First-line Treatment Of Metastatic Non-small Cell Lung Cancer Research Articles

Plasma Proteome-Based Test for First-Line Treatment Selection in Metastatic Non-Small Cell Lung Cancer.

Current guidelines for the management of metastatic non-small cell lung cancer (NSCLC) without driver mutations recommend checkpoint immunotherapy with PD-1/PD-L1 inhibitors, either alone or in combination with chemotherapy. This approach fails to account for individual patient variability and host immune factors and often results in less-than-ideal outcomes. To address the limitations of the current guidelines, we developed and subsequently blindly validated a machine learning algorithm using pretreatment plasma proteomic profiles for personalized treatment decisions. We conducted a multicenter observational trial (ClinicalTrials.gov identifier: NCT04056247) of patients undergoing PD-1/PD-L1 inhibitor-based therapy (n = 540) and an additional patient cohort receiving chemotherapy (n = 85) who consented to pretreatment plasma and clinical data collection. Plasma proteome profiling was performed using SomaScan Assay v4.1. Our test demonstrates a strong association between model output and clinical benefit (CB) from PD-1/PD-L1 inhibitor-based treatments, evidenced by high concordance between predicted and observed CB (R2 = 0.98, P < .001). The test categorizes patients as either PROphet-positive or PROphet-negative and further stratifies patient outcomes beyond PD-L1 expression levels. The test successfully differentiates between PROphet-negative patients exhibiting high tumor PD-L1 levels (≥50%) who have enhanced overall survival when treated with a combination of immunotherapy and chemotherapy compared with immunotherapy alone (hazard ratio [HR], 0.23 [95% CI, 0.1 to 0.51], P = .0003). By contrast, PROphet-positive patients show comparable outcomes when treated with immunotherapy alone or in combination with chemotherapy (HR, 0.78 [95% CI, 0.42 to 1.44], P = .424). Plasma proteome-based testing of individual patients, in combination with standard PD-L1 testing, distinguishes patient subsets with distinct differences in outcomes from PD-1/PD-L1 inhibitor-based therapies. These data suggest that this approach can improve the precision of first-line treatment for metastatic NSCLC.

KN046, a bispecific antibody against PD-L1 and CTLA-4, plus chemotherapy as first-line treatment for metastatic NSCLC: A multicenter phase 2 trial

KN046, a bispecific antibody targeting PD-L1 and CTLA-4, presents a promising therapeutic option for metastatic non-small cell lung cancer (NSCLC). In this multicenter phase 2 trial, patients with nonsquamous (non-sq) NSCLC receive pemetrexed, whereas those with sq-NSCLC receive paclitaxel, plus KN046 and carboplatin. Following four cycles, maintenance therapy includes KN046 with pemetrexed for non-sq-NSCLC and KN046 for sq-NSCLC. The objective response rate is 46.0%, and the median duration of response is 8.1months. The median progression-free and overall survival are 5.8 and 26.6months, respectively. The common adverse events include anemia (87.4%), loss of appetite (72.4%), and neutropenia (70.1%). The most prevalent immune-related adverse event is pruritus (28.7%). These findings indicate that first-line treatment with KN046 and chemotherapy is effective and tolerable in metastatic NSCLC patients, warranting further investigation in a larger phase 3 trial. The trial is registered at ClinicalTrials.gov (NCT04054531).

First-line treatment with durvalumab plus chemotherapy versus chemotherapy alone for metastatic non-small-cell lung cancer in the USA: a cost-effectiveness analysis

ObjectiveThe objective of this study was to evaluate the cost-effectiveness of durvalumab in combination with chemotherapy compared with chemotherapy alone as first-line therapy for metastatic non-small-cell lung cancer (NSCLC) from...

Sex Differences in the Efficacy of Immune Checkpoint Inhibitors in Neoadjuvant Therapy of Non-Small Cell Lung Cancer: A Meta-Analysis.

