Integrating Immunotherapy Into the Management of Renal Cell Carcinoma

Second-Line and Beyond

Nivolumab, a monoclonal antibody (mAb) targeting PD-1, became the first checkpoint inhibitor to earn FDA approval for treatment of patients with mRCC who had progressed after prior treatment with a tyrosine kinase inhibitor (TKI) by demonstrating improved OS versus everolimus in a phase III trial (CheckMate 025).⁸ Although the overall response rate (ORR) for nivolumab-treated patients in this study was a modest 25%, >30% of these responders achieved durable benefit lasting >12 months. This durability of benefit in responders, the so-called “tail” of the survival curve, underscores the true value of nivolumab, and is graphically more evident in an updated survival curve presented at the 2016 International Kidney Cancer Symposium, which reported 29% of nivolumab responders retained response with a median follow-up of 26 months.⁹ At the time of its approval, second-line options outside of a clinical trial for most patients consisted of either a TKI targeting vascular endothelial growth factor (VEGF) receptor (either axitinib, sorafenib, or TKI of choice not used in the first line between sunitinib/pazopanib) or an mTOR inhibitor (everolimus or temsirolimus). A third mechanistic option, interferon alfa plus bevacizumab, was rarely used.¹⁰ Due to its durability of benefit, nivolumab became the de facto second-line option for most patients with mRCC after progression on a TKI.

Since the approval of nivolumab in TKI-refractory mRCC, both lenvatinib (in combination with everolimus) and cabozantinib have achieved FDA approval based on randomized data demonstrating improved progression-free survival (PFS), and in the case of cabozantinib, improved OS as well.^11–13 The availability of these 3 new agents provides new options for patients, but all were tested in the second-line (or beyond) space, and no level 1 data exist comparing them with each other. Within the limitations of cross-trial comparison, one can infer some clues from the available data. All of these contemporary studies tested their drug against a common comparator—everolimus. Both nivolumab and cabozantinib demonstrated an improvement in OS beyond the first-line setting as of December 2016, whereas lenvatinib has exhibited a PFS benefit.^8,12,13 However, the performance of the control everolimus arm differed somewhat across the studies, likely reflecting subtle differences in the populations. PFS for everolimus was 4.4 months in the CheckMate 025 study,⁸ 3.8 months in the METEOR study¹³ with cabozantinib, and a high of 5.5 months in the lenvatinib/everolimus study.¹² Patients in the lenvatinib study could only have received one prior VEGF-targeted therapy (thus a pure second-line study), which may have contributed to the improved responses because this was a healthier population. Patients in the other 2 studies may have been second or third line, or beyond in the cabozantinib study, which included >25% of patients third line or later, whereas patients in the CheckMate 025 trial could not have been beyond third line. The METEOR trial with cabozantinib also allowed treated brain metastases. Thus, the differing efficacy rates reflect the make-up of the included populations. Data supporting the approval of nivolumab and cabozantinib originate from randomized phase III trials, each with >650 patients, whereas the approval of lenvatinib stems from a randomized phase II study of 153 patients over 3 arms (the combination and each drug alone). Nivolumab was overall well-tolerated, with grade ≥3 treatment-related adverse events (TRAEs) occurring in 19% of patients. Notably, 68% of patients receiving cabozantinib experienced TRAEs grade ≥3. There was one grade 5 AE attributed to cabozantinib, with no AEs attributed to nivolumab, and 60% of patients treated with cabozantinib required a dose reduction. In the combination arm of the lenvatinib/everolimus study, 71% of patients experienced a grade 3/4 TRAE and 24% discontinued treatment due to toxicity. Given the totality of these data, nivolumab appears to be the preferred option for treatment for most patients with TKI-refractory mRCC (without a contraindication) given its documented OS benefit, potential of a durable response, and favorable toxicity profile.

