A new class of cancer therapies has set its sights on immune checkpoints. A trio of studies presented at the 2015 Genitourinary Cancers Symposium offered a glimpse into the evolving landscape of treatment for metastatic renal cell carcinoma (mRCC), and the programmed death ligand 1 (PD-L1) and its receptor, programmed death-1 (PD-1), were primary targets.
The first study, presented by Brian I. Rini, MD, Associate Professor of Medicine at the Cleveland Clinic Taussig Cancer Institute in Cleveland, OH, attempted to show the association of PD-1 and PD-L1 protein expression in matched primary and mRCC tumors. As Rini noted, expression of PD-1 and PD-L1 on tumor and infiltrating immune cells in patients with mRCC is associated with a higher response to drugs inhibiting this pathway. However, these associations have been made based on primary tumor expression, whereas therapy is directed against metastatic deposits.
This study consisted of patients with mRCC and metastases who had undergone resection of both the primary and at least 1 metastatic tumor. Samples were evaluated for PD-1 and PD-L1 expression by immunohistochemistry.
“Fifty matched primary and metastatic RCC tissue sets were analyzed with 48 evaluable matched pairs,” reported Rini. PD-1 scores greater than 3 (considered positive) were detected in 9 primary tumors (18%) and 9 metastatic sites (18%). PD-L1 scores greater than 3 were detected in 9 primary tumors (18%) and 12 metastatic sites (24%).
“The expression of PD-1 and PD-L1 in primary clear cell RCC tumors is correlated with metastatic site expression,” concluded Rini, “although there is a substantial percentage of tumors with discordance.”
MPDL3280A plus Bevacizumab
Mario Sznol, MD, Professor of Medicine at Yale School of Medicine in New Haven, CT, presented the second study, a multicenter, phase 1b evaluation of anti–PD-L1 antibody MPDL3280A in combination with bevacizumab in patients with mRCC.
“The combination of MPDL3280A plus bevacizumab was well tolerated in clear cell mRCC patients,” noted Sznol, “and promising preliminary clinical activity and immune modulation of the tumor microenvironment were observed.”
As Sznol explained, MPDL3280A, a human anti–PD-L1 antibody engineered to remove Fc-effector function, prevents PD-L1 binding to the inhibitory receptors PD-1 and B7.1 on activated T cells. Bevacizumab was postulated to enhance the antitumor effects of MPDL3280A by blocking suppressive effects related to the vascular endothelial growth factor (VEGF) on immune function and lymphocyte traffic.
For this study, 10 patients with mRCC with clear cell histology and available pretreatment tumor specimens were enrolled. Bevacizumab 15 mg/kg was given alone on cycle 1 day 1 and concurrently with MPDL3280A 20 mg/kg every 3 weeks thereafter. On-treatment tumor biopsy was performed during cycle 1 and 4 to 6 weeks after the start of cycle 2. The median duration of treatment for MPDL3280A was 288 days.
“Grade 3 to 4 adverse events included postoperative wound infection, hypercalcemia, tumor pain, acute respiratory failure in a patient with influenza (1 patient each), and hypertension (3 patients),” Sznol reported, but “no grade 3 to 4 adverse events were assessed as related to MPDL3280A.”
Among first-line mRCC patients with ?1 tumor assessment (n = 10), the objective response rate was 40% at the time of data cutoff.
MPDL3280A treatment has been shown to increase CD8+ immune cell infiltration as well as expression levels of immune genes. Additionally, activated CD8+ T cells have been shown to transiently increase in blood (peaking at cycle 2) during treatment with MPDL3280A. Increases in immune activity were also detected in patients with mRCC receiving MPDL3280A plus bevacizumab.
A phase 2 trial of MPDL3280A with or without bevacizumab versus sunitinib in patients with previously untreated mRCC is ongoing.
Efficacy of Targeted Therapies After PD-1/PD-L1 Inhibitors
Finally, a multi-institution retrospective cohort, presented by Laurence Albiges, MD, Institut Gustave Roussy, Villejuif, France, sought to show the efficacy of targeted therapies after treatment with PD-1/PD-L1 inhibitors in patients with mRCC.
“This is the first report of targeted therapy efficacy after PD-1/PD-L1 inhibition,” noted Albiges. “In this selected population, median time to treatment failure [TTF] suggests a sustained benefit of both VEGF receptor [VEGFR] tyrosine kinase inhibitors [TKIs] and mTOR inhibitors after PD-1/PD-L1 inhibition.”
For this study, medical records of RCC patients treated with investigational PD-1 or PD-L1 inhibitors who received subsequent treatment with targeted therapies were reviewed in 4 institutions. Baseline characteristics at the time of subsequent therapy and outcome data including TTF, best response, and 1- and 2-year overall survival (OS) were retrospectively collected.
“Of the 99 patients who received PD-1/PD-L1 inhibitors,” Albiges reported, “56 patients have received a subsequent therapy after PD-1/PD-L1 blockade, while 7 patients are still on therapy, and 26 patients did not receive subsequent therapy. Among these 26 patients, 12 died of disease and 14 are still alive off systemic therapies.”
Forty-three patients received VEGFR TKIs and 13 received mTOR inhibitors as first subsequent targeted therapy. Median TTF was 6.6 months (range, 0.2+-23.0), and was 6.9 and 5.7 months in patients who received VEGFR TKIs and mTOR inhibitors, respectively. One-year and 2-year OS from the initiation of subsequent targeted therapy was 58% and 36%, respectively.
Investigator-assessed best response to subsequent targeted therapy was evaluated in 53 of 56 patients. Partial response was found in 13% of patients (n = 7), stable disease in 62% (n = 33), and progressive disease in 25% (n = 13).
“Targeted therapy with VEGF and mTOR inhibitors may have significant activity after discontinuation of PD-1/PD-L1 inhibitors,” concluded Albiges, “but the potential sustained effect of PD-1/PD-L1 inhibitors after therapy discontinuation needs to be further characterized.”
