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6075 Background: Blockade of the PD-1/PD-L1 immune checkpoint improves survival in recurrent/metastatic head and neck cancer. PD-L1 expression is a biomarker that enriches for clinical benefit with anti-PD-1 therapy alone or in combination with chemotherapy in this setting. The role of PD-L1 expression as a predictive biomarker in locoregional human papillomavirus associated (HPV+) head and neck cancer (HNC) treated with induction nivolumab-based chemoimmunotherapy is unknown. We evaluate PD-L1 expression and response to induction chemoimmunotherapy in the context of an investigator initiated trial, OPTIMA II. Methods: Patients with locoregionally advanced HPV+ HNC were enrolled to the prospective OPTIMA II study evaluating induction chemoimmunotherapy followed by response adaptive de-escalated locoregional therapy. Induction therapy consisted of nivolumab, nab-paclitaxel, and carboplatin, for three cycles. Anatomic imaging of the head and neck with either CT or MRI was obtained at baseline and following induction therapy. Expression of PD-L1 was assessed by immunohistochemistry on baseline biopsies and calculation of tumor proportion score (TPS) and combined positive score (CPS) was performed. Response is defined as percentage of tumor shrinkage per RECIST 1.1 criteria. Deep response rate is defined as the proportion of patients with > = 50% tumor shrinkage. Kruskal-Wallis and Mann-Whitney tests were used for analysis. Results: Twenty-nine patients (pts) underwent evaluation of PD-L1 expression and started treatment with induction chemoimmunotherapy. Median age 61 (range 37-81), smoker > 20 pack years in 24%, tonsil primary in 79%, and HPV16 subtype in 97%. The median response following induction was 63% (range 29% to 100%). PD-L1 TPS scores were < 1, 1-19, and > = 20 in 28%, 34%, and 38% respectively. PD-L1 CPS scores were < 20 and > = 20 in 55% and 45% respectively. Median response among PD-L1 TPS of < 1, 1-19, and > = 20 was 49%, 59%, and 66% respectively (p = 0.16). Among PD-L1 CPS of < 20 and > = 20, median response was 57% and 69% respectively (p = 0.11). The deep response rate among PD-L1 CPS < 20 and > = 20 was 69% and 77% respectively. Conclusions: Deep responses were observed following induction chemoimmunotherapy in locoregionally advanced HPV+ HNC. There was a non-significant increase in median response and deep response rate with higher expression of PD-L1. Evaluation of PD-L1 expression as a biomarker for response with induction chemoimmunotherapy is worthy of further investigation in locoregional HPV+ disease. Clinical trial information: NCT03107182.

Purpose Concurrent chemoradiotherapy is standard treatment for patients with stage III non–small-cell lung cancer. Elderly patients may experience increased rates of adverse events (AEs) or less benefit from concurrent chemoradiotherapy. Patients and Methods Individual patient data were collected from 16 phase II or III trials conducted by US National Cancer Institute–supported cooperative groups of concurrent chemoradiotherapy alone or with consolidation or induction chemotherapy for stage III non–small-cell lung cancer from 1990 to 2012. Overall survival (OS), progression-free survival, and AEs were compared between patients age ≥ 70 (elderly) and those younger than 70 years (younger). Unadjusted and adjusted hazard ratios (HRs) for survival time and CIs were estimated by single-predictor and multivariable frailty Cox models. Unadjusted and adjusted odds ratio (ORs) for AEs and CIs were obtained from single-predictor and multivariable generalized linear mixed-effect models. Results A total of 2,768 patients were classified as younger and 832 as elderly. In unadjusted and multivariable models, elderly patients had worse OS (HR, 1.20; 95% CI, 1.09 to 1.31 and HR, 1.17; 95% CI, 1.07 to 1.29, respectively). In unadjusted and multivariable models, elderly and younger patients had similar progression-free survival (HR, 1.01; 95% CI, 0.93 to 1.10 and HR, 1.00; 95% CI, 0.91 to 1.09, respectively). Elderly patients had a higher rate of grade ≥ 3 AEs in unadjusted and multivariable models (OR, 1.35; 95% CI, 1.07 to 1.70 and OR, 1.38; 95% CI, 1.10 to 1.74, respectively). Grade 5 AEs were significantly higher in elderly compared with younger patients (9% v 4%; P < .01). Fewer elderly compared with younger patients completed treatment (47% v 57%; P < .01), and more discontinued treatment because of AEs (20% v 13%; P < .01), died during treatment (7.8% v 2.9%; P < .01), and refused further treatment (5.8% v 3.9%; P = .02). Conclusion Elderly patients in concurrent chemoradiotherapy trials experienced worse OS, more toxicity, and had a higher rate of death during treatment than younger patients.

8505 Background: Although level 1 evidence is lacking, the majority of patients (pts) with LSCLC are treated with a high dose QD TRT regimen in clinical practice. CALGB 30610/RTOG 0538 was designed to determine if administering high dose TRT would improve overall survival (OS), compared with standard 45 Gy BID TRT, in LSCLC pts treated with chemoradiotherapy. Methods: Eligible pts had LSCLC, ECOG performance status (PS) 0-2 and regional lymph node involvement excluding contralateral hilar or supraclavicular nodes. This phase 3 trial was conducted in 2 stages. In the first stage, pts were randomized 1:1:1 to 45 Gy BID over 3 weeks, 70 Gy QD over 7 weeks, or 61.2 Gy concomitant boost (CB) over 5 weeks. For the second stage, the study planned discontinuation of one high dose arm based on interim toxicity analysis with patients then randomized 1:1 in the two remaining arms. TRT was given starting with either the 1st or 2nd (of 4 total) chemotherapy cycles. The primary endpoint was OS measured from date of randomization. Results: The trial opened 03/15/2008 and closed 12/01/2019 upon completing accrual, with the CB arm discontinued 3/11/2013 after interim analysis. This analysis includes 638 pts randomized to 45 Gy BID TRT (n = 313) or 70 Gy QD TRT (n = 325). Median age was 63 years (range 37-81), the majority of pts were Caucasian (86%), female (52%), and with ECOG PS 0-1 (95%). After median follow-up of 2.84 years (IQR:1.35 -5.61) for surviving pts, QD compared to BID did not result in a significant difference in OS (HR 0.94, 95% CI: 0.76-1.2, p = 0.9). Median, 2- and 4-year OS for QD were 30.5 months (95% CI: 24.4-39.6), 56% (95% CI: 0.51-0.62), and 39% (95% CI: 0.33-0.45), and for BID 28.7 months (95% CI: 26.2-35.5), 59% (95% CI: 0.53-0.65), and 35% (95% CI: 0.29-0.42). QD also did not result in a significant difference in PFS (HR 0.96, 95% CI: 0.78-1.18, p = 0.94). Most grade 3+ hematologic and non-hematologic adverse events (AEs) were similar between cohorts. Rates of grade 3+ febrile neutropenia, dyspnea, esophageal pain and dysphagia for QD were 12.6%,7%, 11.6% and 11.3%, and for BID 13.6%, 4%, 11.2 % and 9.5%. Grade 5 AEs were reported in 3.7% and 1.7% of the QD and BID cohorts, respectively. Results will be updated at presentation. Conclusions: High dose QD TRT to 70 Gy did not significantly improve OS compared with standard 45 Gy BID TRT. Nevertheless, favorable outcomes on the QD arm provide the most robust evidence available supporting high dose once-daily TRT as an acceptable option in LSCLC. Outcomes from this study, the largest conducted in LSCLC to date, will help guide TRT decisions for this patient population. Support: U10CA180821, U10CA180882; Clinical trial information: NCT00632853.

8513 Background: A minority of the approximately 40,000 US patients diagnosed annually with stage III NSCLC can be cured by concurrent CRT. Standard adjuvant immune checkpoint inhibitors (ICI) improve outcome for those patients who complete CRT with good performance status (PS) and without disease progression, but most patients diagnosed with unresectable stage III NSCLC will not meet the criteria for adjuvant ICI. AFT-16 investigated safety and efficacy of neoadjuvant and adjuvant atezolizumab as a strategy that may allow more patients to benefit from ICI. Methods: Eligible patients received 4 cycles (cy) of atezolizumab 1200 mg IV q 21 days followed by CRT with 60 Gy + weekly carboplatin and paclitaxel (CP), CP consolidation and adjuvant atezolizumab to complete 1 year of therapy (17 cy). The primary endpoint of disease control rate at 12 weeks (wks) has been reported. Secondary endpoints reported here include overall response rate, safety, and progression-free and overall survival (PFS, OS) measured from the start of induction therapy. Correlative science data and quality of life endpoints will be reported elsewhere. Results: 64 patients with unresectable stage III NSCLC, PS 0-1 and no active autoimmune disease or significant organ dysfunction were enrolled at 13 Alliance for Clinical Trials in Oncology sites from 11/2017 to 7/2019. 62 patients who received at least one dose of atezolizumab are included in this analysis. Median age was 63.9 years (range 38.1-86.5). Patients were 51.6% female, 77.4% white, 88.7% current & former smokers and 56.5% PS 0. All patients are off study treatment. Mean cycles of treatment received was 9 (1-17). 46 patients were alive at median follow up 24.1 mo (range 3 – 34.1 mo). PFS at 12 and 18 mo from start of induction atezolizumab was 66% (95%CI 55-79) and 57% (95%CI 45-71) respectively. Median PFS was 23.7 mo (95%CI 13.2-NE). OS at 18 mo was 84% (95%CI 75-94). Median OS is not yet estimable. Atezolizumab was well tolerated. One grade (gr) 4 Guillain-Barre syndrome and 1 each gr 3 pneumonia, pneumonitis and colitis were attributable to neoadjuvant atezolizumab. The remaining 9 severe adverse events were unrelated to ICI. Conclusions: Atezolizumab prior to and following CRT for stage III unresectable NSCLC was well tolerated with encouraging PFS and OS without unexpected safety signals. Analysis of correlative endpoints and quality of life are ongoing. Further study of induction atezolizumab is warranted in patients with unresectable stage III NSCLC. Support: https://acknowledgments.alliancefound.org ; Clinical trial information: NCT03102242.

