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TPS8589 Background: Increased expression of BCL-2, BCL-xL, and MCL-1 allows certain tumors to evade apoptosis. Pelcitoclax is a novel, dual BCL-2/BCL-xL inhibitor with strong single-agent antitumor activity against tumor cells addicted to BCL-2, BCL-xL, and BCL-w, and exhibits even broader antitumor activity when administered with chemotherapy. Pelcitoclax reduces tumor growth in SCLC and other human cancer xenograft models, with manageable effects on platelet counts. Preliminary findings from the first-in-human study suggested promising antitumor activity and a favorable safety profile. Methods: This open-label study is evaluating the safety and preliminary efficacy of pelcitoclax combined with paclitaxel in adults with R/R SCLC that has progressed on or after initial treatment. Prior treatments may include platinum-based therapy (± thoracic radiation), immunotherapy, or chemotherapeutic agents other than paclitaxel. Eligible patients have an ECOG performance status of 0-2; adequate organ function; no known bleeding diathesis, immune thrombocytopenic purpura, autoimmune hemolytic anemia, serious gastrointestinal bleeding, or concomitant use of most anticoagulants; and no residual grade ≥ 2 adverse events from previous treatment. In the phase Ib study, the pelcitoclax maximum tolerated dose is being determined using a time-to-event continual reassessment method. In this phase, pelcitoclax is administered by IV infusion over 30 minutes on Days 1, 8, and 15 at dose levels of 80, 160, and 240 mg per week, with fixed-dose paclitaxel 80 mg/m2 on Days 1 and 8 of a 21-day cycle. In addition to a baseline scan within 4 weeks before study entry, computed tomography will be performed every two cycles to evaluate antitumor response. Treatment will continue until disease progression, unacceptable toxicity, consent withdrawal, or administrative discontinuation. The primary endpoint of this phase includes dose-limiting toxicity by NCI CTCAE v5.0 over 21 days. After determination of the recommended phase II dose of pelcitoclax in the phase Ib study, the efficacy of pelcitoclax with paclitaxel will be determined in the phase II study using a Simon two-stage design, with overall response rate as the primary endpoint. Other study endpoints in the phase II study include pharmacokinetics of pelcitoclax with paclitaxel, as well as progression-free and overall survival. As of February 8, 2021, 15 of 58 patients had been enrolled. Internal study identifier APG1252SU101. Clinical trial information: NCT04210037.

9089 Background: RET fusions are targetable oncogenic drivers in 1–2% of non-small cell lung cancer (NSCLC). ARROW (NCT03037385) supported the US FDA approval of pralsetinib, a highly potent oral selective RET inhibitor for RET-altered NSCLC and thyroid cancer. Here, we present updated results for a larger population of patients with RET fusion–positive NSCLC enrolled in ARROW. Methods: ARROW is a phase 1/2 open-label study conducted at 84 sites in 13 countries. Phase 2 expansion cohorts included patients with RET fusion–positive NSCLC. Initially, all treatment-naïve patients were not candidates for platinum-based therapy, a requirement removed by protocol amendment in July 2019. Primary objectives are overall response rate (ORR; blinded independent central review [BICR] per RECIST v1.1), assessed for patients with baseline measurable disease, and safety. Results: Updated analyses were completed as of Nov 6, 2020 (data cut-off), for patients who initiated pralsetinib 400 mg QD by May 22, 2020 (enrollment cut-off). Efficacy results, including analyses for treatment-naïve patients enrolled after eligibility criteria were revised to allow candidates for platinum-based therapy, are shown in the Table. Conclusions: Pralsetinib showed rapid, potent, and durable clinical activity in patients with RET fusion-positive NSCLC (regardless of prior therapies), including poor prognosis patients not eligible for platinum-based therapy. Overall, pralsetinib was well-tolerated. These data highlight the need for RET testing early in the course of disease to identify candidates who may benefit from treatment with pralsetinib. Clinical trial information: NCT03037385. [Table: see text]

9001 Background: Pembro monotherapy showed durable antitumor activity as third-line or later therapy for metastatic SCLC, leading to FDA approval in that setting. KEYNOTE-604 was a double-blind, phase 3 study of pembro + EP vs placebo + EP as first-line therapy for ES-SCLC (NCT03066778). Methods: Eligible patients (pts) with previously untreated ES-SCLC and no untreated CNS metastases were randomized 1:1 to pembro 200 mg Q3W or saline placebo for up to 35 cycles plus 4 cycles of standard-dose EP. Pts with CR or PR after cycle 4 could receive PCI at investigator discretion. Randomization was stratified by platinum choice (carboplatin vs cisplatin), ECOG PS (0 vs 1), and LDH (≤ULN vs > ULN). Primary endpoints were OS and PFS (RECIST v1.1, blinded central review) in the ITT population. ORR, DOR, and safety were secondary endpoints. OS and PFS treatment differences were assessed by the stratified log-rank test. The protocol specified 2 interim analyses (IAs) and a final analysis (FA). Prespecified efficacy boundaries were one-sided P = 0.0048 for PFS at IA2 (prespecified final PFS analysis) and 0.0128 for OS at FA. Results: 453 pts were randomized. 223/228 pts assigned to pembro + EP and 222/225 assigned to placebo + EP received ≥1 dose of assigned treatment; 1 pt assigned to pembro + EP received placebo + EP in error. Median age was 65 y, 74% had ECOG PS 1, and 57% had LDH > ULN; more pts in the pembro + EP arm had baseline brain metastases (14% vs 10%). At FA (median follow-up, 21.6 mo), 9% of pts in the pembro + EP arm and 1% in the placebo + EP arm remained on study treatment; 12% and 14% received PCI. At IA2 (median follow-up, 13.5 mo), pembro + EP significantly improved PFS in the ITT population (HR 0.75 [95% CI 0.61-0.91], P = 0.0023; median 4.5 vs 4.3 mo). At FA, pembro + EP prolonged OS in the ITT population, but the significance threshold was not met (HR 0.80 [95% CI 0.64-0.98], P = 0.0164; median 10.8 vs 9.7 mo). In a post hoc analysis of OS in the as-treated population, the nominal P value was smaller than the significance threshold (HR 0.78 [95% CI 0.63-0.97], P = 0.0124). ORR at FA was 71% for pembro + EP vs 62% for placebo + EP; median DOR was 4.2 vs 3.7 mo. Observed AEs were as expected; any-cause AEs were grade 3-4 in 77% vs 75%, grade 5 in 6% vs 5%, and led to discontinuation in 15% vs 6%. Conclusions: Pembro + EP significantly improved PFS and prolonged OS compared with placebo + EP as first-line therapy for pts with ES-SCLC. No unexpected toxicities were seen with pembro + EP. These data support the benefit of pembro-containing regimens for ES-SCLC. Clinical trial information: NCT03066778.

