ASCO 2023: Doublet and Triplet Therapy for Metastatic RCC: The Case for Doublet Therapy

( The 2023 ASCO annual meeting included a session on doublet or triplet therapy for metastatic renal cell carcinoma (RCC), featuring a presentation by Dr. Laurence Albiges discussing the case for doublet therapy. Dr. Albiges started her presentation by highlighting seven reasons (and using these reasons for the format of her talk) for the case for doublet therapy:


  1. It is guideline supported

The current guidelines support utilization of doublet therapy, supporting 3 combinations (lenvatinib + pembrolizumab, axitinib + pembrolizumab, and cabozantinib + nivolumab) for patients with favorable risk disease, as well as those with intermediate or poor risk disease: 



  1. There is rationale for using VEGFR TKI + IO

Using both mechanisms of action is established in the treatment of RCC and are potentially synergetic. Additionally, these mechanisms cover the spectrum of molecular subtypes, as well as addresses RCC’s well established intra tumor heterogeneity.

  1. There is efficacy to support this approach

The IO + TKI double therapy has proven short term endpoints, including better progression free survival and objective response rates (including progressive disease rates) compared to the IO + IO (nivolumab + ipilimumab) combination:doublet trials
However, there is really no difference in benefit between the IO + TKI combinations versus IO + IO when it comes to complete response rates, and survival has very comparable hazard ratios between these regimens, suggesting similar long-term benefit: doublet post table 

Furthermore, for intermediate and poor risk patients, there is very little difference between IO + TKI and IO + IO, however there is a clear benefit to the doublet regimen of IO + TKI for patients with favorable risk disease.

  1. Proven safety

There are known toxicities for IO + TKI double therapy, which is mostly driven by the VEGFR TKI, often requiring dose reduction. However, there are few overlapping GI and liver toxicities. Previously, Dr. Albiges was part of a collaborative group that provided recommendations for daily management of side effects/toxicity: 

doublet flow
Furthermore, when we look at IO + IO, there are several risks, including long-term and life lasting hypothyroidism and a not inconsequential rate of high grade and potentially life threatening additional adverse events.

  1. The new standard of care should exceed this approach

This is currently being assessed in MK6482-012 (NCT04736706) trial randomizing 1,431 patients to pembrolizumab + belzutifan + lenvatinib vs pembrolizumab + quavonlimab + lenvatinib vs pembrolizumab + lenvatinib. The primary endpoint is progression free survival:
doublet options

  1. It is also the new standard of care for all RCCs, including non clear cell RCC

At ESMO 2022, Dr. Albiges presented data from KEYNOTE B61, utilizing lenvatinib + pembrolizumab among 82 patients with non clear cell RCC. The objective response rate for this trial was 47.6%, with a disease control rate of 79.3%, and complete response rate of 3.7%. Thus, this combination showed benefit in the non clear cell RCC population.

  1. We should continue with doublet therapy until we have a new biomarker that helps guide treatment

The CARE-1 RLT trial is the first randomized study platform to optimize biomarkers for treatment in patients with metastatic RCC. Patients will be randomized based on the PDL1 status as shown in the following trial design:treatment naive non clear cell 

Dr. Albiges concluded her presentation discussing the case for doublet therapy with the following take-home points:

  • IO + TKI is the standard of care across all RCC in front line, given the strongest activity upfront with sustained long term benefit
  • IO + TKI is the standard of care to overcome for future trials, with overall survival being the key endpoint (progression free survival is not enough)

Presented by: Laurence Albiges, MD, PhD, Medical Oncology, Gustave Roussy, Université Paris Saclay, Paris, France 

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. Grunwald V, Voss MH, Rini BI, et al. Axitinib plus immune checkpoint inhibitor: Evidence- and expert-based consensus recommendation for treatment optimization and management of related adverse events. Br J Cancer. 2020 Sep;123(6):898-904.