Naomi B. Haas, MD, is the director of the Prostate and Kidney Cancer Program at the Abramson Cancer Center;as well as a professor of medicine (Hematology-Oncology) at the Hospital of the University of Pennsylvania.

Naomi B. Haas, MD, details the rationale for evaluating adjuvant pembrolizumab monotherapy for the treatment of patients with clear cell RCC.

Dr Haas on the Rationale for Evaluating Adjuvant Pembrolizumab in Clear Cell RCC

“KEYNOTE-564 looked specifically at [treatment with] pembrolizumab vs placebo. In KEYNOTE-564, [approximately] 1000 patients were enrolled, with [DFS per] investigators’ assessment being the primary end point. OS and safety were considered key secondary end points.”

Naomi B. Haas, MD, a professor of medicine at the Hospital of the University of Pennsylvania and the director of the Prostate and Kidney Cancer Program at the Abramson Cancer Center, detailed the rationale for evaluating adjuvant pembrolizumab (Keytruda) for the treatment of patients with clear cell renal cell carcinoma (ccRCC) in the phase 3 KEYNOTE-564 trial (NCT03142334).

Most prior trials in the ccRCC landscape included patients with pT2 high-grade disease, Haas began. However, she noted that there was some variability in select studies that permitted patients with all grades of disease. For example, the phase 3 PROSPER EA8143 trial (NCT03055013) was based solely on clinical histology, not pathologic histology, she explained. Notably, other trials were commonly based on pathologic histology because patients on these studies had already undergone kidney surgery and investigators had already established the pathologic staging, she added.

Furthermore, the design of KEYNOTE-564, among other similarly designed studies, had some differences compared with these previous studies, of which some evaluated the duration of therapy of only 6 months, or immune checkpoint inhibitor (ICI) combinations with CTLA-4 inhibitors, Haas continued. Nevertheless, the KEYNOTE-564 assessed the ICI pembrolizumab, which patients on the study were treated with for 1 year, compared with placebo, she noted. The study included patients with histologically confirmed ccRCC who had not previously received systemic therapy, underwent surgery 12 weeks or less before random assignment, had a postnephrectomy intermediate-high risk of recurrence, and had a postnephrectomy high risk of recurrence. Additionally, patients were required to have an ECOG performance status of 0 or 1. The median follow-up was 69.5 months (range, 60.2-86.9). Of note, patients were randomly assigned 1:1 to receive either pembrolizumab monotherapy for up to 17 cycles (n = 496) or placebo for up to 17 cycles (n = 498). The primary end point was disease-free survival; secondary end points included overall survival and safety.

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Dr Haas on Evolutions in Clinical Trial Design in the RCC Treatment Paradigm

"KEYNOTE-564 looked specifically at an ICI—pembrolizumab. Patients received that for 1 year vs placebo."

Naomi B. Haas, MD, a professor of medicine at the Hospital of the University of Pennsylvania and the director of the Prostate and Kidney Cancer Program at the Abramson Cancer Center, discussed the rationale for the phase 3 KEYNOTE-564 trial (NCT03142334) of adjuvant pembrolizumab (Keytruda) in patients with clear cell renal cell carcinoma (RCC).

Several adjuvant clinical trials in RCC have been initiated in recent years, largely driven by the promising efficacy observed with immune checkpoint inhibitors (ICIs) in this disease, Haas began. Most of these studies enrolled patients with clear cell histology, reflecting both the prevalence of this subtype and its inclusion in prior advanced disease trials, she said. The design of these adjuvant and perioperative trials was informed by earlier studies conducted between approximately 2007 and 2011 that evaluated VEGF TKIs in the adjuvant setting, she noted. However, in contrast to earlier studies, the more recent ICI-based trials typically focused on populations at higher risk of recurrence, often including patients with at least pT2 high-grade tumors, although inclusion criteria varied slightly across studies, she explained.

One example of a study with broader inclusion criteria is the phase 3 PROSPER EA8143 trial (NCT03055013) of nivolumab (Opdivo) in patients with localized kidney cancer undergoing nephrectomy, which stratified patients based on clinical staging rather than pathologic staging, according to Haas. This stratification factor made this trial unique among the trials that generally required pathologic confirmation post-nephrectomy, she reported. This reliance on pathologic staging in most studies reflects the enrollment of patients following surgical resection of the primary tumor, she stated.