Non-small cell lung cancer (NSCLC) is one of the world's leading causes of morbidity and mortality. ICIs alone or combined with chemotherapy have become the standard first-line treatment of metastatic NSCLC. The impressive results obtained have stimulated our interest in applying these therapies in early disease stage treatments, as neoadjuvant immunotherapy has shown promising results. Among many of the factors that may influence responses, the role played by sex is attracting increased interest and needs to be addressed. Here, we aim to first review the state of the art regarding neoadjuvant ICIs, whether they are administered in monotherapy or in combination with chemotherapy at stages IB-IIIA, particularly at stage IIIA, before analyzing whether sex may influence responses. To this end, a meta-analysis of publicly available data comparing male and female major pathological responses (MPR) and pathological complete responses (pCR) was performed. In our meta-analysis, MPR was found to be significantly higher in females than in males, with an odds ratio (OR) of 1.82 (95% CI 1.13-2.93; p = 0.01), while pCR showed a trend to be more favorable in females than in males, but the OR of 1.62 was not statistically significant (95% CI 0.97-2.75; p = 0.08). Overall, our results showed that sex should be systematically considered in future clinical trials settings in order to establish the optimal treatment sequence.

Interim survival analysis of the randomized phase III GEMSTONE-302 trial: sugemalimab or placebo plus chemotherapy as first-line treatment for metastatic NSCLC.

The randomized, double-blinded, multi-center, phase III GEMSTONE-302 ( NCT03789604 ) study evaluated the efficacy and safety of sugemalimab versus placebo in combination with chemotherapy as first-line treatment for metastatic non-small-cell lung cancer (NSCLC). In this study, 479 treatment-naive patients with stage IV squamous or non-squamous NSCLC without known EGFR sensitizing mutations, ALK, ROS1 or RET fusions were randomized (2:1) to receive 1,200 mg of sugemalimab (n = 320) or placebo (n = 159) every 3 weeks in combination with platinum-based chemotherapy for up to four cycles, followed by maintenance therapy with sugemalimab or placebo for squamous NSCLC and sugemalimab or placebo plus pemetrexed for non-squamous NSCLC. Placebo-treated patients could cross over to receive sugemalimab monotherapy on disease progression. The primary endpoint was investigator-assessed progression-free survival (PFS) and the secondary endpoints included overall survival (OS) and objective response rate. Sugemalimab plus chemotherapy has demonstrated significant PFS prolongation in the primary analysis as reported previously. As of 22 November 2021, the prespecified interim OS analysis showed significant improvement with the addition of sugemalimab to chemotherapy (median OS = 25.4 versus 16.9 months; hazard ratio = 0.65; 95% confidence interval = 0.50-0.84; P = 0.0008). Sugemalimab plus chemotherapy provided superior PFS and OS compared to placebo plus chemotherapy, supporting the use of sugemalimab as a first-line treatment option for metastatic NSCLC.

Cost-effectiveness analysis of sugemalimab in combination with chemotherapy as first-line treatment in Chinese patients with metastatic NSCLC

