ARIAN protocol: a phase III study of sacituzumab and zimberelimab for the treatment of patients with non-small cell lung cancer

Immune-Related Adverse Events and Outcomes in Patients with Advanced Non–Small Cell Lung Cancer: A Predictive Marker of Efficacy?

Chemotherapy + PD-1/PD-L1 Blockade Should Be the Preferred Option in the Neoadjuvant Therapy of NSCLC

New developments in the field of immune therapy for non-small cell lung cancer (NSCLC) are emerging rapidly and the race to identify new targets and new therapeutic agents within this field is intensifying.1 As part of contemporary practice to select patients for immune therapy, pathologists are performing immunohistochemistry (IHC) for programmed death receptor ligand-1 (PD-L1) as the currently favored predictive biomarker test.2–4 This role seems likely to expand considering the June 2016 publication of a study, first presented in part at previous American Society of Clinical Oncology and European Cancer Congress annual meetings, that found that patients with advanced NSCLC responded to nivolumab monotherapy as a first-line therapy.5–7During the past year, the US Food and Drug Administration (FDA) has approved monoclonal antibodies that block inhibitory immune checkpoint molecules (programmed death receptor-1 [or PD-1] and its ligand, PD-L1) for NSCLC and corresponding companion or complementary diagnostics based on PD-L1 IHC.8–10 To date, the immune checkpoint inhibitors have been approved for second-line therapy of advanced NSCLC after progression on first-line therapies. Positive PD-L1 IHC biomarker tests identify those NSCLC patients who are most likely to benefit from treatment with immune checkpoint inhibitors compared to patients whose biomarker test results are negative. It is important to note that a negative IHC result does not always preclude inhibitory therapy response, presumably due to heterogeneous PD-L1 expression. Discussion addressing if PD-LI IHC is the optimal biomarker test along with strategies to address a multiplicity of PD-L1 antibodies and their interpretation relative to patient response is discussed elsewhere in the literature.3 11–14Last year, the FDA expanded the use of nivolumab for second-line treatment for metastatic NSCLC based on the CheckMate 057 clinical trial and approved the PD-L1 IHC 28-8 PharmDx assay (Dako North America, Carpinteria, California) as a complementary diagnostic for nivolumab.8 9 In June 2016, results of the phase I Checkmate 012 trial were published.7 This trial evaluated nivolumab as a first-line monotherapy in 52 advanced NSCLC patients and found an objective response rate (ORR) of 23% (12 of 52) with 4 ongoing complete responses. ORR was 28% (9 of 32) in patients whose NSCLC had PD-L1 expression of any amount versus 14% (2 of 14) in patients whose NSCLC was negative for PD-L1 expression. There was a trend toward greater response to therapy the greater the PD-L1 expression. Currently, 2 phase III trials of first-line nivolumab therapy, CheckMate 026 and CheckMate 227, are investigating PD-L1 expression as a predictive biomarker for nivolumab efficacy.7The potential use of immune checkpoint inhibitors for first-line therapy of advanced NSCLC has implications for biomarker testing by pathologists.7–9,15 Currently immune checkpoint therapy is offered as a possible salvage option in NSCLC patients whose cancer has progressed on traditional first-line chemotherapy. PD-L1 biomarker status may be less clinically relevant in the second-line setting owing to other considerations, namely the paucity of other options for patients progressing after initial cytotoxic therapy and the low response rate of second-line docetaxel. This likely limits the number of requests for PD-L1 testing. However, PD-L1 biomarker status would be expected to be a more important factor in the decision to initially use a new type of therapy (immune therapy) over conventional chemotherapy with its established record as a first-line treatment.7 15 Since PD-L1 expression is likely to carry more weight in the first-line decision-making process than in second-line salvage options, pathologists can expect increased requests for PD-L1 testing if immune therapy becomes an FDA-approved first-line alternative treatment. This situation would place greater demand on laboratories to provide PD-L1 testing for a larger number of advanced NSCLCs, which represent some 70% of all lung cancers at the time of first diagnosis.89Although controversies to PD-L1 biomarker testing remain, increasing demand for PD-LI testing seems inevitable for the foreseeable future as applications of immune checkpoint inhibition both in different stages and different tumor types inexorably continue to grow.

The Challenges of Third-Generation EGFR Tyrosine Kinase Inhibitors in the Therapy of Advanced NSCLC

Cetuximab in advanced non-small cell lung cancer (NSCLC): the showdown?

