Neoadjuvant Atezolizumab Research Articles

MHCI and FOXP3 predicting outcome to neoadjuvant atezolizumab in sequential urothelial cancer tissue.

541 Background: Biomarker analysis predicting outcome with neoadjuvant atezolizumab in muscle invasive bladder cancer (MIBC) was performed. This includes previously unreported findings with FOXP3 and MHC1. Methods: Sequential tissue obtained from 95 patients in the ABACUSstudy (NCT02662309) which investigated two cycles of atezolizumab prior to cystectomy in MIBC patients. Multiplex immunohistochemistry staining, Foundation One analysis and RNA sequencing was performed on paired pre- and post- treatment samples. CD8+ T cells, fibroblast activation protein (FAP), granzyme – B (GZMB), FOXP3, MHC1, PD-L1 expressions were analyzed and correlated with outcome. Results: After a median follow up of 13.1 months, 31% had a pathological complete response (pCR) and 18% have relapsed. 40% were PD-L1 positive at baseline and 73%, 19% and 8%had inflamed, excluded and desert phenotype respectively. CD8/GZMB and CD8/MHC1 expression prior to therapy was significantly associated with response in inflamed tumors. CD8, PDL1, GZMB and MHC1 expression all increased with treatment in this group of patients. Immune desert phenotype at baseline, showed low and static expression of immune biomarker. TGFb correlated with relapse in excluded phenotypes. Treatment was associated with increase in cell cycle genes and FAP, both of which were associated with relapse. FOXP3 expression correlated with CD8 and increased with therapy in responding tumors. Combining FAP (high) to CD8 (low) and MHC1 (low) increased the positive predictive value for relapse. TMB did not correlate with outcome or increase with therapy. FGF DNA alterations were associated with response. Conclusions: MIBCs have high T effector immune expression, which may account for high pCR rates. Biomarkers at baseline and after treatment can predict outcome. Assessment of multiple biomarker within algorithms improves accuracy in predicting outcome. FOXP3 expression correlates with activated T cell expression, potentially accounting for the counterintuitive findings. Clinical trial information: NCT02662309.

Abstract OT2-01-04: Phase IB-II combination neoadjuvant chemotherapy with docetaxel plus atezolizumab plus herceptin SC and pertuzumab (TAHP) for patients with HER2-positive early breast cancer and subsequent atezolizumab plus herceptin SC and pertuzumab (AHP) adjuvant therapy after surgery (Neo-PATH)