Still, most patients do not benefit from receiving single-agent nivolumab. Thus, ongoing research is geared toward increasing clinical benefit, with 3 viable options to improve patient outcomes: a better immuno-oncology alternative, a suitable combination approach, or a reliable predictive biomarker to identify who is most likely to benefit (or not benefit). Several other PD-1 pathway inhibitors are being explored in TKI-refractory mRCC. Atezolizumab, a mAb targeting the primary ligand for PD-1 (PD-L1) often found on the tumor cell, was evaluated in a phase IA basket trial including patients with mRCC with both clear cell RCC (ccRCC) and non–clear cell RCC (nccRCC).¹⁴ In patients with ccRCC, the ORR was 15%, with median OS (28.9 months) and toxicity data favorably comparable with nivolumab.

First-Line Metastatic

Current standard of care for first-line treatment of most patients with mRCC is either sunitinib or pazopanib, but for a subset of patients, immunotherapy using high-dose IL-2 (HD IL-2) remains a consideration. In the 2016 consensus statement by the SITC RCC task force, there was a lack of consensus regarding the role of HD IL-2 since the emergence of TKIs and ICB, although two-thirds of members still felt the option should be discussed with all appropriate patients.⁷ HD IL-2 has demonstrated the capacity to provide long-term remissions in a small subset of patients, with approximately 7% attaining a complete response, and approximately 5% alive and disease-free after 65 months.^4,5,15 Despite this promise, HD IL-2 administration requires in-patient admission and is associated with marked toxicity appropriate only for patients with optimal clinical and physiologic features.⁷ Consequently, HD IL-2 has become increasingly marginalized and is only available to a small subset of healthy patients with ccRCC and access to treatment at high-volume centers.

ICB (generally in combination therapy) as a first-line option is being evaluated in several randomized trials and may further alter the treatment paradigm, affecting downstream second-line options. Efficacy data on single-agent nivolumab as first-line therapy for mRCC is limited, with the largest published cohort consisting of 24 patients without prior systemic therapy.¹⁶ This group received nivolumab at 10 mg/kg, resulting in 2 complete responses, an ORR of 13%, and a 48-week PFS rate of 39%. These data from a small patient cohort would require further validation, but challenge the long-accepted paradigm that response rates are higher in earlier lines of therapy, and suggest that nivolumab may work better after prior treatment with a TKI, perhaps due to changes to vasculature or tumor antigens occurring in response to VEGF inhibition. Phase III trials of single-agent ICB are not being pursued in the first-line setting.

Combination approaches with ICB are in various stages of clinical testing and are promising potential techniques to increase the percentage of patients who clinically benefit. These approaches are varied and include combined ICB, ICB with a VEGF-targeting TKI, and combining ICB with cytokines or other agents geared to favorably enhance the immune milieu. The goal is to increase efficacy without compromising safety, which so far has proven challenging. Dual checkpoint blockade (ie, adding an agent targeting a separate checkpoint in addition to PD-1) has already garnered approval for improved survival in the first-line treatment of metastatic melanoma using the combination of nivolumab with the cytotoxic T-lymphocyte–associated protein 4 (CTLA-4)–specific mAb ipilimumab. This combination demonstrated improved efficacy over both single agents, but with a consequent increase in grade 3/4 TRAEs.^14,15 This same combination was initially evaluated in mRCC as part of the CheckMate 016 trial, a multiarm phase I study assessing varying combination doses of nivolumab and ipilimumab for patients with both TKI-refractory and untreated mRCC, with updates last reported at the 2016 ESMO Annual Meeting.¹⁶ Combined data across 2 dose combinations demonstrated an ORR of approximately 40% and a disease control rate close to 80% (complete and partial responses plus stable disease). However, grade 3/4 TRAEs occurred in 38% and 61% of patients, respectively, across the 2 dose combinations reported (nivolumab, 3 mg/kg + ipilimumab, 1 mg/kg, or the opposite). The same CheckMate 016 study also included arms combining nivolumab with sunitinib or pazopanib. Due to increased hepatotoxicity on the TKI arms, both arms were ultimately halted for further study, dampening enthusiasm for combination PD-1/TKI approaches.¹⁷ However, hope has been renewed with the presentation at ESMO 2016 of the combination of the PD-1 inhibitor pembrolizumab with axitinib, a multitarget TKI approved for treatment of patients with mRCC who have progressed on a prior TKI. Preliminary results showed the combination to be well-tolerated, with grade ≥3 immune-related AEs occurring in 19.2% of patients and without significant increases in diarrhea or hepatotoxicity.¹⁸ The ORR was an impressive 71.2%, with a disease control rate of 90.4%. Evidence from combinations of ICB with other therapeutic strategies remains too immature for current discussion.

