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Thomas Powles - One of the best experts on this subject based on the ideXlab platform.

  • efficacy and safety of Atezolizumab plus bevacizumab following disease progression on Atezolizumab or sunitinib monotherapy in patients with metastatic renal cell carcinoma in immotion150 a randomized phase 2 clinical trial
    European Urology, 2021
    Co-Authors: Thomas Powles, Michael B Atkins, Bernard Escudier, Robert J Motzer, Brian I Rini, Lawrence Fong, Richard W Joseph, Sumanta K Pal, Mario Sznol, John D Hainsworth
    Abstract:

    Abstract Background The use of immune checkpoint inhibitors combined with vascular endothelial growth factor (VEGF)-targeted therapy as second-line treatment for metastatic clear cell renal cancer (mRCC) has not been evaluated prospectively. Objective To evaluate the efficacy and safety of Atezolizumab + bevacizumab following disease progression on Atezolizumab or sunitinib monotherapy in patients with mRCC. Design, setting, and participants IMmotion150 was a multicenter, randomized, open-label, phase 2 study of patients with untreated mRCC. Patients randomized to the Atezolizumab or sunitinib arm who had investigator-assessed progression as per RECIST 1.1 could be treated with second-line Atezolizumab + bevacizumab. Intervention Patients received Atezolizumab 1200 mg intravenously (IV) plus bevacizumab 15 mg/kg IV every 3 wk following disease progression on either Atezolizumab or sunitinib monotherapy. Outcome measurements and statistical analysis The secondary endpoints analyzed during the second-line part of IMmotion150 included objective response rate (ORR), progression-free survival (PFS), and safety. PFS was examined using Kaplan-Meier methods. Results and limitations Fifty-nine patients in the Atezolizumab arm and 78 in the sunitinib arm were eligible, and 103 initiated second-line Atezolizumab + bevacizumab (Atezolizumab arm, n = 44; sunitinib arm, n = 59). ORR (95% confidence interval [CI]) was 27% (19–37%). The median PFS (95% CI) from the start of second line was 8.7 (5.6–13.7) mo. The median event follow-up duration was 19.4 (12.9–21.9) mo among the 25 patients without a PFS event. Eighty-six (83%) patients had treatment-related adverse events; 31 of 103 (30%) had grade 3/4 events. Limitations were the small sample size and selection for progressors. Conclusions The Atezolizumab + bevacizumab combination had activity and was tolerable in patients with progression on Atezolizumab or sunitinib. Further studies are needed to investigate sequencing strategies in mRCC. Patient summary Patients with advanced kidney cancer whose disease had worsened during treatment with Atezolizumab or sunitinib began second-line treatment with Atezolizumab + bevacizumab. Tumors shrank in more than one-quarter of patients treated with this combination, and side effects were manageable.

  • Atezolizumab plus bevacizumab versus sunitinib for patients with untreated metastatic renal cell carcinoma and sarcomatoid features a prespecified subgroup analysis of the immotion151 clinical trial
    European Urology, 2021
    Co-Authors: Brian I Rini, Thomas Powles, Bernard Escudier, Robert J Motzer, David F Mcdermott, Jens Bedke, Frede Donskov, Robert E Hawkins, Sergio Bracarda, Ugo De Giorgi
    Abstract:

    Abstract Patients with metastatic renal cell carcinoma with sarcomatoid features (sRCC) have a poor prognosis and have shown limited responsiveness to inhibition of the VEGF pathway. We conducted a prespecified analysis of the randomised, phase 3 IMmotion151 trial in previously untreated patients with advanced or metastatic RCC to assess the effectiveness of Atezolizumab + bevacizumab versus sunitinib in a subgroup of patients with sarcomatoid features. Patients whose tumour had any component of sarcomatoid features were included and received Atezolizumab + bevacizumab (n = 68) or sunitinib (n = 74). Baseline characteristics were similar between the groups. Median progression-free survival was significantly longer in the group receiving Atezolizumab + bevacizumab overall (8.3 vs 5.3 mo; hazard ratio [HR] 0.52 95% confidence interval [CI] 0.34–0.79) and in the subset of patients with PD-L1–positive tumours (8.6 vs 5.6 mo; HR 0.45, 95% CI 0.26–0.77). More patients receiving Atezolizumab + bevacizumab achieved an objective response (49% vs 14%), including complete responses (10% vs 3%), and reported greater symptom improvements versus sunitinib. Safety was consistent with the known profiles of each drug and with that reported in the overall safety-evaluable population of IMmotion151. This analysis supports enhanced activity of Atezolizumab + bevacizumab in patients with sRCC. Patient summary In this report, we looked at patients with a specific type of kidney cancer (tumours with sarcomatoid features) that has been hard to treat. A treatment with two drugs (Atezolizumab and bevacizumab) appeared to help patients live longer without the disease getting worse than another drug (sunitinib) that is often used. Patients who took the two drugs also said they were better able to carry out their everyday activities than patients who took sunitinib. The combination of these two drugs may work better in patients with this type of advanced kidney cancer.

  • efficacy of chemotherapy and Atezolizumab in patients with non small cell lung cancer receiving antibiotics and proton pump inhibitors pooled post hoc analyses of the oak and poplar trials
    Annals of Oncology, 2020
    Co-Authors: Myriam Chalabi, Achim Rittmeyer, Thomas Powles, David R Gandara, A Cardona, D R Nagarkar, A Dhawahir M Scala, Matthew L Albert, Marleen Kok, F Herrera
    Abstract:

    Background Preclinical data have shown that proton pump inhibitors (PPI) can modulate the microbiome, and single-arm studies suggested that antibiotics (ATB) may decrease the efficacy of immune checkpoint inhibitors (ICI), but randomized controlled trial data are lacking. This pooled analysis evaluated the effect of ATB and PPI on outcome in patients randomized between ICI and chemotherapy. Patients and methods This retrospective analysis used pooled data from the phase II POPLAR (NCT01903993) and phase III OAK (NCT02008227) trials, which included 1512 patients with previously treated non-small-cell lung cancer (NSCLC) randomly assigned to receive Atezolizumab (n = 757) or docetaxel (n = 755). The main objective of this analysis was to assess the impact of ATB and PPI use on overall survival (OS) and progression-free survival (PFS). Results A total of 169 (22.3%) patients in the Atezolizumab group and 202 (26.8%) in the docetaxel group received ATB, and 234 (30.9%) and 260 (34.4%), respectively, received PPI. Multivariate analysis in all patients revealed that ATB were associated with shorter OS [hazard ratio (HR) 1.20, 95% confidence interval (CI) 1.04–1.39], as was PPI (HR 1.26, 95% CI 1.10–1.44). Within the Atezolizumab population, OS was significantly shorter in patients who received ATB (8.5 versus 14.1 months, HR 1.32, 95% CI 1.06–1.63, P = 0.01) or PPI (9.6 versus 14.5 months, HR 1.45, 95% CI 1.20–1.75, P = 0.0001). PPI use was associated with shorter PFS in the Atezolizumab population (1.9 versus 2.8 months, HR 1.30, 95% CI 1.10−1.53, P = 0.001). There was no association between ATB and PPI use and PFS or OS within the docetaxel population. Conclusion In this unplanned analysis from two randomized trials, data suggest that ATB or PPI use in patients with metastatic NSCLC is associated with poor outcome and may influence the efficacy of ICI.

