Everolimus and bevacizumab against non-clear cell renal carcinoma

7 Sep 2016

Treatment with everolimus (Afinitor) and bevacizumab (Avastin) produced a benefit in patients with advanced non-clear cell renal cell carcinoma (ncRCC), particularly when there was a significant papillary tumor component, according to researchers.

In a phase 2, single-center prospective study of 34 treatment-naive patients with metastatic ncRCC, median progression-free survival, overall survival, and objective response rate were 11 months, 18.5 months, and 29%, respectively, reported Martin H. Voss, MD, of Memorial Sloan Kettering Cancer Center in New York City, and colleagues.

The presence of papillary features was associated with benefit, including unclassified RCC (uRCC), where it correlated with objective response rate, median progression-free survival, and overall survival, they reported. Everolimus is a rapalog-type inhibitor of the mTOR complex 1 (mTORC1), and bevacizumab is a recombinant humanized monoclonal antibody directed against VEGF-A.

Clinical details and results

In the current study, patients received concurrent therapy with everolimus (standard dose of 10 mg by mouth once per day) and bevacizumab (standard dose of 10 mg/kg intravenously every 14 days) until disease progression, intolerable toxicity, or withdrawal of consent. Candidate tissue biomarkers were analyzed using next-generation sequencing. Patients were all ≥18 with histologically confirmed, advanced ncRCC. Advanced disease was defined as unresectable, locally recurrent, or metastatic, and the regimen was to be considered promising if 22 or more patients were progression free at 6 months.

Histologic subtypes included papillary in five patients, chromophobe in five, medullary RCC in two, and unclassified RCC (uRCC) in 23. In those with uRCC, 14 had multinodular, intracystic papillary growth as a major tumor component and nine did not.

In particular, the analysis showed that:

  • Progression-free survival varied by histology and objective response rate was higher in patients with significant papillary (seven of 18) or chromophobe (two of five) elements than for others (one of 11), the study showed.
  • Most patients with a significant papillary component had durable responses with 14 of 18 patients (78%) deemed progression-free at 6 months.
  • Activity was observed in the five patients with chromophobe RCC and three patients who stayed on treatment for more than 12 months. This finding adds to previous reports of benefit with rapalog therapies in this subgroup, the researchers noted.
  • Conversely, patients with medullary RCC and uRCC without papillary features achieved little or no benefit from the treatment. "Novel treatment approaches beyond VEGF- and mTOR-directed therapy are needed for such patients," Voss' groups said.

Although some low-grade toxicities were seen, the treatment was generally well-tolerated. Adverse events of grade 3 or greater included hyperglycemia in 11%, hypertriglyceridemia in 14%, lymphopenia in 20%, hypertension in 29%, and proteinuria 18%. All of these adverse events are established, class-specific events for mTORC1 or VEGF inhibitors, the researchers said.


“Several genetic alterations appeared to segregate by histology”

"This study demonstrates a benefit of everolimus plus bevacizumab in ncRCC, particularly in variants with significant papillary elements," they pointed out, adding that it may also be the first "to report on defined subgroups of uRCC and to identify histologic hallmarks that seem to correlate with treatment benefit."

In addition, the study revealed that several genetic alterations appeared to segregate by histology. Somatic mutations in ARID1A (AT-Rich Interaction Domain 1A), a protein coding gene associated with mental retardation and coffin-siris syndrome, were seen in 5 of 14 patients with papillary growth as a major tumor component. All five patients with ARID1A experienced treatment benefit. ARID1A was not seen in patients with other RCC variants.

These outcomes compare favorably with those reported for patients with papillary histology given first-line sunitinib (Sutent) in the phase 2 ASPEN and ESPN trials," the researchers noted, calling ARID1A "a potential marker of papillary architecture" and "a candidate predictive biomarker in future trials of this promising regimen." They called for future studies that narrow histologic entry criteria.

The small sample size among the study’s limitations

"Although a strong predictive biomarker remains elusive, the signal of activity with bevacizumab plus everolimus in patients with papillary features is compelling," Sumanta K. Pal, MD, of City of Hope Comprehensive Cancer Center in Duarte, Calif., and colleagues stated. And while this study, along with others including ASPEN and ESPN, illustrate how each ncRCC subtype may have a unique response to therapy, its small sample size and multiple histologies are "a major limitation shared with previous studies," they added. "With 35 patients total and fewer than 20 bearing papillary elements, the suggestion of bevacizumab plus everolimus as a standard of care is a challenge, despite good clinical outcomes."

They pointed to a recent randomized phase 2 study demonstrating a significant improvement in relative risks, progression-free survival and overall survival when everolimus was given in combination with the multikinase inhibitor lenvatinib (Lenvima) in patients with treatment-naive metastatic RCC. "This combination paves the way for further studies of this regimen in patients with papillary features, a study well-justified on the basis of the results from the study by Voss et al," the editorialists said, adding that multiinstitutional randomized studies with a specific focus on particular histologic subtypes with detailed molecular characterization are needed.

Source: MedPage Today

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