New insights on personalized cancer treatments: a report from the ESMO Congress

Abstract

The European Society for Medical Oncology (ESMO) Congress is organized by the ESMO every second year, alternating with the European Cancer Organisation–ESMO–European Society for Therapeutic Radiology and Oncology multidisciplinary cancer conference. The ESMO Congress provides current information on the latest research results in medical oncology and offers state-of-the-art educational programs to support medical oncologists in their training and practice. A record number of attendees (16,000 people) made the 35th ESMO Congress a great success, including over 13,000 oncologists and other cancer healthcare professionals, 360 media representatives and 400 cancer patients who participated in a dedicated seminar. To contextualize the magnitude of the data reported, it should be noted that over 63,000 patients have been treated in the randomized studies that were presented.

Randomized Phase III practice-changing studies

Johann de Bono (Institute for Cancer Research and Royal Marsden Hospital, London, UK) presented the results of a randomized double-blind placebo-controlled Phase III study that compared abiraterone acetate (potent and selective inhibitor of CYP17α-hydroxilyase) versus placebo in 1195 patients with castration-resistant metastatic prostate cancer. This is the first clinical trial that prospectively studied hormonal therapy after docetaxel treatment, and the first clinical trial in prostate cancer with prospective collection of circulating tumor cells. It is also the first trial that prospectively used the Prostate Cancer Clinical Trials Working Group Criteria in the context of a randomized Phase III trial. Overall survival data show clear advantages in favor of abiraterone acetate compared with placebo (14.8 vs 10.9 months), and the drug also significantly improved time to prostate-specific antigen progression, radiographic progression-free survival and prostate-specific antigen response rate. A decrease in circulating tumor cell levels matches the overall survival data, and side effects show almost no difference in comparison with placebo. Further follow-up on survival data is awaited, as well as a report on long-term side effects [1].

OPTIMAL is the first prospective Phase III study demonstrating that erlotinib is superior to standard platinum-based chemotherapy in EGF receptor (EGFR)-activating mutation-positive non-small-cell lung cancer (NSCLC) patients. In the Asian population that was studied, progression-free survival was significantly prolonged with erlotinib in comparison with standard chemotherapy (13.1 vs 4.6 months). The objective response rate was also significantly improved in the erlotinib arm (83 vs 36%). Survival data from the study are not yet available, and a confirmatory study in Caucasians is currently underway. The abstract was accompanied by a biomarker analysis including KRAS, EGFR T790M, HER2, BRAF, PIK3CA, PTEN mutations and c-MET amplification status. The study demonstrated that EGFR exon-19 mutation is the best predictor of efficacy and no additional biomarkers were identified to predict greater benefit of erlotinib versus gemcitabine/carboplatin in this patient population [2,3].

Tim Perren (Leeds Teaching Hospitals NHS Trust, Leeds, UK) reported findings from an international Phase III randomized trial that included 1528 women with high-risk early- or advanced-stage epithelial ovarian cancer, primary peritoneal cancer, or Fallopian tube cancer. This is the second large, positive, randomized trial in ovarian cancer patients that met the primary end point of prolonging progression-free survival. Investigators demonstrated that at 12 months, the risk of developing further progression of ovarian cancer was reduced by 15% compared with the risk of progression seen with chemotherapy alone. The major benefit is obtained in suboptimally debulked and advanced-stage patients. The results of ICON7 translational studies should identify the population who benefits from this treatment. The data concerning survival will not be available for another 2 years, but preliminary data show an encouraging early trend with fewer deaths in patients treated with bevacizumab. As an option in the best treatment outcomes currently achieved, the bevacizumab arm should be taken as a standard comparator in further clinical research [4].

Treatment options for advanced neuroendocrine tumors are limited. In 429 patients who are progressing well or have moderately differentiated advanced neuroendocrine tumors and a history of carcinoid symptoms, everolimus – an oral inhibitor of the mTOR pathway – was administered together with octreotide LAR and compared with placebo plus octreotide LAR. The study was presented by Marianne Pavel (Charité University Hospital, Berlin, Germany), who showed a 5.1-month clinically meaningful increase in median progression-free survival for the everolimus combination compared with placebo plus octreotide LAR. This should be considered for changing the current practice, as the alternative treatment is either octreotide or a very aggressive chemoembolization [5]. Another clinically meaningful report on 410 patients with advanced low- or intermediate-grade pancreatic neuroendocrine tumors showed a 65% reduction in the risk of progression, and an increase from 4.6 to 11.0 months in median progression-free survival when everolimus was combined with the best supportive care and compared with placebo plus best supportive care. This study was presented by James Yao (MD Anderson Cancer Center, TX, USA) [6].

