The challenges of neoadjuvant trials, what we learnt from NAXIVA

NAXIVA is the first clinical trial to evaluate neoadjuvant downstaging of patients with the unique biological phenomenon of venous tumour thrombus in kidney cancer. But what did we learn beyond the endpoints?

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Neoadjuvant treatment is where non-surgical treatment is used prior to curative treatment such as surgery to substantially reduce the morbidity of treatment and increase the chances of treatment with curative intent, e.g. radiotherapy to downstage rectal carcinoma prior to surgery. Currently, there are no licenced neoadjuvant treatments for kidney cancer. NAXIVA is the first clinical trial to evaluate neoadjuvant downstaging of patients with the unique biological phenomenon of venous tumour thrombus (VTT) in kidney cancer. A VTT downstaging trial has repeatedly been raised as a need over many years because this subset of patients with tumour growing along the renal vein often into the vena cava and occasionally into the right atrium have a substantially increased risk of perioperative morbidity and mortality (5-15% risk of perisurgical death). As such we undertook this feasibility study of eight weeks of pre-surgical tyrosine kinase inhibitor therapy, with axitinib, in patient with a VTT and biopsy proven clear cell renal cell carcinoma to evaluate whether the tumour thrombus could be substantially down staged to allow safer surgery with less risk of death and complications. The results of NAXIVA, which included 21 patients, indicated that the approach is feasible with acceptable toxicity which did not prevent suitable patients from getting to surgery at the planned date. The primary endpoint, of a reduction in the extent of the tumour thrombus assessed by the Mayo level, a well-established anatomical based classification of the height of the VTT assessed on MRI, showed that 35% of patients had a reduction in the Mayo level equating to a meaningful downstaging. Furthermore, a secondary endpoint of reduction in the extent of surgery showed that 41% of patient required less extensive surgery. Thus, NAXIVA was a positive trial and the first to demonstrate that neoadjuvant systemic therapy can safely be administered in patients with VTT to downstage the disease and reduce the extent of surgery.

Representative schematic of a kidney cancer with associated venous tumour thrombus. Illustration by Claire Cooper.

There are a number of potential advantages of neoadjuvant therapy: (a) downstage the tumour, to enable less invasive surgery with less morbidity and mortality; (b) prevent cancer recurrences after surgery enabling a more successful multimodal approach (i.e. neoadjuvant chemotherapy in bladder cancer which provides a 5% overall survival advantage at 5 years); (c) deliver systemic therapy to a patient at the earliest point in the disease process, patients are more physiologically robust in this pre-surgical timepoint and may be better able to tolerate treatment than following surgery, data from other cancer types has shown that neoadjuvant therapy can be more oncologically effective that adjuvant therapies; (d) enable the study of changes that occur with novel systemic therapies by enabling the collection of pre-treatment, on treatment and end of treatment biosample sets to allow study of the mechanisms of action and develop predictive biomarkers.

However, our ‘story behind the paper’ is around the challenges of neoadjuvant clinical trials. The first emails about NAXIVA were sent in 2013, nine years before the final report was published in BJC. However, as can be seen from figure 2 the trial actually recruited slightly ahead of the two year recruitment target. So why is it that neoadjuvant clinical trials are so challenging to establish? There are several reasons for this. Firstly, pre-surgical trials require the coordination of multiple different specialists across multiple centres. Surgeons with equipoise are fundamental to identifying suitable patients and agreeing to consider treatment prior to surgery. Secondly, there must be a symbiotic relationship with medical oncologists who will be prescribing drug and managing the patient during the drug treatment phase. Thirdly, in NAXIVA (as well as in other neoadjuvant trials) we used a unique primary endpoint of ‘improvement in the Mayo level’ making the skill of the radiologist key, we realised quickly that this would be best done with central review of the imaging rather than per site analysis. Fourthly, pathologist input is essential as they are necessary for the often intricate tissue sampling that is required to understand the exploratory translational endpoints that are key advantages to neoadjuvant trials. Of course, all of this coordination has to have undertaken in a very strict timescale between the time of recruiting the patient to the trial and then starting on drug treatment, during which time imaging and biopsy take place, so that there is not a substantial delay in the time that the person has to wait prior to their surgery.

Recruitment, to schedule, of the NAXIVA trial.

These, often new (at least in the context of a clinical trial), close working relationships are essential and when is a study is being undertaken across multiple centres need to be set up at each of the sites. All-in-all the set-up is not as straightforward as when dealing with a systemic therapy study that primarily requires the input of the medical oncologist. To this end we were delighted the via the NCRI Clinical Studies Group it was possible to establish a cadre of engaged renal cancer surgeons across the United Kingdom and it was from this group that the five centres that recruited to NAXIVA were identified. The close liaison between the various lead surgeons made the study a pleasure to be involved with because there was shared learning and enhancement of recruitment because of the collegiate approach.

In addition to the clinical team the biosampling coordination between the various centres was also challenging but rewarding to get right. In NAXIVA, tissue was sent fresh in medium for single cell dissociation from each site to the coordinating centre. Fresh tissue frozen, plasma double spun, urine preserved in EDTA for cell-free DNA analysis, together with more standard samples such as multi-region FFPE sampling were also undertaken. This pre-analytical quality control of samples was essential to enable consistent translational results to be achieved and indeed some of these are presented in the BJC paper. One of the main advantages of neoadjuvant trials is the ability to obtain pre-treatment biopsy tissue and on-treatment resection samples to evaluate predictive factors that will allow determination of which patients will benefit from the treatment strategy and those that will not and should proceed directly to surgery. We believe it is these predictive features that will drive the design of the next multi-arm definitive trial around neoadjuvant treatment of IVC tumour thrombi in renal cancer.

We are proud of the achievements of this small but significant Phase II clinical trial in a unique clinical cohort starting to address a clinical question that has been asked for many years. The key learnings from this study will be used as we continue to work with the same clinical teams developed during NAXIVA to deliver the definitive phase III clinical trials in this space in the future.

Multispecialty working is essential in neoadjuvant trials, perhaps more so than any other type of clinical trial, and the leadership of surgeons must be championed to enable success.

Grant Stewart

Professor of Surgical Oncology, University of Cambridge