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Càncer de pulmó; Brigatinib; Estudi ALTA-1L Cáncer de pulmón; Brigatinib; Estudio ALTA-1L Lung cancer; Brigatinib; ALTA-1L study PURPOSE Brigatinib, a next-generation anaplastic lymphoma kinase (ALK) inhibitor, demonstrated superior progression-free survival (PFS) and improved health-related quality of life (QoL) versus crizotinib in advanced ALK inhibitor–naive ALK-positive non–small cell lung cancer (NSCLC) at first interim analysis (99 events; median brigatinib follow-up, 11.0 months) in the open-label, phase III ALTA-1L trial (ClinicalTrials.gov identifier: NCT02737501). We report results of the second prespecified interim analysis (150 events). METHODS Patients with ALK inhibitor–naive advanced ALK-positive NSCLC were randomly assigned 1:1 to brigatinib 180 mg once daily (7-day lead-in at 90 mg once daily) or crizotinib 250 mg twice daily. The primary end point was PFS as assessed by blinded independent review committee (BIRC). Investigator-assessed efficacy, blood samples for pharmacokinetic assessments, and patient-reported outcomes were also collected. RESULTS Two hundred seventy-five patients were randomly assigned (brigatinib, n = 137; crizotinib, n = 138). With median follow-up of 24.9 months for brigatinib (150 PFS events), brigatinib showed consistent superiority in BIRC-assessed PFS versus crizotinib (hazard ratio [HR], 0.49 [95% CI, 0.35 to 0.68]; log-rank P < .0001; median, 24.0 v 11.0 months). Investigator-assessed PFS HR was 0.43 (95% CI, 0.31 to 0.61; median, 29.4 v 9.2 months). No new safety concerns emerged. Brigatinib delayed median time to worsening of global health status/QoL scores compared with crizotinib (HR, 0.70 [95% CI, 0.49 to 1.00]; log-rank P = .049). Brigatinib daily area under the plasma concentration–time curve was not a predictor of PFS (HR, 1.005 [95% CI, 0.98 to 1.031]; P = .69). CONCLUSION Brigatinib represents a once-daily ALK inhibitor with superior efficacy, tolerability, and QoL over crizotinib, making it a promising first-line treatment of ALK-positive NSCLC. Supported by ARIAD Pharmaceuticals, Cambridge, MA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited. Professional medical writing assistance was provided by Lauren Gallagher, RPh, PhD, and Lela Creutz, PhD, of Peloton Advantage, Parsippany, NJ, an OPEN Health company, and funded by Millennium Pharmaceuticals. Supported by National Health Service funding to the Royal Marsden Hospital/Institute of Cancer Research NIHR Biomedical Research Centre (S.P.).

9046 Background: Immune checkpoint blockade (ICB) has become a standard pillar of treatment for lung cancer. However, only ̃20% of unselected patients can achieve durable clinical benefits. We performed immunogenomic profiling of tissue specimens from a randomized Phase III trial S1400I on metastatic lung squamous cell carcinoma (SCC) to evaluate if there were factors associated with better prognoses with ICB from single-agent versus combined targeting PD-1/CTLA-4 and evaluate if any differentiated between the treatments. Methods: We utilized FFPE tumor tissue submitted for Lung-MAP screening provided by the SWOG bank. SCC samples from 82 eligible patients treated with combined nivolumab+ipilimumab (N+I) or single agent nivolumab (N) were subjected to multiplex immunofluorescence (mIF, n = 82) and NanoString (ncounter PanCancer Immune Profiling Panel, n = 32). Cell density phenotypes (cells/mm2) were defined using image analysis of staining for cytokeratin, CD3, CD8, granzyme B, CD45RO, FOXP3, PD1, PD-L1, and CD68. Immunogenomic features were associated with response, PFS, and OS derived from data provided by the LungMap team to the CIDC portal. For statistical analyses, non-parametric tests were utilized to assess associations of cell phenotypes versus continuous or categorical variables, and log-rank test analysis was performed to identify cell phenotypes or genes correlated with survival. Results: In both arms higher densities of total CD3+CD45RO+ T cells ( P= 0.041), CD3+PD-1+ T cells ( P= 0.024) and CD3+CD8+PD-1 T cells in stroma ( P= 0.042) and CD3+CD8+GZMB+ T cells in the tumor compartment ( P= 0.011) were positively associated with PFS. In the N+I arm but not in the N arm, higher densities of CD3+CD8+GZMB+ T cells in the tumor compartment were associated with better PFS ( P= 0.015) and higher densities of stroma CD3+CD8-FOXP3+ T cells with worse OS. Spatial analysis showed that the presence of CD8+GZMB+ T cells close to malignant cells (median, ≤19.27 µm) was associated with better PFS ( P= 0.037) in N+I arm and cluster analysis showed low clustering of cells in TMB-high vs. TMB-low tumors (P < 0.01). Gene expression profiling demonstrated that myeloid infiltration, immune recruitment, and inflammation genes were associated with a positive clinical outcome ( P< 0.05). In both arms, BLNK, CD163, FCGR2A were associated with better OS ( P< 0.01), IRF1 and BLNK were associated with increased PFS ( P< 0.01). In the N+I arm but not in the N arm, we observed significantly higher CD45 immune cell scores, including CD8 T cells and neutrophils, in responders versus non-responders. Conclusions: Our findings suggest a potential advantage in PFS and OS with an increased presence of cytotoxic immune cells and genes associated with the recruitment and proliferation of these cell types before therapy.

