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Amplifying Outcomes: Checkpoint Inhibitor Combinations in First-Line Non-Small Cell Lung Cancer.

ABSTRACT: PURPOSE:Lung cancer is one of the most common types of cancer, resulting in approximately 1.8 million deaths worldwide. Immunotherapy using checkpoint inhibitors has become standard of care in advanced non-small cell lung cancer (NSCLC), and there is increasing interest in further improving outcomes through combination with other therapeutics. This systematic review evaluates emerging phase III data on the efficacy and safety of checkpoint inhibitor combinations as first-line treatment for advanced NSCLC. MATERIALS AND METHODS:Published and presented literature was searched using the key search terms "non-small cell lung cancer" AND "checkpoint-inhibitors" (OR respective aliases) AND phase III trials. Seven randomized phase III clinical trials reporting outcomes on checkpoint inhibitor combinations in first-line advanced NSCLC were identified. RESULTS:Four first-line trials reported outcomes for checkpoint inhibitor combinations in nonsquamous NSCLC. Pembrolizumab-chemotherapy, atezolizumab-chemotherapy, and atezolizumab-bevacizumab-chemotherapy showed significantly improved overall survival compared with controls in patients with advanced nonsquamous epidermal growth factor receptor-negative (EGFR-)/ anaplastic lymphoma kinase gene (ALK)- NSCLC. Two trials reported outcomes for squamous NSCLC, with pembrolizumab-chemotherapy reporting significantly improved overall survival (OS) compared with chemotherapy. The combination of nivolumab-ipilimumab in all-comer histology failed to improve OS compared with histology appropriate chemotherapy in patients regardless of their tumor mutational burden status. Based on improved survival and safety, either pembrolizumab monotherapy or pembrolizumab-chemotherapy administered based on PD-L1 status and histology is a preferred treatment option. Outcomes for atezolizumab-bevacizumab-chemotherapy in EGFR+/ALK+ patients are promising and require further exploration. CONCLUSION:First-line checkpoint inhibitors added to standard therapies improve overall survival for nonsquamous EGFR-/ALK- and squamous advanced NSCLC. IMPLICATIONS FOR PRACTICE:Single-agent immune checkpoint inhibitors are now standard of care for advanced non-small cell lung cancer (NSCLC), and emerging data show that combining these agents with established chemotherapy further improves outcomes. The phase III KEYNOTE-189 and IMPower-130 trials showed significantly improved survival using this strategy for nonsquamous NSCLC, and the phase III KEYNOTE-407 trial showed similar results in squamous disease. Checkpoint inhibitor combinations are therefore an important new treatment option for first-line NSCLC. Programmed death ligand-1 expression may inform the use of checkpoint inhibitor combination therapy, and overall tumor mutation burden is also an emerging biomarker for this new treatment strategy.

SUBMITTER: Melosky B

PROVIDER: S-EPMC6964132 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Amplifying Outcomes: Checkpoint Inhibitor Combinations in First-Line Non-Small Cell Lung Cancer.

Melosky Barbara B Juergens Rosalyn R Hirsh Vera V McLeod Deanna D Leighl Natasha N Tsao Ming-Sound MS Card Paul B PB Chu Quincy Q

The oncologist 20190528 1

<h4>Purpose</h4>Lung cancer is one of the most common types of cancer, resulting in approximately 1.8 million deaths worldwide. Immunotherapy using checkpoint inhibitors has become standard of care in advanced non-small cell lung cancer (NSCLC), and there is increasing interest in further improving outcomes through combination with other therapeutics. This systematic review evaluates emerging phase III data on the efficacy and safety of checkpoint inhibitor combinations as first-line treatment f ...[more]

