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TPS818 Background: Albumin-bound ( nab)-sirolimus, a novel mTOR inhibitor (mTORi) that utilizes nanoparticle technology to preferentially target tumors, is approved in the US for the treatment of adults with malignant PEComa. In an exploratory analysis of the AMPECT registrational trial of nab-sirolimus in advanced malignant PEComa (NCT02494570), 8/9 (89%) and 1/5 (20%) patients with TSC1 and TSC2 inactivating alterations, respectively, had confirmed response (Wagner, J Clin Oncol. 2021). Importantly, both TSC1 and TSC2 alterations have been observed in patients with various gastrointestinal cancers (Table). Overall, most treatment-related adverse events (TRAEs) in AMPECT were grade 1/2 and manageable for long-term treatment; no grade ≥4 TRAEs occurred. Methods: PRECISION I (NCT05103358) is a phase 2, open-label, multi-institutional basket trial evaluating efficacy and safety of nab-sirolimus in patients with alterations in TSC1 (Arm A) and TSC2 (Arm B). Patients ≥12 years old with malignant solid tumors harboring pathogenic inactivating alterations in TSC1 or TSC2 (confirmed by central review of next generation sequencing reports) who have progressed on standard therapies and are mTORi-naïve are eligible. nab-Sirolimus 100 mg/m2 will be administered weekly as an intravenous infusion over 30 minutes on Days 1 and 8 of each 21-day cycle. The primary endpoint is overall response rate determined by independent review using RECIST v1.1; other endpoints include duration of response, disease control rate, time to response, progression-free survival by independent radiographic review, overall survival, patient-reported quality of life, and safety. Enrollment is ongoing. The most frequent tumor types expected in this tissue-agnostic trial are bladder, hepatobiliary, endometrial, soft tissue sarcoma, ovarian, and esophagogastric based on the prevalence of TSC1 or TSC2 alterations (Table). Clinical trial information: NCT05103358 . [Table: see text]

Maen Hussein,1 Marina Maglakelidze,2 Donald A Richards,3 Marielle Sabatini,4 Todd A Gersten,5 Keith Lerro,6 Ivan Sinielnikov,7 Alexander Spira,8,9 Yili Pritchett,10 Joyce M Antal,10 Rajesh Malik,10 J Thaddeus Beck11 1Florida Cancer Specialists, Leesburg, FL, USA; 2LLC Arensia Exploratory Medicine, Tbilisi, Georgia; 3Texas Oncology-Tyler, US Oncology Research, Tyler, TX, USA; 4Saint Leon Hospital, Bayonne, France; 5Florida Cancer Specialists, West Palm Beach, FL, USA; 6Regional Medical Oncology Center, Wilson, NC, USA; 7Volyn Regional Oncology Center, Lutsk, Ukraine; 8Virginia Cancer Specialists, Fairfax, VA, USA; 9US Oncology Research, The Woodlands, TX, USA; 10G1 Therapeutics, Inc., Research Triangle Park, NC, USA; 11Highlands Oncology Group, Fayetteville, AR, USACorrespondence: Maen HusseinFlorida Cancer Specialists, Leesburg, FL, USATel +1 352-787-9448Email mhussein@flcancer.comPurpose: Trilaciclib is an intravenous cyclin-dependent kinase 4/6 inhibitor indicated to decrease the incidence of chemotherapy-induced myelosuppression (CIM) by protecting hematopoietic stem and progenitor cells and immune system function from chemotherapy-induced damage (myeloprotection). Here, we investigated the myeloprotective effects of trilaciclib among patients at increased risk of CIM.Patients and Methods: Data were pooled from three randomized, double-blind, placebo-controlled, phase 2 clinical studies of trilaciclib administered prior to chemotherapy in patients with extensive-stage small cell lung cancer (ES-SCLC). Myeloprotective outcomes were evaluated in patient subgroups based on age (< 65 or ≥ 65 years), risk of chemotherapy-induced febrile neutropenia (FN), and risk of anemia or red blood cell (RBC) transfusions. For the FN and anemia analyses, risk factors were identified from published literature and used to classify patients into FN and anemia risk categories. Subgroup analysis based on age was also performed on patient reported outcome (PRO) measures.Results: In total, 123 patients received trilaciclib and 119 patients received placebo. Myeloprotective benefits of trilaciclib were observed regardless of age, with greater effects observed among patients aged ≥ 65 years. Across FN risk factors and categories, trilaciclib had beneficial effects on neutrophil-related endpoints vs placebo, with greater effects observed in patients at higher risk of FN. Effects on RBC-related endpoints favored trilaciclib vs placebo, regardless of anemia risk factors and categories. Improvements in PROs with trilaciclib were observed irrespective of age group, but with greater improvements and less deterioration from baseline observed in older patients.Conclusion: By both decreasing the incidence of CIM and improving quality of life, trilaciclib has the potential to allow patients receiving chemotherapy for ES-SCLC, including patients who are older or more vulnerable to CIM, to receive chemotherapy on schedule and at standard-of-care doses, and to improve the experience for patients receiving chemotherapy to treat ES-SCLC.Clinical Trial Numbers: NCT02499770; NCT03041311; NCT02514447.Keywords: trilaciclib, myelosuppression, myeloprotection, myelopreservation, chemotherapy, small cell lung cancer

Introduction CheckMate 153 (NCT02066636) is a phase 3B/4 study assessing nivolumab in previously treated patients with advanced NSCLC. Eligibility criteria allowed enrollment of patients with poor prognostic features of advanced age or diminished Eastern Cooperative Oncology Group performance status (ECOG PS), which are typically underrepresented in or excluded from randomized controlled trials. Methods Patients with stage IIIB or IV NSCLC and an ECOG PS of 0 to 2 with disease progression after at least one systemic therapy received nivolumab (3 mg/kg every 2 weeks) until progression, unacceptable toxicity, or consent withdrawal. The primary end point was the incidence of grade 3 to 5 select treatment-related adverse events (TRAEs). Results Among 1426 treated patients, 556 (39%) were aged 70 years or older and 128 (9%) had an ECOG PS of 2. The median treatment duration was 3.2 months. Across subgroups and the overall population, the incidences of select grade 3 to 5 TRAEs (6%–9%) and grade 3 or 4 TRAEs (12%–14%) were similar. One grade 5 TRAE was documented. The median overall survival time was comparable in the overall population (9.1 months) and patients aged 70 years or older (10.3 months) but shorter in patients with an ECOG PS of 2 (4.0 months). Patient-reported outcomes generally improved. Conclusions Data from this large predominantly community-based study, which included patients aged 70 years or older and with an ECOG PS of 2, are consistent with registrational studies. As expected, the median overall survival for patients with an ECOG PS of 2 was lower than for the overall population but comparable with historical data.