8583 Background: Immunotherapy has shown efficacy in the treatment of recurrent, extensive-stage small cell lung cancer (ES-SCLC). In the Checkmate 032 trial, ipilimumab and nivolumab combination therapy resulted in a 21% objective response rate in relapsed SCLC. At present, there are no biomarkers used in clinical practice to predict treatment responsiveness in SCLC. Ipilimumab and nivolumab act by blocking key co-inhibitory immune pathways of CTLA-4 and PD-1/PD-L1, respectively, leading to reinvigoration of anti-tumor cytotoxic T cell responses and a decrease in immune suppressive tumor infiltrating leukocytes. The ratio of intratumor Teff (CD8+) cells to Treg (CD4+/Foxp3+) cells (Teff/Treg) could be a more reliable biomarker than effector cell infiltration alone. Methods: In this open-label, single arm trial, we enrolled patients with ES-SCLC who previously received platinum-based chemotherapy; prior anti-PD-1 /PD-L1 therapy was allowed. Patients were treated with nivolumab 1 mg/kg and ipilimumab 3 mg/kg, for a total of 4 doses each and received nivolumab 480 mg beginning with cycle 5, every 4 weeks until progression, unacceptable toxicity or study discontinuation. On-study biopsies were performed prior to initiation of therapy and during week 4 for the biomarker primary objective—to correlate disease response with intratumor Teff/Treg changes. Secondary objectives include determining ORR, DOR, PFS, and OS. Results: Twenty-two patients (median age 63.5 [range 54-80] years, ECOG 0/1/2 [41%/50%/9%], sex M/F [45%/55%]) were enrolled and received treatment. Fourteen (64%) had paired biopsies while on treatment. Fifteen patients were evaluable per RECIST with an ORR of 13% (2/15, 2 partial responses [13%]) and DCR was 40% (6/15, 4 stable disease [27%]). Grade 3 treatment-related adverse events (TRAEs) occurred in 9/22 [40%]. Grade 4 TRAEs occurred in 2/22 [9%] (elevated lipase and elevated bilirubin) and Grade 5 TRAEs occurred in 1/22 patients (hepatic failure). Out of the 9 patients previously treated with anti- PD-1/PD-L1 therapy, 1 had a partial response and 2 had stable disease. Multiplexed quantitative immunofluorescence analysis revealed changes of both CD8+ effector T cells and Tregs in the tumor micro-environment associated with clinical benefit to immunotherapy. Conclusions: Combination immunotherapy with ipilimumab and nivolumab shows clinical efficacy in relapsed extensive-stage SCLC, including those previously treated with anti-PD-1/PDL-1 therapy. Obtaining paired biopsies was shown to be successful in this prospective trial to study the tumor microenvironment in SCLC tumors treated with checkpoint inhibitors. Early biomarker evaluation during week 4 shows local immunomodulatory effect of treatment and supports exploration as predictive biomarker in this population. Clinical trial information: 03670056.

9072 Background: In patients (pts) with crizotinib (CRZ)-refractory advanced ALK+ NSCLC in the phase 2 ALTA trial (NCT02094573), the depth of target lesion response to brigatinib (BRG) correlated with PFS and OS. Here, we examine the association of maximum decrease in target lesions with PFS and OS in ALTA-1L (NCT02737501), a randomized phase 3 trial of BRG vs CRZ in pts with ALK inhibitor-naive advanced ALK+ NSCLC. Methods: Pts were randomized 1:1 to receive BRG 180 mg qd (7-day lead-in at 90 mg; n=137) or CRZ 250 mg bid (n=138). Pts with target lesion assessment by blinded independent review committee (BIRC) were grouped based on greatest decrease from baseline per RECIST v1.1: none–50%, 51%–75%, and 76%–100% shrinkage. Outcomes in the ≤50% target lesion shrinkage group served as the comparator for outcomes in the 51%–75% and 76%–100% groups. Results: At study end (last pt contact: Jan 29, 2021), 124/137 pts in the BRG arm and 125/138 pts in the CRZ arm had ≥1 evaluable target lesion assessment; female (BRG/CRZ), 51%/59%; median age, 57.5/60.0 years. Median follow-up was 40.8/15.7 months. In BRG/CRZ arms, 76%-100% shrinkage was observed in 56%/34% of pts, 51%-75% shrinkage in 27%/30%, and ≤50% shrinkage in 16%/35%, respectively. BRG was associated with significantly more pts with target lesion shrinkage >75% vs CRZ ( P=0.0005), and a Cochran-Armitage trend analysis demonstrated significantly deeper response across all shrinkage groups for BRG compared with CRZ ( P50% had lower risk of a PFS event (BRG HR [95% CI]: 51%–75% shrinkage, 0.58 [0.29–1.18]; 76%–100%, 0.23 [0.12–0.46]; CRZ: 51%–75% shrinkage, 0.68 [0.41–1.12]; 76%–100%, 0.26 [0.15–0.45]) or an OS event (BRG: 51%–75% shrinkage, 0.39 [0.17–0.89]; 76%–100%, 0.15 [0.07–0.35]; CRZ: 51%–75% shrinkage, 0.43 [0.21–0.85]; 76%–100%, 0.23 [0.10–0.50]) than pts with ≤50% shrinkage. Longer median time to PFS and OS and higher 4-year estimated OS rates were associated with depth of response in both arms (Table). Conclusions: In this exploratory post hoc analysis, BRG demonstrated significantly deeper target lesion response vs CRZ. Pts with >75% shrinkage had significantly reduced risk of a PFS or OS event vs pts with ≤50% target lesion shrinkage. Clinical trial information: NCT02737501. [Table: see text]

