San Francisco, CA (UroToday.com) In a case-based session, Dr. Laurence Albiges, Medical Oncologist at Institut Gustave Roussy, discussed the role of neoadjuvant systemic therapy in locally advanced renal cell carcinoma (RCC). The hypothetical case was that of a 65 year man who presented with gross hematuria. CT scan of the abdomen and pelvis revealed a 15 x 12 centimeter right renal mass with level 1 tumor thrombus and a 2.5 centimeter retrocaval lymph node. CT scan of the chest and bone scan were negative.
Neoadjuvant systemic therapy is not a standard of care in localized RCC, however, has a number of theoretical benefits. Cytoreduction as a result of neoadjuvant systemic therapy could allow for partial nephrectomy or ablative techniques in patients who are poor surgical candidates or tumor downstaging to achieve resection of locally advanced, previously unresectable tumors. Early systemic therapy could also theoretically eradicate micrometastatic disease and reduce recurrence rates. Finally, neoadjuvant systemic therapy allows for the correlation of treatment with pathologic response and immune response.
Dr. Albiges first reviewed what we have learned about responses to neoadjuvant therapy in the VEGF tyrosine kinase (TKI) era. A phase 2 trial of neoadjuvant axitinib in 24 patients with locally advanced non-metastatic clear cell RCC demonstrated a median reduction of 28% in the primary tumor; 46% of patients had a partial response by RECIST criteria.1 A second study of neoadjuvant axitinib in 18 patients reported a median reduction in the primary tumor of 17% with 25% of patients experiencing a partial response.2 Thus, neoadjuvant VEGF TKI is feasible and induces downsizing of the primary tumor. Regarding patients with tumor thrombus – like the patient in the case presented – a retrospective analysis of neoadjuvant TKI in patients with tumor thrombus showed minimal clinical effect on the tumor thrombus; a prospective clinical trial of axitinib in RCC patients with tumor thrombus in is ongoing (NCT03494816).
Many clinical trials of neoadjuvant immunotherapy in patients with localized RCC are ongoing. Two of these studies are evaluating neoadjuvant nivolumab with the primary endpoint of safety. A number of additional neoadjuvant studies combine immunotherapy with targeted therapy.
Data supporting primary tumor shrinkage with neoadjuvant immunotherapy can be extrapolated from the M1 (metastatic) setting. An abstract presented at the ASCO 2019 meeting of patients treated with nivolumab alone or in combination with ipilimumab or bevacizumab demonstrated response rates of 43-59%.
Data presented at the ESMO 2019 meeting from the JAVELIN Renal 101 Study suggests that combination therapy with immunotherapy plus a VEGF TKI may be more effective than VEGF TKI alone. In this study of patients with metastatic RCC, patients treated with axitinib plus avelumab had an objective response rate in the primary tumor of 34.5% compared to 9.7% in the sunitinib arm. Dr. Albiges raised the question of what the best endpoint is for determining efficacy in the neoadjuvant setting and suggested that pathologic complete response might be a better surrogate endpoint than an objective response rate.
In addition to the efficacy of neoadjuvant therapy in localized RCC, the safety profile must be assessed. There is a paucity of data regarding this question. Dr. Albiges highlighted a small retrospective series of 11 patients who received immunotherapy for metastatic RCC and achieved a pathologic complete response, then underwent cytoreductive nephrectomy.3 Notably, surgeons reported difficulty in finding dissection planes due to adhesions and inflammatory reactions at the kidney and in surrounding tissues in 9 of these patients (82%). Prospective safety data is needed and will be reported in the ongoing neoadjuvant trials.
A final unanswered question is whether neoadjuvant or adjuvant immunotherapy is a better approach for localized RCC. Dr. Albiges argued in favor of a neoadjuvant approach. PD-(L)1 blockade results in in situ expansion of tumor-specific T-cell clones already within the tumor microenvironment and may also act at the tumor-draining lymph nodes to enhance the production of tumor-specific T cells there as well. The benefit of the neoadjuvant approach is that it leverages higher levels of endogenous tumor antigen present in the primary tumor to enhance T cell priming. Dr. Albiges acknowledged that randomized clinical trials are needed to determine which approach results in superior outcomes. The PROSPEC RCC Trial (NCT03055013), which is testing a peri-operative immunotherapy approach to maximize the tumor immune response is ongoing.
Dr. Albiges concluded with the following take-home points:
- Neoadjuvant trials with immunotherapy are ongoing
- Endpoints of neoadjuvant trials should assess tumor shrinkage, surgical feasibility, long-term disease-free and overall survival benefit, and exploratory biomarkers to understand predictors of response
- Although no head-to-head neoadjuvant versus adjuvant clinical trials are ongoing, there is a strong biological rationale to treat with immunotherapy with the tumor in place
Presented by: Laurence Albiges, MD, Ph.D., Medical Oncologist at Institut Gustave Roussy
Moderated by: Sumanta Pal, MD, Medical Oncologist at City of Hope Comprehensive Cancer Center and Robert Uzzo, MD, MBA, Urologist at Fox Chase Cancer Center
Written by: Jacob Berchuck, MD, Medical Oncology Fellow at the Dana-Farber Cancer Institute (Twitter: @jberchuck) at the 2020 Genitourinary Cancers Symposium, ASCO GU #GU20, February 13-15, 2020, San Francisco, California
References:
- Karam JA, et al. Phase 2 trial of neoadjuvant axitinib in patients with locally advanced nonmetastatic clear cell renal cell carcinoma. Eur Urol. 2014 Nov;66(5):874-80.
- Lebacle C, 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.
- Pignot G, et al. Nephrectomy After Complete Response to Immune Checkpoint Inhibitors for Metastatic Renal Cell Carcinoma: A New Surgical Challenge? Eur Urol. 2020 Jan 3.