  • Atezolizumab plus bevacizumab versus sunitinib in patients with previously untreated metastatic renal cell carcinoma immotion151 a multicentre open label phase 3 randomised controlled trial
    The Lancet, 2019
    Co-Authors: Brian I Rini, Thomas Powles, Michael B Atkins, Bernard Escudier, David F Mcdermott, Frede Donskov, Sergio Bracarda, Cristina Suarez, Walter M Stadler, Jae Lyun Lee
    Abstract:

    Summary Background A phase 2 trial showed improved progression-free survival for Atezolizumab plus bevacizumab versus sunitinib in patients with metastatic renal cell carcinoma who express programmed death-ligand 1 (PD-L1). Here, we report results of IMmotion151, a phase 3 trial comparing Atezolizumab plus bevacizumab versus sunitinib in first-line metastatic renal cell carcinoma. Methods In this multicentre, open-label, phase 3, randomised controlled trial, patients with a component of clear cell or sarcomatoid histology and who were previously untreated, were recruited from 152 academic medical centres and community oncology practices in 21 countries, mainly in Europe, North America, and the Asia-Pacific region, and were randomly assigned 1:1 to either Atezolizumab 1200 mg plus bevacizumab 15 mg/kg intravenously once every 3 weeks or sunitinib 50 mg orally once daily for 4 weeks on, 2 weeks off. A permuted-block randomisation (block size of 4) was applied to obtain a balanced assignment to each treatment group with respect to the stratification factors. Study investigators and participants were not masked to treatment allocation. Patients, investigators, independent radiology committee members, and the sponsor were masked to PD-L1 expression status. Co-primary endpoints were investigator-assessed progression-free survival in the PD-L1 positive population and overall survival in the intention-to-treat (ITT) population. This trial is registered with ClinicalTrials.gov, number NCT02420821. Findings Of 915 patients enrolled between May 20, 2015, and Oct 12, 2016, 454 were randomly assigned to the Atezolizumab plus bevacizumab group and 461 to the sunitinib group. 362 (40%) of 915 patients had PD-L1 positive disease. Median follow-up was 15 months at the primary progression-free survival analysis and 24 months at the overall survival interim analysis. In the PD-L1 positive population, the median progression-free survival was 11·2 months in the Atezolizumab plus bevacizumab group versus 7·7 months in the sunitinib group (hazard ratio [HR] 0·74 [95% CI 0·57–0·96]; p=0·0217). In the ITT population, median overall survival had an HR of 0·93 (0·76–1·14) and the results did not cross the significance boundary at the interim analysis. 182 (40%) of 451 patients in the Atezolizumab plus bevacizumab group and 240 (54%) of 446 patients in the sunitinib group had treatment-related grade 3–4 adverse events: 24 (5%) in the Atezolizumab plus bevacizumab group and 37 (8%) in the sunitinib group had treatment-related all-grade adverse events, which led to treatment-regimen discontinuation. Interpretation Atezolizumab plus bevacizumab prolonged progression-free survival versus sunitinib in patients with metastatic renal cell carcinoma and showed a favourable safety profile. Longer-term follow-up is necessary to establish whether a survival benefit will emerge. These study results support Atezolizumab plus bevacizumab as a first-line treatment option for selected patients with advanced renal cell carcinoma. Funding F Hoffmann–La Roche Ltd and Genentech Inc.

  • siu icud recommendations on bladder cancer systemic therapy for metastatic bladder cancer
    World Journal of Urology, 2019
    Co-Authors: Axel S Merseburger, Daniel P Petrylak, Matthew I Milowsky, Andrea B Apolo, Simon Chowdhury, Noah M Hahn, Matthew D Galsky, Thomas Powles, David I Quinn, Jonathan E. Rosenberg
    Abstract:

    The SIU (Societe Internationale d’Urologie)–ICUD (International Consultation on Urologic Diseases) working group on systemic therapy for metastatic bladder cancer has summarized the most recent findings on the aforementioned topic and came to conclusions and recommendations according to the evidence published. In Europe and the United States, treatment for metastatic UC has changed a great deal recently, mainly involving a move from chemotherapy to immune checkpoint blockers. This is particularly true in platinum-refractory disease, where supportive randomized data exist. Five checkpoint blockers have been approved in this setting by the FDA: avelumab, Atezolizumab, durvalumab, nivolumab, and pembrolizumab. Nivolumab, pembrolizumab, and Atezolizumab have been approved in Europe.

Achim Rittmeyer - One of the best experts on this subject based on the ideXlab platform.

  • efficacy of chemotherapy and Atezolizumab in patients with non small cell lung cancer receiving antibiotics and proton pump inhibitors pooled post hoc analyses of the oak and poplar trials
    Annals of Oncology, 2020
    Co-Authors: Myriam Chalabi, Achim Rittmeyer, Thomas Powles, David R Gandara, A Cardona, D R Nagarkar, A Dhawahir M Scala, Matthew L Albert, Marleen Kok, F Herrera
    Abstract:

    Background Preclinical data have shown that proton pump inhibitors (PPI) can modulate the microbiome, and single-arm studies suggested that antibiotics (ATB) may decrease the efficacy of immune checkpoint inhibitors (ICI), but randomized controlled trial data are lacking. This pooled analysis evaluated the effect of ATB and PPI on outcome in patients randomized between ICI and chemotherapy. Patients and methods This retrospective analysis used pooled data from the phase II POPLAR (NCT01903993) and phase III OAK (NCT02008227) trials, which included 1512 patients with previously treated non-small-cell lung cancer (NSCLC) randomly assigned to receive Atezolizumab (n = 757) or docetaxel (n = 755). The main objective of this analysis was to assess the impact of ATB and PPI use on overall survival (OS) and progression-free survival (PFS). Results A total of 169 (22.3%) patients in the Atezolizumab group and 202 (26.8%) in the docetaxel group received ATB, and 234 (30.9%) and 260 (34.4%), respectively, received PPI. Multivariate analysis in all patients revealed that ATB were associated with shorter OS [hazard ratio (HR) 1.20, 95% confidence interval (CI) 1.04–1.39], as was PPI (HR 1.26, 95% CI 1.10–1.44). Within the Atezolizumab population, OS was significantly shorter in patients who received ATB (8.5 versus 14.1 months, HR 1.32, 95% CI 1.06–1.63, P = 0.01) or PPI (9.6 versus 14.5 months, HR 1.45, 95% CI 1.20–1.75, P = 0.0001). PPI use was associated with shorter PFS in the Atezolizumab population (1.9 versus 2.8 months, HR 1.30, 95% CI 1.10−1.53, P = 0.001). There was no association between ATB and PPI use and PFS or OS within the docetaxel population. Conclusion In this unplanned analysis from two randomized trials, data suggest that ATB or PPI use in patients with metastatic NSCLC is associated with poor outcome and may influence the efficacy of ICI.

