Safety Of Atezolizumab In Combination Research Articles

CTIM-23. SAFETY RUN-IN RESULTS OF A PHASE I/II STUDY TO EVALUATE ATEZOLIZUMAB IN COMBINATION WITH CABOZANTINIB IN PATIENTS WITH RECURRENT GLIOBLASTOMA

Abstract BACKGROUND Immune checkpoint inhibitor therapy has shown limited efficacy in the treatment of glioblastoma (GBM) in both newly diagnosed and recurrent disease which underscores the need for rational combinatorial strategies. Atezolizumab is a humanized monoclonal antibody that targets PD-L1 and has been shown to enhance the magnitude of tumor-specific T cell responses. Combining PD-L1/PD-1 axis inhibition with targeted therapy like cabozantinib which has both anti-tumoral and immunomodulatory properties may result in synergistic effects. Cabozantinib may modulate the myeloid cell population to overcome resistance to anti-PD-1/PD-L1 therapy. METHODS Eligibility criteria were those with recurrent GBM, age >18 yrs with 1st or 2nd recurrence who were naïve to antiangiogenic and receptor tyrosine kinase inhibitor treatment. The primary objective of the phase I run-in was to evaluate the safety of atezolizumab in combination with cabozantinib. RESULTS 1 dose-limiting toxicity (DLT) of a grade 3 ALT elevation was observed in the first 6 DLT evaluable patients treated during the safety run-in phase. Regarding immune related adverse events, 1 of 6 patients developed atezolizumab-related grade 1 hypothyroidism. 1 of 6 patients developed study treatment-related grade 2 diarrhea. 2 patients after completion of 2 cycles of treatment had evidence of a partial radiographic response ( > 50% decrease). 1 patient had a near partial radiographic response (45% decrease). 2 patients had stable disease after completion of 2 cycles of the combinatorial treatment. 1 patient had only completed the first 28-day cycle, DLT period, and had not yet had imaging to reassess disease status. CONCLUSIONS The combination of atezolizumab with cabozantinib was tolerable, and no new safety signals were noted. In this small cohort of recurrent GBM patients, radiographic responses were observed. The phase II component of the trial is recruiting patients (n = 45) to evaluate clinical efficacy. Multi-omic correlative studies and fecal microbiome analyses are planned.

Phase I trial of perioperative chemotherapy plus immunotherapy in localized esophageal and gastroesophageal adenocarcinoma.

400 Background: The management of esophageal cancer (EC) and gastroesophageal junction (GEJ) adenocarcinoma has focused on perioperative approaches that aim to increase pathological complete response (pathCR) rates, decrease or delay metastases, improve resectability, and enhance overall survival. Atezolizumab is a humanized immunoglobulin (Ig) G1 monoclonal antibody that targets PD-L1 and inhibits the interaction between PD-L1 and its receptors, PD-1, and B7-1, both of which function as inhibitory receptors expressed on T-cells. Therapeutic binding of PD-L1 by atezolizumab has been shown to enhance the magnitude and quality of tumor-specific T-cell responses, resulting in improved anti-tumor activity. The use of immunotherapy in combination with chemotherapy in the perioperative setting may improve the response rate in patients with localized EC and GEJ adenocarcinoma. Methods: We conducted a phase I study evaluating the efficacy and safety of atezolizumab in combination with oxaliplatin and 5-fluorouracil (modified FOLFOX) therapy in the perioperative setting. Patients with T1N1 or T2-3 (any N) localized EC and GEJ type I or II adenocarcinoma were included. Treatment consisted of oxaliplatin (85 mg/m2 over 2 hours on days 1 and 15) and 5-fluorouracil (2.4g/m2 (over 48 hours) via infusion pump on days 1 and 15) followed by atezolizumab (840 mg via IV on days 1 and 15) of each 28-day cycle for a total of 6 doses followed by surgery and subsequently postoperative atezolizumab 1200 mg IV on Day 1 of each 21-day cycle for 8 more doses. Results: From April 2019 to November 2020, 20 patients were enrolled with a median age of 61 years old and baseline TNM staging: T2-3N0 (n=8), T3N1-N2 (n=10), and T3N3-NX (n=2). Eighteen patients underwent surgery; two patients (11%, 95% credible interval = 1-28%) achieved the primary efficacy objective (pathCR defined as pathological T0N0), and two additional patients (11%) had near complete pathCR with <1% viable tumor. Fifteen patients (83%) had R0 resection. Grade 4 treatment-related events occurred in 2 patients and grade 2 and 3 treatment related events occurred in 9 and 7 patients respectively. No treatment-related events leading to discontinuation of therapy or treatment-related deaths occurred. Forty-five percent of the patients died and 44% of patients had recurrence with a median disease-free survival of 29 months. Conclusions: Results indicate that atezolizumab in combination with oxaliplatin and 5-fluorouracil has an acceptable safety profile providing high tumor regression. This trial supports further research of atezolizumab for the treatment of patients with localized EC and GEJ in the perioperative setting. Clinical trial information: NCT03784326 .