Summary Background Atezolizumab (a monoclonal antibody against PD-L1), which restores anticancer immunity, improved overall survival in patients with previously treated non-small-cell lung cancer and also showed clinical benefit when combined with chemotherapy as first-line treatment of non-small-cell lung cancer. IMpower130 aimed to assess the efficacy and safety of atezolizumab plus chemotherapy versus chemotherapy alone as first-line therapy for non-squamous non-small-cell lung cancer. Methods IMpower130 was a multicentre, randomised, open-label, phase 3 study done in 131 centres across eight countries (the USA, Canada, Belgium, France, Germany, Italy, Spain, and Israel). Eligible patients were aged 18 years or older, and had histologically or cytologically confirmed stage IV non-squamous non-small-cell lung cancer, an Eastern Cooperative Oncology Group performance status of 0 or 1, and received no previous chemotherapy for stage IV disease. Patients were randomly assigned (2:1; permuted block [block size of six] with an interactive voice or web response system) to receive atezolizumab (1200 mg intravenously every 3 weeks) plus chemotherapy (carboplatin [area under the curve 6 mg/mL per min every 3 weeks] plus nab-paclitaxel [100 mg/m2 intravenously every week]) or chemotherapy alone for four or six 21-day cycles followed by maintenance therapy. Stratification factors were sex, baseline liver metastases, and PD-L1 tumour expression. Co-primary endpoints were investigator-assessed progression-free survival and overall survival in the intention-to-treat wild-type (ie, EGFRwt and ALKwt) population. The safety population included patients who received at least one dose of the study drug. This study is registered with ClinicalTrials.gov, number NCT02367781. Findings Between April 16, 2015, and Feb 13, 2017, 724 patients were randomly assigned and 723 were included in the intention-to-treat population (one patient died before randomisation, but was assigned to a treatment group; this patient was excluded from the intention-to-treat population) of the atezolizumab plus chemotherapy group (483 patients in the intention-to-treat population and 451 patients in the intention-to-treat wild-type population) or the chemotherapy group (240 patients in the intention-to-treat population and 228 patients in the intention-to-treat wild-type population). Median follow-up in the intention-to-treat wild-type population was similar between groups (18·5 months [IQR 15·2–23·6] in the atezolizumab plus chemotherapy group and 19·2 months [15·4–23·0] in the chemotherapy group). In the intention-to-treat wild-type population, there were significant improvements in median overall survival (18·6 months [95% CI 16·0–21·2] in the atezolizumab plus chemotherapy group and 13·9 months [12·0–18·7] in the chemotherapy group; stratified hazard ratio [HR] 0·79 [95% CI 0·64–0·98]; p=0·033) and median progression-free survival (7·0 months [95% CI 6·2–7·3] in the atezolizumab plus chemotherapy group and 5·5 months [4·4–5·9] in the chemotherapy group; stratified HR 0·64 [95% CI 0·54–0·77]; p Interpretation IMpower130 showed a significant and clinically meaningful improvement in overall survival and a significant improvement in progression-free survival with atezolizumab plus chemotherapy versus chemotherapy as first-line treatment of patients with stage IV non-squamous non-small-cell lung cancer and no ALK or EGFR mutations. No new safety signals were identified. This study supports the benefit of atezolizumab, in combination with platinum-based chemotherapy, as first-line treatment of metastatic non-small-cell lung cancer. Funding F. Hoffmann-La Roche.

Summary Background VEGF and VEGF receptor 2 (VEGFR-2)-mediated signalling and angiogenesis can contribute to the pathogenesis and progression of gastric cancer. We aimed to assess whether the addition of ramucirumab, a VEGFR-2 antagonist monoclonal antibody, to first-line chemotherapy improves outcomes in patients with metastatic gastric or gastro-oesophageal junction adenocarcinoma. Methods For this double-blind, randomised, placebo-controlled, phase 3 trial done at 126 centres in 20 countries, we recruited patients aged 18 years or older with metastatic, HER2-negative gastric or gastro-oesophageal junction adenocarcinoma, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and adequate organ function. Eligible patients were randomly assigned (1:1) with an interactive web response system to receive cisplatin (80 mg/m2, on the first day) plus capecitabine (1000 mg/m2, twice daily for 14 days), every 21 days, and either ramucirumab (8 mg/kg) or placebo on days 1 and 8, every 21 days. 5-Fluorouracil (800 mg/m2 intravenous infusion on days 1–5) was permitted in patients unable to take capecitabine. The primary endpoint was investigator-assessed progression-free survival, analysed by intention to treat in the first 508 patients. We did a sensitivity analysis of the primary endpoint, including a central review of CT scans. Overall survival was a key secondary endpoint. This study is registered with ClinicalTrials.gov, number NCT02314117. Findings Between Jan 28, 2015, and Sept 16, 2016, 645 patients were randomly assigned to receive ramucirumab plus fluoropyrimidine and cisplatin (n=326) or placebo plus fluoropyrimidine and cisplatin (n=319). Investigator-assessed progression-free survival was significantly longer in the ramucirumab group than the placebo group (hazard ratio [HR] 0·753, 95% CI 0·607–0·935, p=0·0106; median progression-free survival 5·7 months [5·5–6·5] vs 5·4 months [4·5–5·7]). A sensitivity analysis based on central independent review of the radiological images did not corroborate the investigator-assessed difference in progression-free survival (HR 0·961, 95% CI 0·768–1·203, p=0·74). There was no difference in overall survival between groups (0·962, 0·801–1·156, p=0·6757; median overall survival 11·2 months [9·9–11·9] in the ramucirumab group vs 10·7 months [9·5–11·9] in the placebo group). The most common grade 3–4 adverse events were neutropenia (85 [26%] of 323 patients in the ramucirumab group vs 85 [27%] of 315 in the placebo group), anaemia (39 [12%] vs 44 [14%]), and hypertension (32 [10%] vs 5 [2%]). The incidence of any-grade serious adverse events was 160 (50%) of 323 patients in the ramucirumab group and 149 (47%) of 315 patients in the placebo group. The most common serious adverse events were vomiting (14 [4%] in the ramucirumab group vs 21 [7%] in the placebo group) and diarrhoea (11 [3%] vs 19 [6%]). There were seven deaths in each group, either during study treatment or within 30 days of discontinuing study treatment, which were the result of treatment-related adverse events. In the ramucirumab group, these adverse events were acute kidney injury, cardiac arrest, gastric haemorrhage, peritonitis, pneumothorax, septic shock, and sudden death (n=1 of each). In the placebo group, these adverse events were cerebrovascular accident (n=1), multiple organ dysfunction syndrome (n=2), pulmonary embolism (n=2), sepsis (n=1), and small intestine perforation (n=1). Interpretation Although the primary analysis for progression-free survival was statistically significant, this outcome was not confirmed in a sensitivity analysis of progression-free survival by central independent review, and did not improve overall survival. Therefore, the addition of ramucirumab to cisplatin plus fluoropyrimidine chemotherapy is not recommended as first-line treatment for this patient population. Funding Eli Lilly and Company.

9035 Background: In the Phase 3 POSEIDON study in 1L mNSCLC, adding T to D+CT resulted in statistically significant improvements in PFS and OS vs CT. No new safety signals were identified and treatment discontinuations due to treatment-related AEs (TRAEs) were similar for the T+D+CT and D+CT arms (15.5% and 14.1%). Here we present details of AEs and their management. Methods: 1013 pts with EGFR/ ALK wild-type mNSCLC were randomized 1:1:1 to 1L T+D+CT, D+CT or CT. Safety was assessed in all treated pts. Results: 330, 334 and 333 pts received T+D+CT, D+CT and CT; 78%, 82% and 74% received at least 4 cycles of platinum-based CT. The most common grade 3/4 TRAEs were hematologic (anemia in 17%, 15% and 20% of pts in the T+D+CT, D+CT and CT arms and neutropenia in 16%, 13% and 12%) and most were managed using standard approaches per local practice; 22%, 18% and 16% of pts received colony stimulating factors and 22%, 21% and 26% received blood transfusions. All grade immune-mediated AEs (imAEs) occurred in 34%, 19% and 5% of pts in the T+D+CT, D+CT and CT arms; a higher incidence of diarrhea/colitis, dermatitis/rash and endocrinopathies was seen with the addition of T to D+CT (Table). Grade 3/4 imAEs occurred in 10%, 7% and 2% of pts in the T+D+CT, D+CT and CT arms, and serious imAEs in 10%, 6% and 1%; imAEs led to discontinuation of any study treatment in 6%, 4% and 0.6%, and led to death in 0.6%, 0.3% and 0%. Most imAEs were low grade and manageable with systemic corticosteroids (received by 26%, 13% and 4% of pts in the T+D+CT, D+CT and CT arms) or endocrine therapy (12%, 8% and 1%). Median time from first dose to onset of imAEs (TTO) was generally > 60 days and the majority of non-endocrine imAEs resolved (Table). Conclusions: In POSEIDON, the safety profile of all regimens was manageable per standard guidelines and in line with the known profiles of D, T+D and CT; the most common grade 3/4 TRAEs were those typically associated with CT. As expected, more imAEs occurred with T+D+CT than D+CT, but the incidence of grade 3 or 4 imAEs, imAE-related deaths and treatment discontinuations due to imAEs was generally similar in the IO arms. T+D did not compromise the ability to administer planned CT. Clinical trial information: NCT03164616. [Table: see text]

