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PURPOSE The open-label, phase III POSEIDON study evaluated tremelimumab plus durvalumab and chemotherapy (T + D + CT) and durvalumab plus chemotherapy (D + CT) versus chemotherapy alone (CT) in first-line metastatic non–small-cell lung cancer (mNSCLC). METHODS Patients (n = 1,013) with EGFR/ ALK wild-type mNSCLC were randomly assigned (1:1:1) to tremelimumab 75 mg plus durvalumab 1,500 mg and platinum-based chemotherapy for up to four 21-day cycles, followed by durvalumab once every 4 weeks until progression and one additional tremelimumab dose; durvalumab plus chemotherapy for up to four 21-day cycles, followed by durvalumab once every 4 weeks until progression; or chemotherapy for up to six 21-day cycles (with or without maintenance pemetrexed; all arms). Primary end points were progression-free survival (PFS) and overall survival (OS) for D + CT versus CT. Key alpha-controlled secondary end points were PFS and OS for T + D + CT versus CT. RESULTS PFS was significantly improved with D + CT versus CT (hazard ratio [HR], 0.74; 95% CI, 0.62 to 0.89; P = .0009; median, 5.5 v 4.8 months); a trend for improved OS did not reach statistical significance (HR, 0.86; 95% CI, 0.72 to 1.02; P = .0758; median, 13.3 v 11.7 months; 24-month OS, 29.6% v 22.1%). PFS (HR, 0.72; 95% CI, 0.60 to 0.86; P = .0003; median, 6.2 v 4.8 months) and OS (HR, 0.77; 95% CI, 0.65 to 0.92; P = .0030; median, 14.0 v 11.7 months; 24-month OS, 32.9% v 22.1%) were significantly improved with T + D + CT versus CT. Treatment-related adverse events were maximum grade 3/4 in 51.8%, 44.6%, and 44.4% of patients receiving T + D + CT, D + CT, and CT, respectively; 15.5%, 14.1%, and 9.9%, respectively, discontinued treatment because of treatment-related adverse events. CONCLUSION D + CT significantly improved PFS versus CT. A limited course of tremelimumab added to durvalumab and chemotherapy significantly improved OS and PFS versus CT, without meaningful additional tolerability burden, representing a potential new option in first-line mNSCLC.

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]

8500 Background: Adjuvant platinum-based chemotherapy (chemo) provides only a modest 5-year survival benefit in fully resected, high-risk early-stage NSCLC. We report the primary disease-free survival (DFS) results from the pre-planned interim analysis of IMpower010, a randomized phase 3 open-label trial of adjuvant atezolizumab (atezo; anti–PD-L1) vs best supportive care (BSC) after adjuvant chemo in patients (pts) with early-stage resected NSCLC. Methods: Eligible pts had completely resected (4-12 weeks prior to enrollment) Stage IB (≥4 cm)-IIIA NSCLC (AJCC/UICC v7) and ECOG PS 0-1. A total of 1280 pts were enrolled, and 1269 pts received up to four 21-day cycles of cisplatin-based chemo (plus pemetrexed, docetaxel, gemcitabine or vinorelbine). Of these pts (n=1269), 1005 were subsequently randomized 1:1 to 16 cycles of atezo 1200 mg Q3W or BSC. The primary endpoint of investigator-assessed DFS and secondary endpoint of overall survival (OS) were tested hierarchically: first DFS in the PD-L1 TC ≥1% (SP263) subgroup with Stage II-IIIA disease, then DFS in all randomized pts with Stage II-IIIA disease, then DFS in the ITT population (Stage IB-IIIA) and finally OS in the ITT population. Efficacy assessments were based on randomized pts. Safety was assessed in the safety-evaluable population, defined as pts who received ≥1 dose of atezo or who had ≥1 post-baseline safety assessment if randomized to the BSC arm. Results: At data cutoff (January 21, 2021), median follow-up was 32.2 months in the ITT population. Baseline characteristics were generally balanced between arms. Atezo showed statistically significant DFS benefit vs BSC in the PD-L1 TC ≥1% Stage II-IIIA and all randomized Stage II-IIIA populations; the significance boundary was not crossed for DFS in the ITT population (Table). OS data were immature and not formally tested. Pts in the atezo arm received a median of 16 (range, 1-16) atezo doses. Any-grade AEs occurred in 92.7% (atezo) and 70.7% (BSC); events were Grade 3/4 in 21.8% and 11.5%, respectively. Grade 5 treatment-related AEs occurred in 0.8% of pts in the atezo arm. AEs leading to atezo discontinuation occurred in 18.2% of atezo-treated pts. Conclusions: IMpower010 met its primary endpoint, showing DFS benefit with adjuvant atezo vs BSC after adjuvant chemo in pts with resected Stage II-IIIA NSCLC, with pronounced benefit in the PD-L1 TC ≥1% subgroup. The safety profile of atezo was consistent with prior experience of atezo monotherapy across indications and lines of therapy. Funding: F. Hoffmann-La Roche Ltd. Clinical trial information: NCT02486718. [Table: see text]