e20061 Background: Malignant pleural mesothelioma (MPM) is a disease that is resistant to chemotherapy and there remains an unmet need for better therapeutic options. Nintedanib (BIBF 1120) is an oral multikinase inhibitor impacting VEGFR, FGFR, PDGFR, and other kinase activity such as TGFß signaling pathways. VEGF, FGF, and TGFβ are commonly expressed in MPM. We conducted a phase II trial in patients with recurrent MPM after platinum-based chemotherapy. Methods: Patients (pts) with MPM previously treated with platinum-based chemotherapy, performance status (PS) 0-1, adequate organ function, and no contraindications to anti-angiogenic therapy were eligible for treatment. Nintedanib 200 mg twice per day was administered until disease progression or unacceptable toxicity. The primary endpoint was the 4-month progression-free survival (PFS). A two-stage design was used and > 4 pts had to have a PFS of ≥4 months to proceed to the second stage. Results: Twenty pts. were enrolled. The median age was 70 yrs. (32-81), 90% were male, and 80% were PS = 1. The histology was 70% epithelioidal, 5% sarcomatoid, 10% biphasic, and 15% unknown. 15% had prior bevacizumab. The median follow-up is 16.4 mo. A median of 2 treatment cycles (range 1-18) were delivered. There were no responses but 40% had stable disease. The median PFS was 1.8 mo. (95% CI: 1.68, 3.55) and the PFS rate at 4 mo. was 13%. The median OS was 4.2 mo. (95% CI: 2.53, 8.74) and the OS rate at 4 mo. was 55%. Toxicities were usually grade 1-2 and included diarrhea, fatigue, edema, transaminase elevation, anorexia, nausea, vomiting and dyspnea. Conclusions: The activity of nintedanib in previously treated MPM pts. was modest. The trial did not meet the primary PFS endpoint. However, there was a small subset of pts. that had prolonged stable disease for > 4 months thus potentially deriving some clinical benefit from treatment. Supported by Boehringer Ingelheim. Clinical trial information: NCT02568449.

e21175Background: Three immunotherapy agents are currently FDA-approved for the treatment of NSCLC after platinum-based chemotherapy. These agents have demonstrated superior outcomes and tolerabili...

e20607 Background: The PD-1 inhibitors nivolumab and pembrolizumab are approved for the treatment of advanced non-small cell lung cancer (NSCLC), but little is known about patterns of disease progression when these agents fail. Understanding patterns of failure is key to developing strategies to improve duration of response to these agents. Methods: We gathered clinical and radiographic data on patients treated at the University of Michigan and the Ann Arbor VA for advanced NSCLC with standard-dose nivolumab (n = 68) or pembrolizumab (n = 23) after progression on platinum-based chemotherapy. Sites of disease progression were described as local (within the same lobe as primary disease), nodal (thoracic), or distant. Results: 91 patients were evaluable, of whom 56 (61.5%) had progression of disease after an average duration of therapy of 3.2 months (95%CI, 2.6-3.8). 10 (17.9%) patients had progression at local sites alone, 3 (5.4%) at nodal sites alone, 12 (21.4%) at distant sites alone, and 31 (55.4%) at a combination of sites. Overall, 41 (73.2%) had progression at distant sites. There was no statistically significant difference in clinical factors ( i.e. age, histology, comorbidity index) between progressors vs. non-progressors or distant-progressors vs. non-distant progressors. Of 37 patients who had prior radiation, 17 (45.9%) had progression at an irradiated site, with patients who had local and/or nodal progression more likely to have received radiation at site of progression (p = 0.01). The most common distant sites of progression were liver (13), bone (10), and brain (9). Conclusions: The most common site of disease progression was distant, with the liver being the most commonly involved site. This may be due to the immunotolerogenic environment of the liver, which is characterized by high IL-10 concentration and propagation of suppressive regulatory T cells, which can dampen activation of cytotoxic T cells. Prior irradiation did not seem to prevent disease progression. Our preliminary analysis suggests that the efficacy of checkpoint inhibitors is hindered in immune-privileged sites. Strategies to overcome immune tolerance should be investigated to improve duration of response to these agents.

