A step towards predicting checkpoint inhibitor response in kidney cancer
Authors: Manuel Caitano Maia, Eddy S Yang, Neeraj Agarwal, Sumanta K Pal
Journal: The Lancet Oncology (2017)

In this issue of The Lancet Oncology, Samra Turaljic and colleagues report a heroic undertaking, using whole-exome sequencing data from 5777 patients representing 19 solid tumour types.1Turajlic S Litchfield K Xu H et al.Insertion-and-deletion-derived tumour-specific neoantigens and the immunogenic phenotype: a pan-cancer analysis.Lancet Oncol. 2017; 18: 1009-1021Google Scholar In their series, the presence of frameshift indels across this large pan-cancer cohort was associated with more tumour-specific neoantigens compared with non-synonymous single nucleotide variant (nsSNV) mutations. In renal cell carcinoma, frameshift indels were more prevalent compared with in other tumour types and were associated with enhanced antigen-presenting machinery and T-cell activation. Their analysis helps to resolve a rather perplexing translational conundrum—specifically, that patients with renal cell carcinoma, a disease with a modest mutational load, show responses to checkpoint inhibitors on par with other diseases with considerably higher mutational loads.2Choueiri TK Motzer RJ Systemic therapy for metastatic renal-cell carcinoma.N Engl J Med. 2017; 376: 354-366Google Scholar In non-small-cell lung cancer, melanoma, and other high-mutational burden cancers, emerging evidence supports a link between mutational load and clinical outcome.3Rizvi NA Hellmann MD Snyder A et al.Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer.Science. 2015; 348: 124-128Google Scholar, 4Snyder A Makarov V Merghoub T et al.Genetic basis for clinical response to CTLA-4 blockade in melanoma.N Engl J Med. 2014; 371: 2189-2199Google Scholar By contrast, results from studies linking mutational load to outcome in renal cell carcinoma are mixed at best.5Voss MH Hellmann MD Chen Y et al.Mutation burden and tumor neoantigens in RCC patients (pts) treated with nivolumab.J Clin Oncol. 2016; 34: 514Google Scholar, 6Ball MW Johnson MH Gorin MA et al.Clinical, pathologic, and genomic profiles of exceptional responders to anti–PD1 therapy in renal cell carcinoma.J Clin Oncol. 2016; 34: 625Google Scholar, 7de Velasco G Miao D Shukla S et al.Integrated genomic correlates of response to PD-1 inhibitor nivolumab in metastatic renal cell carcinoma (mRCC).J Clin Oncol. 2016; 34: 545Google Scholar The need to identify a predictor of checkpoint inhibitor response in metastatic renal cell carcinoma has never been greater. PD-1 inhibitor nivolumab has been approved for patients with renal cell carcinoma with previous VEGF-directed therapy, but it is hardly the only choice in this setting.2Choueiri TK Motzer RJ Systemic therapy for metastatic renal-cell carcinoma.N Engl J Med. 2017; 376: 354-366Google Scholar The multikinase inhibitors cabozantinib and lenvatinib (with lenvatinib in combination with everolimus) are also options in this patient population, and no consensus exists as to which regimen should be used. Efforts to develop predictive biomarkers have largely failed—eg, PD-L1 expression has shown a prognostic role, but did not predict outcome with nivolumab in the phase 3 comparison of this drug to everolimus in metastatic renal clear cell. While debates around second-line therapy are undoubtedly heated, even more therapeutic dilemmas exist in the first-line setting. Results of the CABOSUN trial,8Choueiri 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. 2017; 35: 591-597Google Scholar a randomised, phase 2 study comparing sunitinib and cabozantinib, have shown a significant improvement in progression-free survival in intermediate-risk and poor-risk patients with cabozantinib. Checkpoint inhibitors are also moving quickly towards the first-line setting—multiple trials are underway comparing sunitinib to a combination of VEGF-directed therapy and a checkpoint inhibitor. Additionally, two phase 3 studies (NCT02231749) are comparing sunitinib with dual immunotherapy regimens (nivolumab with ipilimumab and pembrolizumab with epacadostat). If multiple studies have positive results, the clinician will need to discern the appropriate patient for either targeted therapy alone (eg, cabozantinib), targeted therapy combined with a checkpoint inhibitor, or immunotherapeutic strategies alone. Despite the poor predictive value of PD-L1 in this setting, other biomarkers show early promise. Atkins and colleagues9Atkins 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).Proc Am Soc Clin Oncol. 