PMID: 31138727

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Project description:BackgroundImmune checkpoint inhibitors (ICIs) possess remarkable clinical effectiveness in non-small cell lung cancer (NSCLC). Different immune profiles of tumors may play a key role in the efficacy of treatment with ICIs. This article aimed to determine the differential organ responses to ICI in individuals with metastatic NSCLC.MethodsThis research analyzed data of advanced NSCLC patients receiving first-line treatment with ICIs. Major organs such as the liver, lung, adrenal glands, lymph nodes and brain were assessed using the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and RECIST-improved organ-specific response criteria.ResultsA retrospective analysis was conducted on a total of 105 individuals with advanced NSCLC with programmed death ligand-1 (PD-L1) expression ≥50% who received single agent anti-programmed cell death protein 1 (PD-1)/PD-L1 monoclonal antibodies as first-line therapy. Overall, 105 (100%), 17 (16.2%), 15 (14.3%), 13 (12.4%), and 45 (42.8%) individuals showed measurable lung tumors and liver, brain, adrenal, and other lymph node metastases at baseline. The median size of the lung, liver, brain, adrenal gland, and lymph nodes were 3.4, 3.1, 2.8, 1.9, and 1.8 cm, respectively. The results recorded mean response times of 2.1, 3.4, 2.5, 3.1, and 2.3 months, respectively. Organ-specific overall response rates (ORRs) were 67%, 30.6%, 34%, 39%, and 59.1%, respectively, with the liver having the lowest remission rate and lung lesions having the highest remission rate. There were 17 NSCLC patients with liver metastasis at baseline, and 6 had different responses to ICI treatment, with remission in the primary lung site and progressive disease (PD) in the metastatic liver site. At baseline, the mean progression-free survival (PFS) of the 17 patients with liver metastasis and 88 patients without liver metastasis was 4.3 and 7 months, respectively (P=0.02, 95% CI: 0.691 to 3.033).ConclusionsThe liver metastases of NSCLC may be less responsive to ICIs than other organs. The lymph nodes respond most favorably to ICIs. Further strategies may include additional local treatment in case of oligoprogression in these organs in patients with otherwise sustained treatment benefit.

Project description:IntroductionClinical evidence suggests that first-line immune checkpoint inhibitor (ICI) combination therapies can improve survival in patients with advanced non-squamous non-small cell lung cancer (nsq-NSCLC). However, the optimal strategy remains unknown without a systematic comparison of their long-term effects.MethodsWe performed a systematic review and network meta-analysis by retrieving up-to-date literature from PubMed® (National Library of Medicine, Bethesda, MD, USA), Embase® (Elsevier, Amsterdam, Netherlands), MEDLINE® (National Library of Medicine), ClinicalTrials.gov (National Library of Medicine), and major international conference publications. Published studies and abstracts comparing first-line ICI combination therapies with other treatments for patients with advanced nsq-NSCLC were included. Restricted mean survival time (RMST) was measured over 12 months for progression-free survival (PFS) and 18 months for overall survival (OS), and the Royston-Parmar model was used to extrapolate and compare data for the long-term outcomes.ResultsWe included a total of 11 trials involving 12 therapies and 6,130 patients. Pembrolizumab plus chemotherapy exhibited the best overall survival (OS) benefit at both 18 and 60 months [RMST = 2.95, 95% confidence interval (CI) 1.96 to 3.97; life-years gained over a 5-year period = 2.18 years]. Nivolumab plus bevacizumab plus chemotherapy was found to present the best progression-free survival (PFS) benefit at 12 months (RMST 3.02, 95% CI 2.11 to 3.91), whereas atezolizumab plus bevacizumab plus chemotherapy showed the best PFS benefit at 36 months (life-years gained over 3 years = 1.22 years). Subgroup analyses showed that among patients with programmed death-ligand 1 (PD-L1) expression ≥ 50%, atezolizumab plus chemotherapy and nivolumab plus ipilimumab resulted in superior OS benefits at 18 and 60 months, respectively. Among patients with PD-L1 expression< 1%, pembrolizumab plus chemotherapy was associated with OS benefits at both 18 and 60 months. Sintilimab plus chemotherapy was associated with relatively fewer grade ≥ 3 adverse events than other ICI combination therapies.ConclusionOur results show that ICI combination therapies showed better survival benefits than chemotherapy. Pembrolizumab plus chemotherapy could provide the best OS benefits to patients with advanced nsq-NSCLC, whereas atezolizumab plus bevacizumab plus chemotherapy could bring the best PFS benefits. The optimal ICI combination therapy varies depending on PD-L1 expression level.Systematic review registrationhttps://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=325005, identifier CRD42022325005.