Observation of Therapeutic Efficacy and Safety of Atezolizumab in Combination with Bevacizumab for Non-Squamous Non-Small Cell Lung Cancer Highly Expressed Programmed Death Ligand-1

Observation of Therapeutic Efficacy and Safety of Atezolizumab in Combination with Bevacizumab for Non-Squamous Non-Small Cell Lung Cancer Highly Expressed Programmed Death Ligand-1

Atezolizumab in combination with bevacizumab in patients with unresectable locally advanced or metastatic mucosal melanoma: Interim analysis of an open-label phase II trial.

9511 Background: Mucosal melanoma is a rare malignant melanoma in Caucasians but ranks the second most common subtype in the Asian population. It is more often diagnosed at an advanced stage and responds poorly to current PD-1/PD-L1 inhibitors. Here we report the interim analysis results of ML41186, an open-label, multicenter, single-arm phase II study, aiming to evaluate the efficacy and safety of atezolizumab in combination with bevacizumab in patients (pts) with advanced mucosal melanoma. Methods: Eligible pts aged 18 to 75 years with histologically confirmed unresectable locally advanced or metastatic mucosal melanoma had at least one measurable lesion per RECIST version 1.1 at baseline, with an ECOG PS 0 or 1 and adequate hematologic and organ function. ML41186 is a Simon two-stage design study, if 22 pts completed ORR evaluation and more than 3 pts respond in stage I, the study then continue to Stage II. Atezolizumab and bevacizumab were administered at a fixed dose of 1200 mg and 7.5 mg/kg Q3W respectively (on day 1 of each 21-day cycle) until unacceptable toxicity or loss of clinical benefit. The primary endpoint is the objective response rate (ORR). The secondary endpoints include progression-free survival (PFS), duration of objective response (DoR), disease control rate (DCR), and safety. Results: By the cut-off date of 9th September 2020, 35 pts has been enrolled, among whom 22 pts in the stage I analysis set has completed two efficacy evaluation, while 28 pts (full analysis set) has completed at least one efficacy evaluation. In ITT populations (n=35), mean age was 58.9 years with 10 (28%) pts had ECOG PS of 1. LDH level elevated in 9 (25.7%) pts. More than half pts (19, 54.3%) had metastatic mucosal melanoma, of whom 3 (15.8%) pts had more than 3 metastasis sites and 4 (21.1%) pts had liver metastasis. In stage I analysis set (n=22), the best confirmed ORR was 36.4% (95% CI, 17.0%-59.3%). Median progression-free survival was 5.32 months (95% CI, 1.58-not reached), and the best confirmed DCR was 59.1% (95%CI, 36.4%-79.3%). The median confirmed DoR was not reached (95% CI, 2.76-NR). In the full analysis set (n=28), the unconfirmed ORR was 42.9% (95%CI, 24.5%-62.8%). In ITT populations (n=35), 28 pts (80%) experienced at least one adverse event (AE) and 5 pts (14.3%) experienced at least one grade 3-4 AEs. Only one patient experienced AE leading to treatment discontinuation. One patient died of autoimmune lung disease. Conclusions: The combination of atezolizumab plus bevacizumab showed promising benefit and was tolerable in pts with advanced mucosal melanoma. At the time of this interim analysis, the primary endpoint did not cross the futility boundary, thus the study will run into Stage II. Clinical trial information: NCT04091217.

ALEXANDRA/IMpassion030: A phase III study of standard adjuvant chemotherapy with or without atezolizumab in early-stage triple-negative breast cancer.

