Developments in precision cancer medicine and regulatory implications

Corinna Alberg

7 May 2015

Clinical oncology is undergoing major change as precision medicine informs molecular diagnosis and therapeutics, based on the genomic profiles of the individual patient’s tumours. The presence of genomic targets can be critical to efficacy in treatment, and cancer therapies are increasingly directed to biologically relevant targets based on the molecular profile of tumour cells. For example, the presence of BRAF mutations in people with metastatic melanoma guides therapies, which has improved health outcomes. Similarly, ductal breast cancer is now seen as a collection of distinct diseases, each managed differently in the clinic.

The rise of panel testing and precision medicine

Next-generation sequencing panels (rapid DNA sequencing of selected genes or regions of genes to identify critical mutations) are increasingly being used to identify the most effective treatment regimes for cancer in clinical settings, with such moves towards precision medicine likely to become the norm. However, what remains unclear is the overall proportion of cancer patients who could now benefit from stratified cancer therapies. A new article published in Molecular Cancer Therapeutics has shed some light on this issue.

Cataloguing cancer genetic changes

Schwaederle and colleagues looked at the molecular tumour profile results from 439 patients with a wide variety of tumours. These patients had undergone molecular tumour testing using an NGS cancer panel covering almost 300 cancer-related genes. The researchers were looking retrospectively to see how many of these patients had genetic alterations (mostly mutations or amplifications) that were either direct targets for, or had a pathway component that could be targeted by, at least one approved or investigational drug.  

The most common primary tumour sites were gastrointestinal (25%), breast (19%) or brain tumours (14%). They found that in 96% of the patients at least one molecular alteration was identified in the tumour, with the median number of alterations being three. Few patients (11%) had only one alteration. Most had tumour mutation molecular profiles that were distinct from any other of the patients, with only seven patients sharing the same molecular tumour profile with another patient. This finding alone highlights the importance of a precision medicine approach to cancer therapeutics. 

Impact on treatment choice

What was particularly significant was that 90% of patients had at least one druggable alteration for experimental drugs undergoing clinical trials, and this finding was observed across the range of different malignancies studied. Of the 10% who did not have a druggable alteration, almost half had no reportable genetic alteration (4%), and the remainder had alterations but the alterations were not actionable. So for almost all the patients, NGS sequencing with an appropriate cancer panel would have provided at least one therapeutic option (including experimental drugs in clinical trials) to be considered by the clinician and patient.     

70% of the patients would have theoretically benefited from one or more approved drugs, whether approved for use in that cancer (on-label) or for use in another disease (off-label). For 20% of patients, there was at least one drug already approved for use in cancer relevant to a specific genetic alteration. 

Implications for funding and approving drug use

If these findings were representative and can be replicated in larger samples, then ensuring that there is appropriate, safe access to off-label drugs for cancer patients could become a crucial issue. In the UK, the Cancer Drugs Fund currently allows clinicians to access off- label drugs, but the Fund was intended to be a short term measure and there is commitment to its existence only until March 2016. While there are valid arguments over whether funding for cancer drugs should be ring-fenced over other equally serious non cancer treatments, there needs to be a mechanism to respond in a timely manner to the developments in new cancer treatment options highlighted by Schwaederle and her colleagues. 

working party was set up in January 2015 to agree a system to replace the Cancer Drugs Fund and find a new way to get new cancer drugs appraised; the group includes representatives from NHS England, the Department of Health, cancer charities, NICE, the Ethical Medicines Industry Group and the Association of the British Pharmaceutical Industry. Wherever responsibility for decision-making is found to lie, any new mechanism should arguably be responsive to the opportunities for improved cancer treatments enabled by precision medicine.