6011 Background: Despite the success of anti-PD-1 in recurrent/metastatic head and neck cancer, incorporation in the curative setting with induction therapy has yet to be investigated. Favorable prognosis of human papillomavirus associated (HPV+) oropharyngeal cancer (OPC) has led to interest in treatment de-escalation. OPTIMA 2 evaluated nivolumab (nivo) with nab-paclitaxel and carboplatin followed by risk/response adaptive de-intensified treatment for locoregionally advanced HPV+ OPC. We report the primary analysis and outcomes. Methods: OPTIMA 2 enrolled locoregionally advanced HPV+ OPC. Nivo, nab-paclitaxel, and carboplatin were administered for 3 cycles. High-risk (HR) included any of the following: T4, N2c-N3 (AJCC 7th edition), > 20 pack year smoking history, non-HPV16 subtype; All others were low-risk (LR). Arm A included LR with ≥50% post-induction shrinkage by RECIST received single-modality de-escalation with low-dose radiation (RT) alone (50 Gy) or transoral robotic surgery (TORS). Arm B included HR with ≥50% shrinkage or LR with

6048 Background: Human papillomavirus (HPV) infection is a primary factor driving the increasing incidence of OPSCC. As patients with HPV+ OPSCC show significantly improved treatment response and prognosis, there is an urgent need to de-escalate treatment of HPV+ OPSCC that optimizes oncologic control while minimizing treatment-related toxicity. Cell-free HPV DNA (cfHPV-DNA) from plasma specimens represents a promising noninvasive surrogate of disease burden in these patients. To enable cfHPV-DNA analysis as a strategy to monitor response to therapy and guide treatment de-escalation, we developed a highly sensitive assay for HPV16/18 detection and quantification in plasma, based on the SafeSEQ next-generation sequencing (NGS) technology. Methods: Longitudinal plasma samples were collected from patients with locoregional HPV+ OPSCC treated on our institutional de-escalation protocol of induction chemoimmunotherapy followed by risk/response stratified de-escalated locoregional therapy, OPTIMA 2 (NCT03107182). Neck CT or MRI was obtained for all patients at baseline and following induction chemoimmunotherapy; radiographic response to induction therapy was assessed per RECIST 1.1 criteria. cfHPV-DNA was quantified in plasma samples collected at baseline and at the end of induction therapy. Changes in cfHPV-DNA levels were correlated with radiographic response. Results: The SafeSEQ HPV assay demonstrates high analytical sensitivity, with ability to detect a single copy of HPV DNA. Replicate testing of contrived samples containing HPV 16/18 DNA at defined levels revealed robust quantitative detection across a dynamic range over 5 orders of magnitude. The assay showed a low level of background signal ( < 0.04 copies per sample) across 20 healthy donor samples, indicating high specificity. In plasma samples collected at baseline from patients enrolled in OPTIMA 2, cfHPV-DNA was detected at levels ranging from 1 to > 30,000 copies/ml. A high correlation was observed between dynamic changes in patients’ cfHPV-DNA levels and radiographic responses following induction therapy. Furthermore, in samples collected longitudinally during induction therapy, changes in cfHPV-DNA levels accurately tracked radiographic responses to therapy. Conclusions: We have developed a highly sensitive and specific cfHPV-DNA detection assay based on SafeSEQ NGS technology and have successfully applied it to monitor therapeutic response in HPV+ OPSCC patients. The assay exhibits robust quantitative detection of HPV across a broad range of levels, even when only a few copies are present, enabling high-resolution molecular monitoring. Prospective studies are underway to further evaluate the kinetics of cfHPV-DNA as a predictor of response to therapy in order to more precisely guide the management of patients with HPV+ OPSCC.

6027 Background: In this study we develop post-treatment imaging surveillance schedules for locally advanced oropharyngeal carcinoma (OPC) specific to the unique recurrence patterns of tumor stage and HPV status, using mathematical models. Current post-treatment imaging surveillance recommendations for OPC are not evidence based. The exception is the use of a positron emission tomography (PET) scan at 3 months post-treatment, after which practice across institutions diverge. An optimized and personalized surveillance schedule for OPC patients can minimize costs and diagnostic delays. Methods: A Markov multi-state model defining local and distant recurrences was trained using 2159 patients from the National Cancer Database. Patients from 2010-2015 treated at an academic or major cancer center with curative radiotherapy were included. Tumors must have been stage III to IVB (AJCC 7th edition) with known p16/HPV status. Model performance was then successfully externally validated using the 2016 International Collaboration on Oropharyngeal cancer Network for Staging (ICON-S) study. Optimized radiographic surveillance schedules were created using this model, assuming a PET at month 3 and including 0 to 6 additional computed tomography (CT) scans of the neck and chest. Optimization was done for minimization of latency, defined as time between disease recurrence and radiographic discovery. Results: Model-selected schedules varied significantly from commonly utilized-surveillance schedules (such as imaging every 3 months within the first year from treatment) and showed lower mean diagnostic latency for every stage and HPV status (shown in Table). In the lowest risk cohort (Stage III HPV+), the optimized schedule had a sensitivity of 65% and latency of 3.1 months. In the highest risk group (Stage IVB HPV-), the optimized schedule had a sensitivity of 76% and latency of 1.9 months. Conclusions: Mathematical model optimization for HPV status and stage is feasible and produces non-intuitive results. These results could be used to inform surveillance if payors reimburse for fewer total scans. Across all cohorts, each added CT scan increases surveillance sensitivity and decreases latency. Incorporation of physical exam and direct visualization results into the model are still needed. Future steps include cost effectiveness research and prospective clinical trials.[Table: see text]

8503 Background: CheckMate 816 (NCT02998528) is a randomized phase 3 study of neoadjuvant NIVO + chemo vs chemo in resectable NSCLC. The study met its first primary endpoint, demonstrating significantly improved pathological complete response (pCR) with neoadjuvant NIVO + chemo. Here we report key surgical outcomes from the study. Methods: Adults with stage IB (≥ 4 cm)–IIIA (per AJCC 7th ed) resectable NSCLC, ECOG PS ≤ 1, and no known EGFR/ ALK alterations were randomized to NIVO 360 mg + platinum-doublet chemo Q3W or chemo Q3W for 3 cycles (n = 179 each). Definitive surgery was to be performed within 6 weeks of treatment. Primary endpoints are pCR (defined as 0% viable tumor cells in lung and lymph nodes) and event-free survival; both are evaluated by blinded independent review. Feasibility of surgery and surgery-related adverse events (AEs) are exploratory endpoints. Results: Baseline characteristics were comparable between arms; 64% of patients (pts) were stage IIIA. Definitive surgery rates were 83% with NIVO + chemo (n = 149) vs 75% with chemo (n = 135). Reasons for cancelled surgery were disease progression (12 and 17 pts, respectively), AEs (2 pts/arm), or other scenarios (14 and 19 pts, respectively; including pt refusal, unresectability, poor lung function). Minimally invasive surgery rates were 30% and 22%, and conversion from minimally invasive to open surgery rates were 11% and 16% for NIVO + chemo and chemo, respectively. Lobectomy was performed in 77% vs 61% of pts, and pneumonectomy in 17% and 25% for NIVO + chemo vs chemo, respectively. AEs were responsible for delays of surgery in 6 pts in the NIVO + chemo arm and 9 pts in the chemo arm. An R0 resection was achieved in 83% vs 78% of pts and median residual viable tumor (RVT) cells in the primary tumor bed were 10% vs 74% for NIVO + chemo vs chemo. There was no increase in median (Q1, Q3) duration of surgery and length of hospitalization between NIVO + chemo vs chemo (184 [130, 252] vs 217 [150, 283] min; and 10.0 [7, 14] vs 10.0 [7, 14] days, respectively). Any-grade and grade 3–4 surgery-related AEs were reported in 41% vs 47% and 11% vs 15% of the NIVO + chemo vs chemo arms, respectively. Grade 5 surgery-related AEs were reported in 2 vs 0 pts in the NIVO + chemo vs chemo arms; 0 vs 3 pts died due to treatment-related AEs, respectively. Conclusions: In CheckMate 816, neoadjuvant NIVO + chemo did not impede the feasibility and timing of surgery, nor the extent or completeness of resection vs chemo alone; treatment was tolerable and did not increase surgical complications. NIVO + chemo led to increased depth of pathological response. The surgical outcome data from CheckMate 816 along with significant improvement in pCR support NIVO + chemo as a potential neoadjuvant option for patients with stage IB to IIIA resectable NSCLC. Clinical trial information: NCT02998528.

Purpose Under-representation of elderly, women, and racial/ethnic minority patients with cancer in clinical trials is of national concern. The goal of this study was to characterize enrollment trends and disparities by age, sex, and race/ethnicity in lung cancer trials. Methods We analyzed data for 23,006 National Cancer Institute cooperative group lung cancer trial participants and 578,476 patients with lung cancer from the SEER registry from 1990 to 2012. The enrollment disparity difference (EDD) and enrollment disparity ratio (EDR) were calculated on the basis of the proportion of each subgroup in the trial population and the US lung cancer population. Annual percentage changes (APCs) in the subgroup proportions in each population were compared over time. Results Enrollment disparity for patients ≥ 70 years of age with non–small-cell lung cancer improved from 1990 to 2012 (test of parallelism, P = .020), with a remaining EDD of 0.22 (95% CI, 0.19 to 0.25) and EDR of 1.65 (95% CI, 1.51 to 1.82) in 2010 to 2012. No improvement was seen for elderly patients with small-cell lung cancer (SCLC), with an APC of 0.20 ( P = .714) among trial participants, despite a rising proportion of elderly patients with SCLC in the US population (APC, 0.32; P = .020). Enrollment disparity for women with lung cancer improved overall, with the gap closing by 2012 (EDD, 0.03 [95% CI, 0.00 to 0.06]; EDR, 1.07 [95% CI, 1.00 to 1.16]). Enrollment disparities persisted without significant improvement for elderly women, blacks, Asians/Pacific Islanders, and Hispanics. Conclusion Under-representation in lung cancer trials improved significantly from 1990 to 2012 for elderly patients with non–small-cell lung cancer and for women, but ongoing efforts to improve the enrollment of elderly patients with SCLC and minorities are needed. Our study highlights the importance of addressing enrollment disparities by demographic and disease subgroups to better target under-represented groups of patients with lung cancer.