  • Atezolizumab in combination with carboplatin plus nab paclitaxel chemotherapy compared with chemotherapy alone as first line treatment for metastatic non squamous non small cell lung cancer impower130 a multicentre randomised open label phase 3 trial
    Lancet Oncology, 2019
    Co-Authors: Howard Jack West, Achim Rittmeyer, Michael Mccleod, Maen A Hussein, Alessandro Morabito, Henry Jacob Conter, Hansgeorg Kopp, D Daniel, Steven Mccune, Tarek Mekhail
    Abstract:

    Summary Background Atezolizumab (a monoclonal antibody against PD-L1), which restores anticancer immunity, improved overall survival in patients with previously treated non-small-cell lung cancer and also showed clinical benefit when combined with chemotherapy as first-line treatment of non-small-cell lung cancer. IMpower130 aimed to assess the efficacy and safety of Atezolizumab plus chemotherapy versus chemotherapy alone as first-line therapy for non-squamous non-small-cell lung cancer. Methods IMpower130 was a multicentre, randomised, open-label, phase 3 study done in 131 centres across eight countries (the USA, Canada, Belgium, France, Germany, Italy, Spain, and Israel). Eligible patients were aged 18 years or older, and had histologically or cytologically confirmed stage IV non-squamous non-small-cell lung cancer, an Eastern Cooperative Oncology Group performance status of 0 or 1, and received no previous chemotherapy for stage IV disease. Patients were randomly assigned (2:1; permuted block [block size of six] with an interactive voice or web response system) to receive Atezolizumab (1200 mg intravenously every 3 weeks) plus chemotherapy (carboplatin [area under the curve 6 mg/mL per min every 3 weeks] plus nab-paclitaxel [100 mg/m2 intravenously every week]) or chemotherapy alone for four or six 21-day cycles followed by maintenance therapy. Stratification factors were sex, baseline liver metastases, and PD-L1 tumour expression. Co-primary endpoints were investigator-assessed progression-free survival and overall survival in the intention-to-treat wild-type (ie, EGFRwt and ALKwt) population. The safety population included patients who received at least one dose of the study drug. This study is registered with ClinicalTrials.gov, number NCT02367781. Findings Between April 16, 2015, and Feb 13, 2017, 724 patients were randomly assigned and 723 were included in the intention-to-treat population (one patient died before randomisation, but was assigned to a treatment group; this patient was excluded from the intention-to-treat population) of the Atezolizumab plus chemotherapy group (483 patients in the intention-to-treat population and 451 patients in the intention-to-treat wild-type population) or the chemotherapy group (240 patients in the intention-to-treat population and 228 patients in the intention-to-treat wild-type population). Median follow-up in the intention-to-treat wild-type population was similar between groups (18·5 months [IQR 15·2–23·6] in the Atezolizumab plus chemotherapy group and 19·2 months [15·4–23·0] in the chemotherapy group). In the intention-to-treat wild-type population, there were significant improvements in median overall survival (18·6 months [95% CI 16·0–21·2] in the Atezolizumab plus chemotherapy group and 13·9 months [12·0–18·7] in the chemotherapy group; stratified hazard ratio [HR] 0·79 [95% CI 0·64–0·98]; p=0·033) and median progression-free survival (7·0 months [95% CI 6·2–7·3] in the Atezolizumab plus chemotherapy group and 5·5 months [4·4–5·9] in the chemotherapy group; stratified HR 0·64 [95% CI 0·54–0·77]; p Interpretation IMpower130 showed a significant and clinically meaningful improvement in overall survival and a significant improvement in progression-free survival with Atezolizumab plus chemotherapy versus chemotherapy as first-line treatment of patients with stage IV non-squamous non-small-cell lung cancer and no ALK or EGFR mutations. No new safety signals were identified. This study supports the benefit of Atezolizumab, in combination with platinum-based chemotherapy, as first-line treatment of metastatic non-small-cell lung cancer. Funding F. Hoffmann-La Roche.

  • Atezolizumab in patients with advanced non small cell lung cancer and history of asymptomatic treated brain metastases exploratory analyses of the phase iii oak study
    Lung Cancer, 2019
    Co-Authors: Shirish M Gadgeel, Keunchil Park, Achim Rittmeyer, Paul Conkling, Rimas V Lukas, J Goldschmidt, Diego Cortinovis, Filippo De Marinis, Jyoti D Patel, Joachim Von Pawel
    Abstract:

    Abstract Objectives To assess the safety and efficacy of Atezolizumab and docetaxel in patients with and without a history of asymptomatic, treated brain metastases in the phase III OAK trial. Materials and methods Patients received 1200 mg Atezolizumab or 75 mg/m2 docetaxel every 3 weeks until unacceptable toxicity, disease progression, or loss of clinical Atezolizumab benefit. Patients with asymptomatic, treated supratentorial metastases were eligible. Patients had brain scans before enrollment; follow-up brain scans and treatment were required when clinically indicated. Results Approximately 14% of patients in each arm had a history of asymptomatic, treated brain metastases (61/425 in the Atezolizumab arm and 62/425 in the docetaxel arm). Fewer treatment-related adverse events (AEs), serious AEs, and treatment-related neurologic AEs were reported with Atezolizumab than with docetaxel, regardless of history of asymptomatic, treated brain metastases. In patients with a history of asymptomatic, treated brain metastases, median overall survival (OS) was longer with Atezolizumab than with docetaxel (16.0 vs 11.9 months; hazard ratio = 0.74; 95% CI: 0.49–1.13). Median OS was also longer with Atezolizumab in patients without a history of asymptomatic, treated brain metastases (13.2 vs 9.3 months; hazard ratio = 0.74; 95% CI: 0.63–0.88). Landmark analyses showed that patients with a history of asymptomatic, treated brain metastases had a lower probability of developing new symptomatic brain lesions with Atezolizumab vs docetaxel at 6–24 months. Patients without a history had a lower probability with Atezolizumab at 18–24+ months. Conclusion Atezolizumab had an acceptable neurologic safety profile, showed a trend toward an OS benefit, and led to a prolonged time to radiographic identification of new symptomatic brain lesions compared with docetaxel in patients who had a history of asymptomatic, treated brain metastases. Clinicaltrials.gov registration number: NCT02008227.

  • Atezolizumab treatment beyond progression in advanced nsclc results from the randomized phase iii oak study
    Journal of Thoracic Oncology, 2018
    Co-Authors: David R Gandara, Julien Mazieres, Achim Rittmeyer, Joachim Von Pawel, Richard Sullivan, Aslaug Helland, Ji Youn Han, Santiago Ponce Aix, Fabrice Barlesi, Toshio Kubo
    Abstract:

    Abstract Introduction Cancer immunotherapy may alter tumor biology such that treatment effects can extend beyond radiographic progression. In the randomized, phase III OAK study of Atezolizumab (anti–programmed death-ligand 1) versus docetaxel in advanced NSCLC, overall survival (OS) benefit with Atezolizumab was observed in the overall patient population, without improvement in objective response rate (ORR) or progression-free survival (PFS). We examine the benefit-risk of Atezolizumab treatment beyond progression (TBP). Methods Eight hundred fifty patients included in the OAK primary efficacy analysis were evaluated. Atezolizumab was continued until loss of clinical benefit. Docetaxel was administered until Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) disease progression (PD)/unacceptable toxicity; no crossover to Atezolizumab was allowed. ORR, PFS, post-PD OS, target lesion change, and safety were evaluated. Results In Atezolizumab-arm patients, ORR was 16% versus 14% and median PFS was 4.2 versus 2.8 months per immune-modified RECIST versus RECIST v1.1. The median post-PD OS was 12.7 months (95% confidence interval [CI]: 9.3–14.9) in 168 Atezolizumab-arm patients continuing TBP, 8.8 months (95% CI: 6.0–12.1) in 94 patients switching to nonprotocol therapy, and 2.2 months (95% CI: 1.9–3.4) in 70 patients receiving no further therapy. Of the Atezolizumab TBP patients, 7% achieved a post-progression response in target lesions and 49% had stable target lesions. Atezolizumab TBP was not associated with increased safety risks. Conclusions Within the limitations of this retrospective analysis, the post-PD efficacy and safety data from OAK are consistent with a positive benefit-risk profile of Atezolizumab TBP in patients performing well clinically at the time of PD.

