PD-1 Pathway Combos Lead the Way in RCC Immunotherapy

The prospects for combining anti–PD-1 pathway agents with other checkpoint blockade inhibitors or with agents that target angiogenesis are among the most promising immunotherapy approaches under development for patients with metastatic renal cell carcinoma.

Mario Sznol, MD

The prospects for combining anti—PD-1 pathway agents with other checkpoint blockade inhibitors or with agents that target angiogenesis are the most promising immunotherapy approaches under development for patients with metastatic renal cell carcinoma (RCC), according to Mario Sznol, MD.

Sznol, one of the architects of successfully targeting the PD-1 pathway in melanoma, presented an overview of research into immunotherapy strategies in RCC during the 8th Annual Interdisciplinary Prostate Cancer Congress in New York City on March 14, which included other genitourinary malignancies for the first time this year.

“The agents that block PD-1 or PD-L1 are highest on the list,” said Sznol, a professor of Medicine at Yale Cancer Center, in an interview. “Those are the most exciting agents right now.” He noted that several later-stage clinical trials currently under way would help define the field. These trials include:

  • Nivolumab, which targets PD-1, is being evaluated in combination with ipilimumab versus sunitinib in patients with previously untreated advanced or metastatic RCC in the phase III CheckMate 214 trial.1 Ipilimumab targets the immune checkpoint CTLA-4, while both bevacizumab and sunitinib interfere with tumor angiogenesis. The study, which aims to enroll 1070 patients, was launched in September 2014 with an anticipated primary completion date of January 2018.
  • MPDL3280A, a monoclonal antibody that inhibits the PD-L1 ligand, is under study as monotherapy or in combination with bevacizumab versus sunitinib in a three-arm phase II trial that is seeking to recruit 300 patients.2 The estimated primary completion date is January 2016. Sznol said a larger phase III study is planned.
  • Nivolumab is being compared with everolimus, an mTOR inhibitor, in a phase III trial that sought to enroll more than 800 patients with advanced or metastatic clear cell RCC who have received prior antiangiogenic therapy.3 Early results from this trial may be available this year, said Sznol.

Nivolumab Evidence Builds

Nivolumab, which has gained FDA approvals in melanoma and non—small cell lung cancer during the past 3 months, showed efficacy in RCC in a phase II study that examined nivolumab activity in 168 patients who received dosages of 0.3 mg/kg, 2 mg/kg, or 10 mg/kg.4

The objective response rates (ORR) ranged from 20% to 22% depending on the dosage. The duration of response ranged from a median of 15.7 months for the lowest dosage and was not yet reached for the other two dosing levels, including one patient who had maintained an ongoing response for 30 months at the time the results were reported.

The response rates rose markedly when nivolumab was combined with ipilumumab in phase I findings presented at the 2014 ASCO Annual Meeting.5 The regimen was tested in 44 patients at two different dosing levels: nivolumab at 3 mg/kg plus ipilimumab at 1 mg/kg, or nivolumab at 1 mg/kg plus ipilimumab at 3 mg/kg. In this trial, the ORR was 43% for the first group and 48% for the second cohort.

“The combination of anti—PD-1 with anti–CTLA-4 looks very exciting,” said Sznol. “The response rate that was reported by Hammers et al at ASCO was in the 45% range, and even thought the combination was more toxic than either of the single agents, a 45% response rate in metastatic kidney cancer is very exciting.”

In terms of overall survival (OS), Motzer et al4 reported OS results that showed nivolumab compared favorably in the phase II trial with outcomes from phase III studies of sorafenib and other targeted agents. The median OS with nivolumab was 18.2 months to 25.5 months, compared with median OS rates ranging from 11.0 months to 16.6 months in trials of other agents.

Anti-PD-L1 Agent Plus Bevacizumab

Researchers are also looking into the possibility that angiogenesis inhibitors can enhance the immune dynamics in the tumor microenvironment and function synergistically with the PD-1 pathway agents. The FDA has approved five agents in RCC that target VEGF-mediated pathways: the tyrosine kinase inhibitors sunitinib, sorafenib, pazopanib, and axitinib, and the monoclonal antibody bevacizumab.6

At the 2015 Genitourinary Cancers Symposium, Sznol presented results of a phase Ib study that combined the novel anti—PD-L1 agent MPDL3280A with bevacizumab,7 which is approved for patients with metastatic RCC as part of a regimen that includes interferon-alfa.