Because of the impressive efficacy of dual ICB with nivolumab and ipilimumab reported in both the first- and second-line settings, albeit with increased toxicity, a randomized phase III trial of this combination versus sunitinib in previously untreated mRCC patients completed accrual (CheckMate 214; ClinicalTrials.gov identifier: NCT02231749), with results pending.¹⁷ Similarly, based on data presented on axitinib and pembrolizumab, an ongoing phase III trial randomizing this combination against standard sunitinib is currently accruing patients (KEYNOTE-426; ClinicalTrials.gov identifier: NCT02853331). Several other first-line combination trials are also ongoing or planned (Table 1). As a result, although TKIs remain the standard for first-line treatment of mRCC outside of a clinical trial, it is highly likely that combination ICB approaches will achieve regulatory approval within the next few years. The difficulty in choosing optimal therapy may prove to be similar to that for TKI-refractory disease, namely that multiple combinations could prove to be superior to sunitinib, but data comparing the combinations directly will be lacking, making it challenging for clinicians to differentiate.

(Neo)Adjuvant

Clearly, the role of immunotherapy for patients with mRCC is rapidly evolving, thus the next frontier appears to be determining whether there is a place for ICB in patients with localized disease. The Sunitinib Treatment of Renal Adjuvant Cancer (S-TRAC) met its primary end point of improving DFS, but without a significant OS benefit to this point; on the heels of the negative results of the adjuvant ASSURE trial (Adjuvant Sorafenib and Sunitinib for Unfavorable Renal Carcinoma), no definitive adjuvant therapy option yet exists.^6,18 Although we await updated survival analysis from S-TRAC and other unreported adjuvant TKI studies, ICB has entered the clinic in several trials in the adjuvant or neoadjuvant setting. The promise and potential upside is clear: eradicating microscopic residual disease to increase the cure rate after curative-intent surgery. Single-agent PD-1 pathway–targeting drugs have repeatedly been shown to be well-tolerated by most patients, thus it is reasonable to offer them before and after surgery. But as these trials begin to enroll patients, several important issues regarding trial design, clinical rationale, and feasibility are worth considering.

First, whether to administer ICB agents preoperatively, postoperatively, or both in the early disease setting is unclear and controversial. A purely adjuvant study is clean and simple, with patients with high-risk disease recruited after recovery from surgery. This allows for a clear workflow of patients being

Table 1.

Combination Phase III Trials Using Immune Checkpoint Blockade in First-Line Metastatic Renal Cell Carcinoma

View Table

There are other issues with planning ICB trials in early-stage disease. The selection of the comparator arm in a randomized trial (ie, placebo vs observation) is imprecise. Observation is the current standard, and thus a fair comparator, but bias in investigator assessment of both toxicity and efficacy is inherent in unblinded clinical trials.²⁰ Placebo-controlled trials can mitigate unintended bias, but patient anxiety regarding placebo may limit accrual, and rules regarding unblinding may affect treatment options for patients who develop metastatic disease. Furthermore, as new data from the adjuvant TKI studies become available, the landscape may change, compelling design amendments that could delay and complicate trial analysis, or compel patients to forgo trials to receive sunitinib. Finally, although the side-effect profile of ICB is generally considered tolerable compared with available standard drugs, the appetite for serious AEs changes from the metastatic to curative setting. When treating an incurable disease, patients and clinicians are more willing to tolerate potentially serious and even fatal AEs. In otherwise healthy patients who may be cured with surgery alone, patients and clinicians may weigh the risks much differently, and this becomes even more relevant when studying dual ICB. Several trials are using ICB in a perioperative setting (Table 2).