8504 Background: The median progression free survival (PFS) and overall survival (OS) following initial chemotherapy in ES-SCLC pts are 2 and 7 months, respectively (Ready N, J Clin Oncol 2015). We evaluated the benefits of maintenance pembro in ES-SCLC pts who had response/stable disease after 4-6 cycles of platinum/etoposide. Methods: Pts were required to begin pembro within 8 weeks of completion of chemotherapy, with restaging scans no more than 3 weeks prior to start of pembro. Prophylactic cranial radiation was permitted. Pts were treated with pembro 200 mg I.V. every 3 weeks for a maximum of 2 years. Disease assessment was done every 2 cycles for the first 6 cycles and then as per investigator discretion. Primary end point of the study was PFS. PFS according to immune related response criteria (irPFS) and OS were also assessed. Tumor tissue was analyzed for PD-L1 expression by the DAKO 22C3 antibody. Any level of expression was considered as positive for PDL1. Blood for circulating tumor cells (CTCs) was collected prior to first, second and third cycle of pembro. Results: Of the 45 pts enrolled, 55% were males and 22% had brain metastases. Median age was 66 years. The median time from end of chemotherapy to start of pembro was 5 weeks. Median number of pembro cycles was 4 (1-20 cycles). 35 pts had measurable disease at study entry. The disease control rate with pembro was 42% (1 CR, 3 PR, 15 SD). At a median follow up of 6 months, the median PFS was 1.4 months (90% CI-1.3-4.0) and the irPFS was 4.7 months (90% CI- 1.8-6.7). The median OS was 9.2 months (90% CI-6.1-15.2). 11 pts are still on therapy (3-20 cycles). The median CTC prior to pembro was 1 (0-256, n=37 pts). Each unit increase in baseline CTC correlated with worse PFS (p = 0.052; adjusted for brain mets, age and sex). PDL1 could be assessed in 35 pts and was positive in 1 pt. Most common adverse events were fatigue, nausea, cough and dyspnea. One pt developed atrio-ventricular conduction block and 1 pt type 1 diabetes. Conclusions: Maintenance pembro did not improve PFS in these patients but favorable OS suggests that some SCLC patients can benefit from maintenance pembro. Biomarkers to identify patients most likely to benefit from pembro need to be defined. Clinical trial information: NCT02359019.

PURPOSE A large community-based cancer registry was analyzed to determine if the clinicopathologic characteristics and/or survival rates of lung cancer patients under 50 years of age at diagnosis differ from those of patients 50 years of age or greater at diagnosis. PATIENTS AND METHODS Data regarding demographics, stage, histology, initial therapy, and survival were obtained on all patients with primary bronchogenic carcinoma registered in the metropolitan Detroit Surveillance, Epidemiology and End Results (SEER) registry from 1973 to 1992. RESULTS Of 31,266 patients, 9.0% were under 50 years of age at diagnosis. Females (40.1% v 31.2%; P < .001) and blacks (28.7% v 21.9%, P < .001) were overrepresented in the younger group compared with the older group. Younger patients had a significantly higher incidence of adenocarcinoma and were less likely to present with local-stage disease (18.6% v 25.2%; P < .001). Younger patients were significantly more likely to undergo surgery and/or combined-modality therapy. Relative survival at 5 years was significantly better in the younger group (16.1% v 13.4%; P < .001), mainly because of better survival in patients with local-stage disease (48.7% v 35.4%; P < .001). In a multivariate analysis, advanced-stage, nonsurgical initial therapy, age 50 years or greater at diagnosis, and male gender were independent negative prognostic factors. CONCLUSION The overrepresentation of females and blacks in the group of younger patients with lung cancer suggests an increased susceptibility to lung carcinogens in these populations. Overall, this study suggests that lung cancer is not a more aggressive disease in younger patients and that all patients with lung cancer should be managed along the same therapeutic guidelines.

9017Background: Immune checkpoint inhibitor (ICPI) therapies, including nivolumab and pembrolizumab, have been FDA-approved in squamous and non-squamous non-small cell (LC). Current IHC based diagnostics are challenged by assay and slide scoring issues, and more robust and comprehensive biomarkers of ICPI efficacy are needed. Methods: Comprehensive genomic profiling (CGP) was performed on FFPE specimens during the course of clinical care. TMB (mutations/Mb) was assessed as the number of somatic, coding, base substitution and indel alterations per Mb of genome. The top quartile of LC was classified as TMB high. Microsatellite instable (MSI-H) or stable (MSS) status was determined using a proprietary computational algorithm. Results: TMB was similar across all LC histologies, but elevated compared to an average TMB of 7.3 for all 60,000+ samples in the database. TMB was consistently low in LC harboring known drivers, with the exception of BRAF or KRAS mutant tumors. (See Table.) 22/5,895 LC cases (0.4%) ass...

In the essay, “Horns of a Dilemma,” Samuel and Subbannan discuss a challenge many of our patients face when confronted with therapeutic options, particularly when none of the available options offer the chance for cure. This is a common situation in the practice of oncology, and one that is becoming more frequent as we develop a broader array of therapeutic options for many malignancies. As occurred in the vignette presented in the essay, the physician’s own discomfort in making a recommendation regarding additional care can exacerbate the dilemma by placing too much of the decision-making burden on a patient who may not be emotionally or psychologically capable of making such choices. Even in our current era of patient autonomy, it is unfair to place the entire burden of decision making on the patient. After presenting the reasonable and acceptable management options, in patients who do not seem to be comfortable making a decision, the physician should make a clear recommendation and share it in a manner that allows the patient to either agree with the decision or gracefully chose an alternative option. Frequently, the physician’s recommendation will serve as a catalyst that clarifies the patient’s own desires and moves the clinical plan forward. Before making a recommendation, physicians need to ensure that their patients understand the goals of care and the potential benefits and risks of each management option. This applies to both the treatment options and the no-treatment option. For example, in a situation like the one in the essay, the physician can unambiguously state that cure is not a realistic goal and that the proposed therapeutic options are usually of limited benefit. Physicians should also acknowledge that there is always some degree of uncertainty in medical prognostication, and that this uncertainty can complicate therapeutic decision making. They should then provide relatively specific information regarding the potential benefits and risks of each clinical option. The benefits should be discussed in terms that the patient can understand, such as probabilities for tumor shrinkage or control, or potential increases in 1-year survival rates. If a particular treatment could prolong survival time, the physician should provide an estimate of whether this prolongation of survival is usually measured in days, weeks, months, or years. Realistic information on the potential risks of additional therapy should also be discussed, taking into account the individual patient’s prior experiences and current performance status. The provision of all of this information will frequently help patients determine their level of interest in pursuing additional therapy. If, however, a patient remains reluctant to voice an opinion regarding his or her care, the physician can offer additional guidance by relating that, given this information, some patients would choose to receive chemotherapy, whereas others would not. The patient should be assured that there is no right answer for all patients in the current situation. It can be helpful to provide a continuum story to illustrate the range in how patients think about therapeutic options. The two ends of the continuum can be illustrated by noting that some patients will opt for supportive care with statements such as, “I’m tired of shots and medicines unless they are really, really good,” whereas others will want additional treatment regardless of high risks and marginal benefits, stating, “I need keep fighting, to be as aggressive as possible.” Patients can then sort through their own feelings toward additional therapy by determining where they fall on this continuum, allowing them to make a decision with which they are comfortable. Importantly, the physician should then fully support whichever decision the patient makes, while also acknowledging that all medical care is dynamic and that the patient has the option of changing their decision in the future. Despite this exercise, some patients will still be unable to make a decision. Given this situation, it may be best for the physician to relieve the burden of decision making from the patient by making a firm recommendation as to the course of additional care. To some, this will seem excessively paternalistic—a throwback to the role played by physicians several decades ago when they routinely made management decisions with minimal patient input. However, it is a role which physicians must be willing to accept. We are still the medical professionals in the relationship, the ones with the training and expertise to sort JOURNAL OF CLINICAL ONCOLOGY T H E A R T O F O N C O L O G Y: When the Tumor Is Not the Target VOLUME 26 NUMBER 13 MAY 1 2008