Among 10 patients with clear-cell RCC who received MPDL3280A plus bevacizumab, there were four ORRs by RECIST criteria, all of which were partial responses. Five other patients had stable disease as their best response. Four of these five had prolonged (≥24 weeks) stable disease.

Role for Interleukin

While scientists are exploring emerging agents in RCC, high-dose interleukin-2 (IL-2) remains a viable option for a subgroup of patients with clear cell histology, said Sznol.

He said IL-2, which the FDA first approved for RCC in 1992, is appropriate for patients with no evidence of cardiovascular disease, good lung function, and well-preserved organ function. The therapy can be less convenient for patients because of the dosing schedules, but that cancer centers experienced with the drug are able to adjust dosing and manage toxicities.

Sznol said the Cytokine Working Group demonstrated ORRs in the 25% to 30% range for high-dose IL-2, which is approximately double the rate of major responses in the clinical trials that paved the way for its initial approval.8 He said that response rate is competitive with the emerging agents for the subset of patients for whom IL-2 would be appropriate.

One avenue of investigation in RCC involves boosting the potency of IL-2. Sznol mentioned one agent in the preclinical stages, NKTR-214, that has shown the ability to increase memory effector T cells and decrease CD4-positive regulatory T cells in mouse models. NKTR-214 consists of a polymer conjugated to IL-2 for more direct delivery of the cell-killing agent, he said.

Preference for Immunotherapy

Although none of the new immunotherapy agents under study has been approved yet in RCC, Sznol said the modality is the preferred choice of therapy for patients with metastatic disease at his institution.

“Usually, it’s immunotherapy first unless there’s something in the clinical history, the clinical presentation, that would make us believe they would not be a good candidate,” said Sznol.

He said factors that would preclude patients from immunotherapy would be rapid disease progression, declining performance status, a need to take steroids, or the presence of an autoimmune disease. Those who are candidates for immunotherapy would be considered for a clinical trial.

Patients who no longer respond to immunotherapy are offered the targeted agents that are approved to treat patients with RCC but those drugs are considered palliative therapy, said Sznol.

“We have a strong belief that immunotherapy is the best chance to give patients durable response,” he said.


  1. NIH Clinical Trials Registry. www.ClinicalTrials.gov. ID: NCT02231749.
  2. NIH Clinical Trials Registry. www.ClinicalTrials.gov. ID: NCT01984242.
  3. NIH Clinical Trials Registry. www.ClinicalTrials.gov. ID: NCT01668784.
  4. Motzer R, Rini B, McDermott D, et al. Nivolumab for metastatic renal cell carcinoma (mRCC): results of a randomized, dose-ranging phase II trial. J Clin Oncol. 2014;32(suppl 5; abstr 5009).
  5. Hammers HJ, Plimack ER, Infante JR, et al. Phase I study of nivolumab in combination with ipilimumab in metastatic renal cell carcinoma (mRCC). J Clin Oncol. 2014;32(suppl 5; abstr 4504).
  6. National Cancer Institute. Stage IV and recurrent renal cell carcinoma. Renal VCell Cancer Treatment (PDQ). http://goo.gl/GQvm45. Updated February 25, 2015. Accessed March 16, 2015.
  7. Sznol M, McDermott DF, Fields Jones S, et al. Phase Ib evaluation of MPDL3280A (anti-PDL1) in combination with bevacizumab (bev) in patients (pts) with metastatic renal cell carcinoma (mRCC). J Clin Oncol. 2015;33(suppl 7; abstr 410).
  8. McDermott DF, Ghebremichael MS, Signoretti S, et al. The high-dose aldesleukin (HD IL-2) “SELECT” trial in patients with metastatic renal cell carcinoma (mRCC). J Clin Oncol. 2010;38:15(suppl; abstr 4514).


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