To best treat patients with clear cell renal cell carcinoma (ccRCC), incorporating precision biomarkers into the current nomogram is essential, according to James J. Hsieh, MD.

Currently, “We see 12 drugs approved and more to come, and I think we have entered what I call the ‘golden age’ of kidney cancer therapeutics,” said Hsieh, who gave a presentation during the 2016 International Kidney Cancer Symposium, adding that treatments for ccRCC have emerged over recent years. “The question now is, ‘how do we now learn to sequence or use combination therapy to benefit our patients?’”

The RECORD-3 study was a large (n = 471) randomized trial in which treatment-naïve patients received either everolimus (Afinitor) followed by sunitinib (Sutent) or sunitinib followed by everolimus as first-line treatment.

 Results showed that first-line progression free survival (PFS) was 10.7 months for sunitinib and 7.9 months for everolimus, affirming the primary role of sunitinib in the frontline setting.

To evaluate the relationship between somatic mutations and treatment response, researchers performed next-generation sequencing (NGS) on 41 genes for 220 patients with ccRCC.

 Of the genes sequenced, 6 were mutated in >10% of patients: 

. The mutation frequency of these genes in the RECORD-3 cohort was compared with the frequencies reported in The Cancer Genome Atlas (TCGA) and 2013 studies.

In the RECORD-3 and previously published cohorts,

 is mutated in 75% and 82% of patients, respectively. The 

 mutation frequency in the TCGA and earlier cohorts is lower (52% and 49%, respectively), but this difference is likely due to the technical difficulty associated with sequencing the GC-rich exon 1 of 

 is the most frequently mutated gene in all 4 cohorts, it is likely the primary genetic event associated with pathogenesis of ccRCC.

Importantly, the RECORD-3 cohort consists of metastatic precancerous metastatic disease, while other studies of mutation frequency consist primarily of stage I to IV disease, a difference that may drive the variability in mutation frequency between these studies. The comparatively high frequency of 

 mutation in the RECORD-3 study suggests a role for these genes in the metastatic progression of ccRCC.

Evaluation of the relationship between gene mutation status and PFS revealed that 3 genes—

—have distinct correlations with treatment selection. Patients with 

 mutations do equally well when treated with sunitinib or everolimus, whereas patients with 

 mutations do poorly on both therapies, especially everolimus. Patients with a 

 mutation fare better when treated with sunitinib.

To evaluate the relationship between mutation status and OS, researchers considered the mutation status of the patients treated with either sunitinib followed by everolimus or everolimus followed by sunitinib. In the sunitinib-everolimus arm, patients performed well irrespective of genotype, reflecting the finding for the overall RECORD-3 cohort.

However, in the everolimus-sunitinib arm, patients with 

 mutations (39.6; 95% CI, 34.0—not estimable) fared better than those with the wild-type allele (16.2; 95% CI, 10.7-26.9) or 

 mutations (9.8; 95% CI, 8.2-22.4). Patients with 

 mutations did exceptionally well (40.3; 95% CI, 5.1-not estimable).

Further analysis divided the cohort into groups: group 1, 

 wild-type/mutant (19% of cohort); group 2, 

Within the sunitinib-everolimus arm, there was not a significant difference in OS between groups. Within the everolimus-sunitinib arm, however, there is a significant difference in median OS between groups: OS was shortest in group 1 (9.8; 95% CI, 7.8—20.0), longest in group 2 (39.6; 95% CI, 31.7–not estimable), and intermediate in group 3 (18.1; 95% CI, 13.7–30.0). When comparing OS for different treatment sequences within each of the molecular groups, there was not a statistically significant difference. However, a trend suggested differences for everolimus-sunitinib versus sunitinib-everolimus in group 1 (HR, 1.5), group 2 (HR, 0.8), and group 3 (HR, 1.2). During the study, investigators uncovered that 

 mutations are also mutually exclusive. Patients with 

 mutations do better in both arms than patients with the wild-type allele.

The results of this study suggest that specific tumor genotype may represent distinct molecular subtypes of ccRCC with potentially predictive vales. Further, tumor genotype may inform treatment sequence to optimize survival outcome, laying the foundation for prospective studies to address the hypothesis generated by this work with independent data sets.