9576 Background: S1400, a BDMP, was designed to address an unmet need in sqNSCLC, run within the National Clinical Trials Network of the National Cancer Institute using a public-private partnership (PPP). The goal of was to establish an infrastructure for biomarker-screening and rapid evaluation of targeted therapies in biomarker-defined groups leading to regulatory approval. Methods: S1400 included a screening part using the FoundationOne assay and a clinical trial part with biomarker-driven studies (BDS) and “non-match” studies (NMS) for patients not eligible for any BDS. Patients could be screened (SaP) at progression or pre-screened (PreS). Results: Between June 2014 and January 2019, 1864 patients enrolled (711 PreS, 1079 SaP), 1674 with biomarker results, and 653 registered to a study with 217 to BDS and 436 to NMS. Six BDS and 3 NMS were initiated in small subsets with all BDS and 2 NMS completed within 2-3 years (see Table). Completed BDS have not demonstrated activity with 0-2 responses. On S1400I, Nivolumab and ipilimumab did not improve survival. Response with durvalumab (S1400A) was 16%. Conclusions: Lung-MAP met its goal to quickly answer targeted and other novel therapy questions in rare sqNSCLC subpopulations, answering questions that likely would not have been otherwise feasible, thereby demonstrating value. Activated just prior to the success of PD-(L)1 therapies in sqNSCLC, the trial had to undergo major design changes. Lessons learned include the need to update based on new science and that the PPP collaboration was essential to success. Lung-MAP continues now with new BDS and NMS in all NSCLC as of January 2019. Clinical trial information: NCT02154490 . [Table: see text]

TPS9080 Background: SCLC is an aggressive neuroendocrine tumor with poor prognosis and few treatment options. Delta-like ligand 3 (DLL3) is an inhibitory Notch ligand that is highly expressed on the surface of most SCLC tumors but minimally expressed in normal tissues. As such, DLL3 may be a promising therapeutic target. AMG 757 is an HLE BiTE immune therapy designed to redirect cytotoxic T cells to cancer cells by binding to DLL3 on cancer cells and CD3 on T cells, resulting in T cell activation and expansion and T cell-dependent killing of tumor cells. In addition to its direct antitumor effect, BiTE immune therapy can inflame the tumor microenvironment. Combining AMG 757 with a PD-1 pathway inhibitor may lead to increased antitumor activity by enabling sustained T cell-dependent killing of tumor cells. Methods: NCT03319940 is an open-label, ascending, multiple-dose, phase 1 study evaluating AMG 757 as monotherapy; the protocol was recently amended to also evaluate AMG 757 in combination with pembrolizumab. The study will include a dose exploration (monotherapy and combination) followed by a dose expansion (monotherapy). Key eligibility criteria: adult patients with relapsed/refractory SCLC whose disease progressed or recurred after at least 1 platinum-based chemotherapy regimen, ECOG performance status 0–2, at least 2 measurable lesions per modified RECIST 1.1, no untreated or symptomatic brain metastases, and adequate organ function. Primary objectives are to evaluate safety/tolerability and determine the maximum tolerated dose or recommended phase 2 dose of AMG 757 as monotherapy and in combination with pembrolizumab. Secondary objectives are to characterize pharmacokinetics and evaluate preliminary antitumor activity; exploratory objectives are to assess immunogenicity and changes in biomarkers in blood and tumor tissue. In the dose exploration phase, dose escalation/de-escalation decisions will be guided by a Bayesian logistic regression model; backfill enrollment at dose levels deemed safe and tolerable will be allowed. The study is open and recruiting patients. Clinical trial information: NCT03319940.

9045 Background: A minority of the > 40,000 patients (pts) diagnosed with stage III NSCLC annually in the US are cured by CRT, more recently followed by adjuvant immune checkpoint inhibitors (ICI). PD-L1 blockade with CRT may attenuate tumor-related immunosuppression via depletion of regulatory T cells and clonal expansion of effector T cells. Further, CRT may expose otherwise hidden antigens that present additional targets to the reconstituting immune system. Adjuvant ICI has improved survival. Whether ICI before CRT will further improve outcomes is unknown. Methods: This Alliance Foundation Trials (AFT) study evaluated safety and efficacy of atezolizumab before and after CRT. 4 cycles of atezolizumab 1200 mg IV q 21 days with restaging after cycles 2 and 4 were followed by carboplatin and paclitaxel (C/P) weekly with 60 Gy radiation and C/P consolidation followed by atezolizumab for 1 year of therapy. Primary endpoint is disease control rate (DCR) (complete response + partial response (PR) + stable disease (SD)) at 12 weeks (wks). Secondary endpoints include overall response rate, progression-free survival, overall survival, safety and quality of life assessed by EORTC QLQ-30. Correlatives include PD-L1 and tumor mutation burden as predictive biomarkers. Tumor tissue was obtained at study entry; plasma and immune cells were isolated at multiple timepoints. Results: 64 pts with stage III NSCLC, performance status (PS) 0-1, no active autoimmune disease or significant organ dysfunction enrolled at 13 Alliance sites from 11/2017 to 7/2019. 62 pts received ≥ 1 dose of atezolizumab and are included in the primary analysis; median age 63.9 years (38.1-86.5), 51.6% female, 77.4% white, 61.3% former smokers, 56.5% PS 0. DCR at 12 wks was 77.4% (80% confidence interval 69.2-84.3%) (30.7% PR, 46.8% SD). 54 pts reported adverse events (AEs) during induction, mostly grade (gr) 1. There were 13 serious AEs, most unrelated to study treatment; 1 gr 3 anaphylactic reaction, 1 gr 3 colitis, and 1 gr 4 Guillain-Barre syndrome were attributable to atezolizumab. Baseline PD-L1 status was available for 49 pts. DCR was 82.4% for pts with PD-L1 negative and 90.9% for pts with PD-L1 positive tumors. Conclusions: Atezolizumab prior to and following CRT for stage III unresectable NSCLC was well tolerated with an encouraging 12-wk DCR. Analysis of secondary endpoints is ongoing. Further study of induction ICI therapy is warranted in patients with unresectable stage III NSCLC. Support: AFT, Genentech; Clinical trial information: NCT03102242.

TPS9077 Background: ALCHEMIST (Adjuvant Lung Cancer Enrichment Marker Identification and Sequencing Trial) is a clinical trial platform of the National Cancer Institute that offers biomarker analysis for high-risk resected non-small cell lung cancer (NSCLC) to support randomized trials of novel adjuvant therapies within the National Clinical Trials Network (NCTN). EA5142, a trial of adjuvant nivolumab for patients (pts) without EGFR / ALK alterations, has completed enrollment. Given the survival benefit seen with 1st-line chemo-immunotherapy (chemo-IO) for advanced NSCLC without EGFR / ALK alterations, there was compelling rationale for the launch of a trial offering concurrent immunotherapy with adjuvant chemo. Here we report updated enrollment to ALCHEMIST as of Jan 14, 2020. Methods: ALCHEMIST includes a screening trial (A151216, 5362 registered) that enrolls pts with completely resected clinical stage IB (≥4 cm)–IIIA (per AJCC 7) NSCLC. Tissue and blood are collected, biomarker testing includes EGFR sequencing, ALK FISH and PD-L1 IHC. 733 active sites are enrolling across the NCTN. Pts with EGFR mutations may enroll to adjuvant erlotinib vs observation (A081105, 352 randomized); those with ALK fusions may enroll to adjuvant crizotinib vs observation (E4512, 99 randomized). A trial offering adjuvant nivolumab vs observation regardless of PD-L1 status (EA5142, 935 randomized) recently completed enrollment. To support ongoing investigation of adjuvant immunotherapy, ALCHEMIST is adding A081801 (opens spring 2020). Pts will be randomized to one of 3 arms: chemo-IO with pembrolizumab during and after chemo vs sequential chemo followed by pembrolizumab vs chemo alone. Pts with pathological N2 nodes are eligible and can undergo postoperative radiotherapy after completing chemo. Pts are eligible if enrolled to A151216, negative for EGFR and ALK alterations, and with PD-L1 testing completed (required for stratification). Local testing for EGFR, ALK and PD-L1 will be accepted for enrollment; central testing will not delay randomization. Pts may not have received any therapy except surgery for the lung cancer and must be age >18, Eastern Cooperative Oncology Group performance status 0-1, have no active autoimmune disease requiring systemic treatment within 2 years, must not be pregnant or nursing, have no active second malignancy within 3 years and meet standard organ function values. By building off the ongoing ALCHEMIST platform, we hope to facilitate rapid enrollment to A081801 across participating NCTN sites. Clinical trial information: NCT02194738.

6575 Background: Human papilloma virus (HPV) associated oropharyngeal cancer is associated with a favorable prognosis, but standard multimodality treatment is associated with substantial treatment related toxicity. A de-escalation treatment paradigm that optimizes oncologic outcomes while reducing toxicity is needed. We sought to further expound on our published OPTIMA data with long-term follow-up and additional pts subsequently treated using the OPTIMA treatment paradigm. Methods: Long-term follow-up of our institutional de-escalation OPTIMA trial (NCT02258659) and retrospective review of additional patients treated subsequently per OPTIMA outline was performed. Pts were classified as low-risk (LR) (≤T3, ≤N2B, ≤10PYH) or high-risk (HR) (T4, ≥N2c, > 10PYH). Pts received induction chemotherapy (IC) of 3 cycles of dose dense carboplatin and nab-paclitaxel (OPTIMA) or paclitaxel (subsequently treated). LR with ≥50% response received low-dose radiotherapy (RT) to 50 Gy. LR with 30-50% response or HR with ≥50% response received intermediate-dose chemoradiotherapy (CRT) to 45Gy. All others received full-dose CRT to 75Gy. Results: 108 pts consented and 107 were treated (61 on study; 46 subsequently) from October 2014 through November 2019. 1 pt transferred care post-enrollment. Median follow-up was 36 months (interquartile range 17-45). Median age was 63 years (range 33-84) and 95% were male. 47% were LR and 53% were HR. ≥50% tumor shrinkage occurred in 78/107 (73%) of pts overall, and 37/51 (73%) among LR; 41/56 (73%) among HR. 82% of pts received de-escalated (C)RT. Overall, 94% of pts were alive at last follow-up (98% LR; 89% HR). 3 pts (2 HR and 1 LR) developed disease recurrence (2.7%), with 2 local recurrences and 1 distant recurrence. Likelihood of G-tube placement was 3% in low-dose RT, 35% in intermediate-dose CRT, and 84% in full-dose CRT. Conclusions: IC followed by risk-adapted dose and volume de-escalated treatment for HPV+ oropharyngeal cancer demonstrates excellent oncologic and functional outcomes with long-term follow-up. Supported by Celgene, Alinea benefit supported by Grant Achatz/Nick Kokonas, and National Cancer Institute of the National Institutes of Health (NIH) through Grant Number P30 CA14599. Clinical trial information: NCT02258659 .

