The evolving role of targeted radioligand therapy in small cell and non-small cell lung cancer: a systematic review.

Commentary: Another win for immunotherapy

Chemotherapy and Survival in Non-Small Cell Lung Cancer: The Old Vexata Questio

PACIFIC: Time for a surgical IIIA uprising

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

Introduction Molecular and Cellular Biological Abnormalities in Lung Cancer and the Potential for Novel Therapeutics Ravi Salgia and Arthur T. Skarin Chemoprevention of Lung Cancer Fadlo R. Khuri, Lamya R. Tannous-Khuri, and Waun Ki Hong Radiologic Staging of Lung Cancer Kitt Shaffer Non-Small-Cell Lung Cancer Surgical Staging Raja M. Flores, Jose J. Norberto, Michael T. Jaklitsch, and David J. Sugarbaker Non-Small-Cell Lung Cancer Role of Video-Assisted Thoracic Surgery in the Diagnosis and Treatment of Non-Small-Cell Lung Cancer Steven J. Mentzer Non-Small-Cell Lung Cancer: Surgery for Stage I and II Disease Malcolm M. DeCamp, Jr. and Raja M. Flores Randomized Trials in Stage I and II Non-Small-Cell Lung Cancer Victoria J. Dorr and Michael C. Perry Superior Pulmonary Sulcus Tumors Harold C. Urschel, Jr. Surgery for Advanced Lung Cancer Raphael Bueno Multimodality Therapy for Stage IIIA and IIIB Non-Small-Cell Lung Cancer Gary M. Strauss and Elizabeth H. Baldini Multimodality Therapy of Stage IIIB Non-Small-Cell Lung Cancer Scott J. Swanson Chemotheraphy of Advanced Non-Small-Cell Lung Cancer Nam H. Dang, Roy S. Herbst, and Arthur T. Skarin Multimodality Therapy for Non-Small-Cell Cancer Metastases to the Brain Rodolfo Hakim, Eben Alexander III, Peter McL. Black, and Jay S. Loeffler Laboratory Models to Evaluate New Agents for the Systemic Treatment of Lung Cancer Beverly A. Teicher and Emil Frei III Small-Cell Lung Cancer Surgery for Small-Cell Lung Cancer Dean M. Donahue and Douglas J. Mathisen Role of Thoracic Radiation Therapy and Prophylactic Cranial Irradiation in the Management of Small-Cell Lung Cancer Parvesh Kumar Chemotherapy of Small-Cell Lung Cancer Anthony L. Boral and Thomas J. Lynch, Jr. High-Dose Therapy for Small-Cell Lung Cancer with Stem Cell Support Anthony D. Elias

Topotecan and Paclitaxel in Previously Treated Patients with Relapsed Small Cell Lung Cancer: Phase II Trial of the North Central Cancer Treatment Group

Objective To observe the clinical efficacy and adverse effects of combination chemotherapy with docetaxel com- bined cisplafin in the treatment of Ⅲ～Ⅳ stage non small - cell lung cancer (NSCLC). Methods Thirty - two patients with Ⅲ- Ⅳ stage NSCLC were enrolled into this study and given treatment of docetaxel combined eisplatin 35 mg/m2 of docctaxel was injec- ted within one hour in the first and eighth day combined with injection of 25 mg/m2 cisplatin in first 3 days. 3 mg of granisetron were injected to prevent vomiting before combination chemotherapy. At least 2 courses were conducted with an interval of 28 days. Imageological examination was done and the diameters of tumor were measured to evaluate the effect of treatment and adverse effects. Results The total responsive rate was 40.63% (13/32), 2 of which were cure recovery(CR) and 11 were partial recovery (PR). Responsive rate was 45.80% (11/24) in patients with Ⅲ stage NSCLC and 25.00% (2/8) in patients with Ⅳ stage NSCLG respectively. The median survival time was 7.5 months. The one year survive rate was 65.63%. The main adverse effect was bone marrow depression. Conclusion Combination chemotherapy with docetaxel combined cisplatin in the treatment of Ⅲ- Ⅳ stage NSCLC has good clinical efficacy, light adverse effects and better tolerance, may be an effective and safe treatment for NSCLC. Key words: Docetaxel; Cisplatin; Combination chemotherapy; Non small -cell lung cancer