TPS598 Background: Early stage triple negative breast cancer (TNBC) is associated with a high risk of distant relapse. Because TNBC does not currently have specific targeted agents approved for use in the early setting it is treated primarily with chemotherapy. TNBC may be more immunogenic than other subtypes of breast cancer and promising clinical activity has been reported with the anti–PD-L1 antibody, atezolizumab, in Phase 1/1b metastatic TNBC trials. Furthermore, the randomized phase 3 IMpassion130 study demonstrated enhanced anti-tumor activity when atezolizumab was co-administered with chemotherapy in the first line metastatic setting, with benefit mainly observed in PD-L1+ cohort. ALEXANDRA/IMpassion030 will evaluate the efficacy and safety of atezolizumab in combination with standard anthracycline/taxane adjuvant chemotherapy in early TNBC patients. Methods: ALEXANDRA/IMpassion030 is a global, prospective, randomized, open-label, phase 3 trial investigating the efficacy, safety and pharmacokinetic profile of adjuvant atezolizumab plus standard chemotherapy versus chemotherapy alone in early TNBC. In total, 2300 patients with operable stage II or III TNBC, confirmed by central pathology review, will be randomized. Patients are stratified by type of surgery, nodal status, and centrally assessed PD-L1 status. Adjuvant treatment will consist of weekly paclitaxel 80 mg/m2 for 12 weeks followed by dose dense anthracycline (epirubicin 90 mg/m2 or doxorubicin 60 mg/m2) and cyclophosphamide 600 mg/m2 for 4 doses every 2 weeks or the same chemotherapy regimen (T-EC/AC) given concomitantly with atezolizumab 840 mg every 2 weeks followed by maintenance atezolizumab 1200 mg every 3 weeks until completion of 1 year of atezolizumab. The primary end-point is invasive disease-free survival (iDFS) and secondary end-points include iDFS by PD-L1 and lymph node status, overall survival, safety, patient functioning and health related quality of life (HRQoL). Tumor tissue and blood samples will be collected for biomarker research. The first patient was enrolled on August 2nd 2018, and approximately 430 sites are expected to be opened globally in 30 countries. Clinical trial information: NCT03498716.

Abstract OT3-05-02: ALEXANDRA/IMpassion030: A phase III study of standard adjuvant chemotherapy with or without atezolizumab in early triple negative breast cancer

Abstract Background: Triple negative breast cancer (TNBC) is a subtype with a high risk of relapse in the early disease setting. Because TNBC does not currently have specific targeted agents approved for use in the early setting it is treated primarily with chemotherapy. A growing body of evidence indicates that TNBC is more immunogenic than other subtypes of breast cancer and promising clinical activity has been reported with atezolizumab (an anti–PD-L1 antibody) in Phase 1/1b metastatic TNBC trials. Furthermore, the anti-tumor activity of PD-1/PD-L1 targeting drugs is hypothesized to be enhanced when co-administered with chemotherapy. ALEXANDRA/IMpassion030 will evaluate the efficacy and safety of atezolizumab in combination with standard adjuvant chemotherapy in early TNBC. Methods: ALEXANDRA/IMpassion030 is a global, prospective, randomised, open-label Phase 3 trial investigating the efficacy, safety and pharmacokinetic (PK) profile of adjuvant atezolizumab plus standard chemotherapy versus chemotherapy alone in early TNBC. In total, 2300 patients diagnosed with non-metastatic operable stage II or III TNBC confirmed by central pathology review will be randomised. TumorPD-L1evaluationwill be performed centrally. Patients will be stratified by type of surgery, nodal status, and PD-L1 status. The adjuvant treatment will consist of weekly paclitaxel 80 mg/m2 for 12 weeks followed by dose dense anthracycline (epirubicin 90 mg/m2 or doxorubicin 60 mg/m2) and cyclophosphamide 600 mg/m2 for 4 doses every 2 weeks or the same chemotherapy regimen (T-EC/AC) given concomitantly with atezolizumab 840 mg every 2 weeks followed by maintenance atezolizumab 1200 mg every 3 weeks until completion of 1 year of atezolizumab. Primary end-point is invasive disease-free survival (iDFS) and secondary end-points include iDFS by PD-L1 and lymph node status, overall survival, safety, patient functioning and health related quality of life (HRQoL). Tumour tissue and blood samples will be collected for biomarker research. The first site was activated in May 4th, and approximately 430 sites are expected to be open globally in 30 countries. This trial is sponsored by Roche and conducted in partnership with the Breast International Group, Frontier Science and Technology Research Foundation, Institute Jules Bordet and Alliance Foundation Trials. Clinicaltrials.gov NCT03498716. Citation Format: Ignatiadis M, McArthur H, Bailey A, Martinez J-L, De Azambuja E, Metzger O, Lai C, Ponde N, Goulioti T, Daly F, Bouhlel A, Balta V, Van Dooren V, Viale G, Maetens M, Dufrane C, Nguyen Duc A, Winer E, Gelber R, Piccart M. ALEXANDRA/IMpassion030: A phase III study of standard adjuvant chemotherapy with or without atezolizumab in early triple negative breast cancer [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 OT3-05-02.