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

9016 Background: MYSTIC, an open-label, Ph3 trial of first-line D (anti-PD-L1) ± T (anti-CTLA-4) vs platinum-based CT, showed an improvement in OS with D vs CT in pts with tumor cell PD-L1 expression ≥25% (PD-L1 TC ≥25%; HR 0.76 [97.54% CI 0.56–1.02], p = 0.036). Exploratory analyses showed bTMB was a predictive biomarker for OS with D±T vs CT. We report further exploratory analyses of OS according to PD-L1 and bTMB. Methods: Immunotherapy/CT-naïve pts with mNSCLC were randomized (1:1:1) to D, D+T or CT. bTMB levels (mut/Mb) were evaluated with the GuardantOMNI platform (Guardant Health), and PD-L1 TC expression with the VENTANA PD-L1 (SP263) IHC assay. Results: D improved OS vs CT in pts with PD-L1 TC ≥25% across bTMB levels (PD-L1 TC ≥25%/bTMB≥20 HR 0.79 [95% CI 0.45, 1.39]; PD-L1 TC ≥25%/bTMB < 20 HR 0.64 [95% CI 0.45, 0.90]). In contrast, D+T improved OS vs CT in pts with bTMB≥20 across different PD-L1 TC expression levels (Table; PD-L1 TC ≥25%/bTMB≥20 HR 0.44 [95% CI 0.23, 0.84]; PD-L1 TC < 1%/bTMB≥20 HR 0.42 [95% CI 0.17, 0.97]). Additional cutoffs and outcomes in subgroups defined by both biomarkers will be presented. Conclusions: These exploratory analyses from MYSTIC support PD-L1 TC expression as an appropriate predictive biomarker for OS with D vs CT, while suggesting bTMB as a predictive biomarker for OS with D+T in mNSCLC. These biomarkers appear to be independent and both may be important for mNSCLC treatment decisions. Interpretation of these data may be limited by small sample sizes; further investigations are warranted. Clinical trial information: NCT02453282. [Table: see text]

