European Multidisciplinary Cancer Congress (EMCC) Stockholm, Sweden, September 23-27th 2011

Until now, European cancer meetings have invariably had to live in the shadow of research and clinical trial data that has already been reported in the United States. With EMCC 2011, all that changed.

Attracting nearly 17,000 cancer specialists from all over the world – and representing the multidisciplinary interests of clinical and medical oncologists, cancer specialist nurses and other healthcare professionals with a specific interest in the treatment of patients with cancer – EMCC 2011 truly came of age, delivering first-time data across a wide range of malignancies. 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 and docetaxel.

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

- iv trastuzumab 6mg/kg (8 mg/kg in cycle 1) + iv docetaxel 75mg/m² (74.2% of those randomised) or 100mg/m2

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.

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 in combination with dacarbazine 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.

A new way of delivering chemoradiation to women with early-stage breast cancer (EBC) has resulted in a 35% reduction in the risk of local recurrence (LR), according to new data from a landmark clinical trial.

Dr Indrajit Fernando (Consultant Clinical Oncologist, University Hospitals Birmingham NHS Foundation Trust, UK) reported that synchronous radiotherapy (RT) – delivered between or during chemotherapy cycles - has minimal adverse effects and no detrimental effect on quality of life (QoL).

He presented findings from the SEquencing of Chemotherapy and Radiotherapy in Adjuvant Breast cancer (SECRAB) study, which was carried out at 48 centres in the UK and is the largest study yet to investigate the synchronous strategy in any detail.

In this randomised phase III trial, data on 2,296 women who had undergone breast-conserving surgery or mastectomy were analysed.

All patients received chemoradiation after surgery, either sequential (1,146 patients) or synchronous, where the radiotherapy was given in the gaps between chemotherapy cycles (1,150 patients). More than 60% of patients received 40Gy in 15 fractions over three weeks.

The aim of this trial was to determine the best schedule for giving radiotherapy with cyclophosphamide/methotrexate/fluorouracil (CMF) or anthracycline–CMF chemotherapy after surgery to women with EBC.

After a median follow-up of 8.8 years, only 41 patients randomised to synchronous chemoradiation experienced LR compared to 63 patients in the sequential arm (5-year LR rate 2.8% vs 5.1%, hazard ratio [HR] 0.65, p=0.03).

Dr Fernando commented: "One breast cancer death can be avoided for every four local recurrences prevented. "Therefore, even small improvements in local control will have a significant long-term benefit."

In a QoL analysis of the data from SECRAB in 565 patients, mild-to-severe skin toxicity was greater in the synchronous arm of the study (24% vs 15%), but no other significant differences in terms of QoL parameters were observed. Neither did synchronous chemoradiation compromise overall survival (5-year survival rates 83% vs 82%).

However, Dr Fernando pointed out: "Only 4% of patients in the synchronous arm had a severe reaction – the vast majority of women experienced moderate skin reactions which would have been resolved within 4-6 weeks with no detrimental effect on their quality of life. Furthermore, since the completion of SECRAB, methods of delivery RT have improved considerably, reducing the risk of acute skin reactions even further."

He added that acute skin toxicity was significantly less in patients being treated with three weeks of synchronous RT (40Gy radiation in 15 fractions) compared to those with schedules of a longer duration (45Gy in 20 fractions over four weeks or 50Gy in 25 fractions over five weeks.

Dr Fernando said that there could also be economic benefits in terms of when patients can return to work. "Shortening the overall treatment time may mean that when patients have finished their last chemotherapy course they can return to their normal life without having to then complete their radiotherapy."

The survival benefit in patients with bone metastases and castration-resistant prostate cancer (CRPC) 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.

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.

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.

He 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."

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 (Head 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 (25mg a day), with or without the oral signal transduction inhibitor everolimus (10mg a day).

Patients were oestrogen receptor-positive advanced breast cancer, refractory to previous treatment with two other aromatase inhibitors, letrozole or anastrozole. Many had also received prior therapy with tamoxifen (48%), fulvestrant (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 that nearly all patients with advanced breast cancer that has metastasised - become resistant to hormonal therapy. 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 grade 3/4 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.

Worldwide regulatory submissions for everolimus as a treatment for oestrogen receptor-positive advanced breast cancer are expected to be submitted by the end of 2011.