New drug formulations, biological agents, combination therapies and the latest pharmaceutical developments designed to improve outcomes in patients with a wide range of cancers were highlighted at EMCC 2001. Here are just a few of the highlights:
Progression-free survival (PFS) in patients with HER2-positive metastatic breast cancer (MBC) cancer was improved by more than 40% in a clinical trial designed to assess the benefit of a new antibody drug conjugate to that of conventional first-line therapy.
Dr Sara Hurvitz (Director, Breast Oncology Program, Division of Hematology/ Oncology, University of California, Los Angeles, US) outlined what she described as “provocative” data from a randomised phase II study in which trastuzumab emtansine - providing intracellular delivery of the cytotoxic agent DM1 while maintaining the anti-tumour activities of trastuzumab – compared to a standard combination of trastuzumab (Herceptin) and docetaxel (Taxotere).
About one in five breast cancer tumours are HER2-positive, and are usually treated with targeted therapy.
In this phase II study, 137 patients were randomised to one of two treatment strategies until disease progression or unacceptable toxicity occurred, with a median follow-up of 13.8 months and 13.5 months, respectively:
- intravenous injections (iv) of T-DM1 3.6mg/kg, every 3 weeks
- iv trastuzumab 6mg/kg (8 mg/kg in cycle 1) + iv docetaxel 75mg/m² (74.2% of those randomized) or 100mg/m2, also every 3 weeks
The data reported by Dr Hurvitz revealed a significant improvement in PFS in the T-DM1 arm (14.2 vs 9.2 months, HR=0.59, p = 0.035). Furthermore, discontinuation of treatment due to side-effects was greater in the conventional therapy arm than it was for T-DM1 (28.8% vs 7.2%), as were grade ≥3 AEs (46.4% vs 89.4%). Serious AEs also occurred less frequently in the T-DM1 arm (18.8% vs 25.8%).
The most common adverse events (AEs) were alopecia (66.7%), neutropenia (63.6%), diarrhoea (45.5%), and fatigue (45.5%) in the standard therapy arm, and fatigue (49.3%), nausea (47.8%), increased AST (39.1%), and pyrexia (39.1%) in the T-DM1 arm.
Dr Hurvitz concluded: “The majority of patients with HER2-positive MBC will face resistance to the currently available HER2-directed therapies. Therefore, dealing with resistance to HER2-targeted therapy remains an unmet need and new, effective therapies for HER2-positive breast cancer are still necessary.”
She added “T-DM1 is unique in that it allows the targeted delivery of chemotherapy to cancer cells. Based on these data, T-DM1 appears to be not only safer than the docetaxel/trastuzumab combination, but it may allow patients to live without disease progression for a significantly longer period of time.
“A safer, more effective treatment is likely to enhance patient quality of life and it may ultimately translate into fewer hospitalisations for complications more commonly reported with docetaxel/trastuzumab use.”
New data from the first clinical trial in nearly 40 years to demonstrate a significant improvement in overall and prolonged survival in the first-line treatment of advanced melanoma has highlighted the superiority of a new monoclonal antibody that inhibits the cytotoxic T lymphocyte antigen-4 (CTLA-4).
Reporting the findings of a phase III clinical trial, Dr Jedd Wolchok (Medical Oncologist, Memorial Sloan-Kettering Cancer Center, New York City, US) revealed that treatment with ipilimumab (Yervoy) in combination with dacarbazine (DCIT) resulted in a 28% survival benefit compared to dacarbazine alone (median overall survival [OS] 11.2 months vs 9.1 months, hazard ratio [HR] 0.716, p=0.0009).
The study involved 502 patients who had not received prior therapy for metastatic melanoma, randomised to receive on of the following treatment protocols:
- intravenous (iv) ipilimumab 10mg/kg every 3 weeks for up to four doses plus chemotherapy with iv dacarbazine 850mg/m² every 3 weeks for 22 weeks
- placebo plus iv dacarbazine at the same dosing schedule
Durable survival at 1, 2 and 3 years was demonstrated for ipilimumab combined with dacarbazine compared with dacarbazine alone, based on estimated survival rates - patients alive at 1 year (47.3% vs 36.3%), at 2 years (28.5% vs 17.9%) and at 3 years (20.8% vs. 12.2%.).
Dr Wolchok also reported consistent efficacy for secondary endpoints:
- 24% reduced risk of progression (progression-free survival [PFS] 2.8 months vs 2.4 months, HR 0.76, p=0.006)
- 15.2% vs 10.3% best overall response rate
- 19.3 months vs 8.1 months median duration of response (p=0.03)
The most common adverse events associated with ipilimumab treatment were immune-related hepatitis, rash, pruritus, diarrhoea, nausea and fatigue. Elevated liver enzyme levels with the ipilimumab/dacarbazine combination included raised alanine transaminases (ALT) 22% vs 0.8%, and aspartate transaminases (AST) 18% vs 1.2%.
