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Updated October 2017.

KCJ Medical Intelligence: ESMO Highlights

CABOSUN Update Affirms PFS Advantage With
Cabozantinib Over Sunitinib in Advanced RCC

MADRID—Patients with untreated advanced renal cell carcinoma (RCC) lived significantly longer without disease progression when they received the multikinase inhibitor cabozantinib  (Cabometyx) as initial therapy versus sunitinib (Sutent), according to results of an independent review of the randomized CABOSUN trial reported at the 2017 European Society of Medical Oncology (ESMO) Congress.

Results showed that cabozantinib-treated patients had a median progression-free survival (PFS) of 8.6 months compared with 5.3 months for patients treated initially with sunitinib. The difference represented a 52% reduction in the hazard for progression or death.The independent review of the data confirmed the primary analysis of the CABOSUN randomized trial, which showed a median PFS of 8.2 months with cabozantinib and 5.6 months with sunitinib by investigator assessment (HR, 0.66; 95% CI, 46%-95%; 1-sided P = 0.012).

“Cabozantinib treatment resulted in clinically meaningful and statistically significant prolongation of progression-free survival per independent review compared with sunitinib as initial targeted therapy in patients with advanced RCC,” Toni Choueiri, MD, director of the Kidney Cancer Center at Dana-Farber Cancer Institute, and collaborators concluded in a poster presentation. An updated review of overall survival (OS) showed a numerical advantage in favor of cabozantinib, but the difference did not achieve statistical significance, which was consistent with the initial investigator review of survival. The CABOSUN trial involved 157 poor- and intermediate-risk patients with advanced RCC, a subgroup of patients with worse prognosis and survival compared with patients who advanced RCC and favorable risk characteristics. Intermediate-risk patients accounted for 81% of the study population.

The patient population had a median age of about 63. Key clinical features included bone metastases in about 36% of patients, prior nephrectomy in 75%, and 3 or more metastatic sites in about 35%. The most common sites of metastasis were lung (70%), lymph nodes (55%), and bone (38%). Patients were randomized 1:1 to receive oral cabozantinib at 60 mg once daily (n = 79) or oral sunitinib at 50 mg daily for 4 weeks on/2 weeks off (n = 78). Treatment was administered until disease progression or intolerable toxicity.

CABOSUN had a primary endpoint of PFS as assessed by trial investigators. A key secondary endpoint was assessment of PFS by an independent review committee. The review was conducted by means of retrospective blinded review of radiographic images.

The independent review of PFS confirmed the primary analysis, and the 3.3-month absolute difference in favor of cabozantinib remained statistically significant, consistent with the primary analysis (HR, 0.48; 95% CI, 0.31-0.74; P = 0.0008). A subgroup analysis favored cabozantinib for all prespecified patient groups, including intermediate or poor risk, presence or absence of bone metastases, and positive or negative MET status. The updated survival analysis occurred after a median follow-up of 30.8 months and showed a median OS of 26.6 months in the cabozantinib arm versus 21.2 months in the sunitinib arm. The difference represented a 20% reduction in the hazard ratio in favor of cabozantinib—a difference that did not achieve statistical significance (HR, 0.80; 95% CI, 0.53-1.21; P = 0.29).

Twice as many patients had objective responses with cabozantinib compared with sunitinib (20% vs 9%). In the cabozantinib group, 16 patients had confirmed partial responses and 43 had stable disease, resulting in a disease control rate (DCR) of 75%. That compared with 7 partial responses, stable disease in 30 patients, and a DCR of 47% in the sunitinib arm. The original report of investigator-assessed outcomes showed DCRs of 78% and 54% for cabozantinib and sunitinib, respectively.


CheckMate-214: Nivolumab + Ipilimumab vs Sunitinib
in First-LineTreatment for Advanced or Metastatic RCC

MADRID—Combined immunotherapy with nivolumab plus ipilimumab resulted in a greater objective response rate (ORR) and prolonged progression-free survival (PFS) compared to sunitinib in intermediate- and poor-risk patients with previously untreated advanced or metastatic renal cell carcinoma (RCC). These results came from the CheckMate-214 study presented at ESMO 2017. Greater benefit was observed in these patients, especially those with higher levels of PD-L1 expression at baseline; however, ORR and PFS were improved with sunitinib in patients with favorable risk, advanced or metastatic disease.