9048 Background: MYSTIC, an open-label, Phase 3 trial of first-line D (anti-PD-L1) ± T (anti-CTLA-4) vs platinum CT in mNSCLC, showed an improvement in overall survival (OS) with D vs CT in pts with tumor cell PD-L1 expression ≥25% (TC ≥25% [primary analysis population]; D vs CT, HR 0.76 [97.54% CI 0.56–1.02], p = 0.036; D+T vs CT, HR 0.85 [98.77% CI 0.61–1.17], p = 0.202). Here we summarize PROs from MYSTIC. Methods: Immunotherapy/CT-naïve mNSCLC pts were randomized (1:1:1) to D, D+T, or CT. Symptoms, function, and global health status/quality of life (QoL) were assessed using the EORTC QLQ-C30 v3 questionnaire and its lung cancer module, QLQ-LC13. A change in score from baseline ≥10 points was predefined as clinically meaningful (CM). Mean changes from baseline (over 12 mos) for prespecified symptoms were analyzed using a mixed model for repeated measures (MMRM). Time from randomization to the first CM deterioration (TTD) was analyzed. Results: Among pts with PD-L1 TC ≥25% (n = 488), there were no differences between arms in symptoms, function, or global health status/QoL at baseline. Compliance with completing the questionnaires was ≥60% to wk 120 in the D±T arms, and to wk 40 (C30) and wk 44 (LC13) in the CT arm. MMRM analysis showed significant between-arm differences in changes from baseline in favor of D for fatigue (difference vs CT −9.5) and appetite loss (−11.9; CM), and D+T for fatigue (−11.7; CM). Significantly longer TTD (median, mos) was seen with D and D+T vs CT for appetite loss (12.8 and 5.6 vs 4.5), constipation (14.6 and 9.0 vs 5.5), nausea/vomiting (16.7 and 9.7 vs 4.5), and dyspnea (10.6 and 7.4 vs 5.6); D vs CT for diarrhea (16.3 vs 9.0), insomnia (9.3 vs 6.2), and hemoptysis (not reached vs 10.3); and D+T vs CT for fatigue (5.6 vs 2.0). Significantly longer TTD (median, mos) was also seen with D and D+T vs CT for function (cognitive [9.1 and 6.6 vs 5.2], physical [9.0 and 7.4 vs 4.2], role [D vs CT only; 7.3 vs 3.7], social [12.9 and 5.4 vs 5.2]), and global health status/QoL (5.9 and 6.8 vs 5.5). Conclusions: Pts with PD-L1 TC ≥25% treated with D±T had a reduced symptom burden over time and longer TTD for symptoms, function, and global health status/QoL compared to pts receiving CT. Clinical trial information: NCT02453282.

Purpose Ipilimumab, which is an anti–cytotoxic T-cell lymphocyte-4 monoclonal antibody, showed a survival benefit in melanoma with adverse events (AEs) managed by protocol-defined guidelines. A phase II study in lung cancer assessed the activity of ipilimumab plus paclitaxel and carboplatin. Patients and Methods Patients (N = 204) with chemotherapy-naive non–small-cell lung cancer (NSCLC) were randomly assigned 1:1:1 to receive paclitaxel (175 mg/m2) and carboplatin (area under the curve, 6) with either placebo (control) or ipilimumab in one of the following two regimens: concurrent ipilimumab (four doses of ipilimumab plus paclitaxel and carboplatin followed by two doses of placebo plus paclitaxel and carboplatin) or phased ipilimumab (two doses of placebo plus paclitaxel and carboplatin followed by four doses of ipilimumab plus paclitaxel and carboplatin).Treatment was administered intravenously every 3 weeks for ≤ 18 weeks (induction). Eligible patients continued ipilimumab or placebo every 12 weeks as maintenance therapy. Response was assessed by using immune-related response criteria and modified WHO criteria. The primary end point was immune-related progression-free survival (irPFS). Other end points were progression-free survival (PFS), best overall response rate (BORR), immune-related BORR (irBORR), overall survival (OS), and safety. Results The study met its primary end point of improved irPFS for phased ipilimumab versus the control (hazard ratio [HR], 0.72; P = .05), but not for concurrent ipilimumab (HR, 0.81; P = .13). Phased ipilimumab also improved PFS according to modified WHO criteria (HR, 0.69; P = .02). Phased ipilimumab, concurrent ipilimumab, and control treatments were associated with a median irPFS of 5.7, 5.5, and 4.6 months, respectively, a median PFS of 5.1, 4.1, and 4.2 months, respectively, an irBORR of 32%, 21% and 18%, respectively, a BORR of 32%, 21% and 14%, respectively, and a median OS of 12.2, 9.7, and 8.3 months. Overall rates of grade 3 and 4 immune-related AEs were 15%, 20%, and 6% for phased ipilimumab, concurrent ipilimumab, and the control, respectively. Two patients (concurrent, one patient; control, one patient) died from treatment-related toxicity. Conclusion Phased ipilimumab plus paclitaxel and carboplatin improved irPFS and PFS, which supports additional investigation of ipilimumab in NSCLC.

