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Early data shows cancer progression associated with increased risk of death in patients with Covid-19
In patients with cancer and Covid-19, cancer that is progressing was independently associated with an increased risk of death, according to data from the Covid-19 and Cancer Consortium (CCC19) registry presented as part of the virtual scientific programme of the 2020 American Society of Clinical Oncology (ASCO) Annual Meeting.
The CCC19 registry contains data from patients who have tested positive for Covid-19 and 43 per cent of patients in the registry also have active cancer.
The presented analysis of 928 patients showed that 13 per cent of patients (121) died within 30 days of Covid-19 diagnosis. After partial adjustment for several baseline factors, patients with progressing cancer were found to be 5.2 times more likely to die within 30 days compared with patients in remission or with no evidence of disease.
Use of a combination of hydroxychloroquine and azithromycin to treat Covid-19 was associated with a 2.89-fold greater risk of 30-day mortality than use of neither drug.
However, there was no significant increase in risk associated with the use of either drug alone. Patients who received hydroxychloroquine and azithromycin and later died were more likely to have had slightly diminished daily physical function, received cancer therapy less than two weeks before Covid-19 diagnosis, have Rh-positive blood type, be of non-Hispanic ethnicity, and use statins at baseline.
“While these findings are provocative, we believe that there is significant confounding by indication and that carefully planned prospective studies are needed to truly demonstrate the risk or benefit of these drugs,” said lead author Dr Jeremy L Warner, Associate Professor of Medicine and Biomedical Informatics at Vanderbilt University Medical Centre in Nashville, US.
In addition, diminished ability to perform daily living activities — measured by an Eastern Cooperative Oncology Group (ECOG) Performance Status score of two or greater — was associated with a 3.89 times greater risk of 30-day mortality compared with greater physical ability (ECOG score of 0/1). Risk of death at 30 days increased nearly two-fold (1.83) with each decade of life.
Furthermore, stable, non-progressing cancer was associated with a 1.79 times greater risk of death than no evidence of disease. Men had a 1.63 times greater risk of 30-day mortality than women. Lastly, former smokers had a 1.6 times greater risk of mortality than non-smokers.
Half of patients included in this analysis (466) were hospitalised following onset of Covid-19. Overall, 14 per cent of all patients were admitted to the intensive care unit. Mechanical ventilation was required for 12 per cent of all patients, and additional oxygen was required by 44 per cent of patients.
The CCC19 registry is open to site-level participation in the US and Canada and is open to inclusion of anonymised individuals in Argentina, Canada, the European Union, the US, and the UK.
As of April 16 2020, breast cancer (21 per cent) was the most common cancer, followed by prostate (16 per cent), gastrointestinal (12 per cent), lymphoma (11 per cent), and thoracic (10 per cent). In all, 43 per cent of patients had active (measurable) cancer, 39 per cent were on cancer treatment, and 45 per cent were in remission.
“This is early and evolving data, and more time and analysis will be needed to confirm and expand on these findings,” said Dr Warner.
Pembrolizumab doubles time to disease progression in patients with advanced colorectal cancer with specific DNA mutations
Front-line therapy with the immune checkpoint inhibitor pembrolizumab doubled progression-free survival vs chemotherapy in patients with a type of advanced colorectal cancer that has a high number of mutations, which previous research suggests may have a poor prognosis for some patients.
This is the first time pembrolizumab has been shown to benefit these patients when used as a front-line therapy. The findings come from an interim analysis of the phase 3 KEYNOTE-177 trial that was presented during the virtual scientific programme of the 2020 ASCO Annual Meeting.
Progression-free survival with first-line pembrolizumab was 16.5 months compared with 8.2 months with chemotherapy with or without targeted therapy, establishing pembrolizumab as the new standard of care for patients with microsatellite instability high/mismatch repair deficient (MSI-H/dMMR) metastatic colorectal carcinoma.
At 12 and 24 months’ follow-up, progression-free survival was 55.3 per cent and 48.3 per cent with pembrolizumab vs 37.3 per cent and 18.6 per cent with chemotherapy, respectively.
The proportion of patients with a reduction in tumour size (objective responsive rate) was also better with pembrolizumab — 43.8 per cent compared with 33.1 per cent for chemotherapy. In addition, 11 per cent of patients receiving pembrolizumab had complete response (no detectable cancer); 32.7 per cent had a reduction in tumour size (partial response); and 30.9 per cent had stable disease. In comparison, 3.9 per cent, 29.2 per cent and 42.2 per cent of patients receiving chemotherapy had complete response, partial response, and stable disease, respectively. Response with pembrolizumab was also longer-lasting, with 83 per cent of patients having a response longer than two years, compared with 35 per cent of patients receiving chemotherapy.