The non-small cell lung cancer (NSCLC) accounts approximately 85% of lung cancers and includes predominantly adenocarcinomas, which is the most common type and squamous cell carcinomas. The treatment options include surgery, radiation therapy, and chemotherapy and the decision depends on the patient’s medical status and stage of disease. From 1970 the standard first line treatment for most patients with unresectable NSCLC and good performance status was the use of a combination of chemotherapy regimens and usually cisplatin-based. The most common combination regimens in use at present are platinum based regimens with gemcitabine, with paclitaxel or docetaxel and with vinorelbine combinations. The addition of the recombinant humanized monoclonal antibody bevacizumab that binds to vascular endothelial growth factor (VEGF) to carboplatin and paclitaxel for the treatment of non-squamous advanced NSCLC has demonstrated to increase response rate (RR), progression free survival (PFS) and overall survival (OS) when compared to chemotherapy alone. Despite recent advances with approval of more active chemotherapeutic and anti-angiogenesis agents for stage IV NSCLC, standard therapy can provide only modest clinical benefits with significant toxicities when used in unselected patients. In 2004, the identification of somatic mutations in the epidermal growth factor receptor (EGFR) gene provided the first glimpse of a possible target for a treatment which could maximize clinical outcome in those patients who could benefit from a personalized therapy. Identifying mutations in oncogenes associated with non-squamous NSCLC can help determine which patients are more likely to benefit from a targeted therapy. Such oncogenes include EGFR, KRAS, and ALK. The presence of an EGFR mutation confers a more favorable prognosis and strongly predicts for sensitivity to EGFR tyrosine kinase inhibitors (TKIs) such as erlotinib, gefitinib, and afatinib. The use of EGFR TKIs is based upon the detection of these mutations. The incidence of EGFR mutations in tumors with non-small-cell histology ranges from ~15% in Caucasians to ~50% in East Asians; 95% of such mutations have been found in adenocarcinomas. Patients bearing EGFR mutations have shown favorable clinical outcomes even with conventional chemotherapy suggesting that EGFR may be a predictive and a prognostic factor. Activation of the EGFR protein stimulates protein tyrosine kinase, which leads to activation of signaling pathways associated with cell growth and survival. Both EGFR overexpression and activating mutations in the tyrosine kinase domain of the EGFR gene lead to tumor growth and progression. Erlotinib, gefitinib and afatinib are examples of EGFR TKIs that can prevent activation of the signaling pathways and improve RRs in selected NSCLC patients. These mutations which are associated with increased sensitivity to EGFR TKIs, predominate in never-smokers, females, and tumors with adenocarcinoma histology. The most common mutations associated with sensitivity to EGFR TKIs include exon 19 deletions and the L858R point mutation and they are associated with RRs of >70%. Other EGFR mutations like T790M and exon 20 insertion, have been associated with much lower response or acquired resistance to TKI’s. The predictive value of EGFR mutations for use of gefitinib has been strengthened by the results of three randomized phase III trials that specifically compared TKIs used as first-line therapy with traditional platinum-based chemotherapy in patients with advanced NSCLC. In 2009 the results of IRESSA Pan-Asia Study were presented. This trial included a big number of Asian ethnicity patients (1,217) who were never smokers or former light smokers with histologic diagnosis of adenocarcinoma. The trial demonstrated an improvement in PFS and RR, with no statistical difference in OS, with the use of gefitinib in EGFR-mutated tumors and better RR and PFS with standard chemotherapy in patients without mutations. The first phase III trial of gefitinib versus chemotherapy as initial treatment of recurrent or advanced NSCLC, based on selection of patients with known activating EGFR mutations was the WJTOG3405 trial, reported in 2010. This trial documented important achievements in RR and PFS with the use of TKIs. Almost the same results were confirmed by another similar Japanese phase III trial, NEJ002, with RR and PFS definitely favoring the use of gefitinib in the first-line setting of metastatic EGFR-mutated NSCLC. Based on the results of the IPASS study, gefitinib was approved for use in Europe for the initial treatment of patients with NSCLC exhibiting EGFR mutations. The positive results of the EURTAC trial, NCT00446225, which was a randomized phase III trial of erlotinib versus standard chemotherapy, suggested that responsiveness in mutation-positive patients was not a function of ethnicity. Afatinib is approved as monotherapy for the treatment of EGFR TKI—naïve adults with locally advanced or metastatic NSCLC with activating EGFR mutations in the EU, and for the first-line treatment of patients with metastatic NSCLC whose tumors have EGFR exon 19 deletions or exon 21 (L858R) substitution mutations as detected by a US FDA-approved test in the US. In two randomized, open-label, multinational phase III trials, progression-free survival was significantly prolonged with afatinib compared with pemetrexed plus cisplatin (LUX-Lung 3) or gemcitabine plus cisplatin (LUX-Lung 6) in treatment-naïve patients with advanced NSCLC with activating EGFR mutations. EGFR-TKIs as a class are generally well tolerated. The two most common toxicities include dermatologic and GI effects, which are mild to moderate, easily managed and reversible. In order to determine whether an EGFR TKI or chemotherapy is the appropriate first-line therapy, the latest guidelines recommend mutation testing for all patients with advanced NSCLC tumor. The aim of this prospective study is to compare the efficacy of gefitinib, erlotinib and afatinib in patients with advanced NSCLC harboring activating EGFR mutations in first line of treatment. These agents are recommended as first line treatments for NSCLCs with such mutations. The primary endpoint will be the PFS and the secondaries will be the OS and the record of the toxicities. In each of the 3 arms will be participate 20 patients with EGFR mutated tumors. The technique for screening NSCLC patients for driver mutations that it will be used is next-generation sequencing, which overcomes many of the shortcomings of direct sequencing. This massively parallel approach, relying heavily on automation, data storage, and computational processing, allows quantitative analysis of infrequent alleles and simultaneous evaluation of multiple genes or even whole genomes, but is not yet used routinely in clinical practice. In addition, KRAS mutation analysis will be performed in patients with known smoking history in order to determine the correlation of type and mutation frequency with smoking.

