Immune Checkpoint Inhibitors for Renal Cell Carcinoma

Houman Nourkeyhani, MD

Roswell Park Cancer Institute,

Buffalo, NY

Saby George, MD, FACP

Roswell Park Cancer Institute,

Buffalo, NY

It is estimated that 1 in 63 individuals in the United States will develop renal cell carcinoma (RCC), making it among the most common cancers in the country.¹Like all malignancies, RCC is known to express cell surface antigens, which, if recognized by the immune system, would lead to an endogenous, cellmediated immune response, as well as an antibody response. However, immune evasion is a hallmark of RCC. Multiple antigens have been identified that play a role in immune evasion and/or blunting of the endogenous immune response. The programmed death-1 (PD-1) signaling pathway is one such pathway. PD-1 is expressed on the surface of activated T cells and B cells. Binding of PD-1 to the ligands B7-H1 and B7-DC plays a part in antitumor immune downregulation,²and thus has emerged as a therapeutic target.

PD-1 Pathway

FIGURE. Static Version: Tumor Plus T Cell and APC Plus T Cell (Nivolumab mechanism of action)

CLICK TO ENLARGE

INF-κB indicates nuclear factor-Kappa B; IFNy=interferon gamma; IFNyR=interferon-gamma receptor; MHC=major histocompatibility complex.

PD-1 and Cancer

Binding of PD-1 to B7-H1 and B7-DC inhibits signaling via phosphatidylinositol-3 kinase and its downstream target, AKT. This inhibition leads to downstream events responsible for decreased T-cell proliferation and survival. It also decreases protein synthesis in T cells and cytokine production.³Therapies based on monoclonal antibodies directed against PD1 and its ligands (immune checkpoint blockade) are emerging as novel therapeutic options for patients with various solid tumors as well as hematologic malignancies, including RCC. Checkpoint inhibitors in RCC will be the subject of this review.Antigen activation of T cells requires antigen presentation via major histocompatibility complex (MHC) and T-cell receptor interaction. This interaction leads to T-cell proliferation. Regulation of lymphocyte activation is critical to preventing autoimmunity, and multiple downregulators and modulators of lymphocyte activation are necessary in maintaining homeostasis. PD-1 is a transmembrane receptor protein, expressed on T-cell, B-cell, and myeloid cell surfaces (Figure 1represents checkpoint inhibition by nivolumab).^4-6In murine models, animals deficient in the PD-1 gene product developed lupus and a graft-versus-host—like syndrome, resulting from an unchecked immune response.⁷Binding of PD-1 to its ligands (PD-L1 and L2) negatively regulates signaling via the T-cell receptor, halting T-cell activation and repressing pro-apoptotic pathways in tumor cells.⁸Therefore, blockage of signal via the PD1—PD-L1 interaction may result in enhanced antitumor immunity.The PD-1 protein is expressed on the cell surfaces of multiple tumors, including melanoma, RCC, breast cancer, and lung cancer. Multiple murine models have been developed, which showed a similar pattern of PD-1 ligand expression. In experimental murine models, tumor cell expression of PD-L1 was associated with a more aggressive tumor phenotype. Most human tumors were found to express high levels of PD-L1 and -L2, including those found in breast cancer, colon cancer, non-small cell lung cancer (NSCLC), RCC, urothelial carcinoma, and gastric carcinoma, among others.⁹

High levels of expression of PD-L1 on tumorinfiltrating lymphocytes (TILs) taken from patients with clear cell RCC have been correlated with poorer survival.¹⁰Multiple reports of PD-1 ligand blockade have emerged, which document tumor regression and increased immune response to tumor cells.^10-12

Specific to RCC, it has been shown that high levels of PD-1 and PD-L1 expression by TILs are associated with a more aggressive biological behavior and poorer survival.^13,14This observation has led to the speculation that pretreatment testing of tumor tissue to determine levels of PD1 and/or PD-L1 may identify potential responders to treatment. The ultimate goal of treatment would be repression of immune checkpoint inhibition, leading to an effective and clinically significant antitumor response. Preliminary data supporting this show no patients with PD-L1—negative tumors had clinical response to nivolumab; conversely, 36% of patients with PD-L1–positive tumors achieved objective responses.¹¹

TABLE 1. Summary of Findings From Trials Presented at ASCO 2014 Annual Meeting Using Anti-PD-1 in Patients With Metastatic RCC