Abstract Background Dual HER2-targeting with trastuzumab and pertuzumab combined with cytotoxic chemotherapy as neoadjuvant treatment increased rate of pathologic complete response to 50-65%. Subset of HER2-positive breast cancer has shown adaptive immune infiltrates which was correlated with better prognosis, including whom treated with dual anti-HER2 treatment. Immune checkpoint inhibitor including anti-PD-L1 modulate tumor microenvironment to restore tumor-induced or antibody-treatment induced immunosuppression. Here we investigate an efficacy of combining immunotherapy with anti-HER2 treatment as a neoadjuvant treatment in clinical stage II-III, HER2-positive breast cancer. Trial design This is a Phase Ib-II single arm study of six cycles of neoadjuvant docetaxel, atezolizumab, trastuzumab SC, and pertuzumab combination in patients with HER2-positive breast cancer. After 6 cycles of TAHP, surgery followed by 12 cycles of adjuvant atezolizumab, trastuzumab SC, and pertuzumab(AHP) will be performed. Patients without pCR will receive additional four cycles of doxorubicin and cyclophosphamide between surgery and adjuvant AHP. Eligibility criteria - Locally advanced, inflammatory, or early stage histologically confirmed invasive carcinoma of breast - HER2-positive breast cancer (immunohistochemistry score 3+, or HER2 SISH (or FISH, CISH) positive) - Primary tumor size>2cm or histologically or cytologically confirmed ipsilateral axillary lymph node metastases by fine needle aspiration (clinical stage IIA-IIIC by TNM 7th staging system) - ECOG Performance status 0-1 Specific aims Primary endpoint is a rate of pathologic complete response (pCR) after neoadjuvant docetaxel, atezolizumab, trastuzumab SC, and pertuzumab. Secondary endpoints are comparison of 3-year event free survival rate, disease free survival, and overall survival according to pCR achievement, toxicities, quality of life parameters, biomarker analyses (PD-L1 expression, immune signature, PIK3CA pathway, tumor mutation burden) for pCR and survival, multiomic profiling of tumor tissue using F1CDx. Statistical methods For sample size calculation, we used a Simon’s two-stage optimal design, with a 80 % power and 10% significance. The expected sample size is 60 to test the null hypothesis of pCR rate of ≤ 50% versus the alternative hypothesis of pCR rate of ≥ 65%. Stage 1: If pCR were observed in ≤ 12 patients among the first 23 patients, the alternative hypothesis will be rejected and the study will be discontinued Stage 2: If pCR were observed in ≥ 13 patients among the first 23 patients, additional 37 patients will be accrued (a total of 60 patients). If pCR were observed in > 34 patients, the null hypothesis will be rejected. Considering drop-out rate of 10%, we will accrue 67 patients. Our planned study duration is 42 months (patients accrual 6 months, follow up duration 36 months). Citation Format: Hee Kyung Ahn, Ji- Yeon Kim, Koung Jin Suh, Gun Min Kim, Sung Hoon Sim, Ki Hyeong Lee, Kyung Hae Jung, Seok- Ah Im, Yeon Hee Park. Phase IB-II combination neoadjuvant chemotherapy with docetaxel plus atezolizumab plus herceptin SC and pertuzumab (TAHP) for patients with HER2-positive early breast cancer and subsequent atezolizumab plus herceptin SC and pertuzumab (AHP) adjuvant therapy after surgery (Neo-PATH) [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 OT2-01-04.

Abstract OT2-04-08: A randomized double-blind phase III clinical trial of neoadjuvant chemotherapy (NAC) with atezolizumab or placebo in patients (pts) with triple negative breast cancer (TNBC) followed by adjuvant atezolizumab or placebo: NSABP B-59/GBG 96-GeparDouze

Abstract Background: TNBC is associated with higher percentages of pathological complete response (pCR) to neoadjuvant chemotherapy (NAC), and women with a pCR have a favorable prognosis. However, previous studies have found that women with residual disease have a substantially higher risk of recurrence than women with other subtypes of breast cancer. Additionally, other recent studies have found that therapeutic blockade of PD-L1 binding by atezolizumab has resulted in relevant anti-tumor efficacy. Design This is a phase III, double blind, placebo-control trial evaluating neoadjuvant atezolizumab with NAC followed by adjuvant atezolizumab in TNBC. Pts are stratified by region (North America; Europe), tumor size (1.1-3.0cm; >3.0cm), AC/EC schedule (q2w; q3w), nodal status (positive; negative), and PD-L1 status (positive; negative or indeterminate) then randomized 1:1 to receive atezolizumab/placebo 1200 mg IV every 3 wks concurrently with both sequential regimens of weekly paclitaxel 80 mg/m2 IV for 12 doses with every 3-wk carboplatin AUC of 5 IV for 4 doses followed by AC/EC every 2-3 wks (per investigator discretion) for 4 cycles. Following surgery, pts resume atezolizumab/placebo 1200 mg IV every 3 wks as adjuvant therapy for 6 months. Radiotherapy based on local standards is co-administered with atezolizumab/placebo. Eligibility criteria Centrally-confirmed ER-neg, PR-neg, HER2-neg invasive breast cancer by ASCO/CAP guidelines. Primary tumor must be stage T2 or T3 if cN0 or cN1 with negative biopsy or T1c, T2, or T3 if cN1 with positive biopsy or cN2 or cN3. LVEF >55% and no significant cardiac history. Statistical methods Co-primary endpoints are event-free survival (EFS) and pCR breast/nodes. Secondary endpoints include pCR breast, overall survival, distant disease-free survival, safety and toxicity. Trial is an academic collaboration between NSABP and GBG with support from Genentech/Roche. As of 7-8-19, 279/1,520 pts have been randomized. NCT03281954 Support: Genentech/Roche. Citation Format: Charles E Geyer Jr., Sibylle Loibl, Priya Rastogi, Sabine Seiler, Joseph P Costantino, Valentina Nekljudova, Patricia Cortazar, Peter C Lucas, Carsten Denkert, Eleftherios P Mamounas, Christian Jackish, Norman Wolmark. A randomized double-blind phase III clinical trial of neoadjuvant chemotherapy (NAC) with atezolizumab or placebo in patients (pts) with triple negative breast cancer (TNBC) followed by adjuvant atezolizumab or placebo: NSABP B-59/GBG 96-GeparDouze [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 OT2-04-08.

