Molecular Subtyping and Surgical Sequencing Broaden Immunotherapy Applications in RCC

Tian Zhang, MD

Future advances in renal cell carcinoma (RCC) management hinge on better defined molecular selection and treatment sequencing, according to Tian Zhang, MD, who noted that the ongoing phase 2 OPTIC RCC trial (NCT05361720) represents the first prospective investigation of molecular selection in this patient population.

OPTIC RCC will use previously established biologic clusters to assign treatment-naïve patients with metastatic clear cell RCC to receive either the immunotherapy combination of ipilimumab (Yervoy) plus nivolumab (Opdivo) or an immunotherapy/TKI combination of nivolumab plus cabozantinib (Cabometyx). Overall response rate (ORR) will serve as the primary end point of this trial, and the investigators hypothesize that using tumor clusters to determine first-line therapy will lead to a 20% greater ORR in these patients compared with the ORRs seen in unselected historical controls in previous trials.¹

“The hope and goal are, should we see some signals regarding efficacy and clinical outcomes of progression-free survival or response rates, potentially we’ll have more of a molecular signature that we can [use to] prospectively select patients for a designated immunotherapy-based combination,” Zhang said of OPTIC RCC in an interview with OncLive^® during the 2023 Kidney Cancer Research Summit.

Additionally, Zhang discussed findings from a retrospective study evaluating outcomes of patients with metastatic RCC who received cytoreductive nephrectomy before or after immunotherapy. This study found that patients who received neoadjuvant immunotherapy treatment were likely to have reduced tumor size and pathologic necrosis at the time of nephrectomy.²

In the interview, Zhang discussed unanswered questions regarding molecular drivers of kidney cancer that the OPTIC RCC trial aims to answer, next steps with this research, and the potential benefits of receiving systemic therapy prior to undergoing cytoreductive nephrectomy for patients with metastatic RCC.

Zhang is an associate professor in the Department of Internal Medicine at the UT Southwestern Medical Center Harold C. Simmons Comprehensive Cancer Center in Dallas, Texas.

OncLive: What was the rationale for the OPTIC RCC trial?

Zhang: OPTIC RCC is focused on prospectively testing transcriptomic signatures to select patients for therapy. It is primarily run and created by Brian Rini, MD, [of the Vanderbilt-Ingram Cancer Center in Nashville, Tennessee], who is running this out of Vanderbilt with Department of Defense funding [in the form of] the [Kidney Cancer Research Program Clinical Trial Award]. [The study] is premised on the fact that we have multiple immunotherapy combinations for frontline metastatic kidney cancer, and it’s hard in the clinic to decide which is the best fit for the patient in front of us.

[Previously,] a series of patients’ genomic signatures were profiled [and] clustered into 7 clusters of gene expression signatures that had different types of phenotypes, [which] drive the tumor characteristics. These came out of the IMmotion trials [with] atezolizumab [Tecentriq] and bevacizumab [Avastin], where many correlative studies were done, and these 7 genomic transcriptomic clusters were identified.

Based on those, some clusters were more angiogenically driven and more responsive to VEGF-targeted therapies, and some were more inflammatory and myeloid, which were responsive to immunotherapies. Because rich correlative studies have been done in large phase 3 trials, this set up the possibility of potentially doing a molecularly selected trial in kidney cancer. We have not had that in kidney cancer. We have never had a prospective molecular selection for a trial.

This is a multicenter trial, [with] 2 cohorts. Patients are selected upfront for treatment with either cabozantinib plus nivolumab or ipilimumab and nivolumab [based on whether their] clusters select for angiogenic signatures or signatures that are more immunotherapy responsive, [respectively]. [Both] treatments are standard of care [SOC].

What is the feasibility of this biologic clustering?

Sometimes we hesitate when we are profiling tumors. It takes a long time for specimen collection, testing, and turnaround to make [a treatment] decision. In a way, it requires an engaged patient who will sign up for this type of study. It takes some time, maybe a few weeks more than their SOC treatment selection otherwise.

However, [with] that process of sending the tissue to the company, in this case, Tempus is running the genomic and transcriptomic signatures, the turnaround time is generally within 7 to 10 days. By the time the tissue comes back, we can stratify, enroll, finish enrolling, and select the treatment option that the patient best qualifies for.

This is a trial in progress. It’s been open at Vanderbilt for approximately 6 to 9 months. [Accrual is] still ongoing. We at UT Southwestern are participating, and so are City of Hope and Cleveland Clinic. Four or 5 centers are participating in the trial.

What was found in the study on the sequencing of cytoreductive nephrectomy in patients with metastatic RCC?

This is a retrospective study. It’s led by 1 of our [postdoctoral scholars] on the lab side, Damla Gunenc, [of UT Southwestern]. She is looking at cytoreductive nephrectomy. In the era [after the phase 3] CARMENA trial [NCT00930033], where the timing of cytoreductive nephrectomy is questioned, we wanted to think about the patients who had undergone cytoreductive nephrectomy at UT Southwestern and see what their outcomes were.

[Data from] approximately 52 patients were collected retrospectively. Approximately one-third of them underwent cytoreductive nephrectomy first, followed by systemic treatment. The other two-thirds underwent systemic treatments first [with] immunotherapy-based combinations, followed by nephrectomy.

What we found was, interestingly, many patients who had received immunotherapy first developed necrosis in their tumors and had some pathologic downstaging at the time of surgery. This represents a unique approach and helps us make decisions in the clinic. It is all retrospective. Ongoing trials like the [phase 3] SWOG cooperative group trial, PROBE [NCT04510597], will hopefully help us answer this question of [to] whom and when [we should] offer cytoreductive nephrectomy in metastatic kidney cancer.

Were the characteristics of the patients who underwent cytoreductive nephrectomy first consistent with the characteristics of patients in whom you would consider this approach?

We offer cytoreductive nephrectomy upfront [based] on a multidisciplinary discussion. It requires a urologist and a medical oncologist to discuss the patient characteristics, and often, patients who undergo cytoreductive nephrectomy first in our current practice are the patients who have the bulk of their tumor burden in the primary tumor. This is often 80% or 90% of their total tumor burden. Those patients are [also] surgically fit.

However, primarily, we need to believe that the metastatic sites won’t cause problems during the time it takes to get a patient through to cytoreductive nephrectomy. It’s certainly still a practice that we do for a select patient population, but it requires multidisciplinary discussions and collaboration to get the patients through surgery and watch them quickly after surgery to discuss pathology and then discuss first-line metastatic treatment.

What other presentations were you excited to see at this year’s KCRS meeting?

There was much great science at KCRS 2023. William G. Kaelyn, Jr., MD [of Dana-Farber Cancer Institute], came from across town to give a talk. He [always] provides great insights in kidney cancer. [I was interested to see] his talk and the great science and collaborations that are shared here. It’s a wonderful opportunity for all these kidney cancer researchers to get together and share their science.

References

1. Chen YW, Beckermann K, Haake SM, et al. Optimal treatment by invoking biologic clusters in renal cell carcinoma (OPTIC RCC). J Clin Oncol. 2023;41(suppl 6):TPS742. doi:10.1200/JCO.2023.41.6_suppl.TPS742
2. Gunenc D, Gerald T, Issa W, et al. Pathologic response and outcomes of patients with metastatic renal cell carcinoma undergoing cytoreductive nephrectomy after immunotherapy regimens. Presented at: 2023 Kidney Cancer Research Summit; July 13-14, 2023; Boston, MA.