Introduction Multilineage myelosuppression is an acute toxicity of cytotoxic chemotherapy, resulting in serious complications and dose modifications. Current therapies are lineage specific and administered after chemotherapy damage has occurred. Trilaciclib is a cyclin-dependent kinase 4/6 inhibitor that is administered prior to chemotherapy to preserve hematopoietic stem and progenitor cells and immune system function during chemotherapy (myelopreservation). Methods In this randomized, double-blind, placebo-controlled phase II trial, patients with previously treated extensive-stage small cell lung cancer (ES-SCLC) were randomized to receive intravenous trilaciclib 240 mg/m2 or placebo before topotecan 1.5 mg/m2 on days 1–5 of each 21-day cycle. Primary endpoints were duration of severe neutropenia (DSN) in cycle 1 and occurrence of severe neutropenia (SN). Additional endpoints were prespecified to further assess the effect of trilaciclib on myelopreservation, safety, patient-reported outcomes (PROs), and antitumor efficacy. Results Thirty-two patients received trilaciclib, and 29 patients received placebo. Compared with placebo, administration of trilaciclib prior to topotecan resulted in statistically significant and clinically meaningful decreases in DSN in cycle 1 (mean [standard deviation] 2 [3.9] versus 7 [6.2] days; adjusted one-sided P

98 Background: Anti-PD-1 antibodies may have synergistic effects with other immunomodulatory or targeted agents. This open-label, Phase II platform trial is investigating ezabenlimab, an anti-PD-1 antibody, combined with other agents. Module C of the platform is assessing ezabenlimab plus BI 836880, a humanized bispecific nanobody targeting VEGF/Ang2. Pts are being enrolled into 5 advanced solid tumor cohorts: gastric/gastroesophageal adenocarcinoma; solid tumors (except non-squamous NSCLC or melanoma) with secondary resistance to anti-PD-(L)1 treatment (progression after at least SD for ≥4 months); solid tumors with primary resistance to anti-PD-(L)1 treatment; microsatellite stable (MSS) CRC; mismatch repair-proficient/MSS endometrial carcinoma. Here, we report data from the CRC cohort which has completed recruitment. Methods: Pts with locally advanced, unresectable or metastatic, MSS CRC were enrolled. Patients had received ≥1 line of prior systemic therapy for metastatic disease but were anti-PD-(L)-1 therapy-naïve. Prior anti-angiogenic therapy was permitted. Pts received BI 836880 720 mg plus ezabenlimab 240 mg iv q3w for 1 year or until disease progression, consent withdrawal or undue toxicity. Primary endpoint: investigator-assessed OR (CR or PR per RECIST v1.1). Secondary endpoints: duration of response, disease control, and PFS; safety is also being assessed. Results: 30 pts have been treated: 57% male; median age 61.5 years. All pts had received prior chemotherapy; most pts (23 [77%]) had received prior bevacizumab. At data cut-off (Sep 2021), median duration (range) of treatment was 115.5 (28–295) days; 6 pts remain on treatment. 1 (3%) pt (who had not received prior bevacizumab) achieved a confirmed PR; 16 (53%) pts had SD. Median duration (range) of SD was 128.5 (42–242) days. 29/17/2 (97/57/7%) pts had an AE (any/G3/G4). The most frequent AEs (any/G3) were nausea (40/10%), fatigue (30/3%), peripheral edema (30/0%), vomiting (27/7%), and hypertension (27/17%). There were two G4 AEs (hypertension; platelet count decreased) and no G5 AEs. 24/10/2 (80/33/7%) pts had a drug-related AE (any/G3/G4); most commonly (any/G3) nausea (33/7%), fatigue (27/3%) and hypertension (27/17%). 3 (10%) pts had an infusion-related reaction (G1, n = 1; G2, n = 2). 2 (7%) pts had an AE leading to discontinuation (G3 bile duct stone and G2 peripheral edema). Immune-related AEs were reported in 6 (20%) pts and serious AEs occurred in 13 (43%) pts. Conclusions: BI 836880 plus ezabenlimab had a manageable safety profile in pts with advanced MSS CRC; however, anti-tumor activity was limited in these pts, the majority of whom had received prior bevacizumab. Clinical trial information: NCT03697304.

PURPOSE Limited data exist on the optimal duration of immunotherapy, including for non–small-cell lung cancer (NSCLC). We present an exploratory analysis of CheckMate 153, a largely community-based phase IIIb/IV study, to evaluate the impact of 1-year fixed-duration versus continuous therapy on the efficacy and safety of nivolumab. METHODS Patients with previously treated advanced NSCLC received nivolumab monotherapy (3 mg/kg every 2 weeks). Those still receiving treatment at 1 year, including patients perceived to be deriving benefit despite radiographic progression, were randomly assigned to continue nivolumab until disease progression or unacceptable toxicity or to stop nivolumab with the option of on-study retreatment after disease progression (1-year fixed duration). RESULTS Of 1,428 patients treated, 252 were randomly assigned to continuous (n = 127) or 1-year fixed-duration (n = 125) treatment (intent-to-treat [ITT] population). Of these, 89 and 85 patients in the continuous and 1-year fixed-duration arms, respectively, had not progressed (progression-free survival [PFS] population). With minimum post–random assignment follow-up of 13.5 months, median PFS was longer with continuous versus 1-year fixed-duration treatment (PFS population: 24.7 months v 9.4 months; hazard ratio [HR], 0.56 [95% CI, 0.37 to 0.84]). Median overall survival from random assignment was longer with continuous versus 1-year fixed-duration treatment in the PFS (not reached v 32.5 months; HR, 0.61 [95% CI, 0.37 to 0.99]) and ITT (not reached v 28.8 months; HR, 0.62 [95% CI, 0.42 to 0.92]) populations. Few new-onset treatment-related adverse events occurred. No new safety signals were identified. CONCLUSION To our knowledge, these findings from an exploratory analysis represent the first randomized data on continuous versus fixed-duration immunotherapy in previously treated advanced NSCLC and suggest that continuing nivolumab beyond 1 year improves outcomes.