9616 Background: Stereotactic body radiotherapy (SBRT) provides high rates of treated metastasis control, stimulates innate and adaptive immune pathways, and is safe in patients treated with anti-PD1 monotherapy following SBRT. We hypothesize that SBRT may improve outcomes for patients receiving immunotherapy through both direct cytoreduction and increased immunogenicity. Within this context, we conducted a phase 1 trial designed to evaluate the safety of combination immune checkpoint blockade with nivolumab and ipilimumab(N/Ip) plus sequential (Seq) or concurrent (Con) multisite SBRT (mSBRT) in patients with stage IV NSCLC. Methods: Treatment naïve patients (EGFR/ALK WT) with advanced NSCLC received SBRT to 1 to 4 metastases. Not all metastases were targeted, and metastases > 65 mL were partially irradiated. Brain metastases were allowed on protocol, and those > 3mm were treated prior to enrollment. SBRT dose varied by anatomic site and ranged from 45 to 50 Gy in 3 to 5 fractions with predefined dose de-escalation if excess dose-limiting toxicities were observed. Patients on Seq arm received N/Ip between 1-7 days after completion of SBRT. Patients in Con arm received N/Ip prior to completion of SBRT. N/Ip continued until progression, development of toxicity, or up to 2 years. Patients underwent pre- and post-treatment biopsy of one irradiated lesion. Results: A total of 35 patients (Seq/Con 19/16) were enrolled and evaluable for toxicity analysis (SBRT and at least 1 cycle N/Ip). Brain metastases were present in 27%. PD-L1 expression: 0% (16), 1-49% (10), >50% (9). Median number of metastases treated with SBRT was 3.2. 6 patients experienced DLT (4 pneumonitis), resulting in dose reduction in central lung Seq cohort of the organs at risk (OAR) by 20%. Median PFS by RECIST (total/Seq/Con) was 5.9 mo, 95% CI: 4.9-13.1/ 6.2 mo, 95% CI: 3.5-12.6/ 5.9 mo, 95% CI: 3.1-18.0. RECIST best response was 11% CR, 57% PR, 6% SD, and 26% PD. Treatment past first progression was allowed, and time to second line therapy (chemotherapy) by arm (Seq/Con) was NR/17.5 months. Median OS has not been reached with median follow up of 15mo. PDL1 status did not impact PFS (p = 0.64) nor OS (p = 0.77). Conclusions: Multisite SBRT and concurrent N/Ip was well tolerated. Responses appear durable as median OS was not reached. Multimodality therapy with mSBRT and dual checkpoint inhibitor therapy resulted in impressive tumor control and clinical benefit with promising efficacy. Clinical trial information: NCT03223155 .

8517 Background: Standard front-line chemotherapy for advanced MPM is (Pem and a platinum; optimal treatment duration is unknown. We performed a randomized phase 2 trial (NCT01085630) to determine if continuation of single-agent Pem after 4-6 cycles of Pem-platinum would improve progression-free survival (PFS). Methods: Eligible pts had histologically confirmed unresectable MPM, and performance status (PS) 0-1. Pts with at least stable disease following 4-6 cycles of Pem-platinum were stratified by first-line regimen (cis- or carboplatin) and histology (epithelioid versus other) and randomized 1:1 to Obs or continuation of Pem until progression. The primary endpoint was PFS. We assumed that Obs produced a median (m) PFS of 3 months (mo) and Pem would yield a 100% improvement in mPFS to 6 mo; 60 eligible pts (30 per arm) were to be randomized. Results: 72 pts from 30 sites registered 12/10-6/16. The study closed early due to slow accrual once 53 pts were randomized; 49 eligible pts (22 Obs, 27 Pem) are included in the efficacy analysis. Pt characteristics (Obs/Pem): age: median (range) 70 (39-85)/70 (52-87); male 68%/78%; PS 0 27%/33%; epithelioid histology 77%/70%; first-line cisplatin 27%/26%. A median of 4 cycles of Pem (range 1-33) was delivered; 22% of pts required dose modification. mPFS was 3 mo on Obs and 3.4 mo on Pem (hazard ratio (HR) 0.99; 95% CI: 0.51-1.90; p=0.9733). Median overall survival (mOS) was 11.8 mo for Obs, and 16.3 mo for Pem (HR 0.86; 95% CI 0.44-1.71; p=0.6737). Toxicities ≥ grade 3 on Pem included anemia 8%, lymphopenia 8%, neutropenia 4%, and fatigue 4%; there were no grade 5 toxicities. A higher baseline level of serum mesothelin related peptide (SMRP) was associated with worse PFS (HR 1.861, p=0.049). Baseline osteopontin did not significantly affect PFS (p=0.3630). Conclusions: Although it was well tolerated, maintenance Pem following initial Pem/platinum doublet chemotherapy does not improve PFS in MPM patients. High baseline SMRP was associated with shorter PFS. Support: U10CA180821, U10CA180882; https://acknowledgments.alliancefound.org . Clinical trial information: NCT01085630.

9088 Background: KEYNOTE-024 established single-agent P as a 1st-line option for pts with metastatic NSCLC without targetable alterations and PD-L1 tumor proportion score (TPS) ≥ 50%. KEYNOTE-189 and 407 established concurrent C + P as a treatment option irrespective of PD-L1 expression. In this randomized phase II selection trial, we explored sequencing of C and P in this pt. population. Methods: Eligible pts were randomized 1:1 to (arm A) C (carboplatin (AUC 6) + pemetrexed 500 mg/m2 (non-squamous) or paclitaxel 200 mg/m2 (squamous)) x 4 cycles followed by P 200 mg x 4 cycles, or the reverse sequence (arm B) of P x 4 cycles followed by C x 4 cycles. After 8 cycles, pts on both arms were eligible to receive maintenance P for up to 24 months. Primary endpoint was objective response rate (ORR) per RECIST 1.1 by independent review. Secondary endpoints included progression free survival (PFS) per RECIST 1.1 and overall survival (OS). Efficacy endpoints were also evaluated by PD-L1 expression. Results: 89 pts (47 arm B & 42 arm A) were enrolled and are included in the analysis (PD-L1 TPS 0/1-49%/≥50% = 24 pts (34%)/25 pts (36%)/21 pts (30%)). There was no significant difference in ORR (36% vs 38%, p = 0.829), median PFS (2.7 vs 5.5 months (mo), HR 1.25, 95% CI 0.77-2.02, p = 0.363) or OS (13.1 vs 19.8 mo, HR 1.25, 95% CI 0.69-2.25, p = 0.4573), arm B (Px4→C) vs arm A (Cx4→P). Multivariable Cox regression analysis demonstrated significant interaction between treatment and PD-L1 TPS ( < 50% vs ≥ 50%) for PFS (HR 6.76, 95% CI 2.14-21.35, p = 0.0011) and a trend for OS (HR 5.02, 95% CI 0.92-27.55, p = 0.0632), arm B vs arm A. Incidence of grade ≥3 adverse events was 71% for arm A and 65% for arm B. No new safety signals were observed. Conclusions: In pts with stage IV NSCLC and PD-L1 TPS ≥ 50% there was an observed improvement in PFS and OS in favor of C followed by P vs P x 4 followed by C. Given small # of pts and trial design, this observation should be considered hypothesis-generating, but supports further exploration of sequential C + P in this setting. Support:Merck Sharp & Dohme Corp.; https://acknowledgments.alliancefound.org Clinical trial information: NCT02591615.

TPS9114 Background: Transforming growth factor β (TGF- β) promotes tumor progression via immune- and non–immune-related processes. M7824 is an innovative first-in-class bifunctional fusion protein composed of 2 extracellular domains of TGF-βRII (a TGF-β “trap”) fused to a human IgG1 monoclonal antibody against PD-L1. Targeting these independent and complementary pathways may restore and enhance antitumor responses. An expansion cohort of the NCT02517398 study of patients with advanced NSCLC (n = 80) treated with M7824 in the second-line setting presented at ESMO 2018 showed an objective response rate of 86% in the subgroup with high PD-L1 tumor expression at the recommended phase 2 dose (1200 mg intravenously [IV] every 2 weeks [Q2W]). Observed data support the hypothesis that M7824 may be superior to other PD-(L)1 inhibitors, including pembrolizumab, for the treatment of NSCLC. Based on the promising antitumor activity and manageable safety profile, this study will evaluate M7824 treatment in patients with advanced NSCLC in the 1L setting. Methods: Here we present a global, randomized trial comparing M7824 vs pembrolizumab in the 1L treatment of patients with metastatic NSCLC with high PD-L1 expression levels. Patients in this study must have a histologically confirmed diagnosis of advanced NSCLC with high PD-L1 expression on tumor cells (defined as either ≥80% by the Dako 73-10 pharmDx kit or ≥50% by the Dako 22C3 pharmDx kit since both assays are expected to select a similar patient population at their respective cut-offs). ECOG performance status must be 0 or 1. Patients must not have received prior systemic treatment for advanced NSCLC. Patients with tumors with actionable mutations (for which targeted therapy is locally approved) are not eligible. Patients will receive 1200 mg Q2W or pembrolizumab 200 mg Q3W as an IV infusion until confirmed disease progression, unacceptable toxicity, or trial withdrawal. Dual primary endpoints are progression-free survival and best overall response; key secondary endpoints include overall survival, duration of response, and safety. Estimated enrollment is 300 patients. Clinical trial information: NCT03631706.

