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The plenary session is always a highlight at ASCO’s Annual Meeting. This year’s event, which was held in McCormick Place in Chicago from 3 to 7 June, proved no exception with the session featuring studies deemed to have the highest merit and greatest impact on oncology research and practice. The following four selected studies were on the subjects of adjuvant aromatase inhibitors, temozolomide chemotherapy, stem cell transplant and combination therapy.
Speaking to the Medical Independent (MI), ASCO President Dr Julie Vose said: “We looked for studies that had a very large impact on patient outcomes or patient survival or patient toxicity and side effects. We also make sure these are studies that are well done, include a large number of patients and really make a difference for patients.”
Extension of adjuvant aromatase inhibitors
A randomised phase 3 clinical trial, MA.17R, found that post-menopausal women with early breast cancer benefit from extending aromatase inhibitor (AI) therapy with letrozole from five to 10 years. Following five years of an AI and any duration of prior tamoxifen, women who received letrozole for five additional years had a 34 per cent lower risk of recurrence than those who received placebo. The trial was led by the Canadian Cancer Trials Group (CCTG) with participation from the National Clinical Trials Network.
The trial enrolled 1,918 postmenopausal women who had received five years of any one of three AI therapies either as initial treatment or after any duration of prior tamoxifen. Although patients were allowed to enroll up to two years after completing previous AI therapy, about 90 per cent began receiving letrozole or placebo within six months of completing prior therapy.
Patient-reported quality-of-life was measured using the standard SF-36 questionnaire, which covered various areas of physical health and mental health, and a menopause-specific questionnaire, MEN- QOL. Of the 1,918 study participants, 1,428 were eligible to complete initial quality-of-life assessments. These were repeated at 12, 24, 36, 48 and 60 months, with more than 85 per cent of women completing the questionnaires at follow-up. Overall, there were no significant differences in either overall quality-of-life or menopause-specific quality-of-life between women who took letrozole for five years and those who received placebo.
A Canadian-led randomised phase 3 trial found that adding temozolomide chemotherapy during short-course radiation therapy, followed by monthly maintenance doses of temozolomide, significantly improved survival of elderly patients with glioblastoma, reducing the risk of death by 33 per cent. This is the first study to test the combination of temozolomide and radiation therapy in older adults, who account for half of all patients with this disease. While side effects were slightly greater among patients receiving temozolomide, overall quality-of-life was similar in both patient groups.
The trial was led by the CCTG with collaboration from the European Organisation for the Research and Treatment of Cancer (EORTC) and the Trans-Tasmin Radiation Oncology Group (TROG). Chemoradiation extended the median overall survival from 7.6 months with radiation therapy alone to 9.3 months. In addition, tumour growth was slower in the temozolomide group, with median progression-free survival of 5.3 months versus 3.9 months. The benefit of temozolomide was greater among 165 patients with MGMT promoter methylation, a genetic abnormality linked to better response to chemotherapy and longer survival in this disease.
“What I think is going to be talked about and what we need to look further into is why the patients that did not have MGMT methylation also seem to benefit,” lead study co-author Dr James R Perry, the Crolla Family Endowed Chair in Brain Tumour Research at the Odette Cancer and Sunnybrook Health Sciences Centres in Toronto, Canada, told MI.
Novel daratumumab-based regimen
Initial findings from a phase 3 trial showed that daratumumab added to a standard two-drug regimen (bortezomib and dexamethasone) markedly improved outcomes for patients with recurrent or refractory multiple myeloma.
The daratumumab combination reduced the risk of cancer progression by 70 per cent, and doubled both very good partial response rates from 29 per cent to 59 per cent and complete response rates from nine per cent to 19 per cent. Daratumumab, the first monoclonal antibody approved for multiple myeloma, targets a protein on the surface of cancer cells called CD-38.
Lead author Dr Antonio Palumbo, Chief of the Myeloma Unit at the Department of Oncology, University of Torino, Italy, told MI the findings were “unprecedented”.
“In other studies, studies that have been conducted until now where bortezomib and dexamethasone was the control arm and was randomised versus a free drug agent with several other agents, the hazard ratio was between 5.6 or 7.5 and here we are at 3.9,” he said.
“So it is the best available hazard ratio among different randomised studies using bortezomib and dexamethasone as a control.”
Under 50 per cent of children with high-risk neuroblastoma live five or more years after diagnosis. A National Cancer Institute (NCI) funded phase 3 trial performed by the Children’s Oncology Group found that adding a second autologous stem-cell transplant to standard therapy improves outcomes for these patients.
At three years, 61.4 per cent of patients who received a double transplant were alive and cancer-free, compared to 48.4 per cent of those who received a single transplant. Side effects were similar between single and double transplant recipients.
Precision medicine and immunotherapy
The promises offered by genetic testing and more targeted treatments for cancer are now bearing fruit. Much of the focus at this year’s ASCO Annual Meeting was on the benefits of precision medicine. Immunotherapy was also a major theme, accounting for about a quarter of all abstracts submitted for the event.