9044 Background: While Immune checkpoint blockade (ICB) is standard treatment for lung cancer there are limited biomarkers that predict benefit, pharmacokinetic on-treatment activity or explain progression. S1400I was a randomized Phase III trial of nivolumab(N)+ipilimumab(I) versus N (NCT02154490, PMID 34264316) for ICB naïve, previously treated stage IV or recurrent squamous cell lung cancer. We performed circulating serum protein analysis of serial blood specimens from patients enrolled in S1400I to evaluate if serum proteins levels changed over time, changes differed by treatment arm, and if they were associated with overall survival. Methods: 561 serial blood specimens (baseline, weeks (wk) 3, 7, 9, and progression [PD]) from 160 of 252 eligible patients enrolled to S1400I were analyzed for 92 immuno-oncology analytes with the Olink proximity extension assay. Protein levels were normalized with use of internal controls and quantified as log2 protein expression (denoted as NPX). Linear mixed models evaluated change in expression from baseline at each time point (wks 3,7,9 and PD), and NPX differences at baseline, wk3, and PD depending on best objective response. A Cox model was used to evaluate the association between baseline NPX and survival. Overall survival and longitudinal cytokine expression were jointly modeled using a linear mixed model to estimate dynamic biomarker changes in NPX and a Cox model for survival. The joint models for time-varying NPX values included a random intercept and modeled time using a natural spline with three knots. Significance was defined as P < 0.05. Results: Serum proteins PCDC1, CXCL9, and CXCL10 were increased from baseline at wks 3,7,9 and at PD. CCL19 was increased at wks 3 and 7 but not at wk 9 and PD. IL10 and IFNγ were increased at wk 3 but subsequently returned to baseline. Change in CXCL13 from baseline to PD was larger for N+I versus N. Baseline CCL23, CSF-1, IL6, and MUC-16 were associated with shorter survival (HR > 1). Joint modeling of survival with cytokines showed an increased risk of death (HR > 1) with higher longitudinal serum levels of CXCL13, MMP12, CSF-1, and IL8. Patients achieving objective response had higher IL4 and LAMP3 and lower IL6 and IL8 at baseline and wk 3 compared to non-responders. Conclusions: Measurements of blood circulating soluble proteins represent easily accessible biomarkers that may be useful as indicators of outcome, and that will need to be prospectively confirmed. Clinical trial information: NCT02154490.

Purpose In two phase III studies, nivolumab, a programmed death-1 (PD-1) inhibitor antibody, improved overall survival (OS) versus docetaxel in pretreated advanced non–small-cell lung cancer (NSCLC). We report 5-year follow-up results from an early phase I study of nivolumab in this patient population and describe characteristics of 5-year survivors. Patients and Methods Patients with pretreated, advanced NSCLC received nivolumab 1, 3, or 10 mg/kg every 2 weeks in 8-week cycles for up to 96 weeks. OS from the time of first dose was estimated by the Kaplan-Meier method. Results The estimated 5-year OS rate was 16% for all treated patients (N = 129); 5-year OS rates were similar for squamous (16%) and nonsquamous (15%) NSCLC. Of 16 5-year survivors, most (88%) were known current or former smokers. Of 10 5-year survivors with quantifiable PD-1 ligand 1 expression, 70% had ≥ 1% PD-1 ligand 1 expression at baseline. Twelve 5-year survivors (75%) achieved a partial response to nivolumab per Response Evaluation Criteria in Solid Tumors, version 1.0, and two each (12%) had stable disease and progressive disease as best response. Nine 5-year survivors (56%) completed the maximum 96 weeks of nivolumab; four (25%) discontinued owing to adverse events and three (19%) owing to disease progression. As of a November 2016 database lock, 12 5-year survivors (75%) received no subsequent therapy and were without evidence of progressive disease at last follow-up. Conclusions Nivolumab treatment resulted in long-term OS and durable responses in a proportion of patients with pretreated advanced NSCLC. Long-term survivors had diverse baseline and on-treatment characteristics.

Purpose Most crizotinib-treated patients with anaplastic lymphoma kinase gene ( ALK)–rearranged non–small-cell lung cancer (ALK-positive NSCLC) eventually experience disease progression. We evaluated two regimens of brigatinib, an investigational next-generation ALK inhibitor, in crizotinib-refractory ALK-positive NSCLC. Patients and Methods Patients were stratified by brain metastases and best response to crizotinib. They were randomly assigned (1:1) to oral brigatinib 90 mg once daily (arm A) or 180 mg once daily with a 7-day lead-in at 90 mg (180 mg once daily [with lead-in]; arm B). Investigator-assessed confirmed objective response rate (ORR) was the primary end point. Results Of 222 patients enrolled (arm A: n = 112, 109 treated; arm B: n = 110, 110 treated), 154 (69%) had baseline brain metastases and 164 of 222 (74%) had received prior chemotherapy. With 8.0-month median follow-up, investigator-assessed confirmed ORR was 45% (97.5% CI, 34% to 56%) in arm A and 54% (97.5% CI, 43% to 65%) in arm B. Investigator-assessed median progression-free survival was 9.2 months (95% CI, 7.4 to 15.6) and 12.9 months (95% CI, 11.1 to not reached) in arms A and B, respectively. Independent review committee–assessed intracranial ORR in patients with measurable brain metastases at baseline was 42% (11 of 26 patients) in arm A and 67% (12 of 18 patients) in arm B. Common treatment-emergent adverse events were nausea (arm A/B, 33%/40%), diarrhea (arm A/B, 19%/38%), headache (arm A/B, 28%/27%), and cough (arm A/B, 18%/34%), and were mainly grades 1 to 2. A subset of pulmonary adverse events with early onset (median onset: day 2) occurred in 14 of 219 treated patients (all grades, 6%; grade ≥ 3, 3%); none occurred after escalation to 180 mg in arm B. Seven of 14 patients were successfully retreated with brigatinib. Conclusion Brigatinib yielded substantial whole-body and intracranial responses as well as robust progression-free survival; 180 mg (with lead-in) showed consistently better efficacy than 90 mg, with acceptable safety.