Re: Clinical Efficacy and Biomarker Analysis of Neoadjuvant Atezolizumab in Operable Urothelial Carcinoma in the ABACUS Trial

Re: Clinical Efficacy and Biomarker Analysis of Neoadjuvant Atezolizumab in Operable Urothelial Carcinoma in the ABACUS Trial

OA13.07 Neoadjuvant Atezolizumab in Resectable NSCLC Patients: Immunophenotyping Results from the Interim Analysis of the Multicenter Trial LCMC3

OA13.07 Neoadjuvant Atezolizumab in Resectable NSCLC Patients: Immunophenotyping Results from the Interim Analysis of the Multicenter Trial LCMC3

P2.04-88 Surgical Outcomes of a Multicenter Phase II Trial of Neoadjuvant Atezolizumab in Resectable Stages IB-IIIB NSCLC: Update on LCMC3 Clinical Trial

P2.04-88 Surgical Outcomes of a Multicenter Phase II Trial of Neoadjuvant Atezolizumab in Resectable Stages IB-IIIB NSCLC: Update on LCMC3 Clinical Trial

Neoadjuvant atezolizumab in resectable non-small cell lung cancer (NSCLC): Interim analysis and biomarker data from a multicenter study (LCMC3).

8503 Background: Small pilot studies (e.g., N Engl J Med. 2018;378:1976) have shown that preoperative immune checkpoint inhibitor therapy may be of benefit in early-stage NSCLC. This large multicenter trial assesses the benefit of neoadjuvant treatment with atezolizumab (atezo; NCT02927301). Methods: Patients (pts) with stages IB to selected IIIB resectable NSCLC receive 2 cycles of atezo 1200 mg (days 1, 22) then undergo resection (day 40 ± 10). Primary tumor +/- node biopsies and blood samples are obtained before atezo and at surgery for biomarker studies. The primary endpoint is major pathological response (MPR), defined as ≤ 10% viable tumor cells in the resection specimen. Secondary endpoints include safety and correlation of response with PD-L1 expression, tumor mutation burden (TMB) and gene expression signatures. Results: For this interim efficacy analysis (5 Sep 2018 data cut), we report on the first 101 of 180 planned pts: 47 males, median age, 64 y; all ECOG PS 0-1; 23 current and 68 former smokers; 66 non-squamous NSCLC; clinical stages IB/IIA/IIB/IIIA/IIIB n = 11/16/28/39/7. There were 2 treatment-unrelated Gr 5 AEs (cardiac death post surgical resection; death due to disease progression), 29 Gr 3-4 AEs (6 [6%] treatment related). 90 pts had surgery. Excluding 8 pts who had driver mutations (7 EGFR, 1 ALK, no MPR), MPR rate was 15/82 (18%, 95% CI 11%-28%), 4 pts had pathological complete response (pCR). By RECIST, 6/82 pts had PR, 72 had SD and 4 had PD. Two of 26 (8%) PD-L1− (TC0 and IC0, clone SP142) and 10 of 35 (29%) PD-L1+ had MPR ( P= 0.055). Five of 44 (11%) TPS < 50 (PD-L1 clone 22C3) and 7 of 20 (35%) TPS > 50 had MPR ( P= 0.040). Exome sequencing data was available for 47/101 pts. Median TMB was 10.4 (range, 1.5-46.5) mutations per Mb and was not different in those with MPR compared with those without MPR. Further analysis of TMB, mutation signatures, and gene expression profiling is ongoing. Conclusions: Atezo in the neoadjuvant setting was well tolerated, and pCR and MPR rates are encouraging in this large multicenter trial. Efficacy interim analysis passed its futility boundary, and study enrollment continues. Safety, efficacy results and ongoing correlative analyses will be presented. Clinical trial information: NCT02927301.