Motzer RJ, Barrios CH, Kim TM, et al. Phase II randomized trial comparing sequential first-line everolimus and second-line sunitinib versus first-line sunitinib and second-line everolimus in patients with metastatic renal cell carcinoma. 

Hsieh J, Chen D, Wang P, et al. Differential overall survival (OS) results in RECORD-3 study based on three distinct mRCC molecular subgroups classified by BAP1 and/or PBRM1 mutations. 

Sato Y, Yoshizato T, Shiraishi Y, Maekawa S, Okuno Y, et al. Integrated molecular analysis of clear-cell renal cell carcinoma. 

Hakimi AA, Ostrovnaya I, Reva B, Schultz N, Chen YB, et al. Adverse outcomes in clear cell renal cell carcinoma with mutations of 3p21 epigenetic regulators BAP1 and SETD2: a report by MSKCC and the KIRC TCGA research network. 

In an effort to address this question, Hsieh’s presentation focused on differential overall survival (OS) results of the RECORD-3 study based on 3 distinct mRCC molecular subgroups, classified by patients who harbored 

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To best treat patients with clear cell renal cell carcinoma, incorporating precision biomarkers into the current nomogram is essential.

RECORD-3 Molecular Analysis Characterizes Poor-Risk Patients With mRCC

Looking ahead to 2020, most participants on an expert panel projected that immunotherapy will be critical to optimizing outcomes in the adjuvant setting for patients with renal cell carcinoma (RCC).

The panel, which convened at the 2016 International Kidney Cancer Symposium after a 6-presentation session on the future of adjuvant therapy, was moderated by Michael Atkins, MD, deputy director and professor at the Georgetown University Lombardi Comprehensive Cancer Center.

Atkins presented the panelists with 5 options of what will become the optimal choice for adjuvant RCC care over the next 5 years: 1) VEGFR TKI followed by anti&shy;—PD-1-based therapy; 2) ipilimumab (Yervoy)/nivolumab (Opdivo) followed by VEGFR TKI and then followed by “other”; 3) VEGF + PD-1 inhibition followed by “other”; 4) Other; and 5) No idea.

Most panelists selected an option that included checkpoint inhibition upfront. Charles Drake, MD, PhD, codirector, Prostate Cancer Multidisciplinary Clinic, professor of Oncology, Johns Hopkins Medicine, commented that VEGF plus PD-1 inhibition followed by “other” may be an optimal choice because of the potential for combinatorial effects. He added that the VEGF/PD-1 treatment is less toxic than the ipilimumab/nivolumab combination and achieves comparable results, while also noting that, since all the data are not yet available, it is impossible to know which approach will be optimal.

David McDermott, MD, associate professor of Medicine at Harvard Medical School and director of the Biologic Therapy Program at Beth Israel Deaconess Medical Center, cited experience in melanoma with patients who have deep and durable responses to ipilimumab as a reason for selecting the ipilimumab/nivolumab regimen. Hans Hammers, MD, PhD, an assistant professor of Oncology at the Sidney Kimmel Comprehensive Cancer Center and Johns Hopkins Medicine, concurred with McDermott, citing positive results with the combination in RCC from the CheckMate-016 trial.

Guru Sonpavde, MD, associate professor of Medicine, director of Urologic Malignancies, UAB School of medicine, also selected dual checkpoint blockade, but warned against a “one-size-fits-all” approach. “I like the idea of ipilimumab plus nivolumab in patients with good performance status, but I think there will be a big subset of patients in the community that will not qualify for the combination. I really think there will be a two-tiered approach—maybe [going] with sequential single-agent therapy [in patients with a higher ECOG performance status].”

Neeraj Agarwal, MD, associate professor in the Division of Oncology, Department of Medicine, director of the Genitourinary Medical Oncology Program, Huntsman Cancer Institute at the University of Utah, opted for VEGF plus PD-1 inhibition, noting that there is no way to know if patients will have a durable response on the ipilimumab/nivolumab regimen, and treatment with VEGF + PD-1 inhibition provides patients with the opportunity to have an immediate and durable response.

Following the panel discussion, the floor was opened for questions from the audience. Expanding on earlier discussion, an audience member asked if, in the absence of toxicity and progression, patients have a deep response to a drug like ipilimumab or nivolumab, what the duration of therapy should be before consideration is given to taking patients off the drug.