IntroductionBecause of its low immunogenicity and associated risk of toxicity, sugemalimab is expected to reshape the first-line treatment landscape for non-small cell lung cancer (NSCLC) in China. However, it remains unclear whether the use of expensive sugemalimab is cost-effective in this population. MethodsA Markov model was constructed based on the GEMSTONE-302 study to assess the efficacy of sugemalimab in combination with chemotherapy for first-line treatment of metastatic NSCLC. Efficacy and safety data were entered, with costs and utility values derived from the literature, and incremental cost-effectiveness ratios (ICERs) were estimated, and univariate sensitivity analyses and probabilistic sensitivity analyses were performed. We also considered cost-effectiveness in two different treatment regimen scenarios after disease progression. ResultsCompared with the placebo plus platinum-based chemotherapy, patients with metastatic NSCLC treated with sugemalimab plus platinum-based chemotherapy saw an increase of 0.56 life-years (LYs) and 0.41 quality-adjusted life-years (QALYs), and patients with squamous NSCLC resulted in an ICER per QALY of $45,280.02. Patients with nonsquamous metastatic NSCLC resulted in an ICER of $45,294.15 per QALY. Univariate sensitivity analysis showed that disease-free survival utility had the greatest impact on the results. Probabilistic sensitivity analysis (PSA) showed that when the willingness-to-pay (WTP) for QALYs was $27,354/QALY, sugemalimab, in combination with platinum-based chemotherapy, was more cost-effective than the placebo. ConclusionFrom a Chinese health care system perspective, first-line treatment of squamous or nonsquamous metastatic NSCLC with sugemalimab plus platinum-based chemotherapy may have cost-effectiveness compared with placebo plus platinum-based chemotherapy at a WTP threshold of $27,354/QALY.

Trial in progress: A phase 2 study of sotorasib as first-line treatment in patients with stage IV non–small cell lung cancer (NSCLC) whose tumors harbor a KRAS p.G12C mutation (CodeBreaK 201).

TPS9150 Background: Chemo-immunotherapy regimens represent a standard of care for the first-line treatment of metastatic NSCLC, yet clinical outcomes in patients bearing tumors that lack PD-L1 expression [PD-L1 Tumor Proportion Score (TPS) &lt; 1%)] or harbor a serine/threonine kinase 11 ( STK11) mutation remain poor. Sotorasib is a selective, irreversible small molecule KRASG12C inhibitor that is approved for the treatment of patients with locally advanced or metastatic KRAS p.G12C-mutated NSCLC following failure of at least one prior line of systemic therapy and has previously demonstrated robust antitumor activity in subgroups of KRAS p.G12C mutant NSCLC with PD-L1 TPS &lt;1% and/or STK11 co-mutations. We hypothesized that sotorasib may represent an effective first-line therapy for subgroups of NSCLC patients who may have suboptimal chemo-immunotherapy outcomes and a high unmet clinical need. Methods: This phase 2, open-label, global study is designed to evaluate the efficacy and safety of sotorasib (960 mg or 240 mg daily) as first-line treatment in approximately 170 patients with KRAS p.G12C-mutated, metastatic NSCLC with PD-L1 TPS &lt;1% as determined by immunohistochemical assay and/or presence of STK11 mutation as determined by next-generation sequencing (NGS). Key eligibility criteria include patients with untreated metastatic NSCLC without active brain metastases. Patients will be stratified by known presence of STK11 mutation. The primary endpoint is objective response assessed by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Secondary endpoints include disease control, duration of response, time to response, progression-free survival per RECIST 1.1, overall survival, safety and tolerability, and pharmacokinetic profile. Enrollment began in January 2022 and is ongoing. Contact Amgen Medical Information for more information. Clinical trial information: NCT04933695.

Pembrolizumab for advanced non-small cell lung cancer (NSCLC): Impact of autoimmune comorbidity and outcomes following treatment completion.

Pembrolizumab, an immune-checkpoint inhibitor, is approved for first-line treatment of metastatic NSCLC in patients with tumours expressing programmed death-ligand 1 (PD-L1) with tumour proportion score (TPS) of ≥50%. We aimed to clarify some uncertainties regarding use of immunotherapy in patients with previous autoimmune (AI) disorders and assess real-world outcomes following treatment completion. We performed a retrospective case record review of 82 patients with tumours expressing PD-L1 at TPS ≥ 50% and receiving first-line Pembrolizumab. Survival was estimated using the Kaplan Meier method. After 36.93 months (IQR: 34.37-40.20) median follow-up, median OS was 13.6 months (95% CI 8.9-19.3). There were 10 patients (12%) with AI co-morbidities and there was a trend toward improved median OS for this group versus those without AI comorbidity, 42 months (14.87-NR) versus 10.7 months (7.3-17.8), p = 0.073. Sixteen patients (20%) with nonprogressive disease at 2 years had significantly better median OS compared to those who did not complete 2 years of treatment, NR (42- NR) and 8.7 (5.8-14.1), p < 0.001.Immune related adverse events (irAE) of any grade occurred in 90% of the AI cohort compared with 70.8% of patients without AI comorbidity. Low grade adrenal insufficiency was the only irAE which occurred at a significantly higher rate in the AI group, p = 0.02. Patients with previous AI diseases tolerate treatment well, and there is a non-significant trend for improved outcomes in this group. Patients who complete the course of pembrolizumab have significantly better survival outcomes than those who do not.

