ESMO 2023: Current Peri-Operative Trial Designs and Endpoints: What Do They Mean?

( The 2023 European Society of Medical Oncology (ESMO) Annual Congress held in Madrid, Spain between October 20th and 24th, 2023 was host to a neoadjuvant and adjuvant therapy in genitourinary cancers session. Dr. Srikala Sridhar discussed the current state of perioperative trial designs and endpoints.

Perioperative trials typically involve systemic treatment administered before and after definitive therapy. They classically include multiple treatment modalities, and, thus, require a well-coordinated, collaborative, multidisciplinary team-based approach. These trials may provide the optimal setting for correlative studies. As the treatment landscape in metastatic kidney and bladder cancers continues to evolve, novel agents could potentially be moved up into the perioperative setting with the ultimate goal of curing more patients.

This paradigm is not unique to genitourinary malignancies, with this approach also proving successful in melanoma. In the SWOG S1801 trial, patients with stage IIIB-IV melanoma were randomized to receive pembrolizumab both before and after surgery versus only adjuvantly following surgical resection. The ‘neoadjuvant-adjuvant’ approach had a significant improvement event-free survival, the primary trial endpoint.
This approach has similarly been successful in the non-small cell lung cancer space with the KEYNOTE-671 trial:
Can such a perioperative ‘neoadjuvant-adjuvant’ similarly work in early-stage kidney or bladder cancer? Before we address this question, we need to consider the rationale for exploring a perioperative approach in these disease sites. For RCC, recurrence rates remain high following definitive surgery. Adjuvant tyrosine kinase inhibitors (TKIs) have shown conflicting efficacy results, with toxicity being a major issue. Immune checkpoint inhibitors are active in metastatic RCC, but mixed results have been noted in the adjuvant setting as well, which questions whether this treatment should be used earlier. However, the use of immune checkpoint inhibitors is supported by pre-clinical studies:
Potential advantages to perioperative immune checkpoint inhibitors include:

  • Downsizing the primary tumor
  • Decreasing the size of a renal vein or IVC thrombus
  • Facilitating a partial versus radical nephrectomy
  • Improving symptoms in select patients with invasive disease
  • Treating micrometastatic disease early
  • Assessment of treatment response
  • Correlative studies

Potential disadvantages include:

  • Inflammatory changes/fibrosis in the tumor
  • Immune-mediate adverse events
  • The need for steroids and other agents affecting surgery
  • Delay in surgery among non-responded
  • Patients may subsequently refuse surgery

One notable perioperative trial in the RCC space is Prosper. This trial randomized any histology RCC patients with cT2 or worse disease, cN+, or oligometastatic disease rendered non-metastatic to either standard of care with surgery alone versus 1 dose of nivolumab neoadjuvantly followed 9 doses of nivolumab adjuvantly. This trial failed to meet its primary endpoint of RFS with no benefit to perioperative nivolumab (HR: 0.97, 95% CI: 0.74 – 1.28, p=0.43).
Dr. Sridhar questioned whether the Prosper patient population was the right one to evaluate such an approach in, and what key considerations we can take away for future perioperative trials in this space:

  • Should these trials include non-clear cell patients? What proportion were clear cell versus non-clear cell in Prosper?
  • Should metastatic disease be included or not?
  • Is a biopsy required in all patients before randomization to confirm diagnosis and collect tissue for correlative studies, or will it just delay surgery?
  • Do we select open label or blinded designs recognizing that this can also impact choice of endpoints?

Can we harmonize the key aspects of trial design? In a trial design such as Prosper in RCC, what is the appropriate type and duration of neoadjuvant treatment? This needs to be considered in light of treatment-related toxicity delaying surgery. And what if patients do not undergo resection for any reason such as prohibitive toxicity or progressive disease, does that count as an event? What about post-surgery? How long should we wait to administer adjuvant therapy, which one, and for how long? With regard to endpoints, we need to select and standardize the most appropriate endpoints across perioperative trials. Additionally, we need to maximize the opportunities for correlative studies including at the time of disease progression.PROSPER trial design
The key available endpoints in clinical trials are summarized below. While OS remains the gold standard, as OS increases in these disease spaces, this will be a more difficult endpoint to evaluate, and, as such, there is a growing need to establish and validate surrogate endpoint of OS. It will become incumbent upon clinicians to have clear discussions with their patients to explain the significance of these surrogate endpoints, such as DFS and event-free survival (EFS). DFS will be a challenging endpoint to utilize in neoadjuvant trials, given that patients who undergo neoadjuvant therapy rarely achieve a complete response. As so EFS, this often a non-specific endpoint that needs additional validation as a surrogate for OS.key endpoints
Many of these trials are adopting an EFS/DFS endpoint. However we need to consider that these drugs sometimes have life-altering toxicity, and some patients could be cured with surgery alone. Ideally, we would like to see an OS benefit for these treatments, or at least benefits ‘trending’ in that direction. One potential solution if drugs are approved based on DFS improvements, prospective real-world data may help us to understand the OS benefits. Importantly, we need biomarkers that could provide an initial and ongoing assessment of disease response. 

What about perioperative trials in urothelial cancer? In muscle invasive bladder cancer (MIBC), neoadjuvant chemotherapy is already established as a standard of care treatment. Despite this approach, outcomes remain poor. Immune checkpoint inhibitors have the potential to change the landscape of this disease. Antibody-drug conjugates and targeted therapies are also active in metastatic urothelial carcinoma. How can we sequence treatments and maximize exposure to effective agents? Will outcomes improve if these agents are moved earlier in the treatment paradigm? 