3011 Background: Telisotuzumab vedotin (ABBV-399; teliso-v [T]) is a c-Met–targeted antibody and MMAE drug conjugate. Activity of T was shown in late-line c-Met+ non-small cell lung cancer (NSCLC) irrespective of EGFR mutation (M+) status. We present mature data from the T+ erlotinib (E) cohort of a phase 1b study (NCT02099058) by EGFR M+ status. Methods: T was administered at 2.4 mg/kg (dose-escalation phase) or 2.7 mg/kg IV Q3W, and E at 150 mg PO QD/prior tolerated dose in adult patients (pts) with advanced NSCLC. Efficacy-evaluable pts were c-Met+ (central lab IHC H-score ≥150 or local lab MET amplification/Ex 14 skipping) and had ≥1 postbaseline scan or discontinued study. EGFR M+ was defined as del19 or L858R by local lab. PK was assessed. Results: As of Dec 2018, 42 NSCLC pts received T+E; 37 were c-MET+ (36 evaluable; 35 H-score≥150, 1 MET amplified). Median age was 65 years, 25 pts (69%) had ECOG PS 1, 29 (81%) were EGFR M+ (97% had prior EGFR TKI, 55% 3rd-generation TKI, 69% TKI as last prior therapy, and 62% platinum doublet). All-grade (Gr; ≥20%) adverse events (AEs) were dermatitis acneiform (38%), diarrhea (36%), peripheral motor/sensory neuropathy (52%; 7% Gr 3), dyspnea, fatigue, hypoalbuminemia (31% each), decreased appetite, nausea (24% each), asthenia, vomiting (21% each). Gr ≥3 (≥10%) AE: pulmonary embolism (14%). PK of T+E was similar to single-agent T. The table presents efficacy data. Conclusions: These data suggest acceptable safety and promising activity of T+E and support further study in EGFR M+ c-Met+ NSCLC pts for whom frontline EGFR TKI failed. Clinical trial information: NCT02099058. [Table: see text]

8510 Background: CRT is standard treatment (Tx) for pts with unresectable stage III NSCLC. Vel, a potent oral PARP1/2 inhibitor, interferes with repair of chemotherapy- or radiation-induced DNA damage. In a phase 2 study, Vel showed favorable efficacy vs placebo when added to C/P in stage IV NSCLC. The reported phase 1 trial assessed the safety and efficacy of Vel + C/P-based CRT in Tx of stage III NSCLC (NCT02412371). Methods: Eligible pts (≥18 yr, unresectable stage III NSCLC, no prior NSCLC therapy) received Vel + CRT of weekly C area under the curve (AUC) 2 + P 45 mg/m2 weekly + 60 Gy (2 Gy/day) RT over 6–9 weeks (wk). Vel was dose escalated from 60 mg twice daily (BID) to 240 mg BID followed by Vel 120 mg BID added to consolidation therapy (CON) once every 3 wk of C AUC 6 + P 200 mg/m2 for 2 cycles (cohort 1–5). Cohort 6 received Vel 240 mg BID + CRT followed by Vel 240 mg BID + CON. Samples for pharmacokinetic (PK) analysis were collected on wk 4 day –3. The primary endpoint was to establish the recommended phase 2 dose (RP2D) of Vel + CRT/Vel + CON. Results: As of Sep 2018, 48 pts enrolled into cohorts 1–6 at Vel 60 mg/120 mg (n = 7), 80 mg/120 mg (n = 9), 120 mg/120 mg (n = 7), 200 mg/120 mg (n = 8), 240 mg/120 mg (n = 12), and 240 mg/240 mg (n = 5) added to CRT/CON; median age 65 yr (range, 48–81). Vel PK was dose proportional; 39 (81.3%) pts completed therapy. Grade ≥3 Tx-emergent adverse events (AEs) were reported in 37 (77.1%) pts; anemia and febrile neutropenia (10.4% each) were the most common. Serious AEs were observed in 19 (39.6%) pts. Dose-limiting toxicities occurred at 200 mg/120 mg (n = 1; influenza and pneumonia), 240 mg/120 mg (n = 1; insomnia), and 240 mg/240 mg (n = 2; febrile neutropenia, neutropenia, thrombocytopenia, esophagitis, suprapubic pain, sepsis); Vel 240 mg BID + CRT/Vel 120 mg + CON was chosen as the maximum tolerated dose/RP2D. Of 41 pts evaluable for tumor assessment, 26 (63.4%) had a confirmed response. Interim median progression-free survival was 24.1 mo (range, 8.9 – not reached); updated results will be reported. Conclusions: Vel 240 + CRT/Vel 120 mg BID + CON was well tolerated with promising antitumor activity in stage III NSCLC and was determined as RP2D. Clinical trial information: NCT02412371.

TPS8574 Background: cCRT improves survival vs RT alone and is a global standard of care in patients (pts) with stage III NSCLC, but survival remains poor for these pts. Combining PD-1/PD-L1-targeting immunotherapies and cCRT may lead to synergistic activity and improved outcomes. Tislelizumab (anti–PD-1) demonstrated clinical activity and tolerability in solid tumors, including NSCLC. This phase III, randomized, double-blind, placebo-controlled study (RATIONALE 001) will evaluate efficacy and safety of tislelizumab + cCRT. Methods: Pts (N ≈ 840) will be randomized 1:1:1 in a 3-arm study design to evaluate whether the timing of giving tislelizumab earlier upfront with cCRT in addition to as consolidation (Arm 1) or giving tislelizumab as consolidation only (Arm 2) will improve outcomes vs cCRT alone (Arm 3; Table). RT will be given in 2 Gy fractions to a target dose of 60 Gy (30 fractions). Chemotherapy will be investigator’s choice of cisplatin + etoposide or carboplatin + paclitaxel. A safety analysis specific to the cisplatin + etoposide component of the cCRT + tislelizumab combination is planned. All sites must pass a radiation quality assurance review process. The primary endpoint is PFS. Secondary endpoints include ORR, OS, OS at 24 months, and safety. As an exploratory endpoint, blood and tumor biomarkers will be assessed for correlations with clinical benefit. With a one-sided α of 1.25%, a total of 580 PFS events are required to allow ≈ 90% power to detect a HR for progression or death of 0.7 for either pairwise comparison (Arm 1 vs Arm 3 or Arm 2 vs Arm 3). Key eligibility criteria are locally advanced, unresectable, stage III NSCLC; FDG-PET and brain imaging confirmation of stage III status; no prior treatment; and ECOG PS ≤ 1. PD-L1 expression assessment is not required prior to randomization. EudraCT number 2018-001132-22. Clinical trial information: NCT03745222. [Table: see text]

Purpose Gemcitabine plus cisplatin is active in malignant mesothelioma (MM), although single-arm phase II trials have reported variable outcomes. Vascular endothelial growth factor (VEGF) inhibitors have activity against MM in preclinical models. We added the anti-VEGF antibody bevacizumab to gemcitabine/cisplatin in a multicenter, double-blind, placebo-controlled randomized phase II trial in patients with previously untreated, unresectable MM. Patients and Methods Eligible patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 and no thrombosis, bleeding, or major blood vessel invasion. The primary end point was progression-free survival (PFS). Patients were stratified by ECOG performance status (0 v 1) and histologic subtype (epithelial v other). Patients received gemcitabine 1,250 mg/m2 on days 1 and 8 every 21 days, cisplatin 75 mg/m2 every 21 days, and bevacizumab 15 mg/kg or placebo every 21 days for six cycles, and then bevacizumab or placebo every 21 days until progression. Results One hundred fifteen patients were enrolled at 11 sites; 108 patients were evaluable. Median PFS time was 6.9 months for the bevacizumab arm and 6.0 months for the placebo arm (P = .88). Median overall survival (OS) times were 15.6 and 14.7 months in the bevacizumab and placebo arms, respectively (P = .91). Partial response rates were similar (24.5% for bevacizumab v 21.8% for placebo; P = .74). A higher pretreatment plasma VEGF concentration (n = 56) was associated with shorter PFS (P = .02) and OS (P = .0066), independent of treatment arm. There were no statistically significant differences in toxicity of grade 3 or greater. Conclusion The addition of bevacizumab to gemcitabine/cisplatin in this trial did not significantly improve PFS or OS in patients with advanced MM.

Purpose Erlotinib is clinically effective in patients with non–small-cell lung cancer (NSCLC) who have adenocarcinoma, are never or limited former smokers, or have EGFR mutant tumors. We investigated the efficacy of erlotinib alone or in combination with chemotherapy in patients with these characteristics. Patients and Methods Patients with advanced NSCLC (adenocarcinoma) who were epidermal growth factor receptor tyrosine kinase inhibitor and chemotherapy naive never or light former smokers (smokers of > 100 cigarettes and ≤ 10 pack years and quit ≥ 1 year ago) were randomly assigned to continuous erlotinib or in combination with carboplatin and paclitaxel (ECP) for six cycles followed by erlotinib alone. The primary end point was progression-free survival (PFS). Tissue collection was mandatory. Results PFS was similar (5.0 v 6.6 months; P = .1988) in patients randomly assigned to erlotinib alone (arm A; n = 81) or to ECP (arm B; n = 100). EGFR mutation analysis was possible in 91% (164 of 181) of patients, and EGFR mutations were detected in 40% (51 of 128) of never smokers and in 42% (15 of 36) of light former smokers. In arm A, response rate (70% v 9%), PFS (14.1 v 2.6 months), and overall survival (OS; 31.3 v 18.1 month) favored EGFR-mutant patients. In arm B, response rate (73% v 30%), PFS (17.2 v 4.8 months), and OS (38.1 v 14.4 months) favored EGFR-mutant patients. Incidence of grades 3 to 4 hematologic (2% v 49%; P < .001) and nonhematologic (24% v 52%; P < .001) toxicity was greater in patients treated with ECP. Conclusion Erlotinib and erlotinib plus chemotherapy have similar efficacy in clinically selected populations of patients with advanced NSCLC. EGFR mutations identify patients most likely to benefit.