In response, McDermott pointed out that there are not many data to guide practice. The phase I studies of nivolumab in RCC only had about 30 patients at the 2-year point when the drug was stopped. In contrast, the melanoma cohort at 2 years had closer to 100 patients. When these patients stopped at 2 years, some of them progressed, and only a subset was responsive to nivolumab when it was reintroduced.

Compared to melanoma studies, the kidney cancer response rate is lower, as is the number of patients who continue to respond off drug. For this reason, there will be a group of patients who come off therapy, progress, and are then unable to respond to salvage treatment.

Another audience member voiced disappointment that the panelists were not convinced that by 2020, physicians would be able to select appropriate treatment based on the patient profiles. Panelists countered that they do believe that they will be able to identify patients most likely to benefit from single-agent PD-1 therapy or VEGF TKIs. Even if combination therapies become first-line therapies, if there is a predictive marker, panelists indicated they would use single-agent PD-1.

“With better technologies and newer samples, I think we can come up with signatures for treatments,” commented McDermott.

Overall, panelists agreed upon the importance of investigating prognostic markers in order to prevent overtreatment or incorrect treatment of RCC and expressed enthusiasm for the forthcoming data on combination therapy selection and sequencing.

View more from the 2016 International Kidney Cancer Symposium

The final panelist, Tian Zhang, MD, a medical oncologist and a medical instructor at the Duke University School of Medicine, said that though she would like to select “other” for vaccine therapy, she thinks that the optimal treatment is likely patient specific: some patients will “certainly have longer responses on VEGF inhibitors, but it will really depend on the patients and their own criteria,” in deciding which treatment is best for them. On a population level, however, she selected the ipilimumab/nivolumab regimen for the duration in response.

Looking ahead to 2020, most participants on an expert panel projected that immunotherapy will be critical to optimizing outcomes in the adjuvant setting for patients with renal cell carcinoma.

RCC Experts Consider Immunotherapy Integral to Optimizing Adjuvant Care

Cabozantinib (Cabometyx) demonstrated consistent benefits compared with everolimus (Afinitor) for patients with advanced, pretreated renal cell carcinoma (RCC) in a subgroup analysis of the phase III METEOR trial that explored MET expression, according to a presentation by Thomas Powles, MD, MBBS, MRCP, at the 2016 International Kidney Cancer Symposium.

In April 2016, cabozantinib was approved by the FDA as a treatment for patients with advanced RCC following prior anti—angiogenic therapy. The TKI blocks multiple VEGF receptors, making it a potent angiogenesis inhibitor. Additionally, the agent uniquely inhibits RET and MET, raising the potential for MET expression to act as a predictive biomarker.

The median overall survival (OS) in those with high MET expression was 22.0 months with cabozantinib versus 15.2 months with everolimus (HR, 0.55; 95% CI, 0.31-0.99). In those with low MET expression, the median OS with cabozantinib was 20.8 versus 18.4 months with everolimus (HR, 0.72; 95% CI, 0.52-1.00).

These data showed a pattern toward greater benefit in patients with high MET expressing tumors; however, this trend was neither clinically meaningful nor statistically significant and was largely driven by small sample size and imbalances in the patient populations, said Powles, leader of the genitourinary cancer group at Barts Cancer Institute (BCI), London, United Kingdom

METEOR was a randomized phase III trial directly comparing the efficacy and safety of cabozantinib and everolimus in 658 patients with advanced RCC who progressed following VEGFR TKI treatment. Patients received daily cabozantinib at 60 mg (n = 330) or everolimus at 10 mg (n = 328). Approximately 30% of patients had received ≥2 prior VEGFR TKIs.

Across the full study by independent radiology review, median OS was 21.4 months (95% CI 18.7-not estimable) with cabozantinib compared with 16.5 months (95% CI, 14.7-18.8) with everolimus (HR, 0.66; 95% CI, 0.53-0.83; 

 = .00026). Median progression-free survival (PFS) was 7.4 months with cabozantinib compared with 3.9 months with everolimus (HR, 0.51; 95% CI, 0.41-0.62; 

 <.0001). Furthermore, cabozantinib achieved a better objective response rate (ORR) of 17% versus 3% with everolimus (

In a secondary analysis of the study, MET expression was quantitated from archival or recently biopsied tumor tissue samples by immunohistochemistry using the SP44 antibody, and classified as MET high or low using a cut off of ≥50% for tumor tissue cells stained with an intensity of ≥2+ by immunohistochemistry. Overall, 15% of patients were classified as MET high, 59% as MET low, and 26% as MET unknown.