TROP-2-directed antibody-drug conjugates in advanced NSCLC: A systematic review and meta-analysis of efficacy, safety, and reconstructed survival outcomes.

背景与目的肺癌的治疗模式以表皮生长因子受体酪氨酸激酶抑制剂（epidermal growth factor receptor-tyrosine kinase inhibitors, EGFR-TKIs）作为EGFR突变的非小细胞肺癌（non-small cell lung cancer, NSCLC）患者一线治疗；同时以程序性死亡受体1（programmed death receptor 1, PD-1）及其配体（programmed death receptor ligand 1, PD-L1）抑制剂为代表的免疫检查点抑制剂（immune checkpoint inhibitors, ICIs）的免疫治疗在肺癌治疗中疗效显著。本研究旨在探讨PD-1和PD-L1在NSCLC中的表达及其与临床病理特征、EGFR突变之间的关系。方法采用免疫组化方法检测127例NSCLC PD-1和PD-L1蛋白表达，同时用定量聚合酶链反应（quantitative polymerase chain reaction, qPCR）检测EGFR基因突变，分析其与临床病理特征之间的关系，研究PD-1、PD-L1表达之间以及其与EGFR突变的关系。结果NSCLC肿瘤细胞及肿瘤浸润免疫细胞PD-1阳性表达53.5%（68/127），肿瘤细胞PD-L1表达57.5%（73/127），PD-1和PD-L1的表达在低分化癌、临床分期Ⅰ期+Ⅱ期明显高于高中分化癌、Ⅲ期+Ⅳ期（均P < 0.05）；EGFR突变率为46.5%（59/127），EGFR突变的患者中女性、无吸烟史、腺癌、高中分化组分别高于男性、吸烟史、鳞癌、低分化组患者（均P < 0.05）；NSCLC患者PD-L1与PD-1蛋白表达存在一致性（kappa=0.107, 5, P=0.487），EGFR突变与PD-1、PD-L1表达存在负相关关系（Φ=-0.209，Φ=-0.221，均P < 0.05）；对NSCLC患者随访，在 < 65岁、腺癌、高中分化癌、PD-L1表达的患者中位总生存期分别高于≥65岁、鳞癌、低分化癌、PD-L1不表达患者（均P < 0.05）。PD-L1低表达患者中位生存期明显高于高表达患者（P=0.04）。结论参照《非小细胞肺癌PD-L1免疫组织化学检测规范中国专家共识》检测非小细胞肺癌PD-L1表达，筛选出抗PD-1/PD-L1治疗的优势人群；同时检测出EGFR突变的患者，并且EGFR突变与PD-1、PD-L1表达存在负相关关系，依据PD-L1表达和EGFR突变状态，可能使NSCLC患者在的个体化治疗中获益，同时65岁以下、腺癌、高中分化、PD-L1低表达的患者有相对好的预后，为NSCLC预后评估提供参考。