NSABP B-59/GBG 96-GeparDouze: A randomized double-blind phase III clinical trial of neoadjuvant chemotherapy (NAC) with atezolizumab or placebo in patients (pts) with triple-negative breast cancer (TNBC) followed by adjuvant atezolizumab or placebo.

TPS605 Background: TNBC is associated with higher percentages of pathological complete response (pCR) to neoadjuvant chemotherapy (NAC), and women with a pCR have a favorable prognosis. However, Liedtke (2008) and Loibl (2017) found that women with residual disease have a substantially higher risk of recurrence than women with other subtypes of breast cancer. Additionally, Adams (2017) and Schmid (2017) found that therapeutic blockade of PD-L1 binding by atezolizumab has resulted in relevant anti-tumor efficacy. Methods: Design: This is a phase III, double blind, placebo-control trial evaluating neoadjuvant atezolizumab with NAC followed by adjuvant atezolizumab in TNBC. Pts are stratified by region (North America; Europe), tumor size (1.1-3.0cm; >3.0cm), AC/EC schedule (q2w; q3w), nodal status (positive; negative), and PD-L1 status (positive; negative or indeterminate) then randomized 1:1 to receive atezolizumab/placebo 1200 mg IV every 3 wks concurrently with both sequential regimens of weekly paclitaxel 80 mg/m2 IV for 12 doses with every 3-wk carboplatin AUC of 5 IV for 4 doses followed by AC/EC every 2-3 wks (per investigator discretion) for 4 cycles. Following surgery, pts resume atezolizumab/placebo 1200 mg IV every 3 wks as adjuvant therapy for 6 months. Radiotherapy based on local standards is co-administered with atezolizumab/placebo. Eligibility criteria: Centrally confirmed ER-neg, PR-neg, HER2-neg invasive breast cancer by ASCO/CAP guidelines. Primary tumor must be stage T2 or T3 if cN0 or cN1 with negative biopsy or T1c, T2, or T3 if cN1 with positive biopsy or cN2 or cN3. LVEF >55% and no significant cardiac history. Statistical methods: Co-primary endpoints are event-free survival (EFS) and pCR breast/nodes. Secondary endpoints include pCR breast, overall survival, distant disease-free survival, safety and toxicity. Trial is an academic collaboration between NSABP and GBG with support from Genentech/Roche. Support: Genentech/Roche. Clinical trial information: NCT03281954.

Neoadjuvant atezolizumab in resectable NSCLC patients: Updated clinical and immunophenotyping results from a multicenter trial.