Differences in trial design were also noted among studies like the KEYNOTE-564 study and others, particularly regarding treatment duration and therapeutic combinations, Haas continued. Some trials explored 6-month treatment durations or included combinations of ICIs and CTLA-4 inhibitors, she added. KEYNOTE-564 specifically evaluated adjuvant pembrolizumab monotherapy—administered for a duration of 1 year—vs placebo. This trial enrolled 994 patients, with investigator-assessed disease-free survival as the primary end point. Overall survival and safety outcomes were included as key secondary end points.

Naomi B. Haas, MD, discusses previously conducted trials that supported the initiation of the KEYNOTE-564 trial of adjuvant pembrolizumab in RCC.

Dr Haas on the Safety Profile of Adjuvant Pembrolizumab in Clear Cell RCC

“There have been no new safety signals observed. The predominant serious adverse effects that were [reported] among patients who received adjuvant pembrolizumab were hypertension and elevated transaminases.”

Naomi B. Haas, MD, the director of the Prostate and Kidney Cancer Program at the Abramson Cancer Center and a professor of medicine (Hematology-Oncology) at the Hospital of the University of Pennsylvania, discussed safety data from the 5-year follow-up of the phase 3 KEYNOTE-564 trial (NCT03142334) of adjuvant pembrolizumab (Keytruda) in patients with clear cell renal cell carcinoma.

 revealed that there have been no new safety signals with pembrolizumab, Haas said. The most common grade 3 or higher adverse effects (AEs) among patients treated with pembrolizumab (n = 488) were hypertension (2.9%), increased alanine aminotransferase (2.3%), diarrhea (1.8%), and increased aspartate aminotransferase (1.6%), she added. All these AEs were reversible, Haas noted. Comparatively, these AEs occurred at grade 3 severity or higher in the placebo arm (n = 496) at respective rates of 2.6%, 0.2%, 0.2%, and 0.2%.

Any-grade AEs were reported at a rate of 96.3% in the pembrolizumab arm compared with 91.3% in the placebo arm. Patients in both arms experienced AEs leading to treatment discontinuation (21.1% vs 2.2%) and death (0.4% vs 0.2%). Any-cause serious AEs (SAEs; 20.7% vs 11.5%), any-grade treatment-related AEs (TRAEs; 79.1% vs 53.0%), grade 3 to 4 TRAEs (18.6% vs 1.2%), TRAEs leading to treatment discontinuation (18.2% vs 0.8%), treatment-related SAEs (11.9% vs 0.2%), immune-mediated AEs and infusion reactions (36.7% vs 7.3%), and grade 3 to 4 immune-mediated AEs and infusion reactions (9.6% vs 0.6%) were reported in both arms. No patients in either arm experienced TRAEs or immune-mediated AEs and infusion reactions that led to death.

Long-term AEs in the pembrolizumab arm included diabetes, Haas said. These AEs have been observed in clinical trials that enrolled patients with advanced disease as well as those in the adjuvant setting, she added. These AEs are not unique to pembrolizumab and have been reported with other immune checkpoint inhibitors, she concluded.

Naomi B. Haas, MD, discusses safety data from the phase 3 KEYNOTE-564 trial of adjuvant pembrolizumab in patients with clear cell renal cell carcinoma.

Dr Haas on 5-Year Outcomes With Adjuvant Pembrolizumab in ccRCC

"The study has now reached a median landmark analysis of 6 years. These are the longest data out there that have been presented for adjuvant immune checkpoint inhibitor therapy [for patients with ccRCC]."

Naomi B. Haas, MD, director of the Prostate and Kidney Cancer Program at the Abramson Cancer Center; as well as a professor of medicine (Hematology-Oncology) at the Hospital of the University of Pennsylvania, discussed long-term follow-up data from the phase 3 KEYNOTE-564 study (NCT03142334), which evaluated adjuvant pembrolizumab (Keytruda) in patients with clear cell renal cell carcinoma (ccRCC).