“I think we know more about [staining] with PD-L1 than we do in this particular area, and it’s a really hard area which I think we need to work on a lot more,” said Powles. “My gut feeling is we’re not going to be doing this in 20 years time,” he added.

When presenting the baseline characteristics of patients by MET status, Powles pointed out that the number of patients with high MET status was relatively small (cabozantinib, n = 50; everolimus, n = 51). In the MET low group, 150 patients were treated with cabozantinib and 162 were treated with everolimus.

The median PFS in those with high MET expression was 7.4 months with cabozantinib versus 3.7 months with everolimus (HR, 0.38; 95% CI, 0.23-0.62). In those with low MET expression, the median PFS with cabozantinib was 7.3 versus 4.2 months with everolimus (HR, 0.57; 95% CI, 0.43-0.76). The median PFS in those with unknown MET status was 9.1 months with cabozantinib versus 3.7 months with everolimus (HR, 0.52; 95% CI, 0.37-0.72).

“PFS is probably the more accurate endpoint that we have in VEGF-targeted therapy,” stated Powles. Overall, cabozantinib was superior for OS, PFS, and ORR regardless of MET status.

Archival tumor MET expression status by immunohistochemistry does not appear to be a predictive biomarker for benefit with cabozantinib in patients with advanced RCC. Although, Powles added that immunohistochemistry may not be the way forward in terms of tissue analysis, rather, molecular profiling of samples will be more informative.

Choueiri TK, Escudier B, Powles T, et al. Cabozantinib versus everolimus in advanced renal cell carcinoma (METEOR): final results from a randomised, open-label, phase 3 trial. 

Cabozantinib demonstrated consistent benefits compared with everolimus for patients with advanced, pretreated renal cell carcinoma in a subgroup analysis of the phase III METEOR trial that explored MET expression.

Cabozantinib Benefits Similar in MET Expressing Advanced RCC

Conflicting results from large adjuvant studies for renal cell carcinoma (RCC) may have been caused by differences between the clinical trial designs, patient populations, and assessment criteria, according to Naomi B. Haas, MD, who discussed the data from these trials at the 2016 International Kidney Cancer Symposium.

In order to fully understand the viability of adjuvant therapy, the nuances that likely impacted the outcomes of each trial need to be fully explored, including differing risk groups, populations, dose ranges, starting dose, duration, endpoints, and statistical definitions of activity, noted Haas, director of the Prostate and Kidney Cancer Program at the Hospital of the University of Pennsylvania.

To date, 3 trials have published results: ARISER, ASSURE, and S-TRAC. Additionally, there are currently several ongoing adjuvant small-molecule inhibitor trials ongoing (SORCE, EVEREST, PROTECT, ATLAS, and E2810), most of which are nearly completely accrued, ensuring the release of a great deal of information within the next year or two.

The ASSURE trial enrolled 1,943 patients with both clear cell RCC (ccRCC) and non-ccRCC, though the study was powered for ccRCC. Patients received either 50 mg/day of sunitinib, 400 mg twice daily of sorafenib, or placebo for 1 year. Following the accrual of 1,300 patients, however, investigators noticed a high drop-out rate from intolerance and side effects, and responded by amending the trial to start patients at a lower dose of sunitinib to 37.5 mg/day.

Overall, the study showed no difference in disease free survival (DFS), which was the primary endpoint, or overall survival (OS) between sorafenib or sunitinib and placebo. The hazard ratio for both treatments was near 1.0 across all populations enrolled.

The S-TRAC study was a 1-year trial that enrolled only patients with high-risk ccRCC. Patients were stratified by the UCLA international staging criteria, and only patients with pT3 disease or higher were enrolled. Patients received 50 mg/day of sunitinib, with the option to reduce the dose to 37.5 mg/day if needed.