99 Background: Targeting PD-L1/PD-1 to activate anti-tumor immunity is associated with improved response and survival compared to chemo in NSCLC pts. We present a preliminary analysis of the clinical efficacy, safety and peripheral blood (PB) immunophenotyping from an ongoing multicenter atezolizumab (atezo) neoadjuvant immunotherapy study in resectable NSCLC. Methods: Pts received 2 cycles of atezo, 1200mg, days 1, 22 before resection. Tumor biopsies and PB were obtained pre-atezo & pre-surgery. The biomarker evaluable population (BEP) included pts with paired PB analyzed within 72 hrs by 10-color flow cytometry (IMMUNOME) and major pathological response (MPR) assessment (defined as ≤ 10% residual tumor). The primary endpoint was MPR. Secondary endpoints included safety, MPR by PD-L1, OS, and DFS. Immunophenotypic analyses were correlated with treatment, MPR and PD-L1 expression. Results: 116 patients have been enrolled as of October 31, 2018 and here we report on 54 of 180 planned pts with follow-up through surgery. 15 pts had Gr 3-4 AEs (3 treatment related), one Gr 5 AE (sudden death) was unrelated. By RECIST there were 3 PR, 49 SD, and 2 PD. 50/54 pts underwent the planned surgery, 47 pts had MPR assessment: 4 pts discontinued study preop (2 radiographic PD, 2 other reasons); 3 were unresectable. Excluding 5 pts with EGFR or ALK mutations, MPR rate was 10/45 (22%, 95% CI 11-37%). Baseline PD-L1 status was evaluable in 44/54 pts; BEP included 31 pts, 23 had tissue PD-L1 status: 16 PD-L1+. We observed significant increases in natural killer (NK) cells, CD8+ T-cells, Th1-response related dendritic cells (DC), and decreases in B-cells after atezo. Non-MPR pts showed significant increases in late activated NK cells, monocytic myeloid cells and Th2 and Th17-response–related DCs. PD-L1+ pts showed significant decreases of senescent T cells, monocytic myeloid cells, and increases of Th1-response–related DCs. We analyzed 22/54 tumor pairs, PD-L1+ cells increased in most pts after atezo treatment. Conclusions: Neoadjuvant atezo was well tolerated and the MPR rate is encouraging. Preliminary immunophenotyping data showed significant changes in PB with immunotherapy. Clinical trial information: NCT02927301.

Abstract OT3-05-01: A randomized double-blind phase III clinical trial of neoadjuvant chemotherapy (NAC) with atezolizumab or placebo in patients (pts) with triple negative breast cancer (TNBC) followed by adjuvant atezolizumab or placebo: NSABP B-59/GBG 96-GeparDouze

Abstract Background: TNBC is associated with higher percentages of pathological complete response (pCR) to neoadjuvant chemotherapy (NAC), and women with a pCR have a favorable prognosis. However, Liedtke (2008) and Loibl (2017) found that women with residual disease have a substantially higher risk of recurrence than women with other subtypes of breast cancer. Additionally, Adams (2017) and Schmid (2017) found that therapeutic blockade of PD-L1 binding by atezolizumab has resulted in relevant anti-tumor efficacy. Methods: Design This is a phase III, double blind, placebo-control trial evaluating neoadjuvant atezolizumab with NAC followed by adjuvant atezolizumab in TNBC. Pts are stratified by region (North America; Europe), tumor size (1.1-3.0cm; >3.0cm), AC/EC schedule (q2w; q3w), and nodal status (positive; negative), then randomized 1:1 to receive atezolizumab/placebo 1200 mg IV every 3 wks concurrently with both sequential regimens of weekly paclitaxel 80 mg/m2 IV for 12 doses with every 3-wk carboplatin AUC of 5 IV for 4 doses followed by AC/EC every 2-3 wks (per investigator discretion) for 4 cycles. Following surgery, pts resume atezolizumab/placebo 1200 mg IV every 3 wks as adjuvant therapy for 6 months. Radiotherapy based on local standards is co-administered with atezolizumab/placebo. Eligibility criteria Centrally-confirmed ER-neg, PR-neg, HER2-neg invasive breast cancer by ASCO/CAP guidelines. Primary tumor must be stage T2 or T3 if cN0 or cN1 with negative biopsy or T1c, T2, or T3 if cN1 with positive biopsy or cN2 or cN3. LVEF >55% and no significant cardiac history. Statistical methods Co-primary endpoints are event-free survival (EFS) and pCR breast/nodes. Secondary endpoints include pCR breast, overall survival, distant disease-free survival, safety and toxicity. Trial is an academic collaboration between NSABP and GBG with support from Genentech/Roche. NCT03281954 Support: Genentech/Roche Citation Format: Geyer, Jr. CE, Loibl S, Rastogi P, Seiler S, Costantino JP, Nekljudova VN, Cortazar P, Lucas PC, Denkert C, Mamounas EP, Jackisch C, Wolmark N. A randomized double-blind phase III clinical trial of neoadjuvant chemotherapy (NAC) with atezolizumab or placebo in patients (pts) with triple negative breast cancer (TNBC) followed by adjuvant atezolizumab or placebo: NSABP B-59/GBG 96-GeparDouze [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr OT3-05-01.

