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PURPOSE Resistance to immune checkpoint inhibition (ICI) in advanced non–small-cell lung cancer (NSCLC) represents a major unmet need. Combining ICI with vascular endothelial growth factor (VEGF)/VEGF receptor inhibition has yielded promising results in multiple tumor types. METHODS In this randomized phase II Lung-MAP nonmatch substudy (S1800A), patients ineligible for a biomarker-matched substudy with NSCLC previously treated with ICI and platinum-based chemotherapy and progressive disease at least 84 days after initiation of ICI were randomly assigned to receive ramucirumab plus pembrolizumab (RP) or investigator's choice standard of care (SOC: docetaxel/ramucirumab, docetaxel, gemcitabine, and pemetrexed). With a goal of 130 eligible patients, the primary objective was to compare overall survival (OS) using a one-sided 10% level using the better of a standard log-rank (SLR) and weighted log-rank (WLR; G[rho = 0, gamma = 1]) test. Secondary end points included objective response, duration of response, investigator-assessed progression-free survival, and toxicity. RESULTS Of 166 patients enrolled, 136 were eligible (69 RP; 67 SOC). OS was significantly improved with RP (hazard ratio [80% CI]: 0.69 [0.51 to 0.92]; SLR one-sided P = .05; WLR one-sided P = .15). The median (80% CI) OS was 14.5 (13.9 to 16.1) months for RP and 11.6 (9.9 to 13.0) months for SOC. OS benefit for RP was seen in most subgroups. Investigator-assessed progression-free survival (hazard ratio [80% CI]: 0.86 [0.66 to 1.14]; one-sided SLR, P = .25 and .14 for WLR) and response rates (22% RP v 28% SOC, one-sided P = .19) were similar between arms. Grade ≥ 3 treatment-related adverse events occurred in 42% of patients in the RP group and 60% on SOC. CONCLUSION This randomized phase II trial demonstrated significantly improved OS with RP compared with SOC in patients with advanced NSCLC previously treated with ICI and chemotherapy. The safety was consistent with known toxicities of both drugs. These data warrant further evaluation.

9060 Background: Inactivating STK11 genomic alterations are prevalent in non-squamous (nsq) NSCLC and define a patient (pt) subgroup with poor prognosis and inferior response to immune checkpoint inhibitors (CPIs). PARP inhibitors (PARPi) can potentiate response to CPIs in preclinical models. We conducted a single arm Phase II study within Lung-MAP to evaluate the efficacy and safety of talazoparib in combination with avelumab in patients (pts) with previously treated nsq NSCLC harboring pathogenic STK11 genomic alterations. Methods: Eligibility: STK11 pathogenic somatic mutation or bi-allelic loss on tumor identified via LUNGMAP screening; stage IV or recurrent nsq NSCLC, receipt of one prior line of anti-PD-1/anti-PD-L1 therapy and platinum-based chemotherapy for stage IV or recurrent disease (sequentially or in combination) and disease progression > 42 days following treatment initiation, a ECOG PS of 0-1, adequate organ function and no previous PARPi exposure. Pts received talazoparib (1000 mg PO daily) plus avelumab (800 mg IV Q2W). Co-primary objectives were to evaluate the best objective response rate (ORR) and disease control rate at 12 weeks (DCR12) after study registration, assessed by RECISTv1.1. Rejection of an ORR of 10% required ≥ 8 responses or rejection of a DCR12 of 30% required ≥18 w/ disease control at 12 weeks and ≥4 responses. Results: 47 pts enrolled from January 16 - November 16, 2020; 42 pts met eligibility (50% male, 50% female). 54% of pts had PD-L1 TPS < 1%. The median TMB was 8.83 Mut/Mb and 45% of pts had KRAS mutations. 52% of the pts had received ≥2 prior lines of treatment for stage IV disease. As of the November 24, 2021 data cutoff, 3 pts remain on treatment, the ORR was 2% (n = 1) and the DCR12 was 40% (n = 17). 