ASCO 2023: Phase 1b/2 Study of Combination 177Lu Girentuximab + Cabozantinib and Nivolumab in Treatment Naïve Patients with Advanced Clear Cell RCC

( The 2023 ASCO annual meeting included a kidney cancer session, featuring trials in progress presentation by Dr. Elshad Hasanov discussing a phase 1b/2 study of combination 177Lu girentuximab + cabozantinib and nivolumab in treatment naïve patients with advanced clear cell RCC. Unfortunately, complete response is still a rare event in patients with advanced clear cell renal cell carcinoma. The combination of nivolumab plus cabozantinib was recently approved for the first-line treatment of clear cell RCC based on the CheckMate 9ER phase III study demonstrating improved progression-free survival and objective response rate in comparison to sunitinib.1 However, the complete response rate in CheckMate 9ER was only 9%. Since the anti-tumor effects of immune checkpoint inhibitors are dependent on the presence of activated tumor-infiltrating T cells, drugs that could synergize with T cells’ anti-tumor activity can allow us to improve complete response rates. Activation of the cGAS-STING pathway, the master regulator of anti-tumor immunity which is induced by radiation-induced DNA damage, is one promising mechanism that has been investigated.


 Several studies have shown that radiation treatment augments immune checkpoint inhibition. However, it is not always possible to radiate all metastatic lesions, and targeted peptide receptor radionuclide therapies have been developed. This happens by conjugating radioisotopes to receptor-binding analogs targeting specific cancer cell surface proteins, thereby delivering targeted radiation to cancer cells in the body with minimal damage to surrounding healthy cells. The following schema describes the scientific rationale for combination treatment:

ASCO 2023_Hasanov_combination 177Lu girentuximab + cabozantinib and nivolumab_0 


 177Lu girentuximab is the first antibody-radioisotope designed for clear cell RCC, targeting carbonic anhydrase IX-expressing cells, which includes > 90% of clear cell RCC.2 It has been tested in metastatic clear cell RCC as a single agent and shown to be safe and effective in stabilizing disease in 57% of patients.3 In this study, Dr. Hasanov and colleagues hypothesize that 177Lu girentuximab-induced DNA damage will potentiate the STING pathway, and this activation will synergize with nivolumab and cabozantinib to promote trafficking and infiltration of activated T cells to tumors and achieve higher complete response rates.

 This study is a single arm phase 1b/2 study that will test the hypothesis that adding 177Lu-girentuximab to cabozantinib + nivolumab will increase the complete response rate when compared to historical outcomes with the nivolumab + cabozantinib doublet. Up to 100 patients with treatment naïve, biopsy-proven clear cell RCC with adequate organ/marrow function with ≥1 evaluable lesion by RECIST 1.1 will be enrolled in this trial. The key inclusion and exclusion criteria are as follows:


ASCO 2023_Hasanov_combination 177Lu girentuximab + cabozantinib and nivolumab_1 


A 5-patient safety lead-in will evaluate myelosuppression, and ongoing safety, and futility monitoring will employ a Bayesian approach. 177Lu-girentuximab 1480 MBq/m(61% of single agent maximal tolerated dose) will be administered every 12 weeks for up to 3 treatment cycles. The clinical trial study design is as follows:


ASCO 2023_Hasanov_combination 177Lu girentuximab + cabozantinib and nivolumab_2 


After the first cycle, nivolumab and cabozantinib will be added starting with the second cycle at standard dose. To explore the effects of the combination therapy on inducing activated T cell infiltration, patients will undergo pre/post-treatment PET scan with [18F]F-AraG radiotracer as well as biopsies for single cell, spatial transcriptomics and proteomics studies. The sample size was chosen for reasonable operating characteristics to distinguish a complete response rate of 18% as better than 9% using a beta (0.09, 0.91) prior. The primary endpoints will be safety defined by CTCAE v5.0 leading to discontinuation, immune-mediated adverse events, and worst grade clinical laboratory values, as well as complete response by RECIST 1.1 by investigator. Secondary endpoints are as follows:

  • Objective response
  • Progression-free survival by RECIST 1.1
  • Duration of response
  • Durable stable disease
  • Clinical benefit: complete response + partial response + durable stable disease
  • Tumor response’
  • Overall survival


Presented by: Elshad Hasanov, MD, PhD, University of Texas MD Anderson Cancer Center, Houston, TX

Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Associate Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, @zklaassen_md on Twitter during the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting, Chicago, IL, Fri, June 2 – Tues, June 6, 2023.


  1. Choueiri TK, Powles T, Burotto M, et al. Nivolumab plus cabozantinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2021 Mar 4;384(9):829-841.
  2. Stillebroer AB, Boerman OC, Desar IM, et al. Phase 1 radioimmunotherapy study with lutetium 177-labeled anti-carbonic anhydrase IX monocolonal antibody girentuximab in patients with advanced renal cell carcinoma. Eur Urol. 2013;64:478-485.
  3. Musalaers CH, Boers-Sonderen MJ, van Oostenbrugge TJ, et al. Phase 2 study of Lutetium 177-labeled anti-carbonic anhydrase IX monoclonal antibody girentuximab in patients with advanced renal cell carcinoma. Eur Urol. 2016;69:767-770.