Everolimus Plus Bevacizumab Effective for First-Line Treatment of Advanced Papillary Variant Renal Cell Carcinoma

Robert Motzer

Everolimus plus bevacizumab demonstrates robust activity in treatment-naïve patients with advanced papillary variant nonclear cell renal cell carcinoma (nccRCC), according to the results of an expanded single-arm, single-institution phase II trial conducted at Memorial Sloan Kettering Cancer Center.

Our findings, published recently in the journal Cancer, are the first to report on the combination of a vascular endothelial growth factor (VEGF) inhibitor plus mammalian target of rapamycin (mTOR) pathway inhibition in nccRCC patients with a particular focus on pRCC. (1)

We previously reported encouraging activity in papillary RCC (pRCC) and unclassified RCC (uRCC) with a major papillary component in the original cohort of 19 patients receiving everolimus plus bevacizumab across various nccRCC histologies. (2) Accordingly, we amended the protocol and enrolled an expansion cohort of 20 additional patients with advanced nccRCC with papillary features to further investigate this activity. (1)

Among 37 evaluable patients across both cohorts, the six-month progression-free survival (PFS) rate was a landmark 78 percent, median PFS was 13.7 months (95% CI, 10.8–16.4), and the objective response rate (ORR) was 35 percent. The median overall survival (OS) was 33.9 months (95% CI, 23.3–71.9). (1) These results compared favorably with historical controls and were actually more comparable to outcomes achieved with everolimus plus bevacizumab in the first-line setting for ccRCC. (3) The regimen was well tolerated by patients, consistent with previous reports. (1)

Next-generation sequencing results for 33 patients using the MSK Integrated Molecular Profiling of Actionable Cancer Targets (MSK-IMPACT™) assay identified responses in patients with a wide spectrum of genomic alterations, including ARID1A, FH, and MET mutations. Similar to the original cohort, alterations in ARID1A and FH were the two most commonly affected genes, observed mostly in patients who benefitted from therapy. (1)

The data support the combination of everolimus plus bevacizumab as a standard first-line treatment option for patients with advanced nccRCC, as recently recognized in the National Comprehensive Cancer Network guidelines. (4) The findings also support moving toward subtype-specific trials versus “all nccRCC” trial designs.

The data support the combination of everolimus plus bevacizumab as a standard first-line treatment option for patients with advanced nccRCC, as recently recognized in the National Comprehensive Cancer Network guidelines.
Robert J. Motzer Section Head, Kidney Cancer, Genitourinary Oncology Service; Jack and Dorothy Byrne Chair in Clinical Oncology

Renal Cell Carcinoma

Renal cell carcinomas (RCCs) are a group of malignancies with multiple variants. Clear cell RCC (ccRCC) accounts for about 75 percent of RCC cases, (5) and the remaining histologies are nccRCCs. Well-defined nccRCC variants include papillary, chromophobe, collecting duct, medullary, and translocation-associated RCC. (6), (7) Cases not meeting criteria for known histological subtypes are categorized as uRCC but may still harbor papillary features. (7)

Despite significant treatment advances in ccRCC, the best way to treat advanced nccRCC remains poorly defined. (8) Outcomes after treatment with vascular endothelial growth factor receptor (VEGFR) inhibitors have appeared worse for patients with nccRCC compared to those with ccRCC. (9) Molecular analysis of aggressive RCC with unclassified histologies has revealed distinct subsets of disease, providing new targets for the development of directed therapies and the potential for improving patient outcomes.

Study Design

In a previous report on our single-institution, single-arm, phase II study of everolimus plus bevacizumab in treatment-naïve patients with advanced nccRCC, we noted promising activity in 19 patients with tumors harboring major papillary components, including those classified as uRCC with papillary features, yet inconsistent with pRCC. The ORR was 43 percent, median PFS was 12.9 months, and median OS was 28.2 months. (2)

To further explore this encouraging efficacy signal, we amended the study protocol (NCT01399918) to include an expansion cohort of 20 additional participants with treatment-naïve advanced nccRCC with a major papillary component.