26 pts (62%) had SD as best objective response. One responding pt remained on treatment for > 14 mo. The median progression-free survival (39 events) was 2.7 mo (95% CI, 1.6-3.9 mo) and the median overall survival (30 events) was 7.6 mo (95% CI, 6.3-12.2 mo). There were no reported grade 5 treatment toxicities and most grade 3-4 toxicities were hematologic. Additional biomarker analysis to assess effects of key co-mutations on clinical outcomes will be presented. Conclusions: Treatment with talazoparib and avelumab did not meet the pre-specified threshold for efficacy in previously treated STK11-mutant NSCLC in this biomarker-driven Phase II study, though durable disease stabilization was observed. Further studies are required to determine optimal therapeutic approaches for this challenging subset of NSCLC pts. Funding: NIH/NCI grants U10CA180888, U10CA180819. Talazoparib was provided by Pfizer. Avelumab was provided by Pfizer, as part of an alliance between Pfizer and the healthcare business of Merck KGaA, Darmstadt, Germany (CrossRef Funder ID: 10.13039/100004755). Clinical trial information: NCT04173507.

9004 Background: Resistance to immune checkpoint inhibitor (ICI) therapy develops in most patients (pts) with advanced non-small cell lung cancer (NSCLC). Tumors that develop resistance to ICI constitute a major unmet need. Combined ICI and VEGF/VEGF receptor inhibition have shown benefit in multiple tumor types through immune modulation. We evaluated pembrolizumab and ramucirumab (P+R) in advanced, ICI-exposed NSCLC, under the aegis of Lung-MAP, a master protocol for pts with stage IV, previously treated NSCLC. Pt characteristics and treatment toxicities were presented at ASCO 2021. Methods: S1800A was a randomized phase II trial for pts ineligible for a biomarker-matched substudy with acquired resistance to ICI defined as previous ICI therapy for at least 84 days with progressive disease (PD) on or after therapy. Eligibility stipulated PD on prior platinum-based doublet therapy (sequential or in combination with ICI) and ECOG PS of 0-1. Pts were stratified by PD-L1 expression, histology, and intent to receive ramucirumab in the standard of care (SOC) arm and were randomized to P+R or SOC (investigator’s choice of docetaxel+R; docetaxel, pemetrexed, gemcitabine). With a goal of 144 total/130 eligible pts, the primary objective was to compare overall survival (OS) between the arms using a 1-sided 10% level log-rank test upon 90 deaths. Secondary endpoints included response, duration of response, investigator assessed-progression free survival and toxicity. Results: From May 17, 2019 to November 16, 2020, 166 pts were enrolled with 137 eligible (69 P+R; 68 SOC [45 +R, 23 w/o R]). Main causes for ineligibility were lack of PD on ICI or chemotherapy (6 SOC, 6 P+R), > 1 line of ICI (2 P+R), ICI discontinued due to toxicity (2 SOC), or lack of measurable disease (2 SOC, 1 P+R). OS was significantly improved with P+R (HR: 0.61 [0.38-0.97], 1-sided p-value = 0.019; median [95% CI] OS of 15.0 (13.2-17) months (mo) for P+R and 11.6 (8.5-13.8) mo in SOC arm). Progression-free survival (PFS) was not different between the arms (HR: 0.86 [0.57-1.31], 1-sided p-value=0.25; median PFS (95% CI) of 4.5 (4.0-6.9) mo for P+R and 5.2 (4.0-6.6) mo in SOC arm). ORR was not different between the arms (p=0.28). OS benefit for P+R was seen in most subgroups. Analysis of survival based on genomic alterations, tumor mutational burden and PD-L1 will be presented. Conclusions: Pembrolizumab + ramucirumab in pts with advanced NSCLC previously treated with chemotherapy and immunotherapy led to improved OS compared to SOC. Discordance of ORR and PFS from OS has been reported in prior ICI trials (Rittmeyer et al. Lancet 2017). This is the first trial in the 2nd line setting without a chemotherapy backbone to demonstrate a potential survival benefit compared to SOC regimens including docetaxel and ramucirumab using the Lung-MAP platform. Clinical trial information: NCT03971474.

