Jose A. Karam, MD, FACS
Associate Professor, Departments of Urology
and Translational Molecular Pathology
The University of Texas MD Anderson Cancer Center
Exciting original research was reported at this year’s 17th International Kidney Cancer Symposium (IKCS) in Miami. With “Emerging Concepts and Therapeutic Trials in Progress in RCC” as one of the themes for the sessions, the Symposium provided a dynamic venue and a comprehensive agenda for more than 300 attendees at this two-day event, one of two international meetings each year sponsored by the Kidney Cancer Association. From early phase clinical trials of novel therapeutics to updates on pivotal, ongoing studies, the IKCS offered a unique opportunity to gauge progress on a broad spectrum of topics and envision how new information could have translational importance. In this report, we will cover a few select presentations of novel data from therapeutic studies that have a potential for becoming practice-changing once fully completed and reported.
Tailoring Therapy to Response: Addressing Therapy Intensification & Discontinuation by Dr Hans Hammers
Dr Hammers described adaptive clinical trials in metastatic RCC patients. BMS-669 is a phase 2 study comparing first-line therapy using nivolumab with salvage nivolu-mab+ipilimumab. Patients (120 ccRCC, 40 nccRCC) initially receive nivolumab only. Patients with a partial response (PR) or complete response (CR) continue nivolumab alone for up to 84 weeks, or until progression of disease (PD) or severe toxicity, while those with progressive disease or stable disease (SD) get re-induced with nivolumab, with the addition of ipilimumab for 4 doses and then receive nivolumab alone until progression of disease or severe toxicity or 48 weeks. Patients who progress on the first arm can be potentially considered for enrollment on the second arm.
TITAN is a phase 2 trial (200 ccRCC) where patients received nivolumab induction, and may continue nivolumab alone if they experience a PR or CR. Patients who have SD or PD receive nivolumab+ipilimumab (2 doses), and can go back to nivolumab alone if they experience CR or PR, or receive another 2 doses of nivolumab+ipilimumab if they experience SD or PD. These patients can go back to nivolumab alone if they experience CR, PR, or SD. Similar to BMS-669, patients who initially responded to nivolumab alone can later receive nivolumab+ipilimumab if they experience PD.
OMNIVORE is a phase 2 trial (58 patients) where patients receive nivolumab and are assessed at 8 weeks initially. If patients experience PR or CR which is con- firmed, nivolumab is discontinued, and restarted at progression. At progression, ipilimumab is added to nivolumab for 2 doses only. If SD, PR, or CR, nivolumab is continued until progression. If PD after nivolumab+ipilimumab, therapy is discontinued. Alternatively, if patients experience SD or PD after induction with nivolumab, then similar to the first arm, ipilimumab is added to nivolumab for 2 doses only. If SD, PR, or CR, nivolumab is continued until progression. If PD after nivolumab+ipilimumab, therapy is discontinued.
Phase 1 trials are investigating cabozantinib+nivo-lumab+ipilimumab, PEG-IL2 with nivolumab or nivo-lumab+ipilimumab, hypofractionated radiation therapy to any RCC site along with treatment with pembro-lizumab (RadVax), SBRT+nivolumab+ipilimumab, cabo-zantinib+ nivolumab with or without ipilimumab, NKTR-214 (pegylated IL-2) + nivolumab with or without ipilimumab.
Other combinations that are reading out from phase 3 trials include avelumab+axitinib (JAVELIN Renal 101), pembrolizumab+axitinib (KEYNOTE-426). PDIGREE was discussed as well, and will be described in more detail below.
A Phase II Trial of Intermittent Nivolumab in Patients with mRCC
Who Have Received Prior Anti-Angiogenic Therapy
by Dr Moshe Ornstein
Dr Ornstein described an ongoing phase 2 clinical trial (target 40 patients, any RCC, 14 patients enrolled) that is studying the feasibility of using intermittent nivo-lumab in patients with metastatic RCC who received prior anti-angiogenic therapy. Patients receive 12 weeks of nivolumab. If patients experience PD, they come off therapy/trial. If the tumor burden decreases by 10% or more, they go to the intermittent phase. If the tumor burden decreases by less than 10%, they continue nivolumab.