Overall, the adverse event rate was similar to that for dacarbazine alone (98.8% vs 94.0%), although grade 3/4 adverse events were higher (56% vs. 28%).
Dr Wolchok concluded that the future of CLTA-4 blockade with agents such as ipilimumab would benefit from the identification of new biomarkers to pinpoint patient populations most likely to respond to this particular treatment strategy.
“There is the potential to combine CTLA-4-based immune therapy with targeted therapies such as inhibitors of the mutated BRAF protein – however, such strategies should be approached with caution,” he emphasised.
Commenting on these data, Professor Alexander Eggermont (General Director, Institut Gustav Roussy, Paris, France) said that it takes time to mobilise with immune system with ipilimumab – indeed, there are often initial indications that the disease has progressed.
“In time, however, there is a durable and positive response which, in some patients at least, could eventually result in a cure,” he said.
Professor Eggermont stressed that the safety profile of ipilimumab differed significantly from that of conventional cytotoxic therapies, and mainly involved cutaneous (e.g. skin rash), gastrointestinal (e.g. colitis, diarrhoea) and endocrine (e.g. inflammation of the thyroid gland) side-effects.
Guidance to manage immune-related adverse events was readily available to pharmacists and other healthcare professionals, he said.
The strategy of combining two drug therapies designed to treat post-menopausal women with advanced breast cancer have proved so successful that a phase III clinical trial was stopped earlier than planned when it became clear that significantly better outcomes were being achieved with the combination than with one of the drugs alone.
Professor José Baselga (Chief of Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, US) highlighted data from BOLERO 2, in which 724 patients (mean age 62 years) recruited from centres in 24 countries were randomised to a combination of the aromatase inhibitor exemestane (Aromasin) 25mg a day, with or without the oral signal transduction inhibitor everolimus (Afinitor) 10mg a day.
Patients were oestrogen receptor-positive advanced breast cancer, refractory to previous treatment with two other aromatase inhibitors, letrozole (Femara) or anastrozole (Arimidex). Many had also received prior therapy with tamoxifen (Nolvadex) 48%, fulvestrant (Faslodex) 16%, and chemotherapy (68%).
At a planned interim analysis of the data, a 57% improvement in locally-assessed progression-free survival (PFS) was reported for the combination compared to exemestane alone (median PFS 6.9 months vs 2.8 months, hazard ratio [HR] 0.43, p<0.0001).
A central evaluation of PFS was also significant (median PFS 10.6 months vs 4.1 months, HR 0.36, p<0.0001).
Prof Baselga commented: "This is a highly significant improvement in the time to disease progression in a patient population that is highly resistant to therapy."
He added that many breast cancer patients - and nearly all patients with advanced breast cancer that has metastasised - become resistant to hormonal therapy.
Meanwhile, everolimus targets mTOR, a protein that acts as an important regulator of tumour cell division, blood vessel growth and cell metabolism. Resistance to hormonal therapy in breast cancer has been associated with over-activation of the mTOR pathway.
“This is the first drug since tamoxifen to demonstrate a beneficial effect in these patients,” said Professor Baselga.Further benefits for adding everolimus to exemestane were seen with regard to response rate (9.5% vs 0.4%, p<0.0001) and clinical superiority (33.4% vs 18.0%, also p<0.0001).
The safety profile of the combination suffered by comparison, but the level of grade3/4 adverse events was low: stomatitis (8% vs 1%), anaemia (5% vs <1%), dyspnoea (4% vs 1%), hyperglycaemia (4% vs <1%), fatigue (3% vs 1%) and pneumonitis (3% vs 0%) proving to be the most troublesome.
“Nevertheless,” said Professor Baselga, “these side-effects did not have a detrimental effect on the quality of life of those patients who stayed in the study until the interim analysis had been undertaken.
He concluded: “The BOLERO 2 data are impressive, suggesting that this combination strategy could represent a new therapeutic option for women with advanced post-menopausal breast cancer who have previously been treated and failed with non-steroidal aromatase inhibitors."
Worldwide regulatory submissions for everolimus as a treatment for oestrogen receptor-positive, advanced breast cancer is expected to be submitted by the end of 2011.
The survival benefit in patients with bone metastases and advanced prostate cancer who were treated with a new alpha-pharmaceutical was so great that a placebo-controlled phase III trial was stopped much earlier than the planned 3-year follow-up.
Dr. Chris Parker (Consultant Clinical Oncologist, Royal Marsden Hospital, London, UK) reported findings from ALSYMPCA, an international investigation into the efficacy and safety of drug radium-223 chloride (Alpharadin).
The study assessed 922 prostate cancer patients (median age 70 years) who were resistant to hormone treatment and had bone metastases (>20 metastases in 40% of those randomised).
