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Combination Therapies Dominate the Agenda of the Worldwide Meeting

The world of oncology once again convened in Chicago for our annual gathering aimed at conquering cancer and celebrating new developments, which are coming ever faster and more furious. Although once considered almost taboo in RCC, many of the most intriguing presentations and abstracts from the American Society of Clinical Oncology’s (ASCO) annual meeting focused on various combination therapies in RCC, especially combinations invol- ving immunotherapies.

Highlights From Combination Studies
Epacadostat and pembrolizumab. The preliminary results of the phase I/II ECHO-202/KEYNOTE-037 study that paired epacadostat with pembrolizumab were quite promising. The phase I portion of the study did not identity a maximum tolerated dose as the combination was relatively well tolerated at all dose levels. The expansion cohort  analyzed 19 patients who had received no prior treatment or one prior treatment; in this population, the overall response rate (ORR) and disease control rate (ORR + stable disease) were 47% and 58%, respectively. There were no responses in patients who had received two or more prior therapies, but a stable disease rate of 36% was achieved. 15% of patients experienced grade 3 or higher adverse events, and 2 subjected discontinued treatment due to toxicity.1

Avelumab and Axitinib. Another combination study that garnered a lot of attention at the meeting was a phase 1b trial that paired avelumab + axitinib for the first-line treatment of advanced RCC.  55 treatment-naïve patients with advanced RCC were treated with the combination. ORR was impressive at 54.5%, including 2 complete responses, toxicity was a concern, but seemed managable for most patients with 52 patients reporting axitinib-related adverse events (including frequent fatigue, diarrhea, hypertension, and dysphonia) and 51 of subjects reporting avelumab-related toxicities (including most frequently, diarrhea and fatigue). Four patients discontinued axitinib and five patients discontinued avelumab due to toxicities. The results certainly warrant further study of this combination.2

Cabozantinib and nivolumab. One of the most interesting combinations reported came from an small, early trial that evaluated the safety and clinical activity of the combination of cabozantinib and nivolumab as well as the triple combination of cabozantinib, nivolu-mab, and ipilumumab in patients with patients with a variety of genitourinary cancer patients, including two patients with conventional RCC and two patients with sarcomatoid dedifferentiation. Both combinations were surprisingly relatively well tolerated with no dose limiting toxicities noted. One of the patients with sarcomatoid dedifferentiation was noted to have a partial response, and responses were also seen in patients with other rare genitourinary malignancies including squamous cell carcinoma of the bladder, urachal, and penile cancers. Larger cohorts of testing the combination in bladder cancers and rare genitourinary tumors are ongoing.3

Atezolizumab and bevacizumab. The IMmotion150 study, another interesting phase II combination trial paired the checkpoint inhibitor atezolizumab with bevacizumab in the first-line setting in patients with previously untreated metastatic RCC and compared this to too other arms, one using only single agent atezolizumab and the other single agent sunitinib. Both comparator arms had the option of crossing over to the combination therapy at progression. In the 54% of PD-L1–positive patients, the median PFS was 14.7 months with the combination, 5.5 months with atezolizumab alone, and 7.8 months in sunitinib alone arm. 60% of patients receiving atezolizumab alone went on to receive the combination and demonstrated a 24% response rate, while 78% of patients receiving sunitinib subsequently crossed over to the combination and achieved an overall response rates of 28%. These outcomes suggest encouraging activity for the combination of atezolizumab + bevacizumab in both the first- and second-line setting for patients with metastatic RCC.4

Multikinase inhibitor and everolimus. CM082A small phase I study tested the combination of CM082, a novel oral multikinase inhibitor targeting VEGFR, PDGFR and CSF1R with a shorter half-life and limited tissue accumulation, designed to lower toxicity and enable combination  with other therapies, everolimus in patients with metastatic renal cell carcinoma. At 200mg dose level, partial responses were noted in 5/14 (36%) patients, with a disease control rate of 71%. The median PFS was noted to be 5.7 months in this cohort. Toxicities were manageable, as well, warranting further investigation of this novel agent and combination.5

Pazopanib and pembrolizumab. Chowdhury et al reported the results of a small phase I/II study evaluating the combination of pazopanib and pembrolizumab. Overall, 35 patients were tested with combinations of pemborlizumab 2mg/kg and pazopanib at 600mg or 800mg; one cohort was treated with a sequential strategy of single-agent pazopanib followed by the combination. The study found that 80-90% of the patients in each cohort experienced grade 3 or 4 toxicities, especially hepatotoxicity, severely limiting the utility of this novel combination.6