Introduction Cytotoxic agents have immunomodulatory effects, providing a rationale for combining atezolizumab (anti-programmed death-ligand 1 [anti–PD-L1]) with chemotherapy. The randomized phase III IMpower131 study (NCT02367794) evaluated atezolizumab with platinum-based chemotherapy in stage IV squamous NSCLC. Methods A total of 1021 patients were randomized 1:1:1 to receive atezolizumab+carboplatin+paclitaxel (A+CP) (n = 338), atezolizumab+carboplatin+nab-paclitaxel (A+CnP) (n = 343), or carboplatin+nab-paclitaxel (CnP) (n = 340) for four or six 21-day cycles; patients randomized to the A+CP or A+CnP arms received atezolizumab maintenance therapy until progressive disease or loss of clinical benefit. The coprimary end points were investigator-assessed progression-free survival (PFS) and overall survival (OS) in the intention-to-treat (ITT) population. The secondary end points included PFS and OS in PD-L1 subgroups and safety. The primary PFS (January 22, 2018) and final OS (October 3, 2018) for A+CnP versus CnP are reported. Results PFS improvement with A+CnP versus CnP was seen in the ITT population (median, 6.3 versus 5.6 mo; hazard ratio [HR] = 0.71, 95% confidence interval [CI]: 0.60–0.85; p = 0.0001). Median OS in the ITT population was 14.2 and 13.5 months in the A+CnP and CnP arms (HR = 0.88, 95% CI: 0.73–1.05; p = 0.16), not reaching statistical significance. OS improvement with A+CnP versus CnP was observed in the PD-L1–high subgroup (HR = 0.48, 95% CI: 0.29–0.81), despite not being formally tested. Treatment-related grade 3 and 4 adverse events and serious adverse events occurred in 68.0% and 47.9% (A+CnP) and 57.5% and 28.7% (CnP) of patients, respectively. Conclusions Adding atezolizumab to platinum-based chemotherapy significantly improved PFS in patients with first-line squamous NSCLC; OS was similar between the arms.

2582 Background: The combination of anti-PD-1 antibodies with other immunomodulatory or targeted therapies has the potential for synergistic effects. This open-label, Phase II platform trial is assessing ezabenlimab, an anti-PD-1 antibody, in combination with other agents. Here, we report preliminary data from Module C, which assesses ezabenlimab in combination with BI 836880, a humanized bispecific nanobody that targets vascular endothelial growth factor (VEGF) and angiopoietin-2 (Ang2). VEGF and Ang2 play key roles in tumor angiogenesis and have an immunosuppressive effect in the tumor microenvironment. Combining anti-VEGF/Ang2 with an anti-PD-1 therapy promotes an immunopermissive state supportive of T-cell-mediated tumor cell death. Methods: Pts are being enrolled into 5 cohorts: locally advanced/metastatic gastric or gastroesophageal adenocarcinoma with ≥1 prior treatment (anti-PD-[L]1 naïve; Cohort 1); any advanced/metastatic solid tumor (excluding non-squamous NSCLC or melanoma) with prior anti-PD-(L)1 treatment, which progressed after achieving at least stable disease (SD) for ≥4 months (Cohort 2); advanced/metastatic solid tumors with no benefit from prior anti-PD-(L)1 treatment (SD or progressive disease [PD] in < 4 months; Cohort 3); locally advanced/metastatic microsatellite stable (MSS) colorectal cancer with ≥1 prior treatment (anti-PD-[L]1 naïve; Cohort 4); advanced MSS and mismatch repair-proficient endometrial carcinoma, which progressed after 1 line of chemotherapy (anti-PD-[L]1 naïve; Cohort 5). Pts will receive BI 836880 720 mg and ezabenlimab 240 mg IV every 3 weeks. The primary endpoint is investigator-assessed objective response (complete response [CR] or partial response per RECIST v1.1). Safety is also being assessed. Results: As of Jan 2021, 29 pts have received ezabenlimab plus BI 836880; 26 pts remain on treatment. Cohorts 1/2/3/4/5 included 0/6/3/19/1 pts; median age 63 yrs; 20 (69%) pts were male . Overall, 22 (76%) pts experienced an adverse event (AE; any-cause), most commonly (all%/G3%) nausea (31/3), hypertension (28/7) and fatigue (21/0). No G4/5 AEs were reported; 5 (17%) pts experienced serious AEs. One pt had an immune-related AE (G1 rash). Eighteen (62%) pts had a drug-related AE, most commonly nausea (24%), vomiting, fatigue, and hypertension (all 14%). Three pts had infusion-related reactions (G1, n = 2; G2, n = 1) and 1 pt had an AE that led to treatment discontinuation (non-related G3 bile duct stone). Of 7 pts evaluable for response prior to cycle 3, 5 have SD (Cohort 2, n = 2; Cohort 4, n = 3), and 2 have PD (Cohorts 3 and 4, n = 1 each). Updated data will be presented. Conclusions: These preliminary data suggest that ezabenlimab in combination with BI 836880 has a manageable safety profile. Cohorts are continuing to recruit (approximately 30 pts per cohort). Clinical trial information: NCT03697304.

e18667 Background: How oncology providers should implement practice transformation for value-based care is unclear, particularly at scale. Organizational size enables efficient “top down” approaches, but also presents challenges such as physician engagement. Dis-economies of scale can be acute in oncology due to physician autonomy and coordination costs. We hypothesized that organizational change based in sense-making models that enhance physician engagement and use a decentralized, iterative microsystems approach will enable practice transformation to scale. Methods: Florida Cancer Specialists & Research Institute (FCS) is a physician led 250-oncologist statewide practice, with regional variation in disease state/mix, patient cohort, etc., making a purely top-down approach to organizational change infeasible. FCS prototyped a transformation strategy starting in June 2017 based on sharing interpreted data with physician and executive leadership. Later implementation directly engaged physicians in a microsystems quality QI strategy focused on regional performance. Interventions targeted disease, health service utilization, location, and individual physicians. Performance was evaluated using data from Medicare’s Oncology Care Model (OCM) and assessed using the one-sided risk target (4% below benchmark). We analyzed 70,239 performance period (PP) episodes at FCS across 35,116 patients. Results: In the pre- intervention period (90% of PP1 episodes, completed by June 2017), FCS was 5.8% above target. Performance was 10.9% above target for the remainder of PP1 (10% of PP1 episodes), then improved to 0.3% above target in PP2 and PP3, and below target by 0.9%, 0.8%, and 0.75% in PP4, PP5, and PP6. Early QI efforts focused on performance in lung cancer, which was 2.5% over target in PP1; it improved to 2.1% under target in PP6. Later regional QI sessions targeted cancer, utilization and providers. Pre-intervention, all 18 regions were above target; by PP6, 11 out of 19 regions were below target. Relative to the pre-intervention period, per-episode inpatient costs increased by 12.1% for the remainder of PP1 and increased by 4.3% and 1.3% in PP2 and PP6; inpatient costs decreased in PP3, PP4, and PP5 by 3.8%, 2.4% and 4.8%. Conclusions: Practice transformation in oncology can achieve scale through models of organizational change that foster physician engagement. Data, when clinically contextualized, is a foundational tool in the sense-making process. Scale can develop through an additive microsystems approach in which QI units are de-centralized, accountability is defined, and iteration becomes part of organizational culture. [Table: see text]

Therapeutic antibodies to immune checkpoints show promising results. Programmed death-ligand 1 (PD-L1), an immune checkpoint ligand, blocks the cancer immunity cycle by binding the PD-L1 receptor (programmed death 1). We investigated PD-L1 protein expression and messenger RNA (mRNA) levels in SCLC.PD-L1 protein expression and mRNA levels were determined by immunohistochemistry (IHC) with SP142 and Dako 28-8 PD-L1 antibodies and in situ hybridization in primary tumor tissue microarrays in both tumor cells and tumor-infiltrating immune cells (TIICs) obtained from a limited-disease SCLC cohort of 98 patients. An additional cohort of 96 tumor specimens from patients with extensive-disease SCLC was assessed for PD-L1 protein expression in tumor cells with Dako 28-8 antibody only.The overall prevalence of PD-L1 protein expression in tumor cells was 16.5%. In the limited-disease cohort, the prevalences of PD-L1 protein expression in tumor cells with SP142 and Dako 28-8 were 14.7% and 19.4% (tumor proportion score cutoff ≥1%) and PD-L1 mRNA ISH expression was positive in 15.5% of tumor samples. Increased PD-L1 protein/mRNA expression was associated with the presence of more TIICs (p0.05). The extensive-disease cohort demonstrated a 14.9% positivity of PD-L1 protein expression in tumor cells with Dako 28-8 antibody.A subset of SCLCs is characterized by positive PD-L1 and/or mRNA expression in tumor cells. Higher PD-L1 and mRNA expression correlate with more infiltration of TIICs. The prevalence of PD-L1 in SCLC is lower than that published for NSCLC. The predictive role of PD-L1 expression in SCLC treatment remains to be established.