In the CheckMate 274 trial, adjuvant nivolumab improved DFS in the intention to treat population from 11 to 21 months (HR: 0.70, p<0.001). But does neoadjuvant chemotherapy followed by adjuvant nivolumab offer improved DFS outcomes? Subgroup analysis of this trial suggests that that may be the case, with patients having received neoadjuvant chemotherapy having a more pronounced DFS benefit with nivolumab (HR: 0.54 versus 0.91).4disease free survival
There are currently numerous ongoing perioperative trials in the MIBC space. These are grouped by the patient population into either trials in the cisplatin eligible or ineligible space, which is of most significance given the differences in the control arms between these two groups:MIBC trials
What are some key design considerations in the cisplatin eligible MIBC studies?

  • How do we define cisplatin eligibility in the curative setting? Classically, it has been defined using the Galsky criteria which are typically used for the metastatic setting. Furthermore, our ability to administer cisplatin-based chemotherapy has significantly improved over the last few decades. As such, does this even matter nowadays, particularly with the emergence of novel agents/combinations such as enfortumab vedotin and pembrolizumab?
  • Do we include variant histologies? What about upper tract disease?
  • Should cystectomy eligibility be assessed upfront or based on treatment response?
  • Can adjuvant treatment be adaptive?
    • What are the ideal correlatives/imaging studies (e.g., ctDNA, urine, microbiome)? 

cisplatin eligible micb
Conversely, what are some key design considerations in the cisplatin ineligible MIBC studies?

  • Is proceeding directly to cystectomy still a reasonable comparator in the control arm?
  • What if a patient declines/is not a candidate for cystectomy? Could they have a bladder-sparing approach?
    • What would the endpoints be in that scenario?

cisplatin ineligible mibc
What about novel designs incorporating bladder-sparing approaches? Presented at ESMO 2023, HCRN GU16-257 is evaluating a bladder sparing approach in patients with MIBC who are given gemcitabine-cisplatin + nivolumab for 4 cycles, followed by which they undergo clinical re-staging with a cystoscopy + biopsy, urine cytology, and MRI. If patients had a clinical complete response based on all these tools, they were offered the option of foregoing a cystectomy and being treated with 8 cycles of nivolumab. The primary outcome in this trial is 2-year MFS in this complete response subgroup. As more of these trials emerge, we will need to consider how we define key endpoints and surrogate endpoints with bladder sparing protocols.HCRN GU16-257 bladder sparing
What about perioperative trials in the node positive disease space? Among many others, key questions for study design include:

  • What imaging modality is best for this patient population?
  • Which drugs should be used for systemic treatment?
  • Should these patients undergo local therapy with cystectomy or trimodality therapy or should maintenance therapy be offered instead?

perioperatie trials
How can biomarkers like circulating tumor DNA (ctDNA) help us? Longitudinal monitoring of ctDNA could identify minimal residual disease or early recurrence prior to being visible on imaging. With earlier detection, could we improve outcomes with earlier treatment? Conversely, in those with negative levels, could this prompt de-escalation strategies? ctDNA
In the IMvigor010 trial, patients with ctDNA+ disease had a worse prognosis but also derived more benefit from atezolizumab.4 Could analogous changes in ctDNA trigger a change in treatment in a perioperative trial? This is currently being evaluated in the IMvigor011 and MODERN trials:IMvigor011 and MODERN trials 
Dr. Sridhar concluded with the following key conclusions:

  • There has been significant progress in metastatic RCC and urothelial carcinoma impacting key aspects of upstream trial design
  • Harmonizing inclusion/exclusion criteria and endpoints on these studies will be increasingly important
  • Multidisciplinary collaboration will be absolutely critical for these trials to accrue
  • We need to get better at selecting which patients for which treatment at which time
  • We need to incorporate correlative studies and novel imaging approaches
  • Looking ahead, can artificial intelligence modeling approaches help us figure out the best endpoints for these studies?

Presented by: Srikala Sridhar, MD, MSc, FRCPC, Professor, Department of Medicine, Princess Margaret Cancer Centre, Toronto, ON

Written by: Rashid K. Sayyid, MD, MSc – Society of Urologic Oncology (SUO) Clinical Fellow at The University of Toronto, @rksayyid on Twitter during the 2023 European Society of Medical Oncology (ESMO) Annual Congress held in Madrid, Spain between October 20th and 24th, 2023

  1. Patel SP, Othus M, Chen Y, et al. Neoadjuvant–Adjuvant or Adjuvant-Only Pembrolizumab in Advanced Melanoma. N Engl J Med. 2023; 388:813-823.
  2. Wakelee H, Liberman M, Kato T, et al. Perioperative Pembrolizumab for Early-Stage Non–Small-Cell Lung Cancer. N Engl J Med. 2023; 389:491-503.
  3. Bajorin DF, Witjes JA, Gschwend JE, et al. Adjuvant nivolumab versus placebo in muscle-invasive urothelial carcinoma. N Engl J Med. 2021 Jun 3;384(22):2102-2114.
  4. Bellmunt J, Hussain M, Gschwend JE, et al. Adjuvant atezolizumab versus observation in muscle-invasive urothelial carcinoma (IMvigor010): A multicentre, open-label, randomized, phase 3 trial. Lancet Oncol. 2021 Apr;22(4):525-537.