Strategies in Clinical Hematology

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Search for a location and select one from the list of suggestions. Life at AstraZeneca At AstraZeneca, our purpose is to help patients all over the world by delivering life-changing medicines as one collaborative team. To date, multiple targeted therapies have been approved by the US FDA, with many more currently in different phases of clinical trial testing [ 81 ].

In this section, we detail key examples that have paved the way for the development of other novel antitumor agents, and discuss efforts and progress made in biomarker discovery for such drugs. Figure 1 illustrates a potential patient pathway in the clinic for rational biomarker and clinical drug development.

Figure 2 highlights key pathways that are targeted by novel anti-cancer therapeutics, as discussed below.


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Patients start with informed consent to access their archived tumor sample. When applicable, circulating tumor cells and plasma DNA are sampled; as well as accessible fresh tumor. Tumor DNA is then purified and sequenced, and the results are presented at a tumor board of experts, where the patient is then allocated to an appropriate trial based on the results.

Fresh tumor can also be grafted into mice to determine if a theraphy is effective, before giving to the patient. Tumor resampling after progression on theraphy is essential to identifying the mechanism of resistance and a new treatment strategy. Molecular pathways in cancer progression. This figure identifies some of the common pathways involved in cancer cell growth and proliferation. Bevacizumab is a humanized monoclonal antibody against vascular endothelial growth factor A VEGF-A , which is a critical factor required for the growth of blood vessels in tumors [ 82 ].

It was the first anti-angiogenic drug approved for the treatment of patients with advanced colorectal cancer [ 83 ]. However, despite its broad clinical activity, no definitive predictive biomarkers of antitumor response have been identified, despite multiple large high profile clinical studies in this area [ 84 ]. For example, Cameron and co-workers undertook a phase III trial assessing the role of bevacizumab in patients with resected triple-negative breast cancer [ 85 ].

In this study, patients were randomly allocated to four or more cycles of anthracycline-based or taxane-based chemotherapy with or without bevacizumab. The primary endpoint of progression-free survival was however not met and importantly grade 3 or worse toxicity was more common with the bevacizumab arm [ 85 ],[ 86 ]. In addition, bevacizumab is the only antiangiogenic drug approved by the FDA for the first-line management of NSCLC and HER2-negative breast cancer, and second-line treatment of glioblastoma, and metastatic renal cell carcinoma [ 87 ].

Bevacizumab efficacy for advanced lung cancer was recently demonstrated in a number of clinical trials, which demonstrated improved OS and PFS, albeit only by a few months [ 88 ]-[ 90 ]. Recently, Lambrechts and colleagues investigated novel promising biomarkers of response for bevacizumab treatment [ 91 ]. The EGFR pathway is another commonly targeted signaling cascade in antibody therapeutics. In comparison, panitumumab is a fully humanized IgG2 monoclonal antibody, which also targets EGFR and is approved for use in metastatic colorectal cancer [ 95 ],[ 96 ].


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It is now clear that KRAS mutations are a negative predictive indicator of response to anti-EGFR therapy in view of downstream pathway activation [ 97 ]-[ 99 ]. In advanced SCCHN, although a survival advantage was demonstrated with cetuximab plus concurrent chemotherapy or radiotherapy, to date, no predictive biomarkers of response have yet been identified [ 94 ].

A subgroup analysis revealed that pnegative tumors treated with anti-EGFR therapy presented a significantly higher survival benefit compared to ppositive tumors. Despite this being a retrospective subgroup analysis, p16 status appears to be a relevant biomarker for patients with SCCHN, and should be explored prospectively in the future [ ]. The development of anti-HER2 targeting agents has dramatically altered the management of HER2-positive breast cancer and is one of the first successes of molecularly targeted therapies in oncology. Currently, three antibodies are approved for the treatment of HER2-positive breast cancer.

In the HER2-positive population, trastuzumab has moderate monotherapy antitumor effects. Compared to trastuzumab, pertuzumab is a monoclonal antibody that sterically blocks the dimerization of HER2 with HER1, 3 and 4 and binds to a different HER2 epitope [ ], resulting in synergistic antitumor effects when combined with trastuzumab. Pertuzumab treatment was approved for use in combination with trastuzumab and standard chemotherapy in HER2-positive metastatic breast cancer after showing significantly prolonged progression-free survival A retrospective study published by Paik and colleagues [ ] showed that HER2-positive patients could also benefit from adjuvant trastuzumab.

Surprisingly, analysis of outcome data revealed that these HER2-positive patients benefited as much from adjuvant trastuzumab as did patients whose tumors displayed HER2 gene amplification. The ability to deliver cytotoxic chemotherapeutic agents directly to cancer cells with targeted conjugates has been an area of interest for some time, although its development has been technically challenging to develop until recent times. T-DM1 is an antibody-drug conjugate consisting of trastuzumab T linked to the small molecule cytotoxic payload mertansine DM1 [ ].

T-DM1 was recently approved for the treatment of patients with HER2-positive metastatic breast cancer that has progressed on prior trastuzumab and taxane chemotherapy [ ]. This combination showed an encouraging safety and tolerability profile with preliminary evidence of efficacy. This indicates a potential resistance mechanism to HER2-targeted therapies. In hematological cancers, the antibody drug conjugate Brentuximab-vedotin has already been approved for relapsed Hodgkin lymphoma and systemic anaplastic large cell lymphoma, and other similar compounds are also currently in development[ ].

Sunitinib, pazopanib and sorafenib are all multikinase inhibitors that block angiongenesis targets among others and have gained FDA-approval in the last five years for renal cell carcinoma RCC and hepatocellular carcinoma HCC. Although there are no validated biomarkers for targeted therapies in advanced RCC or HCC, different groups have undertaken retrospective studies on sunitinib, pazopanib, and sorafenib for potential biomarkers in order to understand the interpatient variability in clinical benefit [ ]-[ ].