Trial Number

Agents

Tumor Type

Results

Toxicity

NCT01472081

Nivolumab+ipilimumab (dose-ranging) versus nivolumab+sunitinib versus nivolumab+pazopanib

Metastatic RCC

N3+I1 arm: ORR 29%; SD 33%; DOR 4.1-22.1+weeks; PFS 4.7-28.1+ weeks

N1+I3 arm: ORR 39%; SD 39%; DOR 6.1-18.3+ weeks; PFS 4.3-26.1 weeks

N+S: ORR 52%; SD 33%; PFS at 25 weeks 78%

N+P: ORR 45%; SD 35%; PFS at 24 weeks 55%

Grade 3-4 nivolumab+ipilimumab arm: elevated lipase (16%), ALT (11%), diarrhea (9%), colitis (5%), elevated amylase (5%)

Grade 3-4 nivolumab + sunitinib arm: elevated ALT (18%); hypertension (15%); hyponatremia (15%); one case of grade 3 pneumonitis

Grade 3-4 nivolumab+pazopanib arm: elevated AST/ALT (20% each); fatigue (15%)

NCT01354431

Nivolumab

Metastatic RCC

0.3 mg/kg: median PFS 2.7 months; ORR 20%; OS 18.2 months

2 mg/kg: median PFS 4.0 months; ORR 22%; OS 25.5 months

10 mg/kg: median PFS 4.2 months; ORR 20%; OS 24.7 months

No grade 3-4 pneumonitis; incidence of grade 3-4 AEs across all doses ≤17%

DOR indicates duration of response; ORR, overall response rate; OS, overall survival; PFS, progression-free survival.

Phase I Trials

While these results are encouraging, it is important to note that tumors can be heterogeneous and that multiple biopsies and adequate sampling may be required to reliably predict response. Furthermore, consideration should also be given to the fact that tumors rich in PD-L1—expressing TILs may have an inherently more favorable prognosis regardless of treatment, due to active immune response and surveillance.The results of the first phase I trial using PD-1 blockade were published in 2010. Thirty-nine patients with treatment-refractory solid tumors, including metastatic melanoma, colorectal cancer, NSCLC, RCC, and castrate-resistant prostate cancer, were enrolled in the study. The patients received MDX- 1106 (nivolumab), a human immunoglobulin G4 monoclonal antibody directed against PD-1. Patients received escalating doses of the anti—PD-1 monoclonal antibody. Of the 39 patients enrolled, 1 patient with colorectal cancer achieved complete remission (CR), while 2 others with RCC and metastatic melanoma achieved partial remissions (PR). In total, 12 patients had at least a mixed response at the first disease assessment. The treatment was well tolerated overall, with no dose-limiting toxicities. Only 1 case of a serious adverse event (AE) was recorded (inflammatory colitis).¹⁵

Another phase I study assessing nivolumab enrolled 296 patients with advanced solid malignancies, including 34 patients with RCC. Treatment-related AEs were generally mild, and grade 3 or 4 AEs occurred in 14% of patients. However, 1% of patients developed significant noninfectious pneumonitis. Clinical response was assessed after each treatment cycle. Disease stability lasting 24 or more weeks was observed in 27% of patients with RCC. Objective response was observed in 24% of patients with RCC (4/17) who were administered a dose of 1 mg/kg, and 31% of patients (5/16) who received a 10-mg/kg dose.¹⁶

Anti-PD-L1 Targeting

The long-term follow-up report of the RCC cohort from the same study was reported separately by Drake et al. The results showed 1-year overall survival of 70% and 3-year survival of 52% (95% CI). Treatment-related grade 3-4 toxicity was observed in 21% of patients and included hypophosphatemia and respiratory disorders. Six percent of patients had to discontinue treatment due to AEs.¹⁷A phase I trial examining anti—PD-L1 monoclonal antibody (BMS-936559) treatment in 207 patients with advanced solid tumors with documented advanced metastatic disease progression after at least one round of tumor-appropriate therapy was conducted. The primary endpoint of the trial was safety profile of this drug. Maximum tolerable dose was not reached and the drug was well tolerated overall. While AEs were noted in 81% of patients, only 9% consisted of grade 3 or above AEs. The secondary endpoint of assessment of antitumor activity demonstrated encouraging responses across multiple tumor types. Specifically, in RCC, 12% of patients had objective response, while an additional 41% had evidence of stable disease lasting at least 24 weeks.¹⁸

