Linda Brookes, MSc
Patients with localized, high-risk clear cell renal cell carcinoma (ccRCC) experience recurrence rates of over 60%.1 Clinical trials in these patients have produced mixed results and there are currently no Food and Drug Administration (FDA) approved neoadjuvant treatments in this setting.
NeoAvAx was a phase 2, single-arm, open-label trial in which patients with non-metastatic ccRCC at high risk of relapse after nephrectomy were given avelumab, an immune checkpoint inhibitor (ICI), in addition to axitinib, an oral tyrosine kinase inhibitor selective for vascular endothelial growth factor receptors (TKI-VEGFR), before nephrectomy.
This combination is currently FDA-approved for frontline treatment of patients with advanced RCC,2 based on the results of the phase 3 JAVELIN Renal 101 trial in which risk of disease progression or death was reduced by 31% in patients with treatment-naive RCC.3 NeoAvAx was the first ever neoadjuvant trial of a combination of an ICI and a VEGFR-TKI in locally advanced high-risk RCC.
The results, reported at the 2022 ASCO GU Cancers Symposium,4 suggested that avelumab/axitinib may be beneficial in these patients. ASCO presenter Axel Bex, MD, PhD, from the Netherlands Cancer Institute, Amsterdam, described the results as “encouraging.”
In a discussion with Thomas Powles, MBBS, MD, (Barts Cancer Centre, London, UK) and Brian Rini, MD (Vanderbilt University, Nashville, TN), Dr Bex, a urologic surgeon who is also based at the Specialist Centre for Kidney Cancer at the Royal Free NHS Foundation Trust in London, UK, recounted how NeoAvAx was carried out, and reviewed the implications of the results.
Dr Bex explained that 40 patients were enrolled, based on tumor clinical classification (cTNM) and biopsy Furhman grade; 90% of patients had stage T3 disease or higher. Between May 2018 and October 2021, patients received axitinib, 5 mg twice daily, plus continuous avelumab 10 mg/kg iv every 2 weeks for a total of 6 courses over 12 weeks. The dose of axitinib could be titrated up to 10 mg twice daily, which was done in 10% of the patients, he noted. Surgery took place 36 hours after the last dosage of axitinib. “We only had one patient who had to postpone his surgery for 3 weeks due to hypothyroidism grade 2,” he recalled.
“We used Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 partial response (PR) in the primary tumor in ≥25% of patients as the primary endpoint of the trial,” Dr Bex noted. “Some urologists get excited about this, because it might downsize or downstage tumors, but in the end, in a single-arm Phase 2 study, it allows us to find the clinical outliers and then do biomarker research to understand why some patients respond and others don’t,” he explained. “From a clinical perspective, what you really want to understand from this is who will be the patient who will benefit from this approach.”
Dr Bex and his colleagues found that 12 (30%) patients had a PR of the primary tumor, from a baseline mean diameter of 10.3 (range 5.6-16.4) cm. Ten (83%) of these patients were disease-free at study data cutoff. Median primary tumor downsizing was 20 (3.8-43.5)% None of the primary tumors progressed by RECIST 1.1. “There were 6 or 7 patients who had no tumor shrinkage and 2 who actually increased by a couple of millimeters, but most of them actually downsized,” Dr Bex recalled.
At the median observation follow-up of 23.5 months, 32.5% of patients had recurred, Dr Bex noted, adding that these patients might benefit from a period of adjuvant treatment, but that “without randomization you would probably never know that.”
Comparing NeoAvAx to Other Trials
Dr Rini recalled that investigators at The University of Texas MD Anderson Cancer Center in Houston carried out a phase 2 clinical trial of axitinib given up to 36 hours before surgery in patients with nonmetastatic biopsy-proven ccRCC.5 “Their results were even better,” Dr Bex acknowledged. “They included 24 patients and their partial response rate by RECIST was 46%.”
In contrast, Dr Powles pointed to a similar trial, PANTHER, that he led in the UK, “with results that were much less impressive, albeit with a different, but equally active drug [pazopanib].” In PANTHER, only 13% of patients had a partial response to therapy.6
“Can you confidently say that the addition of a second drug in NeoAvAx made any difference?” Dr Powles asked. “Currently we can’t confidently say that,” Dr Bex replied, noting that NeoAvAx was not a randomized trial. “I think we shouldn’t overshoot with the conclusions. It was a trial that was ideal to pick up a couple of signals to pick up on the safety and efficacy.”
Dr Bex emphasized the importance of the biomarker analyses carried out in NeoAvAx. “I do believe that we make a difference by adding avelumab, because we saw differences in upregulation of CD8+ densities in individual patients,” he maintained.