Phase II trial with ISIS 5132 in patients with small-cell (SCLC) and non-small cell (NSCLC) lung cancer. A European Organization for Research and Treatment of Cancer (EORTC) Early Clinical Studies Group report

Historical reservations regarding stereotactic radiosurgery (SRS) for small-cell lung cancer (SCLC) brain metastases include concerns for short-interval and diffuse central nervous system (CNS) progression, poor prognoses, and increased neurological mortality specific to SCLC histology. We compared SRS outcomes for SCLC and non-small cell lung cancer (NSCLC) where SRS is well established. Multicenter first-line SRS outcomes for SCLC and NSCLC from 2000 to 2022 were retrospectively collected (n = 892 SCLC, n = 4785 NSCLC). Data from the prospective Japanese Leksell Gamma Knife Society (JLGK0901) clinical trial of first-line SRS were analyzed as a comparison cohort (n = 98 SCLC, n = 814 NSCLC). Overall survival (OS) and CNS progression were analyzed using Cox proportional hazard and Fine-Gray models, respectively, with multivariable adjustment for cofactors including age, sex, performance status, year, extracranial disease status, and brain metastasis number and volume. Mutation-stratified analyses were performed in propensity score-matched retrospective cohorts of epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) positive NSCLC, mutation-negative NSCLC, and SCLC. OS was superior for patients with NSCLC compared to SCLC in the retrospective dataset (median OS = 10.5 vs 8.6 months; P < .001) and in the JLGK0901 dataset. Hazard estimates for first CNS progression favoring NSCLC were similar in both datasets but reached statistical significance in the retrospective dataset only (multivariable hazard ratio = 0.82, 95% confidence interval = 0.73 to 0.92, P = .001). In the propensity score-matched cohorts, there were continued OS advantages for NSCLC patients (median OS = 23.7 [EGFR and ALK positive NSCLC] vs 13.6 [mutation-negative NSCLC] vs 10.4 months [SCLC], pairwise P values < 0.001), but no statistically significant differences in CNS progression were observed in the matched cohorts. Neurological mortality and number of lesions at CNS progression were similar for NSCLC and SCLC patients. Leptomeningeal progression was increased in patients with NSCLC compared to SCLC in the retrospective dataset only (multivariable hazard ratio = 1.61, 95% confidence interval = 1.14 to 2.26, P = .007). After SRS, SCLC histology was associated with shorter OS compared to NSCLC. CNS progression occurred earlier in SCLC patients overall but was similar in patients matched on baseline factors. SCLC was not associated with increased neurological mortality, number of lesions at CNS progression, or leptomeningeal progression compared to NSCLC. These findings may better inform clinical expectations and individualized decision making regarding SRS for SCLC patients.

Systematic Review of Neoadjuvant Immunotherapy for Patients With Non–Small Cell Lung Cancer