Background Chemotherapy-induced damage of hematopoietic stem and progenitor cells (HSPC) causes multi-lineage myelosuppression. Trilaciclib is an intravenous CDK4/6 inhibitor in development to proactively preserve HSPC and immune system function during chemotherapy (myelopreservation). Preclinically, trilaciclib transiently maintains HSPC in G1 arrest and protects them from chemotherapy damage, leading to faster hematopoietic recovery and enhanced antitumor immunity. Patients and methods This was a phase Ib (open-label, dose-finding) and phase II (randomized, double-blind placebo-controlled) study of the safety, efficacy and PK of trilaciclib in combination with etoposide/carboplatin (E/P) therapy for treatment-naive extensive-stage small-cell lung cancer patients. Patients received trilaciclib or placebo before E/P on days 1–3 of each cycle. Select end points were prespecified to assess the effect of trilaciclib on myelosuppression and antitumor efficacy. Results A total of 122 patients were enrolled, with 19 patients in part 1 and 75 patients in part 2 receiving study drug. Improvements were seen with trilaciclib in neutrophil, RBC (red blood cell) and lymphocyte measures. Safety on trilaciclib+E/P was improved with fewer ≥G3 adverse events (AEs) in trilaciclib (50%) versus placebo (83.8%), primarily due to less hematological toxicity. No trilaciclib-related ≥G3 AEs occurred. Antitumor efficacy assessment for trilaciclib versus placebo, respectively, showed: ORR (66.7% versus 56.8%, P = 0.3831); median PFS [6.2 versus 5.0 m; hazard ratio (HR) 0.71; P = 0.1695]; and OS (10.9 versus 10.6 m; HR 0.87; P = 0.6107). Conclusion Trilaciclib demonstrated an improvement in the patient's tolerability of chemotherapy as shown by myelopreservation across multiple hematopoietic lineages resulting in fewer supportive care interventions and dose reductions, improved safety profile, and no detriment to antitumor efficacy. These data demonstrate strong proof-of-concept for trilaciclib's myelopreservation benefits. Clinical Trail number NCT02499770.

TPS152 Background: Combining anti-programmed cell death protein 1 (PD-1) antibodies with other immuno-modulatory or targeted therapies may improve outcomes. NCT03697304 is an open-label, Phase II, platform trial assessing BI 754091, an anti-PD-1 antibody, combined with other agents. Here, we describe Module C in which BI 754091 will be combined with BI 836880, a humanized bispecific nanobody, that targets vascular endothelial growth factor (VEGF) and angiopoietin2 (Ang2). VEGF and Ang2 play key roles in tumor angiogenesis and have an immunosuppressive effect in the tumor microenvironment. Combining anti-VEGF/Ang2 with an anti-PD-1 therapy promotes an immunopermissive state supportive of T-cell-mediated tumor cell death. Methods: Patients are being enrolled in 5 cohorts: 1) locally advanced/metastatic gastric or gastroesophageal adenocarcinoma with ≥1 prior treatment (anti-PD-[L]1 naïve); 2) any advanced/metastatic solid tumor (excluding NSCLC and melanoma) with prior anti-PD-(L)1 treatment, which progressed after achieving at least stable disease (SD) for 4 months; 3) advanced/metastatic solid tumors with no benefit from prior anti-PD-(L)1 treatment (SD

231 Background: Though FL generally has good outcomes, patients with high risk FL have poorer outcomes; proper risk stratification for early intervention has been shown to improve overall benefit in some patients. In a quality improvement (QI) initiative conducted in 4 community oncology systems, we assessed practice patterns involving prognostication and the integration of patient-disease-and treatment-related factors to improve decision-making for patients with FL. Methods: Between 10/17/2019 and 3/4/2020, we surveyed hematology/oncology health care professionals (HCP; N=59) to assess challenges, barriers, and self-reported performance of quality FL care. Electronic medical records (EMR) of 100 patients were audited for demographics, disease characteristics, risk stratification, treatment, and patient-centered metrics. To address suboptimal guideline-aligned care, teams participated in audit-feedback sessions to develop action plans for resolving identified gaps. Results: The EMR audit demonstrated low levels of documentation of staging, grade, and criteria required by risk stratification models (Table). Despite 92% of HCP indicating the use of risk stratification or prognostic models to determine treatment choice, only 23% of charts indicated use of a model for risk stratification. 55% of HCP indicated testing for t(14;18), though no patients had documented evidence of t(14;18) testing results. Survey findings indicated low confidence integrating patient-related factors to determine appropriate risk group (24%). Treatment choice was aligned with guidelines. In surveys, providers reported uncertainty about when to initiate treatment (13%), which treatments are most appropriate for each patient (23%), and engaging patients in shared decision-making (28%) as top barriers to care. During audit-feedback sessions, teams created action plans to improve documentation for variables of risk stratification, patient symptoms, molecular results, and shared decision-making. Further, teams identified the need for improved resources and personnel. Conclusions: These findings reveal important challenges to providing individualized FL care in community settings, such as documentation of clinically important metrics, care coordination, and engaging patients in shared decision-making. These gaps may inform future QI and implementation science initiatives. [Table: see text]

3063 Background: LAG-3, an immune checkpoint receptor involved in T-cell regulation, is frequently co-expressed with PD-1. LAG-3 and PD-1 signaling contributes to immune cell exhaustion and reduces the immune response to tumor cells. Dual inhibition of PD-1 and LAG-3 may reactivate the T-cell response better than blockade of either individual pathway. Here, we report combined safety data from 4 trials investigating BI 754111, an anti-LAG-3 mAb, in combination with BI 754091, an anti-PD-1 mAb, in patients with advanced solid tumors. Methods: Data from 2 phase I dose-escalation/expansion trials, 1 phase I imaging trial, and 1 phase II trial were included. Eligible patients had advanced and/or metastatic solid tumors with measurable disease and an Eastern Cooperative Oncology Group performance status ≤1. Patients received BI 754111 (intravenously [iv], 4–800 mg) in combination with BI 754091 (iv, 240 mg fixed dose) every 3 weeks (q3w). Patients remained on treatment until progressive disease or unacceptable toxicity. In each trial, safety was assessed by incidence and severity of adverse events (AEs), and graded according to Common Terminology Criteria for AEs, version 5. Results: Overall, 321 patients were treated with BI 754111 in combination with BI 754091 (200 [62%] male; median age, 63 years [range 18–88]). Median treatment exposure was 85 days (range 9–625). Of these patients, 282 (87.9%) had any AE (G≥3 in 99 [30.8%]). 285 patients received the 600 mg recommended phase II dose of BI 754111 plus BI 754091 240 mg q3w. Median treatment exposure in these patients was 74 days (range, 8–590). The table shows the 3 most common AEs and 4 most common immune-related AEs, and their frequency. 21 (7.4%) patients had AEs leading to study drug discontinuation, most commonly infusion-related reactions (IRRs) in 6 (2.1%) patients. Serious AEs (all-cause) occurred in 77 patients (27.0%), most commonly pleural effusion in 6 (2.1%) and deep vein thrombosis in 4 (1.4%) patients. 2 patients (0.7%) experienced an AE resulting in death (cardiac tamponade and acute kidney injury, both related to underlying diseases). Conclusions: The combination of BI 754111 and BI 754091 had a manageable safety profile, similar to other checkpoint inhibitors. Clinical trial information: NCT03156114, NCT03433898, NCT03697304, NCT03780725 . [Table: see text]

