chemotherapy Protocols/therapeutic useABSTRACT
Introduction: Lung adenocarcinoma with negative TTF-1 expression is believed to be a poor prognostic factor for certain systemic treatments. Nevertheless, the impact of TTF-1 expression on combined chemoimmunotherapy remains unclear. We aimed to investigate the relationship between tumor TTF-1 expression and the efficacy of combined chemoimmunotherapy in patients with advanced lung adenocarcinoma. Methods: This multicenter prospective observational study included 58 patients with advanced lung adenocarcinoma treated with combined chemoimmunotherapy across 10 institutions in Japan. The expression of TTF-1 in pretreatment tumors was determined using immunohistochemistry. Results: The objective response rate of combined chemoimmunotherapy was significantly higher in TTF-1-positive groups than in TTF-1-negative groups (p = 0.02). The median progression-free survival (PFS) and overall survival were significantly longer in TTF-1-positive groups than in TTF-1-negative groups (10.9 versus 5.0 mo; p = 0.01). Multivariate analysis revealed that TTF-1 expression was an independent favorable prognostic factor for PFS. Moreover, TTF-1 expression in patients with lung adenocarcinoma is significantly associated with programmed death-ligand 1 expression (p = 0.003). The TTF-1-positive group with programmed death-ligand 1 tumor proportion score greater than or equal to 50% had a significantly longer PFS than the other groups (p = 0.02). Conclusions: TTF-1 positivity is associated with better clinical outcomes in patients with advanced lung adenocarcinoma treated with combined chemoimmunotherapy.
ABSTRACT
Introduction: In recent years, programmed cell death-ligand 1 (PD-L1) inhibitor plus platinum-etoposide chemotherapy was found to have favorable clinical outcomes in patients with extensive-stage SCLC (ES-SCLC). The usefulness of early tumor shrinkage (ETS) has been reported in various types of cancers. Nevertheless, there have been few reports evaluating ETS in ES-SCLC. Therefore, this study aimed to evaluate the role of ETS in the clinical outcomes of patients with ES-SCLC receiving chemoimmunotherapy. Methods: We prospectively identified 46 patients with ES-SCLC who received PD-L1 inhibitor plus platinum-etoposide chemotherapy at 10 institutions in Japan between September 2019 and October 2021. Of them, 35 patients were selected for analyses. Results: The responders (progression-free survival [PFS] ≥ 6.0 mo) had significantly greater tumor shrinkage at the first evaluation than the nonresponders (PFS < 6.0 mo) (65.0% versus 53.7%, p = 0.03). We defined the cutoff value for ETS as a 57% change from the baseline on the basis of the receiver operating characteristic results to determine the optimal tumor shrinkage rate at the first evaluation for identifying responders. The patients with ES-SCLC who achieved ETS had longer PFS and overall survival than those who did not achieve ETS (5.6 versus 4.0 mo, log-rank test p = 0.001 and 15.0 versus 8.3 mo, log-rank test p = 0.02). In the multivariate analyses, ETS was significantly associated with PFS and overall survival (hazard ratio = 0.27, 95% confidence interval: 0.12-0.63, p = 0.002 and hazard ratio = 0.34, 95% confidence interval: 0.13-0.85, p = 0.02). Conclusions: Our prospective observational study indicated that ETS was related to favorable clinical outcomes for patients with ES-SCLC receiving PD-L1 inhibitor plus platinum-etoposide chemotherapy.