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8th April 2022
A meta-analysis by researchers from Beijing Tongren Hospital, Capital Medical University, Beijing, China, has concluded that adding radiotherapy to immune checkpoint inhibitors (ICIs)for the treatment of patients with melanoma offers no overall survival benefit despite a significant improvement in 12-month progression-free survival.
According to the World Cancer Research Fund, melanoma is the 19th most commonly occurring cancer in men and women, with nearly 300,000 new cases reported in 2018. Among patients whose melanoma has undergone metastases, ICIs, monoclonal antibodies which target the programmed death cell protein 1 (PD-1), the programmed death-ligand 1 (PD-L1), or the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), represent the standard of care. Nevertheless, while effective, when used as mono-therapy, ICIs produce an overall response rate ranging from 0% to 17%, though these figures increase to more than 33.3% when the agents are combined.
Radiotherapy is routinely used in treatment of solid cancers, such as hepatocellular carcinoma (HCC) and several preclinical and clinical studies have explored the efficacy of combining radiotherapy and ICIs in HCC and with promising outcomes. Moreover, a meta-analysis of 11 studies found that combining ICIs with radiotherapy showed better local efficacy than ICI mono-therapy for treating melanoma brain metastasis.
Despite this, few studies have systematically examined the combined effect of ICIs and radiotherapy in the treatment of patients with melanoma. For the present study, the Chinese team set out to summarise the efficacy of radiotherapy in combination with ICIs in the treatment of non-brain metastatic melanoma. They included all available trials such as single-arm and control studies in which the endpoints of overall response rate (ORR), overall survival (OS) or progression-free survival (PFS) were reported. The team used regression analysis and presented their results using odds ratios.
Immune checkpoint inhibitors and radiotherapy outcomes
After an extensive literature search, 9 articles (7 retrospective studies and 2 prospective cohort trials) involving 624 patients were identified and included in the analysis.
Combing radiotherapy with ICIs led to a higher ORR compared with ICIs alone (35% vs 20.4%, p = 0.004) However, in terms of OS, the 12-month odds ratio (OR) comparing the combination to ICI treatment alone was 1.83 (95% CI 0.32 – 5.52, p = 0.69) and hence not significantly different.
While there was no significant difference between the two treatment options in PFS at 6-months (OR = 0.53, 95% CI 0.26 – 1.08, p = 0.08), this difference became significant at 12-months (OR = 0.48, 95% CI 0.29 – 0.80, p = 0.005).
Commenting on these findings, the authors highlighted that with most studies being retrospective in nature and no randomised trials, there was a need for prospective trials to further explore the efficacy of combining radiotherapy with ICIs in melanoma.
They concluded that while, at present, there was no evidence of a survival benefit by combining the two therapies, an improvement in PFS was evident but further high quality trials were required to confirm these findings.
Yin G et al. Efficacy of radiotherapy combined with immune checkpoint inhibitors in patients with melanoma: a systemic review and meta-analysis Melanoma Res 2022
28th February 2022
Darolutamide combined with androgen-deprivation therapy and docetaxel, provides a better overall survival in men with metastatic, hormone-sensitive prostate cancer compared not using the drug. This was the findings of a randomised trial by researchers from the Genitourinary Malignancies Program, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, US.
Prostate cancer is the second most frequent malignancy in men worldwide and in 2018, there were 1,276,106 new cases and 358,989 deaths, representing 3.8% of all male cancer deaths. Among men with metastatic, hormone-naive, prostate cancer the addition of an androgen-receptor pathway inhibitor such as abiraterone, apalutamide, enzalutamide or docetaxel improves overall survival compared to androgen-deprivation therapy alone.
Darolutamide is an androgen-receptor inhibitor and in the Phase III ARAMIS study, it was found that for men with non-metastatic, castration-resistant prostate cancer, darolutamide treatment, metastasis-free survival was significantly longer with darolutamide than with placebo. However, whether combining darolutamide, androgen-deprivation therapy and docetaxel, would increase survival among patients with metastatic, hormone-sensitive prostate cancer is currently unclear and was the rational for the current study by the US team.
The researchers included adults (> 18 years of age) with an Eastern Cooperative Oncology Group performance status (ECOG) of 0 or 1 (where higher scores, reflect a greater disability). All received androgen-deprivation therapy, in the form of a luteinising hormone-releasing hormone or analogue) or underwent orchiectomy within 12 weeks before randomisation. Participants were randomised 1:1 to darolutamide 600 mg twice daily or matching placebo and received six cycles of docetaxel with prednisolone within 6 weeks after randomisation. The primary endpoint of the trial was overall survival, defined as the time from randomisation until any cause of death. Secondary outcomes included time to castration-resistant prostate cancer and time to pain progression and participants were assessed every 12 weeks.
Darolutamide and overall survival
A total of 1305 men with metastatic disease and a median age of 67 years were included in the final dataset, with most (71.1%) having an ECOG score of 0.
The risk of death was 32.5% lower in the darolutamide group (hazard ratio, HR = 0.68, 95% CI 0.57 – 0.80, p < 0.001). After 4 years, the overall survival was 62.7% in the darolutamide group compared to 50.4% in the placebo arm.
With respect to the secondary outcomes, the time to castration-resistant prostate cancer was significantly lower in the darolutamide group (HR = 0.36, 95% CI 0.30 – 0.42, p < 0.001) as was the time to pain progression (HR = 0.79, 95% CI 0.66 – 0.95, p = 0.01).
In terms of safety, the incidence of adverse effects was similar in both groups (99.5 vs 98.9, darolutamide vs placebo) as was the incidence of a serious adverse event (44.8% vs 42.3%).