e19172 Background: For AML patients who are ineligible for intensive induction, novel therapies have greatly improved treatment options, though practice challenges individualizing care have hindered effective integration. In a quality improvement (QI) program conducted in 3 community oncology systems, we assessed practice patterns and barriers involving the use of novel therapies for AML. Methods: We surveyed 15 hematology team members to assess barriers to quality AML care and audited electronic medical records (EMR) of 100 patients across 3 community oncology centers. EMR demographics, disease characteristics, and treatment selection were reviewed. To address suboptimal guideline-aligned care, teams participated in audit-feedback sessions to develop action plans for resolving identified gaps. Results: The EMR audit demonstrated a lack of documentation for clinically important metrics necessary for individualized treatment selection and monitoring, including performance status and testing for targetable biomarkers (Table). Additionally, there was low documented use of novel therapies, such as venetoclax and gemtuzumab ozogamicin (GO), and no documented use of FLT3 or IDH inhibitors. Further, the audit revealed low adherence to guideline recommendations for frontline regimens – notably, 33.3% patients with FLT3 or IDH mutations (n = 15) were receiving low dose cytarabine alone, and 50% patients with a documented performance status of 3+ (n = 2) received intensive induction therapy. Survey findings indicated very low or low confidence in aligning practice with guidelines (20%), identifying patients who are not candidates for intensive induction (27%), and ordering/interpreting molecular tests (33%). Appropriate treatment selection (47%) and integration of molecular testing (27%) were reported as top challenges for individualized AML care. During audit-feedback sessions, teams identified improved collaboration with hematopathologists, assessment of patient mutational status, and patient engagement in treatment planning as actions they plan to integrate. Conclusions: These findings reveal important performance gaps in individualized AML care in community settings, which may inform future QI initiatives. [Table: see text]

Background: Atezolizumab (atezo) (anti-PD-L1) monotherapy improves overall survival (OS) vs docetaxel in 2L+ NSCLC regardless of PD-L1 status; phase 3, 1L studies have shown clinical benefit of atezo plus chemotherapy and atezo in combination with bevacizumab and chemotherapy. IMpower130 (NCT02367781) evaluated atezo + CnP vs CnP in patients (pts) with measurable (RECIST v1.1) stage IV non-squamous NSCLC. Methods: Pts (randomized 2:1) received atezo (1200 mg IV q3w) + CnP (carboplatin: AUC 6 q3w; nab-paclitaxel: 100 mg/m2 IV qw) (Arm A) or CnP (Arm B), for 4 or 6 21-day cycles and maintenance (Arm A: atezo until loss of clinical benefit; Arm B: best supportive care or pemetrexed q3w until disease progression [PD]). Crossover to atezo at PD was initially permitted for Arm B pts. Co-primary endpoints were investigator-assessed PFS and OS (ITT-WT population: EGFR-WT/ALK-negative). Secondary endpoints were OS and PFS (ITT population and by PD-L1 expression), response rate and safety. ITT population could be formally tested for OS/PFS if ITT-WT OS was positive. Results: 723 ITT (679 ITT-WT) pts were enrolled. Statistically significant, clinically meaningful improvements in OS and statistically significant and clinically meaningful improvements in PFS (ITT and ITT-WT) were observed in Arm A vs Arm B (table). PFS and OS benefit was observed in all PD-L1 subgroups, and consistently across all subgroups, except in pts with liver metastases and EGFR/ALK genomic alterations. In treated pts, 73.2% (Arm A) vs 60.3% (Arm B) had grade 3-4 treatment-related adverse events. Conclusions: Overall, IMpower130 showed statistically significant, clinically meaningful improvements in OS and statistically significant improvements in PFS with atezo + CnP, vs CnP, in 1L, stage IV non-squamous NSCLC, in this predominantly ITT-WT population. No new safety signals were identified. Table.IMpower130 Efficacy AnalysesArm A Atezo + CnPArm B CnPITT-WTn = 451n = 228Median OS (95% CI)18.6 mo (16.0-21.2)13.9 mo (12.0-18.7)HR (95% CI; P value)0.79 (0.64-0.98; 0.033)12-mo OS (95% CI)63.1% (58.59-67.66)55.5% (48.89-62.17)Median PFS (95% CI)7.0 mo (6.2-7.3)5.5 mo (4.4-5.9)HR (95% CI; P value)0.64 (0.54-0.77; < 0.0001)12-mo PFS (95% CI)29.1% (24.83-33.44)14.1% (9.37-18.76)n = 447n = 226Confirmed ORR (investigator assessed) (95% CI)49.2% (44.49-53.96)31.9% (25.84-38.36)n = 220n = 72Median DOR (95% CI)8.4 mo (6.9-11.8)6.1 mo (5.5-7.9)PD-L1 highan = 88n = 42Median OS (95% CI)17.4 mo (14.78-NA)16.9 mo (10.94-NA)HR (95% CI)0.84 (0.51-1.39)Median PFS (95% CI)6.4 mo (5.49-9.76)4.6 mo (3.22-7)HR (95% CI)0.51 (0.34-0.77)PD-L1 lowan = 128n = 65Median OS (95% CI)23.7 mo (18.63-NA)15.9 mo (12.32-25.63)HR (95% CI)0.70 (0.45-1.08)Median PFS (95% CI)8.3 mo (7.16-10.35)6.0 mo (5.29-6.93)HR (95% CI)0.61 (0.43-0.85)PD-L1 negativean = 235n = 121Median OS (95% CI)15.2 mo (12.88-19.15)12.0 mo (8.97-17.71)HR (95% CI)0.81 (0.61-1.08)Median PFS (95% CI)6.2 mo (5.52-7.16)4.7 mo (4.11-5.72)HR (95% CI)0.72 (0.56-0.91)ITTn = 483n = 240Median OS (95% CI)18.1 mo (15.3-20.8)13.9 mo (12.0-18.2)HR (95% CI; P value)0.80 (0.65-0.99; 0.039)Median PFS (95% CI)7.0 mo (6.3-7.3)5.6 mo (4.5-5.9)HR (95% CI; P value)0.65 (0.54-0.77; < 0.0001)a PD-L1 high (TC3 or IC3): Patients with PD-L1 expression in ≥ 50% of tumor cells or ≥ 10% of tumor-infiltrating immune cells; PD-L1 low (TC1/2 or IC1/2): Patients with PD-L1 expression in ≥ 1% and < 50% of tumor cells or ≥ 1% and Citation Format: Howard L. West, Michael McCleod, Maen Hussein, Alessandro Morabito, Achim Rittmeyer, Henry J. Conter, Hans-Georg Kopp, Davey Daniel, Steven McCune, Tarek Mekhail, Alona Zer, Niels Reinmuth, Ahad Sadiq, Venice Archer, Tania Ochi Lohmann, Helen Jessop, Lijia Wang, Marcin Kowanetz, Alan Sandler, Federico Cappuzzo. IMpower130: Progression-free survival (PFS) and safety analysis from a randomized phase 3 study of carboplatin + nab-paclitaxel (CnP) with or without atezolizumab as first-line (1L) therapy in advanced non-squamous NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT200.