Purpose Stereotactic radiosurgery (SRS), whole-brain radiotherapy (WBRT), and epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) are treatment options for brain metastases in patients with EGFR-mutant non–small-cell lung cancer (NSCLC). This multi-institutional analysis sought to determine the optimal management of patients with EGFR-mutant NSCLC who develop brain metastases and have not received EGFR-TKI. Materials and Methods A total of 351 patients from six institutions with EGFR-mutant NSCLC developed brain metastases and met inclusion criteria for the study. Exclusion criteria included prior EGFR-TKI use, EGFR-TKI resistance mutation, failure to receive EGFR-TKI after WBRT/SRS, or insufficient follow-up. Patients were treated with SRS followed by EGFR-TKI, WBRT followed by EGFR-TKI, or EGFR-TKI followed by SRS or WBRT at intracranial progression. Overall survival (OS) and intracranial progression-free survival were measured from the date of brain metastases. Results The median OS for the SRS (n = 100), WBRT (n = 120), and EGFR-TKI (n = 131) cohorts was 46, 30, and 25 months, respectively ( P < .001). On multivariable analysis, SRS versus EGFR-TKI, WBRT versus EGFR-TKI, age, performance status, EGFR exon 19 mutation, and absence of extracranial metastases were associated with improved OS. Although the SRS and EGFR-TKI cohorts shared similar prognostic features, the WBRT cohort was more likely to have a less favorable prognosis ( P = .001). Conclusion This multi-institutional analysis demonstrated that the use of upfront EGFR-TKI, and deferral of radiotherapy, is associated with inferior OS in patients with EGFR-mutant NSCLC who develop brain metastases. SRS followed by EGFR-TKI resulted in the longest OS and allowed patients to avoid the potential neurocognitive sequelae of WBRT. A prospective, multi-institutional randomized trial of SRS followed by EGFR-TKI versus EGFR-TKI followed by SRS at intracranial progression is urgently needed.

9071 Background: BRG is a kinase inhibitor approved for the treatment of patients (pts) with ALK+ metastatic NSCLC; specific details for BRG use vary by indication and country. We report long-term efficacy and safety results of the Phase 1/2 and Phase 2 (ALTA) trials of BRG. Methods: The Phase 1/2 study was a single-arm, open-label trial (NCT01449461) of BRG 30–300 mg/d in pts with advanced malignancies. ALTA (NCT02094573) randomized pts with CRZ-refractory ALK+ NSCLC to receive BRG at 90 mg qd (arm A) or 180 mg qd with 7-d lead-in at 90 mg (arm B). For the Phase 1/2 study, investigator assessments of confirmed objective response rate (cORR; RECIST v1.1), duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety in pts with ALK+ NSCLC are reported. The primary endpoint of ALTA was cORR per investigator; secondary endpoints included cORR per independent review committee (IRC), DoR, PFS, and OS. Results: In the Phase 1/2 study, 137 pts received BRG; of these, 79 pts had ALK+ NSCLC (71/79 had prior CRZ; 28/79 received 180 mg qd [7-d lead-in at 90 mg]; 14/79 received 90 mg qd). In ALTA, 222 pts with CRZ-refractory ALK+ NSCLC were randomized (n = 112/110, arm A/B). At the end of the Phase 1/2 study (Feb 18, 2020), with median 27.7 mo follow-up (̃67 mo after last pt enrolled), 4 pts remained on BRG. At the end of ALTA (Feb 27, 2020), with median 19.6/28.3 mo follow-up in arm A/B (̃53 mo after last pt enrolled), 10/17 pts in arm A/B were still on treatment. Table shows efficacy results from final analyses with long-term follow-up. In ALTA, the IRC-assessed intracranial cORR in pts with measurable baseline brain metastases was 50% (13/26) in arm A and 67% (12/18) in arm B; Kaplan-Meier (KM) estimated median intracranial DoR was 9.4 mo (95% CI, 3.7, not reached [NR]) in arm A and 16.6 mo (3.7, NR) in arm B. With long-term follow-up, no new safety signals were identified. Treatment-emergent adverse events led to dose interruption (Phase 1/2: 59%; ALTA arm A/B: 49%/61%), dose reduction (13%; 8%/33%), or discontinuation (10%; 4%/13%). Conclusions: BRG showed sustained long-term activity, PFS, and manageable safety in pts with CRZ-refractory ALK+ NSCLC. The 180 mg/d dose after 7-d lead-in at 90 mg/d led to numerically higher median PFS and OS. Final results are similar to those reported for other approved ALK tyrosine kinase inhibitors in this setting. Clinical trial information: NCT01449461, NCT02094573. [Table: see text]

Purpose By applying the principles of real-time biopsy, biomarker-based, adaptively randomized studies in non–small-cell lung cancer (NSCLC) established by the Biomarker-Integrated Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE) trial, we conducted BATTLE-2 (BATTLE-2 Program: A Biomarker-Integrated Targeted Therapy Study in Previously Treated Patients With Advanced Non-Small Cell Lung Cancer), an umbrella study to evaluate the effects of targeted therapies focusing on KRAS-mutated cancers. Patients and Methods Patients with advanced NSCLC (excluding sensitizing EGFR mutations and ALK gene fusions) refractory to more than one prior therapy were randomly assigned, stratified by KRAS status, to four arms: (1) erlotinib, (2) erlotinib plus MK-2206, (3) MK-2206 plus AZD6244, or (4) sorafenib. Tumor gene expression profiling–targeted next-generation sequencing was performed to evaluate predictive and prognostic biomarkers. Results Two hundred patients, 27% with KRAS-mutated (KRAS mut+) tumors, were adaptively randomly assigned to erlotinib (n = 22), erlotinib plus MK-2206 (n = 42), MK-2206 plus AZD6244 (n = 75), or sorafenib (n = 61). In all, 186 patients were evaluable, and the primary end point of an 8-week disease control rate (DCR) was 48% (arm 1, 32%; arm 2, 50%; arm 3, 53%; and arm 4, 46%). For KRAS mut+ patients, DCR was 20%, 25%, 62%, and 44% whereas for KRAS wild-type patients, DCR was 36%, 57%, 49%, and 47% for arms 1, 2, 3, and 4, respectively. Median progression-free survival was 2.0 months, not different by KRAS status, 1.8 months for arm 1, and 2.5 months for arms 2 versus arms 3 and 4 in KRAS mut+ patients (P = .04). Median overall survival was 6.5 months, 9.0 and 5.1 months for arms 1 and 2 versus arms 3 and 4 in KRAS wild-type patients (P = .03). Median overall survival was 7.5 months in mesenchymal versus 5 months in epithelial tumors (P = .02). Conclusion Despite improved progression-free survival on therapy that did not contain erlotinib for KRAS mut+ patients and improved prognosis for mesenchymal tumors, better biomarker-driven treatment strategies are still needed.

