IMpassion130: the checkpoint inhibitor promotes defense of the immune system against cancer

Our immune system is not always successful in fighting cancer. Some cancer cells manage to "hide" and escape the immune system of the body. For this, they manipulate some switching points of our immune system, called control points, and thus take precedence over the body's defense response. For example, different types of tumors produce the protein "Death Ligand programmed 1 ", short PD-L1. If this protein interacts with PD-1 and B7.1 receptors on T cells, they will be turned off. This means that: PD-L1 acts as a kind of stop sign for our immune system and that cancer cells can multiply unhindered.

In addition to PD-L1, cancer cells use many other mechanisms to delay the immune response of the immune system. As a result, various immunotherapeutic approaches are currently undergoing research and development. In this context, it could be particularly promising to use regulatory therapies to regulate directly at several points in the cycle of cancerous immune cells.

Atezolizumab – The checkpoint inhibitor supports the body in the fight against cancer (1-14)

Tecentriq (atezolizumab) is a checkpoint inhibitor that restores the defense of the immune system against cancer cells, thus helping the body to fight against cancer. The humanized monoclonal antibody is directed against the PD-L1 protein, which can be produced by both cancer cells and by the infiltrating immune cells in the tumor. If this protein interacts with both B7.1 or PD-1 receptors located on T cells, the T cells or the body's immune response against the tumor are turned off. By binding to PD-L1, Tecentriq inhibits interaction with B7.1 and PD-1. Double signal blocking, which distinguishes Tecentriq from other substances blocking only one of the two signaling pathways, enhances the immune response in the tumor microenvironment and lymph node, while preserving non-tumor tissues.

The aim of the combination of Tecentriq, Avastin and chemotherapy is to create an immunogenic environment in the tumor in order to make the most of the potential of immunotherapy. Thus, treatment with Avastin inhibits VEGF-induced immunosuppression. That's okay. at. favored the infiltration of immune cells into the tumor tissue and made the tumor immunologically "hot". In parallel, Tecentriq supports the activation of T cells and restores the body's anti-tumor immunity. Chemotherapy also promotes the release of tumor antigens and intensifies the immune response.

Source of graphics: Roche Pharma AG (22)

IMpassion130: Triple negative metastatic breast cancer – success with atezolizumab

At probably the largest US congress on cancer 2919 New data on cancer immunotherapy with atezolizumab, an inhibitor of PD-L1, was also of particular interest. The focus has been on patients with advanced or metastatic triple-negative (mTNBC) breast cancer and non-small-cell lung cancer (NSCLC) with liver metastases. Data from the second interim analysis of the IMpassion130 study showed that women with mTNBC positive for PD-L1 IC survived an average of seven months longer when they received a combination of Tecentriq and chemotherapy compared Patients treated with chemotherapy – mortality risk decreased by 29%. (15) Subgroup analysis of crucial liver metastases in NSCLC in the IMpower150 Phase III pivotal study showed a 48% reduction in all-cause mortality with the addition of Tecentriq to the Sandler regimen well established (16).

Diet without chemotherapy

For patients with CLL, the chemotherapy regimen without obinutuzumab chemotherapy, glycerized anti-CD20 antibody, associated with venetoclax BCL-2 inhibitor targeted demonstrated an unprecedented rate of MRD negativity. The authors of the CLL14 study therefore expect even more effective treatment in the long term.

Extended overall survival confirmed

Data from the second interim analysis presented at this year's ASCO confirm the previously observed clinically relevant trend for extended overall survival (OS) in patients with positive PD-L1 expression in ≥ 1% of immune cells. infiltrants in the tumor (CI). Study participants with Tecentriq used chemotherapy seven months later (OS: 25.0 versus 18.0 months in the comparison group). This corresponds to a clinically significant reduction in the risk of death by 29% (HR: 0.71, 95% CI: 0.54 – 0.93). More than half of PD-L1 IC patients treated with Tecentriq were still alive after two years (51% versus 37% in the comparator group).

