PD-L1 Subgroups Research Articles

Nivolumab (NIVO) + ipilimumab (IPI) + 2 cycles of platinum-doublet chemotherapy (chemo) vs 4 cycles chemo as first-line (1L) treatment (tx) for stage IV/recurrent non-small cell lung cancer (NSCLC): CheckMate 9LA.

9501 Background: NIVO + IPI was shown to improve overall survival (OS) and durability of response vs chemo in 1L advanced NSCLC in CheckMate 227 Part 1, regardless of PD-L1 expression. We hypothesized that a limited course of chemo combined with NIVO + IPI could provide rapid disease control while building on the durable OS benefit seen with dual PD-1 and CTLA-4 inhibition. CheckMate 9LA (NCT03215706) is a phase 3 randomized study evaluating NIVO + IPI + 2 cycles chemo vs chemo in 1L stage IV/recurrent NSCLC. Methods: Adults with tx-naive, histologically confirmed stage IV/recurrent NSCLC, ECOG performance status 0–1, and no known sensitizing EGFR/ALK alterations were randomized 1:1 to NIVO 360 mg Q3W + IPI 1 mg/kg Q6W + chemo (2 cycles) (n = 361) or chemo (4 cycles) alone (n = 358), stratified by PD-L1 (< 1% vs ≥ 1%), sex, and histology (squamous vs non-squamous). Chemo was based on histology. Pts with non-squamous NSCLC in the chemo-only arm could receive optional pemetrexed maintenance. Pts were treated with immunotherapy until disease progression, unacceptable toxicity, or for 2 y. The primary endpoint was OS; the interim analysis using Lan–DeMets alpha spending function with O’Brien–Fleming boundary was planned at ~80% information fraction (ie, after observing ~322 total events). Secondary endpoints included progression-free survival (PFS) and objective response rate (ORR) by blinded independent central review, and efficacy by PD-L1 subgroups. Exploratory endpoints included safety/tolerability. Results: Baseline characteristics were balanced across arms. At a preplanned interim analysis (minimum follow-up 8.1 mo), OS was significantly prolonged with NIVO + IPI + chemo vs chemo (HR 0.69, 96.71% CI: 0.55–0.87; P = 0.0006); statistically significant improvements in PFS and ORR were seen. With longer follow-up (minimum 12.7 mo), NIVO + IPI + chemo vs chemo continued to provide longer OS; median 15.6 vs 10.9 mo (HR 0.66, 95% CI: 0.55–0.80); 1-y OS rates were 63 vs 47%. Clinical benefit was consistent across all efficacy measures in key subgroups including by PD-L1 and histology. Grade 3–4 tx-related adverse events were reported in 47 vs 38% of pts in the NIVO + IPI + chemo vs chemo arms, respectively. Conclusions: CheckMate 9LA met its primary endpoint: a statistically significant improvement in OS was observed with NIVO + NSCLC-optimized IPI + a limited course of chemo vs chemo (4 cycles) in 1L advanced NSCLC. No new safety signals were reported. Clinical trial information: NCT03215706 .

Abstract PD5-11: Association of immune gene expression with outcome in the MARIANNE phase 3 clinical trial in HER2-positive metastatic breast cancer (MBC)

Abstract Introduction: Although HER2+ breast cancer (BC) is considered a moderately immunogenic tumor, several studies have shown a role of pre-existing immunity associated with favorable long-term prognosis and better response to treatment. In this study, we performed exploratory analyses to assess whether the efficacy of HER2 targeted treatment in the MARIANNE trial correlated with immune gene expression. Methods: MARIANNE (NCT01120184) is a phase 3 study in patients (pts) with centrally confirmed HER2+ local advanced/metastatic BC naïve to prior treatments in the advanced disease. Pts were randomized (1:1:1) to trastuzumab+taxane (HT), T-DM1, or T-DM1+Petuzumab (P) and the trial showed noninferior PFS of T-DM1 and T-DM1+P vs HT. Gene expression (RNA) analysis was performed on tumor samples by a custom 800-gene codeset on the nCounter platform. PD-L1, CD8 expressions and immune gene signatures (sign) analyses were assessed by multivariate Cox regression models using median (cut-off) as categorical variable and adjusted by prior HT, presence of visceral disease, world region, baseline ECOG, measureable disease at baseline, therapy setting, HER2 mRNA expression, PIK3CA mutation status. Results: MARIANNE randomized 1095 pts (HT, n=365; T-DM1, n=367; T-DM1+P, n=363). Gene expression results were available for 671 pts (61.3% of the intent-to-treat [ITT] population) which was representative of ITT. In ITT, HR below 1 was observed when comparing pts with high (>median) vs low (≤median) immune gene expression by clinical outcome suggesting a potential association of high immune marker expression with improved PFS (Table 1) and to some extent with OS (data not shown). This association was primarily observed in the T-DM1 arm where the HR suggested a risk reduction of disease progression(PD)/death especially in the high Teff, high PD-L1 and high CD8 subgroups, and to some extent in the HT arm (Table 1). When assessing the predictive impact on PFS by comparing T-DM1 vs HT, HR below 1 was observed especially in pts with high Teff signature, high PD-L1 and high CD8 expressions (HR 0.67 (95% CI (0.47-0.95)), HR 0.68 (95% CI (0.48-0.97), and HR 0.64 (95%CI 0.44-0.93), respectively). When comparing T-DM1+P vs. HT, HR below 1 was observed especially in pts with low Teff signature and low PD-L1 expression (HR 0.70 (95% CI (0.50-0.99), and HR 0.68 (95% CI (0.48-0.96) respectively). No clear differences between immune gene expression subgroups was observed when comparing treatment arms in regards to OS (data not shown). Conclusions: In the exploratory analysis from the MARIANNE study, high immune gene expression, especially in the high PD-L1, CD8 and Teff subgroups, showed an association with improved clinical benefit with HRs reflecting for a risk reduction of PD/death for PFS and partially for OS. This association was less obvious in the T-DM1+P arm. When comparing the treatments effect, the data showed a potential impact of high Teff signature, and high CD8 and PD-L1 expressions on T-DM1 and less on HT. The potential opposite association of low Teff signature and low PD-L1 expression with improved benefit in the T-DM1+P arm was unexpected and needs further investigation. Table 1: Prognostic biomarker effect on PFSBiomarker by categories (>Median vs ≤Median)HR (95% CI) ITT n=671HR (95% CI) HT n=220HR (95% CI) T-DM1 n=227HR (95% CI) T-DM1+P n=224Teff sign0.89 (0.73-1.09)0.97 (0.68-1.38)0.64 (0.45-0.91)1.09 (0.75-1.58)Th1 cytokine sign0.91 (0.74-1.11)0.92 (0.64-1.31)0.78 (0.55-1.11)0.96 (0.67-1.36)Checkpoint inhibitor sign0.95 (0.78-1.15)0.91 (0.64-1.29)0.90 (0.64-1.26)1.02 (0.71-1.47)PD-L10.80 (0.66-0.98)0.79 (0.55-1.13)0.62 (0.44-0.87)1.07 (0.74-1.55)CD80.91 (0.75-1.11)1.10 (0.77-1.57)0.66 (0.46-0.93)0.98 (0.68-1.41) Citation Format: Edith A Perez, Sanne Lysbet de Haas, Carlos H Barrios, Wolfgang Eiermann, Masakazu Toi, Young-Hyuck Im, Pier Franco Conte, Miguel Martin, Tadeusz Pienkowski, Xavier B Pivot, Howard A Burris III, Chiara Lambertini, Silke Hoersch, Monika Patre, Paul Anthony Ellis. Association of immune gene expression with outcome in the MARIANNE phase 3 clinical trial in HER2-positive metastatic breast cancer (MBC) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr PD5-11.