Severe treatment-related adverse events (grade 3 or greater) were also less common with pembrolizumab than chemotherapy (22 per cent vs 66 per cent). The profile of toxicities is very different between both groups with immune-mediated adverse events with pembrolizumab (colitis and hepatitis) and classical most frequent chemotherapy toxicities for the chemotherapy arm with diarrhoea, neutropaenia, fatigue, nausea and vomiting, stomatis, alopecia, and neurotoxicity. At the time of data cut-off date for this interim analysis (February 19, 2020), the study included 307 patients with MSI-H/dMMR mCRC. Patients were randomly assigned to receive first-line pembrolizumab for up to two years or the investigator’s choice of six different standard chemotherapy regimens, selected prior to randomisation.
The investigators could choose from mFOLFOX6 (5-fluorouracil, leucovorin, and oxaliplatin); mFOLFOX6+bevacizumab; mFOLFOX6+cetuximab; FOLFIRI (leucovorin, 5-fluorouracil, and irinotecan); FOLFIRI+bevacizumab; or FOLFIRI+cetuximab.
“These long-awaited trial results will change clinical practice,” said lead author Dr Thierry André of the Sorbonne Université and Hôpital Saint Antoine in Paris. “Pembrolizumab works in non-randomised studies in this group of patients with advanced disease. This randomised study demonstrates a huge benefit in first-line with pembrolizumab and should be the new standard of care.”
Approximately 5 per cent of patients with metastatic colorectal cancer have high microsatellite instability.
Post-surgery osimertinib delays disease recurrence in patients with localised non-small cell lung cancer
Treatment with targeted therapy osimertinib following surgery for localised non-small cell lung cancer (NSCLC) with an epidermal growth factor receptor (EGFR) mutation significantly improved disease-free survival in a phase 3 study presented virtually at ASCO 2020.
Of patients with stage II-IIIA NSCLC who received osimertinib, 90 per cent were alive at two years without the cancer recurring, compared with 44 per cent who received a placebo. In stage II-IIIA patients, the risk of disease recurrence or death was reduced by 83 per cent for patients treated with adjuvant osimertinib after surgery compared to placebo.
Results of the multinational, randomised, controlled phase 3 ADAURA trial were compelling enough that the independent data monitoring committee recommended early unblinding. The findings come from an unplanned interim analysis presented at the 2020 ASCO Annual Meeting.
“This trial is a ‘home run’. It exceeded our expectations,” said lead author Dr Roy S Herbst, Chief of Medical Oncology at Yale Cancer Centre and Smilow Cancer Hospital, and Associate Cancer Centre Director for Translational Research at Yale Cancer Centre. “It’s an important advance to see a targeted therapy significantly delay disease recurrence following surgery in patients with non-small cell lung cancer. We can now treat patients earlier.”
Adjuvant chemotherapy is standard of care in patients with stage II-III NSCLC who have undergone complete tumour resection and select patients with stage IB disease; however, recurrence rates are high.
Osimertinib is a third-generation EGFR tyrosine kinase inhibitor and is approved in the US for first-line treatment of patients with metastatic NSCLC with tumours that have EGFR mutations (exon 19 deletions or exon 21 L858R mutations). Results from this trial show efficacy in the adjuvant setting for patients with earlier-stage disease and the same EGFR mutations.
In this trial, 682 patients with primary non-squamous stage IB-IIIA NSCLC and confirmed EGFR mutation were randomised to receive adjuvant osimertinib (339 patients) or placebo (343 patients). Participants were included if they had complete resection of primary NSCLC with full recovery from surgery. Patients receiving osimertinib took 80mg tablets once-daily for up to three years. Postoperative chemotherapy was allowed.
Baseline patient characteristics were balanced across arms, and 31 per cent of patients in both groups had stage IB disease and 69 per cent had stage II/IIIA disease. More patients in both groups were female — 68 per cent and 72 per cent in the osimertinib and placebo groups, respectively.
Patients with stage II-IIIA had an 83 per cent reduction in the risk of disease recurrence or death. Disease-free survival at two years was 90 per cent with osimertinib compared with 44 per cent with placebo in patients with stage II-IIIA NSCLC with an EGFR mutation. In the overall population (stage IB-IIIA), treatment with osimertinib reduced the risk of disease recurrence or death by 79 per cent compared to placebo. Disease-free survival at two years was 89 per cent with osimertinib, compared with 53 per cent with placebo. Overall survival, a secondary end-point, was immature at the time of data analysis.