Purpose Nivolumab, a fully human immunoglobulin G4 programmed death-1 immune checkpoint inhibitor antibody, has demonstrated improved survival in previously treated patients with advanced non–small-cell lung cancer (NSCLC). CheckMate 012, a phase I, multicohort study, was conducted to explore the safety and efficacy of nivolumab as monotherapy or combined with current standard therapies in first-line advanced NSCLC. Here, we report results for nivolumab plus platinum-based doublet chemotherapy (PT-DC). Patients and Methods Patients (N = 56) received nivolumab (intravenously) plus PT-DC concurrently every 3 weeks for four cycles followed by nivolumab alone until progression or unacceptable toxicity. Regimens were nivolumab 10 mg/kg plus gemcitabine-cisplatin (squamous) or pemetrexed-cisplatin (nonsquamous) or nivolumab 5 or 10 mg/kg plus paclitaxel-carboplatin (all histologies). The primary objective was to assess safety and tolerability. Secondary objectives included objective response rate and 24-week progression-free survival rate (per Response Evaluation Criteria in Solid Tumors version 1.1); exploratory objectives included overall survival (OS) and response by tumor programmed death ligand-1 expression. Results No dose-limiting toxicities occurred during the first 6 weeks of treatment. Forty-five percent of patients (25 of 56 patients) reported grade 3 or 4 treatment-related adverse events (AEs); 7% of patients (n = 4) had pneumonitis. Twenty-one percent of patients (n = 12) discontinued all study therapy as a result of treatment-related AEs. Objective response rates for nivolumab 10 mg/kg plus gemcitabine-cisplatin, nivolumab 10 mg/kg plus pemetrexed-cisplatin, nivolumab 10 mg/kg plus paclitaxel-carboplatin, and nivolumab 5 mg/kg plus paclitaxel-carboplatin were 33%, 47%, 47%, and 43%, respectively; 24-week progression-free survival rates were 51%, 71%, 38%, and 51%, respectively; 2-year OS rates were 25%, 33%, 27%, and 62%, respectively. Responses were achieved regardless of tumor programmed death ligand-1 expression. Conclusion The safety profile of nivolumab plus PT-DC was consistent with that expected for individual agents; however, treatment discontinuation related to AEs was greater with the combination. Encouraging activity was observed, especially for the nivolumab 5 mg/kg plus paclitaxel-carboplatin group, with a 2-year OS rate of 62%.

e21061 Background: Stereotactic body radiotherapy (SBRT) and thermal ablation are increasingly used to treat medically inoperable patients with non-small cell lung cancer (NSCLC). The purpose of this study is to assess the cost-effectiveness of microwave (MWA) and stereotactic body radiotherapy (SBRT) for patients with stage I NSCLC. Methods: A decision-analysis model was constructed over a 5-year of Medicare billing data from a health care sector’s perspective using TreeAge Pro Suite 2019 (TreeAge Software LLC, Cambridge, MA). The two evaluated strategies were SBRT and MWA. All clinical, cost and health utility parameters were derived from the literature with preference to long-term prospective trials and assigned appropriate statistical distributions. Costs and health utilities (quantified by quality-adjusted life years (QALY)) associated with procedure, short-term complications, long-term surveillance and disease progression were incorporated. A willingness-to-pay (WTP) threshold of $100,000/QALY was used. One QALY is equivalent to 1 year of life in perfect health. Strategies were compared using incremental cost-effectiveness ratio (ICER). Base case calculations, Monte Carlo Simulations with 10,000 iterations drawing parameters from their respective distributions, and multiple sensitivity analyses were performed. Results: Literature review and interpolation showed that average annual recurrence risk of SBRT and MWA were 4.64% and 10.4% respectively. SBRT yielded 2.33 QALY and MWA yielded 2.31 QALY. The difference in health benefit is equivalent to 1 week of life in perfect health. The overall costs were $225,271 and $195,331. The ICER of MWA in reference to SBRT was $1,480,597/QALY, which is more than 10 times of the WTP threshold currently used in the US, indicating that MWA is the more cost-effective strategy. MWA was the optimal strategy in 99.84% of the Monte Carlo simulations. One-way sensitivity analyses showed that MWA is more cost-effective than SBRT if recurrence risk of MWA is < 18.4% per year or recurrence risk of SBRT is > 1.44% per year, or cost of MWA is lower than or at most $7,500 more than SBRT. One-way sensitivity analysis showed that MWA would achieve a higher health benefit than SBRT if the overall survival after MWA was > 76.9% per year or after SBRT was < 75.6% per year. Conclusions: Our study showed that MWA is more cost-effective than SBRT for medically inoperable stage I NSCLC patients with comparable health benefits based on multiple robust probabilistic and deterministic sensitivity analyses.

Purpose Programmed death 1 is an immune checkpoint that suppresses antitumor immunity. Nivolumab, a fully human immunoglobulin G4 programmed death 1 immune checkpoint inhibitor antibody, was active and generally well tolerated in patients with advanced solid tumors treated in a phase I trial with expansion cohorts. We report overall survival (OS), response durability, and long-term safety in patients with non–small-cell lung cancer (NSCLC) receiving nivolumab in this trial. Patients and Methods Patients (N = 129) with heavily pretreated advanced NSCLC received nivolumab 1, 3, or 10 mg/kg intravenously once every 2 weeks in 8-week cycles for up to 96 weeks. Tumor burden was assessed by RECIST (version 1.0) after each cycle. Results Median OS across doses was 9.9 months; 1-, 2-, and 3-year OS rates were 42%, 24%, and 18%, respectively, across doses and 56%, 42%, and 27%, respectively, at the 3-mg/kg dose (n = 37) chosen for further clinical development. Among 22 patients (17%) with objective responses, estimated median response duration was 17.0 months. An additional six patients (5%) had unconventional immune-pattern responses. Response rates were similar in squamous and nonsquamous NSCLC. Eighteen responding patients discontinued nivolumab for reasons other than progressive disease; nine (50%) of those had responses lasting > 9 months after their last dose. Grade 3 to 4 treatment-related adverse events occurred in 14% of patients. Three treatment-related deaths (2% of patients) occurred, each associated with pneumonitis. Conclusion Nivolumab monotherapy produced durable responses and encouraging survival rates in patients with heavily pretreated NSCLC. Randomized clinical trials with nivolumab in advanced NSCLC are ongoing.