A network meta-analysis of immunotherapy-based regimens for first-line treatment of advanced non-squamous non-small cell lung cancer.

52 Background: Immunotherapy (IO) for initial treatment of patients with advanced non-squamous non-small cell lung cancer (nsqNSCLC) has led to improved progression free survival (PFS) and overall survival (OS) vs chemotherapy. The objective of this network meta-analysis (NMA) was to compare the efficacy of IO-based therapies to chemotherapy in the first-line treatment until progression for advanced nsqNSCLC. Methods: A systematic literature review was conducted to identify randomized controlled trials reporting PFS and/or OS data in adult patients who received first-line treatment for stage IIIB or IV nsqNSCLC until progression. MEDLINE, EMBASE and Cochrane Central Register were searched from the start of databases to June 2018. The NMA used fixed-effects models to estimate hazard ratios (HRs) and credible intervals (Crl) for PFS and OS of IO therapies vs pemetrexed + platinum. A subgroup of patients with PD-L1 tumor proportion score (TPS) ≥50% was also analysed. Results: Evidence networks comprised of 18 studies for the overall population and 3 studies for the PD-L1 TPS ≥50% subgroup. In PFS analysis for the overall population, HRs were lower for atezolizumab + bevacizumab + paclitaxel + platinum (HR 0.62; 95% CrI 0.48, 0.8), ipilimumab + nivolumab (HR 0.55; 95% CrI 0.38, 0.8) and pemetrexed + pembrolizumab + platinum regimens (HR 0.52; 95% CrI 0.43, 0.63) vs pemetrexed + platinum. In the PD-L1 TPS ≥50% subgroup, PFS HRs were lower for pembrolizumab (HR 0.81; 95% CrI 0.67, 0.98) and pemetrexed + pembrolizumab + platinum (HR 0.36; 95% CrI 0.25, 0.52) vs pemetrexed + platinum. In the OS analysis for the overall population, pemetrexed + pembrolizumab + platinum had a lower HR (HR 0.5; 95% CrI 0.4, 0.64) vs pemetrexed + platinum. This difference in OS was magnified in the PD-L1 TPS ≥50% subgroup (HR 0.42; 95% CrI 0.26, 0.68). Conclusions: Among all IO-based therapies in this analysis, pemetrexed + pembrolizumab + platinum had the highest PFS and OS benefit vs pemetrexed + platinum in the first-line treatment until progression for advanced nsqNSCLC for both the overall population and high PD-L1 subgroup. These comparative efficacy data may inform clinicians in treatment selection.

918P - Atezolizumab (atezo) vs chemotherapy (chemo) in patients (pts) with platinum-treated locally advanced or metastatic urothelial carcinoma (mUC): A long-term overall survival (OS) and safety update from the phase III IMvigor211 study

918P - Atezolizumab (atezo) vs chemotherapy (chemo) in patients (pts) with platinum-treated locally advanced or metastatic urothelial carcinoma (mUC): A long-term overall survival (OS) and safety update from the phase III IMvigor211 study

Abstract CT200: 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 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 <10% of tumor-infiltrating immune cells; and PD-L1 negative (TC0 and IC0): Patients with PD-L1 expression in <1% of tumor cells and < 1% of tumor-infiltrating immune cells. Data cut-off: 15 March 2018. Minimum follow up: 13 months. NCT02367781.DOR, duration of response; HR, hazard ratio; IC, immune cells; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; TC, tumor cells. 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.

