A more refined approach to cancer treatment

A large number of gene-targeted personalised cancer therapies are currently under development that will result in more effective treatment and fewer side-effects. Dr Sarah Houlton describes some of the most promising prospects for a new generation of cytotoxics

Herceptin is among the most familiar gene-targeted cancer therapies
Picture courtesy of Roche

Traditional chemotherapy is a blunt instrument: blast the patient with cytotoxic drugs in the hope that the treatment will kill off cancer cells without causing too much collateral damage. The only discrimination, in the main, is that cells that are dividing rapidly are more likely to be susceptible. Of course, this means that non-cancerous cells that divide rapidly will also be killed off, which is why many chemotherapy patients lose their hair. But side-effects, such as nausea and thrombocytopoenia, are also common, and can lead to patients discontinuing treatment as they simply can’t cope with the negative effects of the drugs on the healthy parts of their bodies.

The new breed of personalised cancer medicines is somewhat different. Designed to take advantage of genetic differences between cancer cells and healthy cells rather than attacking everything in sight, they bind to specific receptor targets on tumour cells. The availability of rapid genetic sequencing tools has made tumour typing routine, and in future we may see cancers being reclassified according to their genetic makeup rather than the location in the body at which they occur. While this can mean that far fewer patients may benefit from a specific drug, those who receive one designed to hit a specific genetic target that is present on their tumour cells are much more likely to respond.

A huge number of gene-targeted, personalised cancer therapies are in development, but a number have already been licensed, and the prospects of many patients have already been transformed as a result. Perhaps the most familiar of these is trastuzumab (Herceptin) from Roche.1 The gene HER2 is upregulated in 20–30% of all early stage breast cancers, leading to an overexpression of epidermal growth factor receptors (EGFR) within the cell membrane. The HER2 pathway is a normal part of the cell growth and division process, but when it is upregulated it goes into overdrive, causing cell growth to accelerate, with the ultimate result being the formation of tumours. In cancer cells, HER2 can be overexpressed by a factor of 100 times.

Trastuzumab is a monoclonal antibody that binds to domain IV of the HER2 receptor’s extracellular segment, arresting the cell cycle and thus reducing proliferation. It is also thought to have other activities, including downregulating the HER2 gene, and suppressing angiogenesis.

Significant increase in survival rate

Clearly, if a breast cancer does not overexpress HER2, trastuzumab will not work. But in those patients whose cancer is HER2 positive, there is the potential for a beneficial effect. Indeed, in clinical trials it was shown to extend the overall survival rate in patients with metastatic HER2+ breast cancer by about a quarter, from 20 to 25 months. In the earlier stage of the disease, the chance of the cancer recurring post surgery is cut by about 10% with trastuzumab treatment.

While trastuzumab clearly has some benefits in HER2+ breast cancer, the improvements in outcomes remain modest. What if the HER2-targeting properties of trastuzumab could be combined with a cytotoxic molecule, using it to deliver an otherwise nonselective highly potent chemotherapy drug directly to the tumour? This is exactly the strategy behind Roche’s trastuzumab emtansine (Kadcyla), which was approved in the US earlier this year.2

The drug comprises one antibody molecule reversibly bound to three or four emtansine molecules, which themselves comprise a succinimide-based linker group attached to cytotoxic maytansine molecules by a thioether group. The linker is used to join the whole emtansine fragment to the antibody. Maytansine is a plant-derived macrolide that inhibits microtubule assembly in the cell cycle by binding to, and thus blocking, tubulin. Once the trastuzumab part has bound to the HER2 receptors on the cancer cells, the drug is taken up into the cells by endocytosis, with the cytotoxic part being released within the cell. This reduces the potential for unwanted side-effects, as there is no free cytotoxic agent outside the cancer cells. Various other linkers had also been tried, but these released the maytansine moiety prior to endocytosis via reductive cleavage, resulting in increased toxic effects being observed in patients.

