ICI Treatment May Increase PD-L1 Expression in RCC Tumors Study Suggests

Sasan Setoodeh, MD

Treating clear cell renal cell carcinoma (RCC) with immune checkpoint inhibitors (ICIs) resulted in vascular changes that may make these tumors more vulnerable to combinations of ICIs and VEGF inhibitors, according to data presented at the 18th International Kidney Cancer Symposium.

Sasan Setoodeh, MD, a genitourinary pathology fellow at the University of Texas (UT) Southwestern Medical Center, presented findings from a study evaluating the histopathologic effects of ICIs on RCC.¹

Investigators compared 12 patients who underwent post-ICI nephrectomy at UT Southwestern with 10 patients with comparable clinical characteristics who underwent nephrectomy without neoadjuvant therapy. Nine patients in the study cohort were diagnosed with clear cell RCC, including 1 with sarcomatoid change, and the remaining patients had papillary RCC or TFE-B rearranged RCC. One patient had a pathologic complete response.

Two patients had ³12 cycles of ICIs following treatment with a tyrosine kinase inhibitor or an mTOR pathway inhibitor. Nine patients had £2 cycles of ICIs. Seven patients received nivolumab (Opdivo) alone and 5 received nivolumab plus ipilimumab (Yervoy).

Setoodeh said that ICI therapy was associated with shrinkage of tumor cell cytoplasm and nucleus in all 9 patients with clear cell RCC, prominent fibrin deposition in vessel walls with capillary endothelial hyperplasia in 8 of 9, and prominent fibrous scaring and collagenization in 7 of 9. These effects were either not seen or rarely focal in the ICI-naïve cohort.

“The capillary network is expanded in the treated [tumor] but very delicate in the untreated case,” he said. “The tumor nest also appears smaller in the treated one compared with the untreated one.”

Investigators expected to see more than 20% of RCC tumors positive for PD-L1 expression (³1%), which was the case in the untreated clear cell RCC tumors. They were surprised to learn that 77.7% of the treated tumors were PD-L1 positive.

“PD-L1 expression may increase after ICI therapy,” Setoodeh said.

He added that these results are particularly compelling in the context of recently published findings showing strong results for patients with RCC assigned to VEGF inhibitors along with the ICIs atezolizumab (Tecentriq), pembrolizumab (Keytruda), and avelumab (Bavencio).

In data from the IMmotion151 trial published inLancetearlier this year, 454 patients with previously untreated PD-L1—positive metastatic RCC were randomly assigned to atezolizumab plus bevacizumab (Avastin) and compared with 461 patients assigned to sunitinib (Sutent). Forty percent of patients had PD-L1—positive disease.²

At a median follow-up of 15 months, the median progression-free survival (PFS) was 11.2 months with the combination versus 7.7 months in the sunitinib group (HR, 0.74; 95% CI, 0.57-0.96;P= .0217) in the PD-L1—positive population.

Forty percent of patients in the experimental group experienced treatment-related grade 3/4 adverse events (AEs) compared with 54% in the sunitinib group. Just 5% of patients in the experimental group discontinued treatment due to treatment-related AEs compared with 8% in in the sunitinib group.

In results fromNew England Journal of Medicinepublished in March, investigators compared pembrolizumab plus axitinib (Inlyta) versus sunitinib in patients with treatment-na&iuml;ve advanced clear cell RCC. After a median follow-up of 12.8 months, the 12-month estimated survival rate was 89.9% in the pembrolizumab/axitinib group versus 78.3% in the sunitinib group (HR, 0.53; 95% CI, 0.38-0.74;&nbsp;P<.0001). Investigators found that the survival benefit associated with the combination was consistent across all risk groups and regardless of PD-L1 expression.³

In a third study, patients with treatment-na&iuml;ve advanced RCC were assigned to avelumab plus axitinib (n = 442) or sunitinib (n = 444). Among the 63.2% of patients with PD-L1—positive tumors, the median PFS was 13.8 months with the combination compared with 7.2 months with sunitinib (HR, 0.61; 95% CI, 0.47-0.79;P<.001). Median PFS also favored the combination in the overall population (13.8 vs 8.4 months; HR, 0.69; 95% CI, 0.56-0.84;&nbsp;P<.001).⁴

References:

1. Setoodeh S. Effects of immune checkpoint inhibitors on the morphology of renal cell carcinoma. Presented at: the 18th International Kidney Cancer Symposium; November 15-16, 2020; Miami, FL.
2. Rini BI, Powles T2, Atkins MB, et al; IMmotion151 Study Group. Atezolizumab plus bevacizumab versus sunitinib in patients with previously untreated metastatic renal cell carcinoma (IMmotion151): a multicentre, open-label, phase 3, randomised controlled trial.Lancet. 2019;393(10189):2404-2415. doi: 10.1016/S0140-6736(19)30723-8.
3. Rini BI, Plimack ER, Stus V, et al; KEYNOTE-426 Investigators. Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma.N Engl J Med. 2019;380(12):1116-1127. doi: 10.1056/NEJMoa1816714.
4. Motzer RJ, Penkov K, Haanen J, et al. Avelumab plus axitinib versus sunitinib for advanced renal-cell carcinoma.N Engl J Med. 2019;380(12):1103-1115. doi: 10.1056/NEJMoa1816047.