Chemotherapy in combination with immune checkpoint inhibitors for the first-line treatment of patients with advanced non-small cell lung cancer: A systematic review and literature-based meta-analysis.

e20565 Background: Checkpoint inhibitors plus platinum-based chemotherapy have shown superiority compared to chemotherapy alone as first-line therapy in advanced non–small cell lung carcinoma (NSCLC),To evaluate the relative benefit in term of Overall Survival (OS) and Progression-free Survival (PFS) of checkpoint inhibitors plus chemotherapy versus chemotherapy alone, overall and in subgroups defined by PDL1 expression we have performed a meta-analysis Methods: This meta-analysis searched PubMed and checked references of the selected English language articles to identify further eligible trials. Furthermore, proceedings of the main International meetings (American Society of Clinical Oncology [ASCO] annual meeting, European Society of Medical Oncology [ESMO] annual meeting, International Association for the Study of Lung Cancer [IASLC] World Conference on Lung Cancer), were searched from 2010 onwards for relevant abstracts. Data collection for this study took place from October 1 to October 24, 2018. Results: In total, 8 trials involving 4646 patients with advanced NSCLC, 3.314 (71%) and 1.332 (29%) with a non-squamous and squamous histology, respectively, were included in this meta-analysis. Four trials used atezolizumab, 3 pembrolizumab and 1 nivolumab, accounting for 2.985 (64%), 1.298 (28%) and 363 (8%) of patients, respectively. Checkpoint inhibitors plus chemotherapy were associated with prolonged OS, compared with chemotherapy in the ITT population (HR, 0.74; 95% CI, 0.64-0.87; p = 0.0002, with significant heterogeneity among trials). Within the PDL1 low group (1-49) there was a significant heterogeneity (p = 0.06) between type of drug and efficacy: the combination of chemotherapy plus pembrolizumab showed an OS benefit (HR, 0.56; 95% CI, 0.40-0.78; P< .00007) unlike the atezolizumab backbone trials (HR, 0.92; 95% CI, 0.62-1.37; P< 0.69). However, checkpoint inhibitors plus chemotherapy were associated with prolonged PFS in the ITT (HR, 0.61; 95% CI, 0.56-0.66; P < 0.00001) and across PDL1 subgroups. Conclusions: Checkpoint inhibitors plus chemotherapy compared with chemotherapy, are associated with significantly prolonged OS and PFS in first-line therapy in NSCLC. In the low PDL1 subgroups the benefit was statistically significant only in the pembrolizumab backbone trials.

Subgroup analysis from JAVELIN Renal 101: Outcomes for avelumab plus axitinib (A + Ax) versus sunitinib (S) in advanced renal cell carcinoma (aRCC).

544 Background: In the ongoing phase 3 JAVELIN Renal 101 trial, progression-free survival (PFS) was longer (median, 13.8 vs 8.4 mo; hazard ratio, 0.69; p=0.0001) and the objective response rate (ORR) was higher (51% vs 26%) with A + Ax vs S in patients with previously untreated aRCC. Here we report outcomes from an analysis of several prespecified subgroups. Methods: Patients were randomized 1:1 to receive A (10 mg/kg) IV every 2 weeks + Ax (5 mg) PO twice daily or S (50 mg) PO once daily for 4 wk (6-wk cycle). Primary and key secondary endpoints were PFS per independent review committee (IRC; RECIST v1.1) and OS in patients with PD-L1+ tumors (≥1% of immune cells) and in patients irrespective of PD-L1 expression; other secondary endpoints included OR per IRC (RECIST v1.1). Results: A total of 886 patients were randomized; 560 (63%) had PD-L1+ tumors. At data cut-off (Jun 2018), median follow-up was 12.0 vs 11.5 mo for A + Ax vs S groups. The table shows PFS and ORR by MSKCC and IMDC risk groups (F, favorable; I, intermediate; P, poor) and PD-L1 subgroup. Similar results for prognostic risk were seen in patients with PD-L1+ tumors. Outcome data (including PFS2) for additional clinical subgroups by baseline demographics and features will be presented. Clinical trial information: NCT02684006. Conclusions: A + Ax demonstrated PFS and OR benefit across all prognostic risk groups and PD-L1 subgroups vs S in aRCC.[Table: see text]

Long-term outcomes in elderly patients (pts) from IMvigor210: Atezolizumab (atezo) in metastatic urothelial cancer (mUC).

394 Background: Cisplatin-based chemotherapy is currently the standard 1L treatment for mUC, but many pts are ineligible and progression is common. Atezo (anti–PD-L1) is approved for certain types of mUC, and long-term efficacy and safety have been shown (Balar, ASCO 2018). Elderly pts in particular tend to have poor outcomes and may be chemotherapy intolerant, so this analysis sought to evaluate clinical outcomes in pts aged ≥ 65 and ≥ 75 y from the Phase II IMvigor210 study. Methods: This 2-cohort, single-arm study enrolled pts ineligible for 1L cisplatin and previously platinum-treated pts. Atezo 1200 mg IV q3w was given until PD (Cohort 1) or loss of clinical benefit (Cohort 2). RECIST v1.1 ORR (independent review; primary endpoint) and DOR and OS (secondary) were evaluated in pt subgroups based on PD-L1 status and age. Results: Evaluable pts as of July 12, 2018, are shown in the Table. In Cohort 1 pts ≥ 75 y, ORR was 29% overall, CR rate was 8%, DOR was NE and median OS was 21.4 mo. In Cohort 2 pts ≥ 75 y, ORR was 23%, CR rate was 7%, mDOR was 20.9 mo and mOS was 9.2 mo. Updated safety analyses in elderly pts will be presented. Conclusions: Efficacy outcomes in IMvigor210 elderly pts with mUC, and PD-L1 subgroup analysis appear generally consistent with those in the overall population in this long-term analysis. (Cohort 1; Balar Lancet 2017; NCT02951767). (Cohort 2; Rosenberg Lancet 2016; NCT02108652). Clinical trial information: NCT02951767 and NCT02108652. [Table: see text]

Cost-effectiveness of pembrolizumab in combination with chemotherapy versus chemotherapy and pembrolizumab monotherapy in the first-line treatment of squamous non-small-cell lung cancer in the US