Project description:BackgroundImmune checkpoint inhibitors (ICIs) are increasingly used as first-line therapy for patients with advanced non-small cell lung cancer (NSCLC) harboring no actionable mutations; however, data on their efficacy among patients presenting with intracranial lesions are limited. This study aimed to explore the efficacy and safety of ICIs combined with chemotherapy in advanced NSCLC patients with measurable brain metastasis at initial diagnosis.MethodsOur study retrospectively analyzed clinical data of a total of 211 patients diagnosed with driver gene mutation-negative advanced NSCLC with measurable, asymptomatic brain metastasis at baseline from Hunan Cancer Hospital between January 1, 2019 and September 30, 2021. The patients were stratified into two groups according to the first-line treatment regimen received: ICI combined with chemotherapy ( n = 102) or chemotherapy ( n = 109). Systemic and intracranial objective response rates (ORRs) and progression-free survival (PFS) were analyzed. Adverse events were also compared between the groups.ResultsCompared with the chemotherapy-based regimen, the ICI-containing regimen was associated with a significantly higher intracranial (44.1% [45/102] vs . 28.4% [31/109], χ2 = 5.620, P = 0.013) and systemic (49.0% [50/102] vs . 33.9% [37/109], χ2 = 4.942, P = 0.019) ORRs and longer intracranial (11.0 months vs . 7.0 months, P <0.001) and systemic (9.0 months vs . 5.0 months, P <0.001) PFS. Multivariable analysis consistently revealed an independent association between receiving ICI plus platinum-based chemotherapy as a first-line regimen and prolonged intracranial PFS (hazard ratio [HR] = 0.52, 95% confidence interval [CI]: 0.37-0.73, P <0.001) and systemic PFS (HR = 0.48, 95% CI: 0.35-0.66, P <0.001). No unexpected serious adverse effects were observed.ConclusionOur study provides real-world clinical evidence that ICI combined with chemotherapy is a promising first-line treatment option for driver gene mutation-negative advanced NSCLC patients who present with brain metastasis at initial diagnosis.Clinical trial registrationhttps://www.clinicaltrials.gov/ , OMESIA, NCT05129202.

Project description:BackgroundAs revealed by previous studies, the modified lung immune predictive index (mLIPI) can predict outcomes in patients with lung cancer receiving single-agent immunotherapy. However, the application value of the mLIPI for patients treated with combination immunotherapy requires further investigation. In this study, we aimed to explore the relationship between the mLIPI and the efficacy of treatment together with the prognosis of patients with advanced non-small cell lung cancer (NSCLC) receiving first-line immune checkpoint inhibitors (ICIs) combined with platinum-based chemotherapy.MethodsIn this retrospective study, we enrolled patients with advanced NSCLC treated with ICIs plus chemotherapy from March 2019 to June 2022. The patients were classified into good, intermediate, and poor/very poor groups according to their mLIPI before treatment. We further calculated the disease control rate (DCR), objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) of the three groups. The predictive ability of the mLIPI was evaluated by plotting a time-dependent receiver operating characteristic (ROC) curve and calculating the area under the curve (AUC).ResultsA total of 209 patients were included in this study. There were 75 patients in the good group, 114 patients in the intermediate group, and 20 patients in the poor/very poor group. The median PFS was 11.2 months [95% confidence interval (CI): 8.763-13.704] in the good group; 8.1 months (95% CI: 7.354-8.846) in the intermediate group; and 5.4 months (95% CI: 2.142-8.658) in the poor/very poor group. The median OS was not reached in the good group, 29.5 months (95% CI: 23.555-35.512) in the intermediate group, and 14.5 months (95% CI: 8.567-20.366) in the poor/very poor group (P<0.05). Multivariate analysis showed that the mLIPI was independently associated with PFS and OS (P<0.05); the AUC values of the mLIPI for predicting PFS at 3, 6, and 9 months were 0.673, 0.637, and 0.614, respectively, and for predicting OS at 6, 12, and 24 months were 0.715, 0.655, and 0.625, respectively.ConclusionsThe pretreatment mLIPI could be used to predict outcomes in patients with NSCLC receiving first-line ICIs plus chemotherapy.

