35th Congress of the European Society for Medical Oncology (ESMO): October 8-12, 2010, Milan, Italy.
IntroductionThis year's meeting revealed innovative progress from clinical trials, new drugs and therapy developments. Scientific advancement of genetic and proteomic profiling was highlighted, as well as the identification of microRNAs for diagnosis. The focus of this meeting was on the use of molecular-targeted therapies with acceptable safety profiles to treat different cancers. The quality of the scientific programme at this congress was extremely high, and a number of studies will be remembered because of their implications for oncology practice.
Breast cancer
The addition ofcetuximab to cisplatin increases overall response rate (ORR) and progression-free survival (PFS) in metastatic triple-negative breast cancer (TNBC): Results of a randomized phase II Study (BALI-1) [1]
Epidermal growth factor receptor (EGFR) plays a role in triple-negative breast cancer (TNBC). Cetuximab is an anti-EGFR antibody, and was investigated by the authors for the treatment of metastatic TNBC with cisplatin. Patients (n=173) with histologically confirmed metastasis, were randomly allocated 2:1 to receive: cetuximab (400 mg/m2 initial dose then 250 mg/[m.sup.2] weekly) plus up to six 3-weekly cycles of cisplatin (75 mg/[m.sup.2], day 1); or up to six 3-weekly cycles of cisplatin alone. There was the option, on disease progression (PD), for patients to switch to cetuximab plus cisplatin (PD during the six cisplatin cycles], or cetuximab alone (PD after the six cisplatin cycles). Twenty-seven per cent of patients in both arms had received prior chemotherapy.
The overall response rate (ORR) of 20% (95% Cl 13.1-28.5) was observed among patients in the cetuximab/cisplatin combination group, which was double the rate observed with cisplatin alone (HR 10.3%, 95% CI 3.9-21.2; P=0.11). The addition of cetuximab to cisplatin also increased the median length of PFS from 1.5 to 3.7 months (HR 0,675, 95% CI 0.470-0.969; P=0.032). The adverse reactions included acne-like rash (14% cetuximab/cisplatin versus 0% cisplatin), neutropenia (9.6% versus 5.3%), fatigue (8.8% versus 7.0%) and dyspnoea (6.1 % versus 1.8%).
When combined with cisplatin, cetuximab significantly improved the ORR and PFS rate in this subset of breast cancer patients. This study provided the first evidence to suggest that EGFR might be a target for triple-negative breast cancer.
Efficacy and safety of trastuzumab-DMl versus trastuzumab plus docetaxel in HER2-positive metastatic breast cancer patients with no prior chemotherapy for metastatic disease: preliminary results of a randomized, multicenter, open-label phase 2 study (TDM4450G) [2]
This is the first randomised Phase II study of an antiHER2 antibody-drug conjugate, trastuzumab-DM1 (T-DM1), which is a novel combination for breast cancer treatment. Trastuzumab is a monoclonal antibody, which targets cells that overproduce the protein HER2, whereas DM1 is a chemotherapy agent that targets microtubules. Thus, when trastuzumab binds to the HER2 protein in the cell, the whole trastuzumab-DM1 molecule is internalised and the chemotherapy is strategically targeted inside the cell, thereby minimising adverse effects.
T-DM1 was compared with trastuzumab plus docetaxel in patients with HER2-positive metastatic breast cancer who had not received prior chemotherapy for metastatic disease. Sixty-seven women received T-DM1 [3.6 rng/kg intravenously (IV) every 3 weeks], and 70 received treatment with trastuzumab (6 mg/kg IV; 8 mg/kg in cycle 1) plus docetaxel (75 or 100 mg/[m.sup.2] IV on day 1 every 3 weeks). Patients remained on treatment until disease progression or unacceptable toxicity.
After a median of 6 months' follow-up, 48% (95% CI 35.4-50.3%) of patients in the T-DM1 group showed a complete or partial response compared with 41% (95% CI 30.2-53.8%) in the trastuzumab-plusdocetaxel group. The percentage of patients showing clinical benefit was similar in the two groups. The rates of clinically relevant adverse events (grade >3) were significantly lower in the T-DM1 group (37.3%) compared with the trastuzumab-plus-docetaxel group (75%). The most common adverse effects were alopecia (1.5% versus 66.2%), neutropenia (7.5% versus 57.4%), and diarrhoea (10.4% versus 45.6%) for T-DM1 and trastuzumab plus docetaxel, respectively. As first-line therapy in patients with HER2-positive metastatic breast cancer, TDM-1 confirmed good efficacy and lower toxicity than standard therapy.