Post-treatment tumor samples from patients with recurrence had lower densities of total, intraepithelial, and stromal CD8+ and intra-epithelial CD8+CD39+ compared to patients with no recurrence. A similar trend was seen for total CD8+GZMB+ densities. No clear differences were seen in pre-treatment biopsies. “It’s not across the board,” Dr Bex cautioned. “Overall there was an increase in CD8+ densities; some patients who did not have CD8+ infiltration initially then developed it and in others who had it, it expanded.”
Questioned about the application of the biomarker findings, Dr Bex recalled that in the ADAPTeR study,7 which examined the role of neoadjuvant nivolumab prior to nephrectomy in patients with metastatic ccRCC, the investigators were able to show expansion of T cell receptor clones in responders.
“It would be extremely cool if we could do something like this, for example, from peripheral blood monocytes,” he said. “A tumor that is so heavily perfused as the kidney would probably show the same clones somewhere in the peripheral bloods and you may see an expansion on treatment that could give an early signal that these patients are responding to therapy.”
Future Neoadjuvant vs Adjuvant Trials
There are currently no ongoing randomized neoadjuvant versus adjuvant ICI trials or neoadjuvant versus adjuvant ICI/VEGFR-TKI combination trials in this setting, whereas “in bladder cancer, we’ve got 7 neoadjuvant trials,” Dr Powles remarked. Dr Bex noted that randomized trials with neoadjuvant therapy in ccRCC are difficult to perform. In Europe, he said, “many centers that would be able to do neoadjuvant therapy work closely with their oncologists, but this is not the case for the majority of hospitals, so it is much easier to run an adjuvant trial than a neoadjuvant one.”
Nephrectomy is a comparatively straightforward surgery, so it is easier to remove the kidney and send the patient to the oncologist, Dr Rini commented. He suggested that the next wave of adjuvant trials should incorporate neoadjuvant dosing, as the ongoing PROSPER RCC (NCT03055013) trial is doing,8 priming with neoadjuvant nivolumab prior to nephrectomy and continued adjuvant nivolumab in patients with high risk M0 RCC.
Linda Brookes, MSc is a freelance medical writer/editor based in New York and London.
- Dabestani S, Beisland C, Stewart GD, et al. Long-term outcomes of follow-up for initially localised clear cell renal cell carcinoma: RECUR database analysis. Eur Urol Focus. 2019;5(5):857-866. DOI: 10.1016/j.euf.2018.02.010
- FDA approves avelumab plus axitinib for renal cell carcinoma. News release. Food and Drug Administration (FDA); May 14, 2019. Accessed April 2, 2022. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-avelumab-plus-axitinib-renal-cell-carcinoma
- Motzer RJ, Penkov K, Haanen J, et al. Avelumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2019;380(12):1103-1115. DOI: 1056/NEJMoa1816047
- Bex A, Abu-Ghanem Y, Van Thienen JV, et al. Efficacy, safety, and biomarker analysis of neoadjuvant avelumab/axitinib in patients (pts) with localized renal cell carcinoma (RCC) who are at high risk of relapse after nephrectomy (NeoAvAx). J Clin Oncol. 2022;40(6 suppl):289.Abstract 289. DOI: 10.1200/JCO.2022.40.6_suppl.289
- Lebacle C, Bensalah K, Bernard JC, et al. Evaluation of axitinib to downstage cT2a renal tumours and allow partial nephrectomy: a phase II study. BJU Int. 2019 May;123(5):804-810. DOI: 1111/bju.14581
- Powles T, Sarwar N, Stockdale A, et al. Safety and efficacy of pazopanib therapy prior to planned nephrectomy in metastatic clear cell renal cancer. JAMA Oncol. 2016;2(10):1303-1309. DOI: 1001/jamaoncol.2016.1197
- Au L, Hatipoglu E, de Massy MR, et al; PEACE Consortium, TRACERx Renal Consortium. Determinants of anti-PD-1 response and resistance in clear cell renal cell carcinoma. Cancer Cell. 2021;39(11):1497-1518.e11. DOI: 1016/j.ccell.2021.10.001
- Harshman LC, Puligandla M, Haas NB, et al. PROSPER: A phase III randomized study comparing perioperative nivolumab (nivo) versus observation in patients with localized renal cell carcinoma (RCC) undergoing nephrectomy (ECOG-ACRIN 8143). J Clin Oncol. 2019;37(7 suppl):Abstract TPS684. DOI: 1200/JCO.2019.37.7_suppl.TPS684