Atezolizumab anti-drug antibodies worsen survival in hepatocellular carcinoma

28th October 2022

Atezolizumab anti-drug antibodies are associated with a both a worse progression-free and overall survival in hepatocellular carcinoma

The development of atezolizumab anti-drug antibodies in patients with hepatocellular carcinoma results in both a worse progression-free and overall survival according to the findings of a prospective cohort study by Korean researchers.

Hepatocellular carcinoma (HCC) is the most common form of liver cancer and globally, in 2020 there were an estimated 900,000 new cases and a similar number (830,180) of deaths. Early stages of the disease can are curable by resection, liver transplantation, or ablation although more than 80% of patients with HCC present for treatment at an unresectable stage and research suggests that in patients with unresectable hepatocellular carcinoma, atezolizumab combined with bevacizumab has proven to be an effective therapy. Nevertheless, a recognised problem with immune checkpoint inhibitors, is the development of anti-drug antibodies (ADAs) which can cause a decrease in the amount of drug available, resulting in some cases in decreased anti-tumour activity and a consequent impact on clinical outcomes. According to an analysis of data from ≈ 4500 patients from 12 clinical trials across different tumour types, treatment settings, and dosing regimens, atezolizumab anti-drug antibodies developed in approximately 30% of patients although this ranged from 13-54%. Fortunately, however, the authors also reported that ADAs only increased atezolizumab clearance by 9%. Nevertheless, much less is known about the impact of atezolizumab anti-drug antibodies outside of the clinical trial setting. As a result, in the present study, the Korean researchers examined the clinical and immunological association of highly elevated ADAs, 3 weeks after starting atezolizumab and bevacizumab therapy in patients treated for advanced HCC.

The researchers conducted their study in two phases: an initial discovery cohort who were treated at a single centre and a validation cohort from 4 other centres. Patients were all at least 20 years of age with locally advanced or unresectable HCC and who had received no prior therapy. Blood samples were collected before the first administration of atezolizumab and which served as a baseline measurement and then again before the second dose (C2D1), three weeks later. The researchers assessed the atezolizumab ADA positivity rate and treatment outcomes.

Atezolizumab anti-drug antibodies and treatment outcomes

A total of 132 patients with a median age of 61 years (84.1% male) were included with 50 in the discovery and 82 the validation cohort. The median follow-up time was 19.4 and 13.4 months in the discovery and validation cohorts respectively.

When compared to baseline levels, atezolizumab ADAs were elevated at C2D1 (median values 45.95 vs 0 ng/ml, p < 0.001). Not all patients developed ADAs although this developed to a greater extent in those with progressive disease.

When the researchers examined the clinical outcomes according to ADA status at C2D1, those with the highest atezolizumab ADAs had a lower response. For example, those with high ADA levels at C2D1 in the validation cohort, had a worse progression-free survival (hazard ratio, HR = 2.52, 95% CI 1.27 – 5.01, p = 0.006) and a worse overall survival (HR = 5.81, 95% CI 2.70 – 12.50, p = 0.001) compared to patients with low ADA levels. In fact, those with higher ADAs had a reduced serum atezolizumab levels as well as other impaired markers e.g., CD8-positive T-cell proliferation.

The authors concluded that highly elevated atezolizumab ADAs may be associated with poor clinical outcomes in patients with advanced HCC by reducing atezolizumab exposure and an attenuated anti-cancer drug efficacy.

Citation
Kim C et al. Association of High Levels of Antidrug Antibodies Against Atezolizumab With Clinical Outcomes and T-Cell Responses in Patients With Hepatocellular Carcinoma JAMA Oncol 2022

Atezolizumab and nivolumab prolong overall survival compared with docetaxel in NSCLC

19th November 2021

Atezolizumab and nivolumab both produce similar, higher improvements in overall survival compared to docetaxel in NSCLC patients

Atezolizumab and nivolumab have been found to prolong overall survival (OS) in patients with advanced non-small cell lung cancer (NSCLC) cancer say researchers from Hoffmann-La Roche, Basel, Switzerland. NSCLC accounts for 85% of all lung cancers although nearly 40% of patients are diagnosed at stage 4, which has a poor prognosis, warranting systemic therapy. Treatment of NSCLC can be achieved with platinum-based chemotherapy although many patients relapse and in such cases, mono-therapy with the chemotherapeutic agent, docetaxel, has been found to be effective.

In recent years it has been discovered that developing tumours are capable of evading the immune system by avoiding checkpoint signals designed to prevent uncontrolled activation of T lymphocytes. Monoclonal antibodies including nivolumab and atezolizumab, work to either inhibit checkpoint PD-1 surface receptors (nivolumab) or its ligand, PD-L1 (atezolizumab) thereby blocking these receptors and signals, enabling the immune system to combat the tumour. Although both monoclonal antibodies are approved for use in NSCLC, there is a lack of head-to-head studies comparing these two agents even in comparison to docetaxel.

