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Antibody-Based Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Atezolizumab (TecentriqTM) is a PD-L1-targeted antibody developed by Genentech/Roche. In 2016 the FDA granted accelerated approval for locally advanced or metastatic urothelial cancer after the failure of cisplatin-based chemotherapy. However, the confirmatory trial (to convert the accelerated approval into a full approval) failed to achieve its primary endpoint of overall survival. In 2018, the FDA altered the indication for atezolizumab to a first-line treatment for metastatic bladder cancer in patients not able to receive cisplatin-based chemotherapy but who have high levels of PD-L1. Also, in 2016 it was approved by the FDA for the treatment of metastatic non-small-cell lung cancer (NSCLC) with disease progression following platinum-based chemotherapy. In 2019, it was also approved for the treatment of patients with triple-negative breast cancer. One stipulation of these approvals is that patients with genomic EGFR or ALK mutations taking FDA-approved therapies for these mutations must show disease progression prior to receiving atezolizumab.
Overview of Therapeutic Biomarkers in Cancer
Published in Sherry X. Yang, Janet E. Dancey, Handbook of Therapeutic Biomarkers in Cancer, 2021
Sherry X. Yang, Janet E. Dancey Treatment
Pembrolizumab is approved as first-line single-agent treatment in the context of PD-L1 expression in metastatic NSCLC with no EGFR and ALK genomic aberrations, in which the tumors have high PD-L1 expression with tumor proportion score (TPS) of >50%. The single-agent therapy is also indicated for PD-L1-positive NSCLC patients (TPS > 1%) after progression on platinum-based chemotherapy. Very recently, KEYNOTE-42 clinical trial demonstrated that pembrolizumab improved OS in patients with previously untreated advanced NSCLC without EGFR or ALK mutations and PD-L1 TPS >1%, compared with platinum-based chemotherapy [64]. The US FDA approved atezolizumab with nab-paclitaxel to treat PD-L1-positive metastatic triple-negative breast cancer (TNBC) in 2019. Atezolizumab with nab-paclitaxel is a standard of care in the first-line setting for PD-L1-positive metastatic TNBC [65].
Real-World Evidence from Population-Based Cancer Registry Data
Published in Harry Yang, Binbing Yu, Real-World Evidence in Drug Development and Evaluation, 2021
IMPower 133 is a double-blind, placebo-controlled, phase 3 trial to evaluate atezolizumab plus carboplatin (CP) and etoposide (ET) in patients with extensive-stage SCLC who had not previously received treatment [45]. Patients are randomly assigned in a 1:1 ratio to receive CP and ET with either atezolizumab or placebo for four 21-day cycles (induction phase), followed by a maintenance phase during which they receive either atezolizumab or placebo (according to the previous random assignment) until they had unacceptable toxic effects, disease progression according to Response Evaluation Criteria in Solid Tumors version 1.1, or no additional clinical benefit. The two primary endpoints are investigator-assessed PFS and OS in the intention-to-treat population. A total of 201 patients are randomly assigned to the atezolizumab group, and 202 patients to the placebo group. At a median follow-up of 13.9 months, the median OS is 12.3 months in the atezolizumab group and 10.3 months in the placebo group. The hazard ratio of death is 0.70 with 95% CI (0.54, 0.91) and p-value = 0.007. Based on the published OS curves [45], the OS data are reconstructed using the algorithm described by Guyot et al. [47]. The Kaplan-Meier curves of the placebo and atezolumab groups for the reconstructed IMPower 133 OS data are shown in Figure 3.5. We see that the Kaplan-Meier curves begin to diverge after month 5.
A drug safety evaluation of atezolizumab in locally advanced or metastatic urothelial carcinoma
Published in Expert Opinion on Drug Safety, 2020
Panagiota Economopoulou, Ioannis Kotsantis, Aristotelis Bamias
In conclusion, atezolizumab is a novel anti-PD-L1 monoclonal antibody that is currently approved for locally advanced and metastatic urothelial cancer as second- or first-line treatment in cisplatin-ineligible patients with high PD-L1 expression. Atezolizumab is well tolerated and common AEs include fatigue, decreased appetite, nausea, diarrhea, pyrexia, pruritus, and rash. Randomized trials have shown that atezolizumab has a more favorable toxicity profile than chemotherapy, while these two major therapeutic options for advanced UC can be safely combined. Atezolizumab is expected to move forward and includes additional indications for UC. The results of the phase II ABACUS trial in the neoadjuvant setting are very promising with acceptable safety profile [26]. In addition, the phase III IMVIGOR130 trial confirmed that the combination of atezolizumab and chemotherapy is feasible and offers a PFS benefit. However, the combination failed to show a statistically significant survival benefit as compared to chemotherapy [17].
Atezolizumab for the treatment of renal cell carcinoma
Published in Expert Opinion on Biological Therapy, 2020
Mathilde Lafon, Charlotte Domblides, Amaury Daste, Baptiste Sionneau, Alain Ravaud, Jean-Christophe Bernhard, Marine Gross-Goupil
Due to the observed efficacy in mRCC patients, the possibility of evaluating ICIs alone or in combination at an earlier disease stage has been suggested. Since patients who receive surgery may be at a high risk of recurrence, adjuvant trials were performed [31]. However, following disappointing results from adjuvant trials of antiangiogenic agents, ICI are now being evaluated in phase III trials. For example, atezolizumab is being tested in a pivotal multicenter, randomized, placebo-controlled, double-blind phase III study of 778 patients with RCC at high risk of developing metastasis following nephrectomy (NCT03024996) [32]. The high risk population was defined according to nuclear grade, pathologic stage, and the presence of metastatic lymph nodes (T2N0M0 and Führman grade 4, T3aN0M0 and Führman grade 4 or higher, T3b/c or T4 and any Führman grade, and any T stage or Führman grade with lymph node-positive disease). One unique aspect of this trial compared with others is the inclusion of patients with complete resection of limited metachronous or synchronous metastasis. Atezolizumab is administered every 3 weeks at the standard dose of 1200 mg for 16 cycles or 1 year. The primary outcome, evaluated by an independent review committee, is disease-free survival. The study is closed for recruitment, and the results are pending.
Atezolizumab for the treatment of breast cancer
Published in Expert Review of Anticancer Therapy, 2020
Sangeetha M. Reddy, Emma Carroll, Rita Nanda
Atezolizumab is an Fc-engineered, non-glycosylated, humanized, monoclonal immunoglobulin-G1 (IgG1) antibody that binds to programmed cell death ligand-1 (PD-L1) and blocks its interactions with the programmed cell death-1 (PD-1) and B7.1 (or CD80) receptors [27,28]. PD-L1 may be expressed on tumor cells and/or tumor-infiltrating immune cells. When PD-L1 interacts with PD-1 and B7.1 receptors on T-cells and antigen-presenting cells, suppression of cytotoxic T-cell activity, T-cell proliferation, and cytokine production occurs, inhibiting the anti-tumor immune response in the tumor microenvironment. By blocking the PD-L1/PD-1 interaction, atezolizumab enhances the anti-tumor immune response. Importantly, atezolizumab is FcγR-binding deficient due to an asparagine-to-alanine substitution at position 298 of the CH2 domains of each heavy chain, which inhibits its binding to Fc receptors on phagocytes, and prevents antibody-dependant cellular cytotoxicity (ADCC). Eliminating the potential for ADCC is an important consideration as PD-L1 is present on T-cells and other leukocytes, and ADCC could result in depletion of tumor-specific T-cells [27,28].