Eligible patients in the expansion cohort had advanced pRCC or other nccRCC variants harboring a major papillary component, confirmed by histology by a dedicated genitourinary pathologist at MSK. Cases of uRCC with papillary features were defined as uRCC with papillary growth pattern as a major component yet exhibiting features inconsistent with the diagnostic criteria of pRCC. Advanced disease was defined as unresectable, locally recurrent, or metastatic. Other inclusion criteria included age 18 years or older, no prior therapy with VEGF or mTOR inhibitors, and evidence of disease was measured according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. (10)

We also included tumors suspicious for hereditary leiomyomatosis renal cell carcinoma syndrome-associated RCC but without a known FH germline alteration in the uRCC with papillary growth group. Every effort was made to further classify uRCC tumors and cases with histologic features suspicious for other established variants of RCC by analyzing available tumor material by immunohistochemistry, fluorescence in situ hybridization, or molecular testing, to eliminate patients from the uRCC group. (1)

Study participants self-administered oral everolimus 10 mg once daily and received intravenous infusions of bevacizumab at 10 mg/kg every 14 days at MSK. Therapy was continued until disease progression or treatment intolerance. Dosing interruptions and modifications for toxicities managed according to guidance in the protocol, which allowed for reducing the everolimus dose to 5 mg daily and then to 5 mg every other day. No dose reductions were recommended for bevacizumab, but dosing could be delayed or discontinued if held for more than eight weeks. If one drug was held or permanently stopped for adverse events, the other medication could be continued, provided it was deemed safe. (1)

Cross-sectional imaging occurred every two 28-day cycles until cycle six and then every three cycles until cycle 12, and every four cycles thereafter per response evaluation criteria in solid tumors (RECIST) 1.1. (10) We performed clinical and lab assessments twice during the first cycle and once thereafter, and also conducted urinalysis and fasting blood draw every two cycles. (1)

Finally, we performed next-generation sequencing using the MSK-IMPACT™ assay. (11) The tool is a hybridization capture-based assay with germline comparison for targeted deep sequencing of all exons and selected introns across a panel of 468 genes. We also conducted a dedicated next-generation sequencing analysis for germline events across 76 genes known to predispose patients to hereditary cancers. (1)

Study Results

Thirty-nine patients with papillary variants of RCC enrolled in the trial and were treated in the first-line setting between August 2011 and December 2016, with 19 patients from the original cohort and 20 from the expansion cohort. In our present paper, we reported outcomes for 37 evaluable patients as follows.

One patient with uRCC with papillary features suffered clinically apparent disease progression during the second month of treatment and was taken off the trial before radiographic assessment was obtained. This patient was included in PFS analysis but not ORR, as required by the study protocol. A second patient with pRCC discontinued treatment after a single dose of bevacizumab due to safety concerns related to a large gingival defect that likely preceded study inclusion. This patient was removed from the study, replaced with another patient, and was not included in the PFS or ORR analysis. Both patients were included in the toxicity analysis. (1)

Most patients had uRCC with papillary features (24 patients, 61 percent), one had translocation-associated RCC with papillary features, and the remaining 14 patients (36 percent) had pRCC. Tumors categorized as uRCC with papillary features did not have clear cell features. However, some exhibited other patterns, including tubular, tubulocystic, and solid patterns. Twenty-nine patients (74 percent) had previously undergone nephrectomy. (1)

The six-month PFS rate for nccRCC patients with papillary variants was 78 percent. The ORR for all patients was 35 percent: 43 percent for uRCC with papillary features and 23 percent for pRCC (p = 0.30). Thirty-three of 37 patients (89 percent) had a radiographic decrease in tumor burden, and only three patients (eight percent) had progressive disease as the best-recorded response. (1)