Atezolizumab compared to chemotherapy for first-line treatment in non-small cell lung cancer with high PD-L1 expression: a cost-effectiveness analysis from US and Chinese perspectives.

BackgroundThe IMpower110 trial revealed that atezolizumab treatment had significantly longer overall survival (OS) than chemotherapy in non-small cell lung cancer (NSCLC) patients with high-programmed death ligand 1 (PD-L1) expression. The purpose of the present study was to estimate the cost-effectiveness of atezolizumab versus platinum-based chemotherapy for first-line treatment in metastatic NSCLC with high PD-L1 expression, from the perspective of US and Chinese payers.MethodsA partitioned survival model was constructed based on information from the IMpower110 clinical trial to estimate cost-effectiveness of atezolizumab versus chemotherapy as first-line treatment of metastatic NSCLC. Costs were estimated from US and Chinese payer perspectives. The impact of uncertainty was explored by performing one-way and probabilistic sensitivity analyses.ResultsIn the United States, treatment with atezolizumab was estimated to increase 0.87 quality adjusted life years (QALYs) at a cost of $123,424/QALY. In China, the use of atezolizumab cost an additional $68,489 compared with chemotherapy, yielding an incremental cost-effectiveness ratio (ICER) of $78,936/QALY. Sensitivity analysis indicated that the cost of atezolizumab was the most influential factor in both countries.ConclusionsIn the United States, which had a willingness-to-pay (WTP) threshold of $100,000 to $150,000 per QALY, atezolizumab was a cost-effective strategy for first-line treatment in metastatic NSCLC patients with high PD-L1 expression when compared to chemotherapy. For China, with a WTP threshold of $33,210 per QALY, atezolizumab was not considered good-value treatment for NSCLC, and a price reduction of 52% appeared to be justified.

Immune checkpoint inhibitors for brain metastases in non-small-cell lung cancer: from rationale to clinical application.

Brain metastases (BM) is common in non-small-cell lung cancer (NSCLC) patients. Immune checkpoint inhibitors (ICIs)have gradually become a routine treatment for NSCLC BM patients. Currently, three PD-1 inhibitors (pembrolizumab, nivolumab and cemiplimab), one PD-L1 inhibitor (atezolizumab) and one CTLA-4 inhibitor (ipilimumab) have been approved for the first-line treatment of metastatic NSCLC. It is still controversial whether PD-L1, tumor infiltrating lymphocytes, and tumor mutation burden can be used as predictive biomarkers for immune checkpoint inhibitorsin NSCLC patients with BM. In addition, clinical data on NSCLC BM were inadequate. Here, we review the theoretical basis and clinical data for the application of ICIsin the therapy of NSCLC BM.

Nivolumab plus ipilimumab for the first-line treatment of metastatic NSCLC

ABSTRACT Introduction In the last decade, immune checkpoint inhibitors have revolutionized the treatment of several malignancies including non-small cell lung cancer (NSCLC). The inhibition of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and the programmed death receptor 1 (PD-1) pathways leads to an activation of the immune response against tumor cells. Thanks to a synergistic effect, the combination of the checkpoint inhibitors nivolumab and ipilimumab has the potential to improve outcomes of NSCLC patients. Areas covered We provide an overview of clinical trials evaluating the combination of nivolumab and ipilimumab in the first-line treatment of advanced NSCLC patients. Expert opinion The combination of nivolumab and ipilimumab, alone or with a few cycles of chemotherapy, was demonstrated to be a valid option for first-line treatment of metastatic NSCLC patients without EGFR mutation and ALK rearrangement. However, a better understanding of patients who can benefit from this approach is required.

