David A. Braun, MD, PhD, assistant professor of Medicine (Medical Oncology), Louis Goodman and Alfred Gilman Yale Scholar, Yale Cancer Center and Smilow Cancer Hospital, Yale School of Medicine, discusses the enrichment of SLAMF7-positive, CD8-positive T-cells and their role on nivolumab (Opdivo) resistance in clear cell and non–clear cell renal cell carcinoma (RCC).

Within many tumor types, T cells are the main effector cells and the main mediator of effective anti-tumor immunity, Braun begins. When checkpoint inhibitors work, they are mediated through T cells designed to specifically recognize and effectively kill tumor cells, Braun adds. With this is mind, investigators saw different outcomes from prior studies with single-cell RNA sequencing across disease settings, Braun says.

In this investigation, investigators observed 2 patterns of T cells. One pattern showed T cell that traveled toward a previously observed terminal exhaustion, and the other was a state that had not been characterized before, Braun explains. These T cells still expressed some dysfunction markers, but other markers were observed that were not expected, as well as slightly higher levels of cytotoxicity.

The question derived from this surprising finding was if these T-cell populations have an effect on patient outcomes. Investigators found that those whose disease was dysfunctional and exhaustive, having a lot of those cells didn't make any difference and it didn't have any impact on response or survival. However, when SLAMF7-positive, CD8-positive T-cells were enriched, that's where investigators saw clinical impact. Patients who had a high proportion of SLAMF7-positive T-cells had much worse outcomes, Braun emphasizes.

These patients had higher rates of progressive disease, worse progression-free survival, and a trend toward worse overall survival, Braun concludes.

Videos

David A. Braun, MD, PhD, discusses the enrichment of SLAMF7-positive, CD8-positive T-cells and their role on nivolumab resistance in clear cell and non–clear cell renal cell carcinoma.

Dr. Braun on the Role of SLAMF7+ CD8+ T-cells in Nivolumab-Resistant RCC 

David A. Braun, MD, PhD, physician at Dana-Farber Cancer Institute and instructor of medicine at Harvard Medical School, discusses unanswered questions regarding the utility of PD-1 blockade in advanced renal cell carcinoma (RCC).

PD-1 inhibitors have transformed the treatment of patients with advanced RCC, says Braun; however, not all patients will experience durable clinical benefit. Going forward, a better understanding of the determinants of response, as well as the mechanisms of resistance, is of critical importance.

As opposed to melanoma and non­–small cell lung cancer, kidney cancer has a modest mutational burden but a robust CD8 T-cell infiltration. Therefore, the typical “hot” versus “cold” paradigm does not apply.

Due to the unmet need in the space, future research endeavors will focus on immune and genomic determinants of response and resistance to PD-1 blockade, Braun concludes.

David A. Braun, MD, PhD, discusses unanswered questions regarding the utility of PD-1 blockade in advanced renal cell carcinoma. 

Dr. Braun on Unanswered Questions With PD-1 Blockade in Advanced RCC

David A. Braun, MD, PhD, physician at Dana-Farber Cancer Institute and instructor of medicine at Harvard Medical School, discusses the use of immunotherapy in the frontline treatment of patients with advanced renal cell carcinoma (RCC).

Most patients with advanced RCC should receive immunotherapy in the frontline setting rather than VEGF TKI monotherapy, regardless of their risk status, says Braun. Several combinations are approved for use in this setting, including axitinib (Inlyta)/avelumab (Bavencio), nivolumab (Opdivo)/ipilimumab (Yervoy), and axitinib/pembrolizumab (Keytruda).

Long-term follow-up suggests that patients do just as well, if not better, with immunotherapy versus antiangiogenic therapy alone, adds Braun. As such, immunotherapy should be used in patients with intermediate- and poor-risk as well as favorable-risk disease, concludes Braun.

Dr. Braun on Frontline Immunotherapy in Advanced RCC

David A. Braun, MD, PhD, physician at Dana-Farber Cancer Institute and instructor of medicine at Harvard Medical School, discusses the evolution of immunotherapy in advanced renal cell carcinoma (RCC).

Immunotherapy has been transformative for patients with advanced RCC, says Braun. However, immunotherapy is not a brandnew approach for this disease. Previously, therapeutic options such as interferons and interleukin-2 therapy were used. Then, in the mid 2000s, the introduction of antiangiogenics, blood vessel—blocking agents, transformed the management of kidney cancer at that time.

Recently, with the introduction of the immune checkpoint blockade, often in combination with other drugs, patients with RCC are experiencing dramatic responses. Not only are more patients responding to treatments and living longer, but a tail of the curve can be seen as well, says Braun. The overarching goal in cancer care is to find a cure, and these patients appear to experience long-term and durable responses with immunotherapy.