3564 Background: Patients (pts) with KRAS wild-type (WT) mCRC treated with single agent anti-EGFR therapy (tx) have improved OS compared to BSC but only a 10-15% response rate. Prior EGFR tx may upregulate HER amplification. For pts with quadruple WT mCRC (KRAS, NRAS, BRAF, PIC3KA), data suggest that dual targeting of the MAPK pathway, specifically EGFR and HER2, may be more effective. The purpose of this study was to evaluate the activity of dual MAPK pathway inhibition based on HER2 status: amplified (amp), non-amplified (non-amp), or mutated (mt). Methods: This 2-arm phase II trial enrolled pts with quad WT mCRC with ECOG PS 0-2, adequate organ function, prior oxaliplatin- and irinotecan-based regimens, and known HER2 status. Arm 1: HER2 amp (confirmed as >2.14 copy number by Guardant 360) and prior anti-EGFR tx or HER2 mt (with qualifying mt) with or without prior anti-EGFR tx; Arm 2: HER2 non-amp or HER2 amp without prior anti-EGFR tx. Tx included T 4 mg/kg IV loading dose → 2 mg/kg/wk and N 240 mg po daily (Arm 1) or C 400 mg/m2 IV loading dose → 250 mg/m2/wk and N 240 mg po daily (Arm 2). Imaging was performed every 8 wks with response per RECIST 1.1. Primary end point (EP) of each arm was 6 mo PFS (PFS6). Secondary EPs: Response rate (ORR), clinical benefit rate (CBR), toxicity and exploratory assessments of N pharmacokinetics, genetic and molecular analyses, and evaluation of multiple drug combinations in PDX/PDXO models. We tested H0: PFS6 A: PFS6 >0.47 (α=0.05; power=0.90 to reject HA). Treating 15 pts in each arm, if ≥5 pts are alive and progression free (PFS6 0.33), the arm is worth further testing. Results: From Jul 2018 - Mar 2021, 25 pts enrolled from 9 different centers. Arm 1 closed due to poor accrual (n=4). Those pts have been excluded from further analysis. Arm 2 enrolled 21 pts. with 15 evaluable for response by imaging. Early discontinuation occurred in 6 of 21 pts: 2 withdrew consent, 3 due to toxicity, and 1 physician withdrawal. Of the 15 evaluable pts, there were 6 PR, 5 of 13 HER2 non-amp, 1 of 2 HER2 amp, (duration 120-171 days; mean 140) and 5 SD (duration 59-231 days; mean 124). The ORR (CR/PR) in all pts who received at least one dose of tx is 33% (6/20). 8 of 15 evaluable pts (53%) were progression free at cycle 6. Common grade 3+ AEs (>5%) included diarrhea (24%), rash (8%), and abdominal pain/distension (8%), without any grade 5 AEs. Conclusions: The combination of C+N was reasonably well tolerated with expected toxicities of diarrhea and rash. The ORR, CBR, and PFS compare favorably to pts previously relapsed following oxaliplatin and irinotecan and treated with single-agent anti-EGFR tx. Upon entry, biopsies for PDX implantation had an engraftment success rate of ̃80%. We anticipate using these grafts to establish PDXO models for molecular analyses and further drug testing. Support: NSABP Foundation, Puma Biotechnology. Clinical trial information: NCT03457896.