The clinical vignette presented by Dr Robert J. Weil will likely evoke widely disparate reactions from readers. Some will laud him for listening to his patient, Cheryl, and helping her achieve her limited goals, whereas others will believe his decision to operate demonstrated rather questionable clinical judgment. As physicians, our primary duty is to do what we think is best for each patient based on our professional experience and the available evidence in the medical literature. In doing so, we must keep in mind that statistics and medical evidence do not necessarily apply to any single patient and that there is substantial medical uncertainty regarding individual outcomes. Weighing potential risks versus potential benefits is rarely as objective as we might wish. For these reasons, one might argue that guidelines are never enough to direct appropriate care. In clinical oncology, many management decisions are based largely on clinical judgment because of the lack of specific, high-quality evidence. It is primarily for this reason that the most widely used guidelines, those published by the National Comprehensive Cancer Network (Jenkintown, PA), are not truly evidence based, but are “a statement of consensus” of experts in the field. In light of this, Dr Weil’s statement that surgery is “not indicated” for patients like Cheryl may not be as absolute as it sounds. Yes, the literature and guidelines primarily recommend radiotherapy for patients with one to three brain metastases and extracranial disseminated disease with poor systemic treatment options. However, some experts do maintain that surgery is an option for symptom palliation in patients with significant neurologic dysfunction. Given that the care of each patient must be individualized, it may be useful to explore the whys and why nots of this particular situation and how they might apply to the broader context of oncologic care near the end of life. Why? Dr Weil never addresses his personal rationale for proceeding with surgery. It is tempting to accuse him of acting on emotion rather than sound medical principles, particularly in light of the relative youth of his patient. However, on further assessment, his decision can be supported by rational oncologic reasoning. The primary goals of care for patients with incurable diseases are to optimize quality and quantity of life. In Cheryl’s case, nothing was going to prolong her life, and the neurologic sequelae of her brain metastases were severely impairing her quality of life. Corticosteroids resulted in only mild improvement, and radiotherapy was unlikely to do much more within the time frame of her expected survival. Surgical resection of the brain lesions represented the best, and perhaps only, chance to significantly improve her quality of life in a timely manner. Everyone, including Cheryl and her husband, knew that she was going to die soon. This was not a case of delusional denial and unrealistic expectations. The limited goal of treatment was clear to all. But does the potential benefit outweigh the potential risk? We tend to ask this question only in the context of medical interventions, but it needs to be applied to all options being considered, including nonintervention. Brain surgery obviously carries risk, but modern neurosurgical techniques have remarkably decreased these risks over the past 20 years. Cheryl’s rapid recovery was not an anomaly. In this situation, the risk of surgery may be acceptable when considered against the risk of nonintervention, that she would remain in her debilitated state, unable to enjoy her remaining time with her family. As the risk of intervention improves, the concept of aggressive palliative care becomes more appealing and rational, particularly for those in whom quality of life is severely impaired by a potentially reversible and localizable lesion. Why not? Dr Weil ends his vignette with a thought, initially introduced by his patient, that must have resonated deeply within him. It is a thought we have all fallen back on at times to justify our clinical decisions to ourselves or to others: Why not? Frequently, this question is asked in a rhetorical manner, with no expectation of contrary response. Yet, there are many valid answers to this question, both in regard to this individual case and in the greater context of our health care system. Dr Weil himself raised many of the reasons not to operate during his initial discussion with Cheryl: progressive systemic disease, the lack of supportive evidence, the From the Division of Hematology/Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI.