Objective: To describe the cost-effectiveness of pembrolizumab plus chemotherapy (carboplatin and paclitaxel or nab-paclitaxel; P + C) in metastatic, squamous, non-small-cell lung cancer (NSCLC) patients in the US.Methods: A model comparing P + C versus C alone is developed utilizing partitioned survival analysis. Primary clinical efficacy, treatment utilization, health utility and safety data are derived from the KEYNOTE-407 trial and projected over 20 years. Costs for drugs and non-drug disease management are also incorporated. Additionally, the cost-effectiveness of P + C vs. pembrolizumab monotherapy (P) is evaluated via an indirect treatment comparison, for patient subgroups with PD-L1 Tumor Proportion Score (TPS) ≥ 50% and 1–49%.Results: Overall, P + C is projected to increase life expectancy by 1.95 years vs. C (3.86 versus 1.91). The resultant ICER is $86,293/QALY. In patients with PD-L1 ≥ 50%, 1–49% and <1 the corresponding incremental cost-effectiveness ratios (ICERs) are $99,777/QALY, $85,986/QALY and $87,507/QALY, respectively. Versus P, in the PD-L1 ≥ 50% subgroup, P + C appears cost saving; however, this result should be interpreted with caution as there is considerable uncertainty in the relative efficacy of these comparators.Conclusions: Across all eligible patients, the addition of pembrolizumab to chemotherapy is projected to approximately double life expectancy, yielding an extension to a point not previously seen in metastatic squamous NSCLC. Overall, and within all relevant PD-L1 subgroups, use of P + C yields an ICER below $100,000/QALY, and can be a cost-effective first-line treatment for eligible metastatic squamous NSCLC patients for whom chemotherapy is currently administered. In the PD-L1 ≥ 50% subgroup, additional follow-up within trials of pembrolizumab plus chemotherapy and pembrolizumab monotherapy are needed to better define cost-effectiveness between these comparators.

Abstract CT076: IMpower150: Efficacy of atezolizumab (atezo) plus bevacizumab (bev) and chemotherapy (chemo) in 1L metastatic nonsquamous NSCLC (mNSCLC) across key subgroups

Abstract Introduction: Atezo (anti-PD-L1) + bev + chemo prolonged PFS vs bev + chemo in patients (pts) with 1L non-squamous mNSCLC in the randomized Ph 3 IMpower150 study regardless of PD-L1 expression. This analysis aims to further understand the efficacy of atezo + bev + chemo in key subgroups: PD-L1 expression subgroups defined by the SP142 and SP263 IHC assays, patients with EGFR/ALK genetic alterations and patients with liver metastases at baseline. Methods: Pts received atezo 1200 mg + bev 15 mg/kg + carboplatin (C) AUC 6 + paclitaxel (P) 200 mg/m2 (Arm B) or bev + C + P (Arm C) IV q3w. A co-primary endpoint (EP) was PFS in the ITT-WT (EGFR or ALK wild-type pts); a secondary EP was PFS in subgroups defined by PD-L1 expression on tumor cells (TC) and tumor-infiltrating immune cells (IC) with SP142. Retrospective analysis with SP263 was a prespecified exploratory EP. Results: In Arms B and C of the ITT-WT (n = 692), 503 pts had available tumor sections for SP263 testing (BEP). Pt characteristics in the ITT-WT and BEP were similar. A similar PFS benefit was observed for Arm B vs C across all PD-L1 expression subgroups defined by either assay, including pts with PD-L1-negative and PD-L1-low tumors (Table). PFS benefit with Arm B vs C was also observed in patients with EGFR or ALK genomic alterations, including patients with actionable EGFR mutations, and in patients with liver metastases at baseline (Table). Conclusion: PFS benefit with atezo + bev + chemo was observed across all PD-L1 subgroups, regardless of the IHC assay used. Additionally, clinically meaningful PFS benefit was observed in patients with EGFR/ALK genomic alterations, and in patients with liver metastases with this combination. Table. PFS in Biomarker Subgroups and Other Subgroups of Interest in IMpower150Median PFS, moPFSan (%)HRb (95% CI)P ValueArm BArm CITT-WT692 (100%)0.62 (0.52, 0.74)&amp;lt;0.00018.36.8BEP with SP263 results in ITT-WT503 (73%)0.62 (0.50, 0.76)&amp;lt;0.00018.36.8PD-L1 Expression Subgroups Defined by the VENTANA SP142 Assay (BEP, n=503)PD-L1 negative TC0 and IC0235 (47%)0.77 (0.57, 1.04)0.08368.27.0PD-L1 low TC1/2 or IC1/2167 (33%)0.53 (0.37, 0.76)0.00058.36.1PD-L1 high TC3 or IC3101 (20%)0.49 (0.30, 0.79)0.003211.16.9PD-L1 Expression Subgroups Defined by the VENTANA SP263 IHC Assay (BEP, n=503)PD-L1 negative TC &amp;lt; 1%237 (47%)0.72 (0.53, 0.97)0.02987.27.0PD-L1 low TC &amp;lt; 50% and ≥ 1%140 (28%)0.57 (0.38, 0.84)0.00419.76.9PD-L1 high TC ≥ 50%126 (25%)0.50 (0.33, 0.77)0.00159.16.2Other Subgroups of Interest (ITT, n=800)ITT800 (100%)0.61 (0.52, 0.72)&amp;lt;0.00018.36.8EGFR/ALK+c108 (14%)0.59 (0.37, 0.94)0.02539.76.1EGFR exon 19 deletion of L858R59 (7%)0.41 (0.22, 0.78)0.005010.26.1Liver metastases110 (14%)0.40 (0.26, 0.62)&amp;lt;0.00018.25.4No liver metastases690 (86%)0.64 (0.53, 0.76)&amp;lt;0.00018.37.0BEP, biomarker-evaluable population; IC, tumor-infiltrating immune cell; IHC, immunohistochemistry; PD-L1, programmed death-ligand 1; TC, tumor cell; WT, wild type. TC0 and IC0 = PD-L1 expression on &amp;lt; 1% of TC or IC; TC1/2 or IC1/2 = PD-L1 expression on &amp;lt; 50% and ≥ 1% of TC or &amp;lt; 10% of and ≥ 1% of IC; TC3 or IC3 = PD-L1 expression on ≥ 50% of TC or ≥ 10% of IC. a Investigator assessed b Stratified HR for ITT-WT and ITT; unstratified HR for all other subgroups. c Patients with a sensitizing EGFR mutation or ALK rearrangement must have disease progression or intolerance of treatment with one or more approved targeted therapies. d Other EGFR mutations include L861Q, G719X, S7681, exon 20 insertion, T790M, and other. (NCT02366143) Citation Format: Marcin Kowanetz, Mark A. Socinski, Wei Zou, Mark McCleland, Nancy Yang, Ariel Lopez Chavez, Alexander Spira, Julien Mazières, Fadi Braiteh, David Shames, Alan Sandler, Martin Reck. IMpower150: Efficacy of atezolizumab (atezo) plus bevacizumab (bev) and chemotherapy (chemo) in 1L metastatic nonsquamous NSCLC (mNSCLC) across key subgroups [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT076.