Purpose Cancer and Leukemia Group B conducted a randomized phase II trial to investigate two novel chemotherapy regimens in combination with concurrent thoracic radiation therapy (TRT). Patients and Methods Patients with unresectable stage III non–small-cell lung cancer (NSCLC) were randomly assigned to carboplatin (area under the curve, 5) and pemetrexed (500 mg/m2) every 21 days for four cycles and TRT (70 Gy; arm A) or the same treatment with cetuximab administered concurrent only with TRT (arm B). Patients in both arms received up to four cycles of pemetrexed as consolidation therapy. The primary end point was the 18-month overall survival (OS) rate; if the 18-month OS rate was ≥ 55%, the regimen(s) would be considered for further study. Results Of the 101 eligible patients enrolled (48 in arm A and 53 in arm B), 60% were male; the median age was 66 years (range, 32 to 81 years); 44% and 35% had adenocarcinoma and squamous carcinoma, respectively; and more patients enrolled onto arm A compared with arm B had a performance status of 0 (58% v 34%, respectively; P = .04). The 18-month OS rate was 58% (95% CI, 46% to 74%) in arm A and 54% (95% CI, 42% to 70%) in arm B. No significant difference in OS between patients with squamous and nonsquamous NSCLC was observed (P = .667). The toxicities observed were consistent with toxicities associated with concurrent chemoradiotherapy. Conclusion The combination of pemetrexed, carboplatin, and TRT met the prespecified criteria for further evaluation. This regimen should be studied further in patients with locally advanced unresectable nonsquamous NSCLC.

Purpose Despite high initial remission rates, most lymphomas relapse and require further therapy. The mammalian target of rapamycin (mTOR) pathway is a validated target in mantle cell lymphoma, but has not been extensively evaluated in other lymphomas. Patients and Methods We performed a phase II trial of single-agent temsirolimus 25-mg weekly in patients with relapsed aggressive and indolent lymphomas. The primary objective was overall and complete response rate. Patients were stratified by histology: group A (diffuse large B-cell lymphoma, transformed follicular lymphoma), group B (follicular lymphoma), and group C (chronic lymphocytic leukemia/small lymphocytic lymphoma, and other indolent lymphomas). Results Eighty-nine patients were treated, with outcome strongly dependent on histology. Group A had an overall and complete response rate of 28.1% and 12.5%, respectively, and median progression-free survival (PFS) of 2.6 months and median overall survival (OS) of 7.2 months. Group B had overall and complete response rates of 53.8% and 25.6%, respectively, and median PFS of 12.7 months; median OS has not yet been reached. Group C had a partial response rate of 11% with no complete responders. Toxicity was mainly mild and/or reversible myelosuppression and mucositis; however, four patients developed pneumonitis. Conclusions Single-agent temsirolimus has significant activity in both diffuse large B-cell lymphoma and follicular lymphoma, although the durability of responses and PFS are longer for patients with follicular lymphoma. This is the first report of substantial activity of temsirolimus in lymphomas other than mantle cell lymphoma, and supports further evaluation of mTOR as a target in these diseases.

Purpose Assess efficacy and toxicity of gefitinib, an epidermal growth factor receptor (EGFR) inhibitor, added to, and in maintenance after, concurrent chemoradiotherapy (CCRT) in locally advanced head and neck cancer (LA-HNC) and correlate outcomes with EGFR gene copy number alterations. Patients and Methods Patients with stage III to IV LA-HNC received two cycles of carboplatin/paclitaxel induction chemotherapy (IC) followed by split-course CCRT with fluorouracil, hydroxyurea, twice daily radiotherapy (FHX), and gefitinib (250 mg daily) followed by continued gefitinib for 2 years total. The primary end point was complete response (CR) rate after CCRT. EGFR gene copy number was assessed by fluorescent in situ hybridization. Results Sixty-nine patients (66 with stage IV disease, 37 with oropharynx primary tumors, and 67 with performance status 0 to 1) were enrolled with a median age of 55 years. Predominant grade 3 or 4 toxicities during IC and CCRT were neutropenia (n = 20) and in-field mucositis (n = 59) and dermatitis (n = 23), respectively. CR rate after CCRT was 90%. After median follow-up of 3.5 years, 4-year overall, progression-free, and disease-specific survival rates were 74%, 72%, and 89%, respectively. To date, one patient has developed a second primary tumor in the aerodigestive tract. In 31 patients with available tissue, high EGFR gene copy number was associated with worse overall survival (P = .02). Conclusion Gefitinib can be administered with FHX and as maintenance therapy for at least 2 years, demonstrating CR and survival rates that compare favorably with prior experience. High EGFR gene copy number may be associated with poor outcome in patients with LA-HNC treated with this regimen.

6042Background: Radiation (RT) or (CRT) is a component of treatment (tx) for locoregionally advanced (LA) SCCHN. ALC and lymphocyte subsets are known to decrease as a result of RT for SCCHN. The ch...

e18090Background: Concurrent chemoradiation (CRT) for LA-HNSCC is an effective treatment modality associated with significant acute and long-term toxicities. In pts with a favorable prognosis, name...

6038Background: An elevated neutrophil-to-lymphocyte ratio (NLR) is associated with tumor-induced inflammation and poor prognosis in a variety of treatment settings. Moreover, tumor-derived myeloid...

6031Background: This phase I/II study evaluates safety and efficacy of veliparib, a PARP inhibitor, with induction carbo-tax in patients (pts) with locoregionally advanced HNSCC. Since PARP is invo...

6014Background: Anti-programmed death receptor-1 (PD-1) therapies are approved for recurrent/metastatic head and neck (H&N) cancer progressing on or after platinum-based chemotherapy, and immune co...

6057Background: Immunotherapy efficacy is modulated by immune competence which lacks well established clinical measures. Nutritional status influences immune competence and has been associated with...

6020Background: The current most widely used standard for HPV status testing in head & neck cancer is p16 IHC. However, p16 IHC is a surrogate method which does not test directly for HPV genetic ma...

e18061Background: Cetuximab, a monoclonal antibody against EGFR, is the only approved targeted therapy for head and neck squamous cell carcinoma (HNSCC), with a single agent response rate of 13%. P...

Purpose During the last 25 years, National Cancer Institute (NCI) cooperative trial groups have extended trial networks from academic centers to include certain community and Veterans Health Administration (VHA) centers. We compared trial patients' attributes and outcomes by these enrollment settings. Patients and Methods Studying 2,708 patients on one of 10 cooperative group, randomized lung trials at 272 institutions, we compared patient attributes by enrollment setting (ie, academic, community, and VHA affiliates). We used adjusted Cox regression to evaluate for survival differences by setting. Results Main member institutions enrolled 44% of patients; community affiliates enrolled 44%; and VHAs enrolled 12%. Patient attributes (ie, case-mix) of age, ethnicity, sex, and performance status varied by enrollment setting. After analysis was adjusted for patient case-mix, no mortality differences by enrollment setting were noted. Conclusion Although trial patients with primarily advanced-stage lung cancer from nonacademic centers were older and had worse performance statuses than those from academic centers, survival did not differ by enrollment setting after analysis accounted for patient heterogeneity. An answer for whether long-term outcomes for patients at community and VHA centers affiliated with cooperative trial groups are equivalent to those at academic centers when care is delivered through NCI trials requires additional research among patients with longer survival horizons.

Purpose The optimal treatment for medically inoperable stage I non–small-cell lung cancer (NSCLC) has not been defined. Patients and Methods Cancer and Leukemia Group B trial 39904 prospectively assessed accelerated, once-daily, three-dimensional radiotherapy for early-stage NSCLC. The primary objectives were to define the maximally accelerated course of conformal radiotherapy and to describe the short-term and long-term toxicity of therapy. Entry was limited to patients with clinical stage T1N0 or T2N0 NSCLC (< 4 cm) and pulmonary dysfunction. The nominal total radiotherapy dose remained at 70 Gy, while the number of daily fractions in each successive cohort was reduced. Results Thirty-nine eligible patients were accrued (eight patients each on cohorts 1 to 4 and seven patients on cohort 5) between January 2001 and July 2005. One grade 3 nonhematologic toxicity was observed in both cohort 3 (dyspnea) and cohort 4 (pain). The major response rate was 77%. After a median follow-up time of 53 months, the actuarial median survival time of all eligible patients was 38.5 months. Local relapse was observed in three patients. Conclusion Accelerated conformal radiotherapy was well tolerated in a high-risk population with clinical stage I NSCLC. Outcomes are comparable to prospective reports of alternative therapies, including stereotactic body radiation therapy and limited resection, with less apparent severe toxicity. Further investigation of this approach is warranted.

Purpose Death from noncancer causes (competing mortality) is an important event in head and neck cancer, but studies identifying predictors of this event are lacking. We sought to identify predictors of competing mortality and develop a risk stratification model for competing events. Patients and Methods Cohort study of 479 patients with stage III to IV carcinoma of the head and neck diagnosed between August 1993 and November 2004. Patients were treated on consecutive prospective clinical trials involving organ-preserving chemoradiotherapy and surgery. We used multivariable competing risks regression models to analyze factors associated with the cumulative incidence of competing mortality, locoregional and distant failure, and second malignancies as first events. Results Median follow-up was 52 months median for survivors. The 5-year cumulative incidence of competing mortality was 19.6% (95% CI, 15.8 to 23.4). On multivariable analysis, competing mortality was associated with female sex (hazard ratio [HR], 1.72; 95% CI, 1.13 to 2.63), increasing age (HR, 1.30; 95% CI, 1.04 to 1.62), increasing Charlson Comorbidity Index (HR, 1.24; 95% CI, 1.05 to 1.47), decreasing body mass index (HR, 0.33; 95% CI, 0.13 to 0.84), and decreasing distance traveled to the treating center (HR, 0.65; 95% CI, 0.44 to 0.98). Patients with zero, one, two, and ≥ three risk factors had 5-year competing mortality of 8.9% (95% CI, 3.0% to 14.8%), 12.4% (95% CI, 7.0% to 17.8%), 22.1% (95% CI, 14.5% to 29.7%), and 39.3% (95% CI, 28.6% to 50.1%), respectively. Conclusion Competing mortality in advanced head and neck cancer is associated with several demographic and health status characteristics. Analyses of risk factors for competing mortality may be useful in outcomes reporting and designing clinical trials.

