The February 2014 issue of Nature Reviews Clinical Oncology hosts reports on advances in six tumour types, as seen and interpreted by internationally-renowned experts.
Stephen V. Liu and Giuseppe Giaccone of the Lombardi Comprehensive Cancer Center, Georgetown University, Washington, USA, wrote that several important studies, reported in 2013, have provided valuable insight into the evolving treatment paradigms of non-small cell lung cancer (NSCLC), particularly with regard to targeted therapies.
PROFILE-1007 and LUX-Lung 3 trials confirmed that targeted therapy continues to be a more effective option than chemotherapy, specifically, crizotinib in ALK-positive lung cancer and afatinib in EGFR-mutant lung cancer, whereas NCIC BR19 failed to show superiority of adjuvant gefitinib. In the PointBreak study, combination maintenance therapy with pemetrexed plus bevacizumab after induction with pemetrexed-based chemotherapy was not superior to bevacizumab maintenance alone after induction with a paclitaxel-based regimen.
The authors concluded that genomic-based targeted therapy represents the most important paradigm in the treatment of advanced-stage lung cancer. Although the use of crizotinib and afatinib in molecularly defined populations of advanced NSCLC was supported by big randomised phase III studies, the adjuvant study with targeted agent warns against early adoption and reminds on the need for prospective studies. Similarly, the maintenance study serves as a reminder that more is not necessarily better.
Adrian V. Lee and Nancy E. Davidson of the University of Pittsburgh, USA wrote that the breast cancer research community saw much progress in 2013. Advances in high-throughput technologies continue to refine knowledge of the molecular biology of breast cancer, and begin to give insight into cancer evolution, drug resistance, and how to deploy precision therapeutics. They highlighted the next findings: oestrogen receptor gene (ESR1) is mutated in several hormone-resistant advanced-stage breast cancers, which have altered activity and might represent novel therapeutic targets; breast cancer mutations detected in circulating-free DNA by whole-exome and whole-genome sequencing change with therapeutic resistance and can reflect disease progression.
In 2013, pertuzumab was the first agent to benefit from the FDA new guidelines for the use of pathological complete response as an endpoint to support the development and accelerated approval of new agents and received approval as a neoadjuvant treatment for patients with HER2-positive early stage breast cancer.
In 2013, the results of four large clinical trials designed to optimise the use of active targeted agents were reported (ATLAS, aTTom, PHARE, HERA). In term of findings, the authors concluded that extended adjuvant hormone therapy is more efficacious than short-term therapy, but extended adjuvant trastuzumab therapy is not. The difference between optimal length of adjuvant tamoxifen and trastuzumab therapy could have several explanations, but one might be the relative indolence of ER-positive disease in which endocrine therapies, such as tamoxifen, act to control the dormancy of micrometastases.
Chris Meijer and Peter Snijders of the Vrije University Medical Centre Amsterdam, The Netherlands, wrote that researchers in 2013 confirmed that HPV infection of specific embryonal, cuboidal target cells in the squamocolumnar junction provides a likely explanation for the development of cervical precancer and cancer.
In developed countries, HPV screening revealed superior protection than Pap smear screening. Future perspectives include the development of HPV self-sampling, opening the way to molecular self-screening. For girls who have been vaccinated with prophylactic bivalent or quadrivalent HPV vaccine, the conversion to HPV screening will provide a joint approach to cancer prevention.
In underdeveloped countries, visual inspection with acetic acid screening with well-educated primary health-care workers showed important results in reducing cervical cancer mortality. In India, its application significantly reduced cervical cancer mortality after 12 years. Although these positive results warrant implementation in the short run, long-term prevention strategies should focus on use of prophylactic HPV vaccination at prepubertal age, and HPV testing with a cheap method at an older age (≥30 years).
For women with advanced-stage cervical cancer, improved survival was observed with bevacizumab.
Hans-Joachim Schmoll of the Martin Luther University in Halle and Alexander Stein of the University Cancer Centre Hamburg, both based in Germany, wrote that 2013 brought more options for patients with metastatic colorectal cancer (mCRC), with new ways to combine traditional agents, further refinement of molecular prediction to EGFR inhibitors and a new salvage option.
