Optimizing Combinations Next Challenge in mRCC

Bradley G. Somer, MD

As the treatment paradigm for metastatic renal cell carcinoma (mRCC) continues to evolve, combination therapy is likely to be an important part of the future, said Bradley G. Somer, MD.

For example, in the phase III CheckMate-214 trial, which served as the basis for the nivolumab/ipilimumab FDA approval, overall survival (OS) and response rates were significantly higher with the combination compared with the frontline standard sunitinib (Sutent) in patients with previously untreated RCC.¹

With both immunotherapy and TKIs available as single agents in this space, there have been studies exploring the 2 mechanisms of action in combination.

The combination of avelumab (Bavencio) and axitinib (Inlyta), for example, doubled ORR and significantly improved progression-free survival (PFS) in patients with treatment-naïve advanced RCC compared with sunitinib, regardless of PD-L1 expression, according to findings from the phase III JAVELIN Renal 101 trial.

In the PD-L1—positive population, the median PFS was 13.8 months (95% CI, 11.1-not evaluable) for patients who received avelumab/axitinib compared with 7.2 months (95% CI, 5.7-9.7) in those who were administered sunitinib, translating to a 39% reduction in the risk of disease progression or death (HR, 0.61; 95%, 0.475-0.790; P <.0001).²

Additionally, results of the phase III IMmotion151 trial demonstrated that the combination of atezolizumab (Tecentriq) and bevacizumab (Avastin) significantly improved the median PFS versus sunitinib in the intent-to-treat population (11.2 vs 8.4 months; HR, 0.83; 95% CI, 0.70-0.97).³ The benefit was also observed in the subgroup of patients with PD-L1—positive tumors (11.2 vs 7.7 months; HR, 0.74; 95% CI, 0.57-0.96, P = .02).

OncLive: What are some of the latest advances made in the treatment of mRCC?

In an interview during the 2018 OncLive^® State of the Science Summit™ on Genitourinary Cancers, Somer, an associate professor of hematology/oncology and head of strategic expansion/development at the University of Tennessee West Cancer Center, discussed the potential of these combination regimens for patients with mRCC.Somer: In 2005, when VEGF TKIs were approved by the FDA, they showed significant benefit; however, they only had a slight edge over immunotherapy. Since then, these agents have improved.

Is there ongoing work to combine these different therapies?

In the last few years, checkpoint inhibitors have joined the game. Since 2015, we now face the challenge of deciding how to move forward. Where do these agents fit in [the landscape] and how do they work together? Our goal is to develop the best biologically driven therapy to help patients live longer.Currently, these are distinct approaches, but we have recent data [that have been] reported in the New England Journal of Medicine with 2 checkpoint inhibitors—nivolumab and ipilimumab&mdash;in combination. This [combination] was highly active in the frontline setting for patients with intermediate- and poor-risk disease. [But] beyond that, where are we headed?

Which combinations are showing the greatest synergy?

What factors are currently used to determine treatment selection?

[In the future, we] will probably be combining VEGF TKIs with immunotherapy, or additional immunotherapy agents with checkpoint inhibitors. This is all based on the idea that these mechanisms of action in combination are better than each one on its own and we might get a deeper and much more significant response. [We want this to] translate into longer survival, but the long-term hope is that we will be able to cure these patients in the metastatic setting.Ipilimumab and nivolumab have shown promise, as I mentioned. [Data with the] combination of bevacizumab with atezolizumab, a PD-L1 inhibitor [in comparison with sunitinib, as demonstrated by the IMpower150 study,] have also been encouraging. At the 2018 ESMO Congress, we also saw data with avelumab and axitinib. We also know there is ongoing work with pembrolizumab (Keytruda). There will be positive combinations, but the question will be, “Which ones provide the most efficacy with the least side effects?” We also need a good biomarker predictive of response to these therapies.You want to look at clinical criteria, which includes the general health of the patient and their immune factors; these [factors can] guide you down a certain treatment path. Generally speaking, you want to look at the natural biology of the tumor, because the metastatic sites are important in RCC.

Are there concerns with lingering adverse events associated with these different treatments?

What is the biggest challenge when treating patients with immunotherapy and TKIs?

For example, a small number of pulmonary metastases with otherwise good risk factors would mean the patient is angiogenically driven. You might be able to use active surveillance for these patients. Patients with liver metastases, bone metastases, and brain metastases obviously have an aggressive disease, so you want to use the most aggressive treatment right away. As far as biomarkers, we still aren't sure if PD-L1 is effective or not, but there might be some other molecular factors that could come into play.There is. Nowadays, if you want to be an oncologist of any quality, you need to know the toxicity profile of immunotherapy. That is just standard practice now, because it's so prevalent. You need to be able to address these issues as quickly as possible.A lot of medical oncologists out in the community have struggled to handle this sudden explosion of treatment options. RCC is relatively uncommon, so for oncologists who don't treat patients with this cancer every day, it might be a little bit of a challenge. In the past, it was an issue, and it is becoming even greater of an issue now. People just need to stay updated on advances [made in the space] and should always be willing to go for a second opinion.

References

1. Motzer RJ, Tannir NM, McDermott DF, et al. Nivolumab plus ipilimumab versus sunitinib in advanced renal cell carcinoma. N Eng J Med. 2018;378(14):1277-1290. doi: 10.1056/NEJMoa1712126.
2. Motzer RJ, Penkov K, Hannen JBAG, et al. JAVELIN Renal 101: a randomized, phase III study of avelumab + axitinib vs sunitinib as first-line treatment of advanced renal cell carcinoma (aRCC). In: Proceedings from the 2018 ESMO Congress; October 19-23, 2018; Munich, Germany. Abstract LBA6_PR. doi: 10.1093/annonc/mdy424.036.
3. Rini BI, Huseni M, Atkins MB, et al. Molecular correlates differentiate response to atezolizumab + bevacizumab vs sunitinib: results from a phase III study (IMmotion151) in untreated metastatic renal cell carcinoma. In: Proceedings from the 2018 ESMO Congress; October 19-23, 2018; Munich, Germany. Abstract LBA31.