What’s Next for Advanced Kidney Cancer? A Look Beyond 2019

In February, we all waited with bated breath for the results of KEYNOTE-426 and updated results of JAVELIN-101, examining axitinib/pembrolizumab and axitinib/avelumab, respectively.1,2 In the coming months, we will juxtapose these datasets, and compare and contrast with what we know about nivolumab/ipilimumab from CheckMate-214 and cabozantinib from CABOSUN.3,4 These four trials have collectively changed the landscape of what used to be a simple algorithm for metastatic renal cell carcinoma (mRCC). However, the fact remains that for a proportion of patients (perhaps approximately 20%), these treatments will not result in a response or disease stabilization. Furthermore, in the majority of patients, progression is inevitable. For this reason, we need to keep raising the bar.

There are several strategies we might undertake to improve outcomes for patients with mRCC. The first, and perhaps most obvious, is to develop new drugs. I am particularly excited about glutaminase inhibitors such as telaglenastat.5 In updated data presented at ASCO GU 2019 suggested disease control rates of 100% and response rates of 50% in combination with cabozantinib. Although it is challenging to tease out the impact of cabozantinib in this setting (which alone has substantial activity), the results are nonetheless impressive. NKTR-214 is yet another agent that I am eager to see move forward in mRCC – this pegylated IL-2 works by the same principle as the first generation cytokine, but hopefully with a lesser degree of toxicity.6 The PIVOT-09 study will compare the combination of NKTR-214 with nivolumab to either sunitinib or cabozantinib. Several sites are opening already. 

The second approach to improving outcomes may sound somewhat cliché – developing biomarkers. We have talked about this for a long time, but now we are finally making progress. Trials of bevacizumab/atezolizumab have been particularly helpful in mapping out relevant molecular profiles that can predict selective benefit from angiogenesis inhibitors or checkpoint inhibitors.7 I am of the mindset that there are likely patients who benefit from either class of drugs, with a modest intersect between these populations reflecting patients who truly benefit from the combination. 

The third approach that I’ll highlight here is one that I’m particularly interested in – optimizing the activity of existing therapies using simple, non-pharmacologic interventions. Our group was the first to explore the role of the microbiome in kidney cancer, demonstrating an association between stool bacteriomic profile and the presence or absence of diarrhea with VEGF-TKIs.8 The group from Gustave Roussy, led by Laurence Zitvogel, has since shown that the activity of checkpoint inhibitors similarly is associated with the stool microbial profile.9 My fellow Paulo Bergerot, MD (@paulobergerot) has designed a prospective study looking nivolumab/ipilimumab with or without CBM-588, a probiotic that fortifies the gut with butyric acid producing bacteria. The microenvironment generated therein should increase levels of Bifidobacterium spp and other microbiota that could foster an immune response. While the study at this time carries only biologic endpoints, it could foreseeably one day represent a simple intervention to enhance the activity of a commercially available therapy! 

Written by: Sumanta Kumar Pal, MD,  Associate Clinical Professor, Department of Medical Oncology & Therapeutics Research, Co-director, Kidney Cancer Program, City of Hope's Kidney Cancer Program

References:
1. Rini BI, Plimack ER, Stus V, et al: Pembrolizumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma. N Engl J Med, 2019
2. Motzer RJ, Penkov K, Haanen J, et al: Avelumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma. N Engl J Med, 2019
3. Choueiri TK, Halabi S, Sanford BL, et al: Cabozantinib Versus Sunitinib As Initial Targeted Therapy for Patients With Metastatic Renal Cell Carcinoma of Poor or Intermediate Risk: The Alliance A031203 CABOSUN Trial. J Clin Oncol 35:591-597, 2017
4. Motzer RJ, Tannir NM, McDermott DF, et al: Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma. N Engl J Med 378:1277-1290, 2018
5. Hoerner CR, Chen VJ, Fan AC: The 'Achilles Heel' of Metabolism in Renal Cell Carcinoma: Glutaminase Inhibition as a Rational Treatment Strategy. Kidney Cancer 3:15-29, 2019
6. Diab A, Hurwitz ME, Cho DC, et al: NKTR-214 (CD122-biased agonist) plus nivolumab in patients with advanced solid tumors: Preliminary phase 1/2 results of PIVOT. J Clin Oncol 36, 2018 
7. McDermott DF, Huseni MA, Atkins MB, et al: Clinical activity and molecular correlates of response to atezolizumab alone or in combination with bevacizumab versus sunitinib in renal cell carcinoma. Nat Med 24:749-757, 2018
8. Pal SK, Li SM, Wu X, et al: Stool Bacteriomic Profiling in Patients with Metastatic Renal Cell Carcinoma Receiving Vascular Endothelial Growth Factor-Tyrosine Kinase Inhibitors. Clin Cancer Res 21:5286-93, 2015
9. Routy B, Le Chatelier E, Derosa L, et al: Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science 359:91-97, 2018
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