TABLE 2. Summary of Ongoing Trials Using Anti-PD-1 or Anti-PD-L1 Agents in RCC

Trial Number

Agents

Tumor Type

Trial Type

Status

NCT02210117

Nivolumab alone, nivolumab+bevacizumab, or nivolumab+ipilimumab

Metastatic RCC

Phase II

Not yet recruiting

NCT01441765

Anti-PD-1 monoclonal antibody (CT-011) alone or combined DC/RCC fusion cell vaccination

RCC

Phase II

Active, not recruiting

NCT02133742

Axitinib (AG-013736) I +PD-1 inhibitor (MK-3475)

Advanced RCC

Phase I

Not yet recruiting

DC indicates dendritic cell; RCC, renal cell carcinoma.

Combination Studies of Interest

Further exploring the PD-1 pathway, anti-PD-L1 ligand antibodies have been tested in patients with metastatic RCC. One such agent, MPDL3280A, a monoclonal antibody directed against PD-L1, was tested at various doses in a phase I trial (NCT01375842). Fifty-four patients with metastatic RCC were randomized to receive various doses of MPDL3280A. Regardless of dose, 50% of patients had progression-free survival (PFS) of 24 weeks or greater. The therapy was well tolerated, with no grade 5 pneumonitis.¹⁹Nivolumab has also been studied in a phase I trial as part of combination therapy with ipilimumab (NCT1472081). Forty-four patients with metastatic RCC were randomized to receive nivolumab and ipilimumab. Two dose combinations were studied: 1 CARCINOMAmg/kg nivolumab + 3 mg/kg ipilimumab (N1+I3) versus 3 mg/kg nivolumab + 1 mg/kg ipilimumab by nivolumab 3 mg/kg every 2 weeks until docu-mented progression or toxicity. The regimen’s toxic-ity profile was acceptable, with 7 of 44 patients dis-continuing therapy due to AEs. Grade 3-4 AEs were observed in 43% of patients and included serum el-evations of amylase, lipase, and alanine aminotransferase. Twenty-nine percent of patients had objective response in the N3+I1 group, compared with 39% in the N1+I3 cohort. Response durations ranged from 4 to over 22 weeks in combined cohorts, while PFS ranged from 4.3 to more than 28.1 weeks.20

Phase II Trials

Ongoing Studies

Discussion

Anti—PD-1 compounds have also been investigated in combination with tyrosine kinase inhibitors. These studies are still in preliminary phase, and similar trials are planned.A randomized, dose-ranging, phase II trial (NCT01354431) assessing a primary endpoint of the dose—response relationship of nivolumab was conducted, with secondary endpoints being overall survival (OS), PFS, objective response rate (ORR), and safety. A total of 167 patients were enrolled and randomized to 0.3-mg/kg, 2-mg/kg, and 10-mg/kg doses every 3 weeks. No significant dose-response relationship was noted in terms of PFS. Progression-free survival and ORR were similar across all doses. Overall survival was 25.5 months in the 2-mg/kg and 18.2 months in the 0.3-mg/kg dose. Median duration of response was 17.4 months in the 10-mg/kg group, but the median duration has not been reached in the other dose groups. Twenty out of 35 responses were ongoing and 14 of these remained ongoing for 24 or more months. The toxicity profile was acceptable. No grade 3-4 pneumonitis was observed and the drug was well tolerated overall, with 1%, 6%, and 4% of patients in the 0.3-mg/kg, 2-mg/kg, and 10-due to AEs (Table 1).^21,22A phase I trial examining nivolumab given in conjunction with sunitinib, pazopanib, or ipilimumab in patients with metastatic RCC (NCT01472081) is currently recruiting patients. A phase III study of -static RCC (NCT01668784) is expected to report in 2 to 3 years.²⁴Multiple other phase I, phase II, and phase III trials examining nivolumab either alone or in combination with other agents in patients with malignancies such as NSCLC, metastatic melanoma, ovarian cancer, and chronic myeloid leukemia, are ongoing (Table 2).Immune checkpoint inhibition is an emerging approach for targeted immunotherapy. These therapies have the advantage of the ability to be delivered on an outpatient basis. Preliminary studies are promising, with acceptable toxicity being demonstrated. It would be interesting to evaluate the safety, tolerability, and efficacy of the combination trials that are either under way or in development. A limitation of the checkpoint inhibitor studies thus far has been the lack of clear biomarkers for patient selection. Several large trials have translational endpoints awaiting readout.

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