Second-Line Chemotherapy for Non-small Cell Lung Cancer

Lung Cancer

A small, international, closed-door conference on Novel Agents in the Treatment of Lung Cancer, held in Cambridge, Massachusetts, October 17–18, 2003, was convened to present and discuss findings from recent and ongoing trials of investigational drugs for the treatment of lung cancer. Invited participants from the Netherlands, Italy, Spain, and the United States presented new data regarding the role of molecularly targeted agents in the treatment of advanced lung cancer and discussed their significance for clinical care. The conference format combined brief presentations with extended periods of open discussion. The conclusions reached over the course of the 2-day conference are summarized briefly below and presented at greater length in the individual papers and accompanying discussions that comprise the conference proceedings.Over the past decade we have witnessed a dramatic increase in our understanding of lung cancer biology. This greater knowledge has led to the identification of new therapeutic targets as well as the development of innovative preclinical model systems. Over the past year we have seen the fruit of this effort in the discovery of pemetrexed, gefitinib, and erlotinib as active agents in lung cancer. For the most part, these agents have modest activity when used as single agents in patients with previously treated lung cancer. Preclinical modeling of these agents and drugs such as the antisense molecule to protein kinase C (Affinitac) predicted that they would have synergy with chemotherapy. A major disappointment has been the failure of these novel agents to improve survival when added to standard chemotherapy, calling into question the validity of the preclinical model systems.Much discussion focused on understanding the reasons why so many compounds that appeared promising in preclinical and early-phase clinical studies did not fulfill that promise when taken to large-scale randomized trials. Participants identified several key issues that will need to be addressed in the investigation of other novel compounds still in early development, primarily concerning the selection, interpretation, and reporting of preclinical studies and the design and interpretation of Phase I/II studies. Fundamentally, participants felt that industry has moved too precipitously to bring novel compounds into Phase III clinical trials in a competitive push to be the first with a new class of agents. It is understandable that we are impatient with advanced lung cancer. In its advanced stages, this is a disease that is uniformly fatal with a median survival of 9 months. This accelerated advance to Phase III clinical studies without better understanding of who may benefit from a given novel agent has had the support of regulatory authorities and academic researchers anxious to find effective regimens. A major concern raised by participants in the conference was that the recent pattern of negative Phase III trials threatens the future of the field, if companies and other investors in research decide to reallocate resources to disease conditions with a higher likelihood of successful outcomes.The success rate in proceeding from the preclinical model to the patient in the clinic is markedly lower for oncology compared with other indications. The predictive value of preclinical studies needs to be improved. One issue identified by conference participants is the importance of defining the target for the novel molecular agents and demonstrating (a) that the target is relevant and (b) that the agent in fact has a clinically meaningful impact on the target. Cell lines and xenografts will continue to provide necessary but not sufficient data. At the conference the potential role of genetically engineered mouse models was explored, and great hope was expressed that in the future these might be able to better predict efficacy of novel treatments.In discussing the generally poor predictive value of the preclinical models, conference participants concluded that there is an obvious need not only for better models but also for better utilization of the existing models. Although not optimal, the available cell line and xenograft models provide useful information if they are rationally used and rigorously interpreted. In the past, positive results in selected cell lines have been presented without reporting whether other cell lines were also run and found negative. Many felt strongly that multiple cell lines should be looked at and the full data set should be used to influence the go/no go decision in clinical development. Positive results should be confirmed in different cell lines or different models before proceeding to clinical trial, and all data should be reported with SDs given.In addition to validating target, preclinical models should be used to explore schedule and dose questions. Early use and more thorough interpretation of preclinical pharmacokinetic and pharmacodynamic data might help to design Phase II trials that are more likely to be representative. Conference participants called for more complete and consistent reporting of preclinical data, with an end to the common practice of selective presentation of preclinical data to justify planned clinical trials. The standard for data reporting should be as stringent for preclinical as for clinical studies, with all responses and nonresponses reported.As with the preclinical studies, early-stage clinical trials should include more thorough analysis of clinical data, such as distinguishing the subsets of patients who did or did not respond to the investigational agent. While recognizing the inherent difficulty in obtaining tissue from lung cancer patients, the group felt that, wherever possible, study designs should include at least baseline and posttreatment biopsies to assess or confirm the agent’s efficacy against the molecular target and the tumor itself. Even if the potential targets are not well “flushed out” at the time of the study, tumor tissue should be archived so that it can be looked at in the future because newer technology might clarify potential mechanisms of response or resistance.A number of novel agents that appeared promising in Phase II studies, even those with single-agent activity, have proved disappointing when taken to larger randomized trials. To avoid expending resources in unproductive large trials, statistical models should be used to determine what type of early-phase data (response rate, time to progression, or other surrogate end points), with what magnitude of apparent effect, would be predictive of positive outcomes in larger randomized Phase III trials. Because the typical Phase II trial only enrolls up to 40–50 patients, the duration of follow-up and the number of events must be adequate to allow interpretation. Both Phase I and Phase II trials need to be better powered. Phase I trials should include a pharmacodynamic marker whenever possible to verify that the drug (and the dosing regimen) is in fact hitting the putative target.Clinical studies evaluating novel agents have been designed primarily to gain regulatory approval for an agent. Two study designs have predominated: (a) using the investigational agent as monotherapy and comparing this with standard chemotherapy; or (b) combining the novel agent with a standard chemotherapy regimen to produce a doublet or triplet. Whereas these are certainly reasonable approaches, new designs for Phase II trials should be considered, including adjuvant and preoperative studies, where tumor samples taken from a small number of patients before and after a brief neoadjuvant course of treatment may aid in determining whether the agent has a detectable impact on the tumor. In this setting, multicenter trials that give priority to the collection and analysis of surgical samples may be of service in developing a better understanding of what is happening at a molecular level and in correlating therapy response with population subgroups.There was much discussion about the merits of the randomized Phase II trial. Several conference participants argued in favor of randomized Phase II studies with an active control arm, whereas others cautioned against the risks of overinterpreting the data because the patient numbers are generally too low to permit confident interpretation of the results. Multiple arm early-phase trials were viewed as expending resources that should be reserved for Phase III trials of agents that have established their potential. Participants agreed that there should be more emphasis on multicenter Phase II studies rather than single-institution studies, in which the patient population may not be representative. Conference participants also agreed that an investigational agent should demonstrate antitumor activity as monotherapy in Phase II before it is further evaluated as combination therapy in large Phase III