IO-TKI Combination Therapies: Are They Synergistic or Additive?

EP: 1.Risk Stratification of Patients with Advanced Renal Cell Carcinoma

EP: 2.Comparing Approved First-Line IO-TKI and IO-IO Combination Treatment Regimens in Advanced Clear Cell RCC

EP: 3.Case Presentation: A Patient with Favorable Risk Advanced Clear Cell RCC

EP: 4.Selecting a Treatment Regimen for Favorable Risk Advanced Clear Cell RCC

EP: 5.Single-Agent TKI Therapy in Favorable Risk Advanced Clear Cell RCC

EP: 6.Frontline Therapy in Advanced Clear Cell RCC: The CLEAR Trial

EP: 7.Rationale for Lenvatinib plus Pembrolizumab Therapy in Frontline Setting in Advanced Clear Cell RCC

EP: 8.Dosing Strategies for Lenvatinib in Advanced Clear Cell RCC

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EP: 9.IO-TKI Combination Therapies: Are They Synergistic or Additive?

EP: 10.Managing Adverse Effects During a Lenvatinib plus Pembrolizumab Combination Therapy Regimen

EP: 11.Treatment Regimens for Patients with Advanced Clear Cell RCC and Bone or Liver Metastasis

EP: 12.Advanced Clear Cell RCC with Intermediate-Risk and the CHECKMATE-214 Trial

EP: 13.Advanced Clear Cell RCC and the KEYNOTE 426 Trial

EP: 14.Advanced Clear Cell RCC and the CHECKMATE 9ER Trial

EP: 15.Tolerability of IO/TKI Combination Therapy for Advanced Clear Cell RCC

EP: 16.Tolerability of IO/TKI versus IO/IO Combination Treatments in Advanced Clear Cell RCC

EP: 17.Selecting an Appropriate Combination Therapy for Patients with Advanced Clear Cell RCC

EP: 18.Switching Therapies in Advanced Clear Cell RCC without Dose Reduction

EP: 19.Adjuvant Therapy in Clear Cell RCC

EP: 20.Clear Cell RCC and the KEYNOTE 564 Trial

EP: 21.Design, Criteria, and Endpoints of KEYNOTE 564

EP: 22.Adjuvant Therapy Treatment Approaches for Patients with Advanced Clear Cell RCC

EP: 23.DFS vs OS Primary Endpoints in KEYNOTE 564

Nizar Tannir, MD: Before we move on to the next segment of the program, I want to challenge [a point]. Moshe mentioned that he believes that the IO [immunotherapy]-TKI [tyrosine kinase inhibitor] combination is synergistic and not additive. I personally believe that they’re additive. If they were synergistic, we’d see close to 90% or higher responses. When you look at the monotherapy data with each, an anti–PD-1 and a TKI, when you combine them, you’re basically adding the ORR [overall response rate] of each one individually. Scott, as an immunotherapist, do you believe there’s synergy when you combine an IO and TKI? Or do you believe that they’re just additive?

Scott Tykodi, MD, PhD: In the frontline setting, it’s hard to know. In a population of tumors, we think some respond better to a TKI, some respond better to IO, and some probably respond to either. The unknown is whether there are tumors that only respond to the combination and would be refractory to each drug in isolation. In my mind, that is what we mean by synergy. If we say that the IO and TKI components aren’t all that different from each other, the combination that’s the most robust in pulling patients into that pool and drives a response only because of the combination should be the most effective combination. But I don’t know of any data that show you that’s a true phenomenon.

The place where we can find out if that’s true is in the second-line setting, where you have PD-1–refractory disease, and you ask the question, if I continue PD-1 blockade and add a TKI, is that better than giving the TKI in isolation? There are studies asking that exact question. That’s going to be very instructive. If the answer is that the doublet is clearly better than the TKI alone, that proves that there’s a synergistic component, that maintaining PD-1 blockade plus the TKI is somehow beneficial, and there has to be some biological coordination between the 2 drugs. I’m excited to see the readout from those trials, because that’s a hugely important question in the field.

Nizar Tannir, MD: That’s a good point and well taken. Thank you both for your thoughtful input on this.

Transcript edited for clarity.