Pembrolizumab in First-Line Treatment of Metastatic Clear Cell and Non–Clear Cell Renal Cell Carcinoma

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Matthew R. Zibelman, MD

Matthew R. Zibelman, MD

The treatment paradigm for patients with metastatic renal cell carcinoma has undergone a dramatic shift over the past few years, improving outcomes for many patients but leaving many unanswered questions as to how to optimally choose the best treatment for an individual patient. The changes are most dramatic for patients with clear cell renal cell carcinoma, where the standard of care has near completely shifted from single-agent tyrosine kinase inhibitors as first-line therapy to combination treatment with either two immune checkpoint inhibitors or a checkpoint inhibitor targeting PD-1 combined with a tyrosine kinase inhibitor. All the current reported combinations that have improved survival over sunitinib as a comparator utilize a checkpoint inhibitor targeting PD-1 as a backbone, yet data on single-agent usage of these agents in the first-line setting remain limited. For patients with metastatic papillary and other non–clear cell renal cell carcinomas, the changes in systemic therapy have been less apparent, and the role of immune checkpoint inhibitors has remained less well defined.

In a recent edition of the Journal of Clinical Oncology, McDermott et al reported results from both arms of the KEYNOTE-427 study in two separate publications.1,2 The study, reviewed in this issue of The ASCO Post, explored the role of single-agent pembrolizumab as first-line treatment for metastatic renal cell carcinoma, with Cohort A enrolling patients with locally clear cell renal cell carcinoma and Cohort B investigating patients with non–clear cell histology disease.

KEYNOTE-427, Cohort A: Clear Cell Histology

KEYNOTE-427 was a multicenter, open-label, international phase II trial with two parallel arms exploring the efficacy of single-agent pembrolizumab. Cohort A enrolled only patients with centrally confirmed clear cell histology.1 Eligible patients were required to be treatment-naive, have measurable disease as per Response Evaluation Criteria in Solid Tumor version 1.1, have a Karnofsky performance status of at least 70, and could be of any risk class (as classified by the International Metastatic Database Consortium [IMDC]). Patients received pembrolizumab at 200 mg intravenously every 3 weeks for up to 35 doses. The primary endpoint was objective response rate, as assessed by blinded independent central review, and secondary endpoints included the duration of response, disease control rate, progression-free survival, overall survival, and safety.

“Is there a patient [with clear cell histology] for whom single-agent pembrolizumab might be an option? The answer is definitely maybe.”
— Matthew R. Zibelman, MD

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The trial enrolled 110 patients over 35.9 months. The patients were primarily male (78.2%), were enrolled in North America or Western Europe (74.5%), and had a Karnofsky performance status of at least 90 (80%). Intermediate- or poor-risk patients comprised 61.8% of the cohort.

The primary endpoint of overall response rate was 36.4%, with four patients (3.6%) achieving a complete response. Key secondary endpoints included a disease control rate of 58.2%, a median progression-free survival of 7.1 months, and a median overall survival was not reached. When broken down by IMDC risk group, the response rate was 31.0% in the favorable-risk group and 39.7% in the intermediate/poor-risk group, which included three of the four complete responses. There were no unexpected safety signals.

KEYNOTE-427, Cohort B: Non–Clear Cell Histology

Cohort B was enrolled in parallel to Cohort A with the same design and inclusion criteria, except patients were required to have a non–clear cell histology.2 Pathology was centrally reviewed and confirmed retrospectively, and histologic subtype was ultimately determined by central review.

This cohort included 165 patients, making it the largest interventional trial of patients with non–clear cell histology performed to date. The majority of patients, as expected, had papillary histology (71.5%), with the remaining patients labelled as either chromophobe (12.7%) or unclassified (15.8%). Sarcomatoid features were present in 23.0%, irrespective of histologic subtype. The majority were male (66.1%), had a good Karnofsky performance status (75.2% ≥ 90), and were classified as intermediate/poor risk (67.9%). Unlike Cohort A, there was a more even split between patients accrued in North America or Western Europe (53.4%) vs in the rest of the world (46.7%).