2017; 35 (abstr).: 4505Google Scholar have reported a T-effector gene signature, generated in the context of a randomised, phase 2 study that compared sunitinib, bevacizumab and atezolizumab, and atezolizumab alone. Curiously, the T-effector signature predicted benefit with bevacizumab and atezolizumab versus sunitinib, but did not differentiate benefit from sunitinib and atezolizumab monotherapy. From the same study, an angiogenesis signature was derived—patients with higher expression of genes related to angiogenesis were noted to have greater benefit with sunitinib monotherapy. These results suggest a requisite step for Turaljic and colleagues, namely, to define the predictive value of frameshift indel load for checkpoint inhibitor response in metastatic renal cell carcinoma. Without question, they have shown that frameshift indels occur more frequently in the context of renal cell carcinoma, and that frameshift indels are associated with substantial neoantigen production with greater immunogenicity compared with nsSNV neoantigens. As the authors concede, however, they have yet to show a correlation between frameshift indels and checkpoint inhibitor response in metastatic renal cell carcinoma. They retrospectively predicate the link between frameshift indel load and checkpoint inhibitor response on four datasets, three including patients with melanoma and one including patients with non-small-cell lung cancer. These datasets are heterogeneous in response assessment and in the class of checkpoint inhibitor assessed (eg, CTLA-4 blockade vs PD-1 blockade). Moreover, none of these experiences include randomisation to a non-checkpoint inhibitor control, making it unclear whether frameshift indel load might merely be prognostic rather than predictive. Supporting this premise, in a previous series of 100 patients with non-small-cell lung cancer treated with a non-checkpoint inhibitor, the authors of this report1Turajlic S Litchfield K Xu H et al.Insertion-and-deletion-derived tumour-specific neoantigens and the immunogenic phenotype: a pan-cancer analysis.Lancet Oncol. 2017; 18: 1009-1021Google Scholar found a higher relapse-free survival in those patients with higher frameshift indel load. With a burgeoning array of clinical trials juxtaposing checkpoint inhibitor combinations against VEGF-directed therapies in metastatic renal cell carcinoma, there should be ample opportunity to discern the predictive value of frameshift indel load in metastatic renal cell carcinoma. Such confirmation is essential because certain frequent frameshift indels in renal cell carcinoma (eg, VHL, PBRM1, and KMD5C) might themselves play a role in predicting response to VEGF-directed therapy.10Hsieh JJ Chen D Wang PI et al.Genomic biomarkers of a randomized trial comparing first-line everolimus and sunitinib in patients with metastatic renal cell carcinoma.Eur Urol. 2017; 71: 405-414Google Scholar If validated in randomised trials that compare checkpoint inhibitor interventions with non-checkpoint inhibitor interventions, frameshift indel load could represent a predictive biomarker for immunotherapy benefit that has yet remained elusive in metastatic renal cell carcinoma. SKP reports personal fees from Pfizer, Novartis, Ipsen, Astellas, Bristol-Myers Squibb, Gentech, and Roche, outside of the submitted work. NA reports personal fees from Pfizer, Exelixis, Cerulean Pharma, Medivation/Astellas, Eisai, Merck, Novartis, EMD Serono, Clovis Oncology, and Genentech/Roche, outside of the submitted work. MSM and ESY declare no competing interests. Insertion-and-deletion-derived tumour-specific neoantigens and the immunogenic phenotype: a pan-cancer analysisRenal cell carcinomas have the highest pan-cancer proportion and number of indel mutations. Evidence suggests indels are a highly immunogenic mutational class, which can trigger an increased abundance of neoantigens and greater mutant-binding specificity. Full-Text PDF Open Access