9075 Background: The therapeutic landscape in metastatic NSCLC has dramatically changed with approvals of immunotherapy agents in both treatment-naïve and previously treated cancer patients (pts) and irrespective of histology. Pts with tumors that develop resistance is a significant area of unmet need. Vascular endothelial growth factor (VEGF) has been shown to modulate the tumor immune microenvironment and combination immune checkpoint and VEGF/VEGF receptor inhibition have shown benefit in multiple tumor types. Lung-MAP is a master protocol for pts with stage IV, previously treated NSCLC. Pts who were not eligible for a biomarker-matched substudy enrolled in S1800A. The adverse event profile will be presented. Methods: S1800A is a phase II randomized trial for pts who previously received PD-1 or PD-L1 inhibitor therapy for at least 84 days and platinum-based doublet therapy with ECOG 0-1 stratified by PD-L1 expression, histology and intent to receive ramucirumab in the standard of care (SOC) arm. Pts were randomized 1:1 to pembrolizumab and ramucirumab P+R or SOC (docetaxel +R [SOC w R]; docetaxel, pemetrexed or gemcitabine [SOC wo R]). The primary endpoint was overall survival. Secondary endpoints included response, duration of response, investigator assessed-progression free survival and evaluation of toxicity. Results: From May 17, 2019 to November 16, 2020, 166 pts enrolled and 140 determined eligible [69 (49%) P+R; 46 (33%) SOC w R; 25 (18%) SOC wo R]. Treatments for those who received SOC wo R included 3 on docetaxel (19%); 12 on gemcitabine (75%); and on 1 on pemetrexed (6%). 131 were eligible for adverse event (AE) assessment. The most common AE were fatigue (38%), proteinuria (28%), hypertension (23%), diarrhea (22%) and hypothyroidism (22%) on P+R; fatigue (61%), anemia (48%), diarrhea (41%) and neutropenia (39%) on SOC w R and anemia (56%), leukopenia (56%), fatigue (44%) and neutropenia (44%) on SOC wo R. Grade ≥ 3 treatment-related AEs occurred in 32% of pts on P+R, 54% of pts on SOC w R and 56% of pts on SOC wo R. Cardiac and thromboembolic events occurred in 12% of pts on P+R, 11% of pts on SOC w R and 0% of pts on SOC wo R. Grade 5 AE occurred in 2 pts on P+R (respiratory failure and cardiac arrest), 3 pts on SOC w R (2 respiratory failure and sepsis) and 1 pt on SOC wo R (sepsis). Four patients were diagnosed with COVID-19 (1 on P+R and 3 on SOC) and 3 died (1 on P+R and 2 on SOC). Conclusions: Grade 3 toxicities were lower in P+R compared to SOC arms with or without R. Cardiac and thromboembolic events were similar in arms that included R. P+R was generally well-tolerated. Efficacy outcomes will be presented when data matures. Clinical trial information: NCT03971474.

7503 Background: Optimal initial therapy for mantle cell lymphoma (MCL) remains uncertain. The randomized phase 2 NCTN trial E1411 tested if progression-free survival (PFS) is prolonged by addition of bortezomib (V) (1.6 mg/m2 SC/IV days 1, 8) to bendamustine-rituximab (BVR vs BR) induction and/or by addition of lenalidomide (L) to rituximab (LR vs R) consolidation. Here we report efficacy and toxicity of induction BVR vs BR. Methods: 373 pts, accrued 2012–16, stratified by MIPI and age (≥60) received 1 of 4 arms: A) BR induction x 6 followed by R x 2 yrs, B) BVR followed by R, C) BR followed by LR or D) BVR followed by LR. Eligible pts had untreated MCL, ≥ age 18 (amended from ≥60 when S1106 for < 65 closed), ECOG PS 0-2 and adequate hematologic and organ function. Pts without progressive disease during induction proceeded to consolidation. Primary induction objective was whether adding bortezomib (BVR) (Arms B + D) to BR (Arms A + C) improves PFS, irrespective of consolidation R vs LR. Design of 360 eligible treated pts would provide 93.8% power to detect 10% improvement in 2-yr PFS from 70% hypothesized for BR, corresponding to 37.4% reduction in hazard using stratified log-rank test at 1-sided 10% alpha. Efficacy population was 179 (BVR) and 180 (BR), induction treatment completed in 144 vs 153, progressive disease during induction 6 vs 7 and registration to consolidation 140 vs 145. Results: Baseline demographics did not differ between the groups, with median