Final efficacy and safety results of a randomized phase II study of the PARP inhibitor iniparib (BSI201) in combination with gemcitabine/carboplatin (G/C) in metastatic triple negative breast cancer (TNBC) [3]
Iniparib is a novel small molecule that inhibits PARP1, a nuclear enzyme that promotes DNA repair through the base-excision repair pathway. Triple-negative breast cancer (TNBC) is associated with DNA repair defects such as those inhibited by iniparib. Iniparib also potentiates the effects of gemcitabine and carboplatin (G/C). The authors evaluated iniparib in combination with G/C, compared with G/C alone, in patients with metastatic TNBC.
Patients were randomly allocated (1:1) to G/C alone or G/C plus iniparib. Gemcitabine (1000 mg/[m.sup.2] IV) and carboplatin were given on days 1 and 8, and iniparib (5.6 mg/kg IV) on days 1, 4, 8 and 11 every 21 days. In this Phase II study, 123 women with metastatic triple-negative breast cancer (1:1) received G/C alone (n=62) or G/C plus iniparib (r=61).
Patients who received G/C plus iniparib had a median overall survival of 12.3 months, compared with 7.7 months for patients who received chemotherapy alone (P=0.Q14). The addition of iniparib significantly improved clinical outcomes in patients with metastatic triple-negative breast cancer. PFS was also improved in the group who received iniparib, at 5.9 months versus 3.6 months (HR 0.59, 95% CI 0.39-0.90; P=0.012). Some 55.7% of patients in the iniparib group experienced a complete or partial response, or stable disease, for at least 6 months, compared with 33.9% in the control group. The addition of iniparib to combination chemotherapy was well tolerated and did not potentiate chemotherapy-related toxicities. The common grade 3/4 adverse events encountered were neutropenia, thrombocytopenia, anaemia, fatigue, leukopenia and alanine aminotransferase (ALT) increase, seen in both groups (81% versus 86%). The ORR was 52.5% in the iniparib group and 32.3% in the control group.
Prostate cancer
Abiraterone acetate (AA) plus low dose prednisone (P) improves overall survival (OS) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) who have progressed after docetaxel-based chemotherapy (chemo): Results of COU-AA-301, a randomized double-blind placebo-controlled phase III study. [4] Abiraterone acetate is an oral drug that works by targeting persistent androgen synthesis and androgen receptor signalling from adrenal and intra-tumoral sources. It is a potent and selective inhibitor of CYP17[alpha]-hydroxylase.
The study recruited 1195 patients with castration-resistant metastatic prostate cancer, who had been previously treated with docetaxel. Patients were assigned to treatment with abiraterone acetate 1000 mg plus prednisone 5 mg twice daily (n=797) or placebo plus prednisone (n=398) at 147 centres in 13 countries.
The median overall survival was 14.8 months in the abiraterone group and 10.9 months in the placebo group with a hazard ratio (HR) of 0.65 and 95% confidence interval (CI) of 0.54-0.77. Radiological progression-free survival (PFS) was 5.6 and 3.6 months in the abiraterone and placebo groups, respectively. The adverse effects, reported more in the treatment group, included fluid retention, hypokalaemia, liver-function test abnormalities and cardiac problems.
This Phase III double-blind randomly allocated trial showed good drug tolerance and a 3.9-month improved survival compared to placebo for patients with metastatic castration-resistant prostate cancer.
Palliative care
First randomised trial comparing balloon kyphoplasty (BKP) to non-surgical management among cancer patients with vertebral compression fractures [5]
This is the first study comparing BKP to non-surgical management of metastatic cancer patients with vertebral compression fractures (VCFs). BKP is a minimally invasive procedure for symptomatic patients with VCFs, with a view to reducing pain and disability. Adult patients diagnosed with cancer and fewer than three painful VCFs were randomly assigned to BKP (n=70) or non-surgical management (NSM; n=64) and followed for 12 months. The primary objective was to determine the change identified by the Roland-Morris Disability Questionnaire (RMDQ) at 1 month.
After an interval of 1 month, the BKP-treated patients showed an improvement of -8.3 points in their RMDQ score compared to the NSM group (who showed no significant change) (0.1, P<0.0001 for difference between groups). In comparison with the NSM group, BKP patients reported fewer days with limited activity due to back pain (6.3 fewer days per 2 weeks; treatment effect P<0.0001) and greater improvements in quality of life (QoL) measured by the SF-36 PCS score (treatment effect 8.4 points higher; P<0.0001). Thirty-eight of the 61 NSM patients crossed over and were also assessed for safety and efficacy through the study period--and showed similar benefits with regards to back pain relief, analgesic use, activity level and QoL as those originally assigned to BKP. All BKP patients reported sustained improvements throughout the 12-month period.
