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17th May 2023
Individuals quitting smoking after their diagnosis of renal cell carcinoma potentially have improved overall and progression-free survival, according to new research.
The incidence of renal cell carcinoma (RCC) varies considerably across the globe. Data suggests the highest incidence of this cancer occurs in developed countries and among smokers, people who are obese and those with hypertension.
In fact, cigarette smoking is a recognised, independent risk factor for advanced renal cell carcinoma. In addition, it is also clear that quitting smoking reduces the risks of developing and dying from RCC. While smoking cessation lowers the risk of developing RCC, whether quitting smoking following a RCC diagnosis affects prognosis is uncertain.
For the present study, researchers investigated if post-diagnosis smoking cessation impacted upon disease progression and mortality risks among smokers diagnosed with RCC. The researchers followed newly diagnosed RCC patients over several years and repeatedly assessed smoking behaviour. Using regression models with adjustments for factors such as age, gender and the amount of cigarettes smoked, researchers estimated survival and disease progression.
There were 212 patients with a median age of 56.1 years (80%) with evaluable data and followed for a 8.2 years. Among this cohort, 84 stopped smoking during follow-up.
Over the next eight years, 110 cases of disease progression, 100 total deaths and 77 cancer-specific deaths occurred. Quitting smoking was associated with improved survival based on a lower risk of all-cause mortality (hazard ratio, HR = 0.51, 95% CI 0.31 – 0.85). Additionally, disease progression was also lower among quitters (HR = 0.45, 95% CI 0.29 – 0.71). There was also a reduced risk of cancer-specific mortality for those who stopped (HR = 0.54, 95% CI 0.31 – 0.93).
The benefit of quitting smoking was evident across all of the different subgroups, such as light smokers versus moderate-heavy smokers and those with early-stage versus late-stage tumours. These findings led the authors to conclude that smoking cessation treatments should form part of the management of RCC patients.
1st March 2023
Rucaparib improves progression-free survival in metastatic, castration-resistant prostate cancer with BRAC alteration compared to usual care.
Rucaparib in men with metastatic, castration-resistant prostate cancer and BRAC alteration improved progression-free survival compared to physician’s choice of treatment according to the findings of a randomised trial by the TRITON3 investigators.
The five-year survival of men diagnosed with metastatic prostate cancer has been estimated to be around 28%. Moreover, the presence of inherited mutations in DNA-repair genes such as BRCA2, increase the risk of the cancer being lethal with one analysis finding that such mutations were detected in nearly 12% of metastatic prostate cancers.
In fact, the presence of BRAC 1 and 2 mutations are associated with poor survival outcomes in men with prostate cancer.
The enzyme poly(ADP-ribose) polymerase facilitates DNA repair by binding to DNA breaks and attracting DNA repair proteins to the site of damage. Furthermore, use of PARP inhibitors to selectively kill a tumour, represents a new concept in cancer treatment.
In a phase 2 trial (TRITON2), the use of oral rucaparib, which is a PARP inhibitor, showed that the drug had anti-tumour activity in men with metastatic, castration-resistant prostate cancer and a deleterious BRAC alteration.
In the current study, researchers sought to be build on the success of TRITON2. They undertook a phase 3 trial in men with metastatic, castration-resistant prostate cancer and a BRCA1, BRCA2, or ataxia telangiectasia mutated (ATM) alteration, whose disease had progressed after use of a second-generation androgen-receptor pathway inhibitor.
Participants were randomised 2:1 to oral rucaparib (600 mg twice daily) or a physician’s choice control which was docetaxel or abiraterone acetate or enzalutamide.
The primary outcome as the median duration of imaging-based progression-free survival according to independent review.
A total of 405 men with a median age of 70.5 years were randomised to rucaparib (270) or control. In the rucaparib arm, 201 patients had a BRAC alteration.
After 62 months, the median duration of progression-free survival in those with a BRAC alteration was 11.2 months compared to 6.4 months in the control arm (Hazard ratio, HR = 0.50, 95% CI 0.36 – 0.69, p < 0.001).
Similarly, among the intention-to-treat group, survival was also significantly longer (HR = 0.61, 95% CI 0.47 – 0.80, p < 0.001). However, in an exploratory analysis, the median duration of progression-free survival in the ATM subgroup was not significantly lower (HR = 0.95, 95% CI 0.59 – 1.52).
Citation
Fizazi K et al. Rucaparib or Physician’s Choice in Metastatic Prostate Cancer. N Eng J Med 2023.
17th February 2023
In a randomised controlled trial, an international group of researchers showed that the CAR T-cell therapy, Ide-cel (idecabtagene vicleucel) gave rise to greater progression-free survival than any of five other standard regimens in heavily pre-treated patients with relapsed or refractory multiple myeloma.
Although treatments for multiple myeloma have improved in recent years, evidence suggests that around 16% of patients relapse after 8 months of treatment. Nevertheless, while CD38-targeting monoclonal antibodies have made a significant impact to the treatment of patients with multiple myeloma (MM), those who a refractory to this regime have a poor prognosis. The use of CAR T-cell therapies directed against the B-cell maturation antigen (BCMA) expressed on myeloma cells, have proven to be effective in MM. In fact, one Phase II trial in which Ide-cel was given to relapsed or refractory MM patients, generated a response in over 70% of patients, with 33% experiencing a complete response. While CAR T-cell therapy clearly works in relapsed/refractory MM, there is an absence of comparative studies of the treatment compared to other regimes.