In her essay, Dr Hartmann artfully captures the essence of one of the more frustrating aspects of medical oncology practice. Interactions with patients and families who harbor deep-seated, unrealistic expectations can not only leave the oncologist physically and mentally drained, but can also lead us to question our ability to manage and comfort patients with advanced, incurable malignancies. As was the case with “Louie,” such patients tend to gravitate to academic centers, where we are always expected to have some new promising therapy to offer, even for the most debilitated patients with faradvanced, refractory disease. Frequently, in such situations, the correct thing to do is to reassure the patient and family that they have received appropriate care and that further anticancer therapy would not be beneficial, while offering additional measures aimed at maximizing comfort and optimizing the delivery of palliative support. The distinction between “expectations” and “hopes” can sometimes be blurred during clinical interactions with our patients. The oncologist’s conversations with Louie’s wife suggest that she may actually have realistic expectations (eg, the discussion of the will and of death), but continues to hold out hope for a miracle (eg, the prayer request). Who can blame her for that? Wouldn’t we all wish for the same thing in her situation? However, problems arise when hopes become expectations. In this situation, focus can subtly shift from taking care of the patient to taking care of the cancer, leading to the overwhelming pursuit of futile and potentially toxic therapy that negatively impacts the quality of life of both patients and their families. When I started my Fellowship, there was a sign on one of the solid tumor wards that read, “Expect Miracles.” Initially, I was vaguely uncomfortable with the message conveyed by the sign, but as I became further and further immersed in the reality of patients with advanced cancer, I grew to absolutely hate it. I felt that it bred unrealistic expectations and false hopes. It can be personally encouraging to hope for miracles, but it is a whole different matter to expect them; we, as oncologists, don’t perform them. Twenty years ago when I began caring for patients with advanced cancer, I sensed a much greater degree of fatalism from them, as well as satisfaction, or at least comfort, with their oncologic care. Only a few seemed to be unrealistic, and it appeared that the primary goal of many patients was to avoid abandonment and suffering. Now, the general tone of patients in our clinics is often very different; many seem to want more than what we can offer and are convinced that something better is out there, somewhere. A major cause of this feeling may be the unreasonable hype generated by the media, the Internet, the drug industry, and many of our academic colleagues about the relatively modest advances that have been made in clinical oncology. Patients and their families are constantly hearing about “breakthroughs” in the war on cancer, and become dissatisfied with the care that they are receiving, especially when their own personal cancer seems to be winning. On the societal level, this is not necessarily a bad thing. It would be foolish to think that the current state of oncologic care is adequate, and, frequently, it is dissatisfaction with the status quo that drives From the Department of Internal Medicine, University of Michigan, Ann Arbor, MI.

The argument made by Helft in favor of “necessary collusion” in the discussion of prognosis between patients with cancer and their oncologists is predicated on the presumption that the primary goal of oncologic care is to maintain hope. If this were the case, then it would be difficult to argue against such an approach. However, the primary goal of oncologic service is to care for patients with cancer in a comprehensive manner, with appropriate attention paid to their physical, psychological, and practical needs. Helping patients maintain hope is but one part of this, not the core principle. In order for patients to make rational decisions regarding their treatment, they need to understand the nature of their illness, particularly with regard to how the disease will affect their lives. A clear discussion of the goals of treatment, which inherently must touch on prognosis, is a key factor in this equation. The most important aspect of prognosis that patients must understand to participate in medical decision-making is whether or not the practical goal of treatment is cure. If not, then patients need to be told up front that their disease is not considered curable with currently available therapy. Of course, as noted by Helft, there is the major issue of medical uncertainty, and in light of this reality, a good rule of thumb is to “never say never, never say always.” Along these lines, it is medically dishonest to give someone a quantitative prognosis when they are initially diagnosed with cancer, as it is impossible for us to know how long any one individual will live. Median survival is not meaningful to the individual patient, whereas an honest statement of interval survival (eg, “X percent of people live longer than 1 year and X percent live longer than 2 years”) can provide them with a clear notion of the seriousness of their disease, while also affording them the hope of open-endedness. As pointed out by Groopman, we can all relate stories of our rare outliers who have proven the textbooks wrong. While it may be appropriate to share such optimistic tales with patients, it is necessary to qualify such vignettes with objective measures of probability. It is good to hope for a miracle, but care of the patient with advanced disease can become very difficult when they are led to expect a miracle. It is in the practical application that “necessary collusion” meets its biggest challenges. Patients with a terminal illness need time not only to come to terms with their spiritual being, but also to see to the practical matters in their daily lives. Arrangements may need to be made on the management of the family business or the care of young children or older parents. Lack of honesty regarding prognosis can lead to devastating financial and social consequences when such decisions are put off until it is too late. A related practical concern with collusion is that many patients with advanced cancer suffer precipitous declines in their functional status that preclude the measured use of “forecasting” as proposed by Helft. In such From the Division of Hematology/ Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI.

7522 Background: We have found that FDG-PET response during chemoradiation for patients with NSCLC is heterogeneous and predicts outcome. We hypothesized that dose escalated treatment targeted to the FDG-avid tumor would improve local tumor control. Methods: This is a phase II trial for patients with locally advanced, inoperable/unresectable NSCLC. Conformal radiotherapy (RT) was given in 30 daily fractions. RT dose was individualized to a fixed risk of lung toxicity and adaptively escalated to the residual tumor on mid-tx FDG-PET up to a total physical dose of 86 Gy. Patients had concurrent weekly followed by consolidation carboplatin/paclitaxel. The primary endpoint was local-regional tumor control (LRTC) at 2 years. Survival was calculated from RT start. Results were compared to stage-matched patients treated during the same time period with standard RT dosing (60-66 Gy). The data are presented as median (95% CI) unless otherwise specified. Results: 42 patients were enrolled: median age 63 years (range 45-83); 28 (67%) male; 39 (93%) smokers; 39 (93%) stage III; and 45% squamous cell. The mean gross tumor volume was 154 cc (range 10-617 cc). Median physical dose reached was 84 Gy (range 63-86 Gy), equivalent to 90 Gy in 2 Gy fractions (biological effective dose 108 Gy). 8 patients (19%) had RT-induced lung toxicity and 13 (31%) grade ≥2 esophagitis. Minimum and median follow-up were 10 and 25 months, respectively. The 2-year rates of in-field LRTC, overall LRTC, and LR-PFS were 84% (63-94%), 68% (47-82%), and 43% (27-58%), respectively. 14 patients progressed: 7 (50%) first at distant sites; 5 (36%) at nodal regions; 2 (14%) at primary tumor. Median overall survival was 26 months and 2-year overall survival rate was 51% (34-65%). These results compared favorably to stage-matched patients treated with standard-dose RT [2-year overall survival 23% (8-41%)]. Conclusions: These results support our hypothesis that adapting RT by escalating dose to the FDG avid region detected mid-tx improves 2-year local-regional tumor control. Adaptive RT may also improve overall survival. RTOG 1106 is currently testing this regimen in a randomized fashion. Clinical trial information: NCT01190527.