  • updated efficacy analysis including secondary population results for oak a randomized phase iii study of Atezolizumab versus docetaxel in patients with previously treated advanced non small cell lung cancer
    Journal of Thoracic Oncology, 2018
    Co-Authors: Louis Fehrenbacher, Keunchil Park, Achim Rittmeyer, Toyoaki Hida, David R Gandara, Joachim Von Pawel, Ji Youn Han, Santiago Ponce Aix, Shirish M Gadgeel, Diego Cortinovis
    Abstract:

    Abstract Introduction The efficacy and safety of Atezolizumab versus the efficacy and safety of docetaxel as second- or third-line treatment in patients with advanced NSCLC in the primary (n = 850) and secondary (n = 1225) efficacy populations of the randomized phase III OAK study (respectively referred to as the intention-to-treat [ITT] 850 [ITT850] and ITT1225) at an updated data cutoff were assessed. Methods Patients received Atezolizumab, 1200 mg, or docetaxel, 75 mg/m2, intravenously every 3 weeks until loss of clinical benefit or disease progression, respectively. The primary end point was overall survival (OS) in the ITT population and programmed death-ligand 1–expressing subgroup. A sensitivity analysis was conducted to evaluate the impact of subsequent immunotherapy use in the docetaxel arm on the observed survival benefit with Atezolizumab. Results Atezolizumab demonstrated an OS benefit versus docetaxel in the updated ITT850 (hazard ratio [HR] = 0.75, 95% confidence interval: 0.64–0.89, p = 0.0006) and the ITT1225 (HR = 0.80, 95% confidence interval: 0.70–0.92, p = 0.0012) after minimum follow-up times of 26 and 21 months, respectively. Improved survival with Atezolizumab was observed across programmed death-ligand 1 and histological subgroups. In the immunotherapy sensitivity analysis, the relative OS benefit with Atezolizumab was slightly greater in the ITT850 (HR = 0.69) and ITT1225 (HR = 0.74) than the conventional OS estimate. Fewer patients receiving Atezolizumab experienced grade 3 or 4 treatment-related adverse events (14.9%) than did patients receiving docetaxel (42.4%); no grade 5 adverse events related to Atezolizumab were observed. Conclusions The results of the updated ITT850 and initial ITT1225 analyses were consistent with those of the primary efficacy analysis demonstrating survival benefit with Atezolizumab versus with docetaxel. Atezolizumab continued to demonstrate a favorable safety profile after longer treatment exposure and follow-up.

Luciana Molinero - One of the best experts on this subject based on the ideXlab platform.

  • safety and clinical activity of Atezolizumab plus bevacizumab in patients with ovarian cancer a phase ib study
    Clinical Cancer Research, 2020
    Co-Authors: John W Moroney, Johanna C Bendell, Jessica Spahn, John D Powderly, Christopher H Lieu, Gail S Eckhardt, Chingwei Chang, Luciana Molinero, Patrick Williams, Yvonne G Lin
    Abstract:

    Purpose: Atezolizumab has shown antitumor activity in patients with ovarian cancer. Dual blockade of programmed death-ligand 1 (PD-L1) and VEGF enhances anticancer immunity and augments antitumor activity in several cancers. The safety and efficacy of Atezolizumab plus bevacizumab were evaluated in patients with ovarian cancer. Patients and Methods: In this open-label, multicenter phase Ib study, patients with platinum-resistant ovarian cancer received intravenous Atezolizumab (1,200 mg) and bevacizumab (15 mg/kg) once every 3 weeks. The primary endpoint was safety; secondary endpoints included overall response rate (ORR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Exploratory biomarkers were also evaluated. Results: Twenty patients received treatment. Treatment-related adverse events occurred in 19 patients (95%); seven (35%) had grade 3/4 events. No grade 5 events occurred. The safety profile of Atezolizumab plus bevacizumab was consistent with those of the individual agents. Two patients (10%) discontinued treatment because of pneumonitis and small bowel obstruction. Three patients had partial responses of 11.3–18.9 months9 duration; the ORR was 15%. Eight patients (40%) had stable disease, hence the disease control rate was 55%. The median DOR was not reached (95% confidence interval, 11.3–not reached). Median PFS was 4.9 months (range, 1.2–20.2); median OS was 10.2 months (range, 1.2–26.6). No association was seen between treatment response and PD-L1 expression, tumor histology, or number of prior therapies. Conclusions: Atezolizumab plus bevacizumab led to durable responses and/or disease stabilization in some patients with platinum-resistant ovarian cancer; the safety profiles were consistent with those of each agent.

  • clinical activity and safety of Atezolizumab in a phase 1 study of patients with relapsed refractory small cell lung cancer
    Clinical Lung Cancer, 2020
    Co-Authors: Anne C Chiang, Scott N Gettinger, Marcin Kowanetz, Paul Conkling, Luciana Molinero, Lecia V Sequist, Jill Gilbert, D S Thompson, Paul J Marcoux, Carol Ohear
    Abstract:

    Abstract Background Programmed death-ligand 1 (PD-L1) protein is expressed in various cancers, including small-cell lung cancer (SCLC). Atezolizumab inhibits PD-L1 signaling, thus restoring tumor-specific T-cell immunity. Here, we report results from the first-in-human phase 1 PCD4989g study ( NCT01375842 ) of Atezolizumab, in a cohort of patients with relapsed/refractory SCLC. Patients and Methods Eligible patients with incurable or metastatic SCLC, which was advanced or recurrent since the last antitumor therapy, received Atezolizumab 15 mg/kg or 1200 mg intravenously every 3 weeks for 16 cycles or until loss of clinical benefit. The primary endpoint was safety. Efficacy and biomarkers of antitumor activity were also assessed. Results Seventeen patients were enrolled. Any-grade and grade ≥3 treatment-related adverse events (TRAEs) occurred in 11 (64.7%) and 5 (29.4%) patients, respectively. The most common any-grade TRAE was fatigue (4 patients [23.5%]). Partial response to Atezolizumab was achieved in 1 patient (5.9%) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1), and 3 (17.6%) per immune-related response criteria (irRC). Durations of response were 2.8 to > 45.7 months. Median investigator-assessed progression-free survival (PFS) per RECIST v1.1 and irRC was 1.5 (95% confidence interval [CI], 1.2-2.7) and 2.9 (95% CI, 1.2-6.1) months, respectively. Median overall survival (OS) was 5.9 months (95% CI, 4.3-12.6). Patients with high (≥ median expression) T-effector gene signature and PD-L1 mRNA expression appeared to show a trend toward improved PFS (per irRC) and OS. Conclusion Atezolizumab was generally well tolerated and exhibited antitumor activity in a small cohort of patients with relapsed/refractory SCLC.

