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25th October 2021
Nivolumab represents a treatment that might be beneficial for patients with malignant mesothelioma was the conclusion of a study by a team from the Mesothelioma Research Programme, University of Leicester, Leicester, UK. Malignant mesothelioma is a cancer which mainly affects the tissue that cover each lung (pleural mesothelioma) and leads to around 2,700 cases each year in the UK. In the majority of cases, pleural mesothelioma is caused by exposure to asbestos although it can take 10 to 50 years to emerge after exposure, which helps explain why over half of cases occur in those aged over 75. Prognosis for mesothelioma cancer is poor, with many patients living less than one year and it has 5-year overall survival of only 5%.
Malignant mesotheliomas express the protein PD-L1 which is the ligand for PD-1 and the binding of the two on the surface of T cells inactivates the cell. Nivolumab is a PD-1 immune checkpoint inhibitor which blocks this PD-1 to PD-L1 binding and has been shown to be a promising therapy in malignant mesothelioma. However, to date, there have been no randomised, double-blind trials of mono-therapy with checkpoint inhibitors in patients with relapsed mesothelioma after platinum-based chemotherapy. As a result, the mesothelioma research team established the CheckpOiNt Blockage For the Inhibition of Relapsed Mesothelioma (CONFIRM) trial, to evaluate the efficacy of nivolumab on overall survival and progression-free survival in those with progressive disease after a single course of platinum-based chemotherapy.
Included patients were adults (> 18 years of age) with histologically confirmed pleural or peritoneal mesothelioma and who had radiological evidence of disease progression. Participants were randomised 2:1 (nivolumab:placebo) and given nivolumab at a dose of 240 mg every 2 weeks until disease progression, withdrawal from treatment or for a maximum of 12 months, depending on which came first. The co-primary endpoints were progression-free survival and overall survival.
A total of 332 participants with malignant mesothelioma were included and randomised to nivolumab or placebo. The median age of participants allocated to nivolumab as 70 years (76% female) and the median duration of follow-up was 11.6 months.
The median progression-free survival was 3 months in the nivolumab and 1.8 months in the placebo groups (hazard ratio, HR = 0.67, 95% CI 0.53 – 0.85, p = 0.0012). The proportion of participants with progression-free survival at 1 year was 14.2% and 7.2% in the nivolumab and placebo groups respectively.
The median overall survival was 10.2 vs 6.9 months (nivolumab vs placebo), giving a hazard ratio of 0.69 (95% CI 0.52 – 0.91). The proportion of patients surviving 1 year one year was also higher in the nivolumab group (43.4% vs 30.1%, nivolumab vs placebo).
Serious adverse events occurred in 41% of patients in the nivolumab group and 44% of patients in the placebo group and there were no treatment-related deaths in either group.
The authors reported that they will continue to monitor patients and that a final and updated analysis will be published in due course.
27th September 2021
Around a quarter of metastatic breast cancers over-express human epidermal growth factor receptor 2 (HER2) and which is associated with a worse prognosis. Addition of trastuzumab to chemotherapy in early stage HERS2 positive metastatic breast cancer (MBC), reduces both recurrence and breast cancer mortality by a third. The conjugate T-Dxd (brand name Enhertu) consists of trastuzumab covalently bonded to deruxtecan, which is a topoisomerase I inhibitor and T-Dxd is already approved for the use in HER-2 positive unresectable or MBC. Furthermore, in the UK, NICE has also recommended the use of T-Dxd as option for treating HER2‑positive unresectable or MBC in adults after 2 or more anti‑HER2 therapies.
Results presented at the 2021 European Society for Medical Oncology (ESMO) conference relate to DESTINY-BREAST03, an open-label, phase 3 trial, in which T-Dxd (n = 261) was compared against trastuzumab emtansine (n = 263) in patients with MBC previously treated with trastuzumab and taxane. DESTINY-BREAST03 follows on from two earlier trials, DESTINY-BREAST01 and DESTINY-BREAST02. DESTINY-BREAST01, was published in 2020 and evaluated T-Dxd in adults with pathologically documented HER2-positive MBC who had received previous treatment with trastuzumab emtansine. This was followed by DESTINY-BREAST02, in which T-Dxd was compared against a treatment of the investigator’s Choice for HER2-positive, unresectable and/or metastatic breast cancer, in patients again previously treated with trastuzumab emtansine.
The latest results for DESTINY-BREAST03 and presented at the ESMO are a pre-specified interim analysis in which the primary endpoint was progression-free survival (PFS) in those with MBC. The analysis shows that T-Dxd demonstrated a 72% reduction in the risk of disease progression or death, compared to trastuzumab emtansine (hazard ratio, HR = 0.28, 95% CI 0.22-0.37, p < 0.0001). Furthermore, there was a strong trend towards improved overall survival with T-Dxd (HR = 0.56, 95% CI 0.36 – 0.86) and a higher proportion of patients assigned to T-Dxd were alive after 12 compared to trastuzumab emtansine (94.1% versus 85.9%). However, the median overall survival rate is not yet estimable but given the differences observed to date, researchers are hopeful that the difference will be significant once the study is completed.