Synergistic Effects With Radiation, Check Point Inhibitors
In addition to combinations of systemic therapies, preclinical data suggests that there are synergistic effects between radiation therapy and check point inhibitors. Lin and colleagues sought to explore the immunomodulatory activity of radiation therapy alone or in combination with pembrolizumab in solid tumors, including renal cell cancer. Twelve RCC patients who had progressed after first-line therapy received radiation therapy (8Gy x 1 or 4Gy x 5) followed by pembrolizumab or 1 dose pembrolizumab followed by radiation therapy then were given another dose of pemproliumab. Pre- and post- radiation tumor biopsies were obtained to evaluate PD-L1 expression and flow cytometry was performed before, during, and after treatment to assess immune markers.  Grade 3 adverse effects experienced included fatigue, nausea, hyperglycemia, lymphopenia, thrombocytopenia and AST elevation (post RT for liver mets).  Five patients had stable disease of 18 to 45 weeks and 4 patients had progression within 9 weeks. Preliminary flow cytometry findings showed consistently higher numbers of monocytes in non-responders compared to responders. CD4+, CD8+ and NK cells and other markers are also being analyzed. Overall, these results suggest that the combination of radiation therapy with pembrolizumab is tolerable while exhibiting clinical worth. Additionally, the adverse effect profile was not dramatically different when compared to single agent pembrolizumab.7

Encouraging Progress on Biomarkers
Finding clinically useful biomarkers in RCC has been a thorn in the side of researchers for decades now, still with no suitable candidates finding their way into standard daily practice. But a few studies presented do try to make some headway in this area. A study presented by Escuider sought to validate the 16-gene Recurrence Score in 212 patients with high-risk stage III disease from S-TRAC trial. Primary tissue from these patients was analyzed and it was found that time to recurrence and disease-free survival in patients receiving sunitinib or placebo were significantly predicted using the Recurrence Score. No significant interaction was reported between treatment and the Recurrence Score. The results further support the value of the Recurrence Score, which can be used to identify high-risk patients who may benefit from adjuvant treatment. Further studies to determine the predictive value of the score are necessary before it can be clinically used to select patients for adjuvant therapies.8

In the pursuit of reliable biomarkers in metastatic RCC patients, Arafat and colleagues reported on the development and clinical validation of predictive circulating tumor cell (CTC) biomarkers that will be assessed in the OMNIVORE trial. Findings show that CTC frequency and PDL1/HLA expression are lower in nivolumab responders versus patients with early progression. High but variable HLA expression suggests resistance mechanisms are variable. CTCs were found in 26 out of 27 patients using the RCC-specific CA IX antibody. Staining with CAXII and PAX8 confirmed CTC were of renal origin. The findings report the identification of  clear cell RCC circulating tumor cells using CAIX, CAXII and PAX8 as confirmatory markers. The authors plan to further study the usefulness of these biomarkers in the phase II OMNIVORE trial, which examines ipilumimab efficacy in patients with stable or progressive disease on nivolumab alone.9

Adjuvant Therapy: New Results From PROTECT
Of course, an effective adjuvant therapy for RCC has been an elusive holy grail sought after almost as much as a reliable biomarker. Results of a randomized phase III trial of adjuvant pazopanib versus placebo after nephrectomy, called the PROTECT study, were presented. This large study included 1538 subjects with locally advanced RCC post-nephrectomy who were randomized to receive pazopanib vs placebo for 1 year following surgery. The dose of pazopanib had to be decreased from 800 mg to 600 mg to improve tolerability, and the primary endpoint of the study was changed to disease-free survival in 1135 patients. In the intent-to-treat population with the 800-mg dose a 31%  reduced risk of recurrence was reported and in the much larger group of patients treated with 600mg a 20% reduction in risk of recurrence was noted; however, the primary endpoint was not met with pazopanib 600 mg. Treatment was discontinued frequently due to tran-saminitis.10

In the single arm phase II NeoSun trial, researchers sought to identify efficacy and safety of neoadjuvant and adjuvant sutinib in treatment naive metastatic RCC patients. 14 patients received neoadjuvant sunitinib at 50mg daily with 10 out of the 14 taking the total planned 12 doses. All 14 underwent total cytoreductive nephrectomy, and 13 received adjuvant sunitinib on a repeating 6 week cycle consisting of 4 week-on and 2 week-off, until disease progression. 58.3% of patients achieved confirmed response while 91.7% achieved clinical benefit. Median overall survival was 33.7 months and median progression free survival was 15.7 months. Among the patients who received partial or complete response, the median response time was 8.7 months. It is important to note that there were no unexpected surgical or sunitinib-related toxicities experienced showing sunitinib is safe when given in the neoadjuvant and adjuvant setting.11