  • Atezolizumab plus nab paclitaxel as first line treatment for unresectable locally advanced or metastatic triple negative breast cancer impassion130 updated efficacy results from a randomised double blind placebo controlled phase 3 trial
    Lancet Oncology, 2020
    Co-Authors: P Schmid, Andreas Schneeweiss, Luciana Molinero, Carlos H Barrios, Hiroji Iwata, Sylvia Adams, Hope S Rugo, V Dieras, Volkmar Henschel, Stephen Y Chui
    Abstract:

    Summary Background Immunotherapy in combination with chemotherapy has shown promising efficacy across many different tumour types. We report the prespecified second interim overall survival analysis of the phase 3 IMpassion130 study assessing the efficacy and safety of Atezolizumab plus nab-paclitaxel in patients with unresectable, locally advanced or metastatic triple-negative breast cancer. Methods In this randomised, placebo-controlled, double-blind, phase 3 trial, done in 246 academic centres and community oncology practices in 41 countries, patients aged 18 years or older, with previously untreated, histologically documented, locally advanced or metastatic triple-negative breast cancer, and Eastern Cooperative Oncology Group performance status of 0 or 1 were eligible. Patients were randomly assigned (1:1) using a permuted block method (block size of four) and an interactive voice–web response system. Randomisation was stratified by previous taxane use, liver metastases, and PD-L1 expression on tumour-infiltrating immune cells. Patients received Atezolizumab 840 mg or matching placebo intravenously on day 1 and day 15 of every 28-day cycle and nab-paclitaxel 100 mg/m2 of body surface area intravenously on days 1, 8, and 15 until progression or unacceptable toxicity. Investigators, patients, and the funder were masked to treatment assignment. Coprimary endpoints were investigator-assessed progression-free survival per Response Evaluation Criteria in Solid Tumors version 1.1 and overall survival, assessed in the intention-to-treat population and in patients with PD-L1 immune cell-positive tumours (tumours with ≥1% PD-L1 expression). The final progression-free survival results were previously reported at the first interim overall survival analysis. The prespecified statistical testing hierarchy meant that overall survival in the subgroup of PD-L1 immune cell-positive patients could only be formally tested if overall survival was significantly different between the treatment groups in the intention-to-treat population. This study is registered with ClinicalTrials.gov , NCT02425891 . Findings Between June 23, 2015, and May 24, 2017, 902 patients were enrolled, of whom 451 were randomly assigned to receive Atezolizumab plus nab-paclitaxel and 451 were assigned to receive placebo plus nab-paclitaxel (the intention-to-treat population). Six patients from each group did not receive treatment. At the second interim analysis (data cutoff Jan 2, 2019), median follow-up was 18·5 months (IQR 9·6–22·8) in the Atezolizumab group and 17·5 months (8·4–22·4) in the placebo group. Median overall survival in the intention-to-treat patients was 21·0 months (95% CI 19·0–22·6) with Atezolizumab and 18·7 months (16·9–20·3) with placebo (stratified hazard ratio [HR] 0·86, 95% CI 0·72–1·02, p=0·078). In the exploratory overall survival analysis in patients with PD-L1 immune cell-positive tumours, median overall survival was 25·0 months (95% CI 19·6–30·7) with Atezolizumab versus 18·0 months (13·6–20·1) with placebo (stratified HR 0·71, 0·54–0·94]). As of Sept 3, 2018 (the date up to which updated safety data were available), the most common grade 3–4 adverse events were neutropenia (38 [8%] of 453 patients in the Atezolizumab group vs 36 [8%] of 437 patients in the placebo group), peripheral neuropathy (25 [6%] vs 12 [3%]), decreased neutrophil count (22 [5%] vs 16 [4%]), and fatigue (17 [4%] vs 15 [3%]). Treatment-related deaths occurred in two ( Interpretation Consistent with the first interim analysis, this second interim overall survival analysis of IMpassion130 indicates no significant difference in overall survival between the treatment groups in the intention-to-treat population but suggests a clinically meaningful overall survival benefit with Atezolizumab plus nab-paclitaxel in patients with PD-L1 immune cell-positive disease. However, this positive result could not be formally tested due to the prespecified statistical testing hierarchy. For patients with PD-L1 immune cell-positive metastatic triple-negative breast cancer, Atezolizumab plus nab-paclitaxel is an important therapeutic option in a disease with high unmet need. Funding F Hoffmann-La Roche and Genentech.

  • safety clinical activity and biological correlates of response in patients with metastatic melanoma results from a phase i trial of Atezolizumab
    Clinical Cancer Research, 2019
    Co-Authors: Omid Hamid, David F Mcdermott, John D Powderly, Indrani Sarkar, Luciana Molinero, Christopher R Bolen, Jeffrey A Sosman, Eva Munozcouselo, Harriet M Kluger, Marcus Ballinger
    Abstract:

    Purpose: Atezolizumab [anti–programmed death-ligand 1 (PD-L1)] selectively targets PD-L1 to block its interaction with receptors programmed death 1 and B7.1, thereby reinvigorating antitumor T-cell activity. We evaluated the long-term safety and activity of Atezolizumab, along with biological correlates of clinical activity endpoints, in a cohort of patients with melanoma in an ongoing phase Ia study (NCT01375842). Patients and Methods: Patients with unresectable or metastatic melanoma were enrolled to receive Atezolizumab 0.1 to 20 mg/kg or ≥10 mg/kg every 3 weeks. Primary study objectives were safety and tolerability. Secondary objectives included investigator-assessed efficacy measures; pharmacodynamic and predictive biomarkers of antitumor activity were explored. Results: Forty-five patients were enrolled and were evaluable for safety. Most treatment-related adverse events (AE) were grade 1/2 (60%). Fatigue (44%), pruritus (20%), pyrexia (18%), and rash (18%) were the most common treatment-related AEs of any grade. No treatment-related deaths occurred. Overall response rate was 30% among 43 efficacy- evaluable patients, with a median duration of response of 62 months [95% CI, 35–not estimable (NE)]. Clinically meaningful long-term survival was observed, with a median overall survival of 23 months (95% CI, 9–66). Baseline biomarkers of tumor immunity [PD-L1 expression on immune cells, T effector (Teff), and antigen presentation gene signatures) and tumor mutational burden (TMB) were associated with improved response, progression-free survival, and overall survival. Conclusions: Atezolizumab was well tolerated, with durable responses and survival in patients with melanoma. PD-L1 expression, TMB, and Teff signatures may indicate improved benefit with Atezolizumab in these patients.

  • Atezolizumab plus nab paclitaxel in the treatment of metastatic triple negative breast cancer with 2 year survival follow up a phase 1b clinical trial
    JAMA Oncology, 2019
    Co-Authors: Sylvia Adams, Chingwei Chang, Wei Zhang, Jennifer R Diamond, Erika Paige Hamilton, Paula R Pohlmann, Sara M Tolaney, Koho Iizuka, Paul Foster, Luciana Molinero
    Abstract:

