Ziad Bakouny, MD, MSc, internal medicine resident, Brigham and Women’s Hospital, Harvard Medical School,discusses understanding the biology of translocation renal cell carcinoma (tRCC).

It is important to understand the biology of tRCC for many reasons, Bakouny says. This disease is aggressive and the patients it affects typically have poor outcomes, Bakouny explains. Moreover, tRCC disproportionately affects young patients​, particularly young women; therefore, tRCC confers a significant disease burden for this patient population, Bakouny says.

Overall, if the biology of this disease does not become more widely understood, it will not be possible to target it with effective treatment, Bakouny continues. Currently, extrapolation from data in other disease subtypes, such as clear cell RCC, has not yielded optimal insight into treating patients with tRCC, Bakouny says. Therefore, research is needed to understand the biology of tRCC, target the disease, and improve outcomes for patients, Bakouny conclude.

Videos

Ziad Bakouny, MD, MSc, discusses understanding the biology of translocation renal cell carcinoma. 


Dr. Bakouny on Understanding the Biology of Translocation RCC 

Ziad Bakouny, MD, MSc, postdoctoral genitourinary oncology research fellow, Dana-Farber Cancer Institute, discusses the rate of disease progression in sarcomatoid carcinoma.

Despite recent advances in the sarcomatoid carcinoma armamentarium with therapies​, such as ​the introduction of checkpoint inhibitors, patients with sarcomatoid carcinoma tend to progress very rapidly, says Bakouny.

As such, it ​is important to note that ​patients' tumors may develop ​into a more severe and symptomatic disease presentation if patientsdo not respond to therapy, ​Bakouny explains.

In the clinical setting, nurses tend to be sensitive to the risk of disease progression among patients with sarcomatoid carcinoma, Bakouny concludes.

Ziad Bakouny, MD, MSc, discusses the rate of disease progression in sarcomatoid carcinoma.








Dr. Bakouny on the Rate of Disease Progression in Sarcomatoid Carcinoma 

Ziad Bakouny, MD, MSc, postdoctoral genitourinary oncology research fellow, Dana-Farber Cancer Institute, discusses the utility of checkpoint inhibitors in renal cell carcinoma (RCC) with sarcomatoid differentiation.

Sarcomatoid differentiation with or without rhabdoid differentiation is an aggressive subtype of RCC that accounts for 20% to 25% of all metastatic RCC, says Bakouny. This subtype is not common among patients with localized disease. However, patients with clear cell RCC or non-clear cell RCC who present with metastatic disease or who relapse may develop sarcomatoid differentiation, says Bakouny.

Therapies such as TKIs and rapalogs have expanded the armamentarium in RCC. However, patients with sarcomatoid differentiation have not historically derived significant benefit from these treatments, explains Bakouny.

However, novel combination regimens with immune checkpoint inhibitors such as nivolumab (Opdivo)/ipilimumab (Yervoy), avelumab (Bavencio)/axitinib (Inlyta), atezolizumab (Tecentriq)/bevacizumab (Avastin), and pembrolizumab (Keytruda)/axitinib appear to elicit significant activity and high complete response rates in this subgroup of RCC, concludes Bakouny.

Ziad Bakouny, MD, MSc, discusses the utility of checkpoint inhibitors in renal cell carcinoma with sarcomatoid differentiation.



Dr. Bakouny on the Utility of Checkpoint Inhibitors in Sarcomatoid RCC

Ziad Bakouny, MD, MSc, postdoctoral genitourinary oncology research fellow, Dana-Farber Cancer Institute, discusses the role of cytoreductive nephrectomy in metastatic renal cell carcinoma (mRCC).

Historically, patients treated with cytokines derived benefit from cytoreductive nephrectomy, says Bakouny. However, its utility for patients treated with targeted therapy is more controversial.

The role of cytoreductive nephrectomy for patients treated with immune checkpoint inhibitors is not well established, says Bakouny.

A retrospective analysis of 4,639 patients treated with either targeted therapy or a checkpoint inhibitor showed a significant improvement in overall survival with cytoreductive nephrectomy versus without in both patient cohorts.

Additionally, the study showed that younger patients with low-risk mRCC underwent cytoreductive nephrectomy, explains Bakouny. These patients tended to have adverse histologic features which confers lack of benefit to systemic therapies.