Pembrolizumab Plus Ipilimumab or Placebo for Metastatic Non-Small-Cell Lung Cancer With PD-L1 Tumor Proportion Score ≥ 50%: Randomized, Double-Blind Phase III KEYNOTE-598 Study.

Pembrolizumab monotherapy is standard first-line therapy for metastatic non-small-cell lung cancer (NSCLC) with programmed death ligand 1 (PD-L1) tumor proportion score (TPS) ≥ 50% without actionable driver mutations. It is not known whether adding ipilimumab to pembrolizumab improves efficacy over pembrolizumab alone in this population. In the randomized, double-blind, phase III KEYNOTE-598 trial (ClinicalTrials.gov identifier: NCT03302234), eligible patients with previously untreated metastatic NSCLC with PD-L1 TPS ≥ 50% and no sensitizing EGFR or ALK aberrations were randomly allocated 1:1 to ipilimumab 1 mg/kg or placebo every 6 weeks for up to 18 doses; all participants received pembrolizumab 200 mg every 3 weeks for up to 35 doses. Primary end points were overall survival and progression-free survival. Of the 568 participants, 284 were randomly allocated to each group. Median overall survival was 21.4 months for pembrolizumab-ipilimumab versus 21.9 months for pembrolizumab-placebo (hazard ratio, 1.08; 95% CI, 0.85 to 1.37; P = .74). Median progression-free survival was 8.2 months for pembrolizumab-ipilimumab versus 8.4 months for pembrolizumab-placebo (hazard ratio, 1.06; 95% CI, 0.86 to 1.30; P = .72). Grade 3-5 adverse events occurred in 62.4% of pembrolizumab-ipilimumab recipients versus 50.2% of pembrolizumab-placebo recipients and led to death in 13.1% versus 7.5%. The external data and safety monitoring committee recommended that the study be stopped for futility and that participants discontinue ipilimumab and placebo. Adding ipilimumab to pembrolizumab does not improve efficacy and is associated with greater toxicity than pembrolizumab monotherapy as first-line treatment for metastatic NSCLC with PD-L1 TPS ≥ 50% and no targetable EGFR or ALK aberrations. These data do not support use of pembrolizumab-ipilimumab in place of pembrolizumab monotherapy in this population.

Cost-effectiveness analysis of pembrolizumab plus chemotherapy for previously untreated metastatic non-small cell lung cancer in the USA

ObjectivesEvaluating the cost-effectiveness of pembrolizumab plus standard chemotherapy in the first-line setting for patients with metastatic non-small cell lung cancer (NSCLC) from the US payer perspective.DesignA Markov model was constructed...

Cost Effectiveness of PD-L1-Based Test-and-Treat Strategy with Pembrolizumab as the First-Line Treatment for Metastatic NSCLC in Hong Kong.