Dr Aditya Bardia of Massachusetts General Hospital, Harvard Medical School, MA, USA, said that the efficacy results presented at the ESMO are quite compelling. He added that “it is wonderful to see such significant improvement in survival for patients with HER2-positive metastatic breast cancer, and the results will likely change practice, establishing T-DXd as the preferred therapy in the second-line setting.”
Lung cancer is extremely common and figures from 2018, suggest a global incidence of 17 million cases and 9.6 million associated deaths. Primary lung cancers can be either small cell or non-small cell, with the latter being the most common, accounting for around 80 to 85% of all lung cancer cases. Research has identified the presence of various genetic mutations in lung cancer, one of which is a mutation in the human epidermal growth factor 2 (HER2). This mutation is present in roughly 2 to 4% of non-small cell lung cancer (NSCLC) cases. Given the over-expression of HER2, potential treatments include the anti-HER2 agent, trastuzumab, but when used in combination with chemotherapy, there was a lack of benefit. The antibody-drug conjugate, trastuzumab deruxtecan, has been shown to be effective in both HER2 positive gastric and breast cancers but data on its efficacy in NSCLCL is limited to a single phase 1 trial in 11 patients, which showed an objective response rate in 72.7% (8/11) of patients.
Based on these preliminary findings, an international team, the DESTINY-Lung01 trial investigators, conducted a multi-centre, phase 2 trial of trastuzumab deruxtecan given at a dose of 6.4 mg/kg body weight, to patients with metastatic HER2-mutant NSCLC that was refractory to standard treatment. Eligible patients had unresectable or metastatic non-squamous NSCLC with at least one measurable lesion as defined according to the Response Evaluation Criteria in Solid Tumours (RECIST), which provides a simple and pragmatic methodology to evaluate the activity and efficacy of a new anti-cancer therapy in solid tumours. The primary end point was confirmed objective response, independently assessed on the basis of RECIST. Secondary endpoints included the duration of response, disease control and progression-free survival and overall survival. The study also examined the safety of treatment.
A total of 91 patients with a median age of 60 years (66% female) were enrolled in the study and who had a median of 2 previous cancer therapies. There were 50 (55%) patients who achieved a confirmed objective response, with one patient having a complete response and just over half (54%) having a partial response. In addition, the majority (91%) of patients had disease control and a reduction in tumour size. The median progression-free survival time was 8.2 months and the median overall survival, 17.8 months. In terms of safety, 51% of patients experienced a grade 1 – 2 adverse event and grade 3 or higher drug-related adverse events occurred in 41% of patients. The most common adverse effects were nausea (64%) and fatigue (46%) although these were mainly of grade 1 – 2 severity.
The authors concluded that the use of trastuzumab deruxtecan had shown a response in a high number of patients and durable clinical benefit and that a further randomised trial to further evaluate the drug conjugate is underway.
Li BT et al. Trastuzumab Deruxtecan in HER2-Mutant Non–Small-Cell Lung Cancer. N Eng J Med 2021.
24th September 2021
Small cell lung cancer (SCLC) is an aggressive high-grade neuroendocrine malignancy with a high metastatic potential and is associated with poor clinical outcomes. Patients with extensive-stage small cell lung cancer (ES-SCLC) are normally treated with combination chemotherapy which includes carboplatin or cisplatin plus etoposide. In 2019 the CASPIAN study was published which compared combination chemotherapy, consisting of etoposide + cisplatin/carboplatin (EP), in treatment-naive patients with ES-SCLC with the addition of either durvalumab or tremelimumab. The results showed that addition of durvalumab (D + EP) led to a 27% reduction in the risk of death (Hazard ratio, HR = 0.73, 95% CI 0.59-0.91; p=0.0047) compared to chemotherapy alone. In a 2020 study update, the manufacturer, AstraZeneca, announced that after two years of follow-up, durvalumab (brand name Imfinzi), maintained a 25% reduction in the risk of death versus chemotherapy alone (HR of 0.75; 95% CI 0.62, 0.91; nominal p=0.0032).
The latest results for the CASPIAN trial were presented at the ESMO 2021 conference. These show that after a median follow-up of 39.4 months, durvalumab and EP continued to maintain a 29% survival benefit (HR = 0.71, 95% CI 0.60–0.86; nominal p=0.0003) over chemotherapy. In terms of survival, 22.9% vs 13.9% of patients given durvalumab plus chemotherapy were alive at 24 months and 17.6% vs 5.8% of patients were alive at 36 months with D + EP vs EP.
The incidence of serious adverse events was broadly similar at 32.5%, and 36.5% for durvalumab and EP and EP alone respectively. Adverse events leading to death occurred 5.3%, and 6.0% (D +EP vs ES alone).
Given the overall survival benefit, the authors of the abstract concluded that their data further established D + EP as standard of care for the first-line treatment of ES-SCLC.
Source: AstraZeneca release 2021