Ziad Bakouny, MD, MSc, discusses the role of cytoreductive nephrectomy in metastatic renal cell carcinoma.

Dr. Bakouny on the Role of Cytoreductive Nephrectomy in mRCC

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.

New Perioperative Strategies Emerge for High-Risk, Resectable RCC

According to the 2018 Globocan report, over 400,000 cases of renal cell carcinoma (RCC) are diagnosed yearly, resulting in more than 175,000 deaths around the world.

 One-third of patients with RCC have unresectable locally advanced or metastatic disease, and 20% to 40% of patients presenting with localized disease eventually have metastatic relapses.

 Among the histological types of RCC, clear-cell RCC is the most frequent type by a wide margin.

Significant advances in the treatment of metastatic RCC occurred during the past decade, with multiple targeted therapies added as treatment options for this disease. These therapies were either of the antiangiogenic class, including sunitinib (Sutent), sorafenib (Nexavar), axitinib (Inlyta), pazopanib (Votrient), cabozantinib (Cabometyx), lenvatinib (Lenvima), and bevacizumab (Avastin), or the mammalian target of rapamycin (mTOR) inhibitor class, such as temsirolimus (Torisel) and everolimus (Afinitor).

 However, some tumors are inherently resistant to these therapies and most tumors that initially respond will eventually progress.

Furthermore, in contrast to the wide array of available therapies in the metastatic setting, in patients with localized disease, the results of trials investigating adjuvant systemic therapy after nephrectomy have so far been underwhelming. Sunitinib is currently the only therapy shown to confer a statistically significant benefit compared with placebo in the adjuvant setting, but only for diseasefree survival, not overall survival, and with conflicting results between 2 pivotal trials.

Immune checkpoint inhibitors (ICIs) are a new class of drugs designed to augment a patient’s immune response against a tumor by targeting immune checkpoints that physiologically limit immune activation. The immune checkpoints that are the targets of FDA-approved drugs are PD-1, PD-L1, and CTLA-4.

ICIs have thus far shown significant survival benefit in a large number of tumor types, including RCC,5 and at the time of this writing, 6 PD-1/PD-L1 inhibitors and 1 CTLA-4 inhibitor have been approved by the FDA. A few, such as nivolumab (Opdivo) and ipilimumab (Yervoy), are approved for use in RCC, although others are undergoing testing in this disease type.

In the metastatic setting, nivolumab was the first ICI to show significant efficacy in the treatment of RCC. The landmark CheckMate-025 phase III trial randomized patients with at least 1 prior line of systemic therapy to either nivolumab or everolimus, showing a hazard ratio (HR) for overall survival (OS) of 0.73 (98.5% CI, 0.57-0.93; 

 = .002) and an overall response rate (ORR) of 25%.

 Subsequently, atezolizumab (Tecentriq) and pembrolizumab (Keytruda) showed ORRs of 25% and 38.2% in treatment-naïve patients in the phase II IMmotion150 and KEYNOTE-427 trials, respectively.

Although these results were considered significant advances in the treatment of metastatic RCC, it was hypothesized that patient treatment outcomes could be further improved by combining ICIs with other drugs.

To that end, multiple ICI-based combinations have been tested. In the pivotal CheckMate-214 trial, the combination of nivolumab and ipilimumab significantly improved OS in patients with intermediate-/poor-risk untreated metastatic RCC (HR, 0.63; 99.8% CI, 0.44-0.89; 

 <.001) and in the overall patient population (HR, 0.68; 99.8% CI, 0.49-0.95; 

 <.001) compared with sunitinib. In the intermediate-/poor-risk subgroup, nivolumab plus ipilimumab conferred a significant benefit over sunitinib for ORR (42% vs 27%; 

 <.001), with only a trend in favor of nivolumab and ipilimumab for progression-free survival (PFS) (HR, 0.82; 99.1% CI, 0.64-1.05;

 = .03). However, in the favorable-risk population, the nivolumab with ipilimumab combination led to significantly worse PFS (HR, 2.18; 99.1% CI, 1.29-3.68; 

leading to the current FDA approval only for those presenting with intermediate- and poor-risk disease.