Shepherd and colleagues provided an interesting look at how dynamic changes in clinical labs might help predict survival outcomes in patients receiving VEGF-targeted therapy for advanced clear cell RCC. Multiple models show that markers of systemic inflammatory response have prognostic value in ccRCC prior to starting treatment, but little is known about how dynamic changes in these markers occurring during therapy might be used to predict outcomes. These investigators conducted a retrospective analysis of data form a phase II study evaluating cediranib vs cediranib and saracatinib in patients with relapsed metastatic clear cell RCC. Specifically, they analyzed how haemoglobin, neutrophil count, platelet count, lactate dehydrogenase levels, and C-reactive protein were recorded at randomization, at 8-weeks into the study and at progression for 138 patients. Changes at each time point were compared. This analysis found that a rise in and C-reactive protein or neutrophil count at 8 weeks was predictive of poor outcome, while a fall in hemoglobin was predictive of poor outcomes and progressive disease. Certainly, additional investigation in this area is warranted.12

METEOR Offers Insights on Cabozantinib,
Regardless of Nephrectomy
The debate regarding the usefulness of cytoreductive nephrectomy in the era of targeted therapies continues. Tannir, et al sought to provide more data to drive the discussion, by analyzing data from the phase 3 METEOR trial. This widely known trial compared cabozantinib to everolimus in 658 patients with advanced clear cell RCC who had previously received at least one VEGFR TKI. 85% of patients enrolled had a prior nephrectomy (7% partial). Tannir’s analysis showed that baseline characteristics were less favorable for those 15% of subjects who had no prior nephrectomy. The analysis showed that cabozanitinib improved progression-free survival, overall survival, OS, and objective response rate when compared with everolimus regardless of nephrectomy status. The median overall survival was longer in the nephrectomy subgroup for both treatment arms (22.0 in those treated with cabozatinib who had a prior nephrectomy, 17.2 months in the everolimus prior nephrectomy group, 16.3 months in those treated with cabozantinib who had no nephretomy, and 12.5 months in patients treated with evero-limus and no prior nephrectomy), but these outcomes may be more related to the differences in baseline characteristics than effects of nephrecotmy status.13

There is limited data about outcomes and predictors of patients with long-term response to targeted therapy, but Tannir and colleagues attempted to fill in some of this gap, but analyzing data from the COMPARZ study. They sought to identify patients from COMPARZ who exhibited a long-term response (10 months of greater) to pazopanib and sunitinib and to determine time to response while describing the clinical characteristics of patients who achieved such response. They found that among the 1,110 patients treated on the study, 14% had long-term responses to pazopanib and 13% had long-term responses to sunitinib. PFS was similar in both groups, however, in those treated with pazopanib, there was noted to be a shorter time to achieve a response (11.9 weeks [95% CI, 11.3–12.1] in the pazaopnib group compared to 17.4 weeks; [95% CI, 12.7–18.0]) in the sunitinib group, suggesting that this may be a more appropriate therapy for patients who require a more rapid response.14

While prospective clinical trial data is still the gold standard but which data in the field is judged, there is a more and more understanding as eligibility criteria for trials continues to tighten that outcomes data for real world populations (especially those not eligible for enrollment in prospective clinical trials) is sorely needed. Steven Yip and colleagues retrospectively reviewed real-world outcomes in metastatic RCC patients treated with immunotherapy using data from the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC). They identified 312 patients and found an ORR of 29% in all patients, which was consistent regardless of the line of therapy. They divided those patients treated with immunotherapy in the second-line setting into favorable, intermediate, and poor risk categories using the IMDC criteria and found that while the duration of treatment rate was not reached for those in the favorable risk category, patients in the intermediate risk category had a risk 8.6 months and those in the poor risk category remained on treatment only 1.9 months. Age did not appear to affect outcomes with the therapies.15

Drilling Down Into Data on Rare Kidney Cancers
Uncommon forms of RCC and rare diseases associated with the development of kidney tumors were also discussed at the meeting. Eric Jonasch of MD Anderson Cancer Center, who runs one of the world’s only von Hippel- Lindau clinics that focuses on a multidisciplinary approach to treating the kidney tumors and other manifestations of the disease, presented the results of a phase II study of pazopanib in patients with von Hippel-Lindau disease (VHL). This study—the largest prospective VHL-specific study to dates—included 32 patients with confirmed VHL and evaluated the ability of pazopanib to shrink lesions associated with the disease. Of the 31 evaluable patients in the study,18 exhibited stable disease, while 13 had confirmed responses. None had progressive disease. Dose reductions were required in 12 patients and 8 patients had adverse events requiring discontinuation of the treatment (4 due to transaminitis). These results suggest that pazopanib may be an alternative to surgical intervention in some VHL cases.16