The first interim analysis of the study had already caused a sensation, as it showed a significant advantage in terms of progression-free survival for patients in the intention-to-treat population (PFS: 7.16 vs. 5.49 months, HR 0.80, 95% CI 0.69-0.92, p = 0.0025). (17) In patients with a positive PD-L1 IC status, the risk of progression was significantly reduced by 38% (PFS: 7.46 vs 4.96 months in the placebo group, HR: 0.62: 95% CI 0.49-0.78, p <0.0001). The first-line combination was safe and well tolerated. The adverse events observed (grades 3 to 4) corresponded to the safety profiles already known from the one-offs.

These results are all the more remarkable as triple-negative breast cancer at a metastatic or locally advanced stage is considered an aggressive tumor form with poor prognosis and difficult to treat. Until now, no targeted therapy has demonstrated the benefits of overall survival. The IMpassion130 study provides the first positive phase III data on cancer immunotherapy in the treatment of mTNBC, signaling significant therapeutic advances for affected patients. In March 2019, Tecentriq was approved in the United States in combination with nab-paclitaxel as the first immunotherapy for triple negative breast cancer.

NSCLC with liver metastases: mortality risk almost halved

Tecentriq has been approved in the EU since March 2019 for the first-line treatment of locally advanced and metastatic NSCLC with non-squamous epithelial histology (18). It is based on the results of the IMpower150 randomized, open-label phase III study. A peculiarity was that the study had been prospectively stratified on the group of patients with liver metastases, considered a marker of poor prognosis. For the first time, this combination of patients combined with an anti-cancer immunotherapeutic agent demonstrated a benefit in terms of ILI: (19,20) The risk of death was reduced by 48% during treatment with Tecentriq, Avastin® (bevacizumab) and by chemotherapy (OS: 13.3 vs 9.4 months, HR = 0.52, 95% CI: 0.33-0.82).

The data presented at ASCO also characterize the group of 162 patients with liver metastases (followed by at least 20 months) (16). These patients had median branching at three different sites and, initially, a median largest diameter (SLD) of 109 mm target lesions (range: 10-249 mm). The results show that the combination of Tecentriq in combination with Avastin and carboplatin / paclitaxel, multiplied by four, showed a very high response rate of 60.8% in these high-risk patients and significantly prolonged the median progression-free survival. more than SG (MPF: 8.2 vs 5, 4 months, HR 0.41, 95% CI: 0.26-0.62). The supraadditive effect of Tecentriq and Avastin with chemotherapy also resulted in a median long response of 10.7 months with a high response (mDOR 10.7 vs. 4.6 months, HR 0.39, 95% CI: 0.21). 0.73), so that most patients have benefited from the therapy for a long time (16). Patients also received maintenance treatment without chemotherapy from Tecentriq and Avastin. The first-line combination with Tecentriq was safe and sound without any new security signals.

LLC: A Time-Limited Schedule Without Chemotherapy Promotes Long-Term Efficacy

Patients with chronic lymphocytic leukemia are generally older and are therefore more likely to have comorbidities. Therefore, modern therapies aim for diets as gentle as possible. The CLL14 study investigated the combination of the anti-CD20 antibody Gazyvaro (obinutuzumab, G) and the targeted BCL-2 inhibitor venclyxto (Venetoclax, Ven) as a first-line treatment in this patient population. It was compared to the combination of Gazyvaro and chlorambucil (G-Clb).

G-Ven achieved better overall (OR) and complete (CR) responses than G-Clb (OR: 85 vs. 71%, p = 0.0007, CR: 50 vs. 23%, p <0 0.001). In addition, G-ven showed a progression-free survival / SSP significantly prolonged (HR: 0.35, CI: 0.23, 0.53, p <0.0001) after a median observation period of 28 months, although the median PFS is still absent. The arm was reached. In addition, as emphasized by the authors of the German CLL study group, the much higher rate of patients without molecular indication of residual disease (MRD-negative) ** indicates an effective long-term treatment with G-Ven ( 76% versus 35% in the peripheral blood). 57 vs. 17% in the bone marrow). This therapy thus achieved the highest rate of MRD negativity of all previous, prospective and randomized trials. The severity and frequency of adverse events were similar in both arms (21).

* Venclyxto is a registered trademark of Abbvie
** Measurement 3 months after the end of ASO-PCR, sensitivity <10-4


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