age 67 (range 42-90) and 13% < 60 yr, 73% men, ECOG PS 0-1 97%, MIPI Low/Med/Hi 37/29/34%. Estimated PFS at 2 yrs 79.6% BVR (95% CI 73.8-85.9) vs 74.5% BR (95% CI 68.2-81.4) (1-sided stratified log-rank p = 0.268). With median PFS follow-up 51 mos, median PFS estimated at 64.1 and 64.0 mos. Overall response rate (ORR) for BVR was 88.9% (CR 65.5%) vs 89.5% (CR 60.5%) BR (z-test 1 sided p = 0.577 for ORR). Treatment related deaths during induction were 2 in BVR (cardiac arrest, hepatitis) and 1 in BR (tumor lysis). Grade ≥ 3 toxicities were 88.1% (163/185) BVR vs 77.5% (145/187) BR. For BVR vs BR grade ≥ 3 neutropenia occurred in 52 vs 39 pts, though febrile neutropenia (7 vs 6), anemia (7 vs 8) and thrombocytopenia (18 vs 16) did not differ. Peripheral neuropathy (PN) grade 2 was 8 sensory for BVR vs 2 sensory/1 motor for BR, while grade 3 PN was 6 sensory/1 motor for BVR vs 0 with BR. The only non-hematologic grade ≥ 3 toxicity in > 5% of pts was rash (9 vs 12 pts). Conclusions: Bortezomib did not significantly improve the primary endpoint of PFS when added to BR as initial MCL therapy. ORR and CR rates at end of induction were also similar. Follow-up continues to assess the entire treatment regimen, including consolidation R vs LR, but the PFS > 5 yrs, high ORR and MRD negativity rate (Smith et al ASH 2019) in this BR-based trial support BR as a platform for MCL induction therapy. Clinical trial information: NCT01415752.

TPS4593 Background: Bone metastases are prevalent in approximately 30% of pts with advanced RCC. Pts with bone metastases have a worse prognosis compared to pts without bone metastases and are at risk of symptomatic skeletal events (SSEs). Cabozantinib, a multitargeted inhibitor of multiple kinases, including vascular endothelial growth factor (VEGF) receptor and MET, has improved survival in pts with metastatic RCC and has enhanced activity in bone. Ra-223, an alpha-emitting radioisotope with natural bone-seeking proclivity, has been shown to prolong survival in men with castration-resistant prostate cancer. We previously conducted a pilot study of Ra-223 with VEGF inhibition and demonstrated safety and declines in markers of bone formation and resorption with the combination (McKay et al, CCR 2018). Given that decreasing rates of SSEs and improving outcomes for pts with RCC with bone metastases are unmet needs in pts with RCC, we designed a randomized phase 2 study through the National Clinical Trials Network (NCTN) investigating cabozantinib with or without Ra-223 in patients with RCC with bone metastases. Methods: This is an open-label multicenter study. Eligible pts have metastatic RCC of any histology with ≥2 metastatic bone lesions untreated with prior radiation therapy and no more than 2 prior lines of systemic therapy. Pts with non-clear cell RCC are eligible and will be capped at 20% of the total accrual goal. Pts must have a Karnofsky performance status of ≥60%, have symptomatic bone pain defined as a prior SSE or need of analgesics, and be on osteoclast-targeted therapy unless otherwise contraindicated. Pts are randomized 1:1 to cabozantinib with (Arm A) or without (Arm B) Ra-223. Starting dose of cabozantinib for Arm A is 40 mg by mouth daily to be escalated to 60 mg daily after cycle 1 (1 cycle = 28 days) if no persistent grade 2 or grade ≥3 toxicity. Ra-223 is administered at a fixed dose of 1.49 microcurie/kg IV every 28 days x 6 doses. The primary endpoint is SSE-free survival. Secondary endpoints include safety, progression-free survival, overall survival, quality of life measures, and correlative analyses including liquid biopsy studies and tumor tissue analysis. The study has 90% power to detect an improvement in 6-month SSE-free survival rate from 65% to 78% with one-sided α = 0.025 significance. To ensure 191 evaluable patients, target accrual is 210 pts. This design includes a safety run-in and an interim analysis for futility when 50% of the expected number of events (72 SSE events) have been observed. Final data analysis will occur when 143 events have been observed. The study was activated in December 2019 and accrual is currently ongoing throughout the NCTN. Clinical trial information: NCT04071223.