e19009 Background: Bevacizumab has increased survival in NSCLC patients (pts) when added to standard chemotherapy. However, whether radiographic features at baseline and/or post-treatment can predict benefit from addition of anti-angiogenic therapy to standard chemotherapy remains unknown. In addition, the impact of VEGF-targeted therapy on CT parameters is not fully characterized. Methods: A retrospective review was performed using CT scans of pts enrolled into a prospective phase II clinical trial of pemetrexed, gemcitabine and bevacizumab in stage IV chemo-naïve, non-squamous, NSCLC pts (Wozniak A, et al. IASLC2011). Treatments were repeated every 2 wks (1 cycle). CT scans were obtained at baseline and at the end of every 4 cycles. The radiographic CT features of the primary tumors were retrospectively reviewed at baseline and after first 4 cycles. RECIST 1.1 and Morphology, Attenuation, Size, and Structure (MASS) criteria were used to assess tumor radiographic response. Results: Twenty-four pts (43% males; median age, 62 y [range: 41-82]), were evaluable for this analysis. On baseline CT, median tumor size was 2.9 cm (range: 1.6. to 6.3 cm), median attenuation was 56 HU (range: 31 to 87 HU), 81% of tumors had heterogeneous enhancement, and 50% of tumors demonstrated invasion of adjacent structures. Well-defined margins were noted in 43% of tumors and 81% had < 30% necrosis. On post-4 cycle CT, 63% of tumors had decreased long diameter (median 15% decrease), 81% had decreased attenuation (median 21% HU reduction) and 50% had increased necrosis. RECIST-defined PR was seen in 37%, SD in 56%; and PD in 1 (4%) based on size despite > 75% necrosis. MASS criteria response was favorable in 25% and non-favorable in 75% of tumors. Pts with tumors that demonstrated FR response by MASS after 4 cycles were more likely to have prolonged progression free survival (HR 2.94; p= 0.175). Conclusions: In tumors treated with anti-angiogenic therapy, imaging response criteria that include changes in tumor morphology, attenuation, and size may capture anti-tumor effect more accurately than size-based RECIST criteria alone. These results support the need for prospective investigation of the efficacy of MASS criteria.

7527 Background: The VEGF/VEGFR and PDGF/PDGFR pathways are potential therapeutic targets in mesothelioma. Cediranib, a VEGFR/PDGFR inhibitor, showed anti-tumor activity in a salvage monotherapy study S0509. Methods: S0905 combined cediranib (2 dose cohorts 30 mg and 20 mg daily) with cisplatin and pemetrexed for 6 cycles followed by maintenance cediranib in unresectable chemo-naïve MPM patients. Results: A total of 20 patients (7 to cohort 1 - 30 mg, 13 to cohort 2 - 20 mg) were enrolled. In first cohort, 2 patients reported grade 3 DLTs of diarrhea and fatigue. Cohort 2 DLTs included 2 patients with grade 3 hyponatremia/dehydration and mucositis. For all cycles, 12 patients reported Grade 3 AEs, the most common being diarrhea (4), dehydration (3), fatigue (3) and neutropenia (3). Two grade 4 thrombocytopenia were reported with 1 treatment-related death (cohort 2) due to pneumonia/sepsis. Based on the toxicity profile, a decision was made to proceed with cediranib 20 mg daily for the remaining phase I/II trial. Two radiographic response measurements were utilized (RECIST 1.1, modified RECIST). 18/20 patients were evaluable for response by RECIST 1.1 (7 - 30 mg cohort, 11 - 20 mg cohort). The RECIST 1.1 RR was 22% (95% CI: 6% - 48%) and median PFS was 14 months (95% CI: 8 – 17). Two patients had inadequate assessments and are classified as non-responders. There were 19 patients measurable by modified RECIST with RR 53% (95% CI: 29%-76%) and median PFS 10 months (7-13). For all patients, the median OS was 16 months (95% CI: 11-19). One patient in the 30 mg cohort remains on trial after 25 cycles of therapy; 2 patients at the 20 mg cohort remain on trial on cycles 19 and 15 of therapy. Conclusions: Cisplatin-pemetrexed-cediranib shows significant clinical activity and acceptable toxicity with cediranib 20 mg/day. The randomized phase II portion of the trial is ongoing. Clinical trial information: NCT01064648. [Table: see text]

e18018 Background: Clinical trials have failed to demonstrate that age is a significant prognostic indicator among patients treated for non-small cell lung cancer (NSCLC). Clinical trials do not necessarily represent real-world experience, however. We sought to analyze the impact of age on survival in patients in the National Comprehensive Cancer Network (NCCN) NSCLC Outcomes Database. Methods: We performed a retrospective analysis of 6,834 NSCLC patients from the NCCN NSCLC Database representing 8 NCCN institutions. Of this population, 4,943 patients were eligible for our analysis. Exclusion criteria included the following: alive patients with < 180 days of follow-up, patients with incomplete staging, and patients with a prior cancer diagnosis. The study population was separated into five age quintiles with equal number of patients in each group. Variables included institution, smoking status, gender, race, Charlson comorbidity score, ECOG performance status (PS), histology, stage, and receipt of resection, drug and radiation therapy. Multivariable Cox model was performed for the effect of age on survival after adjusting for the above variables. Model assumptions were evaluated via graphs and residual tests. Results: Across the five quintiles (< 54, 54-60, 61-66, 67-72 and ≥ 73) there was a trend towards lower stage and higher Charlson score with increasing quintile. In addition, there was an increased proportion of patients with squamous cancer in the older age group. In the adjusted Cox model, there was a statistically significant longer survival in each of four younger quintiles compared to the reference group of ≥ 73 years of age (p=0.01). The adjusted hazard ratio of death for patients < 54 was .82 (95% CI = .72 to .94), for patients 54-60 was .86 (95% CI = .76 to .97), for patients 61-66 was .84 (95% CI = .74 to .95), and for patients 67-72 was .84 (95% CI = .74 to .95). There were no statistically significant pairwise interactions among age, smoking status and stage. Conclusions: Even after adjusting for institution, comorbidity scores, smoking status, race, gender, ECOG PS, histology, stage and treatment, NSCLC patients who were ≥ 73 years of age had a worse survival when compared to younger age groups.