Abstract CT116: Nivolumab (Nivo) vs investigator's choice (IC) in recurrent or metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN): 2-yr outcomes in the overall population and PD-L1 subgroups of CheckMate 141

Abstract Aim: Nivo is the only immunotherapy to significantly improve overall survival (OS) in patients (pts) with R/M SCCHN who have progressed on or after platinum-based therapy. Here we report long-term data from the randomized, open-label, phase 3 CheckMate 141 study (NCT02105636). Patients: Pts with R/M SCCHN who progressed on or after platinum-based therapy were randomized 2:1 to nivo 3 mg/kg q2wk (n = 240) or IC (methotrexate, docetaxel, or cetuximab; n = 121). Endpoints: OS (primary), progression-free survival (PFS), safety. Minimum follow-up: 24.2 mo (data cut: Sep 2017). Results: Nivo improved OS significantly vs IC in the overall population (median [95% CI]: 7.7 [5.7, 8.8] mo vs 5.1 [4.0, 6.2] mo; HR [95% CI]: 0.68 [0.54, 0.86]). 2-yr OS rate (95% CI) was 16.9% (12.4, 22.0) with nivo vs 6.0% (2.7, 11.3) with IC. 8.3% of pts in the IC arm received subsequent immunotherapy. Outcomes by PD-L1 and HPV subgroups are shown in the Table. In pts with tumor PD-L1 &amp;lt;1%, risk of death at 2 yrs was reduced by 27% with nivo vs IC with the HR trending lower with longer follow-up; HR (95% CI) = 0.89 (0.54, 1.45), 0.83 (0.54, 1.29), and 0.73 (0.49, 1.09) at 6 mo (Dec 2015 data cut), 1 yr (Sep 2016 data cut), and 2 yrs of follow-up, respectively. Nivo also continued to improve OS vs IC in pts with tumor PD-L1 ≥ 1%. Complete responses were noted in both PD-L1 ≥ 1% and &amp;lt;1% groups. Key baseline characteristics, including PD-L1 expression and HPV status, were similar among patients who survived 2 yrs compared with all patients in the nivo arm. Grade 3-4 treatment-related adverse events occurred in 15.3% (nivo) vs 36.9% (IC) of pts; toxicity-related deaths in 2 pts (0.8%) and 1 pt (0.9%), respectively. Conclusion: With 2-yr follow-up, nivo continued to significantly improve OS and maintain a favorable safety profile vs IC. Nivo is the only immunotherapy to demonstrate OS benefit irrespective of PD-L1 expression in pts with SCCHN. Table: Outcomes by PD-L1 expression and HPV statusMedian OS (95% CI), monthsMedian PFS (95% CI), monthsNivoICHR (95% CI)NivoICHR (95% CI)PD-L1 &amp;lt; 1%6.5 (4.4, 11.7)5.5 (3.7, 8.5)0.73 (0.49, 1.09)2.0 (1.9, 2.1)2.7 (2.0, 4.6)1.13 (0.75, 1.71)PD-L1 ≥ 1%8.2 (6.7, 9.5)4.7 (3.8, 6.2)0.55 (0.39, 0.78)2.1 (2.0, 3.5)2.0 (1.9, 3.1)0.59 (0.41, 0.84)HPV+9.1 (6.5, 11.8)4.4 (3.0, 9.8)0.60 (0.37, 0.97)2.0 (1.9, 3.3)2.0 (1.6, 2.8)0.75 (0.46, 1.23)HPV−7.7 (4.8, 13.0)6.5 (3.9, 8.7)0.59 (0.38, 0.92)2.1 (1.9, 3.1)3.3 (1.9, 4.0)1.01 (0.65, 1.56) Citation Format: Robert L. Ferris, George R. Blumenschein, Jerome Fayette, Joel Guigay, A Dimitrios Colevas, Lisa Licitra, Kevin J. Harrington, Stefan Kasper, Everett E. Vokes, Caroline Even, Francis Worden, Nabil F. Saba, Lara Carmen Iglesias Docampo, Robert Haddad, Tamara Rordorf, Naomi Kiyota, Makoto Tahara, Mark Lynch, Vijayvel Jayaprakash, Li Li, Maura L. Gillison. Nivolumab (Nivo) vs investigator's choice (IC) in recurrent or metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN): 2-yr outcomes in the overall population and PD-L1 subgroups of CheckMate 141 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT116.

Two-year Update From CheckMate 141: Outcomes With Nivolumab (Nivo) vs Investigator's Choice (IC) in Recurrent or Metastatic (R/M) Squamous Cell Carcinoma of the Head and Neck (SCCHN) in the Overall Population and PD-L1 Subgroups