9022 Background: This signal finding study was designed to evaluate the clinical efficacy of a PARP inhibitor, talazoparib, in advanced stage squamous cell lung cancer harboring HRRD. Methods: Eligible patients (pts) identified through the parent S1400 screening platform were required to have a deleterious mutation in any of the study-defined HRR genes [ATM, ATR, BARD1, BRCA1, BRCA2, BRIP1, CHEK1, CHEK2, FANCA, FANCC, FANCD2, FANCF, FANCM, NBN (NBS1), PALB2, RAD51, RAD51B (RAD51L1), RAD54L, RPA1) defined as the full eligible population (FEP). The primary analysis population (PAP) is defined by a subset of genes [ATM, ATR, BRCA1, BRCA2, PALB2]. Pts have platinum sensitive disease (at least stable disease on platinum doublet) and progressed on most recent line of systemic therapy, a Zubrod performance status of 0-1, adequate organ function, and not have been previously exposed to a PARP inhibitor and not be on systemic therapy within 21 days of registration. A 2-stage design with exact 93% power and 1-sided 0.07 level type I error required enrollment of 40 patients in the PAP in order to rule out an ORR of 15% or less if the true ORR is 35% or greater. At least 3 or more responses were needed in the first 20 pts in order to proceed to full enrolment of 40 pts in the PAP. The total accrual goal was 60 FEP assuming 67% of patients would be in the PAP. Results: The study enrolled 51 patients of whom 47 are eligible and analyzable for response (FEP) with 24 in the PAP. In the FEP, median age 66.7 yrs; M/F 39/8 (83/17%); 85% White and 15% Black; 77% of the pts received at least 1 prior line of treatment for stage IV. The study was closed for futility with only one response in the PAP. In the PAP (n = 24, median age 68 yrs), ORR was 4% (95%CI: 0, 21) and DCR was 54% (95%CI: 33, 74); median PFS of 2.4 months (95%CI: 1.5-2.8) and median OS was 5.2 months (95%CI: 3.8-10, 7). There were five responders in the FEP with ORR of 11%; DCR of 53% and median DoR was 1.8 months (95% CI: 1.3, 4.2); median PFS was 2.5 months (95%CI: 1.6-3.0) and median OS was 5.7 months (95% CI: 4.5-8.7). The most frequent grade ≥3 adverse event in the FEP were: Anemia (14.9%), thrombocytopenia (12.8%); lymphopenia (8.5%) and nausea (6.4%). Conclusions: S1400G failed to show sufficient level of efficacy for talazoparib in a biomarker defined subset of squamous lung cancer with HRRD. There were no new safety signals and hematologic toxicities were the most frequent adverse events. Clinical trial information: NCT02154490.

2532Background: The TAPUR Study is a phase II multi‐basket study that evaluates the anti‐tumor activity of commercially available targeted agents in pts with advanced cancers with genomic alteratio...