Breast cancer has many different subtypes depending on factors such as whether or not it is oestrogen-dependent and which receptors it expresses

Breast cancer is a very heterogeneous disease, with many different subtypes depending on factors such as whether or not it is oestrogen-dependent, and which receptors it expresses. The most common combination is oestrogen receptor positive, HER-2 negative, thought to account for nearly two-thirds of all cases of breast cancer in postmenopausal women. Pfizer’s palbociclib is being investigated in this form of cancer.3 It has shown promising early results in Phase II trials in combination with the aromatase inhibitor antihormone therapy letrozole (Femara, Novartis).

The drug inhibits cyclin-dependent kinases 4 and 6. These have a number of biological roles – not only are they involved in cell cycle regulation, they also play a part in transcription and mRNA processing. The inhibition of these two kinases prevents the deactivation of retinoblastoma susceptibility gene protein, a protein that suppresses tumours, and also interferes with tumour cell progression. As well as breast cancer, it is being investigated in ovarian cancer, multiple myeloma and acute lymphoblastic leukaemia.

Another drug being developed for the same target is from Eli Lilly. LY2835219 is in the earlier stages of clinical trials for advanced solid tumours and mantle cell lymphoma.4

Genetic aberration

Pfizer’s crizotinib (Xalkori) has been approved to treat non-small cell lung cancer, and other solid tumours.5 While NSCLC most commonly occurs in older smokers, crizotinib is particularly effective in younger patients who have never smoked – the cause of their disease is genetic rather than environmental. Around 4% of all NSCLC patients have a genetic aberration in which a fusion gene is generated via a chromosomal rearrangement between the genes echinoderm microtubule-associated protein-like 4 (EML4) and anaplastic lymphoma kinase (ALK). This fusion gene’s kinase activity encourages malignant growth, and the kinase inhibitor crizotinib blocks it.

Crizotinib

While only about 45,000 of the million-plus new cases of NSCLC diagnosed around the world every year have this ALK-fusion abnormality, the effectiveness of crizotinib as a treatment in the correct subset of patients is striking. In a clinical trial carried out in 82 patients whose NSCLC was ALK-fusion-positive, tumour shrinkage of at least 30% was observed in 57% of the group; typically, one might expect just 10% of unscreened NSCLC patients to achieve a response to drug treatment.

Numerous other companies are also investigating the potential of ALK as a target. For example, the next-generation ALK inhibitor in the pipeline at Novartis, LDK378, is in Phase II, and has been given ‘breakthrough’ status by the FDA.6 This new initiative by the FDA is designed to accelerate potentially transformative drugs like this through the pipeline and into patients – Novartis has said it hopes to apply for FDA approval next year, just three years into development. In trials, it showed an 80% response rate in patients whose non-small cell lung cancer had progressed after treatment with crizotinib.

FDA breakthrough programme
The FDA’s new breakthrough therapy designation was launched late last year. The aim is to speed up the development and regulatory review of drugs to treat serious and life-threatening conditions. To gain this designation, a company must have preliminary clinical evidence that the drug may give a substantial improvement over existing therapies in at least one clinically significant endpoint.
Drugs granted this status will not only be given the advantages of a fast-track designation, but also more intensive FDA guidance on running an efficient drug development programme. The Agency will hold meetings with the drug company and the review team throughout the development process, and give timely advice on what data will be needed for submission. It will also advise on trial design, so as few patients as possible will be exposed to potentially less effective therapy.
As of the middle of June, 20 applications for breakthrough status had been approved. While not all are for cancer therapies, the lion’s share are because of the great potential for transformation of outcomes that some of these targeted medicines may have.

One of the earliest examples of success in personalised medicine for cancer treatment, Novartis’ imatinib (Glivec), treats chronic myeloid leukaemia patients who are positive for the BCR-ABL fusion gene.7 Bruton’s tyrosine kinase, or Btk, is another target in blood cancers that looks like it will lead to important new drugs. Pharmacyclics’ ibrutinib falls squarely into this category; it is now in Phase III and the company hopes to file for approval later this year.8

The oral drug binds irreversibly to Btk, inhibiting its activity, which stops both the activation of B-cells and the signalling they mediate. The result is an inhibition of the growth of the B-cells that express Btk – important as the expression of Btk is associated with an increase in both proliferation and survival of tumour cells. FDA is keen on the drug’s potential, too – it has given it breakthrough status for three separate cancer indications.