8511 Background: The PACIFIC study showed that consolidative Programmed Death Ligand 1 inhibition (PD-L1i) after chemoradiation therapy (CRT) improves PFS and OS in patients with Stage IIII NSCLC (Antonia et al. NEJM 2017, 2018). Limited data, however, exist regarding the incorporation of PD-L1i concurrently during CRT. We sought to assess the safety and toxicity of PD-1i using pembrolizumab (pembro) during definitive CRT for Stage III NSCLC. Methods: In this multi-center prospective Phase I clinical trial using a 3+3 design, we evaluated the timing and dosing of pembro combined with chemotherapy (carboplatin + paclitaxel weekly) and definitive RT (60 Gy in 2 Gy/day x 30 fractions) for unresectable, locally advanced Stage III NSCLC (AJCC 7thEd). Dose Cohorts (C) evaluated were--C1: full dose (FD) pembro (200 mg IV Q3 weeks) 2-6 weeks after CRT; C2: reduced dose (RD) pembro (100 mg IV Q3 weeks) starting Day 29 of CRT; C3: FD pembro starting Day 29 of CRT; C4: RD pembro starting on Day 1 of CRT; C5: FD pembro starting on Day 1 of CRT. For each cohort, pembro was continued Q3 weeks for up to 18 cycles (as monotherapy after CRT in either RD or FD based on initial dose assignment). Dose Limiting Toxicity (DLT) was defined as Grade ≥4 pneumonitis within 21 days of cycle 1 of pembro. Results: We enrolled 23 subjects from 8/2016-11/2018; median follow up (f/u) was 11.4 mo (range, 3.1 mo- 25.2 mo). Median age was 69 yrs (range 53-85); 52% were women. No DLTs were observed in any of the cohorts (C1 to C5). Grade ≥3 immune-related adverse events (irAE) occurred in 4 patients (18%). irAE’s included: Grade 5 (bilateral), 3, 2 pneumonitis (n=1, 1, 4, respectively (6 total)); Grade 3 hyperglycemia (n=1); Grade 3 interstitial nephritis (n=1); Grade 2 thyroiditis (n=4); Grade 2 myositis (n=1); Grade 1-2 transaminitis (n=3). Median PFS for patients who received ≥2 doses (n=18) of pembro was 20.3 mo. Conclusions: Combined treatment with PD-Li and CRT for stage III NSCLC was well tolerated with promising PFS to date but showed an increased risk for irAEs, particularly pneumonitis. Based on these encouraging results, further prospective study of PD-1i and CRT for Stage III NSCLC is warranted. Clinical trial information: NCT02621398.

8545 Background: To determine the potential benefit of combining local and systemic therapy in stage IV non-small cell lung cancer (NSCLC). Methods: Data from stage IV NSCLC patients receiving systemic therapy alone, surgical resection and systemic therapy, or external beam radiation therapy/thermal ablation (EBRT/TA) and systemic therapy were acquired from the 2010-2015 National Cancer Database (NCDB). EBRT and TA patients were combined to enhance the power of the study. Overall survival (OS) was evaluated via multivariable Cox proportional hazards models. Comparison was made between EBRT/TA and systemic therapy alone utilizing 1:1 propensity matching analysis. A multivariable logistic regression model was used to determine variables predictive of lung cancer treatment. Significant variables (p < 0.05) were used to calculate the propensity score, and patients receiving EBRT/TA and systemic therapy were 1:1 matched using a greedy (nearest-neighbor) approach. Results: 46,964 patients from the NCDB database fulfilled inclusion criteria (surgical resection n = 1,235; EBRT/TA n = 12,456; systemic therapy alone n = 33,273.) Treatment differed across patient demographics and disease characteristics. Surgical resection demonstrated superior OS compared to EBRT/TA and systemic therapy alone, even after multivariable adjustment (compared to systemic therapy alone HR = 0.54, 95% CI: 0.50-0.58, p < 0.001; compared to EBRT/TA HR = 0.56, 95% CI: 0.52-0.60, p < 0.001). EBRT/TA treatment demonstrated superior survival compared to systemic therapy alone after accounting for confounders via propensity score matching (HR = 0.95, 95% CI: 0.93-0.98, p = 0.002). Interaction analyses indicated heterogeneous effectiveness of EBRT/TA according to patient demographics and cancer factors: the survival benefit of EBRT/TA over systemic therapy alone was especially pronounced in stage IV squamous cell carcinoma patients with limited nodal and metastatic disease (HR = 0.78, 95% CI: 0.71-0.85, p < 0.001 compared to systemic therapy alone; OS rates at 1-year = 50.9% vs. 42.4%; 2-years = 26.6% vs. 19.8%; 3-years = 17.2% vs. 10.1%). Conclusions: Stage IV NSCLC patients who received EBRT/TA or surgical resection in addition to systemic therapy demonstrated prolonged survival. EBRT/TA in combination with systemic therapy should be preferred in selected patients that are ineligible surgical candidates.