trials. However, exceptions may be possible when novel agents are working primarily as sensitizers of chemotherapy or radiotherapy, and their major role is expected only in combination.Ultimately, better surrogate markers of antitumor activity are needed than clinical response rate or time to progression (an end point that is dependent on the frequency of follow-up). Early-phase trials should include efforts to validate both biomarkers of optimal drug dosing and surrogate markers of drug efficacy. Too many agents have gone on to Phase II/III trials without resolving these issues, and agents that failed in large trials in the general population might have shown efficacy if the dosing and the proper surrogate markers had been determined in the preliminary trials. In this regard, a biomarker that measures pharmacokinetics should not be substituted for a surrogate marker. The latter must be validated as correlating with both target-related changes within the tumor and clinical outcomes.In vivo imaging in humans may prove to be a powerful tool in elucidating the effects of the targeted therapies, and incorporation of imaging studies such as positron emission tomography or dynamic contrast magnetic resonance imaging in early-phase trials may also prove of utility in determining which agents should move forward to randomized trials. One recently developed study design treats all patients for a predetermined time, at which point all patients are imaged to identify response or lack of response, permitting an early determination of whether the drug has an effect on time to progression.Obtaining biopsy tissue is a difficult goal in lung cancer trials. Patients with metastatic lung cancer often have a diagnosis made by just a fine-needle aspiration. Often there is no archival tissue. In breast cancer, by contrast, the majority of patients have had the removal of a primary tumor, and paraffin samples are available. Only with great commitment will it be possible to obtain this tissue. Surrogate tissue is also a possibility. In early-phase trials it is feasible to biopsy surrogate tissue to look for markers of response. This will be much harder to coordinate in larger Phase III studies involving multiple sites of care.Participants were asked to determine the relevant benchmarks that should serve as standards by which to compare new treatments for stage IV non-small cell lung cancer (NSCLC). The group agreed that two distinct standards had evolved for interpreting a Phase III study as positive. For industry-sponsored multi-institution studies, the benchmark was a 10-month median survival with a 35% response rate and a 4.5-month median time to progression. In contrast, for cooperative group studies, the benchmark has been an 8-month median survival, 25% response rate, and a 4-month median time to progression. These differences may largely be explained by different patient characteristics and, in particular, by the entry of many stage III patients in drug company-sponsored studies as compared with cooperative group studies, in which the patient population is often limited to patients with mainly stage IV disease.In designing trials of the novel targeted agents, there is the issue of whether enrollment should be restricted to patients whose tumor expresses the target. In principle, the answer to this question should be yes. However, often we do not appreciate the relevant target. In a disease like chronic myelogenous leukemia, the presence of the bcr-abl is pathognomonic for the disease. In most solid tumors the genetic changes that produce malignancy are complex and incompletely understood. An agent that is highly effective for a small subset of patients may go unappreciated if that subset is not included in the clinical study. This strategy becomes problematic with agents such as the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors, for which the mechanism of action is, at best, poorly understood. In this example, clinical efficacy has not correlated with expression of the presumed target. Ultimately, there is no simple answer to this question. When it is clear what the target of interest is (which is the exception in lung cancer), it makes sense to enrich the population for such patients. When it is not known, it makes more sense to enroll broadly, collect tumor tissue, and ask correlative questions in a post hoc manner.Novel targeted agents are not the only drugs for which we need to improve our ability to predict response. Platinum-based combination therapy only helps a minority of patients with advanced NSCLC. Understanding chemotherapy sensitivity and resistance is a major goal as well. The mRNA expression levels of several genes (ERCC1, RRM1 and XPD) in the nucleotide excision repair pathway are implicated in cisplatin resistance, and RRM1appears to be a marker for gemcitabine/cisplatin resistance. Trials to further evaluate the prognostic significance of RRM1mRNA should be done to test the hypothesis that patients with low levels of RRM1 will benefit from gemcitabine/platinum chemotherapy.Genomic polymorphisms are another potential predictive marker of response and toxicity to chemotherapy. Pharmacodynamics is a potentially powerful tool for determining the effects of therapy and the tumor characteristics of those likely to respond. Predictive markers of therapeutic response need to be carefully distinguished from prognostic factors. For example, in untreated patients, expression of some poor prognosis markers, such as cyclooxygenase (COX)-2, may increase in response to therapy and serve as a valid target.For a marker to be predictive of response, a given drug has to have activity. In lung cancer, erlotinib and gefitinib showed activity in recent studies, but predictive markers of response have not yet been identified, although several leads have been reported. In terms of predictive markers, mitogen-activated protein kinase has potential and should be more carefully studied. It needs to be demonstrated that phospho-specific antibodies accurately detect phosphorylated receptor if there is a delay in processing the tissue specimen. More uniform methods of collecting and analyzing tissue for predictive markers should be developed before the validity of this and other markers can be confirmed. Another potential mechanism, PTEN loss and resultant phosphatidylinositol 3′-kinase/Akt pathway constitutive activation, may be important in mediating resistance to gefitinib. Given the redundancy of the pathways, it is likely that several markers, rather than one, may need to be elucidated.The participants were in agreement with regard to the current status of chemotherapy for metastatic NSCLC. All agreed that in metastatic disease, platinum-based combination chemotherapy provides a modest survival benefit compared with best supportive care. Two-drug regimens offer improved response and survival rates compared with one drug, whereas three-drug regimens do not improve survival in advanced NSCLC. Studies attempting to determine optimal therapy duration have found that prolonging treatment beyond three to four cycles increases toxicity with no increase in response or survival.During the 1990s, at least five “new” chemotherapeutic agents that had activity in lung cancer (paclitaxel, docetaxel, vinorelbine, gemcitabine, and irinotecan) have shown single-agent activity in advanced NSCLC. These agents are usually used in combination with a platinum compound, either cisplatin or carboplatin. Nonplatinum doublets have not been found to offer an advantage over platinum doublets, and decreased survival has been observed in two trials in the nonplatinum arms. In combination with a platinum agent, the newer agents appear to offer a slight improvement in outcome compared with older regimens. The randomized trials that have evaluated these modern platinum-based doublets have not shown that any specific combination is superior when survival is the primary measure of outcome. Some studies have suggested that cisplatin doublets are superior to carboplatin doublets, but such a difference has not been consistently observed. More research is needed to determine the optimal regimen for performance status 2 patients and for the elderly, a heterogeneous and understudied group of patients.Docetaxel remains the standard of care for second-line therapy for NSCLC. This agent has been shown to prolong survival compared with best supportive care. Recently, pemetrexed has been shown to have activity similar to that of and is with and of is also a to The participants felt that second-line treatment for advanced is an that is for potential therapeutic Both and pemetrexed are with which to novel may a prognosis in lung cancer, but there are many any effect is In lung cancer has been shown to and and tumor cell and are This is the for as an important target in lung cancer. Although was found to be expressed in over of the the level of expression did not with clinical