For the intermittent phase, patients hold nivolumab for 12 weeks and are reassessed. If tumor burden increases by 10% or more, patients resume nivolumab until PD or tumor burden reduction by 10% or more. If PD, they come off therapy/trial, and if tumor burden decreases by 10% or more, they can hold nivolumab. If after 12 weeks of nivolumab hold, patients do not have an increase of tumor burden of more than 10%, they can continue to hold nivolumab for another 12 weeks and get reassessed.
Using Cryotherapy to Stimulate the Immune System in RCC
by Dr Matthew Campbell
Dr. Campbell presented an ongoing pilot study in metastatic RCC (target 30 patients, any RCC, 29 enrolled) where patients are randomized to either 2 doses of tremelimumab followed by surgery or biopsy, or to cryoablation of a metastatic site, followed by 2 doses of tremelimumab followed by surgery or biopsy. Patients then continue tremelimumab until PD. Preliminary immune correlate analysis has shown an increase in CD3+ T cells in patients with ccRCC who received cryotherapy, as well as an increase in the frequency of an ICOS+ CD8+ T-cell subset, and that VEGF and IFN pathway genes are significantly higher in patients with ccRCC compared to nccRCC.
Rationally Targeting the Bone with Radium Pus Cabozantinib
by Dr. Rana McKay
Dr McKay described a new clinical trial (RADICAL) for patients (target 132 patients) with any RCC histology with 2 or more untreated bone metastases, where patients are randomized to either cabozantinib alone or cabozantinib+Radium-223, with primary endpoint being symptomatic skeletal event-free survival.
Trials in Progress – PDIGREE
by Dr Tian Zhang
Dr Zhang presented the PDIGREE trial (Alliance A031704), which should be starting in 2019. PDIGREE plans to enroll 1044 patients with mRCC where all patients receive nivolumab+ipilimumab for 4 doses. In case of CR, patients continue with nivolumab alone. If case of PD, patients switch to cabozantinib. Patients with PR/SD (around 696 patients) will be randomized to nivolumab alone or nivolumab+cabozantinib. The primary endpoint is 3-year overall survival, with key secondary endpoints such as 1-year CR rate, PFS, ORR and toxicity of combination therapy. Correlative studies are planned and will include using tissue-based markers (PD-L1 and MET IHC, tumor mutational burden and neoantigen load, gene expression profiling, TILs), circulating markers (IL-6 and other cytokines, ctDNA), quality of life measures, and imaging correlates.
Treatment-Free Internval Following Discontinuation of First-Line
Nivolumab Plus Ipilimumab or Sunitinib in Patients with Advanced RCC
by Dr Thomas Powles
Dr Powles described a posthoc analysis of CheckMate 214 studying treatment-free survival (TFS) after discontinuation of nivolumab+ipilimumab or sunitinib. Only patients with IMDC intermediate/poor-risk were included. The study demonstrated that the combination therapy delayed time from randomization to second-line therapy by almost 7 months compared with sunitinib. Time from randomization to second-line therapy and TFS analyses showed durable response/disease control with combination therapy despite treatment discontinuation. Delay to second-line treatment and TFS benefit with combination therapy compared with sunitinib was noted regardless of whether patients achieved objective response or disease control, and regardless of baseline tumor PD-L1 expression. Dr Powles noted that a full TFS analysis of CheckMate 214 is being performed, and will include the intention-to-treat analysis and favorable-risk patients.
Safety and Activity of Immune Checkpoint Inhibitors in Patients
with Advanced RCC and Pre-existing Autoimmune Disorders
by Dr Nieves Martinez Chanza
Dr. Martinez Chanza reported on a retrospective study that included 25 patients with well-controlled autoimmune disorders (AD) treated with checkpoint inhibitors. CTCAE grade 1/2 and 3/4 AD exacerbations were noted in 6 and 2 patients, respectively, while CTCAE grade 1/2 and 3/4 immune-related adverse events (irAE) were noted in 10 and 2 patients, respectively. 1 patient received systemic corticosteroids for AD exacerbation and 4 patients for new irAE. Ultimately, 1 patient discontinued checkpoint inhibitor therapy due to AD exacerbation and 2 for irAE. Median follow up in this study was 15 months, with median time from checkpoint inhibitor therapy to AD exacerbation or to new irAE of almost 3 months. Overall response rate was 44% and 2-year OS was 54% in this small cohort. The authors concluded that while some patients with AD could benefit from checkpoint inhibitor therapy, there is a risk for AD exacerbation and new irAEs, which are manageable, but require careful monitoring and multidisciplinary care.
