Despite Setback, Expert Sees Novel Immunotherapy Combos on Horizon in mRCC

Martin H. Voss, MD

The combination of the investigational PD-1 inhibitor MEDI0680 and durvalumab (Imfinzi) did not appear to show an improvement in efficacy compared with single-agent nivolumab (Opdivo) in patients with previously treated metastatic renal cell carcinoma (mRCC), according to results of a phase I/II trial (NCT02118337).

Despite these disappointing data, lead study author Martin H. Voss, MD, said that other immunotherapy combinations are still poised to demonstrate superiority to single-agent checkpoint inhibitors in this patient population.

Results showed that there were no significant differences in overall response rate (ORR), progression-free survival (PFS), or overall survival (OS) demonstrated between the 2 arms. Moreover, no patient subgroups appeared to derive additional benefit from the combination versus the monotherapy.

Moreover, grade 3/4 treatment-related adverse events (TRAEs), as well as treatment discontinuations, were more common with the combination compared with single-agent nivolumab.

"This study did not meet its primary endpoint, so there is no plan to develop this regimen in mRCC," said Voss. "Nonetheless, it is relevant to think about combination therapies and co-inhibition of various checkpoints. There are a large number of ongoing clinical trials exploring other combinations in comparison to checkpoint inhibitor monotherapy."

In an interview with OncLive^®, Voss, a medical oncologist at Memorial Sloan Kettering Cancer Center, discussed the phase I/II trial evaluating MEDI0680 plus durvalumab in mRCC and what similar research efforts lie ahead.

OncLive: What was the rationale for this study?

Voss: This was a phase I/II clinical trial that was conducted across several institutions in a number of countries. The first portion of the study [evaluated] the safety and tolerability of the combination of MEDI0680, a PD-1—directed monoclonal antibody, with durvalumab, a PD-L1–directed monoclonal antibody.

Conceptually, this trial tested the standard PD-1—directed monotherapy [with nivolumab] compared with the investigational arm of PD-1– plus PD-L1–directed immunotherapy [with MEDI0680 and durvalumab.

Safety had been established in both drugs across solid tumor cohorts. [They have] been used in a number of diseases, including RCC, with an efficacy signal.

The dosing schedule was determined in the phase I portion of the trial. There was an early efficacy signal for a number of solid malignancies, including RCC. That motivated the design and [the rationale to] conduct the phase II portion of this study.

How was the phase II portion of the trial designed?

This was a randomized, open-label, phase II trial comparing an investigational arm of MEDI0860 plus durvalumab versus single-agent nivolumab in a 2:1 randomized [fashion].

The research hypothesis behind the trial is that if we gave monotherapy, some cell-cell interactions would remain unaffected and could inhibit the tumor immune microenvironment. [Utilizing] a PD-1— plus PD-L1–directed combination may more comprehensively block cell-cell interactions.

Patients who were eligible had advanced clear-cell RCC. They must have been exposed to 1 to 3 prior lines of therapy. Patients could not have received prior immunotherapy in the metastatic setting. Once [patients were enrolled], they received treatment on either of the 2 arms intravenously every 2 weeks. Treatment was continued, as long as it was tolerated and efficacious, for up to 2 years.

The study's primary endpoint was investigator-assessed ORR. The statistical design assumed on the control arm was a 21.5% ORR, which is taken from the package insert for nivolumab, versus an aim of up to 47.5% ORR in the investigational arm. The study had a 76% power with a 1-sided [significance level] of 0.10.

Could you highlight the most updated results from this study?

We presented the primary efficacy results, as well as some of the secondary endpoints. The primary endpoint was ORR, and the secondary endpoints were PFS, OS, and safety of the 2 regimens.

In terms of the primary endpoint analysis, there was no significant difference [found] between the ORR on the investigational arm and the standard arm. Additionally, there was no notable difference in PFS or OS, which was not reached on either arm.

The ORRs did not differ between specific patient subgroups. We looked at Memorial Sloan Kettering Cancer Center risk groups and patients whose tumors were overexpressing PD-L1 by immunohistochemistry. There was no clear signal that a subcategory derived additional benefit from the combination compared with nivolumab alone.

What were the differences in safety with MEDI0680/durvalumab versus nivolumab?

TRAEs were numerically somewhat more frequent in the combination arm than the control arm. There was no clear difference between regimens regarding high-grade TRAEs. The rate of treatment discontinuation due to toxicity was comparable as well.

Voss MH, Azad AA, Hansen AR, et al. Results from a randomized phase I/II trial evaluating the safety and antitumor activity of anti—PD-1 (MEDI0680)/anti–PD-L1 (durvalumab) vs anti–PD-L1 (nivolumab) alone in metastatic clear cell renal cell carcinoma (ccRCC). Ann Oncol. 2019;30(suppl 5):v516. doi:10.1093/annonc/mdz253.094.