response to tyrosine kinase in the studies of the trials, the tyrosine kinase gefitinib showed antitumor activity in and of patients with previously treated advanced NSCLC. Another of patients had disease as their best response. In both patients with disease and patients with response, improved. gefitinib has been for the treatment of advanced in the United States by the and and in The trials, failed to find a benefit in the for gefitinib added to standard chemotherapy regimens or These major negative findings raised questions regarding the preclinical models that had shown or effects of chemotherapy and response to gefitinib did not with in the trials a improvement in was observed in patients who on to an that, if may be useful in clinical patients with and were more likely to respond to gefitinib. treatment response and the of toxicity was reported in the studies, in contrast to the studies with erlotinib summarized Patients with appear to a distinct who have only limited response to chemotherapy but superior response rates to tyrosine kinase Studies of response in these patients may serve to identify predictive markers of efficacy for the agents in other patient is well and Phase II studies have suggested it may be an to in the second-line Phase III studies comparing gefitinib with in terms of survival and of are studies are to assess the possible role of gefitinib as therapy after chemotherapy for stage IV disease and after for stage III the with gefitinib, erlotinib demonstrated activity in the second-line setting, but trials showed no advantage to erlotinib in with standard chemotherapy. are issues in dosing with both erlotinib and gefitinib because they are given as a dose individual differences in In the second-line trials, response to erlotinib was correlated with the and of an that provides a for the dose in individual patients to a level that detectable large randomized Phase III trial of erlotinib as therapy best supportive care is and the results of this trial will be important in whether the tyrosine kinase can a meaningful in terms of survival improvement of lung cancer is a that in cell and expression of Preclinical studies potential and a number of chemotherapeutic agents, including cisplatin and In this synergy has been demonstrated clinically in cancer and and cancer. Positive results have been reported in combination with chemotherapy. An ongoing study is evaluating as monotherapy in patients with who have failed platinum-based chemotherapy. with the tyrosine kinase inhibitors, molecular mechanisms response to therapy are not well understood. Some that which a different mechanism of may be more effective than the tyrosine kinase when combined with chemotherapy. However, this is a preliminary that has not yet been confirmed by clinical is a against growth In a randomized Phase II trial in patients with advanced metastatic the addition of to standard chemotherapy the time to progression with a increase in response rate as well. Several Phase II trials in combination with chemotherapy or with a targeted agent, such as are A large randomized study comparing standard chemotherapy with standard chemotherapy is by the trials will issues of optimal and with chemotherapy and with other targeted therapies, as well as the of that have been the most issue in the lung cancer is an agent with antitumor activity demonstrated in a number of solid including NSCLC. with and has the and toxicity seen in early studies of pemetrexed, permitting more In single-agent activity has been demonstrated in the and second-line in Phase II trials. A randomized Phase III trial comparing pemetrexed with as second-line therapy in advanced has shown similar activity and has also shown activity in Phase II combination trials with platinum compounds and vinorelbine, and about the optimal of pemetrexed and gemcitabine, and a current Phase III trial is different dosing regimens of these two agents to this trials with other novel agents as are is a antisense designed to to its and protein is an protein implicated in the development of resistance to both chemotherapy and However, conference participants felt that the clinical significance of as a target has not been in lung cancer. expression to with poor prognosis in a number of but the data are and on this in NSCLC. Several participants also that there are issues with effects of antisense of small preliminary studies with are It is not clear whether is best used as a single agent, given the that other can for or in combination with other targeted agents. It is in combination with carboplatin and as therapy in small cell lung cancer and with as second-line therapy in or is a that in preclinical models cell and It has been by the United States and for use in patients with multiple A randomized Phase II study is evaluating with or without in second-line therapy of advanced NSCLC. is also a Phase II trial of single-agent as second-line therapy of advanced small cell lung cancer. Several ongoing combination Phase I trials are evaluating in combination with platinum-based chemotherapy. It is that may more to chemotherapy by However, there are issues with the use of and chemotherapy that study because preclinical data the of or with chemotherapy, on the two are or with pemetrexed, different cell lines have is a kinase that cell In preclinical studies, provides effects when after a whereas it is if given or to the Phase I trials have the effects of when with or with A randomized Phase II study of and is is regarding the optimal dosing for to the lack of pharmacodynamic end to confirm target The conference participants felt that although may not have the that it an optimal agent, this target remains a valid one for in lung cancer. more kinase are clinical trials, and the results are and are investigational designed to and cell and In preclinical studies, growth in small cell lung cancer and cell lines and in xenograft models. Phase II trials have evaluated and in advanced untreated and in small cell lung cancer. responses were reported in any of these trials, and the drugs had no single-agent activity, although the trial of in showed some of disease in a small minority of patients. The latter trial at least of activity in of the patients, that the drug was the effect in surrogate have shown activity in other and biomarkers identified in these tumors may allow identification of a lung cancer for combining the molecularly targeted agents with standard chemotherapy needs to be therapy may have rather than effects if the regimens selected are not on of the and mechanisms of action of both of agents. preclinical studies are needed to explore of molecularly targeted agents with the agents may in fact with the effects of chemotherapy if their effect is to cell trials with such as or A have had disappointing In primary with or to increase the of lung cancer in interest in for lung cancer has focused on the selective and is highly expressed in lung In expression of has been with decreased Some studies have reported a in lung cancer with use of or whereas other studies have failed to find a effect for It is what the optimal dosing is for the either as primary or in with chemotherapy. A trial of a is also expression is also in the of using the agents for One trial has been to test the tyrosine kinase gefitinib in the of of the and another trial the study design would the These two trials, the of Trials Lung Cancer, have been on of issues raised by the United States and Although these are both studies, the and for studies in these trials is also discussion of as a possible target for of current treatment trials with antisense with positive results and data. All such trials need to issues for a disappointing trial results seen with a number of the molecularly targeted have the of our current understanding of lung cancer biology. A more thorough of the multiple growth and of the of and of mechanisms is to targeted effective for more than small, of patients. More research needs to be at understanding mechanisms of tumor growth and resistance. developed mouse models will be important for this in addition to a more determined effort to obtain biopsies and to study available archival tissue using agents have if activity. are well and they are in the The primary research issue that needs to be addressed is determining the clinical or markers that predict which patients are likely to respond to these agents. is a general conference participants that tumor tissue studies at of response to should be given a priority to specific patient with a greater of response. Although to the group felt strongly that studies which correlated outcome to end had the ability to improve our understanding of lung cancer and, the treatment of patients with this at the Conference on Novel Agents in the Treatment of Lung Cancer, October 17–18, 2003, Cambridge, for of and of these were made possible by from and and were by