CheckMate 214 Retrospective Analyses
by Dr Nizar Tannir
Dr Tannir described a posthoc analysis of CheckMate 214 focusing on the outcomes of 112 patients (intermediate/poor-risk) with sarcomatoid dedifferentiation treated with either nivolumab+ipilimumab (60 patients) or sunitinib (52 patients). Confirmed ORR was 56.7% (18.3% CR) in the nivolumab+ipilimumab group and 19.2% (no CR) in the sunitinib group. Median PFS and OS were 8.4 months and 31.2 months in the nivolumab+ipilimumab group, respectively, and 4.9 months and 13.6 months in the sunitinib group, respectively. These exploratory analyses show a remarkable efficacy of checkpoint blockade combination in the treatment of this generally treatment-refractory disease, with similar safety profile to the general study population.
Phase 1b Study of Cabozantinib in Combination with Atezolizumab
by Dr Neeraj Agarwal
Dr Agarwal described the COSMIC-021 phase 1b study using first-line cabozantinib+atezolizumab in 12 patients with metastatic RCC (10 ccRCC, 2 nccRCC). This combination was noted have an acceptable safety profile and promising activity with responses in 8 of 10 patients with ccRCC.
Second-Line VEGF Receptor TKI Outcomes afer
First-Line Immune Checkpoint Bloackade in mRCC
by Dr Ritesh Kotecha
Dr Kotecha reported on a retrospective study from 2 cancer centers whereby VEGFR TKI was used as second line therapy in 70 patients who had already received checkpoint inhibitors as first line therapy. The authors report an ORR of 41.2%, with 52.9% SD. Median PFS was 13.2 months (1-year PFS 52.5%) and median OS was not reached (1-year OS 79.6%). Second line VEGFR TKI median duration was 10.1 months, with 47% of patients discontinuing therapy due to PD. The authors have demonstrated in this cohort that tolerability was similar to first line therapy historic controls and that second line VEGFR TKI can be safely used after first line checkpoint inhibitors, with good outcomes.
Ipilimumab plus Nivolumab as Salvage Therapy
in Patients with Immunotherapy-Refractory mRCC
by Dr Kimberly Allman
Dr Allman reported on a retrospective study from 2 cancer centers whereby ipilimumab+nivolumab was used as second line therapy in 14 patients who had already received other checkpoint inhibitors as first line therapy, and showed that ipilimumab+nivolumab was well-tolerated in this setting, and generated a 33% PR rate. Additional centers are being recruited into this project in order to increase the size of this retrospective study.
The Next 10 years: The Next Therapeutic Targets
This session included 5 different presentations covering early phase clinical trials of novel therapeutics being investigated in patients with RCC.
- Dr Ranjit Bindra discussed oncometabolite-induced homologous recombination suppression (IDH1/2, FH, and SDH mutants), and its targeting in solid tumors, with a focus on the PARP inhibitors olaparib and BGB290, alone or in combination with established therapies.
- Dr Abhishek Tripathi discussed the rationale behind using adenosine pathway inhibitors (Anti-CD73 and Adenosine 2a Receptor antagonists) in patients with RCC. One phase 1 trial has studied CPI-444 (A2aR antagoinst) in combination with atezolizumab in 30 patients with RCC refractory to anti-PD-1 therapy. Other trials of anti-CD73 and A2aR antagonists are planned, in combination with checkpoint inhibitor therapy, in patients with metastatic RCC.
- Dr Thomas Powles delineated the biology and roles of TGFb in differentiation and immune inhibition, along with data in RCC suggesting TGFb is overexpressed in patients with poor prognosis. Dr Powles also discussed data on targeting both PD-L1 and TGFb to enhance the efficacy and infiltration of T cells into immune excluded tumors. This could be done either with a combination of a TGFb-R1 kinase inhibitor (Galunisertib) with a PD-L1 inhibitor, or with a novel fusion protein (M7824) that consists of an IgG1 monoclonal antibody against PD-L1 with a TGFb trap.
- Dr Thai Ho focused on treatment of patients with SETD2-deficient tumors, and described a phase 2 study of adavosertib (AZD1775) to target nucleotide metabolism in patients with these tumors.
- Dr Toni Choueiri described a phase 1 study that will be using a new personalized neoantigen peptide vaccine NeoVax (in combination with local injection of ipilimumab) in 20 patients with fully resected stage III RCC or with M1 that is completely resected with subsequent absence of disease. KCJ