Results from the fourth prespecified interim analysis of KEYNOTE-564 trial, presented at the 

, further support the benefit of pembrolizumab monotherapy as an adjuvant regimen in patients with ccRCC at increased risk of recurrence following surgery, Haas stated. KEYNOTE-564 established pembrolizumab as the first adjuvant therapy to demonstrate significant improvements in both disease-free survival (DFS) and overall survival (OS) compared with placebo in patients with ccRCC, Haas reported. These latest data from the 6-year landmark analysis, represent the longest follow-up currently available for adjuvant immune checkpoint inhibitor therapy in this setting, she said.

The DFS benefit with pembrolizumab continued to translate to a robust separation of curves that emerged early in the trial and remained consistent over time compared with placebo, reinforcing the durability of benefit, Haas detailed. Importantly, the OS benefit with pembrolizumab also maintained a separation of the curves between the arms, an observation that underscores the potential long-term effect of adjuvant pembrolizumab on survival outcomes, she noted. Notably, the trial did not show the attritional effect that sometimes occurs in long-term studies, where patient drop-out may attenuate survival differences over time, she added.

Safety results were consistent with those seen in prior analyses, with no new serious treatment-related adverse effects identified for the past 3 years, Haas continued, stating that this finding further supports the long-term tolerability of pembrolizumab in the adjuvant setting. The benefit of adjuvant pembrolizumab was also observed consistently across all key subgroups evaluated for both DFS and OS. Taken together, these data reinforce pembrolizumab’s role as a standard-of-care option for patients with ccRCC at increased risk of recurrence following surgery, cementing its place in the evolving adjuvant treatment paradigm, Haas concluded.

Naomi B. Haas, MD, shares 5-year follow-up data with adjuvant pembrolizumab in patients with clear cell renal cell carcinoma.
 

Naomi B. Haas, MD, director, Prostate and Kidney Cancer Program, associate professor of medicine, Hospital of the University of Pennsylvania, discusses the role of prostate-specific membrane antigen (PSMA) in prostate cancer.

PSMA is an antigen expressed on the cell surface that offers an important target for prostate cancer therapy, Haas says.

PSMA is not only a viable target in prostate cancer, Haas adds. Neovascular PSMA expression is common in several other tumor types.

In prostate cancer, as castrate resistance develops, PSMA is overexpressed. As such, patients with castration-resistant disease have more PSMA than patients with early-stage disease, Haas concludes.

Naomi B. Haas, MD, discusses the role of prostate-specific membrane antigen in prostate cancer.

Dr. Haas on the Role of PSMA in Prostate Cancer 

Naomi B. Haas, MD, director, Prostate and Kidney Cancer Program Associate Professor of Medicine at the Hospital of the University of Pennsylvania, discusses results of 2 ongoing clinical trials looking at adjuvant therapy options in renal cell carcinoma (RCC).

There are currently 8 adjuvant clinical trials in the United States and Europe, Haas explains. In the last 2 years, 2 of those trials have reported data. One of them, the ASSURE trial, which was a randomized study of sunitinib (Sutent), sorfaenib (Nexavar), or placebo for 1 year. Patients enrolled on the trial were divided by cohorts of intermediate- and high-risk classification with clear cell and non-clear cell histology. Following approximately 1300 patient accrual, there was a higher discontinuation rate than expected due to toxicity and intolerability. Due to this, the study was amended to include patients with a -1 dose level with a mandatory dose escalation.

The second study, the S-TRAC trial, enrolled patients with clear cell histology with a slightly higher risk stratification who were treated with 1 year of full-dose sunitinib versus placebo. The study was not amended; all patients started at the full dosage. A dose reduction was permitted at 37.5, Haas says. This trial had an endpoint of disease-free survival, which was reported as positive, Haas explains.

View more from the 2016 International Kidney Cancer Symposium

Dr. Haas on Adjuvant VEGF-Targeted Therapy in RCC

Naomi B. Haas, MD, associate professor, Abramson Cancer Center of the University of Pennsylvania, discusses the phase III ASSURE trial which looks at sorafenib or sunitinib for locally advanced renal cell carcinoma (RCC).

It was hypothesized that sorafenib or sunitinib could extend disease-free survival in the adjuvant setting. To test this, patients were classified based on risk (intermediate-high or very high), clear or non-clear histology, ECOG performance status, and surgery approach and treated for a year with either sunitinib, sorafenib, or placebo.

It was found that neither sorafenib nor sunitinib improved outcomes when administered after surgery to patients with RCC.

View more from the 2015 GU Cancer Symposium

Naomi B. Haas, MD

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