Phase III trials are under way in combination with rituximab and bendamastine, in patients with relapsed or refractory chronic or small lymphocytic leukaemia. The potential treatment is also being evaluated in other blood cancers, notably diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma and multiple myeloma.

'Breakthrough' status

Another drug that has been given the new ‘breakthrough’ status is Roche’s obinutuzumab.9 The company has already filed for approval in chronic lymphocytic leukaemia, and it is also being investigated for non-Hodgkin lymphoma and diffuse large B-cell lymphoma. Obinutuzumab is a new breed of glycoengineered antibody, directed against CD20 antigens, and unlike classical antibodies against CD20, it has high affinity to the type II epitope, which gives it as much as a 100-fold greater ability to induce cytotoxicity than the earlier antibodies targeting this antigen such as rituximab.

In a Phase III trial in CLL patients, its effectiveness in combination with chlorambucil was compared with the combination of rituximab and chlorambucil, or chlorambucil alone. It more than doubled the time to disease progression compared with single agent chlorambucil, while the overall response rate for the obinotuzumab combination was 76%, with a 22% complete response rate, compared with 66% and 8% for the rituximab combination.

Also with great potential as a target in blood and other cancers is the PI3K/Akt/mTOR pathway. It is involved in apoptosis, with phosphoinisitide 3 kinase (PI3K) activating Akt (also known as protein kinase B), which, in turn, activates mammalian target of rapamycin (mTOR). The furthest advanced drug against this pathway is perifosine, being developed by Keryx Pharmaceuticals under licence from Aeterna Zentaris, which inhibits both PI3K and Akt.10 Although it failed Phase III trials in colon cancer, it continues to be developed for multiple myeloma and neuroblastoma, for which it has orphan status.

Perifosine

In the much earlier stages of development is AstraZeneca’s AZD5363, which inhibits three forms of Akt: Akt1, Akt2 and Akt3. In a recently reported Phase I trial of the drug as a single agent, one patient with ovarian cancer and a second with cervical cancer achieved a partial response, both of whom had a mutation in either Akt1 or PIK3CA. Another ovarian cancer patient with the PIK3CA mutation achieved long-term stable disease.11

Various other kinases are also being investigated, albeit in the much earlier stages of research. For example, the first Axl kinase inhibitor to reach patients, BGB324 from Norwegian biotech BerGenBio, started in Phase I trials in June this year.12 The selective oral Axl receptor tyrosine kinase inhibitor is being investigated in both solid and blood cancers. It blocks the epithelial–mesenchymal transition, or EMT, which is a key driver of both metastasis and drug resistance.

EMT is the process by which epithelial cells lose their gene expression patterns, and gain the phenotypic traits of mesenchymal cells, a process that is important in embryonic development, and also takes place during wound healing. However, there is now good evidence that the interactions between tumour cells and their microenvironment can lead to EMT being induced in some of the tumour cells, promoting metastasis. Therefore, blocking it may prevent metastasis.

More than 75,000 people are likely to be diagnosed with melanoma in the US in 2013

Melanoma is another cancer whose treatment is being revolutionised by personalised medicine. With estimates from the National Cancer Institute that more than 75,000 people will be diagnosed with melanoma in the US in 2013, and nearly 10,000 will die of the disease, it is the leading cause of death from skin disease. Treatment of this aggressive form of cancer is difficult if it is not caught very early. However, three new targeted drugs have been approved by the FDA since 2011, improving the prospects of patients with metastatic or unresectable melanoma.

The drugs – vemurafenib (Zelboraf, Roche),13 dabrafenib (Tafinlar, GlaxoSmithKline)14 and trametinib (Mekinist, also GSK)15 – are all targeted at cancers with some form of mutation in the BRAF gene. About half of all melanomas have a BRAF gene mutation. Vemurafenib and trametinib are both MEK inhibitors that are active in melanomas with the BRAF V600E mutation, interrupting the B-Raf/MEK step on the B-Raf/MEK/ERK pathway. Dabrafenib inhibits the enzyme B-Raf, and targets a different mutation, BRAF V600I. While these drugs on average delay tumour growth by two or three months, for such difficult-to-treat cancers as advanced melanoma this represents a real step forward.

Vemurafenib

References

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