The overall response rate was 26.7%, with 6.7% achieving a complete response, and the disease control rate was 43.0%. The median progression-free survival was 4.2 months, and the median overall survival was 28.9 months. In the predominant papillary subgroup, the response rate was 28.8%. It was even higher in the unclassified group at 30.8% and was lower at 9.5% in patients with a chromophobe histology, which is notoriously difficult to treat.

Placing KEYNOTE-427 in Context

KEYNOTE-427 is the largest trial investigating the role of single-agent anti–PD-1 therapy in patients with metastatic renal cell carcinoma. It provides some basis from which to view the expected contribution of these agents in the now commonly used combination regimens. However, because this is essentially two parallel, single-arm, phase II trials, it is difficult to glean which patients to select to receive pembrolizumab alone.

For those with clear cell histology, the standard of care for most patients should be combination therapy. In patients with intermediate/poor-risk disease, either ipilimumab/nivolumab or a tyrosine kinase inhibitor/anti–PD-1 combination may be suitable (axitinib/pembrolizumab, cabozantinib/nivolumab, or lenvatinib/pembrolizumab), as all have demonstrated improved survival compared with sunitinib (although lenvatinib/pembrolizumab is not yet U.S. Food and Drug Administration–approved in this setting).3-6 For favorable-risk patients, the tyrosine kinase inhibitor/anti–PD-1 combinations are preferred, with single-agent tyrosine kinase inhibitors or observation reserved for those for whom immune checkpoint inhibitors would be contraindicated or who do not require systemic therapy.7

So, is there a patient for whom single-agent pembrolizumab might be an option? The answer is definitely maybe. Based on the -KEYNOTE-427 Cohort A results, about one-third of such patients will respond to single-agent therapy, with many responses being durable; however, another third of patients (30% in the intention-to-treat population) will have primary disease progression. Moreover, only 3.6% of patients achieved a complete response.

In CheckMate 214, which established the efficacy of nivolumab and ipilimumab, the response rates were only modestly higher, but the complete response rate was about 11%.3 In the combination tyrosine kinase inhibitor trials, response rates of the combination arms ranged from 56% to 71%, and complete response rates ranged from 8% to 16% thus far.4-6 The disease control rate is higher than 80% with all the tyrosine kinase inhibitor combinations.

Despite the limitations of comparing results from a single-arm phase II trial with larger randomized studies, there appears to be a clear decline in upfront disease control and long-term efficacy with a single-agent checkpoint inhibitor. However, that trade-off does come with a favorable toxicity profile. Combination checkpoint blockade in the CheckMate 214 study resulted in grade ≥ 3 treatment-related adverse events in 46% of patients, many of whom required high-dose steroids and/or experienced long-term morbidity vs only 30% in KEYNOTE-427. The combination tyrosine kinase inhibitor trials all had even higher percentages of grade ≥ 3 treatment-related adverse events, although many of them are reversible and managed with tyrosine kinase inhibitor dose holds and reductions. Thus, for a patient with asymptomatic disease unable to receive a tyrosine kinase inhibitor and averse to the excess adverse immune events associated with combination checkpoint blockade, single-agent pembrolizumab may be worth considering.

Clinical Scenario Less Clear for Non–Clear Cell Histology

The situation for patients with metastatic non–clear cell renal cell carcinoma may be even less clear. The response rates of 26.7% for the intention-to-treat population and 28.8% for the papillary subset compare favorably with historic controls, such as in the ESPN and ASPEN trials.8,9 The median progression-free survival of 4.2 months was somewhat disappointing, though consistent with checkpoint blockade trials, in which the majority of patients were primary progressors. The median overall survival, however, was impressive at 28.9 months, suggesting that the subset of patients who respond have durable survival, despite only 6.7% of patients achieving a complete response.