8523 Background: Veliparib (V), a PARP inhibitor, may potentiate the antitumor effect of CRT in NSCLC. Methods: Eligibility included newly diagnosed unresectable stage III NSCLC. Patients were randomized to receive concurrent CRT with weekly carboplatin (AUC 2) and paclitaxel (45 mg/m2) with V at 120 mg or placebo (P) twice daily during CRT followed by 2 cycles (every 21 days) of consolidation carboplatin (AUC 6), paclitaxel (200 mg/m2) with V at 80 mg or P (per randomized arm) orally on days 1-7 of each cycle. Progression-free survival (PFS) was the primary endpoint. The accrual goal was 132 patients. Results: The dose-finding study results were previously presented (ASCO 2016;A8537). V 120 mg twice daily was the recommended phase II dose. A total of 31 eligible and evaluable patients were enrolled in the phase II randomized trial: 17 on V and 13 on P (1 patient in the V arm withdrew prior to starting any treatment, thus was not evaluable). The study was closed to accrual early due to the positive results from the PACIFIC trial that changed standard practice. Median follow-up among alive patients was 16 months. During CRT, the following grade (G) 3-4 adverse events (AE) were seen with V vs P: any G3 AE (6 vs 6), any G4 AE (2 vs 3), G3 pneumonitis (0 vs 1), G3 esophagitis (1 vs 1), G3 oral mucositis (1 vs 0), G3 anorexia (1 vs 1), G3 hyponatremia (0 vs 3), G3 anemia (1 vs 0), G3 neutropenia (3 vs 1), G3 thrombocytopenia (1 vs 0), G4 hypoglycemia (0 vs 1). Also, 2 patients per arm had G4 lymphopenia. During consolidation (11 evaluable patients with V; 10 with P), G3 anemia (1 vs 0), G3 anorexia (1 vs 0), G3 weight loss (0 vs 1), G3 dehydration (1 vs 0), G3 dysphagia (2 vs 0), G3 fatigue (1 vs 0), G3 hypomagnesemia (0 vs 1), G3 nausea (1 vs 0), G4 hyperglycemia (0 vs 1), G3-4 neutropenia (3 vs 0), G3 thrombocytopenia (1 vs 0), G3-4 lymphopenia (2 vs 1); a G5 pneumonitis occurred in the P arm. Response rates were 56% (95% CI, 31-78%) and 69% (95% CI, 38-91%) on the V and P arms, respectively. PFS at 1 year was 47% (95% CI, 23% - 68%) with V and 46% (95% CI, 19% - 70%) with P. Overall survival (OS) at 1 year was 89% (95% CI, 61%-97%) with V and 54% (95% CI, 25%-76%) with P. Adding the 6 patients treated at 120 mg in the phase I part, 1-year with V was 91% (95% CI, 69%-98%). Conclusions: V in combination with CRT was tolerable with expected toxicities that relate to the backbone regimen. In the small number of randomized patients there was a suggestion of promising survival with V that may provide rationale for future trials of PARP inhibitors with CRT. Clinical trial information: NCT01386385.

9014 Background: Lung-MAP is a master protocol for patients (pts) with stage IV previously treated SqNSCLC. S1400I enrolled pts who were not eligible for a biomarker-matched sub-study. Methods: S1400I is phase III randomized trial for immunotherapy-naïve patients with ECOG 0-1 not selected by PD-L1 expression. Pts were assigned 1:1 to nivolumab and ipilimumab (N+I) vs nivolumab (N). N was given at 3 mg/kg q 2w, I was given at 1 mg/kg q 6w. The primary endpoint was overall survival (OS). Secondary endpoints: investigator-assessed progression-free survival (IA-PFS), response by RECIST 1.1, and toxicity. Results: From December 18, 2015 to April 23, 2018, 275 pts enrolled and 252 determined eligible (125 N+I and 127 N). The study was closed for futility at an interim analysis. Baseline characteristics were similar across arms. mOS was 10.0 m (8.0-12.8) and 11.0 m (8.2-13.5) for N+I and N. HR 0.97 (0.71-1.31), p 0.82. mPFS was 3.8 m (2.3-4.2) and 2.9 m (1.8-3.9) for N+I and N. HR 0.84 (0.64-1.09), p 0.19. Outcomes based on PD-L1 and TBM subsets are shown in table. Response rates were 18% (12-25%) and 17% (11-24%) for N+ I and N. Median follow up for patients still alive was 17.4 m. Grade ≥3 treatment-related AEs occurred in 48(39%) of pts on N+I vs 38(31%) on N. irAE reported in 39% of pts on N+I and 34% of patients on N. Drug-related AEs led to discontinuation in 25% and 16% of pts on N+I and N. There were 5 grade 5 AE in N+I arm and 1 in N arm. Conclusions: S1400I failed to show improvement in outcomes with N+I. Study was closed for futility at interim analysis. Toxicities were not different between two arms. Clinical trial information: 02785952. [Table: see text]

TPS2648 Background: Adoptive cell therapy (ACT) with tumor infiltrating lymphocytes (TIL) has demonstrated durable complete responses in immunogenic tumors with high mutational burden in metastatic melanoma patients who had not received prior immune checkpoint inhibitors (ICI); CR rate 24%. Pembrolizumab is an approved agent for the treatment of metastatic melanoma and head & neck cancers, among others. Further, ICI have been reported to potentially enhance the efficacy of TIL therapy. One aim of this study is to improve the efficacy response for early line patients by combining TIL with anti-PD-1 in ICI-naïve patients with metastatic melanoma (Cohort 1) and head & neck cancers (Cohorts 2). In Cohort 3, TIL therapy alone is offered to NSCLC patients who have received prior systemic therapy, including ICI. Methods: IOV-COM-202 is a prospective, Phase 2 multicenter, open-label study in which 36 patients (12 per cohort) are to be enrolled in one of three cohorts; Cohorts 1 and 2: TIL therapy in combination with pembrolizumab, or Cohort 3: TIL therapy alone. Patients will have tumors resected at local centers and shipped to a central GMP facility to undergo a 22-day manufacturing process that yields cryopreserved infusion product (LN-144/LN-145) that is shipped back to treating center. All patients receive TIL therapy consisting of 1 week of preconditioning cyclophosphamide/fludarabine, followed by a single infusion of LN-144/LN-145 (Day 0) and up to 6 doses of IL-2 (600,000 IU/kg). Patients in Cohorts 1 and 2 also receive pembrolizumab on Day -1 and then Q3W for up to 2 years or until disease progression or acceptable toxicity. Co-primary endpoints for each cohort are objective response rate (ORR) per RECIST 1.1, and safety (grade ≥ 3 TEAE). Eligibility criteria: Cohorts 1 (melanoma) and 2 (head & neck): patients must not have received prior ICI (eg, anti-PD-1, anti-CTLA-4) and may have received up to 3 lines of prior systemic therapy, Cohort 3 (NSCLC): patients must have received 1-3 prior lines of systemic therapy including ICI. After tumor resection for TIL manufacturing, patients must have additional measurable disease for assessment per RECIST 1.1. Adequate bone marrow/organ function and ECOG PS of 0 or 1 is required. Clinical trial information: NCT03645928.