A second approach to ICI-based combinations for RCC is combining ICIs with inhibitors of the vascular endothelial growth factor (VEGF) pathway, which could augment the efficacy of ICIs by attenuating tumor immunosuppression.

 In particular, in previously untreated patients with metastatic RCC, the recent phase III IMmotion 151 study showed a significant PFS advantage (HR, 0.74; 95% CI, 0.57-0.96; 

 = .02) of an atezolizumab-plusbevacizumab combination over sunitinib in the subset of patients with PD-L1 ≥1% on tumor-infiltrating immune cells, as well as an ORR of 43% (vs 35% for sunitinib).

 Phase I clinical trials have yielded promising results with combinations of pembrolizumab plus axitinib (ORR,73%, untreated patients),

 pembrolizumab plus lenvatinib (ORR, 63%, untreated and previously treated patients),

 avelumab (Bavencio) plus axitinib (ORR, 58%, untreated patients),

 and cabozantinib with nivolumab plus/minus ipilimumab (ORR, 54% in the sarcomatoid RCC subset of the trial, previously treated patients) (

Multiple ongoing trials are also awaited to further define optimal ICI-based combinations for the treatment of metastatic RCC, including phase III trials of cabozantinib plus nivolumab compared with sunitinib (CheckMate 9ER, NCT03141177), axitinib plus avelumab compared with sunitinib (JAVELIN Renal 101, NCT02684006), lenvatinib plus pembrolizumab or lenvatinib plus everolimus compared with sunitinib (NCT02811861), and axitinib plus pembrolizumab compared with sunitinib (KEYNOTE-426, NCT02853331).

Given the disappointing results of most trials investigating adjuvant treatment for RCC, improving the cure rates of surgery for localized RCC constitutes an important unmet need. Multiple trials are investigating whether adjuvant ICI therapy could improve outcomes for localized RCC, including IMmotion-010 (NCT03024996, atezolizumab vs placebo), KEYNOTE-564 (NCT03142334, pembrolizumab vs placebo), RAMPART (NCT03288532, durvalumab plus tremelimumab vs durvalumab vs observation), and CheckMate-914 (NCT03138512, nivolumab plus ipilimumab vs placebo).

The Need for Biomarkers of Response to ICIS

A novel approach to using ICIs in the localized setting involves perioperative immune checkpoint inhibition both in the neoadjuvant and adjuvant settings. The rationale is that more tumor antigens are available to participate in the activation of the immune system before tumor resection, optimizing the ICI-induced response and hypothetically improving cure rates.

 PROSPER RCC (NCT03055013) is an ongoing phase III trial that randomizes patients with high-risk localized RCC to either 1 month of neoadjuvant nivolumab followed by nephrectomy and 9 months of adjuvant nivolumab versus nephrectomy alone. The results of this perioperative ICI trial along with those of the adjuvant ICI trials could add important treatment options for patients with localized but high-risk disease.

Considering that tumor responses to ICIs and ICI-based combinations are relatively limited, with only half of patients responding at best, identifying patients most likely to respond to ICIs is of paramount importance. PD-L1 expression has been proposed as a possible biomarker of response to ICI; PD-L1 has been found to be overexpressed in about a quarter of clear-cell RCC tumors and to be associated with poorer outcomes.

 However, although PD-L1 expression ≥1% tended to be associated with superior outcomes, with the combination of nivolumab plus ipilimumab in CheckMate-214,

 it was only of prognostic value in patients treated with nivolumab alone (vs everolimus) in CheckMate-025.

Figure. ORRs of ICIs and ICI-Based Combinations (With Sunitinib Added for Comparison)

Moreover, discrepancies in where PD-L1 is measured (tumor cells, tumor-infiltrating immune cells, or both types of cells), differences in cutoffs, and the type of antibody used may limit the role of PD-L1 as a universal biomarker for response to ICIs in advanced RCC. Some specific molecular alterations have been shown to predict response to ICIs in RCC, with one study’s results showing that loss of function of the PBRM1 gene is associated with a higher rate of clinical benefit in advanced RCC.

 In solid tumors in general, other biomarkers for ICI response are under investigation, such as tumor mutational burden,

 and composition of the microbiome of the digestive tract.