When data from a planned interim analysis on 809 evaluable patients were revealed, it was clear that not offering active treatment to those taking placebo would have been unethical, said Dr Parker.
Patients randomised to radium-223 were found to have a 30% lower risk of death (median overall survival [OS] 14.0 months vs 11.2 months, hazard ratio [HR] 0.695, p=0.00185). Time to first skeletal-related metastatic event also favoured treatment with the alpha-pharmaceutical (HR 0.61, p=0.00046.
Outlining the background to this study, Dr Parker said that more than 90% of patients with advanced castration-resistant prostate cancer (CRPC) have evidence of bone metastases – representing a major cause of early death, disability, reduced quality of life and increased treatment costs. “Current therapies have no impact on survival,” he emphasised.
Dr Parker explained that radium-223 delivers minute, highly charged and targeted doses of damaging radiation to bone metastases. Cells that are more than 100 microns distant are spared. “It has the potential to become a new gold standard for this disease,” he insisted.
Dr Parker said that, compared to chemotherapy, radium-223 has a completely different safety profile. Indeed, the ALSYMPCA trial was unusual in that toxicity was slightly greater in the placebo arm than it was in those treated with radium-223 (any grade 3/4 toxicity 51% vs 59%).
In general, he reported, side effects with radium-223 are minor - nausea, occasional loose stools, and a very small effect on bone marrow.
Dr Parker and his colleagues now intend to submit the ALSYMPCA data for regulatory approval. “I would hope that the authorities will approve radium-223 as a treatment for bone metastases in advanced prostate cancer soon,” said Dr. Parker.
He pointed out that this study was restricted to those men who were not going to receive chemotherapy for prostate cancer. “It would be interesting to use radium-223 chloride before chemotherapy, since it might be even more effective in that setting.”
He added: “It could also be used in many other types of cancers which metastasise to bone, regardless of the primary site. We believe that our trial may have paved the way for improvements in survival for very many cancer patients.”
A “designer” protein approach to tumour angiogenesis suggests survival benefit for patients with metastatic colorectal cancer (CRC), according to new data reported by Professor Josep Tabernero (Head of Oncology, Vall D’Hebron University Hospital, Medical Oncology Department, Barcelona, Spain).
Aflibercept (Eylea) is a new anti VEGF/PlGF fusion protein. Previously reported clinical evidence data from the phase III VELOUR study showed significant improvements, both in overall survival (OS) (13.5 months vs 12.06 months, hazard ratio [HR] 0.817, p=0.0032) and progression-free survival (PFS) (6.90 months vs 4.67 months, HR 0.758, p=0.00007) in favour of aflibercept.
A total of 1,226 patients with previously treated metastatic CRC were randomised to either 1-hour intravenous (iv) aflibercept (4 mg/kg), with or without FOLFIRI (leucovorin, 5-FU, irinotecan).
In this presentation, Professor Tabernero outlined details of a number of sub-group analyses of the VELOUR data – including performance status, age, gender, race, prior hypertension, number of organs involved, liver metastases only and primary cancer location (colon/sigmoid/rectum).
Supported by the lack of evidence of interaction among subgroups (p>0.1) the positive effect of aflibercept on OS was consistent across all subgroups but one – the presence or absence of liver metastases.
A significant interaction was observed between the treatment arm and liver metastases only, indicating a greater treatment effect in patients with only liver metastases (HR 0.649, p= .0899) than in patients with disease not confined to the liver (HR 0.868). Similar results were observed for PFS.
In the aflibercept arm, 186 patients had prior treatment with bevacizumab (Avastin), while 426 did not. There was no significant interaction between treatment and prior bevacizumab exposure on efficacy outcomes – OS (HR 0.862, p=0.7231), PFS (HR 0.661, p=0.6954).
The incidence of grade 3/4 anti-VEGF class events such as hypertension (16.6% vs 20.5%), haemorrhage (3.2% vs 2.8%), venous and arterial thromboembolic events (8.0% vs 7.8% and 2.1% vs 1.7%, respectively) were similar in patients with and without prior bevacizumab.
Professor Tabernero concluded: “These data confirm the robust nature of the original VELOUR findings, demonstrating that the addition of aflibercept to FOLFIRI improves OS and PFS in metastatic colorectal cancer not previously treated with oxaliplatin (Eloxatin). Furthermore, consistency of effect was seen among patients who had and had not received prior bevacizumab.
Commenting upon what he described as a “designer” protein approach to blocking tumour angiogenesis, Professor David Kerr (Head of Cancer Therapeutics, University of Oxford, UK, and current President of the European Society of Medical Oncology) said that the value of the VELOUR data was somewhat restricted by the multiplicity of sub-group analyses.
“What is needed,” he added, “are plausible biomarkers to guide patient selection. The overall survival data may well be clinically meaningful, but being able to apply new therapies to those most likely to benefit should be the goal.”
Last updated on: 11/10/2011 12:32:50
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