A large-scale genomic analysis has found that patterns of genetic changes detected in blood samples (liquid biopsy), closely mirror those identified in traditional tumour biopsy. With blood samples from more than 15,000 patients and 50 different tumour types, this is one of the largest cancer genomics studies ever conducted.
The study, which was presented by Dr Philip Mack, Professor and Director of Molecular Pharmacology at the University of California Davis Comprehensive Cancer Centre, US, included 15,191 patients with advanced lung cancer (37 per cent), breast cancer (14 per cent), colorectal cancer (10 per cent), and other cancers (39 per cent). Each patient provided one or more blood samples for analysis of ctDNA.
The study assessed the accuracy of liquid biopsies, as compared to tumour samples, in two ways. First, it compared the patterns of genomic changes in ctDNA to those found in 398 patients with available results of genetic testing of the tumour tissue. When ctDNA was positive for key abnormalities in EGFR, BRAF, KRAS, ALK, RET, and ROS1 that drive tumour growth, the same mutations were reported in tissue 94-100 per cent of the time. Most ctDNA alterations were found at very low levels. Half occurred at a frequency below 0.4 per cent of the total DNA in circulation. The accuracy of the liquid biopsy assay remained high even at these low levels.
The authors also assessed consistency in the frequencies of specific changes in ctDNA against previously published data from genomic analyses of tumour tissue, including data from the Cancer Genome Atlas. The findings suggest that liquid biopsy provides an accurate snapshot of the genomic landscape of the tumour.
Across multiple cancer genes and different classes of alterations correlations typically ranged from 0.92-0.99. However, one general exception was found in which ctDNA findings were often not seen in tumour biopsies: Detection of new genomic alterations associated with resistance to targeted cancer drugs, such as the EGFR T790M resistance mutations in patients on EGFR inhibitor therapy. The authors hypothesize that these alterations were absent in the tissue-based population data because those patients had yet to receive treatment.
Based on the genetic changes the blood test revealed, the researchers provided the study participants’ doctors with lists of possible treatment options, including FDA-approved drugs and/or clinical trials. Overall, ctDNA testing revealed a possible treatment option for nearly two-thirds of patients tested (63.6 per cent), which included FDA-approved drugs as well as eligibility for clinical trials.
In another study, researchers reported encouraging early results from a phase 2 trial that matches patients with molecular abnormalities in the tumour to corresponding targeted treatments. Twenty-nine of 129 patients with 12 different types of advanced cancers responded to drugs outside of FDA-approved indications. MyPathway is an ongoing (39 currently participating sites) non-randomised, open-label trial that evaluates four treatment regimens in patients with advanced cancer for whom no beneficial treatment is available.
To be eligible for the study, patients must have had previous molecular studies of the cancer showing abnormalities in the HER2, BRAF, Hedgehog or EGFR pathways.
Regarding immunotherapy, the findings from a European phase 2 study showed that the novel, first-in-class antibody IMAB362 can significantly extend median survival when added to standard chemotherapy (13.2 months versus 8.4 months) for patients with advanced gastric cancer. This therapy targets a protein called claudin18.2, and patients in the study with the highest levels of claudin18.2 had an even longer median overall survival (16.7 months).
“As claudin18.2 is abundant in gastric tumours, we estimate that half of all patients with advanced gastric cancer may be candidates for this new treatment,” said lead study author Dr Salah-Eddin Al- Batran, a medical oncologist and Director at the Institute of Clinical Cancer Research, Nordwest Hospital in Frankfurt am Main, Germany. “In addition, this unique target is not present in any healthy tissues except the lining of the stomach, thereby minimising treatment side effects.”
Aside from gastric cancer, claudin18.2 is found in a variety of other tumours, including pancreatic, lung, oesophageal, and ovarian. Claudin18.2 belongs to a family of proteins that make tight junctions, which control the flow of molecules between cells in a layer. In tumours, however, tight junctions become disrupted and claudin proteins lose their primary role.
IMAB362 is the first antibody to target claudin18.2. When the antibodies attach to claudin18.2 on the surface of cancer cells, various types of cellular and soluble immune effectors respond by killing the cancer cells that are coated with antibodies. These processes are known as antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC).
According to the authors, the treatment was well tolerated. Vomiting (34.5 per cent of patients with grade 1/2 and 3.6 per cent with grade 3/4 in control arm versus 55.8 per cent of patients with grade 1/2 and in 10.4 per cent with grade 3/4 in IMAB362 arm) and low blood counts or neutropaenia (21.4 per cent of patients with grade 1/2 and 21.4 per cent with grade 3/4 in control arm versus 23.4 per cent of patients with grade 1/2 and in 32.5 per cent with grade 3/4 in IMAB362 arm) were slightly more common in the IMAB362 group. The rates of severe adverse effects were not increased with IMAB362 compared to chemotherapy alone.
A phase 3 study is planned for launch in early 2017. The researchers are also planning a phase 2 study of IMAB362 in patients with pancreatic cancer.