Novel targeted agents & randomized trials

David Spigel (Sarah Cannon Research Institute, TN, USA) reported the results of a study that included 128 patients with advanced NSCLC. Patients were randomly assigned to treatment with either erlotinib plus placebo, or erlotinib plus novel agent MetMAb, a monoclonal antibody that binds specifically to the MET receptor. This is the second trial in lung cancer where targeting of the MET receptor in combination with erlotinib suggests a better outcome. Immunohistochemically MET-positive populations derived a benefit in progression-free survival, as well as an almost statistically relevant overall survival benefit. A note of caution is that these Phase II results should be validated in a Phase III trial [7].

Georgina Long (Melanoma Institute Australia and Westmead Hospital, NSW, Australia) reported the results in a subgroup of ten melanoma patients with previously untreated brain metastases from the international Phase I/II trial with the selective oral inhibitor of V600 mutant BRAF kinase. The investigators described the activity of this targeted agent in brain metastasis. All patients experienced control, and almost all experienced reductions in the overall size of their brain metastases. The overall reductions ranged from 20 to 100% of brain metastases that were 3 mm or larger before treatment. Furthermore, the authors observed that the response in brain metastasis correlated with extracranial tumor response. The ability to inhibit oncogenic BRAF is the most important development in the history of drug treatment of melanoma [8].

No established therapy exists for NSCLC patients who fail chemotherapy and erlotinib or gefitinib. Although the LUX-Lung 1 study did not meet its primary end point of extending overall survival, this does not diminish the potential value of afatinib (BIBW2992). The fact that this new irreversible inhibitor of EGFR/HER1 and HER2 induced objective regressions in heavily pretreated NSCLC patients and led to a better progression-free survival, with improvements in some cancer-related symptoms, demonstrates the usefulness of this compound for oncologists working in the field of lung cancer [9].

New formulations of old drugs to innovate the therapeutic armamentarium against cancer

EndoTAG-1 is an innovative formulation that tries to capitalize on the potential antiangiogenic proprieties of paclitaxel. In this new drug, paclitaxel is embedded in cationic liposomes and targets activated endothelial cells of tumor vessels. It is also innovative since it targets the environment and not the tumor cell itself. Results from the first randomized Phase II study of EndoTAG-1 targeting tumor endothelial cells in advanced triple-negative breast cancer are somewhat disappointing since EndoTAG-1 alone does not seem to be a valid option, with progression-free survival rate at week 16 inferior to paclitaxel alone, albeit with overlapping confidence intervals. Nevertheless, the apparent benefit of the combination arm (also with overlapping confidence intervals) merits further evaluation in a subsequent study [10].

Hedgehog inhibition

The presentations of five reports on Hedgehog inhibition was the logical follow-up of the proof-of-concept study in basal cell carcinoma (1 year ago), presenting new observations in the pathway, evidence of acquired resistance to therapy and the development of new targeted agents. Two Phase II placebo-controlled randomized studies were designed to assess the efficacy and safety of GDC-0449 in first-line treatment of metastatic colorectal cancer, and as maintenance therapy in patients with ovarian cancer in second or third complete remission [11,12]. In both settings, results do not demonstrate a clinical benefit, and early drug discontinuation due to adverse events may suggest a lower tolerance in the maintenance setting. Another potent, selective Hedgehog inhibitor, LDE225, has been assessed in the ‘first-in-human study’ with observed good tolerance, a favorable pharmacokinetic profile and target modulation. An anti-tumor response was noted in patients with recurrent medulloblastoma, and disease stabilization in patients with basal cell carcinoma, spindle cell carcinoma and osteosarcoma [13]. A report of the first clinical experience of IPI-926 shows preliminary evidence of clinical activity in patients with basal cell carcinoma, medulloblastoma and chondrosarcoma [14]. In addition, a small preclinical study shows heterogeneous expression patterns of the Hedgehog pathway in biliary tract cancer cell lines. Even though markers predicting the efficiency of pathway inhibition are yet to be identified, such an approach may prove valid for novel treatment strategies in these difficult-to-treat cancers [15]. Most of the currently active pancreatic cancer studies are recruiting well.

Randomized trials in surgery for palliation of painful metastases

Leonard Bastian (Klinikum Leverkusen, Germany) led the first international randomized trial testing a minimally invasive surgical technique, balloon kyphoplasty, to nonsurgical management in the treatment of cancer patients with vertebra compression fractures. The investigators found that this new technique offers effective relief in cancer patients with painful and debilitating spinal fractures and led to improved quality of life [16].

Conclusion

The 35th European Society for Medical Oncology Congress helped in making a further step towards understanding the biology of cancer and molecular observations that should drive the treatment of the right patient, at the right time, with the right drug and the right dose.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.