BackgroundPembrolizumab, a monoclonal antibody against programmed death ligand 1 (PD-L1), is approved by several regulatory agencies for first-line treatment of metastatic non-small-cell lung cancer (NSCLC) with a PD-L1 tumor proportion score (TPS) ≥ 50% and no epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase genomic tumor aberrations. This study was conducted from the perspective of the Hospital Authority in Hong Kong and aimed to evaluate the cost effectiveness of a biomarker (PD-L1) test-and-treat strategy (BTS), in which patients with a TPS ≥ 50% received pembrolizumab and other patients received platinum doublet chemotherapy versus all patients receiving platinum doublet chemotherapy.MethodsThe model used a partitioned survival approach to estimate the incremental cost-effectiveness ratio (ICER) expressed as the cost per quality-adjusted life-year (QALY) gained. The clinical efficacy, utility and safety data were derived from the KN024 trial. Costs and health outcomes were projected over a 10-year time horizon and discounted at 3% per year. Costs for drug acquisition, PD-L1 testing, drug administration and disease management were used. Sensitivity analyses were conducted to evaluate the robustness of results.ResultsThe BTS approach led to an increase of 0.29 QALYs at an additional cost of Hong Kong dollars (HK$) 249,077 (US$31,933) compared with platinum doublet chemotherapy, resulting in an ICER of HK$865,189 (US$110,922) per QALY gained. This is lower than the World Health Organization cost-effectiveness threshold of three times the 2016 gross domestic product (GDP) per capita for Hong Kong of HK$1017,819 (US$130,490). Probabilistic sensitivity analyses showed a 59.4% chance that the ICER would be below this threshold.ConclusionFirst-line treatment with pembrolizumab in a BTS to identify patients with NSCLC with PD-L1 TPS ≥ 50% can be considered cost effective in Hong Kong compared with platinum doublet chemotherapy based on a three-times GDP per capita threshold. However, local data on clinical efficacy and safety were not available to estimate overall survival (OS) and progression-free survival (PFS) specific to patients with NSCLC in Hong Kong. Further, uncertainty is inherent in the survival projections/extrapolation of PFS and OS beyond the trial period, and future research may help to further inform these parameters.Electronic supplementary materialThe online version of this article (10.1007/s41669-019-00178-7) contains supplementary material, which is available to authorized users.

From Biology to Therapy: Improvements of Therapeutic Options in Lung Cancer.

Lung cancer is the leading cause of cancer-related mortality around the world, despite effective chemotherapeutic agents, the prognosis has remained poor for a long time. The discovery of molecular changes that drive lung cancer has led to a dramatic shift in the therapeutic landscape of this disease. In "in vitro" and "in vivo" models of NSCLC (Non-Small Cell Lung Cancer), angiogenesis blockade has demonstrated an excellent anti-tumor activity, thus, a number of anti-angiogenic drugs have been approved by regulatory authorities for use in clinical practice. Much more interesting is the discovery of EGFR (Epithelial Growth Factor Receptor) mutations that predict sensitivity to the anti-EGFR Tyrosine Kinase Inhibitors (TKIs), a class of drugs that has shown to significantly improve survival when compared with standard chemotherapy in the first-line treatment of metastatic NSCLC. Nevertheless, after an initial response, resistance often occurs and prognosis becomes dismal. Biomolecular studies on cell line models have led to the discovery of mutations (e.g., T790M) that confer resistance to anti-EGFR inhibitors. Fortunately, drugs that are able to circumvent this mechanism of resistance have been developed and have been recently approved for clinical use. The discovery of robust intratumor lymphocyte infiltration in NSCLC has paved the way to several strategies able to restore the immune response. Thus, agents interfering with PD-1/PD-L1 (Programmed Death) pathways make up a significant portion of the armamentarium of cancer therapies for NSCLC. In all the above-mentioned situations, the basis of the success in treating NSCLC has started from understanding of the mutational landscape of the tumor.

PC08.08 Debate #3: Brain Metastases with a Driver Mutation Should Be Treated with Systemic Therapy First (CON)

PC08.08 Debate #3: Brain Metastases with a Driver Mutation Should Be Treated with Systemic Therapy First (CON)

Neutrophil lymphocyte ratio (NLR) as a predictive biomarker for PD-1/PD-L1 directed therapy in metastatic non-small cell lung cancer (NSCLC).