Purpose Vorinostat, a histone deacetylase inhibitor, exerts anticancer effects by both histone and nonhistone–mediated mechanisms. It also enhances the anticancer effects of platinum compounds and taxanes in non–small-cell lung cancer (NSCLC) cell lines. This phase II randomized, double-blinded, placebo-controlled study evaluated the efficacy of vorinostat in combination with carboplatin and paclitaxel in patients with advanced-stage NSCLC. Patients and Methods Patients with previously untreated stage IIIB (ie, wet) or IV NSCLC were randomly assigned (2:1) to carboplatin (area under the curve, 6 mg/mL × min) and paclitaxel (200 mg/m2 day 3) with either vorinostat (400 mg by mouth daily) or placebo. Vorinostat or placebo was given on days 1 through 14 of each 3-week cycle to a maximum of six cycles. The primary end point was comparison of the response rate. Results Ninety-four patients initiated protocol therapy. Baseline patient characteristics were similar between the two arms. The median number of cycles was four for both treatment arms. The confirmed response rate was 34% with vorinostat versus 12.5% with placebo (P = .02). There was a trend toward improvement in median progression-free survival (6.0 months v 4.1 months; P = .48) and overall survival (13.0 months v 9.7 months; P = .17) in the vorinostat arm. Grade 4 platelet toxicity was more common with vorinostat (18% v 3%; P < .05). Nausea, emesis, fatigue, dehydration, and hyponatremia also were more frequent with vorinostat. Conclusion Vorinostat enhances the efficacy of carboplatin and paclitaxel in patients with advanced NSCLC. HDAC inhibition is a promising therapeutic strategy for treatment of NSCLC.

Purpose A randomized phase II trial of two novel treatment strategies in the first-line management of advanced non–small-cell lung cancer patients with performance status (PS) 2. Patients and Methods Patients were assigned to docetaxel 30 mg/m2 on days 1, 8, and 15 every 28 days in combination with either cetuximab 400 mg/m2 loading dose followed by 250 mg/m2 weekly (D + C) or bortezomib 1.6 mg/m2 on days 1, 8, and 15 every 28 days (D + B) for up to 4 cycles. Patients with responding or stable disease continued cetuximab or bortezomib until progression. The primary end point was progression-free survival (PFS) rate at 6 months. Results Sixty-four patients were enrolled and 59 were included in this analysis. Complete or partial response rates were 13.3% and 10.3% for D + C and D + B, respectively. Median PFS was 3.4 months in the D + C arm and 1.9 months in the D + B arm. Corresponding figures for 6-month PFS were 27.8% and 13.8% and 5.0 and 3.9 months for median survival, respectively. Grade 3/4 hematologic toxicity was 16% for D + C and 21% for D + B, whereas nonhematologic toxicities were observed in 63% and 44% of patients, respectively. There was one treatment-related death in each arm. Conclusion These results confirm the poor prognosis associated with a PS of 2 and the difficulty in translating recent advances in targeted therapy to this subset of patients. While the results in the D + C arm are numerically superior, neither combination met the prespecified PFS end point to justify further research in this setting.

Purpose To evaluate 74 Gy thoracic radiation therapy (TRT) with induction and concurrent chemotherapy in stage IIIA/B non–small-cell lung cancer (NSCLC). Patients and Methods Patients with stage IIIA/B NSCLC were randomly assigned to induction chemotherapy with either carboplatin (area under the curve [AUC], 6; days 1 and 22) with paclitaxel (225 mg/m2; days 1 and 22; arm A) or carboplatin (AUC, 5; days 1 and 22) with gemcitabine (1,000 mg/m2; days 1, 8, 22, and 29; arm B). On day 43, arm A received weekly carboplatin (AUC, 2) and paclitaxel (45 mg/m2) while arm B received biweekly gemcitabine (35 mg/m2) both delivered concurrently with 74 Gy of TRT utilizing three-dimensional treatment planning. The primary end point was survival at 18 months. Results Forty-three and 26 patients were accrued to arms A and B, respectively. Arm B was closed prematurely due to a high rate of grade 4 to 5 pulmonary toxicity. The overall response rate was 66.6% (95% CI, 50.5% to 80.4%) and 69.2% (95% CI, 48.2% to 85.7%) on arm A and B, respectively. The median survival time (MST) and 1-year survival rate was 24.3 months (95% CI, 12.3 to 36.4) and 66.7% (95% CI, 50.3 to 78.7) and 12.5 months (95% CI, 9.4 to 27.6) and 50.0% (95% CI, 29.9 to 67.2) for arms A and B, respectively. The primary toxicities included esophagitis, pulmonary, and fatigue. Conclusion Arm A reached the primary end point with an estimated MST longer than 18 months and will be compared with a standard dose of TRT in a planned randomized phase III trial in the United States cooperative groups.

PurposeTo assess the pharmacogenomic and pharmacokinetic determinants of skin rash and diarrhea, the two primary dose-limiting toxicities of the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor erlotinib.Patients and MethodsA prospective clinical study of 80 patients with non–small-cell lung cancer, head and neck cancer, and ovarian cancer was performed. Detailed pharmacokinetics and toxicity of erlotinib were assessed. Polymorphic loci in EGFR, ABCG2, CYP3A4, and CYP3A5 were genotyped, and their effects on pharmacokinetics and toxicities were evaluated.ResultsA novel diplotype of two polymorphic loci in the ABCG2 promoter involving −15622C/T and 1143C/T was identified, with alleles conferring lower ABCG2 levels associated with higher erlotinib pharmacokinetic parameters, including area under the curve (P = .019) and maximum concentration (P = .006). Variability in skin rash was best explained by a multivariate logistic regression model incorporating the trough erlotinib plasma concentration (P = .034) and the EGFR intron 1 polymorphism (P = .044). Variability in diarrhea was associated with the two linked polymorphisms in the EGFR promoter (P < .01), but not with erlotinib concentration.ConclusionAlthough exploratory in nature, this combined pharmacogenomic and pharmacokinetic model helps to define and differentiate the primary determinants of skin and gastrointestinal toxicity of erlotinib. The findings may be of use both in designing trials targeting a particular severity of rash and in considering dose and schedule modifications in patients experiencing dose-limiting toxicities of erlotinib or similarly targeted agents. Further studies of the relationship between germline polymorphisms in EGFR and the toxicity and efficacy of EGFR inhibitors are warranted.

Purpose Expression of erbB2 and/or epidermal growth factor receptor (EGFR) is associated with biologic aggressiveness and poor prognosis in malignant salivary gland tumors (MSGTs). This phase II study was conducted to determine the antitumor activity of lapatinib, a dual inhibitor of EGFR and erbB2 tyrosine kinase activity, in MSGTs. Patients and Methods Patients with progressive, recurrent, or metastatic adenoid cystic carcinoma (ACC) immunohistochemically expressing at least 1+ EGFR and/or 2+ erbB2 were treated with lapatinib 1,500 mg daily, in a two-stage cohort. Patients with non-ACC MSGTs were treated as a separate single-stage cohort. Results Of 62 patients screened, 29 of 33 (88%) ACC and 28 of 29 (97%) non-ACC patients expressed EGFR and/or erbB2. Forty patients with progressive disease were enrolled onto the study. Among 19 assessable ACC patients, there were no objective responses, 15 patients (79%) had stable disease (SD), nine patients (47%) had SD ≥ 6 months, and four patients (21%) had progressive disease (PD). For 17 assessable non-ACC patients, there were no objective responses, eight patients (47%) had SD, four patients (24%) had SD ≥ 6 months, and nine patients (53%) had PD. The most frequent adverse events were grade 1 to 2 diarrhea, fatigue, and rash. Eight paired tumor biopsies for correlative studies were procured; results did not correlate with clinical outcome. Conclusion Although no responses were observed, lapatinib was well tolerated, with prolonged tumor stabilization of ≥ 6 months in 36% (95% CI, 21% to 54%) of assessable patients. The antitumor effects of lapatinib in MGSTs appear mainly cytostatic, hence evaluation of other molecular targeted agents, or combinations with lapatinib, may be considered. Continued efforts should be made to gain better understanding into the biology of this heterogeneous group of malignancies.

Purpose Standard therapy for unresectable stage III non–small-cell lung cancer includes concomitant chemoradiotherapy. In Cancer and Leukemia Group B 39801, we evaluated whether induction chemotherapy before concurrent chemoradiotherapy would result in improved survival. Patients and Methods Between July 1998 and May 2002, 366 patients were randomly assigned to arm A, which involved immediate concurrent chemoradiotherapy with carboplatin area under the concentration-time curve (AUC) of 2 and paclitaxel 50 mg/m2 given weekly during 66 Gy of chest radiotherapy, or arm B, which involved two cycles of carboplatin AUC 6 and paclitaxel 200 mg/m2 administered every 21 days followed by identical chemoradiotherapy. The accrual goal was 360 patients. Results Thirty-four percent of patients were female, 66% were male, and the median age was 63 years. Grade 3 or 4 toxicities during induction chemotherapy on arm B consisted mainly of neutropenia (18% and 20%, respectively). During concurrent chemoradiotherapy, there was no difference in severity of in-field toxicities of esophagitis (grade 3 and 4 were, respectively, 30% and 2% for arm A v 28% and 8% for arm B) and dyspnea (grade 3 and 4 were, respectively, 11% and 3% for arm A v 15% and 4% for arm B). Survival differences were not statistically significant (P = .3), with a median survival on arm A of 12 months (95% CI, 10 to 16 months) versus 14 months (95% CI, 11 to 16 months) on arm B and a 2-year survival of 29% (95% CI, 22% to 35%) and 31% (95% CI, 25% to 38%). Age, weight loss before therapy, and performance status were statistically significant predictive factors. Conclusion The addition of induction chemotherapy to concurrent chemoradiotherapy added toxicity and provided no survival benefit over concurrent chemoradiotherapy alone. The median survival achieved in each of the treatment groups is low, and the routine use of weekly carboplatin and paclitaxel with simultaneous radiotherapy should be re-examined.

