Making progress to increase drug-radiotherapy combination treatments

Drug-radiotherapy combinations are as important as drug-drug combinations. We’re part of a unique collaboration to reignite this field of research.

At Cancer Research UK (CRUK), we have been part of a revolutionary Joint Working Group uniquely made up of academia, industry, patient representatives and regulatory bodies. Today the Joint Working Group published their landmark paper of consensus statements that will boost the number of novel drugs being successfully registered in combination with radiotherapy.

We anticipate the publication of these consensus statements will play a key role in reigniting the field of drug-radiotherapy combination studies, providing the necessary support for academics, industry and regulators working in this field. As a result, we hope to see more drug-radiotherapy combination studies based on sound scientific radiobiology, translating the most promising results from preclinical models in to the most appropriate trial designs and eventually in to better treatment options for patients.

Drug-radiotherapy treatments offer great potential

Radiotherapy already helps to cure many millions of people with cancer worldwide. There is clear evidence that drug-radiotherapy combinations, where drugs are used to exploit the harmful biological consequences of radiotherapy, improve survival in cancer patients.

Professor Ricky Sharma, from University College London and lead author of the paper, sees great potential in drug-radiotherapy combination treatments.

“Although we made significant progress between the 1970s and 1990s in combining traditional cytotoxic drugs with radiotherapy, we haven’t made much progress in combining newer targeted agents with radiotherapy. In order to improve cure rates we need to rethink the way we combine drugs with radiotherapy. This is particularly important for the emerging field of immuno-radio-oncology where we’re using radiotherapy to stimulate a response to the immunotherapy drug.”

Now is the time for change

Sharma recalls the conversation that sparked the formation of the National Cancer Research Institute (NCRI) Clinical and Translational Radiotherapy Research Working Group (CTRad) Academia-Pharma Joint Working Group.

“I was having a conversation with Ruth Plummer (Clinical Professor of Experimental Cancer Medicine at Newcastle University and co-author of the paper) about how little progress has been made around these combination treatments in the last decade compared to previous decades. We thought we should use the academic strength of CTRad combined with the industry contacts of CRUK’s Combinations Alliance to get everyone in a room together to talk about this lack of progress”

In fact, this is exactly what happened. In a pivotal moment for the field academics, industry, regulatory bodies and patient representatives came together for the first time, initially to identify the barriers to progress, and then to co-create the vitally important consensus statements published today.

Collaboration is crucial

Traditionally these types of trials have not been a high priority for industry and are often led by academics instead. With industry working to a clear line of sight towards approval and registration of drugs for use in patients, they typically don’t consider combining treatments with radiotherapy until much further along in the drug development lifecycle. This has led to a slowing of progress and a lack of registrations of drug-radiotherapy combinations in recent years, alongside the concern that we’re not taking full advantage of the many novel targeted agents in development.

A key recommendation in the paper works to address this, calling for the early engagement of industry with academia and the running of combination programmes in parallel with the core programme of drug development.

“There was a large voice from pharma saying we needed to write a seminal paper they could use when making the case within their companies for combining drugs with radiotherapy” says Sharma.

Although there is not currently a clear pathway to registration for drug-radiotherapy combinations the Joint Working Group are eager to point out that this should not be a disincentive. Regulatory bodies are keen to engage early in the development process; their participation in the Joint Working Group is proof of their commitment to driving development in this area. As an example, CRUK was recently invited, along with Sharma, to meet with the Medicines and Healthcare products Regulatory Agency (MHRA) and European Medicines Agency (EMA) to discuss these ongoing issues. We will continue to work together with them to develop appropriate regulatory guidelines for drug-radiotherapy combination studies.

Consensus statements: recommendations for change

We’ve outlined a brief summary of the Joint Working Group’s consensus statements, however the full versions can be found in the paper.

1. Drug-radiotherapy combinations

Drug-radiotherapy combinations are as important as drug-drug combinations and industry and academia must work together to make progress. Proposed combinations should have sound scientific basis in radiobiology, immuno-oncology, molecular biology and pharmacology.

2. Route to registration

With no published guidelines for trial design and limited regulatory guidelines, the development of drug-radiotherapy combinations should be seen as similar in concept to novel drug-drug combinations. Early engagement with regulators, the academic community, and patients will ensure that access to new treatments can be reached in the shortest feasible time frames.

3. Clinical end points

Researchers and regulators should discuss meaningful clinical end points for each tumour type and patient population to speed up clinical development. Regulatory bodies are increasingly recognising the value of patient-reported outcomes as end points of trials.

4. Changing the standard of care

Potential changes in the standard of care must be predicted by clinical experts. The current standard of care and treatment intent must be defined, including any variation across geographic locations.

5. Clinical trial methodology

Trial designs must be fitting, appropriate end points outlined and robust statistical strategies put in place. Early stage trials could take advantage of gaps between planning and starting radiotherapy, or between radiotherapy and surgery.

6. Radiotherapy quality assurance

Quality assured radiotherapy is critical. There should be a transparent description of the chosen technique including target volume definition and the minimisation to surrounding normal tissues. Reviews of radiotherapy planning and delivery must be determined for each study.

7. Preclinical dataset and target population

A standard does not currently exist. The dataset should: i) demonstrate that the drug improves radiotherapy in clinically relevant models; ii) define an effective dose schedule; iii) provide an assessment of normal tissue toxicity; and iv) identify potential responsive patient subpopulations and related biomarkers.

8. Patient and consumer involvement and raising awareness

Patients and consumer groups should be involved from the concept stage to give a clear appreciation of patient priorities and what will be considered acceptable in a clinical trial.

The publication of the consensus statements is only the beginning. Academics, industry, patients and regulatory bodies must continue to work together to realise the potential of drug-radiotherapy combinations for cancer patients. The Joint Working Group will meet again in five and ten years’ time to assess progress following the publication of this seminal paper.

Sharma believes that by involving all parties — from academia and industry to regulatory bodies and patient groups — in this uniquely collaborative approach, the consensus statements will be well-positioned to initiate real change in this field.

“Five years down the line we hope to see more clinical trials that are registered on clinicaltrials.gov using rational combinations of drugs with radiotherapy based on solid science and with good clinical trial design. Ten years from now we hope there are more registrations for drug-radiotherapy combinations — actually changing clinical practice as a result of well-designed clinical trials.”

We hope the publication of the consensus statements will ultimately result in better treatment options for patients, giving them the best possible chance of successfully treating their disease.

If you work in academia or industry and are considering a drug-radiotherapy combination, the Joint Working Group are keen to support you. Please get in touch by emailing Dr Julie Stock (Radiotherapy-Drug Combinations (RaDCom) Project Manager, Centre for Drug Development).

CRUK are one of six funders of CTRad. To find out more about CTRad please visit http://ctrad.ncri.org.uk/