Despite the wealth of new agents in the treatment of metastatic RCC, in both the first- and second-line settings, there are little data about optimal sequences of regimens. Multiple ongoing trials are therefore attempting to address such questions, with NIVOSWITCH (NCT02959554) evaluating a planned switch post TKI response, from TKI to nivolumab, compared with continuation of TKI; SUAVE (NCT03035630) comparing an avelumab/sunitinib sequence with sunitinib/ avelumab; and CheckMate-800 (NCT03029780) comparing coadministration and sequential administration of nivolumab/ipilimumab. The results of such trials should allow clinicians to better define the optimal sequencing of the different ICI drugs and targeted therapies.

Furthermore, to minimize toxicities and optimize efficacy, studies are evaluating whether ICI-regimen administration can be tailored to each patient’s response: HCRN GU16-260 (NCT03117309), OMNIVORE (NCT03203473), TITAN RCC (NCT02917772), and SAKK 07/17 (NCT03297593) are evaluating nivolumab with conditional addition or discontinuation of ipilimumab depending on response or progression. Moreover, CASE 5816 (NCT03126331) is evaluating administration of single-agent nivolumab tailored to the extent of tumor shrinkage.

Another common problem in clinical practice is whether patients with brain metastases can be efficiently and safely treated with ICIs. Unfortunately, there are little data

 to address ICI therapy in this significant subset of patients. CheckMate-21414 and -02511 excluded patients with brain metastases, whereas IMmotion-15012 and -15116 excluded all active brain metastases and have not specifically reported outcomes on patients with brain metastases. Data from the French NIVOREN study

 suggest that beyond first-line treatment with nivolumab for metastatic RCC yields an intracranial ORR of 16%, with 18/55 (32.7%) patients presenting clinical neurological deterioration requiring steroid therapy. Of these 18 patients, 17 (94.4%) had not received prior local therapy (radiotherapy or surgery) for their brain metastases, thus suggesting that patients with nonpretreated brain metastases may have worse outcomes. The Italian expanded access program study

 reported an ORR of 18.7% for patients with brain metastases (compared with 23.2% in the overall population of patients) but did not specifically report intracranial response or the outcomes of patients with nonpretreated brain metastases.

Treatment toxicity is another consideration for all classes of oncologic therapy, but the immune-related adverse events (irAEs) of ICIs merit special discussion considering their atypical characteristics.

Immune-related adverse events often occur within weeks to months of the start of therapy but may be delayed or occur after discontinuation of the ICI.

 These irAEs probably reflect a state of general immune activation but the precise mechanisms underlying these irAEs are still unclear.

 The mainstay of treatment for irAEs is immunosuppression with glucocorticoids, with additional agents, such as infliximab (Remicade), as necessary. The ICIs should be temporarily held in some cases or definitely discontinued when the irAEs are serious.

Although many patients who do not develop irAEs benefit from ICIs, some studies’ findings have suggested that patients who develop irAEs may have superior responses compared with patients who do not.

 Thus, it is currently unclear whether patients who discontinue ICIs because of irAEs should be restarted on the same drug or a drug with a different mechanism of action (eg, PD-1 inhibitor vs CTLA-4 inhibitor

); however, reports suggest that patients who discontinue because of irAEs may have prolonged clinical benefit without resumption of therapy.

 Moreover, with the proliferation of ICI-based combinations, treatment toxicities have exponentially increased and the trade-off between improved efficacy and increased toxicity should be tailored to the characteristics of each patient.

ICIs represent promising agents for the management of metastatic RCC. Although ICIs and ICI-based combinations will become part of the standard of care for patients with metastatic RCC, studies are still ongoing to determine the role of ICIs in the management of highrisk localized RCC. Biomarkers of response are needed to better define which patients respond to these therapies. Trials investigating treatment sequencing, as well as tumor response—based adaptation of therapy, could also help optimize efficacy and minimize irAEs. Furthermore, the efficacy of ICIs in subsets of patients who are known to respond poorly to therapy, such as those with brain metastases and non–clear cell RCC, remains to be fully defined. Optimal management of irAEs and whether to restart therapy after discontinuation because of irAEs are still the focus of ongoing research.

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In contrast to the wide array of available therapies in the metastatic setting of renal cell carcinoma, in patients with localized disease, the results of trials investigating adjuvant systemic therapy after nephrectomy have so far been underwhelming.