Upfront four-drug regimen FOLFOXIRI in combination with bevacizumab has shown to be superior to standard three-drug combinations.
A retrospective analysis of the PRIME study demonstrated that within the 'classic' KRAS wild-type population (patients without mutations in exon 2), patients with mutations in other KRAS exons (exon 3 and 4) or in NRAS (exon 2 and 3) did not benefit from the addition of panitumumab to FOLFOX. These data led to the change in the registration label for panitumumab. The need to investigate all types of mutations in KRAS and NRAS is additionally strongly supported by the preliminary reports of the first two trials that compared VEGF versus EGFR inhibitors in combination with chemotherapy (FIRE-3 and PEAK trials).
In 2013, the 'bevacizumab beyond progression' approach prolonged median overall survival by 1.4 months and progression-free survival by 1.6 months. Notably, adverse events did not increase when continuing bevacizumab in second-line treatment. These data are in accordance with the efficacy of aflibercept, another VEGF inhibitor, in patients for whom chemotherapy and bevacizumab treatment had failed, and indicate that the supportive effect of VEGF inhibition together with chemotherapy is maintained at least in the first-line and second-line setting.
Numerous phase III trials evaluating different tyrosine kinase inhibitors (TKIs) (vatalanib, sunitinib and cediranib) in combination with chemotherapy showed similar efficacy and less tolerability compared to chemotherapy with and without bevacizumab. Regorafenib finally succeeded as the first TKI to be licensed as a single agent in the last-line treatment setting for patients with mCRC.
Instead of using single molecular or biochemical markers, six clinically different subtypes have been identified by gene-expression profiling, each showing different degrees of activation of Wnt signalling and 'stemness', and chemotherapy response as well as survival in the adjuvant and metastatic settings. Apart from showing the sensitivity or resistance to available treatments, some subtypes might be sensitive to inhibition of MET. This strategy seems to be promising for accelerated drug development and testing.
Besides the evaluation of new agents, particularly in molecularly defined subgroups such as BRAF-mutant or HER2-positive mCRC, trials applying liquid biopsy will enable real-time tumour information.
Augusto Villanueva of the King's College, London, UK and Josep Llovet of the IDIBAPS-Hospital Clínic, University of Barcelona, Spain wrote that next-generation sequencing analysis and characterisation of the microenvironment 'field-effect' that promotes hepatocellular carcinoma (HCC) development has revealed critical players and potential targets for chemoprevention. In particular, they stated that HCC has reached 'the end of beginning' in term of genome characterisation. There is an overall picture of the mutation rate and distribution, but whether these events have a driving role in HCC progression or if they define oncogenic addiction loops in human HCC is still unclear. The most prevalent mutations in HCC affect the TERT promoter, TP53 and CTNNB1m and IL-6 is emerging as a reliable target for chemoprevention strategies.
In term of changes in clinical decision-making in HCC management, not much progress was made in 2013. After the approval of sorafenib, six randomised controlled trials that could have potentially changed the standard of care for patients with HCC, assessing drugs that included brivanib, erlotinib, linifanib and everolimus have reported negative findings in the first- and second-line settings. However, the results from negative phase III trials reinforce the concept that molecular information should be incorporated in the drug development process for HCC.
Dirk Schadendorf of the University Hospital Essen and Axel Hauschild of the University Hospital in Kiel, both based in Germany, reported that in 2013 major molecular understandings emerged in term of key somatic events, such as mutations in BRAF, NRAS or CKIT. These findings rapidly translated into pivotal drug development and subsequently into clinical management with improved overall survival, but also to the emergence of acquired resistance.
Besides targeted therapy with BRAF or MEK inhibitors, a second distinct approach has emerged, the modulation of the immunological checkpoint. In 2013, antibodies against PD-1 and PD-L1 emerged as breakthrough compounds for melanoma with high response rates and long durability. Breaking the immune tolerance at the tumour site with anti-PD-1 antibodies and the potential for a simultaneous blockade of multiple immune inhibitory checkpoints by combining different agonistic antibodies opens the door for long-term tumour control. Potential synergies between immune checkpoint inhibitors and MAPK-targeted therapy are emerging, but unexpected adverse events have occurred and combination strategies are currently recommended in clinical trials only.