The duration of response to immune checkpoint inhibitors (ICIs) varies because of tumor immune heterogeneity, and employing programmed death receptor ligand 1 (PD-L1) expression to evaluate the efficacy of anti-programmed cell death-1 (PD-1)/PD-L1 antibodies remains controversial. A total of 138 advanced non-small cell lung cancer (NSCLC) patients were subdivided into 2 groups - 52 patients with a PD-L1 Expression≥50% and 86 patients with a PD-L1 Expression <50% - based on next-generation sequencing (NGS) to analyze multiple-dimensional data types, including tumor mutation burden (TMB), gene alterations, gene enrichment analysis, therapy response, and immune-related adverse events (irAEs). High levels of PD-L1 expression were significantly associated with advanced age and TMB status. The PD-L1≥50% cohort presented mutations of KRAS, NOTCH1, and FAT, while the PD-L1<50% group exhibited mutations of EGFR, PTEN, or LATS1/2. Except for the ascertained DNA damage response regulation. Even though there was no significant difference between PD-L1≥50% and PD-L1<50% cohorts on therapy response, patients with a PD-L1 Expression≥ 50% elicited a high irAEs incidence rate and increased plasma interleukin 6 (IL-6) concentration. This real-world retrospective study suggested that high expression of PD-L1 exhibited inappropriate activation of different pathways and collaborated with anti-cytokines and chemokines therapy may optimize clinical therapy efficacy.