TPS477 Background: In pts with LAPC, more effective systemic therapies may be associated with improved local control, delay of metastasis, and overall survival (OS). The phase III MPACT trial in pts with metastatic PC demonstrated longer OS (median, 8.7 vs 6.6 mos; HR, 0.72; P < 0.001) and an ≈ 3-fold greater shrinkage of primary tumors with nab-P + Gem vs Gem alone (−22.15% vs −7.02%), raising the possibility of improved local PC control with nab-P + Gem. LAPACT will assess the efficacy and safety of nab-P + Gem in LAPC. Methods: LAPACT will enroll treatment-naive pts (planned n ≈ 110) in the United States, Canada, and Europe with Eastern Cooperative Oncology Group performance status ≤ 1, confirmed unresectable LAPC, no distant metastases, and adequate organ function. Pts with mixed-origin tumors, any other malignancy within 5 years, peripheral neuropathy grade > 1, or clinically significant ascites are ineligible. Pts will receive nab-P 125 mg/m2 + Gem 1000 mg/m2 on days 1, 8, and 15 of each 28-day cycle. Pts without progressive disease (PD) or unacceptable toxicity after 6 cycles will receive investigator’s choice of surgery, chemoradiotherapy, or continued nab-P + Gem. If a major response is observed, surgery may occur prior to completing 6 cycles of nab-P + Gem. The primary endpoint is time to treatment failure (TTF; time from first therapy dose to discontinuation due to PD, start of a new non–protocol-defined anti-cancer therapy, or death). The study design allows for 80% power at a 1-sided α of 0.05 to detect a 30% increase over the 5.1-month median TTF observed for nab-P + Gem in the MPACT study. The secondary endpoints are disease control rate (DCR) after 6 cycles, overall response rate, progression-free survival, OS, safety, and quality of life. The exploratory endpoint is correlation of changes in circulating nucleic acids with PD and treatment response. An interim DCR analysis will occur after all pts have completed 6 cycles of nab-P + Gem, discontinued therapy due to PD, died, or started a new non–protocol-defined therapy before completing 6 cycles of therapy. Enrollment is ongoing (first pt enrolled in April 2015). Clinical trial information: NCT02301143.

e19082 Background: Poor performance status is a negative prognostic variable for survival and a risk for increased toxicities with standard chemotherapy. A phase 2 study combining erlotinib (E) and bevacizumab (B) demonstrated encouraging efficacy in the treatment of recurrent NSCLC with acceptable toxicity. We, therefore, tested this regimen in untreated PS 2 patients with advanced NSCLC. Methods: Single-arm phase 2 trial in treatment-naïve patients with advanced non-squamous NSCLC and either a PS of 2 or age >75. Only patients eligible for bevacizumab per label were allowed onto study. Patients received E 150 mg orally daily and B 15 mg/kg IV on day 1 every 21 days for up to 6 cycles. The primary end-point was the rate of non progressive disease at 4 months (alternative hypothesis P>60%). Other end-points included overall survival, progression free survival (PFS), toxicity evaluations and patient-reported PS (PRPS) measures. Results: 25 patients were enrolled. Patient characteristics: 56% female, median age 77 years (range: 52–90); 88% stage IV; 92% were PS 2; 20% were never or remote smokers (> 30 years) The PRPS was 1, 2, 3 in 32%, 52%, 8% respectively with data on 2 patients missing. The rate of non-progression at 4 months was 40%; overall best response: 5% PR, 40% SD, 50% PD and 5% unevaluable; median PFS 2.6 months, 95% CI (1.3–5.1); MST 5.8 months, 95% CI (3.8- 8.7). 2 patients had G3 rash. G3 diarrhea, G3 hemorrhage, G3 proteinuria, G3 duodenal ulcer and G3 pneumonitis each developed in one patient. Conclusions: E + B is an active regimen with an acceptable toxicity profile; however, this study did not meet its’ primary endpoint. Further study of this combination will not be pursued in the Hoosier Oncology Group for this patient population. [Table: see text]