The safety profile in this study was consistent with the known safety profile of osimertinib, and the drug was generally tolerable.
TAPUR study shows encouraging results for olaparib in BRCA-mutated advanced prostate and pancreatic cancers
Positive results from two cohorts of the Targeted Agent and Profiling Utilisation Registry (TAPUR) study provide real-world evidence to support recent clinical trial data that demonstrate a role for the PARP inhibitor olaparib in the treatment of advanced prostate and pancreatic cancers with BRCA1/2 inactivating mutations. The findings were presented as part of the virtual scientific programme of the 2020 ASCO Annual Meeting.
In two small cohorts, olaparib treatment resulted in objective responses or stable disease for at least 16 weeks in more than two-thirds (68 per cent) of patients with advanced prostate cancer and BRCA1/2 inactivating mutations, and nearly a third (31 per cent) of patients with advanced pancreatic cancer and BRCA1/2 inactivating mutations.
“It makes sense that a targeted therapy that works well and has been approved for one type of cancer with a particular mutation could also be effective for other types of cancer with the same mutation,” said Chief Medical Officer and Executive Vice President Richard L Schilsky, FASCO. “TAPUR provides data from a broader population of patients than were included in pivotal trials of olaparib in these indications and supports its safety and effectiveness in patients with extensive prior treatment.”
The first presented study included 29 patients with advanced prostate cancer with germline or somatic BRCA1/2 inactivating mutations. Patients had no remaining standard treatment options, measurable disease, adequate organ function and an Eastern Co-operative Oncology Group (ECOG) Performance Status of 0-2. Twice daily, patients received either olaparib capsules or tablets. Treatment continued until disease progression.
In the 25 patients evaluable for efficacy, 68 per cent of patients had either an objective response (nine patients) or stable disease for at least four months (eight patients). Three patients had at least one grade 3 adverse or serious adverse event possibly related to olaparib. Reported events were consistent with the drug label.
This data supports the recent FDA approval of olaparib for treatment of adult patients with deleterious or suspected deleterious germline or somatic homologous recombination repair (HRR) gene-mutated metastatic, castration-resistant prostate cancer (mCRPC).
The second cohort included 30 patients with advanced pancreatic cancer and BRCA1/2 inactivating mutations previously treated with platinum-based therapy. These patients had no standard treatment options remaining, measurable disease, adequate organ function, and an ECOG performance status of 0-2. Twice-daily, patients received either olaparib capsules or tablets until disease progression.
In the 26 patients evaluable for efficacy, 31 per cent of patients had either an objective response (partial response in one patient) or stable disease for at least four months (seven patients). Four patients had at least one grade 3 adverse or serious adverse event possibly related to olaparib. Reported events were consistent with the drug label.
These findings support the recent FDA approval of olaparib for the maintenance treatment of adult patients with deleterious or suspected deleterious germline BRCA-mutated (gBRCAm) metastatic pancreatic adenocarcinoma and potentially extend its use to patients with more advanced disease.
With nearly 1,900 patients enrolled at more than 115 participating cancer centres, hospitals and oncology practices in the US, the TAPUR study is the first clinical trial conducted by ASCO.
It is a basket trial that groups tumours by specific genomic alterations, regardless of the location in the body where the cancer originates. Focusing on patients with advanced cancers without remaining treatment options, TAPUR investigates whether specific targeted therapies can benefit patients based on specific genomic profiles of the tumours and lead to more personalised therapies.
Olaparib has been shown to have efficacy against several tumours with germline BRCA mutations.
Chemotherapy within three months of Covid-19 diagnosis associated with an increased risk of death in patients with thoracic cancer
Among patients with lung and other thoracic cancers also diagnosed with Covid-19, prior use of chemotherapy — alone or in combination with other treatments — was associated with increased risk of death, according to an analysis presented as part of the virtual scientific programme of the 2020 ASCO Annual Meeting. The data comes from the Thoracic cancERs international Covid 19 cOLlaboraTion (TERAVOLT) registry and is the most recent data available.
“In less than a week we had a study enrolling patients,” said lead author Dr Leora Horn, who is Ingram Associate Professor of Cancer Research and Director of the Thoracic Oncology Programme at Vanderbilt University Medical Centre. “We have seen clinical trials being funded, approved and begin enrolling patients within weeks, when it can often take months or years to get approval for a trial.”