Nivo is the only immuno-oncology (I-O) agent to significantly improve overall survival (OS) in patients (pts) with R/M SCCHN who have progressed on or after platinum-based therapy and for whom long-term prognosis has historically been poor (median OS ≤6 mo). Here we report the first long-term (2-yr) data with immune checkpoint inhibition in pts with R/M SCCHN who have progressed on or after platinum-based therapy from the randomized, open-label, phase 3 CheckMate 141 study (NCT02105636). Eligible pts were randomized 2:1 to nivo 3 mg/kg q2wk (n = 240) or IC (methotrexate, docetaxel, or cetuximab; n = 121). The primary endpoint was OS; other endpoints included progression-free survival (PFS) and safety. Minimum follow-up for the current analysis: 24.2 mo (data cut: Sep 2017). 2-yr OS rate (95% CI) was 16.9% (12.4, 22.0) with nivo versus 6.0% (2.7, 11.3) with IC. Nivo continued to improve OS significantly vs IC in the overall population (median [95% CI]: 7.7 [5.7, 8.8] mo vs 5.1 [4.0, 6.2] mo; hazard ratio (HR) [95% CI]: 0.68 [0.54, 0.86]). PFS remained similar between treatment arms. Outcomes by PD-L1 and HPV subgroups are shown in the Table 1. In pts with tumor PD-L1 <1%, risk of death at 2 yrs was reduced by 27% with nivo versus IC with the HR trending lower with longer follow-up; HR (95% CI) = 0.89 (0.54, 1.45), 0.83 (0.54, 1.29), and 0.73 (0.49, 1.09) at 6 mo (May 2016 data cut), 1 yr (Sep 2016 data cut), and 2 yrs of follow-up, respectively. Nivo also continued to improve OS versus IC in pts with tumor PD-L1 ≥ 1%. Grade 3-4 treatment-related adverse events occurred in 15.3% (nivo) versus 36.9% (IC) of pts; toxicity-related deaths in 2 pts (0.8%; pneumonitis and hypercalcemia) and 1 pt (0.9%; treatment-related lung infection), respectively. With longer follow-up (2 yrs), nivo continued to significantly improve OS and maintained a favorable safety profile versus IC in the overall population in CheckMate 141. Nivo is the only I-O therapy to demonstrate OS benefit irrespective of PD-L1 status (<1% and ≥1%) in pts with SCCHN.Abstract LBA10; Table 1Outcomes by PD-L1 expression and HPV statusMedian OS (95% CI), moMedian PFS (95% CI), moNivoICHR (95% CI)NivoICHR (95% CI)PD-L1 < 1%6.5 (4.4, 11.7)5.5 (3.7, 8.5)0.73 (0.49, 1.09)2.0 (1.9, 2.1)2.7 (2.0, 4.6)1.13 (0.75, 1.71)PD-L1 ≥ 1%8.2 (6.7, 9.5)4.7 (3.8, 6.2)0.55 (0.39, 0.78)2.1 (2.0, 3.5)2.0 (1.9, 3.1)0.59 (0.41, 0.84)HPV+9.1 (6.5, 11.8)4.4 (3.0, 9.8)0.60 (0.37, 0.97)2.0 (1.9, 3.3)2.0 (1.6, 2.8)0.75 (0.46, 1.23)HPV−7.7 (4.8, 13.0)6.5 (3.9, 8.7)0.59 (0.38, 0.92)2.1 (1.9, 3.1)3.3 (1.9, 4.0)1.01 (0.65, 1.56) Open table in a new tab

Clinical Efficacy of atezolizumab (atezo) in PD-L1 subgroups defined by SP142 and 22C3 IHC assays in 2L+ NSCLC: Results from the randomized OAK study

Clinical Efficacy of atezolizumab (atezo) in PD-L1 subgroups defined by SP142 and 22C3 IHC assays in 2L+ NSCLC: Results from the randomized OAK study

Comparative effectiveness of immune-checkpoint inhibitors for previously treated advanced non-small cell lung cancer – A systematic review and network meta-analysis of 3024 participants

IntroductionRole of PD-L1 expression to guide immunotherapies in previously treated advanced NSCLC remains unclear and there is a lack of data comparing immune checkpoint inhibitors (ICIs) with each other. This network meta-analysis (NMA) aims to compare survival with ICIs to docetaxel and perform indirect comparisons between ICIs in the PD-L1 unselected population and by PD-L1 expression levels. MethodsPubMed was searched and study screening was performed by two independent reviewers. NMA of survival outcomes in the PD-L1 unselected population and by PD-L1 expression levels <1%, >=1%,>=5%,>=10%, and >=50% was performed. Head-to-head indirect comparisons were constructed and treatment rankings were provided. Potential survival benefits by PD-L1 expression level as compared to a PD-L1 unselected population were estimated. Results5 trials with 3024 total patients were included for meta-analysis. Overall, ICIs improved survival across PD-L1 expression levels compared to docetaxel, although there was only weak evidence of benefit for individual ICI nivolumab or atezolizumab in PD-L1<1%. PD-L1 subgroups suggested positive dose-response relationship between PD-L1 expression levels with survival benefits. In addition, there were also survival benefits due to selecting for PD-L1 in the PD-L1>=10% and >=50% subgroups as compared to the PD-L1 unselected population. Indirect comparisons of ICIs showed little evidence of differences between nivolumab, pembrolizumab and atezolizumab. DiscussionICIs improve survival in previously treated advanced NSCLC patients across PD-L1 expression levels compared to docetaxel. There is a positive dose-response relationship between PD-L1 expression and survival benefits, and little evidence of survival differences between nivolumab, pembrolizumab and atezolizumab.

1049PD - Relationship between PD-L1 expression and survival in head and neck squamous cell carcinoma (HNSCC) patients (pts)