8505 Background: Multi-lineage myelosuppression is an acute toxicity of cytotoxic chemotherapy leading to hematologic adverse events and dose reductions and delays. Current therapies are lineage specific and administered after chemotherapy damage.Trilaciclib (T), a highly selective, reversible CDK4/6 inhibitor, is designed to preserve hematopoietic stem and progenitor cells and immune system function during chemotherapy (myelopreservation). We have shown that T mitigates myelosuppression in patients with newly diagnosed extensive-stage small cell lung cancer (ES-SCLC) receiving 1st-line chemotherapy. Methods: In this blinded, placebo-controlled, multicenter Phase 2 study, patients with previously treated ES-SCLC were randomized to T (240 mg/m2) + 0.75 mg/m2 topotecan, T (240 mg/m2) + 1.5 mg/m2 topotecan, or placebo (P) + 1.5 mg/m2 topotecan IV on days 1-5 of 21-day cycles. Patients had access to standard supportive care, except in cycle 1 where prophylactic growth factors were not allowed. Eligible patients had adequate organ function, measurable disease, ECOG PS 0-2, and disease progression during or after prior 1st/2nd-line chemotherapy. Objectives included safety, tolerability, measures of myelosuppression and tumor efficacy. Results: 91 patients were randomized: 30 patients received T + 0.75 mg/m2 topotecan, 32 patients received T + 1.5 mg/m2 topotecan and 28 patients received P + 1.5 mg/m2 topotecan. In patients receiving 1.5 mg/m2 topotecan, T treatment reduced occurrence [40.6% (T) vs 75.6% (P), p = 0.016], and duration in cycle 1 [2 days (T) vs 8 days (P), p = < 0.0001] of severe neutropenia. T-treated patients had fewer RBC transfusions on/after 5 weeks on study, GCSF administrations, and all-cause dose reductions. Chemotherapy efficacy was comparable in both arms (P and T) treated with 1.5 mg/m2 topotecan (median PFS (T) 4.2 months vs (P) 4.2 months, HR = 0.83). OS data is immature. Conclusions: T combined with topotecan mitigated chemotherapy-induced myelosuppression and improved tolerability of topotecan vs P. Results suggest the addition of T to cytotoxic chemotherapy for the treatment of ES-SCLC is clinically beneficial. Clinical trial information: NCT02514447.

196 Background: There is a paucity of data describing the effect of treatment on symptom burden and health status for patients with ED-SCLC receiving care in US community oncology centers. This study explores ED-SCLC patient-reported outcomes independently for either first-line (1L), second-line (2L) or third-line (3L) therapy. Methods: CA209-118 is a prospective observational study of adult patients with lung cancer, including patients with ED-SCLC, in 70 US community practices enrolled between 2014-2017. Participants completed the Lung Cancer Symptom Scale (LCSS) and Euro-QoL 5-D (EQ-5D) utility index and visual analog scale (VAS) at the start of 1L, 2L, or 3L treatment and at follow-up visits. The LCSS is summarized in 3 scales: LCSS total scale which ranges from 0 – 100, average symptom burden scale (ASBI) ranging from 0 – 100, and a three-item global scale (3-IGI) ranging from 0 – 300 (lower scores reflect reduced burden). The EQ-5D scale is a preference based measure of health status with higher scores reflecting better quality and ranges from 0 to 1.0 (index) or 0 – 100 (VAS). LCSS and EQ-5D values at 60 days were predicted in a repeated measures model for patients having a score at baseline and at least 1 follow-up. Results: The mean LCSS and EQ-5D scores at the start of each line of therapy and predicted 60 day change are presented in the table . 60-day improvement was observed only for appetite and cough in 1L. A slight declining trend was seen in 2L and 3L. Conclusions: Patients with ED-SCLC treated in the community reported a high symptom burden at the start of each line of therapy which did not diminish throughout 60 days of treatment. [Table: see text]

Meeting abstracts The majority of lung cancer in the U.S. is treated in the community. A prospective cohort study of stage IV NSCLC and extensive disease (ED) SCLC is being conducted in 70 U.S. community practices to assess outcomes during the pre- and post-immunotherapy eras of lung cancer

LBA9000 Background: Atezolizumab (atezo; anti–PD-L1) demonstrated OS benefit vs docetaxel in 2L+ NSCLC regardless of PD-L1 status or tumor histology. Because cytotoxic agents can exhibit positive immunomodulatory effects, combining atezo with chemotherapy may further improve outcomes. IMpower131 (NCT02367794) was designed to evaluate atezo + carboplatin (carbo) + paclitaxel (pac) or nab-paclitaxel (nab-pac) in 1L stage IV squamous NSCLC. Methods: Patients (pts) were randomized 1:1:1 to Arm A (atezo 1200 mg q3w + carbo AUC 6 q3w + pac 200 mg/m2 q3w), Arm B (atezo + carbo + nab-pac 100 mg/m2 weekly) or Arm C (carbo + nab-pac). Pts received chemotherapy for 4 or 6 cycles and atezo until loss of clinical benefit. We present the primary analysis of investigator (INV)-assessed PFS per RECIST v1.1 in the ITT population for Arm B vs Arm C. Data cutoff: 22 January 2018. Results: 338 pts (Arm A), 343 pts (Arm B) and 340 pts (Arm C) were enrolled. Minimum follow-up was 9.8 mo. INV-assessed median PFS was 6.3 mo in Arm B vs 5.6 mo in Arm C (HR, 0.715; 95% CI: 0.603, 0.848; P = 0.0001). PFS benefit was enriched in all PD-L1–positive IHC subgroups and was most pronounced in TC3 or IC3. AEs related to any treatment (TRAEs) were 91.3% (Arm A), 94.6% (Arm B) and 90.7% (Arm C); Grade 3-4 TRAEs were 42.8% (Arm A), 68.0% (Arm B) and 56.9% (Arm C); serious TRAEs were 22.3% (Arm A), 20.4% (Arm B) and 10.5% (Arm C). Preliminary OS data will be presented. Conclusions: IMpower131 met its co-primary endpoint of INV-assessed PFS in the ITT population in Arm B vs Arm C. The safety profile of atezo + carbo + nab-pac or pac was consistent with the known risks of the individual treatment components; no new safety signals were identified. Clinical trial information: NCT02367794. [Table: see text]

e20567Background: Limited 2L therapy options and no established 3L standard of care make treating relapsed ED-SCLC challenging. This study explores current treatment and outcomes in patients receiv...