Project description:BackgroundThe evidence of combined therapies of multi-target agents in first-line treatment of advanced non-small cell lung cancer (NSCLC) was limited. This study aimed to evaluate the safety and efficacy of anlotinib combined with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), chemotherapy, or immune checkpoint inhibitor (ICI) in advanced NSCLC.MethodsThis open-label, three-arm, prospective study (NCT03628521) enrolled untreated locally advanced/metastatic NSCLC patients. Patients with EGFR mutation NSCLC received anlotinib and erlotinib (cohort A). Patients without EGFR/ALK/ROS1 mutation received anlotinib combined with carboplatin plus pemetrexed/gemcitabine (cohort B), or sintilimab (cohort C). The primary outcomes were safety and objective response rate (ORR). The secondary endpoints included progression-free survival (PFS), disease control rate (DCR), and overall survival (OS). Treatments were performed for at least 2 cycles and efficacy was evaluated every 2 cycles using RECIST version 1.1. Safety was assessed throughout the study.ResultsA total of 30, 30, and 22 patients were enrolled in cohorts A, B, and C, respectively. There were 3 patients did not complete the treatment in cohort A. In cohorts A and B, ≥ grade 3 treatment-related adverse events (TRAEs) occurred in 77.3% and 60.0% of patients, respectively. The most common TRAEs were rash (10.0%) and decreased platelet count (30.0%) in cohorts A and B, respectively. The ORRs were 92.9% and 60.0% in cohorts A and B, respectively, and DCRs were 96.4% and 96.7%, respectively. The ORR and incidence of ≥ grade 3 TRAEs of cohort C were, which 72.7% and 54.5%, which had been published previously. Median PFSs [95% confidence interval (CI)] were 21.6 (15.6 to 24.9), 13.0 [10.5 to not estimated (NE)], and 15.6 (12.9 to NE) months in cohorts A, B, and C, respectively. Median OS was 28.1 (95% CI: 21.82 to NE) months in cohort B. The 24-month OS rates in cohorts A and C were 87.1% and 83.9%, respectively.ConclusionsAnlotinib-based combinations with EGFR-TKI, chemotherapy, and ICI are well-tolerated and encouraging as first-line therapies for advanced NSCLC, which could be verified in future studies. Anlotinib-based combination might provide multiple choices for first-line treatment in patients with advanced NSCLC.

Project description:BackgroundMany studies have explored the cost-effectiveness of immunotherapy versus chemotherapy alone. However, there is paucity of evidence on direct pharmacoeconomic studies related to immunotherapy combinations. Thus, we aimed at assessing the economic outcomes of first-line immunotherapy combinations in the treatment of advanced non-small cell lung cancer (NSCLC) from the Chinese health care perspective.MethodsThe mutual hazard ratios (HRs) of ten immunotherapy combinations and one chemotherapy regimen for the overall survival (OS) and progression-free survival (PFS) were obtained from a network meta-analysis. Based on proportional hazard (PH) assumption, adjusted OS and PFS curves were established to make the effects comparable. With the parameters of cost and utility, and of scale and shape from the fit of adjusted OS and PFS curves obtained from previous studies, a partitioned survival model was designed to estimate the cost-effectiveness of immunotherapy combinations versus chemotherapy alone. Parameter uncertainty in model inputs was assessed using one-way deterministic and probabilistic sensitivity analyses.ResultsThe incremental cost of camrelizumab plus chemotherapy versus chemotherapy alone was $13,180.65, the lowest among all the other immunotherapy combinations. Furthermore, sintilimab plus chemotherapy (sint-chemo) provided the highest quality-adjusted life-year (QALY) benefit versus chemotherapy alone (incremental QALYs = 0.45). Sint-chemo yielded the best incremental cost-effectiveness ratio (ICER) versus chemotherapy alone (ICER = $34,912.09/QALY), at the current price. The cost-effectiveness probabilities were 32.01% and 93.91% for pembrolizumab plus chemotherapy, and atezolizumab plus bevacizumab plus chemotherapy, respectively (if the original price of the pembrolizumab, atezolizumab, and bevacizumab were decreased by 90%).ConclusionsBased on the fact that there is fierce competition in the PD-1/PD-L1 market, pharmaceutical enterprises should strive for greater efficacy, and optimal pricing strategy for therapies.