Previous studies in metastatic RCC have demonstrated a potential correlation between baseline soluble protein levels and efficacy for sunitinib [ ], and sorafenib [ ]. The approval of tyrosine kinase inhibitors TKIs such as erlotinib and gefitinib was a key milestone for the treatment of NSCLC, by presenting a model for targeted therapy development and genetic profiling of this disease. Retrospective analysis and subsequent prospective clinical trials have demonstrated that EGFR mutant lung adenocarcinoma benefits from anti-EGFR therapy, although some controversy still exists regarding how best to select these patients.

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Two recent studies reviewed published data regarding this topic; Lee and colleagues in their meta-analysis concluded that EGFR mutations are a predictive biomarker of PFS benefit to anti-EGFR TKIs; Goss and co-workers confirmed this conclusion, and also suggested that an activating mutation predicts a greater likelihood of antitumor response and that there are a proportion of EGFR wild-type patients with NSCLC who will still gain some benefit from this therapy [ ],[ ]. In preclinical studies, these drugs overcome resistance via TM mutation threonine to methionine at the locus, the most common resistance mechanism , however the concentration required to overcome TM activity is not achievable in patients [ ],[ ] due to dose-limiting toxicity related to non-selective inhibition of wild-type EGFR [ ].

A range of strategies combining TKIs with other therapies have recently been explored [ ]. Despite favorable preclinical data suggesting an increase in efficacy by combining dual anti-EGFR blockade e. In contrast to patient benefit observed with inhibiting the EGFR pathway with cetuximab in conjunction with cytotoxic chemotherapy in gastrointestinal malignancies, gefitinib and erlotinib showed no clinical benefit and an increase of drug-related toxicities when combined with conventional chemotherapy agents in lung cancer [ ],[ ]. The 4-year period from the identification of the oncogenic ALK gene rearrangement ALK- positive in NSCLC to crizotinib approval was incredibly rapid, and an excellent example of hypothesis-testing, biomarker-driven drug development [ ].

Most tumors develop resistance to crizotinib therapy after one to two years of treatment, and two studies involving a small series of crizotinib-resistant patients have recently been published [ ],[ ]. In these studies, secondary ALK mutations were the most common drug-resistance mechanism, present in up to one third of the target population, predominantly affecting the tyrosine kinase domain LM.

Strategies in Clinical Hematology - K P Hellriegel, R Gross - Häftad () | Bokus

In , vemurafenib was approved for the treatment of BRAF-mutant melanoma patients [ 6 ]. Dabrafenib has since also been approved as the second BRAF inhibitor to achieve FDA approval for the treatment of advanced melanoma [ ]. Although response rates with vemurafenib in patients with VE BRAF -mutated melanoma have been impressive, this inhibitor is associated with a PFS of only months, likely due to the development of compensatory mechanisms of resistance described below [ ],[ ].

Recently, the MEK inhibitor trametinib was also approved by the FDA for advanced melanoma, after showing increased survival compared to chemotherapy in a phase III trial [ ]. Critically, BRAF and MEK inhibitors may have better results when given concomitantly rather than sequentially, with concurrent treatment associated with increased antitumor responses to therapy and a reduction in the severity of toxicities observed [ ],[ ].

Multiple resistance mechanisms have been identified with these drugs, including those secondary to the reactivation of the MAPK pathway e. Clinical trials have demonstrated benefit with imatinib in unresectable or metastatic GIST [ ]-[ ], and also in the adjuvant setting for resectable primary tumours [ ],[ ]. Mutational analysis has a key role in this disease, both to confirm the initial diagnosis, and for the characterization of prognostic and response biomarkers for the administration of molecularly targeted therapies [ ].

For example, GIST responds better to imatinib therapy if it harbours a mutation in exon 11, versus tumors with mutations in exon 9 or without any mutations detected [ ]-[ ]. Interestingly, while the appearance of certain secondary mutations may be associated with imatinib resistance, they may remain sensitive to other tyrosine kinase inhibitors such as sunitinib, masitinib, nilotinib or dasatinib therapy.

In addition, secondary KIT exon 13 and 14 mutations have been associated with better survival rates compared to KIT exon 17 and 18 mutations [ ]. Vismodegib is a first-in-class, small-molecule inhibitor of SMO, a key component of the hedgehog pathway. It was approved for the treatment of metastatic or locally advanced basal cell carcinoma BCC not suitable for local salvage therapies.

Strategies for modern biomarker and drug development in oncology

This is an encouraging example of a rationally-driven study based on the dysregulation of the hedgehog signaling pathway in BCC leading to antitumor activity. In addition, vismodegib has demonstrated patient benefit in those with basal cell nevus syndrome involving germline PTCH1 alterations [ ],[ ].

Introduction

There are currently ongoing studies which are exploring new schedules of vismodegib to minimize drug toxicities, and other trials assessing the activity of vismodegib in the adjuvant setting NCT, NCT, NCT [ ]. In recent years, the field of tumor immunotherapy has taken center stage in oncology drug development.

Ipilimumab is an IgG1 monoclonal antibody against the extracellular domain of CTLA-4, which consequently leads to the inhibition of an early point in T-cell activation. In late phase trials, ipilimumab has demonstrated antitumor activity in patients with advanced melanoma [ ],[ ]. For example, in a randomized first-line phase III trial that enrolled patients with advanced melanoma, the dacarbazine plus ipilimumab combination prolonged overall survival compared to dacarbazine plus placebo.

The combination arm was however also associated with a high frequency of Grade adverse events [ ].

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