MA04.09 Neoadjuvant Atezolizumab in Resectable Non-Small Cell Lung Cancer (NSCLC): Updated Results from a Multicenter Study (LCMC3)

MA04.09 Neoadjuvant Atezolizumab in Resectable Non-Small Cell Lung Cancer (NSCLC): Updated Results from a Multicenter Study (LCMC3)

Abstract 4688: Single-cell discrimination of altered human T cell states in the bladder tumor microenvironment

Abstract Bladder cancer can be responsive to immunotherapies such as anti-PD-1 and anti-PD-L1 checkpoint inhibitors, but overall response rates are low. Tumor-resident T cells demonstrate considerable heterogeneity as far as antigenic repertoire and phenotype. Whether the bladder tumor environment is enriched for specific types of T cells with a particular functional profile and antigenic specificity, and whether these tumor-specific populations are associated with treatment or response to immunotherapy, remains unclear. We performed single-cell RNA sequencing of CD4+ and CD8+ T cells from localized human bladder tumors and paired adjacent non-malignant bladder. We also assessed resected bladder tumors treated with neoadjuvant chemotherapy or atezolizumab (anti-PD-L1) as part of an ongoing phase II trial. We find both known and unexpected CD4+ T cell functional populations that are specific to the tumor microenvironment, including regulatory T cells and a novel population of cytotoxic CD4+ T cells. Furthermore, by combining whole-transcriptome data with paired T cell receptor identification on single cells, we find that tumor-specific CD4+ populations are clonally expanded and utilize an antigenic repertoire which is distinct from uninvolved bladder. These findings provide evidence for specialization of both phenotype and antigenic specificity of CD4+ T cells in the bladder tumor environment, and indicate that a limited number of tumor-specific antigens may drive in situ expansion and differentiation of specialized CD4+ subsets whose function may be critical to tumor control. Citation Format: David Yoonsuk Oh, Serena S. Kwek, Serghei Mangul, Siddharth S. Raju, Sasha Targ, Arun Burra, Eric Chow, Dvir Aran, Sima Porten, Maxwell V. Meng, Terence W. Friedlander, Chun Jimmie Ye, Lawrence Fong. Single-cell discrimination of altered human T cell states in the bladder tumor microenvironment [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 4688.

Neoadjuvant atezolizumab in resectable non-small cell lung cancer (NSCLC): Initial results from a multicenter study (LCMC3).

8541Background: Platinum-based chemotherapy, before or after surgery, provides only a 5% benefit in 5yr. OS in locally advanced NSCLC. A recent pilot study (JCO 2017 35:15suppl, 8508) showed that p...

A phase II study investigating the safety and efficacy of neoadjuvant atezolizumab in muscle invasive bladder cancer (ABACUS).

4506Background: Atezolizumab is a PD-L1 inhibitor which is licenced in metastatic urothelial cancer. This study investigates the efficacy and safety of neoadjuvant atezolizumab given prior to cystectomy in operable muscle invasive transitional cell carcinoma bladder cancer. Methods: This single arm phase 2 study investigated 2 cycles of atezolizumab (1200mg Q3) prior to cystectomy in muscle invasive transitional cell cancer (T2-4N0M0). Pathological complete response (pCR) occurring in ≥20% of patients was the primary endpoint. Biomarker analysis on sequential tissue was a co-primary endpoint. Cross sectional imaging was performed at baseline and prior to cystectomy which occurred 4 - 8 weeks after starting atezolizumab. Radiological response was assessed. Adverse events (AEs) and surgical complications were assessed using CTCAE v4.03 and the Clavien-Dindo classification. The IDMC reviewed the first 69 patients (of 85) and supported this interim presentation. Results: The median age of the 69 patients was ...