David A. Braun, MD, PhD, discusses the evolution of immunotherapy in advanced renal cell carcinoma.

Dr. Braun on Evolution of Immunotherapy in Advanced Renal Cell Carcinoma

Postdoctoral Genitourinary Oncology Research Fellow

Dana-Farber Cancer Institute's Lank Center for Genitourinary Oncology Boston, Massachusetts

The current management of metastatic renal cell carcinoma (RCC) reflects the progress of medical oncology throughout the past several decades. The standard of care has evolved from cytokine-based therapies to targeted molecular therapies and immune checkpoint inhibitor—based strategies.

However, no overall survival (OS) benefit has yet been achieved with the use of systemic agents in the localized disease context when therapy with curative intent is often still possible.

 This is an important unmet need, because the risk of relapse can be as high as 80% in the most aggressive forms of the disease.

 Although adjuvant approaches employing VEGFR-directed tyrosine kinase inhibitors (TKIs) have largely been ineffective, innovative strategies based on immune checkpoint inhibition (ICI) may reshape the field of perioperative therapy for RCC.

Targeted Therapies for Localized RCC Disappoint

In the neoadjuvant setting, 2 single-arm prospective trials evaluated axitinib (Inlyta) for up to 12 weeks

 and pazopanib (Votrient) for up to 16 weeks

 before surgery for localized or locally advanced RCC. Axitinib resulted in tumor volume reduction in all 24 patients evaluated, and 93% of 25 patients had reduction in tumor volume with pazopanib. However, these findings have not been investigated in larger cohorts, and most importantly, the effect of these strategies on long-term survival outcomes has not been assessed, limiting their translation into clinical practice.

These agents have been more thoroughly evaluated in the adjuvant setting, where 6 phase III randomized trials have tested the VEGFR TKIs in patients at high risk of relapse (based on tumor, node, metastasis [M], and grade staging). Only the S-TRAC trial,

 which randomized patients to 1 year of adjuvant sunitinib (Sutent) or placebo after resection of high-risk clear cell RCC, achieved its primary end point, with a median improvement in disease-free survival (DFS) of 1.2 years with sunitinib compared with placebo (6.8 years vs 5.8 years; HR, 0.76; 

These results were in contrast to those reported in the ASSURE trial,

 which evaluated sunitinib or sorafenib (Nexavar) for 1 year versus placebo and did not show improvement in DFS or OS with either agent compared with placebo. Although some of the discrepancies in the sunitinib results may be due to differences in trial design (ASSURE included patients with non—clear cell histologies and of lower stage and allowed lower sunitinib starting doses and lower levels of dose reductions), both highlighted the potential toxicity of sunitinib in this setting, with little to no survival benefit.

Despite no improvement in OS and the negative results of the ASSURE trial, the FDA approved sunitinib in this indication. However, the use of adjuvant sunitinib remains limited to select cases in clinical practice.

Other trials of adjuvant pazopanib (for 1 year),

 and the anti-CAIX antibody girentuximab (24 weeks)

 in high-risk localized disease were also found to not improve either DFS or OS.

Table. Selected Ongoing Trials of Immunotherapy in the Perioperative Treatment of Resectable Renal Cell Carcinoma (Click to Enlarge)

Prospects for Immunotherapy in Resectable RCC Generate Excitement

With most of the targeted therapy trials in the perioperative treatment of RCC yielding negative results, the focus of ongoing trials has shifted toward investigating ICI agents in this setting.

In particular, with the FDA approval of the PD-1 inhibitor nivolumab (Opdivo) in the treatment of RCC after first-line targeted therapy in the metastatic setting,

 as well as the subsequent approval of nivolumab plus the CTLA-4 inhibitor ipilimumab (Yervoy ),

 the PD-L1 inhibitor avelumab (Bavencio) plus axitinib,

 and the PD-1 inhibitor pembrolizumab (Keytruda) plus axitinib

 in the first-line treatment of metastatic RCC, ICI has become an essential component of managing metastatic RCC.

Because RCC is a highly immune-infiltrated tumor that has historically been among the most immune-responsive tumors (including with treatments such as interleukin- 2 and interferon alfa before the ICI era),

 harnessing the potency of immunotherapy in this disease to improve cure rates in the perioperative setting is a very promising prospect.

Multiple clinical trials are evaluating immunotherapy-based approaches in this setting (

). KEYNOTE-564, RAMPART, CheckMate 914, and IMmotion010 are ongoing phase III randomized clinical trials evaluating ICI monotherapies or combinations in the adjuvant treatment of high-risk RCC.