Purpose Patients with intermediate-stage squamous cell carcinoma of the head and neck traditionally have been treated with initial surgical resection followed by radiotherapy (RT) alone or chemoradiotherapy. A previous study in this patient population reported a 91% locoregional control rate and 65% overall survival (OS) rate at 5 years, with chemoradiotherapy used as primary treatment. This study was undertaken to assess whether shortening treatment duration with hyperfractionated RT would be feasible and improve locoregional control, organ preservation, and progression-free survival. Methods Eligible patients with stage II or III disease received fluorouracil, hydroxyurea, and RT given twice daily on a week-on/week-off schedule. Quality-of-life scores were measured using three validated indexes. Results All 53 patients enrolled are included in the analysis, with a median follow-up of 42 months (range, 5 to 98 months). Grade 3 or 4 in-field mucositis was observed in 77% and 9%, respectively. No patients required surgical salvage at the primary tumor site (pathological complete response rate, 100%). The 3-year progression-free and OS rates are 67% and 78%, respectively. The 3-year disease-specific mortality rate is 7%. At the time of analysis, 87% of surviving patients do not require enteral feeding support. Quality-of-life and performance assessment indicated that, although acute treatment toxicities were severe, most patients returned to pretreatment function by 12 months. Conclusion Concurrent chemoradiotherapy with hyperfractionated RT is feasible in this patient population and yields high local control and cure rates. Compared with our historical control using once-daily fractionation, hyperfractionation is accompanied by increased acute in-field toxicity.

The response of patients to drug therapy is variable and unpredictable. The current focus of pharmacogenetics is to find common genetic variants that are predictors of clinical phenotypes associated with drug therapy. This goal is usually pursued by genotyping patients for a particular polymorphism (a genetic variant occurring in 1% of the population), a set of polymorphisms in the same gene, or different polymorphisms in different genes. The genes of interest in pharmacogenetics are those involved in the mechanism of action and/or disposition of a certain drug. For the classic cytotoxic agents commonly used in oncology, the elucidation of potential genetic predispositions of patients to severe toxicity has been of interest with a goal of improving their therapeutic index. The pharmacogenetics of irinotecan (irinogenetics) indicate that a common polymorphism in the uridine diphosphateglucuronosyltransferase 1A1 (UGT1A1) gene predisposes patients to severe toxicity. This variant is a TA repeat promoter polymorphism reducing the expression of the UGT1A1 gene. In this issue, Han et al analyzed the association between common variants in several UGT1A genes, including UGT1A1, and evaluated the impact of these variants on toxicity and efficacy of irinotecan administered with cisplatin in a population of Korean non– small-cell lung cancer (NSCLC) patients. This article indicates that, in addition to the TA repeat polymorphism, another common variant found only in individuals of East Asian descent might have a predictive role. Moreover, this article suggests that these polymorphisms might have an impact on the antitumor efficacy of irinotecan. To have a better understanding of the findings of Han et al, we need to clarify the structure of the UGT1A gene. In humans, there are nine functional UGT1A enzymes with different patterns of tissue distribution. As partly shown in Figure 1 of the article by Han et al, UGT1A isoforms are generated from a single UGT1A gene by splicing of individual exons 1 with common exons 2 to 5, spanning more than 200 Kb of genomic sequence on chromosome 2. Polymorphisms in the common exons are relatively uncommon but would potentially affect the expression or function of all UGT1A isoforms. However, there are many common polymorphisms that affect the expression or function of single isoforms, either in their exon 1 or in the upstream promoter area. Irinotecan is mainly used in metastatic colorectal cancer patients. Regimens containing irinotecan are often relegated to second-line therapy because of unpredictable toxicity and the availability of equally effective agents (eg, oxaliplatin). Irinotecan causes severe diarrhea and neutropenia in 20% to 35% of patients. The late-onset grade 3 or 4 diarrhea often does not respond to the recommended loperamide therapy and can require hospitalization, irinotecan dose modifications, and/or dose interruptions, potentially compromising efficacy. Fatal events (up to 5.3% prevalence) during single-agent irinotecan treatment have been reported, and concerns have been expressed regarding an excessive rate of early deaths in colorectal cancer patients receiving irinotecan/fluorouracil regimens. Despite this discouraging scenario, recent studies have shown that irinotecan is an active drug with an important role in standard-of-care treatment regimens for colorectal cancer. Overall survival of metastatic colorectal cancer patients can be excellent if patients receive all active drugs, including irinotecan, during their course of treatment. The understanding of irinotecan pharmacology and genetic variability of key genes has made possible the identification of a subset of patients who are genetically predisposed to severe toxicity. In normal and tumor tissues, the hydrolysis of irinotecan leads to the formation of SN-38, a potent topoisomerase inhibitor. SN-38 formation within the tumor may be an important determinant of antitumor activity. The inactivation of SN-38 occurs by glucuronidation to SN-38 glucuronide (SN-38G), mainly through UGT1A1, an isoform expressed in the liver and also in extrahepatic tissues. In addition to UGT1A1, other UGT1A isoforms (including UGT1A6, UGT1A7, UGT1A9, and UGT1A10) are capable of metabolizing SN-38. It is likely that the exposure of patients to SN-38 is the ultimate result of the contribution of several UGT1As, in particular those that are highly expressed in the liver. High interpatient variability in irinotecan clearance and SN-38 area under the curve (AUC) has been observed, but there is no consistency across different studies on whether the AUC of irinotecan, SN-38, SN-38G, or a combination of these three parameters (the biliary index) is the strongest predictor of either severe neutropenia or diarrhea. However, it is certainly clear that changes in function of the UGT1A1 gene in patients will affect the exposure to SN-38, resulting in different susceptibility to toxicity among patients. The most studied polymorphism in irinogenetics is a common TA repeat variant in the UGT1A1 promoter. In the population, five, six, seven, and eight TA repeats can be found. UGT1A1 expression in individuals is inversely correlated with the number of TA repeats. In pharmacogenetics, gene variants are numbered with a “*” (star) preceding a number. The *1 allele of a gene is the allele of the reference sequence (previously referred to as wild-type allele, a term that is becoming obsolete). Hence, the six TA repeat allele is JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 24 NUMBER 15 MAY 2

Purpose Among patients with small-cell lung carcinoma, African Americans have lower survival rates than non–African Americans. We investigated whether the disparity in survival would persist when patients were treated with similar therapies (ie, phase II/III Cancer and Leukemia Group B [CALGB] trials). Patients and Methods We assessed 995 patients (928 non–African American and 67 African American) receiving chemotherapy in CALGB studies for extensive-stage small-cell lung cancer (ES-SCLC). Clinical and demographic characteristics, treatment received, and survival data were obtained from the CALGB database. The Cox proportional hazards model was used to assess the effect of race/ethnicity on survival after adjustment for other known prognostic factors. All statistical tests were two sided. Results The unadjusted survival distribution of African American patients was not significantly different from that of non–African American patients; median survival was 11.5 months (95% CI, 9.4 to 13.4 months) for African American patients versus 9.9 months (95% CI, 9.6 to 10.3 months) for non–African American patients. Multivariable adjustment for the effect of treatment arm, histology, and metastatic site at presentation did not alter the outcome for African American patients. Survival was similar even though African American patients were more likely to have a poorer performance status, present with significant weight loss, and be Medicaid recipients (20% v 6%), which is an indicator of lower socioeconomic status. Conclusion African American patients tended to present with prognostic features associated with a worse survival. However, when offered equivalent therapy, the outcome for African American patients was the same as that observed for non–African American patients.

Purpose Vascular endothelial growth factor (VEGF) plays a key role in the biology and prognosis of pancreatic cancer. Inhibitors of VEGF suppress the growth of pancreatic cancer in preclinical models. The objectives of this phase II study were to assess the response rate and overall survival of pancreatic cancer patients who received gemcitabine with the recombinant humanized anti-VEGF monoclonal antibody bevacizumab. Patients and Methods Patients with previously untreated advanced pancreatic cancer received gemcitabine 1,000 mg/m2 intravenously over 30 minutes on days 1, 8, and 15 every 28 days. Bevacizumab, 10 mg/kg, was administered after gemcitabine on days 1 and 15. Tumor measurements were assessed every two cycles. Plasma VEGF levels were obtained pretreatment. Results Fifty-two patients were enrolled at seven centers between November 2001 and March 2004. All patients had metastatic disease, and 83% had liver metastases. Eleven patients (21%) had confirmed partial responses, and 24 (46%) had stable disease. The 6-month survival rate was 77%. Median survival was 8.8 months; median progression-free survival was 5.4 months. Pretreatment plasma VEGF levels did not correlate with outcome. Grade 3 and 4 toxicities included hypertension in 19% of the patients, thrombosis in 13%, visceral perforation in 8%, and bleeding in 2%. Conclusion The combination of bevacizumab plus gemcitabine is active in advanced pancreatic cancer patients. Additional study is warranted. A randomized phase III trial of gemcitabine plus bevacizumab versus gemcitabine plus placebo is ongoing in the Cancer and Leukemia Group B.

Purpose This study aimed to assess the antitumor activity of imatinib in adenoid cystic carcinoma (ACC) of the salivary gland expressing c-kit. A high level of c-kit expression has been identified in more than 90% of ACCs. Imatinib specifically inhibits autophosphorylation of the bcr-abl, platelet-derived growth factor receptor beta, and c-kit tyrosine kinases. Patients and Methods In a single-arm, two-stage, phase II clinical trial, adult patients with unresectable or metastatic ACC measurable by Response Evaluation Criteria in Solid Tumors Group criteria and expressing c-kit by immunohistochemistry were treated with imatinib 400 mg orally bid. Response was assessed every 8 weeks. Results Sixteen patients have been enrolled onto the study; 10 were female. Median age was 47 years (range, 31 to 69 years). Median Eastern Cooperative Oncology Group performance status was 1 (range, 0 to 2). Fourteen patients had lung metastases, 14 had prior radiotherapy, and six had prior chemotherapy. Toxicities occurring in at least 50% of patients included fatigue, nausea, vomiting, diarrhea, anorexia, edema, dyspnea, and/or headache, usually of mild to moderate severity. In 15 patients assessable for response, no objective responses have been observed. Nine patients had stable disease as best response. Six patients had progressive disease after two cycles. Conclusion Because of the lack of activity, the study has been stopped after the first stage and additional evaluation of imatinib in this population is not warranted. Overexpression of wild-type c-kit was not sufficient for clinical benefit from imatinib in ACC. Accrual to this study was rapid for a relatively rare cancer, encouraging additional efforts to identify more effective systemic therapy for these patients.