    Importance The humanized monoclonal antibody Atezolizumab targets programmed death-ligand 1 and has demonstrated durable single-agent activity in a subset of metastatic triple-negative breast cancers. To extend the observed activity, combinatorial approaches are being tested with standard cytotoxic chemotherapies known to induce immunogenic tumor cell death. Objective To examine the safety, tolerability, and preliminary clinical activity of Atezolizumab plus nab-paclitaxel in metastatic triple-negative breast cancers. Design, Setting, and Participants This phase 1b multicohort study enrolled 33 women with stage IV or locally recurrent triple-negative breast cancers and 0 to 2 lines of prior chemotherapy in the metastatic setting from December 8, 2014, to April 30, 2017, at 11 sites in the United States. The median follow-up was 24.4 months (95% CI, 22.1-28.8 months). Interventions Patients received concurrent intravenous Atezolizumab and intravenous nab-paclitaxel (minimum 4 cycles). Main Outcomes and Measures The primary end point was safety and tolerability. Secondary end points included best overall response rate by Response Evaluation Criteria in Solid Tumors, version 1.1; objective response rate; duration of response; disease control rate; progression-free survival; overall survival; and biomarker analyses. Results The 33 women had a median age of 55 years (range, 32-84 years) and received 1 or more doses of Atezolizumab. All patients (100%) experienced at least 1 treatment-related adverse event, 24 patients (73%) experienced grade 3/4 adverse events, and 7 patients (21%) had grade 3/4 adverse events of special interest. No deaths were related to study treatment. The objective response rate was 39.4% (95% CI, 22.9%-57.9%), and the median duration of response was 9.1 months (95% CI, 2.0-20.9 months). The disease control rate was 51.5% (95% CI, 33.5%-69.2%). Median progression-free survival and overall survival were 5.5 months (95% CI, 5.1-7.7 months) and 14.7 months (95% CI, 10.1-not estimable), respectively. Concurrent nab-paclitaxel neither significantly changed biomarkers of the tumor immune microenvironment (programmed death-ligand 1, tumor-infiltrating lymphocytes, CD8) nor impaired Atezolizumab systemic immune activation (expansion of proliferating CD8+ T cells, increase of CXCL10 chemokine). Conclusions and Relevance In this phase 1b trial for metastatic triple-negative breast cancers, the combination of Atezolizumab plus nab-paclitaxel had a manageable safety profile. Antitumor responses were observed, including in patients previously treated with a taxane. Trial Registration ClinicalTrials.gov identifier:NCT01633970

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  • clinical activity and safety of Atezolizumab in a phase 1 study of patients with relapsed refractory small cell lung cancer
    Clinical Lung Cancer, 2020
    Co-Authors: Anne C Chiang, Scott N Gettinger, Marcin Kowanetz, Paul Conkling, Luciana Molinero, Lecia V Sequist, Jill Gilbert, D S Thompson, Paul J Marcoux, Carol Ohear
    Abstract:

    Abstract Background Programmed death-ligand 1 (PD-L1) protein is expressed in various cancers, including small-cell lung cancer (SCLC). Atezolizumab inhibits PD-L1 signaling, thus restoring tumor-specific T-cell immunity. Here, we report results from the first-in-human phase 1 PCD4989g study ( NCT01375842 ) of Atezolizumab, in a cohort of patients with relapsed/refractory SCLC. Patients and Methods Eligible patients with incurable or metastatic SCLC, which was advanced or recurrent since the last antitumor therapy, received Atezolizumab 15 mg/kg or 1200 mg intravenously every 3 weeks for 16 cycles or until loss of clinical benefit. The primary endpoint was safety. Efficacy and biomarkers of antitumor activity were also assessed. Results Seventeen patients were enrolled. Any-grade and grade ≥3 treatment-related adverse events (TRAEs) occurred in 11 (64.7%) and 5 (29.4%) patients, respectively. The most common any-grade TRAE was fatigue (4 patients [23.5%]). Partial response to Atezolizumab was achieved in 1 patient (5.9%) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1), and 3 (17.6%) per immune-related response criteria (irRC). Durations of response were 2.8 to > 45.7 months. Median investigator-assessed progression-free survival (PFS) per RECIST v1.1 and irRC was 1.5 (95% confidence interval [CI], 1.2-2.7) and 2.9 (95% CI, 1.2-6.1) months, respectively. Median overall survival (OS) was 5.9 months (95% CI, 4.3-12.6). Patients with high (≥ median expression) T-effector gene signature and PD-L1 mRNA expression appeared to show a trend toward improved PFS (per irRC) and OS. Conclusion Atezolizumab was generally well tolerated and exhibited antitumor activity in a small cohort of patients with relapsed/refractory SCLC.

  • fir efficacy safety and biomarker analysis of a phase ii open label study of Atezolizumab in pd l1 selected patients with nsclc
    Journal of Thoracic Oncology, 2018
    Co-Authors: David R Spigel, Scott N Gettinger, Jamie E Chaft, Laura Quan Man Chow, P Schmid, Bo H Chao, L Dirix, Rodney J Hicks, Larry Leon, Jill Fredrickson
    Abstract:

    Abstract Introduction The FIR phase II study (NCT01846416) evaluated the efficacy and safety of anti–programmed death-ligand 1 (PD-L1) Atezolizumab in advanced NSCLC selected by tumor cell (TC) or tumor-infiltrating immune cell (IC) PD-L1 expression. Methods Patients with PD-L1 TC2/3 (PD-L1 staining on ≥5% of TC) or IC2/3 tumors (PD-L1 staining on ≥5% of IC; determined by SP142 PD-L1 immunohistochemistry assay) with paired fresh and archival histology samples were recruited into cohort 1 (chemotherapy-naive/>6 months between adjuvant chemotherapy and recurrence), cohort 2 (≥ second-line without brain metastases), or cohort 3 (≥ second-line with treated brain metastases). Patients received 1200 mg Atezolizumab on day 1 (21-day cycles). Primary endpoint was investigator-assessed modified Response Evaluation Criteria in Solid Tumors, objective response rate (Response Evaluation Criteria in Solid Tumors v1.1). Secondary endpoints were overall survival, progression-free survival, duration of response, and safety. Results Patients (N = 138) were enrolled (137 evaluable for response: cohort 1, n = 31; cohort 2, n = 93; and cohort 3, n = 13). Investigator-assessed objective response rate was 32%, 21%, and 23% for cohorts 1, 2, and 3, respectively. Treatment-related adverse events were reported in 81%, 67%, and 69% of patients, respectively, including grade 3–4 treatment-related adverse events in 16%, 19%, and 15%, respectively. Moreover, 88.6% (86 of 97) paired baseline tumor samples had Conclusions Atezolizumab monotherapy showed clinical activity in patients with NSCLC, including those with brain metastases; safety was consistent with previous trials. Atezolizumab has completed phase III monotherapy studies in second-line. Front-line trials are ongoing, confirming these favorable results.

  • long term survival follow up of Atezolizumab in combination with platinum based doublet chemotherapy in patients with advanced non small cell lung cancer
    European Journal of Cancer, 2018
    Co-Authors: Stephen V Liu, Scott N Gettinger, Ross D Camidge, Giuseppe Giaccone, Rebecca S Heist, Stephen F Hodi, Neal Ready, Wei Zhang, Jeffrey Wallin, Roel Funke
    Abstract:

    Abstract Background Before the availability of immunotherapy, chemotherapy was standard first-line therapy for non–small-cell lung cancer (NSCLC) lacking actionable gene alterations. Preclinical evidence suggests chemotherapy is immunomodulatory, supporting chemotherapy/immunotherapy combinations. Atezolizumab, anti-programmed death ligand-1 (PD-L1) antibody, blocks programmed cell death protein-1 and B7.1 interaction with PD-L1. GP28328 ( NCT01633970 ) assessed Atezolizumab with chemotherapy in multiple tumours; we report results for advanced, treatment-naive NSCLC. Methods Patients received Atezolizumab plus carboplatin with paclitaxel (Arm C: atezo/cb/pac), pemetrexed (Arm D: atezo/cb/pem, maintenance pemetrexed permitted), or nab-paclitaxel (Arm E: atezo/cb/nab-pac), four–six cycles, then Atezolizumab maintenance. Primary end-point was safety; secondary end-points were objective response rate (ORR), progression-free survival (PFS) and overall survival (OS). Results Seventy-six NSCLC patients were enrolled (n = 25, 25 and 26 for Arms C, D and E, respectively). Common treatment-related grade III/IV adverse events were neutropenia (36% atezo/cb/pac, 36% atezo/cb/pem, 42% atezo/cb/nab-pac) and anaemia (16% atezo/cb/pac, 16% atezo/cb/pem, 31% atezo/cb/nab-pac). Confirmed ORRs were 36% atezo/cb/pac, 68% atezo/cb/pem (one complete response [CR]) and 46% atezo/cb/nab-pac (four CRs). Median PFS was 7.1 months, (95% confidence interval [CI]: 4.2–8.3), 8.4 months (95% CI: 4.7–11) and 5.7 months (95% CI: 4.4–14.8), respectively. Median OS was 12.9 months (95% CI: 8.8–21.3), 18.9 months (95% CI: 9.9–27.4) and 17.0 months (95% CI: 12.7–not evaluable), respectively. Conclusion Atezolizumab with chemotherapy was well tolerated with encouraging efficacy, though the analysis was limited by small numbers. NSCLC chemotherapy combination studies are ongoing. ClinicalTrials.gov identifier NCT01633970 .

  • safety and clinical activity of Atezolizumab monotherapy in metastatic non small cell lung cancer final results from a phase i study
    European Journal of Cancer, 2018
    Co-Authors: Leora Horn, Scott N Gettinger, Michael Gordon, Lecia V Sequist, Roy S Herbst, Leena Gandhi, Enriqueta Felip, David R Spigel, Scott J Antonia, Ani Sarkis Balmanoukian
    Abstract:

    Abstract Introduction Atezolizumab, an anti-programmed death-ligand 1 (PD-L1) antibody, inhibits PD-L1:PD-1 and PD-L1:B7.1 interactions, restoring anticancer immunity. Here, we report final analyses from the non-small-cell lung cancer (NSCLC) cohort of the first Atezolizumab phase I study. Methods Patients with NSCLC received Atezolizumab 1–20 mg/kg or 1200 mg intravenously every 3 weeks. Baseline PD-L1 expression on tumour cells (TCs) and tumour-infiltrating immune cells (ICs) was assessed (VENTANA SP142 immunohistochemistry assay). Exploratory subgroup analyses investigated responses by baseline PD-L1 expression and oncogenic mutational status. Results Eighty-nine patients, 98% of whom had received previous systemic therapy, were evaluable for safety and antitumour activity. Atezolizumab was well tolerated, with grade III/IV treatment-related adverse events (TRAEs) observed in 10 patients (11%). All-grade TRAEs occurring in >10% of patients were fatigue, nausea and decreased appetite; grade III/IV TRAEs occurring in >2% of patients were fatigue, dyspnoea, hyponatremia and hypoxia. One patient died from treatment-unrelated pneumonia. Objective response rate (ORR) was 50% (95% confidence interval [CI], 28%–72%), 33% (20%–48%), 29% (18%–41%) and 11% (1%–35%) for the TC3 or IC3, TC2/3 or IC2/3, TC1/2/3 or IC1/2/3 and TC0 and IC0 subgroups, respectively. All-patient ORR was 23% (95% CI, 14%–33%). Median duration of response was 16.4 months (range, 7.2–53.4+). One-, 2-, and 3-year survival rates were 63% (95% CI, 53%–73%), 37% (26%–47%) and 28% (18%–38%), respectively. Conclusions Single-agent Atezolizumab was well tolerated with long-term clinical benefits, including durable responses and survival, in pretreated NSCLC. Improved responses and survival rates were seen with increasing baseline PD-L1 expression. ClinicalTrials.gov identifier NCT01375842 .

  • phase ii trial of Atezolizumab as first line or subsequent therapy for patients with programmed death ligand 1 selected advanced non small cell lung cancer birch
    Journal of Clinical Oncology, 2017
    Co-Authors: Solange Peters, Scott N Gettinger, Melissa Lynne Johnson, Pasi A Janne, Marina Chiara Garassino, Daniel C Christoph, Naiyer A Rizvi, Jamie E Chaft, Enric Carcereny Costa
    Abstract:

    PurposeBIRCH was designed to examine the efficacy of Atezolizumab, a humanized anti–programmed death-ligand 1 (PD-L1) monoclonal antibody, in advanced non–small-cell lung cancer (NSCLC) across line...

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  • cabozantinib in combination with Atezolizumab for advanced renal cell carcinoma results from the cosmic 021 study
    Journal of Clinical Oncology, 2021
    Co-Authors: Sumanta K Pal, Cristina Suarez, Bradley Alexander Mcgregor, Chekai Tsao, William Kevin Kelly, Ulka N Vaishampayan, Lance C Pagliaro, Benjamin L Maughan, Yohann Loriot
    Abstract:

    #Cabozantinib w #Atezolizumab has substantial activity in clear & non-clear #kidneycancer --> ongoing P3 trials

  • safety and clinical activity of Atezolizumab in patients with metastatic castration resistant prostate cancer a phase i study
    Clinical Cancer Research, 2021
    Co-Authors: Daniel P Petrylak, Paul Conkling, Yohann Loriot, David R Shaffer, Fadi Braiteh, John D Powderly, Lauren C Harshman, Jeanpierre Delord, Michael Gordon, Joseph Kim
    Abstract:

    Purpose: Atezolizumab [anti–programmed death-ligand 1 (anti-PD-L1)] is well tolerated and efficacious in multiple cancers, but has not been previously evaluated in metastatic castration-resistant prostate cancer (mCRPC). This study examined the safety, efficacy, and biomarkers of Atezolizumab monotherapy for mCRPC. Patients and Methods: This phase Ia, open-label, dose-escalation and dose-expansion study (PCD4989g) enrolled patients with mCRPC who had progressed on sipuleucel-T or enzalutamide. Atezolizumab was given intravenously every 3 weeks until confirmed disease progression or loss of clinical benefit. Prespecified endpoints included safety, efficacy, biomarker analyses, and radiographic assessments. Results: All 35 evaluable patients [median age, 68 years (range, 45–83 years)] received Atezolizumab after ≥1 prior line of therapy; 62.9% of patients had received ≥3 prior lines. Treatment-related adverse events occurred in 21 patients (60.0%), with no deaths. One patient had a confirmed partial response (PR) per RECIST 1.1, and 1 patient had a PR per immune-related response criteria. The confirmed 50% PSA response rate was 8.6% (3 patients). Median overall survival (OS) was 14.7 months [95% confidence interval (CI): 5.9–not evaluable], with a 1-year OS rate of 52.3% (95% CI: 34–70); 2-year OS was 35.9% (95% CI: 13–59). Median follow-up was 13.0 months (range, 1.2–28.1 months). Biomarker analyses showed that Atezolizumab activated immune responses; however, a composite biomarker failed to reveal consistent correlations with efficacy. Conclusions: Atezolizumab was generally well tolerated in patients with mCRPC, with a safety profile consistent with other tumor types. In heavily pretreated patients, Atezolizumab monotherapy demonstrated evidence of disease control; however, its limited efficacy suggests a combination approach may be needed.