e20633 Background: PD-1/PD-L1 directed therapy is approved in the second and first-line treatment of metastatic NSCLC. While PD-L1 expression can be predictive of outcomes with such therapy, there remains a need for additional biomarkers to guide patient (pt) selection. NLR is an easy to use biomarker that was predictive for clinical outcomes in the treatment of kidney cancer and melanoma. This study evaluated NLR as a predictor of response rate (RR), PFS and OS in metastatic NSCLC pts treated with PD-1/PD-L1 inhibitors as second line therapy. Methods: A retrospective chart review of NSCLC pts treated with PD-1/PD-L1 inhibitors was conducted. Data were collected on pt demographics, smoking status [&lt;10 pack years (PY) and ≥10 PY], histology, NLR pre-therapy and NLR post 3 doses. Correlation with RR, PFS and OS was evaluated by univariate and multivariate analyses. Results: 58 pts with NSCLC were included in the analyses. Median age was 62.5 yrs (39-85) and 34(59%) were male. 36 (62%) were Caucasian, 16(28%) African American and 6(10%) Asian. 39 (63%) had adenocarcinoma histology, 23 (40%) patients smoked &lt;10 PY and 35(60%) ≥10 PY. On Day 1, 33 (57 %) had NLR &lt;4 and 28 (48%) had NLR &lt;4 after cycle 3. 43 (74%) pts had disease control with 2 (3%) complete remissions, 22 (38%) partial responses. Pre-therapy NLR ≥4 was associated with shorter PFS (HR = 1.79 p=0.10) and shorter OS (HR =2.57; p=0.04). NLR≥4 post 3doses was associated with shorter PFS (HR= 2.14,p=0.04) and shorter OS (HR= 3.11; p=0.04). In multivariate analysis, heavy smoking (≥10 PPY) was associated with longer PFS; HR=0.50 (95% CI 0.25-1.01; p=0.05); but had no effect on OS with a HR 0.58(95%CI 0.21-1.56; p=0.28). Squamous histology appeared to have longer PFS HR=0.62 (95% CI 0.61-2.35: p =0.61), though not statistically significant. Conclusions: Pretherapy NLR ≥4 was found to be associated with shorter OS in NSCLC pts treated with PD-1/PD-L1 therapy. This suggests that NLR may be a predictive factor for benefit with PD1/PDL1 therapy. A larger sample study is warranted to validate this observation. [Table: see text]

Next-Generation EGFR Tyrosine Kinase Inhibitors for Treating EGFR-Mutant Lung Cancer beyond First Line.

Tyrosine kinase inhibitors (TKIs) against the human epidermal growth factor receptor (EGFR) are now standard treatment in the clinic for patients with advanced EGFR mutant non-small-cell lung cancer (NSCLC). First-generation EGFR TKIs, binding competitively and reversibly to the ATP-binding site of the EGFR tyrosine kinase domain, have resulted in a significant improvement in outcome for NSCLC patients with activating EGFR mutations (L858R and Del19). However, after a median duration of response of ~12 months, all patients develop tumor resistance, and in over half of these patients this is due to the emergence of the EGFR T790M resistance mutation. The second-generation EGFR/HER TKIs were developed to treat resistant disease, targeting not only T790M but EGFR-activating mutations and wild-type EGFR. Although they exhibited promising anti-T790M activity in the laboratory, their clinical activity among T790M+ NSCLC was poor mainly because of dose-limiting toxicity due to simultaneous inhibition of wild-type EGFR. The third-generation EGFR TKIs selectively and irreversibly target EGFR T790M and activating EGFR mutations, showing promising efficacy in NSCLC resistant to the first- and second-generation EGFR TKIs. They also appear to have lower incidences of toxicity due to the limited inhibitory effect on wild-type EGFR. Currently, the first-generation gefitinib and erlotinib and second-generation afatinib have been approved for first-line treatment of metastatic NSCLC with activating EGFR mutations. Among the third-generation EGFR TKIs, osimertinib is today the only drug approved by the Food and Drug Administration and the European Medicines Agency to treat metastatic EGFR T790M NSCLC patients who have progressed on or after EGFR TKI therapy. In this review, we summarize the available post-progression therapies including third-generation EGFR inhibitors and combination treatment strategies for treating patients with NSCLC harboring EGFR mutations and address the known mechanisms of resistance.