e18118 Background: In vitro and in vivo studies have demonstrated the antiproliferative effects of 1, 25 (OH)2D3 (calcitriol) as single agent and antitumor synergy with cisplatin. The goals of this Phase I/II study were to determine the maximum tolerated dose (MTD) of 1, 25 (OH)2 D3 in combination with cisplatin and docetaxel, and to evaluate the efficacy in patients (pts) with metastatic NSCLC.Methods: The study was a multicenter, open-label study in pts with metastatic NSCLC. Pts were adults 18 yrs., PS 0-1 with normal liver/kidney function. For the phase I study, pts (3–6 per cohort) received 1, 25 (OH)2 D3 I.V. every 21 days prior to docetaxel and cisplatin. The starting dose of 1,25 (OH)2D3 was 15 mcg/m2 at sequential ascending dose levels (DL) (15, 30, 60 and 80 mcg/m2) using a 3+3 design targeting a dose-limiting toxicity (DLT) rate of 2 and cisplatin 75mg/m2 following 1, 25 (OH)2 D3 for 4 cycles. We analyzed SNPs in the CYP24A1 gene.Results: 37 pts were enrolled (16 in phase I and 21 in phase II) with a median age of 54 (range 34–79) yrs.; M: F, 12:17. At the 80 mcg/m2 dose level, 2/4 pts had DLT of grade 4 neutropenia. There were no cases of hypercalcemia or azotemia. The MTD and recommended Phase II dose was 60 mcg/m2. Among 6 response-evaluable Phase I pts, and 21 phase II pts, there were: 2 confirmed partial responses (PR), 6 unconfirmed PRs and 10 pts with stable disease. The median time to progression was 6.9 months (95% CI 4.4, 12.9) and the median overall survival was 8.3 months (95% CI 5.8, 14.9). Of the CYP24A1 SNPs, the IVS4-308C>G was associated with progressive disease (Chi-Square=0.0062)Conclusions: The MTD of 1,25 (OH)2D3 in combination with docetaxel and cisplatin was 60 mcg/m2 IV every 21 days. Pre-specified endpoint of a 50% response rate was not met in the phase II study. However, disease control in 66% of patients argues for further study of 1,25 (OH)2D3 as maintenance therapy. The CYP24A1 polymorphism IVS4-308C>G may be associated with resistance to a 1,25 (OH)2D3 based therapeutic regimen

7537 Background: Aggressive EOL cancer care is a health care quality and cost issue. As lung cancer is the leading cause of cancer-related death in the U.S., and NCCN member institutions are consid...

7634 Background: The NCCN Clinical Practice Guidelines (GL) allow many systemic therapy options for patients (pts) with mNSCLC. The primary aims of this analysis were to identify first-line regimens for the treatment of mNSCLC pts and examine concordance with NCCN NSCLC GL. Methods: The database was queried to identify pts with mNSCLC treated with first-line systemic therapy at 8 NCCN institutions presenting between September 2006 and March 2009. Pt characteristics, regimens utilized, and GL concordance were analyzed. Systemic therapy was categorized as cytotoxic doublet (CD), combination cytotoxic/targeted therapy (C/T), targeted therapy alone (T), or cytotoxic single agent (SA). Results: A total of 983 eligible pts were identified, as follows: 51% male; median age 64 years; performance status (PS) was documented in 77% (82% PS 0 or 1; 11% PS 2; 7% PS 3 or 4). There were 729 pts (74%) treated with systemic therapy, 123 (17%) of which participated in a clinical trial. Most common reasons for not receiving...

e17509 Background: Esophageal uptake of FDG is commonly seen in patients with non-small cell lung cancer (NSCLC), but the relationship of the uptake to radiation esophagitis has not been delineated...

e18041 Background: The prognosis for patients (pts) with ES SCLC is poor, with a median progression-free (PFS) and overall survival (OS) of 5 mo. and 9 mo., respectively. This trial was designed to evaluate the efficacy/toxicity of maintenance sunitinib after platinum-based chemotherapy in pts with ES SCLC. Methods: Treatment consisted of cisplatin 75 mg/m2 IV or carboplatin AUC 5 on day 1 plus etoposide 100 mg/m2 IV on days 1-3 every 21 days for 4 cycles. If no evidence of disease progression was identified, sunitinib was given at 50 mg orally QD for 4 wks of a 6-wk cycle continuously until disease progression or unacceptable toxicity. The primary endpoint was proportion of pts progression-free 4 mo. after starting sunitinib. Treatment was deemed not interesting if the 4-mo. PFS rate after starting sunitinib was < 35%; target enrollment of 21 pts in first stage. Results: 16 pts were enrolled: median age 66 yrs (range 34-80); 8 men: 8 women; PS 0/1/2 = 5/10/1. Responses to platinum/etoposide were CR/PR/SD...