Based on these findings, the authors concluded that darolutamide combined with androgen-deprivation therapy and docetaxel in men with metastatic, hormone-sensitive prostate cancer, led to a significantly longer overall survival.
Smith MR et al. Darolutamide and Survival in Metastatic, Hormone-Sensitive Prostate Cancer New Engl J Med 2022
20th January 2022
Smoking cessation at the time of a lung cancer diagnosis is linked to an improved survival from both non-small and small cell lung cancer, according to the findings of a systematic review by a team from the Institute for Cancer Research, Prevention and Clinical Network, Florence, Italy
Data from the World Health Organization shows that in 2020, globally, there were 2.21 million cases of lung cancer and which led to 1.8 million deaths. In addition, lung cancer has a poor prognosis and Cancer Research UK suggests that only around 15% of those with lung cancer will survive for 5 years or more after diagnosis. Cigarette smoking is a major factor in the development of lung cancer, with one analysis of the burden of respiratory tract cancers indicating that smoking contributed to an estimated 64·2% of all deaths from tracheal, bronchus, and lung cancer and 63·4% of all deaths from larynx cancer in 2019.
Although one study with 517 smokers, found that smoking cessation at the time of a lung cancer diagnosis can reduce the risk of future lung cancer, for the present study, the Italian team sought to provide a more robust estimate of the overall prognostic value of smoking cessation at or around the time of a lung cancer diagnosis. They searched for articles which included those who continued to smoke and those who quit in relation to their cancer diagnosis and the associated changes in survival. The team calculated relative risks for the association between smoking cessation and the survival from lung cancer.
A total of 21 studies were included in the systematic review with patients diagnosed with non-small cell lung cancer (10 studies, 5315 patients) and small cell lung cancer (5 studies, 1133 patients), together with a further six studies of both cancer subtypes or where the subtype was not specified. The mean age of lung cancer diagnosis across the studies ranged from 60 to 70 years and the proportion of men ranged from 40.2% to 91.8%. The duration of follow-up also ranged from 12 months to 27.7 years.
Smoking cessation at or around the time of diagnosis was associated with a better overall survival regardless of lung cancer type. For smoking cessation at any time, compared to those who continued smoking (used as the reference group), the relative risk for non-small cell lung cancer was 0.77 (relative risk, RR = 0.77, 95% CI 0.66 – 0.90) and this reduction was broadly similar compared to those stopping strictly at or after their diagnosis or up to 12 months before the diagnosis. For small cell lung cancer, overall survival was also broadly similar (RR = 0.75, 95% CI 0.57 – 0.99). Even in studies where the cancer subtype was not specified, there were survival benefits among quitters (RR = 0.81, 95% CI 0.68 – 0.96).
The authors calculated an overall benefit for those who undertook smoking cessation at or around the time of their lung cancer diagnosis, finding that such individuals had a 29% improvement in their overall survival compared to those who continued to smoke (RR = 0.71, 95% CI 0.64 – 80).
The authors concluded that advice to quit smoking at or around the time of a lung cancer diagnosis, should arguably become a non-optional part of the management of these patients.
Caini S et al. Quitting smoking at or around diagnosis improves the overall survival of lung cancer patients: a systematic review and meta-analysis J Thorac Oncol 2022
19th November 2021
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.
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.
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
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.
Kidney transplant patients with prostate cancer still achieve the same benefits in terms of overall survival as those without the cancer, according to the results of a retrospective analysis by researchers from the Division of Nephrology, University Hospitals, Ohio, US. End stage kidney disease (ESKD) which requires maintenance with dialysis or a kidney transplant for survival is associated with an increased risk of death. For example, one retrospective analysis of 242 patients with ESKD, observed an annual mortality rate of 7.4%. Nevertheless, other data has found that the mortality risk from ESKD has actually decreased over the last 15 years although some work indicates how ESKD have higher levels of prostate cancer.
Kidney transplant patients have an improved quality of life compared to those continuing with dialysis but there is uncertainty over whether or not the presence of prostate cancer impacts on mortality risk in those either with ESKD or after transplantation. These were the questions to which the Ohio researchers sought answers in the present study. They turned to the US renal data system and included men aged 40 to 79 years of age with ESKD and took the main exposure to be incident prostate cancer which developed after the initiation of dialysis but before a kidney transplant. Since the clinical characteristics of patients with ESKD and prostate cancer might differ to those without prostate cancer, the researchers used propensity matching with a control group of ESKD patients but without prostate cancer and set the outcomes of interest as the time to kidney transplant and death.
There were 15,554 patients with ESKD and prostate cancer who were matched with controls, the majority of whom (47%) were aged 70 to 79 years with 42% aged 55 to 69 years. Within the matched cohort, 77.6% of patients with prostate cancer died compared to 77.1% of control patients during a mean follow-up of 3.1 years for those with prostate cancer and 3.5 years for controls. The presence of prostate cancer was associated with a 22% lower likelihood of having a kidney transplant (Hazard ratio, HR = 0.78, 95% CI 0.72 – 0.85) and an 11% higher mortality risk (HR = 1.11, 95% CI 1.08 – 1.14) compared to controls.
However when considering kidney transplant patients and using patients without a prostate cancer and no transplant as the reference point, the hazard ratios for the time to death were 0.20 (95% CI 0.18 – 0.21) for transplant patients with prostate cancer and also 0.20 for transplant patients without prostate cancer.
The authors concluded that the presence of prostate cancer in those with ESDK was associated with only a modest increased risk of death but that once these patients had a kidney transplant, the survival benefits were identical to those without cancer. The suggested the these findings indicate that in kidney transplant patients, the presence of prostate cancer should be a barrier to provision of a new kidney.
27th September 2021
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.