Next-generation EGFR/HER tyrosine kinase inhibitors for the treatment of patients with non-small-cell lung cancer harboring &lt;em&gt;EGFR&lt;/em&gt; mutations: a review of the evidence

Tyrosine kinase inhibitors (TKIs) against human epidermal growth factor receptor (EGFR/HER) family have been introduced into the clinic to treat cancers, particularly non-small-cell lung cancer (NSCLC). There have been three generations of the EGFR/HER-TKIs. First-generation EGFR/HER-TKIs, binding competitively and reversibly to the ATP-binding site of the EGFR TK domain, show a significant breakthrough treatment in selected NSCLC patients with activating EGFR mutations (actEGFRm) EGFRL858R and EGFRDel19, in terms of safety, efficacy, and quality of life. However, all those responders inevitably develop acquired resistance within 12 months, because of the EGFRT790M mutation, which prevents TKI binding to ATP-pocket of EGFR by steric hindrance. The second-generation EGFR/HER-TKIs were developed to prolong and maintain more potent response as well as overcome the resistance to the first-generation EGFR/HER-TKIs. They are different from the first-generation EGFR/HER-TKIs by covalently binding to the ATP-binding site, irreversibly blocking enzymatic activation, and targeting EGFR/HER family members, including EGFR, HER2, and HER4. Preclinically, these compounds inhibit the enzymatic activation for actEGFRm, EGFRT790M, and wtEGFR. The second-generation EGFR/HER-TKIs improve overall survival in cancer patients with actEGFRm in a modest way. However, they are not clinically active in overcoming EGFRT790M resistance, mainly because of dose-limiting toxicity due to simultaneous inhibition against wtEGFR. The third-generation EGFR/HER-TKIs selectively and irreversibly target EGFRT790M and actEGFRm while sparing wtEGFR. They yield promising efficacy in NSCLC patients with actEGFRm as well as EGFRT790M resistant to the first- and second-generation EGFR-TKIs. They also appear to have a lower incidence of toxicity due to the reduced inhibitory effect on wtEGFR. Currently, the first-generation EGFR/HER-TKIs gefitinib and erlotinib and second-generation EGFR/HER-TKI afatinib have been approved for use as the first-line treatment of metastatic NSCLC with actEGFRm. This review will summarize and evaluate a broad range of evidence of recent development of EGFR/HER-TKIs, with a focus on the second- and third-generation EGFR/HER-TKIs, in the treatment of patients with NSCLC harboring EGFR mutations.

Une ≪ population spéciale ≫ : les sujets âgés

The subjects aged 70 years and over account for nearly 50 % of patients with non-small cell lung cancer (NSCLC). This is a “special population”, because of its potential frailty. Elderly patients should receive a careful assessment in order to evaluate the risk of mortality (related to NSCLC or comorbidities) and the risk of treatment toxicity. The Comprehensive Geriatric Assessment (CGA) is probably useful in this setting, as well as geriatric screening tools. Lobectomy is the standard treatment for localized NSCLC, but more limited resections may be considered. Radiotherapy with curative intent, in particular stereotactic body radiotherapy, and radiofrequency ablation are alternatives to surgery. Definitive radiotherapy and sequential chemo-radiotherapy are reasonable therapeutic options for locally advanced NSCLC. In the absence of molecular alteration, the combination of carboplatin and weekly paclitaxel is recommended as first-line treatment for metastatic NSCLC in elderly patients with good performance status and limited comorbidities. For unfit elderly patients, single-agent chemotherapy is preferred. EGFR tyrosine kinase inhibitors and crizotinib are the treatment of choice in patients with EGFR mutation-positive tumors and ALK-rearranged tumors, respectively.