Background: Programmed cell death 1 (PD-1) and its ligand 1 (PD-L1) are up-regulated in many cancers. The purpose of this study was to explore the relationship between PD-L1 expression and overall survival (OS) in HNSCC. Methods: A retrospective study was conducted using data from pt medical records and analysis of archival tumor samples. Sample ages ranged from 8.2 to 227.5 months. Pts ≥18 years old diagnosed with HNSCC between 1989 and 2015 were selected. Demographic and tumor characteristics were compared by PD-L1 expression status. PD-L1 testing was performed using the Ventana PD-L1 SP263 assay. PD-L1 expression was scored separately using tumor cell (TC) and immune cell (IC) membrane staining and exploratory cut-offs of 1%, 5%, 10%, 25% and 50%. OS was calculated as the number of months from initial HNSCC diagnosis until death and estimated using the Kaplan–Meier method. The log-rank test was used to compare survival curves by PD-L1 status. PD-L1 status as a prognostic indicator of OS was further examined in Cox proportional hazards (PH) models. Results: We identified 214 HNSCC pts with data available for date of death/last follow-up and PD-L1 status. Mean (SD) tumor sample age was 93.3 (40.5) months. Mean (SD) pt age was 62.3 (13.4) years and 70% were male. The Table presents baseline characteristics by PD-L1 subgroup. Median OS was similar between PD-L1 high and low/negative pts classified using the TC ≥ 25%, IC ≥ 1%, and IC ≥ 25% cut-offs. However, median OS was 21.2 months longer in PD-L1 high versus low/negative pts (68.9 vs. 47.7 months, respectively; P=0.03) in analyses using the TC ≥ 1% cut-off. This latter relationship remained after adjusting for baseline covariates using Cox PH models.Table1049PD Baseline characteristicsCharacteristicTC PD-L1 expressionHigh (≥25%)Low/negative (<25%)High (≥1%)Low/negative (<1%)No. of pts (%)33 (15.4)181 (84.6)118 (55.1)96 (44.9)Mean (SD) age, years57.3 (12.3)63.2 (13.4)61.1 (12.9)63.8 (13.8)HPV positive, %42.445.345.843.8Present smoker, %24.236.531.438.5Stage IV, %33.351.448.349.0African American, %27.316.622.912.5Median OS, monthsNot reached62.968.947.7p-value*log-rank p-value comparing high vs. low/negative groups0.270.03IC PD-L1 expressionHigh (≥25%)Low/negative (<25%)High (≥1%)Low/negative (<1%)No. of pts (%)11 (5.1)203 (94.9)150 (70.0)64 (30.0)Mean (SD) age, years63.8 (10.1)62.2 (13.6)61.3 (13.4)64.6 (13.2)HPV positive, %8 (72.7)88 (43.4)75 (50.0)21 (32.8)Present smoker, %3 (27.3)71 (35.0)53 (35.3)21 (32.8)Stage IV, %6 (54.5)98 (48.3)68 (45.3)36 (56.3)African American, %4 (36.4)35 (17.2)31 (20.7)8 (12.5)Median OS, months157.168.979.052.5p-value*log-rank p-value comparing high vs. low/negative groups0.310.07* log-rank p-value comparing high vs. low/negative groups Open table in a new tab Conclusions: PD-L1 high expression based on a TC ≥ 1% cut-off appears to be associated with improved OS in this sample of pts with HNSCC. A small number of samples and resulting low statistical power limited our ability to assess prognosis for TC ≥ 25% and IC ≥ 25%, yet OS was numerically higher among PD-L1 high pts in these subgroups. Legal entity responsible for the study: AstraZeneca Funding: AstraZeneca Disclosure: M. Stokes: Employment (Evidera) and research funding (Evidera). R. Wang: Employment (Evidera) and Stock ownership (Evidera). S. Wildsmith, H.K. Angell, C. Barker, J. Walker, P. Scorer, N. Shire: Employment (AstraZeneca) and Shareholder (AstraZeneca). M. Secrier: Employment (AstraZeneca) Corporate sponsored research (AstraZeneca) and Shareholder (AstraZeneca). M.C. Rebelatto: Employment (AstraZeneca/MedImmune) and Shareholder (AstraZeneca/MedImmune).

1296O - Clinical efficacy of atezolizumab (Atezo) in PD-L1 subgroups defined by SP142 and 22C3 IHC assays in 2L+ NSCLC: Results from the randomized OAK study

1296O - Clinical efficacy of atezolizumab (Atezo) in PD-L1 subgroups defined by SP142 and 22C3 IHC assays in 2L+ NSCLC: Results from the randomized OAK study

PL04a.02: OAK, a Randomized Ph III Study of Atezolizumab vs Docetaxel in Patients with Advanced NSCLC: Results from Subgroup Analyses

Atezolizumab inhibits PD-L1 binding to its receptors PD-1 and B7.1, thereby restoring tumor-specific T-cell immunity. Primary analysis of the Phase III OAK study in previously-treated NSCLC revealed superior survival for atezolizumab vs docetaxel in the ITT population (mOS, 13.8 vs 9.6 months; HR, 0.73) and in patients expressing ≥1% PD-L1 on TC or IC (TC1/2/3 or IC1/2/3; mOS, 15.7 vs 10.3; HR, 0.74). Here we present further subgroup analyses. OAK evaluated atezolizumab vs docetaxel in an unselected NSCLC population who had failed prior platinum-containing chemotherapy. Patients were stratified by PD-L1 expression, prior chemotherapy regimens and histology, and randomized 1:1 to atezolizumab (1200 mg) or docetaxel (75 mg/m2) IV q3w. PD-L1 expression by IHC and mRNA was centrally evaluated by VENTANA SP142 IHC assay and Fluidigm, respectively. Data cutoff, July 7, 2016. For the first 850 of 1225 randomized patients (primary study population), OS was improved with atezolizumab vs docetaxel regardless of histology and this benefit was observed across PD-L1 subgroups within each histology (Table). PD-L1 gene expression showed a similar association with OS as PD-L1 IHC. In nonsquamous patients ORR was 14.4% vs 15.2%; in squamous patients ORR was 11.6% vs 8.2% (atezolizumab vs docetaxel). OS benefit vs docetaxel was seen across subgroups including patients with treated baseline brain metastases (n=85; mOS 20.1 vs 11.9 mo; HR 0.54, 95% CI 0.63-0.89) and never smokers (n=156; mOS 16.3 vs 12.6 mo, HR 0.71, 95% CI 0.47-1.08). Further secondary endpoints and exploratory biomarker analyses for these subgroups and by age and EGFR/KRAS status will be presented. OAK demonstrated clinically relevant improvements with atezolizumab in the ITT population, including in both histology subgroups regardless of PD-L1 expression (measured by IHC or tumor gene expression), and among other subgroups including never smokers and in patients with baseline brain metastases.Tabled 1OSAtezolizumabDocetaxelHRa 95% CInMedian, monMedian, moNonsquamousTC3 or IC34922.5478.70.35(0.21-0.61)TC2/3 or IC2/38918.79911.30.61(0.42-0.88)TC1/2/3 or IC1/2/317117.616211.30.72(0.55-0.95)TC0 and IC014014.015011.20.75(0.57-1.00)All31315.631511.20.73(0.60-0.89)SquamousTC3 or IC32317.51811.60.57(0.27-1.20)TC2/3 or IC2/34010.4379.70.76(0.45-1.29)TC1/2/3 or IC1/2/3709.9608.70.71(0.48-1.06)TC0 and IC0407.6497.10.82(0.51-1.32)All1128.91107.70.73(0.54-0.98)aUnstratified HRs.TC=tumor cell, IC=tumor-infiltrating immune cell. Open table in a new tab

Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial

First-line chemotherapy for patients with cisplatin-ineligible locally advanced or metastatic urothelial carcinoma is associated with short response duration, poor survival, and high toxicity. This study assessed atezolizumab (anti-programmed death-ligand 1 [PD-L1]) as treatment for metastatic urothelial cancer in cisplatin-ineligible patients. For this single-arm, multicentre, phase 2 study, in 47 academic medical centres and community oncology practices in seven countries in North America and Europe, we recruited previously untreated patients with locally advanced or metastatic urothelial cancer who were cisplatin ineligible. Patients were given 1200 mg intravenous atezolizumab every 21 days until progression. The primary endpoint was independently confirmed objective response rate per Response Evaluation Criteria in Solid Tumors version 1.1 (central review), assessed in prespecified subgroups based on PD-L1 expression and in all patients. All participants who received one or more doses of atezolizumab were included in the primary and safety analyses. This study was registered with ClinicalTrials.gov, number NCT02108652. Between June 9, 2014, and March 30, 2015, we enrolled 123 patients, of whom 119 received one or more doses of atezolizumab. At 17·2 months' median follow-up, the objective response rate was 23% (95% CI 16 to 31), the complete response rate was 9% (n=11), and 19 of 27 responses were ongoing. Median response duration was not reached. Responses occurred across all PD-L1 and poor prognostic factor subgroups. Median progression-free survival was 2·7 months (2·1 to 4·2). Median overall survival was 15·9 months (10·4 to not estimable). Tumour mutation load was associated with response. Treatment-related adverse events that occurred in 10% or more of patients were fatigue (36 [30%] patients), diarrhoea (14 [12%] patients), and pruritus (13 [11%] patients). One treatment-related death (sepsis) occurred. Nine (8%) patients had an adverse event leading to treatment discontinuation. Immune-mediated events occurred in 14 (12%) patients. Atezolizumab showed encouraging durable response rates, survival, and tolerability, supporting its therapeutic use in untreated metastatic urothelial cancer. F Hoffmann-La Roche, Genentech.

PD27-12 PRIMARY ANALYSIS OF IMVIGOR 210: ATEZOLIZUMAB IN PLATINUM-TREATED ADVANCED UROTHELIAL CARCINOMA

Robert Dreicer*, Charlottesville, VA; Michiel S. van der Heijden, Amsterdam, Netherlands; Petros Grivas, Cleveland, OH; Jean Hoffman-Censits, Philadelphia, PA; Yohann Loriot, Villejuif, France; Margitta Retz, Munich, Germany; Nicholas J Vogelzang, Las Vegas, NV; Jose Luis Perez-Gracia, Pamplona, Spain; Arash Rezazadeh Kalebasty, Louisville, KY; Sergio Bracarda, Arezzo, Italy; Evan Y Yu, Seattle, WA; Christopher Hoimes, Cleveland, OH; Joaquim Bellmunt, Boston, MA; David I Quinn, Los Angeles, CA; Daniel P. Petrylak, New Haven, CT; Syed A Hussain, Liverpool, United Kingdom; Na Cui, Sanjeev Mariathasan, Fatema Legrand, South San Francisco, CA; Jonathan E. Rosenberg, New York, NY

IMvigor 210, a phase II trial of atezolizumab (MPDL3280A) in platinum-treated locally advanced or metastatic urothelial carcinoma (mUC).

355 Background: The ORR and survival of mUC patients (pts) who progress after platinum-based chemotherapy (pctx) are poor. Atezolizumab (atezo) reinvigorates antitumor immunity by targeting PD-L1 and has shown promising Ph 1 activity in mUC. Methods: IMvigor 210 cohort 2 (NCT02108652) enrolled 316 mUC pts who progressed during or following pctx. Pts received atezo at 1200 mg IV q3w until loss of clinical benefit. The SP142 IHC assay centrally assessed PD-L1 expression. Pts/investigators were blinded to PD-L1 status. Co-primary endpoints were confirmed ORR by RECIST v1.1 per central review (IRF) and modified (m) RECIST per investigator, which were met if null hypothesis (ORR = 10%) was rejected (α = 5%). ORR endpoints were stratified by PD-L1 tumor-infiltrating immune cell (IC) status: IC2/3, IC1/2/3, all comers. Results: Efficacy/safety-evaluable pts (N = 311) had a median age of 66 y, CrCl &lt; 60 mL/min (35%) and ≥ 2 prior regimens for mUC (40%). Many had poor prognostic factors (Table). At 5/5/15 data cutoff (follow up ≥ 24 w), 43/47 responding pts had ongoing responses. Both IRF (Table) and mRECIST ORR correlated with IC status. Durable responses were seen including poor prognostic subgroups (Table). mDOR was not reached in any PD-L1 or prognostic subgroup. mPFS was 2.1 mo in all PD-L1 subgroups. Median treatment duration was 12 w (range 0-46). Treatment-related AEs (most commonly fatigue) occurred in 66% of pts (all Grade); 15% had G3-4 related AE and 4% had G3-4 immune-mediated AE. 27% of AEs led to dose interruption and 3% led to withdrawal. No renal toxicity was seen. Conclusions: IMvigor 210, the first Ph 2 study targeting PD-L1/PD-1 in mUC, demonstrated significantly improved ORR vs historic controls. Responses were durable and associated with higher PD-L1 IC expression; poor prognostic factors did not preclude response. Atezo was well tolerated, and a randomized Ph 3 study vs ctx is ongoing (IMvigor 211; NCT02302807). Clinical trial information: NCT02108652. [Table: see text]