Project description:ImportanceImmunotherapy is now a cornerstone of treatment for advanced non-small cell lung cancer (NSCLC), but its uptake and effectiveness among older patients outside clinical trials remain poorly understood.ObjectiveTo understand treatment patterns and evaluate the overall survival associated with checkpoint inhibitor immunotherapy, cytotoxic chemotherapy, and combined chemoimmunotherapy for older patients who have advanced NSCLC and Medicare coverage.Design, setting, and participantsThis retrospective cohort study included Medicare-insured patients in the US aged 66 to 89 years who initiated first palliative-intent systemic therapy for lung cancer between January 1, 2016, and December 31, 2018. Survival follow-up continued through March 31, 2020. A total of 19 529 patients who had advanced lung cancer and were insured by a Medicare fee-for-service plan were included in the analysis.ExposuresRegimens included pembrolizumab monotherapy (n = 3079), combined platinum-based drug (ie, cisplatin or carboplatin [hereinafter, platinum]) and pemetrexed disodium (n = 5159), combined platinum and a taxane (ie, paclitaxel, nab-paclitaxel, or docetaxel) (n = 9866), and combined platinum, pemetrexed, and pembrolizumab (n = 1425), as ascertained using Medicare claims from the Centers for Medicare & Medicaid Services.Main outcomes and measuresThe primary outcome was overall survival, which was measured using the restricted mean survival time (RMST) with propensity score adjustment for clinical and sociodemographic characteristics. Median survival was also reported for comparison with outcomes from registrational trials.ResultsA total of 19 529 patients (54% male, 46% female; median age, 73.8 [interquartile range, 69.9-78.4] years) were identified for analysis. The uptake of pembrolizumab-containing regimens in the Medicare population was rapid, increasing from 0.7% of first-line treatments in the second quarter of 2016 to 42.4% in the third quarter of 2018. Patients who were older (≥70 years, 2484 [81%]), were female (1577 [51%]), and/or had higher Risk Stratification Index scores (highest quintile, 922 [30%]) were more likely to receive single-agent pembrolizumab than chemotherapy. After propensity score adjustment, pembrolizumab was associated with survival similar to platinum/pemetrexed (RMST difference, -0.2 [95% CI, -0.5 to 0.2] months) or platinum/taxane (RMST difference, -0.7 [95% CI, -1.0 to -0.4] months). Patients receiving platinum/pemetrexed/pembrolizumab chemoimmunotherapy also had adjusted survival similar to those receiving platinum/pemetrexed chemotherapy (RMST difference, 0.5 [95% CI, 0.1-0.9] months). The unadjusted median survival was 11.4 (95% CI, 10.5-12.3) months among patients receiving single-agent pembrolizumab, approximately 15 months shorter than observed among pembrolizumab-treated participants in the KEYNOTE-024 trial. The unadjusted median survival was 12.9 (95% CI, 11.8-14.0) months among patients receiving platinum/pemetrexed/pembrolizumab chemoimmunotherapy, approximately 10 months shorter than observed among platinum/pemetrexed/pembrolizumab-treated participants in the KEYNOTE-189 trial.Conclusions and relevanceImmunotherapy has been incorporated rapidly into treatment for patients with advanced NSCLC. However, survival estimates in the Medicare population are much shorter than those reported in registrational trials. These results provide contemporary estimates of survival for older patients with advanced NSCLC treated in routine practice, facilitating patient-centered decision-making.

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Amplifying Outcomes: Checkpoint Inhibitor Combinations in First-Line Non-Small Cell Lung Cancer.

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Amplifying Outcomes: Checkpoint Inhibitor Combinations in First-Line Non-Small Cell Lung Cancer.

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