105Background: Pembro plus pemetrexed and carboplatin resulted in superior objective response rate (ORR), progression-free survival (PFS) and overall survival (OS) for untreated pts with non-sq NSCLC. Pembro is active in sq NSCLC, so combining with chemo is a rational next step. Methods: KEYNOTE-407 (NCT02775435) is a randomized, placebo-controlled, global study of 560 untreated pts with metastatic sq NSCLC with ECOG 0-1. Pts were stratified by type of taxane, PD-L1 (TPS

e19024 Background: The SQUIRE study demonstrated that the addition of necitumumab (N) to gemcitabine-cisplatin (GC) improved survival in patients (pts) with stage IV sq-NSCLC. This retrospective an...

e19023 Background: As previously reported, the SQUIRE study demonstrated that the addition of N to GC chemotherapy significantly improved survival in patients (pts) with stage IV squamous NSCLC. He...

7531 Background: IPI is a fully human monoclonal antibody that potentiates immune response by selectively inhibiting CTLA-4. CA184- 041 is a randomized, double-blind phase II study of first-line IPI in recurrent/metastatic lung cancer in combination with P (175 mg/m2)/C (AUC=6). Methods: 203 pts with chemotherapy-naive, recurrent or stage IIIb/IV NSCLC were randomized 1:1:1 to receive either: IPI (10 mg/kg IV q3wks) + concurrent (CON) IV P/C (175 mg/m2 and AUC=6, q3wks); or IPI + sequential (SEQ) P/C, or P/C alone (PBO). After P/C, IPI was administered as continuation maintenance therapy q12 wks until toxicity or disease progression. Efficacy was assessed by mWHO and novel immune- related response criteria (irRC), providing a more comprehensive evaluation of immunotherapeutics (Clin Canc Res 2009;15:7412). The primary objective compared immune-related progression-free survival (irPFS) between CON and PBO and SEQ and PBO using a log-rank test with one-sided alpha of 0.1. Results: Baseline characteristics w...

3577 Background: AT-101 inhibits the Bcl-2 protein family (Bcl-2, Bcl-xL, Mcl-1, Bcl-W) with broad preclinical activity including synergy with D. Methods: We conducted a randomized, double-blind, P-controlled phase 2 study. Patients had received 1 prior chemotherapy regimen for advanced NSCLC. Patients received AT-101 (40 mg b.i.d. days 1–3) or P with D (75 mg/m2 day 1) Q 21 days. Primary endpoint was progression-free survival (PFS) by independent review (IR). Secondary endpoints were overall survival (OS) and investigator determined PFS. 102 patients were planned for 70 events (80% power, HR 0.6, 1-sided alpha 0.1). A biomarker of AT-101 activity was developed by treating 55 NSCLC cell lines with AT-101 and using the corresponding gene expression data to identify a genomic predictor of sensitivity to AT-101. Results: 106 patients were randomized. Baseline factors were balanced. Median OS for patients on AT-101+D was 7.3 months versus 5.6 months for P + D arm (HR 0.60, p = 0.05). The median investigator determined PFS was 12.6 weeks and 10.7 weeks for AT-101+D and P+D arms respectively (HR 1.0, p = 0.49); IR is ongoing. Common adverse events were fatigue (18%), anemia (18%), and dyspnea (18%). Grade 1/2 headaches occurred more frequently in the AT-101 arm. Analysis of gene expression data by Bayesian regression revealed a robust 500 gene predictor of sensitivity to AT-101 that was cross validated in a leave one out analysis and in an independent cohort of 32 NSCLC cell lines. Validation of the predictor in patient samples from the trial is ongoing. Conclusions: In this phase II trial AT-101, an oral pan Bcl-2 family inhibitor, had favorable OS compared to placebo when combined with docetaxel in previously treated NSCLC and was well tolerated. A genomic predictor of AT-101 sensitivity is likely to enrich for responders and identify novel therapeutic combinations for future [Table: see text]