“The real question for non–clear cell renal cell carcinoma remains an unanswered one: Can combination therapy benefit these patients as well?”
— Matthew R. Zibelman, MD

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The most relevant contemporary comparator to this trial is the recently published PAPMET trial, a randomized phase II trial run by the Southwest Oncology Group and recently reported at the 2021 Genitourinary Cancers Symposium.10,11 This trial randomly assigned patients with papillary renal cell carcinoma to one of four tyrosine kinase inhibitors, three of which are thought to target MET, a key pathway in this cancer, or sunitinib. Two of the arms were stopped early for futility, leaving the cabozantinib and sunitinib arms. Final results demonstrated an improvement in the cabozantinib-treated patients, with a median progression-free survival of 9 months, a median overall survival of 20 months, and a response rate of 23%. The authors of this study concluded that their findings established cabozantinib as the standard of care for patients with papillary renal cell carcinoma based on level one evidence from a randomized trial.

Since KEYNOTE-427 does not have a comparator arm, it is impossible to say how pembrolizumab would perform against cabozantinib or another tyrosine kinase inhibitor. In practice, however, the KEYNOTE-427 study provides an alternative option for patients and clinicians who are willing to accept some level of uncertainty for the chance of a long-term benefit with papillary renal cell carcinoma. For patients with nonpapillary, non–clear cell disease, the standard of care remains uncertain. The real question for non–clear cell renal cell carcinoma remains an unanswered one: Can combination therapy benefit these patients as well? Several ongoing trials seek to answer this question, hopefully further moving the field for patients with non–clear cell disease. 

Dr. Zibelman is employed in the Department of Hematology/Oncology, Fox Chase Cancer Center, Temple Health, Philadelphia.

DISCLOSURE: Dr. Zibelman has received honoraria from Pfizer; has served as a consultant or advisor to EMD Serono, Horizon Pharma, Janssen, and Pfizer; has received institutional research funding from Bristol Myers Squibb, Exelixis, Horizon Pharma, and Pfizer; and has held other relationships with the Association for Community Cancer Centers.


1. McDermott DF, Lee JL, Bjarnason GA, et al: Open-label, single-arm phase II study of pembrolizumab monotherapy as first-line therapy in patients with advanced clear cell renal cell carcinoma. J Clin Oncol 39:1020-1028, 2021.

2. McDermott DF, Lee JL, Ziobro M, et al: Open-label, single-arm phase II study of pembrolizumab monotherapy as first-line therapy in patients with advanced non-clear cell renal cell carcinoma. J Clin Oncol 39:1029-1039, 2021.

3. Motzer RJ, Tannir NM, McDermott DF, et al: Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N Engl J Med 378:1277-1290, 2018.

4. Rini BI, Plimack ER, Stus V, et al: Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med 380:1116-1127, 2019.

5. Choueiri TK, Powles T, Burotto M, et al: Nivolumab plus cabozantinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med 384:829-841, 2021.

6. Motzer R, Alekseev B, Rha SY, et al: Lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma. N Engl J Med. February 13, 2021 (early release online).

7. Rini BI, Dorff TB, Elson P, et al: Active surveillance in metastatic renal-cell carcinoma: A prospective, phase 2 trial. Lancet Oncol 17:1317-1324, 2016.

8. Tannir NM, Jonasch E, Albiges L, et al: Everolimus versus sunitinib prospective evaluation in metastatic non-clear cell renal cell carcinoma (ESPN): A randomized multicenter phase 2 trial. Eur Urol 69:866-874, 2016.

9. Armstrong AJ, Halabi S, Eisen T, et al: Everolimus versus sunitinib for patients with metastatic non-clear cell renal cell carcinoma (ASPEN): A multicentre, open-label, randomised phase 2 trial. Lancet Oncol 17:378-388, 2016.

10. Pal SK, Tangen C, Thompson IM Jr, et al: A comparison of sunitinib with cabozantinib, crizotinib, and savolitinib for treatment of advanced papillary renal cell carcinoma: A randomised, open-label, phase 2 trial. Lancet 397:695-703, 2021.

11. Pal SK, Tange C, Thompson IM, et al: Sunitinib versus cabozantinib, crizotinib or savolitinib in metastatic papillary renal cell carcinoma: Results from the randomized phase II SWOG 1500 study. 2021 Genitourinary Cancers Symposium. Abstract 270. Presented February 11, 2021.

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