2528 Background: Vorinostat is an inhibitor of histone deacetylase 6, which results in the acetylation of tubulin and the stabilization of microtubules. Since taxanes bind to stabilized microtubules, the administration of vorinostat followed by docetaxel, we hypothesized, should result in synergistic cytotoxicity. A phase I trial was conducted to determine the dose level of vorinostat plus docetaxel that would result in dose-limiting toxicity (DLT) in ≤ 30% of patients (pts). Methods: Eligible pts had castration-resistant prostate cancer (CRPC) or relapsed urothelial or non-small-cell lung cancer (NSCLC) after ≥1 prior chemotherapy regimen not containing docetaxel, a performance status of 0–2 and adequate organ function. Vorinostat was given orally for 14 days beginning on day 1 of a 21-day cycle. Docetaxel was given intravenously over 1 hour on day 4. The time-to-event continuous reassessment method guided dose escalation. Dose levels (DL) -1, 0, 1 and 2 corresponded to vorinostat 100, 100, 200 and 200 mg plus docetaxel 50, 60, 60, and 75 mg/m2, respectively. Blood was collected on days 1 and 4 of cycle 1 to measure drug levels by HPLC. Results: 12 pts were enrolled: median age 65 yrs (49–74); gender 9M:3F; 4 CRPC, 5 urothelial, 3 NSCLC. The median number of cycles was 2. 2 pts were treated at DL -1, 4 pts at DL 0, 5 pts at DL 1 and 1 pt at DL 2. 5 DLTs occurred in 5 pts: grade 4 neutropenic fever/sepsis (n = 2), anaphylactic reaction (n = 1), myocardial infarction (n = 1) and GI bleed (n = 1). Other toxicities included grade 4 neutropenia (n = 2), pulmonary embolus (n = 1) and GI bleed (n = 1). The estimated probability of DLT for DL -1 was .32 (90% posterior probability interval [PI], .11 to .53) for DL 0, .38 (90% PI, .16 to .58) and for DL 1, .43 (90% PI, .23 to .64). The trial was stopped due to excessive toxicity. No responses were noted. Conclusions: Combination vorinostat plus docetaxel was poorly tolerated with excessive DLTs requiring study termination. PK analysis will be presented. Supported in part by a grant from Merck & Co., Inc. [Table: see text]

22177 Background: Although Transforming growth factor-beta (TGF-β) is a key player, radiation-induced lung toxicity (RILT) involves numerous cytokines of multiple pathways. We hypothesized that TGF...

7548 Background: We hypothesized that the radiation induced elevation of transforming growth factor β1 (TGF-β1) during radiation therapy (RT) correlates with radiation-induced lung toxicity (RILT) ...

17089 Background: The prognosis for patients (pts) with ES SCLC is poor, with a median survival of 9 mo. This trial was designed to evaluate the efficacy and toxicity of cisplatin plus irinotecan followed by maintenance imatinib (Gleevec) in pts with c-kit positive ES SCLC. Methods: Immunohistochemistry for c-kit was performed on paraffin-embedded tissue prior to enrollment. Treatment consisted of irinotecan 65 mg/m2 IV on days 1 and 8 plus cisplatin 60 mg/m2 IV on day 1 repeated every 21 days for 4 cycles. If no evidence of disease progression was identified, Gleevec was given at 400 mg orally BID until disease progression or unacceptable toxicity. Results: 14 pts have been enrolled: median age 61 yrs (range 47–73); 9 men: 5 women; PS 0/1/2 = 3/10/1. 6 pts did not begin Gleevec due to disease progression (4), persistent grade 3 emesis (1), and referral for radiation therapy (1). 8 pts had a PR with cisplatin/irinotecan and received Gleevec. Median number of wks on Gleevec was 6.1 (range 4.6–25.1). Reasons for discontinuation of Gleevec were disease progression (7) and persistent neutropenia (1). Median progression-free survival was 4.7 mo. (range 0.7–16.3) for all pts and 5.5 mo. (range 4.7–16.3) for pts receiving Gleevec. There were no objective responses to Gleevec, but 3 pts (21%) had stable disease for 12, 15 and 25 wks. Median survival was 8.1 mo. (range 3.7–19.6) for all pts and 10.0 mo. (range 7.1–19.6) for those receiving Gleevec. Myelosuppression was mild (grade 1–2 ANC 13%, anemia 76%, platelets 13%) with one pt with grade 3 neutropenia. Non-heme toxicity included grade 1–2 nausea 76%, diarrhea 51% and peripheral edema 75%. Conclusions: Gleevec did not appear to maintain disease stability after response to chemotherapy in the majority of pts despite c-kit tumor positivity. Although disease stability with Gleevec was noted in 3 pts (12–25 wks) and therapy was well tolerated, this approach does not appear to warrant further clinical study. Supported by Novartis Pharmaceuticals. No significant financial relationships to disclose.

4090 Background: The prognosis for patients (pts) with CUP is poor, with a median survival of 4–6 mos. This trial was designed to evaluate the efficacy and toxicity of a novel chemotherapy combinat...

7102 Background: Weekly (DOC) is active and well tolerated in elderly or PS2 patients with advanced NSCLC. Cyclooxygenase-2 (COX-2) promotes tumor growth through the production of prostaglandin E2 (PGE2) and the induction of vascular endothelial growth factor (VEGF). Pre-clinical data show that celecoxib (CEL), a COX-2 inhibitor, has antitumor activity and enhances taxane efficacy.Methods: We are conducting a phase II study of CEL plus weekly DOC in elderly or PS2 pts with stage IIIB (pleural effusion)/IV NSCLC. Eligibility criteria include: age ≥ 70 yrs (PS 0–2) or age < 70 yrs with PS2; normal hepatic, renal and bone marrow function. CEL 400 mg po bid (daily) is started 7 days before the first dose of DOC 36mg/m2 IV given on days 1, 8, 15 of a 28 day cycle. Blood is collected pre-treatment, on day 8 of CEL, and on days 8 and 29 after first dose of DOC for VEGF and PGE2 levels. Results: 21 eligible pts have been treated: Median age 73 yrs (51–79 yrs); Gender 17M:4F; PS2 - 11; ≥70 yrs-14;PS2–11;adenocarci...