Abstract OT2-07-03: IMpassion031: A phase III study comparing neoadjuvant atezolizumab vs placebo in combination with nab-paclitaxel–based chemotherapy in early triple-negative breast cancer (TNBC)

Abstract Background Atezolizumab is an anti–programmed death-ligand 1 (PD-L1) monoclonal antibody that blocks the binding of PD-L1 to PD-1 and B7.1 receptors, thereby restoring tumor-specific immunity. TNBC is characterized by PD-L1 expression on tumor-infiltrating immune cells (IC), high levels of tumor-infiltrating lymphocytes (TILs), and a higher mutation rate compared with other breast cancers suggesting a therapeutic opportunity for atezolizumab. Atezolizumab alone and in combination with nab-paclitaxel is well tolerated, with promising clinical activity in metastatic TNBC. Furthermore, cytotoxic chemotherapies like nab-paclitaxel can enhance anti-tumor immune responses via neoantigen release. Taken together, this supports the investigation of atezolizumab in combination with nab-paclitaxel in early-stage TNBC. IMpassion031 is a global Phase III, double-blind, randomized, multicenter, placebo-controlled study being conducted to evaluate the efficacy and safety of neoadjuvant treatment with nab-paclitaxel → doxorubicin + cyclophosphamide and either atezolizumab or placebo in invasive stage II/III early TNBC. The selection and sequence of chemotherapy has been chosen to maximize the opportunity for a robust immune response. Methods: Eligible patients are those with previously untreated, central laboratory–confirmed invasive TNBC with primary tumor size > 2 cm and ECOG PS 0-1. Exclusion criteria include history of invasive breast cancer, stage IV disease, bilateral breast cancer, prior systemic therapy for the treatment or prevention of breast cancer, prior immunotherapy and a history of autoimmune disease. Approximately 204 patients will be randomized 1:1 to receive atezolizumab (840 mg q2w) or placebo with nab-paclitaxel (125 mg/m2 qw) for 12 weeks. Subsequent atezolizumab (840 mg q2w) or placebo with doxorubicin (60 mg/m2 q2w) + cyclophosphamide (600 mg/m2 q2w) will be given for 4 cycles prior to surgery. Post-surgery, patients will be unblinded. Patients in the atezolizumab arm will continue to receive atezolizumab (1200 mg q3w × 11 doses) post-surgery. Stratification factors include stage II vs III TNBC at diagnosis and PD-L1 expression on tumor-infiltrating IC (IC0 < 1% vs IC1/2/3 ≥ 1% with the VENTANA SP142 IHC assay). The primary endpoint is pathologic complete response (pCR); key secondary endpoints include pCR according to PD-L1 IC status, patient-reported outcomes, event-free survival and overall survival. Tumor samples will be taken at baseline, on treatment (optional), at surgery and post-recurrence for the assessment of biomarkers associated with treatment response and immune escape. (NCT pending). Citation Format: Mittendorf E, Barrios CH, Harbeck N, Miles D, Saji S, Zhang H, Duc A-N, Rafii S, Lai C. IMpassion031: A phase III study comparing neoadjuvant atezolizumab vs placebo in combination with nab-paclitaxel–based chemotherapy in early triple-negative breast cancer (TNBC) [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr OT2-07-03.

212TiP - IMpassion031: A phase III study comparing neoadjuvant atezolizumab (atezo) vs placebo in combination with anthracycline/nab-paclitaxel (nab-pac)–based chemotherapy in early triple-negative breast cancer (eTNBC)

212TiP - IMpassion031: A phase III study comparing neoadjuvant atezolizumab (atezo) vs placebo in combination with anthracycline/nab-paclitaxel (nab-pac)–based chemotherapy in early triple-negative breast cancer (eTNBC)

A phase II study of atezolizumab as neoadjuvant and adjuvant therapy in patients (pts) with resectable non-small cell lung cancer (NSCLC).