8568 Background: Chemotherapy (chemo) has significant clinical utility, however consequent damage to hematopoietic stem and progenitor cells (HSPCs) and the immune system may limit activity. If chemo-mediated anti-tumor activity was maximized, while minimizing myelosuppression and immunosuppression, patient outcomes would be improved. Trilaciclib (T) is an intravenous CDK4/6 inhibitor in development to reduce myelosuppression and preserve immune system function during chemo. HSPCs are dependent on CDK4/6 for proliferation. Preclinical data demonstrated that transient T-induced G1 cell cycle arrest renders HSPCs resistant to chemo cytotoxicity, allowing faster hematopoietic recovery, preservation of long-term function, and enhancement of anti-tumor immunity and activity. Methods: Objectives of this ongoing multicenter Phase 1b/2a study are to assess dose limiting toxicities (DLTs), safety, tolerability, hematological profile, PK, and anti-tumor activity of T administered prior to EP. Phase 1b was open-label, dose-finding, and the ongoing Phase 2a is randomized (1:1), double-blind. Eligible pts had confirmed diagnosis of ES-SCLC, adequate organ function, ECOG PS 0-2, no prior chemo, and no symptomatic brain metastases. Results: 19 pts were enrolled in the Phase 1b: 10 pts received T 200 mg/m2 + EP and 9 pts received T 240 mg/m2 + EP. T + EP was well tolerated. 2 pts at T 200 mg/m2 and 1 pt at T 240 mg/m2 experienced asymptomatic DLTs in cycle 1. 2 pts (1 at each dose) had an ANC < 1500 on cycle 2 day 1, delaying the start of cycle 2, and 1 pt at the T 200 mg/m2dose had grade 4 thrombocytopenia. There were no cases of febrile neutropenia or bleeding. PK analysis showed no drug interactions between T and EP. 17/19 pts were evaluable: 1 pt had CR, 14 had PR (confirmed ORR = 88%); 1 pt had SD (clinical benefit rate = 94%). Conclusions: In the Phase 1b part of the study, T + EP was well tolerated. Early activity results are promising with a confirmed objective response rate of 88%. This novel approach allowing the administration of chemotherapy while preserving HSPC and immune system function could potentially improve treatment outcomes for SCLC pts. Clinical trial information: NCT02499770.

3539 Background: VEGF-A and ANG-2 have complementary roles in regulation of tumor angiogenesis. Targeting VEGF-A with BEV in combination chemotherapy (CT) in mCRC has proven to increase PFS and OS. ANG-2 is overexpressed and associated with poor outcome of mCRC pts receiving BEVcontaining treatment. Hence, dual blockade of VEGF-A and ANG-2 by the bispecific mAb VAN with standard CT may improve clinical activity in mCRC. Methods: All pts received mFOLFOX-6 and were randomized 1:1 to also receive intravenous VAN 2000 mg every other week (Q2W) (Arm A) or BEV 5 mg/kg Q2W (Arm B). The primary end point was investigator assessed progression-free survival (PFS). Key eligibility criteria included pts with non-resectable mCRC, no prior therapy for advanced disease, PS 0-1, adequate organ functions, and no history of GI fistula/perforation or intraabdominal abscess within the last 6 months. Results: 192 pts were randomized (Arms A/B, n = 95/97) by 39 sites in 7 countries, between Oct 2014 and May 2016. Median follow-up was 17.6 months (range 2.8 – 20.7). In the ITT population (n = 189; Arms A/B, n = 94/95), median PFS in Arms A and B was 11.3 and 11.0 months (stratified hazard ratio (HR) 1.00 (95%CI 0.64-1.58; p = 0.985)), respectively. Objective response rate was 52.1% vs 57.9%. Relevant prognostic factors incl. RAS/BRAF status and tumor sidedness were balanced between arms and did not significantly influence outcome. Baseline plasma ANG-2 levels were prognostic in both arms but not predictive for response to VAN. The overall incidence of adverse events (AEs) grade ≥ 3 was similar (Arms A/B, 83.9%/82.1%); AEs grade ≥ 3 attributed to the mode of action of VAN/BEV included hypertension (37.6%/18.9%), hemorrhage (2.2%/1.1%), thromboembolic events (venous 6.5%/2.1%; arterial 1.1%/3.2%) and GI perforations incl. GI fistula & abdominal abscess (10.6%/8.4%). Conclusions: The combination of VAN and FOLFOX did not improve PFS and was associated with a marked increase in hypertension compared with BEV plus FOLFOX. Our results strongly suggest that ANG-2 is not a relevant therapeutic target in the setting of first line mCRC. Clinical trial information: NCT02141295.

Background: The current study explores T-cell (TC) clonality and molecular factors associated with this metric. Tumors employ multiple mechanisms to evade antitumor immune responses. One process involves TC inhibition via upregulation of immune checkpoint (IC) ligands in the tumor microenvironment (TME). Gradual upregulation of inhibitory receptor at their cellular surface results in a decreased capacity to proliferate and activate cytotoxic pathways against tumor cells presenting antigenic peptides.1 In melanoma, this subset of exhausted TCs has been described as highly clonal, where the majority of PD-1-expressing TC population shares the same TCR sequence specific against the same antigenic fragment.2 Previous studies have demonstrated that a clonal TCR repertoire appears to be associated in part with therapeutic responses during IC blockade.3 Methods: We performed TCR sequencing on 82 blood and 73 archival tumor tissue samples collected from ED SCLC patients (pts) in an ongoing longitudinal cohort study in US community oncology practices. Of these, 82 blood and 48 tissue samples had sufficient material available to quantify a clonality metric. To quantify TC abundance as a fraction of total nucleated cells, 82 blood and 58 tissue samples had sufficient material available. Results: Within the subset of 48 tumor samples, a more clonal (ie, less diverse) TCR repertoire was associated with less necrosis (P≤0.012) and lower levels of inflammatory cell infiltration in the local TME (P≤0.021). When pts were divided into 2 equal groups according to the median clonality level, pts with a less clonal TCR repertoire (n = 24/48) who were treated with non-immune-targeted therapy trended toward a longer overall survival (OS; 446 vs 301 days; P≤0.039). In contrast, the percentage of TCs in the TME did not correlate with improved survival (P≤0.412), necrosis (P≤0.131), and inflammation (P≤0.615). This observation differs from results in melanoma describing the impact of IC blockade where pts responding to therapy were associated with a more clonal TME TC population and increased CD8 TCs in the tumor compartment and at the invasive margin.3 In blood, while a less clonal TCR repertoire was associated with a similar but non-significant trend toward longer survival (P≤0.148), pts with increased TC abundance had longer OS (P≤0.025). No association was observed between clonality in TME and clonality (P≤0.571) or TC abundance (P≤0.965) in blood. Conclusion: We hypothesize that a diverse TCR repertoire in the TME and increased peripheral TC abundance are 2 predictors of longer OS in ED SCLC. To further explore factors that may influence TC responses in ED SCLC, the current TCR sequencing results will be integrated with transcriptome and whole genome sequencing analyses. References 1. Wherry EJ. Nat Immunol. 2011;12:492-99. 2. Gros A, et al. J Clin Invest. 2014;124:2246-59. 3. Tumeh PC, et al. Nature. 2014;515:568-71. Citation Format: Maen Hussein, Sharon Wilks, Marc Monte, Donald A. Richards, Jerome H. Goldschmidt, David Waterhouse, Lisu Wang, Saumya Pant, Erik Yusko, Ryan O. Emerson, Darin M. Taverna, Kaushal Desai, Spyro Mousses, Zhenhao Qi, Jason D. Hipp, Harlan Robins, Kimary Kulig, Cory Batenchuk. Characterization of the T-cell receptor (TCR) repertoire in extensive disease small cell lung cancer (ED SCLC). [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4159.

e18555Background: MDS is a heterogeneous group of clonal acquired hematologic disorders which is prevalent in the elderly population. Despite an intensive prognostic scoring system (IPSS-R) there a...

3013 Background: NIVO, a fully human IgG4 programmed death-1 (PD-1), immune checkpoint inhibitor antibody, has demonstrated durable responses and tolerability in heavily pretreated pts with advance...