For this study, the primary endpoint was DFS by blinded independent central review, and sunitinib had a statistically significant advantage over placebo. Remarkably, the curves for sunitinib and placebo stay well separated both 3 and 5 years out.

The third completed clinical trial, ARISER,

 was a 6-month study of carbonic anhydrase antibody girentuximab versus placebo. Patients were divided into three high-risk groups: pT3/pT4Nx/N0M0, pTanyN+M0, or pT1b/pT2Nx/N0M0. The investigators evaluated carbonic anhydrase membrane staining; however, concerns surrounding validation prohibited the use of membrane staining as an endpoint. Instead, the staining was used only for staging.

Overall, patients treated with girentuximab had no statistically significant DFS compared with placebo. However, patients with low carbonic anhydrase-IX (CAIX) scores (0-100) were more likely to recur and die than those with high CAIX scores (201-300).

These contrasting results, specifically for the studies exploring VEGF-directed therapies, raised several questions regarding adjuvant therapy, with answers that may be found within the trials themselves. “We might look at different parts of the trials and how we might learn something,” proposed Haas.

Patient populations in these studies were selected based on histopathology and risk nomograms. While the ASSURE study included both ccRCC and non-ccRCC, and patients with lower stages of disease, in the S-TRAC study patients all had ccRCC and ST-3 disease or higher.

There were differences between the 2 trials in terms of what measures are used as risk nomograms. Further, American Joint Committee on Cancer (AJCC) criteria for staging has been refined and imaging technology has improved since some of the recurrence data was collected, raising the possibility that micrometastatic disease may not have been detected in earlier studies. In spite of these advances, it remains difficult to assess risk of recurrence in patients with pT2 and pT3 disease, where risk of recurrence could be 20% to 60%. Also confounding a direct comparison was the fact that the S-TRAC trial used central radiology review while the ASSURE trial did not.

One weakness of DFS as a sole endpoint is that the frequency of scanning is not uniform among studies. Though more frequent scanning may lead to the end of the study more quickly, it may limit the ability to compare DFS between studies. For adjuvant therapy, cure is a laudable goal, and future studies should be powered for OS, a step that requires regulatory support.

For patients with early stage disease, the side effects of VEGF-TKIs are significant, and patients may not need to be exposed. As a result of this, host factors and toxicity should also be considered when examining the studies. Overall, 66% of patients in the ASSURE trial had grade 3 toxicity or higher, and 60% of patients in S-TRAC had grade 3 toxicity or higher.

“Because TKIs have a lot of side effects, we really have to understand our populations well to be able to convince patients of why they should do these trials,” added Haas. One very important “lesson learned” from these trials, she noted, was that redefining who is treated could prevent unnecessary exposure to toxicity for patients less likely to relapse.

An ASSURE clinical trial sequencing project will explore samples from 700 patients from each arm of the trial. The study will attempt to retrospectively validate a 16-gene Oncotype DX recurrence scores for predicting recurrence. The outcomes of this study will permit dovetailing of molecular profiles with established staging practices and other risk nomograms to identify higher-risk patients.

Haas NB, Manola J, Uzzo RG, et al. Adjuvant sunitinib or sorafenib for high-risk, non-metastatic renal-cell carcinoma (ECOG-ACRIN E2805): a double-blind, placebo-controlled, randomised, phase 3 trial. 

Ravaud A, Motzer RJ, Pandha HS, et al. Adjuvant Sunitinib in High-Risk Renal-Cell Carcinoma after Nephrectomy. 

Chamie K, Donin NM, Klopfer P, et al. Adjuvant Weekly Girentuximab Following Nephrectomy for High-Risk Renal Cell Carcinoma: The ARISER Randomized Clinical Trial. 

“Retrospective validation of potentially poor risk markers is something that we can do, that is something that will be done with both of these trials,” noted Haas.

Conflicting results from large adjuvant studies for renal cell carcinoma may have been caused by differences between the clinical trial designs, patient populations, and assessment criteria.

Ginny Vachon, PhD

Articles

RECORD-3 Molecular Analysis Characterizes Poor-Risk Patients With mRCC

RCC Experts Consider Immunotherapy Integral to Optimizing Adjuvant Care

Cabozantinib Benefits Similar in MET Expressing Advanced RCC

Expert Examines Conflicting Adjuvant RCC Results