Immunotherapy Combinations on the Rise for RCC

David McDermott, MD

The combination of PD-1 or PD-L1 inhibitors with existing frontline therapies could represent a superior approach for some treatment-naïve patients with renal cell carcinoma (RCC), with biomarker findings shedding light on ideal subgroups, according to a presentation by David F. McDermott, MD, at the 2017 SUO Annual Meeting.

“The questions that we focused a lot of our research on is how do you overcome innate and acquired resistance through combination therapy, and will combination therapy allow you to overcome that resistance?” McDermott, director of the Biologic Therapy and Cutaneous Oncology Programs at Beth Israel Deaconess Medical Center, said in his presentation.

“In a variety of tumor models, if you inhibited VEGF, you could improve the immune response to the tumors. This suggested VEGF was promoting [regulatory T cells], the myelo-derived suppressive cells, preventing the T cells from getting into the tumor, and then if you targeted VEGF you can reverse some of this,” he added.

In the phase II IMmotion150 trial, the PD-L1 inhibitor atezolizumab (Tecentriq) as a monotherapy (n = 103) or in combination with bevacizumab (Avastin; n = 101) was compared with sunitinib (Sutent) alone (n = 101) for untreated patients with advanced RCC. For patients with PD-L1—positive tumors, the median progression-free survival (PFS) for the combination was 14.7 months compared with 7.8 months with sunitinib (HR, 0.64; 95% CI, 0.38-1.08). In the intent-to-treat (ITT) population, the median PFS with the combination was 11.7 versus 8.4 months with sunitinib.

“When you look at the primary endpoint, which was progression-free survival for all comers in the ITT population, there was no difference between the treatment groups,” McDermott noted, “but for the first time in kidney cancer, when we looked at immunohistochemistry for PD-L1 on tumor immune cells, the more expression a patient had of PD-L1 in the microenvironment, the more likely they were to respond to the combination.”

The trial also demonstrated that single-agent PD-L1 blockade can be active in untreated metastatic RCC, as the median PFS was 6.1 months in the ITT analysis with the single-agent. The added efficacy with the combination suggests that VEGF blockade may enhance the immune response for some patients, McDermott said, leading to a deeper analysis of data from the trial.

In the biomarker assessment, patients were categorized into subgroups based on their T-effector, angiogenic, and myeloid expressions. Patients who were T-effector—high and myeloid-low did just as well, if not better, with atezolizumab monotherapy than patients who received sunitinib alone, but those who were T-effector–high and myeloid-high did poorly on atezolizumab monotherapy, suggesting that myeloid cells could have been immune suppressive, or were a pathway of innate resistance, that might be overcome by the addition of bevacizumab. The angiogenic-high group did better with sunitinib.

“We were able to come up with a signature of a group of patients who were able to benefit from sunitinib alone, which is important because at least a third of patients are going to receive no benefit from immune therapy, and in this trial, those who were angiogenic-high did well with sunitinib,” McDermott said.

In addition to some patients being ideal for sunitinib, not all need to receive combination therapies, given the single-agent activity seen for patients with the T-effector—high and myeloid-low signature; however, he cautioned, these findings still need to be confirmed in future trials. For now, PD-L1 expression can be used to help select patients.

Biomarkers will remain a critical component of future trials, to narrow down the patients who are most likely to benefit. Future trials are looking to find better predictive biomarkers of response along with markers for pseudoprogression, progression, and resistance. These goals will be dependent on biomarker screening pretreatment and next-generation assays beyond immunohistochemistry to enhance development of biomarkers, McDermott said.

“If you think about the true benefits of immune therapy, they’re ‘tail of the curve’ benefits. We’re judging these combinations largely based on endpoints designed for molecularly targeted agents like response rate and PFS, but what matters most to patients—and I think what should matter to us—is long-term survival, the ability to develop remissions and cures,” McDermott said.

McDermott DF, Atkins MB, Motzer RJ, et al. A phase II study of atezolizumab (atezo) with or without bevacizumab (bev) versus sunitinib (sun) in untreated metastatic renal cell carcinoma (mRCC) patients (pts). [ASCO abstract 431]. J Clin Oncol. 2017;35(suppl).