  • partial response and stable disease correlate with positive outcomes in Atezolizumab treated patients with advanced urinary tract carcinoma
    European urology focus, 2020
    Co-Authors: Jens Bedke, Daniel P Petrylak, Jonathan E. Rosenberg, Axel S Merseburger, Yohann Loriot, Ignacio Duran, Daniel Castellano, Ernest Choy, Robert Dreicer, Jose Luis Perezgracia
    Abstract:

    Abstract Background The value of a complete response to immune checkpoint inhibitor treatment for urothelial cancer is well recognised, but less is known about long-term outcomes in patients with a partial response or the benefit of achieving disease stabilisation. Objective To determine clinical outcomes in patients with a partial response or stable disease on Atezolizumab therapy for advanced urinary tract carcinoma (UTC). Design, setting, and participants Data were extracted from three prospective trials (IMvigor210 cohort 2, SAUL, and IMvigor211) evaluating single-agent Atezolizumab therapy for platinum-pretreated advanced UTC. The analysis population included 604 Atezolizumab-treated and 208 chemotherapy-treated patients (229 achieving a partial response and 583 achieving stable disease). Intervention Atezolizumab 1200 mg every 3 wk until progression or unacceptable toxicity or single-agent chemotherapy for patients in the control arm of IMvigor211. Outcome measurements and statistical analysis Baseline characteristics, treatment exposure, overall survival, duration of disease control. Partial response and stable disease populations were analysed separately. Results and limitations The population of patients with a partial response included more patients with programmed cell death ligand 1 (PD-L1) expression on ≥5% of tumour-infiltrating immune cells than the stable disease population. The median time to best response was 2.1 mo across trials and treatments, regardless of the type of response. Atezolizumab-treated patients with a partial response had sustained disease control (median overall survival not reached); durations of disease control and overall survival were longer with Atezolizumab than with chemotherapy. In patients with stable disease, median overall survival was numerically longer with Atezolizumab (exceeding 1 yr) than with chemotherapy. Irrespective of treatment, durations of disease control and survival were shorter in patients with stable disease than in those achieving a partial response. These analyses are limited by their post hoc exploratory nature and relatively short follow-up. Conclusions Stable disease and partial response are meaningful clinical outcomes in Atezolizumab-treated patients with advanced UTC. Patient summary In this report, we looked at the outcomes in patients whose tumours responded to treatment to some extent, but the tumour did not disappear completely. We aimed to understand whether a modest response to treatment was associated with meaningful long-term outcomes for patients. We found that on average, life expectancy was >1 yr in patients whose disease was stabilised and even longer in those whose tumours showed some shrinkage in response to treatment.

  • safety and efficacy of Atezolizumab in patients with autoimmune disease subgroup analysis of the saul study in locally advanced metastatic urinary tract carcinoma
    European Journal of Cancer, 2020
    Co-Authors: Yohann Loriot, Daniel Castellano, Cora N Sternberg, Sjoukje F Oosting, Herlinde Dumez, Robert Huddart, Karina Vianna, Teresa Alonso Gordoa, Iwona Skoneczna, Andre P Fay
    Abstract:

    Abstract Aim Patients with pre-existing autoimmune disease (AID) are typically excluded from clinical trials of immune checkpoint inhibitors, and there are limited data on outcomes in this population. The single-arm international SAUL study of Atezolizumab enrolled a broader ‘real-world’ patient population. We present outcomes in patients with a history of AID. Methods Patients with locally advanced/metastatic urinary tract carcinoma received Atezolizumab 1200 mg every 3 weeks until loss of clinical benefit or unacceptable toxicity. The primary end-point was safety. Overall survival (OS) was a secondary end-point. Subgroup analyses of AID patients were prespecified. Results Thirty-five of 997 treated patients had AID at baseline, most commonly psoriasis (n = 15). Compared with non-AID patients, AID patients experienced numerically more adverse events (AEs) of special interest (46% versus 30%; grade ≥III 14% versus 6%) and treatment-related grade III/IV AEs (26% versus 12%), but without relevant increases in treatment-related deaths (0% versus 1%) or AEs necessitating treatment discontinuation (9% versus 6%). Pre-existing AID worsened in four patients (11%; two flares in two patients); three of the six flares resolved, one was resolving, and two were unresolved. Efficacy was similar in AID and non-AID patients (median OS, 8.2 versus 8.8 months, respectively; median progression-free survival, 4.4 versus 2.2 months; disease control rate, 51% versus 39%). Conclusions In 35 Atezolizumab-treated patients with pre-existing AID, incidences of special interest and treatment-related AEs appeared acceptable. AEs were manageable, rarely requiring Atezolizumab discontinuation. Treating these patients requires caution, but pre-existing AID does not preclude Atezolizumab therapy. Trial registration NCT02928406.

  • Atezolizumab mpdl3280a monotherapy for patients with metastatic urothelial cancer long term outcomes from a phase 1 study
    JAMA Oncology, 2018
    Co-Authors: Daniel P Petrylak, Thomas Powles, Yohann Loriot, Beiying Ding, Fadi Braiteh, Joseph Kim, Joaquim Bellmunt, Howard A Burris, Rafael Moralesbarrera, Constanze Kaiser
    Abstract:

    Importance Atezolizumab (anti–programmed death ligand 1) has demonstrated safety and activity in advanced and metastatic urothelial carcinoma, but its long-term clinical profile remains unknown. Objective To report long-term clinical outcomes with Atezolizumab therapy for patients with metastatic urothelial carcinoma. Design, Setting, and Participants Patients were enrolled in an expansion cohort of an ongoing, open-label, phase 1 study. Median follow-up was 37.8 months (range, >0.7 to 44.4 months). Enrollment occurred between March 2013 and August 2015 at US and European academic medical centers. Eligible patients had measurable disease per Response Evaluation Criteria in Solid Tumors version 1.1, Eastern Cooperative Oncology Group performance status 0 to 1, and a representative tumor sample. Programmed death ligand 1 expression on immune cells was assessed (VENTANA SP142 assay). Interventions Atezolizumab was given intravenously every 3 weeks until unacceptable toxic effects, protocol nonadherence, or loss of clinical benefit. Main Outcomes and Measures Primary outcome was safety. Secondary outcomes included objective response rate, duration of response, and progression-free survival. Response and overall survival were assessed in key baseline subgroups. Results Ninety-five patients were evaluable (72 [76%] male; median age, 66 years [range, 36-89 years]). Forty-five (47%) received Atezolizumab as third-line therapy or greater. Nine patients (9%) had a grade 3 to 4 treatment-related adverse event, mostly within the first treatment year; no serious related adverse events were observed thereafter. One patient (1%) discontinued treatment due to a related event. No treatment-related deaths occurred. Responses occurred in 26% (95% CI, 18%-36%) of patients. Median duration of response was 22.1 months (range, 2.8 to >41.0 months), and median progression-free survival was 2.7 months (95% CI, 1.4-4.3 months). Median overall survival was 10.1 months (95% CI, 7.3-17.0 months); 3-year OS rate was 27% (95% CI, 17%-36%). Response occurred in 40% (95% CI, 26%-55%; n = 40) and 11% (95% CI, 4%-25%; n = 44) of patients with programmed death ligand 1 expression of at least 5% tumor-infiltrating immune cells (IC2/3) or less than 5% (IC0/1), respectively. Median overall survival in patients with IC2/3 and IC0/1 was 14.6 months (95% CI, 9.0 months to not estimable) and 7.6 months (95% CI, 4.7 to 13.9 months), respectively. Conclusions and Relevance Atezolizumab remained well tolerated and provided durable clinical benefit to a heavily pretreated metastatic urothelial carcinoma population in this long-term study. Trial Registration clinicaltrials.gov Identifier:NCT01375842