Four patients were still receiving treatment at the time of data lock. The median PFS was 13.7 months (95% CI, 10.8–16.4 months), with no observed difference between the two subgroups (13.7 months for uRCC with papillary features versus 8.4 months for pRCC (hazard ratio, 1.67; 95% CI, 0.66–4.17; p = 0.27). With a median follow-up of 17.6 months (range 1.6–44.4 months), the median OS was 33.9 months (95% CI, 23.3–71.9) and was longer for patients with underlying uRCC compared to those with pRCC at 42.1 versus 23.3 months, respectively (hazard ratio, 4.4; 95% CI, 1.19–16.1 months; p = 0.02). (1)

The everolimus plus bevacizumab combination was well tolerated overall, with similar toxicities as observed previously and class-specific effects for both drugs. Grade 3 and 4 adverse events included hypertension (31 percent), lymphopenia (23 percent), hyperglycemia (18 percent), hypertriglyceridemia (10 percent), and proteinuria (5 percent). Two patients died while on treatment: one due to hematemesis, the other due to multiple brain infarcts from sepsis. The median time on treatment was 301 days (range 12 to 842 days). The median time on bevacizumab was 238 days (range 10 to 770 days). Ten patients (25 percent) discontinued bevacizumab permanently and continued taking everolimus alone due to treatment-induced proteinuria. (1)

MSK-IMPACT™ results revealed recurrent somatic mutations consistent with prior efforts characterizing pRCC and uRCC, (12) (13) including alterations in FH, MET, ARID1A, and NF2. Similar to the original cohort, alterations in ARID1A and FH, the two most commonly affected genes, were mostly observed in patients who benefitted from therapy. All patients with somatic ARID1A mutations achieved a PFS greater than six months, as did 88 percent of patients with somatic and/or germline FH mutations. However, conclusions on these observations are limited by the small sample size. ARID1A is a chromatin-remodeling tumor suppressor gene found in a broad range of human cancers, (14) but its exact cancer-promoting effects are largely unknown. FH deficiency affects cellular metabolism by disrupting the tricarboxylic acid cycle, altering it toward aerobic glycolysis, known as the Warburg effect. (15)

Advancing Kidney Cancer Outcomes

Our research underscores the importance of referring patients with kidney cancer to academic centers with genitourinary oncology expertise for nccRCC cases. At MSK, medical oncologists collaborate with surgical oncologists, radiation oncologists, and other specialists with expertise in renal cell carcinoma to develop individualized treatment plans for each patient.

MSK has a long history of providing leadership in clinical trials of targeted agents for treating advanced RCC, including everolimus. (16) We are currently conducting 25 clinical trials testing investigational therapeutic approaches, including combinations of immunotherapies and targeted therapies for patients with kidney cancer, such as our ongoing phase II study testing nivolumab plus cabozantinib in nccRCC (NCT03635892).

This investigator-initiated trial was supported by Novartis International AG (Basel, Switzerland), the Kidney Cancer Foundation, and the National Institutes of Health (Cancer Center Support Grant P30 CA008748).

Dr. Feldman has received research support from Novartis, Astellas, Decibel, and Seattle Genetics. Dr. Motzer has received personal fees from Pfizer, Eisai, Exelixis, Novartis, Genentech/Roche, Merck, Incyte, and Eli Lilly; grants from Pfizer, Eisai, Novartis, Bristol- Myers Squibb, Genentech/Roche, and GlaxoSmithKline; and travel/accommodation expenses from Bristol-Myers Squibb. Dr. Voss has received grants from Bristol-Myers Squibb, Genentech/Roche, and Pfizer; has received nonfinancial support from AstraZeneca/Medimmune; has received personal fees from Novartis, Pfizer, Exelixis, Eisai, Corvus, Calithera, and Merck; has received travel/accommodation expenses from Eisai, Novartis, and Takeda; and has been a consultant/advisory board member for Alexion Pharmaceuticals, Bayer, Calithera Biosciences, Corvus Pharmaceuticals, Exelixis, Eisai, GlaxoSmithKline, Natera, Novartis, OnQuality Pharmaceuticals, and Pfizer. For disclosures from other study authors, please refer to the paper.

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