TPS8580 Background: Trials of neoadjuvant and adjuvant chemotherapy have demonstrated an absolute survival benefit of 5% for patients with early stage disease. Atezolizumab is a humanized IgG1 monoclonal antibody that inhibits PD-L1 from binding to its receptors PD-1 and B7.1, thereby restoring anti-tumor immune response. In the OAK trial, a randomized phase III trial of patients with metastatic NSCLC who progressed on platinum based chemotherapy, atezolizumab improved overall survival in patients regardless of PD-L1 expression compared with docetaxel (13.8 months vs. 9.6 months, HR 0.73 [95% CI 0.62 – 0.87]) with a manageable safety profile. Methods: NCT02927301 is a phase II, open-label, single-arm study designed to evaluate the efficacy and safety of atezolizumab as a neoadjuvant and adjuvant therapy in patients with Stage IB, II, or IIIA NSCLC prior to curative-intent resection. Approximately 180 patients with NSCLC will be enrolled in this study at 15 academic medical centers in the United States. The study has two parts: the primary part will evaluate the ability of neoadjuvant atezolizumab to produce pathologic responses in patients with early stage NSCLC. Atezolizumab 1200 mg IV will be given every 3 weeks for two doses. Surgical resection of tumors following treatment will allow determination of pathologic response rates and potential predictive biomarkers. Part 2 is exploratory and will evaluate atezolizumab adjuvant therapy for up to 12 months in patients who demonstrate clinical benefit in Part 1. The primary endpoint is major pathologic response rate (defined as ≤ 10% of viable tumor tissue) based on surgical resection. Secondary end points include overall response rate by status of mutation load, neoantigen score and gene expression signatures. OS and DFS are exploratory end points. This trial presents a unique opportunity to evaluate exploratory biomarkers given the availability of pre- and post-treatment biopsy specimens for assessment of evolution of immune related markers associated with response. The study opened to accrual in January 2017. Clinical trial information: NCT02927301.

P2.06-019 A Phase II Study of Atezolizumab as Neoadjuvant and Adjuvant Therapy in Patients (pts) with Resectable Non-Small Cell Lung Cancer (NSCLC): Topic: Phase II + NK

There is no curative treatment for patients with NSCLC who develop metastatic disease after resection. Trials of neoadjuvant and adjuvant chemotherapy have demonstrated an absolute survival benefit of 5% for patients with stages IB, II, and IIIA disease. Clearly, developing new treatment strategies to improve survival following resection is critical to improving outcomes for this patient population. Immunotherapy with checkpoint inhibitors such as antibodies to PD-1 and PD-L1 has demonstrated superior survival compared to chemotherapy in randomized clinical trials. PD-L1 expression is being investigated as a predictive biomarker for these therapies, but its ability to predict response has varied in published trials. Atezolizumab is a humanized IgG1 monoclonal PD-L1 antibody that was recently evaluated in the POPLAR trial (NCT01903993), a phase II randomized trial of patients with NSCLC who progressed on platinum based chemotherapy. Atezolizumab therapy improved overall survival compared with docetaxel (12.6 months vs. 9.7 months, HR 0.73 [95% CI 0.53 – 0.99]) with a manageable safety profile. Improvement in survival correlated with PD-L1 immunohistochemistry expression of tumor and tumor-infiltrating immune cells. Trial design: This phase II, open-label, single-arm study is designed to evaluate the efficacy and safety of atezolizumab as a neoadjuvant therapy in patients with Stage IB, II, or IIIA NSCLC prior to curative-intent resection. Approximately 180 patients with NSCLC will be enrolled in this study at 15 academic medical centers in the United States. There are two parts to this study: the first/primary part will evaluate the ability of neoadjuvant atezolizumab to produce objective pathologic responses in patients with early stage NSCLC. Atezolizumab 1200 mg IV will be given every 3 weeks for two doses. Surgical resection of tumors following treatment will allow determination of pathologic response rates and potential predictive biomarkers. Part 2 is exploratory and will evaluate atezolizumab adjuvant therapy for up to 12 months in patients who demonstrate clinical benefit (evidence of pathologic response or absence of radiographic progression) in Part 1. After surgical resection, patients may receive SOC adjuvant chemotherapy (with or without radiation) before starting atezolizumab adjuvant therapy in Part 2. The primary objectives are safety and major pathologic response based on surgical resection. Secondary objectives include overall response rate based on PD-L1 status, mutational load, antigen burden, and RNA-sequencing. This trial presents a unique opportunity to evaluate exploratory biomarkers, including pre- and post-treatment biopsy assessment of evolution of immune related markers associated with response. Section not applicable. Section not applicable.