Although these trials share many design features, a few distinguishing characteristics may be crucial in helping to define the optimal regimen and patient selection for adjuvant ICI treatment. For instance, 2 of these 4 trials (KEYNOTE-564 and IMmotion010) will allow inclusion of patients with previously resected metastatic disease, also called M1 NED, who are at the highest risk of recurrence

 and therefore may benefit most from these regimens.

For instance, RAMPART allows inclusion of patients with non—clear cell RCC (a basket term used for a heterogeneous group of rarer RCC histologies) that may be less responsive to ICI and differs from clear cell RCC in terms of its immune microenvironment.

Another important distinction will be the balance of toxicity and expected efficacy of these ICI regimens. As we have learned from the TKI experience in the adjuvant treatment of RCC, regimens that are relatively well tolerated in the metastatic setting may be judged less tolerable by patients when used in the adjuvant setting.

 Therefore, it will be important to evaluate the treatment discontinuation rates due to toxicity in each of these trials, especially those employing ICI combinations, such as the RAMPART combination arm and CheckMate 914.

However, because most of the tumor antigen load is expected to diminish substantially after tumor resection of high-risk RCC, other trials are attempting to circumvent the decrease in immune-activating antigens in the adjuvant setting by employing alternative trial designs or therapy regimens.

For instance, PROSPER-RCC, an innovative international academically led phase III trial, is evaluating the use of nivolumab before (neoadjuvant) and continuing after (adjuvant) nephrectomy for RCC, with the goal of initially stimulating the immune response when the bulk of the antigen load is still in place (before nephrectomy) and continuing to engage the immune response adjuvantly.

 PROSPER-RCC is the only phase III study to evaluate both presurgical and adjuvant dosing and that allows M1 NED and non—clear cell histologies and does not subject patients to placebo. Two phase I studies have shown preliminary safety and feasibility of giving 3 or 4 doses of neoadjuvant nivolumab for M0 RCC planned for nephrectomy (NCT02575222 and NCT02595918; personal communication), and a phase Ib trial of durvalumab (Imfinzi) with and without tremelimumab showed that this regimen is feasible and significantly affects immune checkpoint expression on circulating and tumor- infiltrating myeloid derived stem cells.

Another trial, NEOAVAX, is a phase II study evaluating the combination of avelumab plus axitinib in the neoadjuvant treatment of RCC, with the objective of both optimizing the immune response when the kidney is still in place and facilitating localized RCC resection by downsizing the primary tumor through neoadjuvant therapy.

Finally, personalized immunotherapy approaches are emerging, including a phase I adjuvant study evaluating intradermal and subcutaneous delivery of a personalized neoantigen vaccine. The vaccine is custommade based on predicted neoantigens in a patient’s tumor. The neoantigen cancer vaccine is coinjected with locally delivered ipilimumab with the aim of improving T-cell priming and activation against the vaccine neoepitopes to both optimize efficacy and minimize ICI toxicity.

Although targeted therapies and ICI have revolutionized the treatment of metastatic RCC in recent years, our ability to improve cure rates through systemic therapy in the perioperative setting has, unfortunately, lagged those advances.

Because targeted therapies have thus far been disappointing in this setting, the field is moving toward immunotherapy-based approaches to improve cure rates. As these immunotherapy-based approaches are developed, identification of immunotherapyspecific biomarkers for recurrence in the perioperative setting is needed to optimize selection of patients who are most likely to benefit from these novel approaches.

Similarly, in the postmetastectomy setting when patients had no evidence of disease (M1 NED), adjuvant systemic therapy with pazopanib for 1 year in the E2810

 trial and sorafenib for 1 year in the RESORT

 trial did not demonstrate improvement in DFS versus placebo or observation. Although findings from the adjuvant phase III trial of everolimus (Afinitor; NCT01120249) have not been reported yet, the disappointing results of previous targeted therapy trials in this setting have tempered expectations.

Articles

The current management of metastatic renal cell carcinoma reflects the progress of medical oncology throughout the past several decades. The standard of care has evolved from cytokine-based therapies to targeted molecular therapies and immune checkpoint inhibitor–based strategies.

David A. Braun, MD, PhD

Articles

Dr. Braun on the Role of SLAMF7+ CD8+ T-cells in Nivolumab-Resistant RCC

Dr. Braun on Unanswered Questions With PD-1 Blockade in Advanced RCC

Dr. Braun on Frontline Immunotherapy in Advanced RCC

Dr. Braun on Evolution of Immunotherapy in Advanced Renal Cell Carcinoma

New Perioperative Strategies Emerge for High-Risk, Resectable RCC