Landmark Studies

Renal Cell Carcinoma Studies

RANDOMIZED TRIALS FOR ADJUVANT IMMUNOTHERAPY for ADVANCED RCC

CHECKMATE214 (2018) 1st line Nivolumab plus ipilimumab (NI) superior to Sunitinib (1096 patients) in intermediate and poor risk patients previously untreated advanced RCC (7)

Combo better for intermediate and poor risk patients (IMDC stratification ) but Sunitinib better for good risk
Nivolumab (PD1i), Ipilimumab (CTLA4i)
18mo OS 75% w/ NI vs. 60% w/ Sunitinib alone
9% complete response w/ NI vs. 1% w/ Sunitinib
Median OS not reached yet w/ NI, 26.0 mo w/ Sunitinib
High side effect rate for both: grade 3 or 4 events 46% in NI, 63% in Sunitinib
22% discontinued in NI vs. 12% in Sunitinib
60% of combo required IV corticosteroids for adverse effects
PFS better in PDL1+ but not PDL1- paatients. OS better in both groups, moreso in PDL1+
On April 16, 2018 FDA approved nivolumab (Opdivo) and ipilimumab (Yervoy) in combination for the treatment of intermediate- or poor-risk, previously untreated advanced renal cell carcinoma (RCC).

INMOTION151 - 1st line Bevacizumab/atezolizumab vs. sunitinib in treatment naive advanced/metastatic RCC (10)

Allowed sarcomatoid histology in addition to clear cell
PFS better with combo in PDL1+
CR 9% in combo vs. 4% in sunitinib
16% of combo group required corticosteroids
Less adverse effects than sunitinib
OS data immature

METEOR (NCT01865747) and CABOSUN (NCT01835158) - cabozantinib tx has significantly higher progression-free survival, overall survival, and overall response rates than have patients treated with other inhibitors; also had significant side effects including more than half with diarrhea and fatigue

S-TRAC (Sunitinib) (615 patients) - 1 yr sunitinib improved recurrence-free survival by 1.2 years in high risk local recurrence (2) and in a subgroup of high risk patients by 2.2 years. No OS benefit at 5 years follow-up

Included more high grade disease, pT3 or greater: more than 1/3 of patients with high grade T1 or T2 disease that were included in ASSURE would not have been included in S-TRAC
Only clear cell histology
Doses were reduced by 12.5mg but only if required, resulting in 1/3 patients with dose reduction
45% drop out rate due to toxicity
More frequent imaging than ASSURE
Independent non-blinded central review (2)

Sunitinib vs. IFN -

750patients w/ treatment naive mRCC
Median overall survival was greater in the sunitinib group than in the IFN-alpha group (26.4 v 21.8 months (9)

RANDOMIZED TRIALS FOR ADJUVANT IMMUNOTHERAPY in NON-METASTATIC RCC
ASSURE (Sunitinib or Sorafenib) (1943 patients) - no recurrence-free survival benefit over placebo in adjuvant therapy (1)

Included patients w/ pT1b or greater grade 3 to 4 disease
Median DFS of the placebo group 1 year longer in ASSURE than S-TRAC, reflecting the worse disease grade in S-TRAC
20% had non-clear cell histology, which is not driven by aberrant VHL/HIF1alpha pathway; however further subroup analysis of clear cell only histology failed to shows survival benefit
Doses were decreased from 50mg to 37.5mg in all patients in 2009 and increased as tolerated
44% drop out rate due to toxicity
Blinded investigator assessed end-points

CYTOREDUCTIVE NEPHRECTOMY
CARMENA - Nephrectomy + Sunitinib (13.9mo OS) is inferior to Sunitinib alone (18.4mo OS) in intermediate and poor risk patient with mRCC. (8)

RANDOMIZED TRIALS FOR LYMPHADENECTOMY
EORTC 30881 (5)

no survival benefit for clinically negative nodes
however, 77% of patients were low grade with 4% LN involvement
this population likely doesn't represent those who would likely benefit

ASSURE - no survival benefit in a review of patients undergoing lymphadenectomy

OTHERS
SORCE (Sorafenib in Treating Patients at Risk of Relapse after Undergoing Surgery to Remove Kidney Cancer, NCT00492258) - results pending
ATLAS (Adjuvant Axitinib Therapy of Renal Cell Cancer in High Risk Patients, NCT01599754) - clear cell T3 or T4 - results pending
EVEREST (Everolimus in Treating Patients with Kidney Cancer Who Have Undergone Surgery, NCT01120249) clear or papillary w/ high grade T1b or T2 to T4 tumors to everolimus or placebo for 1 year
PROTECT (A study to evaluate Pazopanib as an Adjuvant Treatment for Localized RCC, NCT01235962)
CHECKMATE025 (Nivolumab vs. Everolimus in pretreated advanced or metastatic clear cell RCC, NCT01668784) (3)

OS 5.4mo longer w/ nivolumab
Nivolumab has significantly lower number of side effects and improved quality of life (4)

PROSPER (adjuvant Nivolumab, NCT03055013)
INMOTION010 (adjuvant Atezolizumab in patients w/ high risk of developing metastasis, NCT03024996)
PT2385 is the first medication from a new class of drugs called hypoxia-inducible factor-2α (HIF-2α) antagonists.

Complete response, partial response, and stable disease as best response were achieved by 2%, 12%, and 52% of patients, respectively.
Most common side effects of anemia (grade 1 to 2, 35%; grade 3, 10%), peripheral edema (grade 1 to 2, 37%; grade 3, 2%), and fatigue (grade 1 to 2, 37%; no grade 3 or 4) (6)

STUDY 111 - multiple receptor tyrosine kinase inhibitor lenvatinib (Lenvima) in combination with Merck’s anti–programmed cell death protein 1 therapy pembrolizumab (Keytruda) for the potential treatment of patients with advanced and/or metastatic renal cell carcinoma (RCC).