For the present study, researchers examined real-world studies contained within the US nationwide electronic health record, in which patients with advanced NSCLC and prior platinum-based therapy, who had been started on either atezolizumab, nivolumab or docetaxel. They included adults (18 years and over) diagnosed with locally advanced and/or metastatic NSCLC, none of whom had been previously treated with one of the three agents. The team also only included patients with at least 6 months of follow-up data and set the primary endpoint as overall survival.

Findings

In total, 3336 patients were included in the analysis with 206 receiving atezolizumab, 500 docetaxel and 2630 nivolumab. Patients in the atezolizumab and nivolumab groups were of a similar mean age, 68.3 and 67.3 years respectively while those in the docetaxel group were slightly younger with a mean age of 65.6 years.

Compared to docetaxel, use of atezolizumab was associated with a significantly longer survival (adjusted hazard ratio, aHR = 0.79, 95% CI 0.64 – 0.97, p = 0.02) even among those with different cancer stages. In contrast, the adjusted hazard ratio for atezolizumab compared with nivolumab was 1.07 (95% CI 0.89 – 1.28, p = 0.47) and this did not differ between patients at different cancer stages. However, the authors recognised that their analysis may not have been sufficiently powered to detect a difference between these two treatments.

The authors concluded that their real-world data suggested that atezolizumab and nivolumab produced a longer overall survival than docetaxel among those who had failed to respond to platinum-based chemotherapy.

Citation

Ramagopalan S et al. Comparative Effectiveness of Atezolizumab, Nivolumab, and Docetaxel in Patients With Previously Treated Non–Small Cell Lung Cancer. JAMA Netw Open 2021

NICE recommends atezolizumab for metastatic urothelial cancer

5th October 2021

Atezolizumab has been approved by NICE for untreated advanced or metastatic urothelial cancer in adults where PD-L1 levels exceed 5%.

Urothelial carcinoma is the most common form of bladder cancer, accounting for more than 90% of all bladder cancers in the UK. The main symptom is haematuria in around 80% of cases although other symptoms include increased frequency of urination, pain or a burning sensation when passing urine and weight loss. According to Cancer Research UK, between 2016 and 2018, there were approximately 10,300 new cases of bladder cancer in the UK every year.

Atezolizumab is licensed as mono-therapy for the treatment of adult patients with locally advanced or metastatic urothelial carcinoma, either after prior platinum-containing chemotherapy, or in patients who are cisplatin ineligible and whose tumours have a PD-L1 expression ≥ 5%. The checkpoint protein, programmed death-ligand 1 (PD-L1) which is present on the surface of tumour cells, normally binds to programmed death-1 (PD-1) on the surface of T-cells and prevents the T-cells from killing the tumour cells. Atezolizumab is a checkpoint inhibitor that prevents the binding of PD-L1 to PD-1 and thus restores tumour T-cell activity.

Clinical efficacy

Patients with advanced and metastatic urothelial carcinoma have a poor prognosis with 5-year survival rates as low as 6%. The standard treatment is cisplatin-based chemotherapy however, in a 2017 study 119 previously untreated patients who were cisplatin ineligible, were given atezolizumab at a dose of 1200 mg every 3 weeks until progression. The primary outcome was an objective response and which occurred in 23% of patients and a complete response was seen in 9%. The approval by NICE was based on more data, which came from IMvigor130, a multi-centre, Phase III trial, in which 1213 patients were randomised to either atezolizumab plus platinum-based chemotherapy, atezolizumab mono-therapy or placebo plus platinum-based chemotherapy. In its appraisal, NICE only considered a subgroup of 93 people, with untreated PD-L1-positive (tumour expression of 5% or more) locally advanced or metastatic urothelial cancer and who were ineligible to be treated with cisplatin.

The median overall survival was 18.6 months for atezolizumab and 10.0 months for platinum-based chemotherapy. The stratified hazard ratio was 0.50 (95% CI 0.29 to 0.87, p=0.0125), indicating that treatment with atezolizumab was associated with a significant improvement in overall survival compared with platinum-based chemotherapy. Moreover, the median progression-free survival for atezolizumab was 6.4 months compared with 6.0 months for platinum-based chemotherapy.

In its final appraisal document, NICE stated that “atezolizumab meets NICE’s criteria to be considered a life-extending treatment at the end of life. The cost-effectiveness estimates are likely to be within what NICE considers an acceptable use of NHS resources. So atezolizumab is recommended.“

Source. NICE 2021