Novel Agents in the Treatment of Lung Cancer (2004)

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 for which the of at understood. In this clinical efficacy has not with of the target. there is no answer to this it is what the target of is is the in lung it to the population for such it is not it more to tumor and in a targeted agents are not the only drugs for which we need to improve our to predict response. combination therapy only a of patients with advanced chemotherapy and is a major goal as The of several and in the are in and to be a marker for to further the significance of should be to the that patients with low of will benefit from are potential predictive marker of response and to chemotherapy. is a powerful tool for determining the effects of therapy and the tumor characteristics of those likely to markers of therapeutic response need to be from For in patients, of poor such as may increase in response to therapy and serve as a a marker to be predictive of response, a given drug has to have In lung cancer, erlotinib and activity in recent studies, but predictive markers of response have not been several have been In of predictive protein kinase has potential and should be more It needs to be that receptor if there is a in the tissue of and tissue for predictive markers should be developed before the validity of this and other markers can be potential and may be in to the of the it is likely that several rather than may need to be participants were in with to the of chemotherapy for metastatic agreed that in metastatic combination chemotherapy a modest survival benefit compared with care. response and survival compared with whereas do not improve survival in advanced to determine optimal therapy duration have found that treatment to with no increase in response or the at least agents that had activity in lung cancer and have shown single-agent activity in advanced These agents are used in combination with a or have not been found to an over and survival has been in two trials in the In combination with a the newer agents to a in compared with regimens. The randomized trials that have evaluated these have not shown that combination is when survival is the primary of studies have that are to but such a has not been research is needed to determine the optimal regimen for patients and for the a and group of the standard of for therapy for This agent has been shown to survival compared with care. has been shown to have activity to that of and is with and of is also a to The participants felt that treatment for advanced is an that is for potential therapeutic Both and are with which to novel may a in lung cancer, but there are many effect is In lung cancer has been shown to and and tumor cell and are This is the for as an target in lung cancer. Although was found to be expressed in over of the the level of did not with clinical response to tyrosine kinase in the studies of the trials, the tyrosine kinase antitumor activity in and of patients with previously treated advanced of patients had disease as their response. In both patients with disease and patients with response, improved. 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 added to standard chemotherapy or These major negative findings raised regarding the preclinical models that had shown or effects of chemotherapy and response to did not with in the trials a in was in patients who on to an that, if may be useful in clinical patients with and were more likely to respond to treatment response and the of was reported in the studies, in contrast to the studies with erlotinib summarized Patients with to a distinct who have only limited response to chemotherapy but response to tyrosine kinase 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 it may be an to in the Phase III studies comparing with in of survival and of are studies are to assess the possible role of as therapy after chemotherapy for stage IV disease and after for stage III the with gefitinib, erlotinib activity in the setting, but trials no to erlotinib in with standard chemotherapy. are issues in dosing with both erlotinib and because they are given as a dose individual differences in In the trials, response to erlotinib was with the and of an that a for the dose in individual patients to a level that detectable large randomized Phase III trial of erlotinib as therapy is and the results of this trial will be in whether the tyrosine kinase can a meaningful in of survival of lung cancer is a that in cell and of Preclinical studies potential and a number of agents, including and In this synergy has been 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 chemotherapy. with the tyrosine kinase molecular mechanisms response to therapy are not well understood. that which a different of may be more effective than the tyrosine kinase when combined with chemotherapy. However, this is a preliminary that has not 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 Several Phase II trials in combination with chemotherapy or with a targeted 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 in a number of solid including with and has the and seen in early studies of pemetrexed, permitting more In single-agent activity has been in the and in Phase II trials. A randomized Phase III trial comparing with as therapy in advanced has shown activity and has also shown activity in Phase II combination trials with compounds and and about the optimal of and and a Phase III trial is different dosing 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 in the development of to both chemotherapy and However, conference participants felt that the clinical significance of as a target has not been in lung cancer. to with poor in a number of but the data are and on this in Several participants also that there are issues with effects of antisense of small preliminary studies with are It is not whether is used as a single given the that other can for or in combination with other targeted agents. It is in combination with and as therapy in small cell lung cancer and with as 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 therapy of advanced is also a Phase II trial of single-agent as therapy of advanced small cell lung cancer. Several ongoing combination Phase I trials are evaluating in combination with 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, 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 may not have the that it an optimal this target a 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 and in small cell lung cancer. responses were reported in of these trials, and the drugs had no single-agent activity, the trial of in of disease in a small of 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 selected are not on of the and mechanisms of 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 in for lung cancer has focused on the selective and is highly expressed in lung In of has been with 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 as primary or in with chemotherapy. A trial of a is also is also in the of using the agents for One trial has been to the tyrosine kinase in the of of the and trial the study design would the These two trials, the of 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 treatment trials with antisense with positive results and data. such trials need to issues for a disappointing trial results seen with a number of the molecularly targeted have the of our 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 research needs to be at understanding mechanisms of tumor growth and developed mouse models will be for this in addition to a more determined effort to obtain biopsies and to study available archival tissue using agents have if 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 patient with a greater of response. Although to the group felt strongly that studies which to end had the 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