Randomized multicenter double-blind placebo-controlled phase II study evaluating MetMAb, an antibody to MET receptor, in combination with erlotinib, in patients with advanced non-small-cell lung cancer [6]
MetMAb is a unique monovalent antibody that binds to the Met receptor. It prevents hepatocyte growth factor from binding to MET receptors, which in turn blocks receptor stimulation. This inhibits the MET signalling pathway, which is implicated in the resistance to EGFR inhibition of EGFR-mutated NSCLC.
OAM4558g is a global randomised, double-blind Phase II study comparing MetMAb (15 mg/kg IV every 3 weeks) plus erlotinib (ME) to placebo plus erlotinib (PE) in second-/third-line NSCLC. Patients (n=128) were randomly allocated from March 2009 to March 2010 to ME (n=64) or PE (n=64). Tissue was evaluable for Met in n=121 and for EGFR and KRA5 mutations in n=112. Both a PFS benefit (HR 0.56, 95% CI 0.31-1.02; P=0.05,) and an OS benefit (HR 0.55, 95% Cl 0.25-1.16; P=0.11) were observed in the Met-positive patients treated with ME. However, in the Metnegative population, PFS (HR 2.01, 95% Cl 1.04-3.91; P=0.04) and OS (HR 3.26, 95% Cl 1.20-8.80; P=0.01) were worse. HR for PFS and OS in the intent-to-treat (ITT) population were 1.09 (95% CI 0.71-1.67; P=0.70) and 1.13 (95% CI 0.64-1.97; P=0.68), respectively.
The combination of MetMAb and erlotinib in patients with Met-positive NSCLC improved both PFS and OS and with manageable toxicities. Conversely, Met-negative NSCLC patients had worse PFS and OS when treated with ME, and a higher incidence of grade 3 adverse events.
ICON7: a phase III randomised Gynaecologic Cancer Intergroup trial of concurrent bevacizumab and chemotherapy followed by maintenance bevacizumab, versus chemotherapy alone in women with newly diagnosed epithelial ovarian (EOC), primary peritoneal (PPC) or fallopian tube cancer (FTC) [7]
ICON 7 is the second largest ovarian trial undertaken to date, to evaluate the safety and efficacy of adding bevacizumab to standard chemotherapy with carboplatin and paditaxel in the first-line treatment of EOC, PPC or FTC. Eligible women with high-risk early [FIGO stage I or Ha (grade 3 or clear cell), capped <10%) or advanced (stage llb-IV) EOC, PPC or FTC were randomly allocated (1:1) to six cycles of 3-weekly chemotherapy (carboplatin AUC 6 and paditaxel 175 mg/m2) alone, or the same chemotherapy given concurrently with bevacizumab (7.5 mg/kg) for six cycles followed by maintenance bevacizumab continued 3-weekly for 12 additional cycles or until progression--whichever was the earlier.
A total of 1528 women (90% with EOC) were randomly allocated from 263 centres in seven Gynaecologic Cancer Intergroup (GCIG) groups. Subsequently, 759 (50%) progressions/deaths--a hazard ratio of 0.81 (95% CI 0.70-0.94) and P-value (log-rank test) of 0.0041, favouring the bevacizumab arm--were observed. The major benefit was observed in the suboptimally debuIked/advanced-stage patients. Hence, the researchers concluded that, in addition to the standard treatment for these patients, oevacizumab should be a standard comparator in future clinical research.
A randomized, double-blind, placebo-controlled, multicenter phase III trial of everolimus + octreotide LAR vs placebo + octreotide LAR in patients with advanced neuroendocrine tumors (NETHRADIANT-2) (8)
Everolimus has demonstrated promising activity in combination with octreotide in patients with advanced NET in Phase II studies. Four hundred and twenty-nine uatients, with progressing well or moderately differentiated advanced NET and a history of carcinoid symptoms, were randomly assigned to everolimus 10 mg per day orally + octreotide LAR 30 mg intramuscularly (IM) every 28 days [(E+O), n=216]; or olacebo + octreotide LAR [(P+O), n=213].