Purpose Bevacizumab and erlotinib have been shown to improve survival in stage IV non–small-cell lung cancer (NSCLC). This phase I/II trial was designed to incorporate these agents with induction and concurrent chemoradiotherapy in stage III NSCLC. Patients and Methods Patients received induction chemotherapy (carboplatin area under the curve [AUC] 6, paclitaxel 225 mg/m2, and bevacizumab 15 mg/kg on days 1 and 22) followed by concurrent chemotherapy (carboplatin AUC 2 and paclitaxel 45 mg/m2 weekly with bevacizumab 10 mg/kg every other week for four doses) and thoracic conformal radiation therapy (TCRT) to 74 Gy. In the phase I portion, cohort 1 received no erlotinib, whereas cohorts 2 and 3 received erlotinib at 100 and 150 mg, respectively, Tuesday through Friday, during TCRT. Consolidation therapy with erlotinib (150 mg daily) and bevacizumab (15 mg/kg every 3 weeks) was planned 3 to 6 weeks later for six cycles. Results Forty-five eligible patients were enrolled. The objective response rates to induction and overall treatment were 39% (95% CI, 24% to 55%) and 60% (95% CI, 44% to 75%), respectively. The median progression-free and overall survival times were 10.2 months (95% CI, 8.4 to 18.3 months) and 18.4 months (95% CI, 13.4 to 31.7 months), respectively. The principal toxicity was esophagitis (29% grade 3 or 4 esophagitis, with one patient with grade 3 tracheoesophageal fistula), which was often prolonged. Consolidation therapy with bevacizumab and erlotinib was not feasible. Conclusion The use of bevacizumab and erlotinib as administered in this trial is not recommended given the lack of an efficacy signal and the substantial risk of esophageal toxicity.

Purpose IPI-504 is a novel, water-soluble, potent inhibitor of heat-shock protein 90 (Hsp90). Its potential anticancer activity has been validated in preclinical in vitro and in vivo models. We studied the activity of IPI-504 after epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) therapy in patients with advanced, molecularly defined non–small-cell lung cancer (NSCLC). Patients and Methods Patients with advanced NSCLC, prior treatment with EGFR TKIs, and tumor tissue available for molecular genotyping were enrolled in this prospective, nonrandomized, multicenter, phase II study of IPI-504 monotherapy. The primary outcome was objective response rate (ORR). Secondary aims included safety, progression-free survival (PFS), and analysis of activity by molecular subtypes. Results Seventy-six patients were enrolled between December 2007 and May 2009 from 10 United States cancer centers. An ORR of 7% (five of 76) was observed in the overall study population, 10% (four of 40) in patients who were EGFR wild-type, and 4% (one of 28) in those with EGFR mutations. Although both EGFR groups were below the target ORR of 20%, among the three patients with an ALK gene rearrangement, two had partial responses and the third had prolonged stable disease (7.2 months, 24% reduction in tumor size). The most common adverse events included grades 1 and 2 fatigue, nausea, and diarrhea. Grade 3 or higher liver function abnormalities were observed in nine patients (11.8%). Conclusion IPI-504 has clinical activity in patients with NSCLC, particularly among patients with ALK rearrangements.

8573Background: 5-10% of EGFR-mutant ACs undergo SCLC/neuroendocrine transformation (SCLC-T) but the clinical course of such pts is poorly characterized. Methods: We identified 50 pts with EGFR-mut...

9099Background: We report final Phase I results of a Phase I/II prospective trial assessing safety and tolerability of SBRT and concurrent pembrolizumab. Methods: Eligible patients had metastatic N...

3006Background: PIVOT is an ongoing, open-label, phase 1/2 study of NKTR-214 (214; CD122-biased agonist) plus PD-1 inhibitor nivolumab (N) in patients (pts) with advanced cancers (MEL, RCC, NSCLC, TNBC, and UC). 214 monotherapy increases newly proliferative CD8+ T cells in tumors and increases cell surface PD-1 and PD-L1 expression, demonstrating a potentially synergistic mechanism with anti-PD-1 therapy. Methods: In P1 dose escalation, pts received 214 (0.003, 0.006 or 0.009 mg/kg) with N (240 mg or 360 mg) administered IV as outpatient Q2W or Q3W; in P2 expansion, the RP2D of 214 (0.006 mg/kg) with N (360 mg) Q3W was administered concurrently. Response was assessed Q8W by RECIST v1.1. Matched tumor samples were evaluated for changes from baseline in immune cell populations, gene expression, and T cell receptor repertoire. Tumor baseline and on treatment PD-L1 protein expression was assessed (28-8 IHC assay). Results: As of 7FEB2018, 162 pts (P1, n = 38; P2, n = 124) were evaluable for safety. The most c...

9056Background: Exon 19 deletions (ex19 dels) account for ~50% of EGFR-mutant NSCLCs. The E746_A750 ex19 del accounts for 75% of these cases. Two frequent uncommon ex19 dels are L747_P753 > S and L...