References
1. Lara P, Bauer TM, Hamid O, et al. Epacadostat plus pembrolizumab in patients with advanced RCC: Preliminary phase I/II results from ECHO-202/KEYNOTE-037. J Clin Oncol. 35, 2017 (suppl; abstr 4515)
2. Choueiri TK, Larkin JMG, Oya M, et al. First-line avelumab + axitinib therapy in patients (pts) with advanced renal cell carcinoma (aRCC): Results from a phase Ib trial. J Clin Oncol. 35, 2017 (suppl; abstr 4504).
3. Apolo AB, Mortazavi A, Stein MN. A phase I study of cabozantinib plus nivolumab (CaboNivo) and cabonivo plus ipilimumab (CaboNivoIpi) in patients (pts) with refractory metastatic (m) urothelial carcinoma (UC) and other genitourinary (GU) tumors. J Clin Oncol. 35, 2017 (suppl; abstr 4562).
4. 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).
5. Sheng X, Yan X, Chi BTZ, et al. A phase I clinical trial of CM082 (X-82) in combination with everolimus for treatment of metastatic renal cell carcinoma. J Clin Oncol. 35, 2017 (suppl; abstr 4575)
6. Chowdhury S, McDermott DF, Voss MH, et al. A phase I/II study to assess the safety and efficacy of pazopanib (PAZ) and pembrolizumab (PEM) in patients (pts) with advanced renal cell carcinoma (aRCC). J Clin Oncol. 35, 2017 (suppl; abstr 4506).
7. Lin J, Hoffman-Censits JH, Kelly WK, et al. An exploratory study to investigate the immunomodulatory activity of radiation therapy in combination with pembrolizumab in patients with renal cell cancer. J Clin Oncol. 35, 2017 (suppl; abstr e16058).
8 . Escudier BJ, Rini BI, Martini J-F, et al. Phase III trial of adjuvant sunitinib in patients with high-risk renal cell carcinoma (RCC): Validation of the 16-gene Recurrence Score in stage III patients.J Clin Oncol. 35, 2017 (suppl; abstr 4508).
9. Arafat W, Desotelle J, Rodems T, et al. Development and clinical validation of circulating tumor cell (CTC) biomarkers in clear cell renal cell carcinoma (ccRCC) for the OMNIVORE clinical trial. J Clin Oncol. 35, 2017 (suppl; abstr 4579).
10. Motzer RJ, Haas NB, Donskov F, et al. Randomized phase III trial of adjuvant pazopanib versus placebo after nephrectomy in patients with locally advanced renal cell carcinoma (RCC) (PROTECT). J Clin Oncol. 35, 2017 (suppl; abstr 4507).
11. Welsh S, Fife K, Matakidou A, et al. A phase II clinical study evaluating the efficacy and safety of neoadjuvant and adjuvant sunitinib in previously untreated patients with metastatic renal cell carcinoma (mRCC)(NeoSun). J Clin Oncol. 35, 2017 (suppl; abstr e16087).
12. Shepherd STC, Hall P, Brown JE. Can dynamic changes in prognostic markers predict survival in patients receiving VEGF-targeted therapy in clear cell renal cell carcinoma? J Clin Oncol. 35, 2017 (suppl; abstr e16061).
13. Tannir NM, Powles T, Escudier BJ, et al. Clinical outcomes by nephrectomy status in METEOR, a randomized phase 3 trial of cabozantinib (cabo) vs everolimus (eve) in patients (pts) with advanced renal cell carcinoma (RCC). J Clin Oncol. 35, 2017 (suppl; abstr 4570).
14. Tannir NM, Camillo P, Gruenwald V, et al. Long-term response and time to response to pazopanib (PAZ) and sunitinib (SUN) in metastatic renal cell carcinoma (mRCC): COMPARZ subanalysis. J Clin Oncol. l 35, 2017 (suppl; abstr 4572).
15. Yip S, Wells C, Moreira RB, et al. Checkpoint inhibitors in metastatic renal cell carcinoma patients including elderly subgroups: Results from the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC). J Clin Oncol. 35, 2017 (suppl; abstr 4580).
16. Jonach E, Gombos D, Waguespack S, et al. Phase II study of pazopanib in patients with von Hippel-Lindau disease. J Clin Oncol. 35, 2017 (suppl; abstr 4516).
17. Pal SK, Geynisman DM, Ali SM, et al. Comprehensive genomic profiling (CGP) of advanced papillary renal cell carcinoma (PRCC) to reveal distinctions from TCGA dataset. J Clin Oncol. 35, 2017 (suppl; abstr 4517). KCJ

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