Erlotinib-related skin toxicities: Treatment strategies in patients with metastatic non-small cell lung cancer

To evaluate the impact of histology on efficacy of pemetrexed in Chinese non-small cell lung cancer (NSCLC) patients. This report summarized the results of two clinical trials of pemetrexed in Chinese patients with advanced NSCLC in 2nd line setting and maintenance setting after 1st line (JMID study and Chinese subgroup from JMEN study) treatment. For the Chinese JMID study (second-line), Chinese patients with locally advanced or metastatic (stage IIIA, IIIB or IV) NSCLC who had prior chemotherapy were enrolled. The study was designed to investigate the noninferiority of pemetrexed (500 mg/m(2), day 1 of each 21-day cycle) to docetaxel (75 mg/m(2), day 1 of each 21-day cycle) in terms of overall survival (OS). For the global JMEN study (maintenance), patients initially diagnosed with IIIB or IV NSCLC, those who had not progressed after completing at least four cycles of platinum-based chemotherapy were enrolled to test for the superiority of pemetrexed (500 mg/m(2), day 1 of each 21-day cycle) over placebo with progression free survival (PFS) as primary endpoint. In JMID study, the OS was similar between the pemetrexed group (Pem group) and docetaxel group (Doc group). Retrospective histological subtype analysis showed survival benefits (both OS and PFS) numerically of non-squamous patients over squamous patients in the Pem group (OS: HR 0.74, 95% CI 0.45-1.21, P = 0.2267, median 11.7 vs. 9.7 months; PFS: HR 0.77, 95% CI 0.44-1.34, P = 0.3585, median 3.0 vs. 1.7 months). In the Chinese subgroup of JMEN study, the median PFS in the Pem group for squamous and nonsquamous patients was 4.2 and 1.5 months for squamous patients, the median OS in the Pem group for squamous and nonsquamous patients was 22.5 and 6.2 months for squamous patients. In JMEN China subgroup analysis, the HR on histology was not analyzed due to the small sample size. In terms of safety profile, drug-related grade 3 or 4 hematological toxicities (leukocytopenia and neutropenia) events occurring after second-line treatment were significantly lower in the Pem group than in the Doc group (both P < 0.001). Similarly in patients receiving pemetrexed maintenance after first-line treatment, incidences of toxicity events were low. Consistent with global results, in Chinese NSCLC patients, histology has an impact on the efficacy of pemetrexed, in which non-squamous histology predicts a positive outcome for patients treated with pemetrexed. In terms of overall safety, pemetrexed is better than docetaxel with a lower incidence of adverse events and anticipates manageable safety profile in NSCLC patients. Based on consistent Chinese data from the two studies, pemetrexed is recommended as a standard chemotherapy regime in both second-line and maintenance setting after first-line treatment for Chinese non-squamous NSCLC patients.

P1.04-61 Neutrophil-Lymphocyte Ratio: A Predictive Biomarker of Immunotherapy in Lung Cancer?