Bernard Escudier, MD Institut Gustave Roussy, Villejuif, France presented the results of the phase III, randomised, open-label CheckMate-214 study evaluating the combination of nivolumab and ipilimumab compared to sunitinib in patients with previously untreated advanced or metastatic RCC. The 550 patients in the combination arm were treated with nivolumab at 3 mg/kg plus ipilimumab at 1 mg/kg every 3 weeks for 4 doses, followed by nivolumab at 3 mg/kg every 2 weeks and 546 patients received sunitinib at 50 mg once daily for 4 weeks and 2 weeks off in 6-week cycles. After approximately 17.5 months of follow-up, CheckMate-214 met the co-primary endpoint of ORR in intermediate/poor risk patients, which was 41.6% for the nivolumab/ipilimumab combination compared to 26.5% for sunitinib (P < 0.0001) with 9.4% of patients receiving combination therapy achieving complete response (CR) compared to1.2% of patients on sunitinib. There was an improvement in median PFS with the combination in this cohort; median PFS was 11.6 months for the nivolumab and ipilimumab combination versus 8.4 months with sunitinib, hazard ratio [HR] 0.82 (P = 0.03).

The efficacy outcomes differed according to the levels of PD-L1 expression and IMDC risk group. Both the ORR per independent committee and PFS significantly favored nivolumab plus ipilimumab over sunitinib in intermediate/poor risk patients having baseline PD-L1 expression ≥1% where the ORR was 58% versus 25%, and median PFS was 22.8 (95% CI 9.4, NR) months versus 5.9 (95% CI 4.4, 7,1) months, respectively, HR 0.48 (95% CI 0.28, 0.82; P = 0.0003). The investigators found that baseline tumor PD-L1 expression was lower in the cohort of patients at favorable risk where 11% of patients on combination had PD-L1 levels ≥1% versus12% of patients on sunitinib compared to 26% versus 29% of patients at intermediate or poor risk in the respective treatment arms.

In patients at favorable risk, both the ORR and PFS were higher with sunitinib over combination; in this cohort, ORR was 29% with nivolumab/ipilimumab versus 52% with sunitinib (P = 0.0002) and median PFS was 15.3 (95% CI 9.7, 20.3) months versus 25.1 (95% CI 20.9, NR) months, respectively, HR 2.17 (95% CI 1.46, 3.22; P < 0.0001). In the overall composite of patients at any risk, no significant difference between treatments was demonstrated in ORR (P = 0.0191) or PFS (P = 0.819). Any grade drug-related adverse events (AEs) occurred in 509 (93%) of patients in the nivolumab/ipilimumab cohort and in 521 (97%) of patients receiving sunitinib. With the combination, 54% of patients had a grade 3 to 4 AE, and with sunitinib 63% of patients had a grade 3 to 5 AE.


Progression-free Rate Unaffected by Sequence of Cytoreductive
Nephrectomy and Sunitinib in Patients with Synchronous mRCC

MADRID—Treating primary tumors by administering targeted therapy with sunitinib prior to cytoreductive nephrectomy (CN) did not improve the progression-free rate at 28 weeks over a sequence of immediate CN followed by sunitinib in patients with synchronous metastatic renal cell carcinoma (mRCC), according to findings from a randomized trial presented at ESMO 2017.

Axel Bex, Surgical Oncology-Urology, The Netherlands Cancer Institute in Amsterdam, Netherlands and colleagues investigated whether the outcome after sequential cyto-reductive nephrectomy (CN) followed by targeted therapy with sunitinib could be improved with the opposite sequence. They randomized 99 patients with mRCC to immediate CN followed by sunitinib (n=50) versus three cycles of sunitinib followed by CN plus sunitinib (n=49). The study (EORTC 30073 SURTIME NCT01099423) included patients with histologically confirmed clear-cell subtype, and a resectable asymptomatic primary tumor plus 3 or fewer surgical risk factors.

After 5.7 years the study included 99 patients from 19 institutions. The immediate CN arm had 50 patients and the deferred CN arm had 49 patients. The majority of patients were male in both arms with a median age of 60 compared to 58 years, and MSKCC intermediate risk was reported for 86% versus 87.7% of patients, respectively. In the respective arms, WHO performance status (PS) was 0 and 1 in 72% and 28% versus 63.3 % and 36.7%; 86% versus 93.9% of patients had ≥ 2 measurable metastatic sites and the mean (standard deviation) size of the primary tumor was 93.1 (37.8) mm versus 96.8 (31.3) mm. Patients in each arm derived different benefit from each sequence. At a median follow-up of 3.3 years, 46 of 50 patients underwent CN in the immediate CN arm and 40 of these patients had received post-CN sunitinib. In the deferred CN arm, 48 of 49 patients had been treated with sunitinib prior to CN; of these patients, 40 underwent CN and 26 also received post-CN sunitinib.  KCJ