Lung Cancer in Germany

PL05.03: Radio-Oncology

Background: Small cell lung cancer (SCLC) is a highly lethal malignancy characterized by rapid growth, early metastasis and poor prognosis. SCLC shows distinct molecular and clinical features when compared to other lung cancer subtypes. Previous analyses by us and others have identified genomic and proteomic differences between SCLC and Non-Small Cell Lung Cancer (NSCLC). Epigenetic alterations are some of the earliest events that could also lead to oncogenic changes and thus play an essential role in tumor initiation and progression. However, epigenetic differences between SCLC and NSCLC contributing to the alterations in gene and protein expression patterns, distinct biological features and therapeutic response have not been well characterized. Here, we investigate the differences in the methylation patterns of SCLC and NSCLC to provide novel insights into epigenetic associated gene alterations to identify potential therapeutic targets in SCLC. Material and Methods: A genome-wide DNA methylation profiling of SCLC and NSCLC cell lines was used for this investigation. We correlated DNA methylation status with gene expression and protein expression levels in 31 SCLC and 73 NSCLC lines to identify the relationship of epigenetic with genomic and proteomic features distinguishing SCLC from NSCLC. Results: SCLC and NSCLC lines exhibited different methylation profiles and we identified 484 genes that had a significant inverse correlation between methylation status and mRNA expression levels (Rho ≤ -0.5 and FDR = 0.01), (“genes regulated by methylation,” GRM) that distinguished SCLC from NSCLC. Ingenuity pathway analysis of the 484 genes identified significant associations with neuregulin signaling, immune trafficking, integrin signaling, glioma invasiveness canonical pathways. Proteomic profiling by Reverse Phase Protein Array (RPPA) validated the different expression of some of the 484 genes identifying nine that were hypermethylated and downregulated at protein levels in SCLC compared to NSCLC lines (PTEN, CyclinD1, Caveolin, Notch3, TAZ, HSP27, STAT6 and both total and phosphorylated levels of receptor tyrosine kinases such Her2 and, MET). Conclusions: Genome wide methylation, mRNA expression, and detailed proteomic analyses have identified specific epigenic differences between SCLC and NSCLC that impact on important signaling pathways including widespread loss of PTEN function and receptor tyrosine kinase (RTK) expression in SCLCs which need to be considered in developing new rationale therapies for SCLC. Citation Format: Seema Mukherjee, Bonnie S. Glisson, John D. Minna, Robert J. Cardnell, Luc Girard, Adi Gazdar, Lixia Diao, Jing Wang, Lauren A. Byers. Characterization of methylation profiles reveals distinct epigenomic patterns in SCLC and NSCLC. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2961. doi:10.1158/1538-7445.AM2015-2961

Sec62 Bridges the Gap from 3q Amplification to Molecular Cell Biology in Non–Small Cell Lung Cancer

Lung cancer is the leading cause of cancer-related deaths in industrialized countries and non small cell lung cancer (NSCLC) accounts for 85% of all lung cancers. Cisplatin doublet based chemotherapy, which is the recommended regimen in first line therapy in advanced or metastatic NSCLC, improves survival but in low proportion. Monoclonal antibodies (mAbs) are a novel promising therapeutic class used with great results in inflammatory diseases such as rheumatoid arthritis. Antibodies are natural proteins with modular structure, specific pharmacodynamics and pharmacokinetics and possibly produced against any antigens, thus giving them several advantages over small drug therapeutics. In solid tumors, therapeutic mAbs improved progression free survival (PFS) and overall survival (OS) of patients with breast and colon cancers and had considerably changed the treatment in clinical practice. In NSCLC, bevacizumab, an anti-VEGF mAb, and cetuximab, an anti-EGFR mAb, are the most studied antibodies. Bevacizumab acts on angiognenesis and improved PFS of non squamous NSCLC but in low proportion as shown in two large phase III trials. It was approved by European Medicines Agency (EMEA) and Food and Drug administration (FDA) as a first line therapy in combination with cisplatin doublet chemotherapy. Cetuximab slightly enhanced OS but did not improve PFS in two large phase III trials. These results added to high adverse effect lead to cetuximab refusal by EMEA and FDA in NSCLC. At first glance, the results of mAbs in NSCLC are somewhat disappointing, in contrast to the benefits obtained with mAb treatments in other solid tumors. However, many other mAbs directed against novel targets, such as IGF1-R or CTLA-4, and new mAbs targeting VEGFR and EGFR pathways with different pharmacodymamical and pharmacokinetic properties are under evaluation and may change our vision of taking care of patients with NSCLC. In conclusion, it seems that mAbs therapy in NSCLC clearly marks the start of a new era in NSCLC treatment, with promises in improving patient survival and quality of life.