In the current study, researchers recruited MM patients who were refractory to between two and four prior regimes. Eligible participants were then randomised 2:1 to Ide-cel or one of five standard regimens and which included immunomodulatory agents, proteasome inhibitors and daratumumab. The primary endpoint was set as progression-free survival whereas secondary endpoints included the overall response and survival.
Ide-cel and progression-free survival
A total of 386 patients with a median age of 63 years (60.5% male) received either Ide-cel (254) or one of the standard regimes. Among the entire cohort, 66% had triple-class refractory disease and 95% daratumumab-refractory disease.
After a median of 18.6 months follow-up, the median progression-free survival in the Ide-cel group was 13.3 months compared to 4.4 months in the standard regime groups (hazard ratio for disease progression or death, HR = 0.49, 95% CI 0.38 – 0.65, p < 0.001). In fact, 12-month progression-free survival was 55% for Ide-cel but only 30% in the standard regimen. Furthermore, a complete response occurred in 39% of the intervention group and on 5% in the standard therapy group. Data on overall survival were immature. In addition, adverse effects of either grade 3 or 4 were more frequent in the Ide-cel group (93% vs 75).
Based on these results, the authors concluded that Ide-cel gave rise to an improved response compared to standard therapy in patients who failed to respond to two to four prior regimens.
Citation
Rodriguez-Otero P et al. Ide-cel or Standard Regimens in Relapsed and Refractory Multiple Myeloma. N Engl J Med 2023
7th July 2022
Apatinib addition to pegylated liposomal doxorubicin (PLD) led to a significant improvement in progression-free survival compared to patients given PLD alone in platinum-resistant ovarian cancer, according to the results of a randomised trial by Chinese researchers.
Across the world in 2020, there were an estimated 313,959 incident cases of ovarian cancer (1.6% of all cancers) and which resulted in 207,252 deaths. The symptoms of epithelial ovarian cancer are generally non-specific, and include for instance, abdominal bloating, fatigue, headaches and this probably explains how around 75% of patients present with advanced (stage III or IV) disease.
Although adjuvant chemotherapy with carboplatin/paclitaxel has become standard, round 70 % of ovarian cancer patients still relapse after primary cyto-reductive surgery and first-line chemotherapy. In such cases, an emerging therapeutic option is mono-therapy with pegylated liposomal doxorubicin (PLD), docetaxel, paclitaxel, or topotecan.
However, addition of monoclonal antibodies to mono-therapy is being seen as another treatment strategy. For example, the monoclonal antibody bevacizumab, which targets all isoforms of vascular endothelial growth factor (VEGF)–A is an effective option as demonstrated in the AURELIA trial, where adding bevacizumab to chemotherapy produced a statistically significant improvement in progression-free survival and overall response rate.
Apatinib is an oral tyrosine kinase inhibitor that selectively inhibits VEGF receptor 2 and apatinib addition to oral etoposide showed promising efficacy and manageable toxicities in patients with platinum-resistant ovarian cancer.
Nevertheless, a limitation with the study was that apatinib was added to etoposide hence the authors were unable to measure the comparative effectiveness of either agent alone.
For the present study, the Chinese researchers examined the efficacy and safety of apatinib addition to PLD compared to PLD alone in platinum resistant ovarian cancer. They performed an open label, randomised trial in adult women with ovarian cancer and who had experienced disease progression during or within 6 months of discontinuing any prior platinum-based chemotherapy.
Individuals were randomised 1:1 to receive either PLD alone (40 mg/m2) intravenously every 4 weeks or apatinib addition to PLD (250 mg, orally once daily). The primary outcome of interest was progression-free survival (PFS) and which was defined as the time from randomisation to the first documented tumour progression or death.
Apatinib addition to PLD
A total of 152 patients were randomised to either apatinib and PLD (78) or PLD alone. The median age of those using the combination was 54 years.
Overall, 47.4% of patients assigned to the combination and 67.6% of those using PLD alone experienced a progression event or death. The median PFS was 5.8 months for the combination and 3.3 months in the PLD arm (hazard ratio, HR = 0.44, 95% CI 0.28 – 0.71, p < 0.01).
A post hoc analysis of updated overall median survival was found to be 23 months for the combination but only 14.4 months for PLD alone.
The most frequent grade 3 or higher treatment-emergent adverse events were a decreased neutrophil counts (14.9%) in the combination group compared with 8.3% in the PLD group.
The authors concluded that apatinib addition to PLD showed promising efficacy and could represent a new alternative treatment for women with platinum-resistant ovarian cancer.
Citation
Wang T et al. Effect of Apatinib Plus Pegylated Liposomal Doxorubicin vs Pegylated Liposomal Doxorubicin Alone on Platinum-Resistant Recurrent Ovarian Cancer: The APPROVE Randomized Clinical Trial JAMA Oncol 2022
25th October 2021
In malignant mesothelioma with evidence of disease progression, use of nivolumab significantly improved overall survival.
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 two 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 one 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 one 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.
Citation
Fennell DA et al. Nivolumab versus placebo in patients with relapsed malignant mesothelioma (CONFIRM): a multi-centre, double-blind, randomised, phase 3 trial. Lancet 2021.
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.
DESTINY-BREAST03
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.
Findings
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.
Citation
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
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