Median PFS with E+O was 16.4 months (95% CI 13.67-21.19) versus 11.3 months (95% CI 8.4414.59) for P+O. E+O was associated with a 23% reduction in risk of progression [HR 0.77, 95% CI 0. 59-1.00; P=0.026 (log-rank test one-sided P-value did not meet the prespecified significance level of P=0.0246)]. Median PFS, by investigator review, was 12 months (95% CI 10.61-16.13) and 8.6 months (95% CI 8.08-11.14) for E+O and P+O, respectively. E+O was associated with a 22% reduction in risk of orogression (HR 0.78, 95% CI 0.62-0.98; P=0.018).
This large. Phase III, randomised controlled trial showed that everolimus plus octreotide LAR provided a 5.1-month clinically meaningful increase in median PFS, as compared to placebo + octreotide LAR.
Conclusion
Studies presented at the meeting revealed a drive towards biomarker identification and targeting to enhance patient selection of treatments. The main focus of this conference was on improving cancer outcomes with use of newer targeted therapies. Personalised treatment for individuals, based on their cancer characteristics, should be the goal of researchers in future clinical trials. More information is available at www.esmo.org/events/milan-2010-congress.html.
References
[1.] Baselga J, Gomez P, Awada A et al. The addition of cetuximab to cisplatin increases overall response rate (ORR) and progressionfree survival (PFS) in metastatic triple-negative breast cancer (TNBC): Results of a randomized phase II study (BALI-1). Ann Oncol, 2010, 21(Suppl 8), Abstr. 2740.
[2.] Perez EA, Diri* L, Kocsis J era/. Efficacy and safety of trastuzumab-DM1 versus trastuzumab plus docetaxel in HER2oositive metastatic breast cancer patients with no prior chemotherapy for metastatic disease: preliminary results of a "andomized, multicenter, open-label phase 2 study (TDM4450G). Ann Oncol, 2010, 2t(Suppl 8), Abstr. LB A3.
[3.] O'Shaughnessy J, Osborne C Pippen J etal. Final efficacy and safety results of a randomized phase II study of the PARP nhibitor iniparib (BSI-201) in combination with gemcitabine/carboplatin (G/C) in metastatic triple negative breast cancer (TNBC). Ann Oncol, 2010, 21(Suppl 8), Abstr. LBA11.
[4.] De Bono JS, Logothetis CJ, Fizazi < er al. Abiraterone acetate (AA) plus low dose prednisone (P) improves overall survival (OS) n patients (pts) with metastatic castration-resistant prostate cancer (mCRPO who have progressed after docetaxel-based chemotherapy (chemo): Results of COU-AA-301, a randomized double-blind placebo-controlled phase III study. Ann Oncol. 2010, 21(Suppl 8), Abstr. U3A5.
[5.] Bastian L, Pflugmacher R, Berenson JR etal. First randomised trial comparing balloon kyphoplasty (BKP) to non-surgical management among cancer patients with vertebral compression fractures. Ann Oncol. 2010, 21(Suppl 8), Abstr. 11810.
[6.] Spigel D, Ervin T, Daniel D er al. Randomized multicenter double-blind placebo-controlled phase II study evaluating MetMAb, an antibody to MET receptor, in combination with erlotinib, in patients with advanced non-small-eel I lung cancer. Ann Oncol. 2010, 21(Suppl 8), Abstr. LBA15.
[7.] Perren T, Swart AM, Pfisterer J et al. ICON7: a phase III randomised Gynaecologic Cancer Intergroup trial of concurrent bevacizumab and chemotherapy followed by maintenance bevacizumab, versus chemotherapy alone in women with newly diagnosed epithelial ovarian (EOC), primary peritoneal (PPC) or fallopian tube cancer (FTC). Ann Oncol. 2010, 21 (Suppl 8), Abstr. LBA4
[8.] Pavel M, Hainsworth JD, Baudin E ei al. A randomized, double-blind, placebo-controlled, multicenter phase III trial of everolimus + octreotide LAR vs placebo + octreotide LAR in patients with advanced neuroendocrine tumors (NET)(RADIANT-2). Ann Oncol, 2010, 21 (Suppl 8), Abstr. LB A3.
Maryam Alfa-Wali (1) and Anand Sharma (2)
(1) Department of Surgery and Cancer, Imperial College London, South Kensington Campus, London, UK
(2) Department of Medical Oncology, University College London Hospital, London, UK
Correspondence to. Anand Sharrna
Department of Medical Oncology
University College London Hospital
250 Euston Road
London NW1 2PG, UK
(email: drandy2003@gmail.com)
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| Title Annotation: | Conference Report |
|---|---|
| Author: | Alfa-Wali, Maryam; Sharma, Anand |
| Publication: | Advances in Breast Cancer |
| Article Type: | Conference notes |
| Date: | Dec 1, 2010 |
| Words: | 2747 |
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