Only patients treated with chemotherapy (alone or in combination with other therapies) within three months of Covid-19 diagnosis had a significantly increased risk (64 per cent) of dying from the virus, compared with patients not receiving chemotherapy. Of the 144 patients who died, 79.4 per cent (112) died due to Covid-19 and 10.6 per cent (15) due to cancer.
Patients with thoracic malignancies — which include lung cancer, mesothelioma, thymic neoplasms and carcinoid tumours — are considered high-risk, given their older age, multiple comorbidities and pre-existing lung damage, among other factors.
In this study, treatment with corticosteroids prior to infection with the SARS-CoV-2 virus was associated with 1.5 times greater risk of death in patients with thoracic cancer, compared with patients not on corticosteroids, after controlling for a number of other factors.
These findings regarding prior anticoagulant treatment are also of interest, given published reports of clotting in patients with Covid-19, which have prompted some physicians to recommend anticoagulation prophylaxis in all patients with this disease. However, there were too few patients for multivariate analysis. More data will be needed to understand how Covid-19 affects clotting in patients with thoracic cancer.
The type of treatment given specifically for Covid-19 did not appear to affect a patient’s risk of death. The proportions of patients receiving anticoagulants, antibiotics, antivirals, antifungals, corticosteroids, drugs targeting IL-6, and hydroxychloroquine were the same or similar for patients who recovered and who died. For example, 27 per cent of patients who recovered received antibiotics vs 27 per cent who died; for anticoagulants, it was 24 per cent vs 23 per cent; for steroids, it was 10 per cent vs 16 per cent; and for hydroxychloroquine, it was 23 per cent vs 19 per cent.
As more data is collected, findings from the registry are intended to provide insights into the management of both thoracic cancer and Covid-19 in patients with both diseases. Data collection is ongoing, and additional analyses are planned.
Immunotherapy avelumab shows potential in rare gynaecologic cancer resistant to chemotherapy
In a small phase 2 study of a very rare cancer that develops inside a woman’s uterus during or after pregnancy, treatment with the checkpoint inhibitor avelumab potentially cured eight out of 15 women with cancer that was resistant to single-agent chemotherapy. This is the first trial exploring use of immunotherapy in patients with gestational trophoblastic tumours (GTT) and suggests that avelumab may be a new therapeutic option for these patients. The results were presented during ASCO’s online 2020 Annual Meeting.
“This proof-of-concept study shows that treatment with the immunotherapy avelumab works against these tumours when resistance to single-agent chemotherapy develops,” said lead author Dr Benoit You, medical oncologist at Centre Hospitalier Lyon-Sud and Lyon Investigational Centre for Treatments in Oncology and Haematology in France.
“Although more evidence is needed before changing clinical practice, these are highly promising results, suggesting that avelumab could prevent patients with chemo-resistant disease from the severe toxicity of chemotherapy combinations.”
The majority of trophoblastic tumours relapse within six months, if not within the 12 months after treatment discontinuation.
This multi-site study included 15 patients (median age 34 years) with GTT that was resistant to mono-chemotherapy; 47 per cent were stage III with metastases. All patients had progressed on treatment with methotrexate; one patient had also progressed on actinomycin-D. Patients received avelumab until hCG levels returned to normal, followed by three additional cycles.
Eight of 15 patients (53 per cent) with GTT that was resistant to single-agent chemotherapy methotrexate or antibiotic actinomycin-D had no sign of disease relapse at 29 months’ follow-up. If disease has not relapsed after 12 months and monitoring of human chorionic gonadotropin (hCG) has concluded, researchers consider the patient cured. The hormone hCG is used as a biomarker for GTT.
Seven patients achieved normal levels of hCG during treatment with avelumab, and one had normalisation after discontinuation of avelumab. Disease in these patients has not relapsed after 29 months’ follow-up, and normal levels of hCG have been maintained.
One patient who was successfully treated with avelumab later went on to have a healthy pregnancy. It was the first report of a normal pregnancy after a curative treatment with an immunotherapy agent.
Avelumab resistance was observed in the remaining seven patients (47 per cent), requiring chemotherapy with actinomycin-D or polychemotherapy with/without surgery.
Side-effects were generally mild, with 93 per cent of patients having grade 1-2 drug-related adverse events. Fatigue was the most common (33 per cent of patients), followed by nausea and vomiting (33 per cent), and infusion-related reactions (27 per cent). “Drug tolerance was much better with avelumab than with chemotherapy,” said Dr You.
The researchers are now conducting a similar trial for avelumab in the first-line setting, before resistance to therapy can develop, treating low-risk tumours with methotrexate and avelumab.