Lead Investigator Discusses Atezolizumab/Bevacizumab in mRCC

Michael Atkins, MD

Atezolizumab (Tecentriq) plus bevacizumab (Avastin) demonstrated encouraging antitumor activity for patients with metastatic renal cell carcinoma (mRCC), according to the results from the IMmotion150 trial presented at the 2017 Annual ASCO Meeting.

OncLive: Can you provide an overview of the IMmotion150 trial?

In an interview with OncLive, lead investigator Michael B. Atkins, MD, deputy director, Georgetown-Lombardi Comprehensive Cancer Center, professor of oncology and medicine, Georgetown University School of Medicine, discussed the latest IMmotion150 findings and additional developments with immunotherapy in mRCC.Atkins: For kidney cancer, we know that VEGF inhibitors are a predominant treatment approach, but we’ve also seen activity with checkpoint inhibitors. There is some data to suggest that VEGF in the tumor microenvironment may inhibit the immune system, creating an interest in potentially combining checkpoint inhibitors with VEGF inhibitors to determine whether that might enhance the effect of immunotherapy.

There have been many trials that have launched to attempt to explore that hypothesis. IMmotion150 was the first of those trials to be randomized and to report data. IMmotion150 is a hypothesis-generating, phase II trial that took patients with treatment-naïve, metastatic kidney cancer and randomized them to either atezolizumab alone, atezolizumab plus bevacizumab, or sunitinib.

The initial results of this trial were presented at the 2017 ASCO Genitourinary Cancers Symposium, which showed that…there was [approximately] a doubling of progression-free survival (PFS) and response rate for the atezolizumab plus bevacizumab group compared to sunitinib [among PD-L1—positive patients].

At [the] AACR [Annual Meeting], there was data presented by Dr David McDermott that looked at tumor microenvironment factors and how that might have predicted the response for the 3 arms. There was gene expression profiling that divided tumors into whether they were angiogenesis high or angiogenesis low, or myeloid expression high versus low. He reported the relationship of those various factors to the efficacy outcome in the frontline setting.

One of the most interesting results from that analysis was in the tumors that were myeloid low. There seemed to be the best efficacy with atezolizumab alone or atezolizumab plus bevacizumab compared to sunitinib. While in the T effector myeloid high subset, atezolizumab monotherapy did very poorly but appeared to be rescued by the addition of bevacizumab. This suggests a mechanism by which bevacizumab might be enhancing the immune responsiveness of atezolizumab by inhibiting myeloid derived immune-suppressive cells in the tumor microenvironment.

At ASCO 2017, I presented a follow-up to that study, which was a crossover component that took the monotherapy arms, sunitinib or atezolizumab alone, and crossed them over to receive the combination of atezolizumab plus bevacizumab.

We saw that the atezolizumab plus bevacizumab combination was active in both the atezolizumab and sunitinib refractory population with response rates in the 24% to 28% range. There also appeared to be higher responses in these patients to their crossover therapy then to what these patients achieved with their frontline monotherapies. There was also a prolongation of PFS in the second-line treatment compared to [what] these patients achieved in their frontline treatment.

We then looked at those gene expression signatures to determine whether or not the myeloid high patients on the atezolizumab alone arm who failed to respond could be rescued by the atezolizumab/bevacizumab combination in the second-line setting. Although we were only looking at 9 patients, the data supported the hypothesis that the PFS and responses were greater in that group of patients who were T effector and myeloid high, supporting the initial frontline diagnosis.

Any update on IMmotion151?

If this combination is eventually approved, what do you think would be the overall impact on clinical practice?

All of this is hypothesis-generating information that will be potentially validated with the ongoing phase III IMmotion151 trial comparing the atezolizumab/bevacizumab [combination] to sunitinib [in the frontline setting].The phase III trial completed accrual in October 2016 and will report out sooner or later. There are now several phase III trials ongoing, all with sunitinib as a control arm. These are looking at either a combination immunotherapy of nivolumab (Opdivo) and ipilimumab (Yervoy) compared to sunitinib or are looking at a VEGF inhibitor with a PD-L1 inhibitor. There are also VEGF receptor TKI inhibitors that are being combined with anti—PD-1 agents that are being studied in the phase III setting.

We’re going to have to see the results of those trials, which will all come out by 2020. They are never going to be compared directly to each other, so we’re going to look at those trials compared to the sunitinib control arm to determine which treatments produce the best outcomes for which patients.

Was this combination well tolerated?

What are the challenges in terms of sequencing with combination agents?

I still think that there may be a role for many patients for immunotherapy alone, rather than immunotherapy with VEGF. For those patients who may have a T effector high myeloid suppression low signature, there may be a role for combination immunotherapies, such as atezolizumab and bevacizumab, that have other immune-suppressive elements in the tumor microenvironment myeloid cells. There may be other combinations with anti—PD-1 besides bevacizumab that may do that as well without exhausting the VEGF inhibition pathway. There were no unusual toxicities other than what would be expected for the single agents. The toxicity was similar in the crossover population to what we saw with this combination in the frontline setting. I think a big issue will be whether you should give your first-line and second-line therapies together versus giving them in sequence. That is particularly a question for the VEGF receptor TKIs combined with the anti—PD-1. Those combinations must not only be better for PFS, but also better than the PFS of the 2 approaches given in sequence. We have to see more complete responses where we can stop the therapy and have the benefit maintained in order for them to be wholeheartedly adopted.

I think the other issue that is going to come up is that the immune therapies are all now being tested in the adjuvant setting in kidney cancer. There are 4 or 5 trials that are investigating that and will likely be reporting out in 2025, further upsetting where we place the different therapies.

Atkins MB, McDermott DF, Powles T, et al. IMmotion150: A phase II trial in untreated metastatic renal cell carcinoma (mRCC) patients (pts) of atezolizumab (atezo) and bevacizumab (bev) vs and following atezo or sunitinib (sun). J Clin Oncol. 35, 2017 (suppl; abstr 4505).